CN86106980A - The alkylsulfonyl that 2-oxo-1-{[(replaces)-and amino] carbonyl } azetidine-typed - Google Patents

The alkylsulfonyl that 2-oxo-1-{[(replaces)-and amino] carbonyl } azetidine-typed Download PDF

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CN86106980A
CN86106980A CN198686106980A CN86106980A CN86106980A CN 86106980 A CN86106980 A CN 86106980A CN 198686106980 A CN198686106980 A CN 198686106980A CN 86106980 A CN86106980 A CN 86106980A CN 86106980 A CN86106980 A CN 86106980A
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赫尔曼·布鲁尔
乌韦·D·特罗纳
威廉·H·科斯特
罗伯特·扎尔勒
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ER Squibb and Sons LLC
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Abstract

Have a 3-amido substituting group and on the 1-position, have an activating group 2-azetidin ketone demonstrate anti-microbial activity, the R in this activating group is Or

Description

The alkylsulfonyl that 2-oxo-1-{[(replaces)-and amino] carbonyl } azetidine-typed
But the salt of formula I compound and hyoscine thereof demonstrates anti-microbial activity.
Figure 86106980_IMG15
Symbol definition in formula I and this specification is as follows: R is
Figure 86106980_IMG16
Or
Figure 86106980_IMG17
R 1Be acyl group from carboxylic acid derivatives;
R 2And R 3Can be identical or different, the phenyl of respectively do for oneself hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, replacement, or 4,5,6 or 7 yuan of heterocycles (are hereinafter remembered and are made R X), or R 2And R 3In one be hydrogen, another be azido-, halogenated methyl, dihalo methyl, trihalomethyl group, alkoxy carbonyl, 2-phenyl vinyl, 2-phenylacetylene base, carboxyl ,-CH 2X 1(this X 1Be azido-, amino (NH 2), the phenyl of hydroxyl, carboxyl, alkoxy carbonyl, alkanoyl amido, phenylcarbonyl group amino, (phenyl of replacement) carbonylamino, alkylsulfonyloxy, phenyl sulfonyloxy, (phenyl of replacement) sulfonyloxy, phenyl, replacement, cyano group,
Figure 86106980_IMG18
,-S-X 2, or-O-X 2(the A here, X 2, X 6And X 7To be defined hereinafter)) ,-S-X 2Or-O-X 2(this X 2Be alkyl, phenyl, the phenyl of replacement, phenylalkyl, (phenyl of replacement) alkyl, alkanoyl, phenyl alkanoyl, (phenyl of replacement) alkanoyl, phenylcarbonyl group, (phenyl of replacement) carbonyl of alkyl, replacement, or the heterocyclic aryl carbonyl),
Figure 86106980_IMG19
(this X 3And X 4In one be hydrogen, another is a hydrogen or alkyl, or X 3And X 4Form a cycloalkyl together with the carbon atom that connects them; X 5Be formyl radical, alkanoyl, phenylcarbonyl group, (phenyl of replacement) carbonyl, phenylalkyl carbonyl, (phenyl of replacement) alkyl-carbonyl, carboxyl, alkoxy carbonyl, aminocarboxyl
Figure 86106980_IMG20
, (amino of replacement) carbonyl or cyano group (C ≡ N)) or (this A is-CH=CH-,-(CH 2) - m,-(CH 2) m-O-,-(CH 2) m-NH-, or-CH 2-S-CH 2-, m is 0,1 or 2, X 6And X 7Can be identical or different, the phenyl of respectively do for oneself hydrogen, alkyl, phenyl or replacement, or X 6Be hydrogen, and X 7Be amino, alkanoyl amino or alkoxyl group amino, that replace, or X 6And X 7The nitrogen-atoms that connects with them forms 4,5,6 or 7 yuan of heterocycles);
Be a singly-bound,
Figure 86106980_IMG23
-NH-or
A 2Be a singly-bound ,-NH-,-CH 2-CH 2-NH-, or
Figure 86106980_IMG24
A 3Be-(CH 2) p-wherein (p is 0 or 1),
Figure 86106980_IMG25
,-NH-CH 2-,-O-CH 2-
Figure 86106980_IMG26
A 4Be-NH--(CH 2) p-,-(CH 2) y-NH-,
Figure 86106980_IMG27
Wherein X is hydrogen, carboxyl or formamyl, and P is 0 or 1, and Y is 2,3 or 4;
A 5Be a singly-bound ,-CH 2-,-NH-CH 2-,-N=CH-or
Figure 86106980_IMG28
, q wherein equals 0 or 1;
A 6Be a singly-bound ,-CH=CH-or-(CH 2) t-, wherein t is 1,2,3 or 4.
With above-mentioned symbol (A for example 1, A 2, A 3, A 4, A 5And A 6) represent polyatomic group, these groups insert in the structural formula shown in this article by symbol order (from left to right promptly) in its expression formula, for example, if R is
Figure 86106980_IMG29
, A 1Be
Figure 86106980_IMG30
, then R is
Figure 86106980_IMG31
Rather than
Figure 86106980_IMG32
Listed the definition that is used to describe each used term of beta-lactam of the present invention below, these definition are applicable in the whole specification sheets that discrete or conduct are than the term (unless being limited) of the some of macoradical in a certain specific examples.
" alkyl " and " alkoxyl group " both comprised the group that also comprises side chain of straight chain.Preferably carbonatoms is those groups of 1 to 10.
Term " cycloalkyl " and " cycloalkenyl " refer to the cycloalkyl and the cycloalkenyl of 3,4,5,6 or 7 carbon atoms.
Term " alkyl of replacement " refers to the alkyl that is replaced by one or more (preferably 1,2 or 3) following radicals: azido-, amino (NH 2), halogen, hydroxyl, carboxyl, cyano group, alkoxy carbonyl, aminocarboxyl, alkanoyloxy, alkoxyl group, phenoxy group, (phenyl of replacement) oxygen base, sulfydryl, alkylthio, phenyl sulfo-, (phenyl of replacement) sulfo-, alkyl sulfinyl or alkyl sulphonyl.
Term " alkane acyl " base, " alkenyl " and " alkynyl " had both referred to straight chain, also referred to the group of side chain, preferably contained the group of 2 to 10 carbon atoms.
Term " halogen " and " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " phenyl of replacement " refers to the phenyl that is replaced by 1,2 or 3 following radicals: amino (NH 2), halogen, hydroxyl, trifluoromethyl, alkyl (1 to 4 carbon atom), alkoxyl group (1 to 4 carbon atom), alkanoyl oxygen, aminocarboxyl, or carboxyl.
Said " 4,5,6 or 7 yuan of heterocycles " (note is made " R x") refer to and replace and the unsubstituted fragrant or non-aromatic group that contains one or more (preferably 1,2 or 3) nitrogen, oxygen or sulphur atom.Typical substituting group has: the phenyl of the alkyl of oxo (=0), halogen, hydroxyl, nitro, amino, cyano group, trifluoromethyl, 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom, alkyl sulphonyl, phenyl, replacement, furfurylidene ammonia (
Figure 86106980_IMG33
, base, benzylidene is amino and the alkyl (alkyl wherein has 1 to 4 carbon) that replaces.One of the type of " 4,5,6 or 7 yuan of heterocycles " is " heteroaryl ", and term " heteroaryl " refers to 4,5,6 or 7 yuan aromatic heterocycle.Typical heteroaryl group be replace with unsubstituted pyridine base, furyl, pyrryl, thienyl, 1,2,3-triazoles base, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrimidyl, oxazolyl, triazinyl and tetrazyl.Typical nonaromatic heterocycles (being all or part of saturated heterocyclic group) is that replace and unsubstituted following radicals: azepine cyclobutyl Evil fourth cyclic group (oxetanyl), thiophene fourth cyclic group (thietanyl), piperidyl, piperazinyl, imidazolidyl, oxazolidinyl, pyrrolidyl, tetrahydro-pyrimidine base, dihydro-thiazolyl and six hydrogen azatropylidene bases.4 of replacement; 5; 6 or 7 yuan of typical heterocycles have: 1-alkyl-3-azelidinyl; 2-oxo-1-imidazolidyl; 3-alkyl sulphonyl-2-oxo-1-imidazolidyl; 3-benzylidene amino-2-oxo-1-imidazolidyl; 3-alkyl-2-oxo-1-imidazolidyl; 3-phenyl (or the phenyl that replaces)-2-oxo-1-imidazolidyl; 3-benzyl-2-oxo-1-imidazolidyl; the 3-(2-amino-ethyl)-2-oxo-1-imidazolidyl; 3-amino-2-oxo-1-imidazolidyl; 3-((alkoxy carbonyl) amino)-2-oxo-1-imidazolidyl; 3-(2-((alkoxy carbonyl) amino) ethyl)-2-oxo-1-imidazolidyl; 2-OXo-1-pyrrolidine base; 2-oxo-3-oxazolidinyl; 4-hydroxyl-6-methyl-2-pyrimidyl; 2-oxo-1-six hydrogen azepines
Figure 86106980_IMG34
Base, 2-oxo-3-pyrrolidyl, 2-oxo-3-tetrahydrofuran base, 2,3-dioxo-1-
Figure 86106980_IMG35
Piperazine base, 2,5-dioxo-1- Piperazine base, 4-alkyl-2,3-dioxo-1-piperazinyl and 4-phenyl-2,3-dioxo-1-
Figure 86106980_IMG37
The piperazine base.
Term " amino of replacement " refers to general formula-NX 8X 9Group, X wherein 8Be phenyl, phenylalkyl or (phenyl of replacement) alkyl of hydrogen, alkyl, phenyl, replacement; X 9Be phenyl, phenylalkyl, (phenyl of replacement) alkyl, hydroxyl, cyano group, alkoxyl group, phenyl alkoxyl group or the amino (NH of alkyl, phenyl, replacement 2).
Term " acyl group " refers in organic acid (the being carboxylic acid) molecule and removes the whole organic groups that obtain behind the hydroxyl, and some acyl group is preferred certainly, but should not be considered as restriction to scope of the present invention to these preferred acyl groups.Typical acyl group is those acyl groups that are used for the acidylate beta-Lactam antibiotics in the past; it comprises 6-amino-penicillanic acid and derivative thereof; 7-amino-cephalosporanic acid and derivative thereof; for example compile referring to Flynn; (Cephalosporins and penicillins) (cephalosporins and the penicillins) that Science Press (1972) publishes; on October 10th, 1978 disclosed German prospectus 2; 716; 677; on December 11st, 1978 disclosed belgian patent 867; 994; on May 1st, 1979 laid-open U.S. Patents 4; 152; 432; on July 27th, 1976 laid-open U.S. Patents 3; 971; No. 778; on October 23rd, 1979 laid-open U.S. Patents disclosed English Patent 1 on March 27th, 4,172,199 and 1974; 348, No. 894.Describe the some of these documents of various acyl groups and also list this paper in as a reference.List some acyl groups below further illustrating term " acyl group ", but should not think that " acyl group " only is confined to these.They are:
(a) its formula is Aliphatic group, R wherein aBe alkyl, cycloalkyl, alkoxyl group, alkenyl, cycloalkenyl; Cyclohexadienyl; Or be one or more halogens, cyano group, nitro, amino, sulfydryl, alkylthio, or the alkyl or the alkenyl of cyanomethylthio replacement.
(b) have the carbocyclic aromatic group of following structural formula:
Figure 86106980_IMG39
Figure 86106980_IMG40
In above-mentioned formula: n is 0,1,2 or 3; R b, R cAnd R dAll can be the alkyl of hydrogen, halogen, hydroxyl, nitro, amino, cyano group, trifluoromethyl, 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom separately independently, or amino methyl; R eBe carboxyl, formyloxy, sulfonate, sulfoamino-salt, azido-, halogen, diazanyl, alkyl diazanyl, phenyl diazanyl or ((alkylthio) sulphomethyl) sulfenyl of amino, hydroxyl, carboxylate salt, protection.
Preferred carbocyclic ring aroyl comprises the group with following formula:
Figure 86106980_IMG41
(c) have the aromatic heterocycle group of following structural formula:
Figure 86106980_IMG42
Figure 86106980_IMG43
In above-mentioned formula: n equals 0,1,2 or 3; R eDefinition the same; R fFor replace or unsubstituted contain 1,2,3 or 4(be preferably 1 or 2) 5-, 6-or 7 yuan of heterocycles of individual nitrogen, oxygen and sulphur atom, representative heterocycle is: thienyl, furyl, pyrryl, pyridyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidyl, thiadiazolyl group and tetrazyl.Representational substituting group is: the alkyl of the amino of halogen, hydroxyl, nitro, amino, protection, cyano group, trifluoromethyl, 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom or
Figure 86106980_IMG44
Preferred aromatic heterocycle acyl group group comprises those groups of said structure formula, wherein, and R fBe 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidine base-2,5-amino-1,2,4 thiadiazolyl groups ,-3,2-thienyl, 2-furyl or 6-aminopyridine base-2.
(d) have following structural formula (((4-replace-2,3-dioxo-1-
Figure 86106980_IMG45
The piperazine base) aryl ethanoyl amino carbonyl)),
Figure 86106980_IMG46
R in this structural formula gFor aryl (comprises isocyclic aryl group, as structural formula is
Figure 86106980_IMG47
Those groups and R fIncluded aromatic heterocycle group in the range of definition); R hBe alkyl, replacement alkyl (this alkyl for by alkyl that one or more halogen, cyano group, nitro, amino or sulfydryl replaced), aryl methylene amino (promptly-N=CH-R g, this R gThe regulation as above), aromatic carbonyl amino (promptly
Figure 86106980_IMG48
, this R gDefine the same) or alkyl-carbonyl-amino.
Preferably (((4-replace-2,3-dioxo-1-
Figure 86106980_IMG49
The piperazine base) amino carbonyl)) the aryl acetyl group comprises R wherein hThose groups for ethyl, phenylmethylene amino or 2-furyl methene amido.
(e) have
Figure 86106980_IMG50
(oximido of replacement) aryl acetyl group of structural formula is in this structural formula: R gDefinition the same, R jBe hydrogen, alkyl, cycloalkyl,
Figure 86106980_IMG51
, 2 or 3,2-pyrazolyl methyl, (2-oxo-3-pyrrolidyl) methyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl (promptly
Figure 86106980_IMG52
, this R gDefine the same) or the alkyl that replaces (wherein alkyl is replaced by one or more following substituting groups: halogen, cyano group, nitro, amino, sulfydryl, alkylthio, aromatic group are (by R gDefine it), carboxyl (salt that comprises them), amido, alkoxy carbonyl, phenyl methoxycarbonyl, phenylbenzene methoxy base carbonyl, hydroxy alkoxy base phosphinyl, dihydroxyl phosphinyl, hydroxyl (phenyl methoxyl group) phosphinyl, dialkoxy phosphinyl or tetrazyl).
Preferably (oximido of replacement) aryl ethanoyl comprises R wherein gBe those aryl ethanoyl of 2-amino-4-thiazolyl, R wherein iThose aryl ethanoyl that are methyl, ethyl, carboxyl methyl, 1-carboxyl-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxyl cyclopropyl also are preferred.
(f) its structural formula is
Figure 86106980_IMG53
(amido) aryl acetyl group, R wherein gDefine the same, R jBe
Figure 86106980_IMG54
Amino, alkylamino, (cyano group alkyl) amino, amido, alkyl amido, (cyano group alkyl) amido,
Figure 86106980_IMG55
Or
In the said structure formula preferably (acyl amino) aryl acetyl group comprise wherein R jBe those groups of amino or amido, also have these groups, wherein R preferably gThe group that is phenyl or 2-thienyl is also better.
(g) has (((3-replacement-2-oxo-1-imidazolidyl) carbonyl) amino) aryl acetyl group of following structural formula
Figure 86106980_IMG57
Wherein: R gDefinition the same, R KBe hydrogen, alkyl sulphonyl, aryl methylene amino (promptly-N=CH-R g, R wherein gDefinition the same)
Figure 86106980_IMG58
(R mBe the alkyl that hydrogen, alkyl or halogen replace), (definition is with top R for aromatic group g), the alkyl (wherein, alkyl is replaced by one or more halogens, cyano group, nitro, amino or sulfydryl) of alkyl or replacement.
Preferred ((3-replacement-2-oxo-1-imidazolidyl) carbonyl) amino of said structure formula) the aryl acetyl group comprises wherein R gBe those aryl acetyl group, wherein R of phenyl or 2-thienyl KThe aryl acetyl group that is hydrogen, methyl sulphonyl, phenylmethylene amino or 2-furyl methene amido also is preferred.
Within the compound of the present invention and the scope of the invention each is inorganic to form various subsalt with organic bases.The various salt that also comprise ammonium salt, an alkali metal salt, alkaline earth salt, organic bases (as dicyclohexylamine, benzyl star, N-methyl D-glucosamine, Kazakhstan amine etc.) at these salt.Though other salts also are useful.For example when the isolated or purified product; But but the salt of hyoscine is preferred.
Some compound of the present invention can carry out crystallization or recrystallization with aqueous solvent, at these occasions, able to generate hydrate.The present invention has thought over the compound of the water of the non-quantitative that meets stoichiometric hydrate.
The beta-lactam of I formula contain at least a chiral centre-with acyl ammonia substituting group (" R 1-NH-") carbon atom on 3 of the beta-lactam core that links to each other.What the present invention relates to is top those beta-lactams of having introduced, wherein: in the stereochemistry of the chiral centre of the 3-position of these beta-lactam cores and the configuration of the carbon atom of the 6th of naturally occurring penicillins (for example penicillin G) is identical, and also the carbon atom configuration with the 7th of naturally occurring cephamycin (for example cephamycin C) is identical.The racemic mixture that contains above-mentioned beta-lactam also belongs to scope of the present invention.
But the beta-lactam of formula I and the salt of hyoscine thereof all have activity to gram-positive microorganism and Gram-negative bacteria.These compounds of the present invention can be used as the treatment Mammals, as the medicine of domestic animal (dog, cat, ox, horse etc.) and human body infectation of bacteria (comprising urinary tract infection and respiratory tract infection).
For treating mammiferous infectation of bacteria, can take compound of the present invention on demand, the about 1.4 milligrams/kg/day of dosage is to about 350 milligrams/kg/day, and preferably about 14 milligrams/kg/day is to about 100 milligrams/kg/day.All adopt in the past so that penicillins and cephalosporin drug affact the administering mode of infection site.Beta-lactam of the present invention is considered also that in advance these route of administration comprise oral, quiet notes, intramuscular injection to adopt.And suppository.
But with structural formula is the amino-2-azetidinone preparation formula I beta-lactam of the 3-protection of II,
Figure 86106980_IMG59
In the structural formula II and in this explanation in full, symbol " R 4" refer to an amino protecting group.These groups are on record in beta-lactam chemistry field, as for selecting for use that group not strict.Typical blocking group has benzyloxycarbonyl, trityl and uncle-butoxy carbonyl.With formula II beta-lactam and formula III O=C=N-SO 2Just-Y isocyanate reaction can make corresponding formula IV compound, the Y in the formula III is a leavings group, as chlorine,
Figure 86106980_IMG60
Reaction is preferably carried out in a kind of inert organic solvents, as the mixture of ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, methylene dichloride, acetonitrile or these solvents., can be chosen in alkali and have (as triethylamine) down with group " R " the displacement leavings group " Y " that needs as desire, finish with suitable nucleophilic reagent (V),
Product is corresponding VI formula compound
Ⅴ????RH，
Figure 86106980_IMG61
Perhaps replace this leavings group by the IV formula compound and the reaction of the compound V of protection form, after replacement(metathesis)reaction, the technology of knowing in available this area is removed this blocking group to obtain VI formula compound.
The formula V compound of protection form and all reaction reagents that contain 3-hydroxyl-4-pyridone parent described herein, comprising: its hydroxyl is protected, and its hydroxyl and ring are gone up classes of compounds such as nitrogen two oxygen protected and wherein pyridone have been all protected.Silyl (trimethyl silyl), benzyl and acyl group (for example ethanoyl) are typical blocking groups.As use silyl, the then available hydrolysis of the deprotection of back or realize by the cracking of fluorochemical mesomeric; As use benzyl, then deprotection thereafter can be realized with hydrogenolysis; As use acyl group, then realize with hydrolysis.
With routine techniques VI formula compound deprotection can be produced corresponding key intermediate (VII)
Figure 86106980_IMG62
Or its salt.Certainly, adopt any special deprotection reaction to depend on the blocking group (" R of existence actually 4").For example, if R 4Be a uncle-butoxy carbonyl blocking group, then usable acid (for example formic acid or trifluoroacetic acid) is handled VI formula compound and is finished deprotection; R and for example 4Be a benzyloxycarbonyl blocking group, then can carry out catalytic hydrogenation and carry out deprotection VI formula compound.Perhaps, after the and then above-mentioned replacement(metathesis)reaction, R 4Blocking group is removed with other blocking groups of pyridone.
Available well-known acidylate technology changes formula VII intermediate into corresponding formula I product.Typical acidylate technology comprises VII formula compound and carboxylic acid (R 1-OH), or corresponding carboxylic acid halogenide or anhydride reaction.With carboxylic acid be reflected at for example dicyclohexyl carbodiimide and can form the easiest carrying out in the presence of the material of active ester at " scene " of carbodiimide as this class of N-hydroxybenzotriazole.In these examples, as acyl group (R 1) when containing functional group's (as amino or carboxyl) of tool reactive behavior, be necessary at first to protect these functional groups, and then carry out acylation reaction, at last the product that generates is carried out deprotection.
Also can adopt other step to come preparation, promptly at first the 3-amino-2-azetidinone of formula VIII be carried out acidylate (above the acidylate technology having been done introduction) with preparation intermediate (IX)
Figure 86106980_IMG63
On 1 of IX formula compound, introduce active group by the step of introducing above
Figure 86106980_IMG64
To prepare corresponding I formula product.As acyl side-chain " R wherein 1" when containing functional group's (as amino) of reactive behavior, be necessary at first to protect these functional groups, on its 1-position, introduce active group then, remove the blocking group of product at last again.
Preparation also has other synthetic method, and it comprises use formula X compound (3-azido--2-azetidinone),
Figure 86106980_IMG65
The step that employing is introduced above just can be introduced one on 1 of X formula compound
Figure 86106980_IMG66
Activating group is to make the corresponding compounds that its structural formula is an XI
Figure 86106980_IMG67
The reduction of intermediate XI is obtained the corresponding intermediates VIII
Figure 86106980_IMG68
This reduction reaction can or be used such as zinc or this class reductive agent of triphenyl phosphine and realize by catalytic hydrogenation (for example making catalyzer with the palladium charcoal or with platinum oxide).As mentioned above, from these key intermediates (VII formula compound), adopt conventional acidylate technology.Can preparation formula I product.
In addition, also the 3-azido--2-azetidinone of structural formula X can be reduced to corresponding 3-amino-2-azetidinone (VIII)
Figure 86106980_IMG69
Reduction can be adopted catalytic hydrogenation (for example with the palladium charcoal or use platinum oxide) or use the reductive agent such as zinc or triphenyl phosphine to realize.3-amino-2-the azetidinone of formula VIII can carry out above-mentioned reaction and (promptly carry out acidylate earlier, and then handle to introduce an active group on its 1 with the method for introducing above
Figure 86106980_IMG70
) can generate I formula product.
Preparation R wherein 2And R 3Another synthetic method that all is the I formula compound of hydrogen is to make raw material with 6-acyl amino penicillin alkanoic acid or its salt of structural formula XII.
Figure 86106980_IMG71
Adopt the step of introducing in the document, can make 3-amide group-2-azetidinone by the 6-amido penicillanic acid of corresponding formula XII, for example referring to 28 phases of Chem.Soc.SpecialPublication, 288 pages (1977), The Chemistry of Penicillins, Princeton University Press, 257 pages and Synthesis, 494 pages (1977).
As what introduced in the document, 6-amido penicillanic acid or its salt can by with the Raney nickel reduction and desulfurization to produce the compound of structural formula VIII, this reaction can be carried out under reflux conditions in water.
Figure 86106980_IMG72
After the carboxyl of X III formula compound replaced with ethoxycarbonyl, the hydrolysis that continues promptly got the 3-amido-2-azetidinone of corresponding structure formula X IV
Handle X III formula compound with venus crystals and lead tetraacetate in organic solvent (for example acetonitrile), acetate moiety just can be replaced carboxyl, in the presence of sodium borohydride, can realize the hydrolysis of this resultant with salt of wormwood.
The step that using chats face to face states can be introduced active group on 1 of X IV formula compound
Figure 86106980_IMG74
(product is R wherein 2And R 3It all is the I formula compound of hydrogen.）
Also the another kind of method of available above-mentioned route of synthesis prepares wherein R 2And R 3All be hydrogen I formula compound this comprise: earlier with 6-amino-penicillanic acid desulfurization, acidylate gained compound with preparation X III formula compound, and then handle by above-mentioned steps.At first obtaining having the 3-amide group-2-azetidinone of formula X IV, then is I formula product thereafter.
I formula azetidin ketone also possible constructions formula is that the amino acid of X V prepares
Figure 86106980_IMG75
At first use a blocking group " R 4" (for example uncle-butoxy carbonyl) protection amino group, in the presence of carbodiimide, this through the amine reaction that the amino acid whose carboxyl and the structural formula of protection are the X VI, can be made the compound that structural formula is the X VII then
In the X VI, Z is alkyl, benzyl or trityl group.
Figure 86106980_IMG76
Use such as Methanesulfonyl chloride or pyridine-SO 3This class reagent of mixture changes the hydroxyl of compound X VII into leaving group state (" OL ").
Handle just with alkali such as salt of wormwood can Cheng Huan for the X VIII formula compound of protection fully, and this annulation preferably under refluxad carries out in the mixture of organic solvent or organic solvent/water, and the generating structure formula is the compound of X IX.
Figure 86106980_IMG77
Perhaps the ring of X VII formula compound also can not be converted into leavings group with its hydroxyl earlier.But X VII formula compound is handled with triphenyl phosphine and diethylazodicarboxylate, obtain the compound of formula X IX.
The representational step that changes X VIII formula compound into X IX formula compound is at J.Amer.Chem.Sos., 102 volumes, and 7026 pages (1980) and J.Org.Chem., 47 volumes have been done introduction in 5160 pages (1982).
Above two kinds of closed-loop policies of disclosed X VII formula compound caused having R 2And R 3Two substituent carbon atoms are (as its R 2And R 3Stereochemical transformation not simultaneously).
When Z is alkyl, can removes blocking group on 1 of X IX formula compound azetidinone by sodium reduction, and generate the intermediate II
Figure 86106980_IMG78
R in this structural formula 2And R 3Have at least one to be hydrogen, if Z is a benzyl, catalysis (as using the palladium charcoal) hydrogenation will obtain corresponding N-oxy-compound at first, handle with titanous chloride again, promptly obtain the intermediate of II formula; If Z is a trityl group, its acetic acid/water with formic acid or 70% is handled.At first, will obtain corresponding N-oxy-compound.
Use above-mentioned steps, can on 1 of II formula compound, introduce an active group
Figure 86106980_IMG79
The product that generates can deprotection and acidylate.
R is
Figure 86106980_IMG80
And A 1And A 2Respectively for the preparation method of single bonded V formula compound nucleophilic reagent is, with the 2-imidazolidone
Figure 86106980_IMG81
Silylated derivative or the negatively charged ion also derivatives reaction of due care activated of the 2-imidazolidone that forms with strong non-nucleophilicity alkali with sour XX, behind deprotection, promptly get corresponding formula X XI compound
Figure 86106980_IMG82
This reaction can be such as dimethyl formamide, acetonitrile, methylene dichloride, or carries out in this class inert solvent of tetrahydrofuran (THF).Structural formula is the sour available dicyclohexyl carbodiimide of XX, or dicyclohexyl carbodiimide and hydroxybenzotriazole be used in combination activate.Derivative activated and that give the XX of due care also can be corresponding chloride of acid (using following reagent preparation, for example phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenyl phosphine/tetracol phenixin) or mixed acid anhydride (with the reagent preparation as hexichol phosphoryl chloride, pivalyl chloride or carbonochloridic acid isobutyl ester and so on).
Work as A in the compound of formula XX 6When being a singly-bound.The method preparation of introducing in the available following document: referring to Helv.Chem.Acta, 43 volumes, 469 pages (1960) and J.Med.Chem., 17 volumes, 1 page (1974).
A wherein 6Be-preparation method of the compound XX of C=C-is; the compound of due care (X XII) is oxidized to corresponding aldehyde (XX III) (due care); the derivative of aldehyde XX III and carboxy protective (XX IV) reaction, deprotection promptly gets compound (XX V) again.
A wherein 6Be-(CH 2) t -, and t=2, the preparation method of 3 or 4 compound XX is, with the compound XX III of due care and the Wittig reagent XX VI generation conjugation of its carboxyl due care, and then the exocyclic double bond that generates of hydrogenation, deprotection again.Promptly obtain compound (XX VII), t=2 wherein, 3 or 4.
Work as A 6Be-C(CH 2) preparation method of compound XX of t-and t=1 is that with the compound (XX VIII) and the prussiate reaction of due care, hydrolysis that continues and deprotection promptly get compound XX VII, wherein t=1.Compound XX VI can be by the compound X XII of due care, prepare with the method for knowing in this skill field (as thionyl chloride or methylsulfonyl chloride/triethylamine).
Figure 86106980_IMG86
L in the compound XX VII aBe a leavings group, for example muriate, bromide, methylsulfonyl oxygen or tolylsulfonyl oxygen.
When R is
Figure 86106980_IMG87
A 1Be singly-bound, A 2Be-preparation method of the nucleophilic reagent V of NH-is, derivative activated and the compound XX of protection selectively and 1-amino-2-imidazolidone (
Figure 86106980_IMG88
) reaction, promptly get compound (XX IX) behind the deprotection
Figure 86106980_IMG89
When R wherein is
Figure 86106980_IMG90
, A 1Be singly-bound, A 2Be-CH 2-CH 2The preparation method of the nucleophilic reagent V of-NH-is, with activatory, the derivative XX and the 1-(2-aminoethyl of the compound XX of protection selectively)-the 2-imidazoles (
Figure 86106980_IMG91
)
Reaction promptly gets compound (XXX) behind the deprotection
Figure 86106980_IMG92
When R wherein is
Figure 86106980_IMG93
, A 1Be singly-bound, A 2 The preparation method of nucleophilic reagent V be, with the 2-imidazolidone reaction of compound (XX XI) with the silylanizing form, with the 2-imidazolidone negatively charged ion of non-nucleophilicity highly basic form, or in the presence of organic bases, react, obtain compound (XX XII) with the 2-imidazolidone.Catalytic hydrogenation compound XX XII promptly gets compound (XXX III), it can with activatory, the derivative coupling of compound XX of protection selectively, behind the deprotection, obtain compound (XXX IV).
Figure 86106980_IMG95
Figure 86106980_IMG96
Perhaps, the preparation of the also available other method of compound XXX III, promptly at first make 1-chloroformyl-hydrazine reaction that 2-imidazolidone and uncle-butoxy carbonyl are protected, obtain compound (XXX V), again deprotection and getting.
Figure 86106980_IMG97
When its R is
Figure 86106980_IMG98
, A 1Be
Figure 86106980_IMG99
, A 2Be that single bonded nucleophilic reagent V can be with the preparation of following method, with behind the compound (XXX VI) and the hexamethyldisilazane reaction of due care, hydrolysis, the deprotection compound (XXX VII).With the compound X XI silylation form, selective protection and phosgene reaction, can prepare the compound XXX VI of due care.
Perhaps, the also available another kind of method preparation of compound XXX VII is about to protect the compound X XI and the chloro sulfonyl isocyanate reaction of form, and protecting group is removed in the intermediate and the cracking of the hydrolysis gained that continues.
When R wherein is
Figure 86106980_IMG101
, A 1Be , A 2Be-preparation method of nucleophilic reagent V is compound (XXX VIII) (symbol wherein " prot " can be the blocking group of an amino, as uncle-butoxy carbonyl or benzyloxycarbonyl) and the phosgene reaction with the silylanizing form during NH-.Obtain compound (XXX IX), it reacts with hexa methyl silazane again.Behind the deprotection, obtain compound (XL).Compounds X L and selective protection, the compound XX reaction of activated form behind deprotection, obtains compound (XLI).
Figure 86106980_IMG103
Perhaps, the also available another kind of method of compounds X L prepares.With compound (X L II) and chloro sulfonyl isocyanate reaction, hydrolysis obtains compound (X L III), and this compound is handled with aqueous acids again, obtains the salt of compound X L.
Figure 86106980_IMG104
When R is
Figure 86106980_IMG105
, A 1Be
Figure 86106980_IMG106
, A 2Be-CH 2-CH 2The preparation method of the nucleophilic reagent V of-NH-is; at first with the 1-(aminocarboxyl)-3-(2-(((uncle-butoxy) carbonyl) amino) ethyl)-2-imidazolidone deprotection; again with the compound XX of gained compound and activated form (protection selectively) coupling; behind the deprotection, obtain compound (X L IV).
Figure 86106980_IMG107
When R wherein is , A 1Be
Figure 86106980_IMG109
, the time, the nucleophilic reagent V can will have compound XXX IV and the phosgene reaction protection selected, the silylanizing form with the preparation of following method, continue again with the hexamethyldisilazane reaction, behind hydrolysis and the deprotection, obtain compound X L V.
Perhaps compound X L V can be with another kind of method preparation, with the compound XXX IV of protection form and the intermediate that chloro sulfonyl isocyanate reacts, hydrolysis generates, cracking deprotection group.Perhaps; with compound XX XII and chloro sulfonyl isocyanate reaction; the intermediate of its generation of hydrolysis that continues; obtain compound (X L VI), hydrogenolysis is sloughed its protecting group, gets compound (X L VII); its energy and activatory; and the derivative coupling of the compound XX of the protection selected is arranged, behind the deprotection, obtain compound X L V.
Figure 86106980_IMG111
When R wherein is
Figure 86106980_IMG112
, A 1Be-NH-, A 2The preparation method who is single bonded nucleophilic reagent V is, compound XXX VIII with the compound XX coupling protection selected, activated form is arranged, after blocking group is sloughed in cracking, obtain compound X L VIII.
Figure 86106980_IMG113
When R wherein is
Figure 86106980_IMG114
, A 1Be-NH-, A 2Be-the nucleophilic reagent V of NH-can be with following method preparation; (preferably using uncle-butoxy carbonyl or benzyloxycarbonyl) 1 with single protection; the compound XX of 3-diamino-2-imidazolidinone derivatives and activated form (protection of selection is arranged) coupling; the gained compound is sloughed protection, obtain compound X L IX
Figure 86106980_IMG115
Perhaps, compound X L IX also can be carried out nitrosylation by the compound XX IX that will protect form, restores nitroso-group, and cracking is removed its protecting group and made.
When R wherein is , A 1Be-NH-, A 2Be-CH 2-CH 2The preparation method of the nucleophilic reagent V of-NH-is, with the compound XXX nitrosylation of due care, promptly obtains compound (L I) after obtaining compound (L) (due care), reduce and slough protection
Figure 86106980_IMG117
A 1Be-NH-, A 2Be
Figure 86106980_IMG118
The preparation method of nucleophilic reagent V be, the protected derivative of compound XXX IV is carried out nitrosylation, reduction and deprotection, obtain the compound L II
Figure 86106980_IMG119
Perhaps the also available following method of compound L II makes; compound XXX VIII and phosgene reaction; obtain the compound L III; exist down with its hydrazine reaction in alkali with single protection; obtain compound L IV (two blocking groups in the L V must be different); remove the blocking group of hydrazides selectively, obtain compound (L V).This compound L V again with activatory, the coupling of compound XX, the deprotection of the protection selected are arranged, obtain the compound L II.
Figure 86106980_IMG120
When R wherein is , A 1Be
Figure 86106980_IMG122
, A 2The preparation method who is single bonded nucleophilic reagent V is; exist down with compound XXX VI (the preferably derivative of its protection) and hydrazine (preferably single protection form) reaction in alkali; or with the hydrazine of itself and silylanizing form or the hydrazine reaction of single protection; obtain the derivative of the protection of compound L VI, carry out deprotection with ordinary method again.
Figure 86106980_IMG123
Perhaps, also can be, slough protection with compound XX (due care) reaction of compound XXX V (its silylated derivative or the negatively charged ion that the reaction of itself and highly basic is formed) and activated form, promptly get the compound L VI.
When R wherein is A 1Be
Figure 86106980_IMG125
, A 2Be-nucleophilic reagent V during NH-can remove the non-hydrazides blocking group of L IV compound selectively with following method preparation, continue again with activatory, the compound XX coupling of the protection selected is arranged, behind the deprotection, promptly get the compound L VII
When R wherein is
Figure 86106980_IMG127
, A 1Be , A 2Be-CH 2-CH 2The preparation method of the nucleophilic reagent V of-NH-is; at sillylation reagent; as N-methyl-N-(trimethyl silyl) the trifluoroacetamide existence is down; successively with compound XXX (or derivative of its protection) and phosgene; again with hydrazine (or derivative of its single protection) reaction; after sloughing protection, obtain the compound L VIII
Figure 86106980_IMG129
Perhaps; also can be with the 1-(2-amino-ethyl)-derivative and the phosgene reaction of the amido protecting of 2-imidazolidone (silylanizing selectively); in alkali or silylation reagent (as N-methyl-N-(trimethyl silyl) trifluoroacetamide or two (trimethyl silyl) ethanamide) exist down; with the derivatives reaction of single protection of hydrazine, obtain the derivative of the protection of (L IX) compound again
Figure 86106980_IMG130
Selection is used to protect the blocking group of L IX compound terminal amino group, and the protecting group on the amino-ethyl can optionally be removed.Resulting singly go to protect compound can with sour XX (or derivative of its protection) coupling of activated form, slough protecting group after, obtain the compound L VIII.
Wherein R is
Figure 86106980_IMG131
, A 1Be
Figure 86106980_IMG132
The preparation method of nucleophilic reagent V be, with compound XX XII (available sometimes its silylated derivative) and phosgene reaction, obtain the derivative of the protection of L X, it again with the hydrazine derivative coupling of protection, obtain the derivative of the protection of (L XI).When selecting the protecting group of compound L XI terminal amino group, one of them protecting group can optionally be removed.The compound of the single protection that obtains with the sour XX coupling protection selected, activated form is arranged, slough protection after, obtain the compound L VIII.
Figure 86106980_IMG133
Figure 86106980_IMG134
That utilization is introduced above, prepare wherein that R is
Figure 86106980_IMG135
The similar approach of nucleophilic reagent V, can preparing wherein, R is
Figure 86106980_IMG136
Nucleophilic, but with suitable 2,3-
Figure 86106980_IMG137
Piperazine two ketone reagent replace 2-imidazolidine ketone reagent.
Wherein R is , A 1Be singly-bound, A 5Be that single bonded nucleophilic reagent V can prepare with compound L X derivative III, due care.
Figure 86106980_IMG139
Method (the Chem.Ber. that people such as the available K.Heyns of compound (L X IV) introduce; 87 volumes, 1440 pages (1954)), change the compound L X V of protection form the compound L X IV of protection form into; and then slough its protection, by self obtaining compound L XI V.
Compound L X V can prepare with the compound L X III of due care form, and its method is to change it into ester (as Z base or methyl), again with hydrazine reaction, deprotection.Perhaps, also can be with the hydrazine reaction of compound L X III due care, activated form with single protection, slough protection after, make compound L X V.Compound L X IV (or derivative of its due care) and 2-(chloroethyl) reaction of isocyanic ester (can carry out in the presence of alkali (as triethylamine) or silylation reagent, promptly obtain compound (L X VI) behind the deprotection
Figure 86106980_IMG141
With alkaline purification compound L X VI (or derivative of its due care), deprotection, obtain compound (L X VII)
Figure 86106980_IMG142
Wherein R is
Figure 86106980_IMG143
, A 1Be singly-bound, A 5Be-CH 2-nucleophilic reagent V preparation method be, with compound (L X VI) (or derivatives thereof (wherein pyridine watt department by due care and primary amine is not protected)) and 2-(chloroethyl) isocyanate reaction, behind the deprotection, obtain compound (L X IX)
Figure 86106980_IMG144
Compound L X IX (or derivative of its due care) is obtained following compound with alkaline purification
LXX
Figure 86106980_IMG145
Compound L X VIII is prepared as follows: handle compound XX VIII (due care) with trinitride, again with trinitride reduction, deprotection.
Wherein R is
Figure 86106980_IMG146
, A 1Be singly-bound, A 5Be-N=CH-or-NH-CH 2-the nucleophilic reagent V can be with the preparation of following method, with 1-amido-2-imidazolidone and the aldehyde XX III condensation of selecting protection, (sloughing the protection back) obtains compound (L X XI)
Figure 86106980_IMG147
L X XI compound (due care) with catalytic hydrogenation or with the sodium cyanoborohydride reduction, is obtained compound L X XII
Wherein R is
Figure 86106980_IMG149
, A 1Be singly-bound, The preparation method of nucleophilic reagent V be; with 1-chloroformyl-2-imidazolidone and compound (L XX III) (or derivative of its due care) react in the presence of alkali; or with the silylated derivatives reaction of compound L XX III, slough protection, obtain compound (L XX IV)
Figure 86106980_IMG151
Wherein R is
Figure 86106980_IMG152
, A 1Be The preparation method of nucleophilic reagent V be; derivative and phosgene reaction with the due care of compound L X VII, L XX, L X XI, L X XII or L XX IV; obtain the derivative of the protection of compound (L XX V); it can react with hexa methyl silazane; after deprotection and hydrolysis, obtain compound (L XX VI)
Figure 86106980_IMG154
Perhaps, wherein R is
Figure 86106980_IMG155
, A 1Be
Figure 86106980_IMG156
The also available following method preparation of nucleophilic reagent V, the derivative of the due care of compound L X VII, L XX, L XX I, L X XII or L XX IV is reacted with chloro sulfonyl isocyanate, behind hydrolysis and the deprotection, promptly obtain compound L XX VI.
Wherein R is
Figure 86106980_IMG157
, A 1Be-preparation method of the nucleophilic reagent V of NH-is; with derivative nitrosylation (for example using nitrous acid), the reduction gained compound (for example under acidic conditions, using zinc) of the due care of compound L X VII, L XX, L X XI, L X XII or L XX IV, slough protection, obtain compound L XX VII
Figure 86106980_IMG158
Perhaps, A wherein 5Be
Figure 86106980_IMG159
Compound L XX VII can in the presence of alkali or sillylation reagent, the compound L X IV or the L X VIII of compound XXX IX and due care form be reacted with the preparation of another kind of method, behind the deprotection, obtain compound (L XX VIII)
Figure 86106980_IMG160
Perhaps, A wherein 5Be-N=CH-or-NH-CH 2-compound L XX VII also available another kind of way preparation, with 1 of single protection, 3-diamino-2-imidazolidone and compound XX III (or its derivative of having protected) are reacted, product are sloughed protection, obtain wherein A 5Be-derivative of the L XX VII of N=CH-, reduce this derivative, obtain wherein A 5Be-NH-CH 2-compound L XX VII.
Wherein R is
Figure 86106980_IMG161
, A 1Be
Figure 86106980_IMG162
The preparation method of nucleophilic reagent V be, in the presence of alkali or sillylation reagent, with the compound L XX V of due care and the hydrazine reaction of single protection, slough protection after, obtain compound (L XX IX)
Figure 86106980_IMG163
Wherein R is
Figure 86106980_IMG164
, A 1Be singly-bound, A 5Be singly-bound or-CH 2-the preparation method of nucleophilic parent agent V be, with compound L X IV or L X VIII (or derivative of their due care) and aziridine or activatory aziridine (with group as acyl group or alkylsulfonyl and so on.Activation) reaction promptly, gets compound (L XXX) behind the deprotection
The compound of formula L XXX (or derivative of its due care) can react (in case of necessity deprotection) again with dialkyl oxalate to be changed into and wishes to get
Figure 86106980_IMG166
Piperazine diketone (L XX XI)
Wherein R is
Figure 86106980_IMG168
, A 1Be singly-bound, A 5Be-N=CH-or-NHCH 2-the nucleophilic reagent V can with introduce above (preparing wherein, R is
Figure 86106980_IMG169
, A 1Be singly-bound, A 5Be-N=CH-or-NHCH 2The method in-time prepares, but will use 1-amino-2,3-
Figure 86106980_IMG170
The piperazine diketone replaces 1-amino-2-imidazolidone.The compound that obtains is (a L XX XII) and (L XXX III)
Wherein R is
Figure 86106980_IMG172
, A 1Be
Singly-bound, A 5Be
Figure 86106980_IMG173
The preparation method of nucleophilic reagent V be, in the presence of alkali or sillylation reagent, with the derivative and compound L XX III (or derivative of its due care) reaction of the due care of compound (L XXX IV).Intermediate deprotection with obtaining obtains following compound.
Figure 86106980_IMG174
R wherein is
Figure 86106980_IMG175
, A 1Be-the nucleophilic reagent V of NH can be prepared as follows; derivative nitrosylation (as using nitrous acid) with the protection of compound L XX XI, L XX XII, L XXX III or L XXX V; reduction products therefrom (using zinc under at acidic conditions) and deprotection obtain following compound.
Figure 86106980_IMG176
A wherein 5Be-N=CH-or-NH-CH 2-the also available following method preparation of compound L XXX VI: will single protection 1,4-two amidos-2,3-
Figure 86106980_IMG177
Piperazine diketone and compound XX III (or derivative of its protection) reaction are sloughed protection with product and are obtained compound L XXX VI, wherein A 5Be-N=CH-that it can be reduced and obtain wherein A then 5Be-NH-CH 2-L XXX VI; Also can reduce earlier-N=CH-, again deprotection.
R wherein is
Figure 86106980_IMG178
, A 1Be The nucleophilic reagent V can take the preparation of following method; derivative and phosgene reaction with the due care of compound L XX XI, L XX XII, L XXX III or L XXX V; obtain compound (L XXX VII); it can react with hexamethyldisilazane, promptly gets compound (L XXX VIII) after deprotection and the hydrolysis
Perhaps, wherein R is
Figure 86106980_IMG181
, A 1Be
Figure 86106980_IMG182
The another kind of preparation method of formula nucleophilic reagent be that derivative and chloro sulfonyl isocyanate reaction with the due care of compound L XX XI, L XX XII, L XXX III or L XXX V behind hydrolysis and the deprotection, obtain compound L XXX VIII.
Wherein R is
Figure 86106980_IMG183
, A 3Be-(CH 2) the nucleophilic reagent V of p-is described, referring to compound L X IV and L X VIII.
Wherein R is
Figure 86106980_IMG184
, A 3Be
Figure 86106980_IMG185
The nucleophilic reagent V can adopt the preparation of following method, in the presence of alkali or sillylation reagent,, then remove all blocking groups with compound XX XI and compound L XI V or L X VIII (having selection to protect) reaction.
Perhaps, wherein R is
Figure 86106980_IMG186
, A 3Be
Figure 86106980_IMG187
The also available following method preparation of nucleophilic reagent V, with compound L X IV or the L X VIII and the phosgene reaction of due care form, in the presence of alkali or sillylation reagent, also slough protection again with single hydrazine derivative processing of protecting.
Wherein R is
Figure 86106980_IMG188
, A 3Be
Figure 86106980_IMG189
The nucleophilic reagent V can be with the preparation of following method, with the glycine derivative of activatory N-protected and compound L X IV or L X VIII (have select protect) coupling, then slough protection again.
Wherein R is
Figure 86106980_IMG190
, A 3Be-NH-CH 2-the nucleophilic reagent V can be with the preparation of following method, make the hydrazine reaction of derivative and hydrazine or single protection of the selection protection of aldehyde XX III, then reduce carbon-nitrogen pair key, deprotections again
Perhaps, also available compound XX VIII (due care) makes the free amine group monoalkylation of the hydrazine of single protection, deprotection again, and the R that obtains wherein is
Figure 86106980_IMG191
, A 3Be-NH-CH 2-the nucleophilic reagent V.
Wherein R is
Figure 86106980_IMG192
, A 3Be-O-CH 2-the preparation method of nucleophilic reagent V be; under Mitsunobu condition (promptly in the presence of triphenyl phosphine and the diethylazodicarboxylate); derivative and the reaction of N-hydroxyphthalimide with the due care of compound X XII; obtain the derivative of the protection of compound (L XXX IX), it can be obtained compounds X c by deprotection
Figure 86106980_IMG193
Perhaps, also available another kind of method prepares compounds X c, in the presence of alkali, with the compound XX VIII and the reaction of N-hydroxyphthalimide of due care.
Wherein R is
Figure 86106980_IMG194
, A 4Be-preparation method that the nucleophilic of NH-is attempted V is, with the activatory of the hydrazine of protection and sour XX, have and select the derivatives reaction protected, obtains compound (X C I) after sloughing protection
Figure 86106980_IMG195
Perhaps, compound X C I also has another kind of preparation method, with the derivative carboxylicesters and the hydrazine reaction of the due care of compound XX, deprotection then.
R wherein is
Figure 86106980_IMG196
, A 4Be-(CH 2) preparation method of nucleophilic reagent V of p, p=0 is, with the activatory of ammonia or hexamethyldisilazane and sour XX, the derivatives reaction of the protection selected is arranged, obtains following compound behind the deprotection.
Preparing wherein, R is
Figure 86106980_IMG198
, A 4Be-(CH 2) p-, the preparation method of the nucleophilic reagent V of p=1 is: with the due care of compound XX, the activatory derivative handles with diazomethane, that continues uses the salt acid treatment, obtains the derivative of the protection of compound (X C III), " Lb " in the X C III is chlorine.Handle wherein with the salt (as sodium iodide or lithiumbromide) of iodide or bromide that Lb is the compound X C III of chlorine, obtain Lb wherein and be the derivative of protection of the compound X C III of bromine or iodine.Leavings group " Lb " (wherein Lb is chlorine, bromine or iodine) is replaced, is reduced thereupon with trinitride and sloughs protection, obtains compound (X C IV).
Figure 86106980_IMG199
Preparing wherein, R is
Figure 86106980_IMG200
, A 4Be-(CH 2) the nucleophilic reagent V of y-NH makes compound (X C V) (single protecting group of selection is arranged) (NH 2-(CH 2) y-NH 2) with the activatory of sour XX, the derivatives reaction of the protection selected is arranged, obtain compound (X C VI) behind the deprotection
Figure 86106980_IMG201
Preparing wherein, R is , A 4Be
Figure 86106980_IMG203
The nucleophilic reagent V: in the presence of sillylation reagent, with the compound X C I of due care and compound (X C VII) (protection
Figure 86106980_IMG204
) reaction, remove blocking group again.
Preparing wherein, R is
Figure 86106980_IMG205
, A 4Be
Figure 86106980_IMG206
The nucleophilic reagent V: in the presence of alkali or sillylation reagent, will
Figure 86106980_IMG207
With the activatory of structural formula XX, the derivatives reaction that has selection to protect, obtain compound (X C VIII) behind the deprotection
Figure 86106980_IMG208
Preparing wherein, R is
Figure 86106980_IMG209
, A 4Be
Figure 86106980_IMG210
The nucleophilic reagent V: with the hydrazine derivative of due care
With the activatory of sour XX, the derivatives reaction of due care, behind the deprotection, obtain following compound.
Figure 86106980_IMG211
Perhaps, X wherein is that the another kind of preparation method of the Compound C of hydrogen is: with carboxylates derivatives (or derivative of its due care) reaction of methyl hydrazine and sour XX.
In the compound of formula I, its R is
Figure 86106980_IMG212
The person is preferred.And preferably wherein R represent
Figure 86106980_IMG213
Those chemical compounds Is.
R wherein 1Be (Rg be 2-amino-4-thiazolyl and Ri be methyl, ethyl, carboxymethyl, 1-carboxyl-1-methylethyl, 1-carboxyl-1-ethyl or
Figure 86106980_IMG215
, the S=1 here, 2 or 3) formula I chemical compounds I also be preferably.
Use these R preferably 1The product that acyl group obtains is to exist with the form of cis or trans-isomer(ide) or with the form of isomer mixture.Cis-isomeride demonstrates stronger activity than trans-isomerism object.
Embodiment 1
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 2-(methylol)-5-(phenyl methoxyl group)-4H-pyrans-4-ketone
The sodium of 69 grams (3 moles) are dissolved in 5 liters of methyl alcohol, add 425.3 gram (3 moles) 5-hydroxyl-2-(methylols subsequently)-4H-pyrans-4-ketone and transparent until solution in 30 ℃ of following stirrings.Add 595 gram (3.5 moles) bromotoluenes, stirred 1 hour down in refluxing, this is warm and solution that color is very dark is poured in 15 liters of frozen water, product crystallization is immediately separated out, and collects crystal, wash with 8 premium on currency earlier, use 2.5 liters of ether washed twice again, product is placed spent the night, following dry 16 hours in 50 ℃ at last, product weighs 646 grams, productive rate 92.6%.
B) 4-oxo-5-(phenyl methoxyl group)-4H-pyrans-2-carboxylic acid
With 232 gram (1 mole) 2-(methylols)-5-(phenyl methoxyl group)-4H-pyrans-4-ketone is poured in 10 liters of flasks that fill 6.6 liters of acetone and 400 ml waters in stirring down, with ice bath this settled solution is cooled to 5 ℃, keeping under 5 °～10 ℃ of its temperature, in 1 hour, dripping 640 milliliters of Jones reagent (CrO 3202 grams, 600 milliliters in water, H 2SO 4174 milliliters), spread the deicing bath and continue stirring 2 hours, this reaction mixture is filtered through sintered glass, with 500 milliliters of washing with acetone sap green resistatess, evaporating this filtrate all volatilizees until acetone, in this aqueous partial crystallization product, add 1.2 liters of methyl alcohol and heat this mixture until its boiling temperature, gained sap green solution is put into ice bath allows its crystallization separate out, the filtering for crystallizing product, with containing 500 milliliters of cold mixed solvent washings that 250 ml methanol and 250 ml waters are formed, final drying, product weigh 195 grams, productive rate 79%.Also can from mother liquor, reclaim 5% product.
C) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid
With 300 gram (1.22 moles) 4-oxo-5-(phenyl methoxyl groups)-4H-pyrans-2-carboxylic acid pours in the flask, in stirring careful down 5 liters of NH of adding 4OH(33%).Stir this reaction mixture down in refluxing then.After 3 hours, add 33% NH more slowly 4The OH1 liter, and in the continuation stirring down 2 hours that refluxes, evaporate this solution to separate out until crystallization, again it is refunded in the reaction flask, add water until obtaining (about 5 liters of transparent solution, pH6.38), dripping concentrated hydrochloric acid under high degree of agitation is 3 until pH, filters the white product of separating out, water thoroughly washs, drying, product weigh 273 grams (1.12 moles), productive rate 91.8%.
D) 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidyl)-5-(phenyl methoxyl group)-the 2-pyridine carboxamides
1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid (0.05 mole of 12.26 gram) and 1-amino-2-imidazolidone (5.56 restrain 0.055 mole) be suspended in 120 milliliters of dimethylamino benzophenone acid amides.In this suspension, add 0.3 gram Dimethylamino pyridine and 0.4 gram N-hydroxybenzotriazole.After stirring 30 minutes under the room temperature, be added dropwise to 50 milliliters of dimethyl formamide solutions of 11.35 gram (0.055 mole) dicyclohexyl carbodiimides, and under room temperature, stir and spend the night, leach throw out (dicyclohexylurea (DCU)), with the filtrate vaporising under vacuum, handle residual syrup to carry out crystallization with sodium bicarbonate aqueous solution, obtain title compound 11.7 grams, 158～160 ℃ of fusing points.Also recrystallize goes out 0.8 gram product, 162～164 ℃ of fusing points from contain filter liquor.
E) 1,4-dihydro-5-hydroxyl-4-oxo-N-(2-oxo-1-imidazolidyl)-the 2-pyridine carboxamides
In 12 gram (0.0365 moles) 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidyl)-5-(phenyl methoxyl group)-add 36.1 milliliters of (0.146 mole) two (trimethyl silyl) ethanamides to form muddy slightly solution in the suspension of 2-pyridine carboxamides in 150 milliliters of acetonitriles.After the filtration, add the palladium-carbon of 6 grams 10%, and make the reaction mixture of hydrogen by stirring.After the hydrogenation 60 minutes, leach catalyzer, add 15 milliliters of methyl alcohol, 2 milliliters of acetate.Continue to stir the crystallization of spending the night and separate out title compound, weigh 6.6 grams, 270～275 ℃ of fusing points.
F) (3S)-(1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl
In 13.8 gram (S)-3-(((phenyl methoxyl group) carbonyl) the amino)-suspension of 2-azetidinone in 500 milliliters of ethyl acetate, add 5.63 milliliters of (0.0626 mole) chloro sulfonyl isocyanates.Under room temperature, stir this mixture 1 hour to form (S)-1-(((chlorosulfonyl) amino) carbonyl)-3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone solution.Be cooled to 0 ℃, under this temperature, slowly add silylated 1,4-dihydro-5-hydroxyl-4-oxo-N-(2-oxo-1-imidazolidyl)-(this solution is by 14.9 gram (0.0626 moles) 1 to 2-pyridine carboxamides solution, 4-dihydro-5-hydroxyl-4-oxo-N-(2-oxo-1-imidazolidyl)-the 2-pyridine carboxamides in 500 milliliters of ethyl acetate suspension, add 46.4 milliliters of N-methyl-N-(trimethyl silyls) three fluoro ethanamides (0.25 mole) and stir 30 minutes the preparation).Add 150 milliliters of methylene dichloride then, mixture is stirred under room temperature spend the night.In this transparent solution, add 26.2 milliliters of (0.188 mole) triethylamines, 200 milliliters in 300 grams on the rocks more thereupon, water, pH is 6.5.Stir after 1.5 hours, separate two-phase, water layer washs 3 times with ethyl acetate, each 200 milliliters.After removing the residual acetic acid ethyl ester under the vacuum, add the pH to 2 that 2N hydrochloric acid (47 milliliters) is regulated water layer down slowly in cooling.Leach crystallization and be suspended in 200 milliliters of ethyl acetate and stirred 1 hour.Leach crystallization then, respectively wash 2 times with 30 milliliters of ethyl acetate, 50 milliliters of sherwood oils respectively, dry under the vacuum, obtain 190～200 ℃ of title compound 28.6 gram fusing points, (decomposition).
G) (3S)-3-amino-N-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetate (1: 2)
Under room temperature; with 4 the gram (0.00713 mole) (3S)-(1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo 1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azetidinyl) the carboxylamine benzene methyl under 10 ℃, join in the mixture of 15 milliliters of trifluoroacetic acids and 3.5 milliliters of thioanisoles.Stir this clear solution down in 10 ℃ and spend the night, handle residual syrup with ether after the vacuum-evaporation under the room temperature, obtain title compound, be the light yellow solid thing, its productive rate almost is quantitative.
H) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo-ethylidene) amino) oxygen)-the phenylbenzene methyl esters of 2 Methylpropionic acid
In 3.08 the gram (0.007 mole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-add 2.9 milliliters of (0.021 mole) triethylamines in 70 milliliters of dimethyl formamide solutions of 4-thiazolyl acetic acid, after in nitrogen atmosphere, being cooled to-30 ℃, add 1.55 milliliters of (0.007 mole) diphenyl phosphate chlorides again, mixture stirred 1 hour down at-30 ℃.Add 1.95 milliliters of triethylamines (0.014 mole); and then ((3-(((1 to add 0.007 mole of 3S-3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetate (1: 2), this reaction mixture was then stirred 1 hour for 0 ℃ time in-10 ℃ of following stirrings in 2 hours.Remove under the vacuum and desolvate, resistates water and ethyl acetate are handled, and obtain insolubles, handle just with ether and solidify, and crude product weighs 8.0 grams.
I) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azetidinyl) amino)-2-oxo-ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
With crude product (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azetidinyl) amino)-2-oxo ethylidene) amino) oxygen)-benzhydryl ester of 2 Methylpropionic acid (8 gram) is suspended in the 15ml methyl-phenoxide.After being cooled to-10 ℃, dropping 80ml trifluoroacetic acid also stirred 1 hour under-10 ℃.Add ether under 0 ℃, precipitation is separated out the trifluoroacetate (crude product 4.1 grams) of free acid product.This crude product is suspended in the water, regulates pH to 5.5 with sodium hydrogen carbonate solution, with this solution lyophilize, this crude product sodium salt is with HP-20 post macroreticular styrene-divinylbenzene copolymer resin, and Mitsubishi chemical industrial company sells) carry out chromatogram purification.Product dilute with water, product weigh 0.52 gram.
Nucleus magnetic resonance (DMSOd 6) measure: δ=1.35(s, 3H); 1.40(s, 3H), 3.37(dd, 1H); 3.47(t, 2H); 3.81(t, 2H+dd, 1H); 5.05(m, 1H); 6.75(s, 1H); 7.27(s, 1H); 7.72(s, 1H); 11.52(wide s, 1H).
Embodiment 2
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides
1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid (61.3 grams, 0.25 the mole) in the room temperature low suspension in 500 milliliters of dimethyl formamides, continue add again 39.65 the gram (0.3 mole) uncles N-(-butoxy carbonyl) hydrazine, 1.5 the gram Dimethylamino pyridines and 2.0 the gram N in 30 minutes-hydroxybenzotriazole, under room temperature, mixture was stirred 30 minutes, and then under agitation be added dropwise to 57.7 gram (0.28 mole) dicyclohexyl carbodiimides (being dissolved in 100 milliliters of dimethyl formamides), and mixture stirred under room temperature spend the night.Elimination precipitation (dicyclohexylurea (DCU)) is with the filtrate vaporising under vacuum, and residual syrup is handled with dilute solution of sodium bicarbonate and carried out crystallization.This crude product of doing obtains title compound 69.5 grams, 173～175 ℃ of fusing points with 2 liters of re-crystallizing in ethyl acetate.Product 3.2 gram again behind the mother liquid evaporation, 160～165 ℃ of fusing points.
B) 1,4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid, hydrazides 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides (69 grams, 0.191 mole) is added under 0 ℃ in 370 milliliters of trifluoroacetic acids.Under room temperature, stirred 1 hour, then evaporation.Residual syrup is handled with ether, and it is thick 1 to obtain 68.2 grams, 4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, hydrazides, trifluoroacetate (1: 2) solid.
With this crude product 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-and 2-Pyridinecarboxylic Acid hydrazides trifluoroacetate (1: 2) is dissolved in 250 milliliters of acetonitriles, stirs 1 hour under cooling, and the elimination crystallization also is suspended in 600 milliliters of acetonitriles.Palladium-the charcoal that adds 28 grams 10% behind two (trimethyl silyl) ethanamides (135 milliliters) of adding again.Make hydrogen by this solution under stirring then, after 90 minutes hydrogenation complete, filter the back and add 70 ml methanol and 2 milliliters of acetate.Stirring is spent the night, and leaches the crystallization of generation, obtains title compound 19.4 grams, and 290～340 ℃ of fusing points decompose.
C) (3S)-and (1-((((((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) the carboxylamine benzene methyl
Under stirring at room, restrain (0.0236 mole) chloro sulfonyl isocyanates with 2.05; join 5.19 grams (0.0236 mole) (S)-under room temperature, stir in 160 milliliters of ethyl acetate suspension of 3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone and formed (S)-1-(((chlorosulfonyl) amino) carbonyl)-3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone solution in 1 hour; add 80 milliliters of methylene dichloride after this solution is cooled to 0 ℃; add 9.9 milliliters of (0.0707 mole) triethylamines and silylated 1 again; 4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid; hydrazides is (by 3.99 gram (0.0236 moles) 1; 50 milliliters of ethyl acetate and 8.75 milliliters of N-methyl-N-(trimethyl silyls of 4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid hydrazides) trifluoroacetamide (8.75 milliliters=0.0472 mole) suspension preparation); mixture stirred under room temperature spend the night; add frozen water; continue to stir 30 minutes; add ethyl acetate; water is divided into one deck; it is acidified to pH2.5; stir and separate out crystallization after 1 hour, obtain title compound 6.6 grams.
The evaporation of acetic acid methacrylate layer is handled with sherwood oil, second part of title compound, 1.4 grams of getting back.
D) (3S)-3-amino-N-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetate (1: 2)
With (3S)-(1-((((((1; 4-dihydro-4-oxo-5-(phenyl methoxyl group)-and the 2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl (6.6 grams; 0.0133 mole) join under stirring at room in the mixture of being made up of 22 milliliters of trifluoroacetic acids and 5.3 milliliters of thioanisoles, stirring is spent the night under the room temperature.Under vacuum, remove trifluoroacetic acid, remaining syrup is handled with ether, get the title compound of quantitative yield.
E) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl) 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
In 5.84 the gram (0.0133 mole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1; 1-dimethyl-2-oxo oxyethyl group) imido grpup)-add 5.6 milliliters of triethylamines in 135 milliliters of dimethyl formamide solutions of 4-pyrazolyl acetic acid; after being cooled to-30 ℃ then; add 3.57 gram (0.0133 mole) diphenyl phosphate chlorides again; stirred 1 hour down at-30 ℃; add 3.72 milliliters of triethylamines; that continues adds 0.0133 mole of (3S)-3-amino-N-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl)-2-oxo-1-azetidin yl-carboxamides trifluoroacetate (1: 2) again.
Under-10 ℃, stirred the mixture 2 hours, and, removed solution under the vacuum in 0 ℃ of restir 1 hour, remaining syrup is handled with 150 milliliters of ethyl acetate and 70 milliliters of frozen water, added 2N hydrochloric acid and regulate pH1.5～2, remove insolubles, with the ether development, obtain crude product 5.3 grams.
F) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amido) oxygen)-the 2 Methylpropionic acid disodium salt.
With (3S(Z))-((((((((2-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-carbonyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester (5.3 grams; 0.0069 mole) be suspended in 10.6 milliliters of methyl-phenoxides; after being cooled to-10 ℃; add 53 milliliters of trifluoroacetic acids down in stirring; and under this temperature, stirred 1 hour; under-10 ℃, add 200 milliliters of ether then to be settled out the trifluoroacetate of this title compound free acid, weigh 7.3 grams.
This crude product is dissolved in 100 ml waters and the 50 milliliters of acetone mixed solutions, regulates under pH5～5.5 vacuum and remove acetone, with remaining aqueous solution lyophilize, obtain crude product 8.1 grams, carry out chromatogram purification with HP-20, water elution, the product of chromatogram purification weigh 1.05 grams.
Nucleus magnetic resonance (DMSOd 6) measure: δ=1.40(S, 3H); 1.42(S, 3H); 3.25(dd, 1H); 3.70(dd, 1H); 5.10(M, 1H); 6.75(S, 1H); 7.40(S, 1H); 7.80(S, 1H); 11.32(wide S, 1H).
Embodiment 3
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2-acetate disodium salt
A) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2-acetate benzhydryl ester
In 2.06 grams (0.005 mole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-2-oxo oxyethyl group) imido grpup)-add 2.1 milliliters of (0.015 mole) triethylamines in 100 milliliters of dimethyl formamide solutions of 4-thiazolyl acetic acid, be cooled to-30 ℃, add 1.1 milliliters of (0.005 mole) diphenyl phosphate chlorides down in stirring.After stirring 1 hour under-30 ℃; add 1.4 milliliters of triethylamines (0.1 mole) down in-30 ℃ again; add 2.7 gram (3S)-3-amino-N-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetates (1: 2) more thereupon
This reaction mixture was stirred 2 hours down in-10 ℃, then stirred 1 hour down in 0 ℃, vacuum boils off solvent, and the oily residue is suspended in water, regulate pH of suspension to 2 with 2N hydrochloric acid, under room temperature, this suspension was stirred 30 minutes, filters, with its solid suspension in water, refilter, use the Vanadium Pentoxide in FLAKES drying in a vacuum, get crude product 5.0 grams, this crude product can be used on the next step and need not purifying.
B) oxygen (3S(Z)-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo)-3-azelidinyl) amino)-2-oxo ethylidene) amino))-2-acetate disodium salt
Under-10 ℃; with 5.0 gram crude products (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2-acetate benzhydryl ester is suspended in the mixed solution of 10 milliliters of methyl-phenoxides and 50 milliliters of trifluoroacetic acids.Stirred this reaction mixture 1 hour down in-10 ℃, add 100 milliliters of ether then carefully, weigh 3.7 grams with the crude product trifluoroacetate that is settled out title compound.In the mixed solution of 30 ml waters and 60 milliliters of acetone, pH to 5～5.5 with 0.1N sodium hydroxide adjusting mixed solution boil off acetone with this dissolving crude product, and the water lyophilize obtains crude product 3.9 grams, carries out chromatogram purification with Hp-20.Water (each 10 milliliters) wash-out will contain the elutriant component lyophilize of product, obtain 0.6 gram product, carry out the chromatogram purification second time with Hp-20 again, get pure product and weigh 0.25 gram.
Embodiment 4
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid
A) 2-(methylol)-5-(phenyl methoxyl group)-4(1H)-pyridone
With the 2-(methylol)-the 5-(benzyloxy)-4H-pyrans-4-ketone (9.65 grams, 41.59 mole), 95 milliliters of strong aquas and 20 milliliters of alcoholic acid mixture heating up reflux and spend the night, add 75 milliliters of ammonium hydroxide again, the 2 hours postcooling that reflux again leach the brown solid thing of generation, wash with water until elutant to neutral, this crude product is suspended in the ethanol, filters, use the ethanol hexane wash, dry under the vacuum, obtain title compound 7.61 grams.
B) 2-(chloromethyl)-5-(phenyl methoxyl group)-4(1H)-pyridone-hydrochloride
Under argon atmospher with the 2-(methylol)-5-(phenyl methoxyl group)-4(1H)-suspension of pyridone (3 gram, 12.99 mmoles) in chloroform (15 milliliters) is cooled to 0 ℃ and with 6.1 milliliters of (83.62 mmole) thionyl chlorides processing.Can get homogeneous phase solution in several minutes, continue to stir 5 minutes, promptly precipitation is separated out the coloured solid of paste.Spread cryostat, reflux 45 minutes is cooled to 0 ℃, leaches white depositions, and is dry under the vacuum with chloroform, hexane wash, obtains title compound 3.65 grams.
C) 2-(azido methyl)-5-(phenyl methoxyl group)-4(1H)-pyridone
Under argon atmospher, under the room temperature with the 2-(chloromethyl)-5-(phenyl methoxyl group)-4(1H)-pyridone-hydrochloride (3.59 the gram, 12.54 mmole), sodiumazide (4.08 grams, 62.7 mmole) and (2.19 milliliters of diisopropylethylamine, 12.54 mmole) mixture in 70 milliliters of dimethyl formamides stirred 3.5 days, add sodiumazide 4.08 grams again, this mixture heated 2 hours down in 45～50 ℃, pour into after the cooling in 500 ml waters, insoluble white solid appears, with dilute hydrochloric acid the pH of supernatant liquid is reduced to 7.5 from 8.5, leach white precipitate, through water, acetone, the solid that hexane wash is crossed is dry under vacuum.Obtain 2.81 gram title compounds.
D) 2-(amino methyl)-4-(phenyl methoxyl group)-4(1H)-pyridone
Under atmospheric nitrogen atmosphere of room temperature, with the 2-(azido-methyl)-5-(phenyl methoxyl group)-4-(1H)-pyridone (2.03 gram, 7.93 mmoles) and the mixture stirring of platinum oxide (200 milligrams) in 100 milliliters of dimethyl formamides 6 hours.Remove by filter catalyzer, concentrated solution under vacuum obtains 1.5 gram (productive rate 82%) title compounds, the gray powdery.
E) (3S)-and (1-((((((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) the carboxylamine benzene methyl
2-(amino methyl under stirring)-5-(phenyl methoxyl group)-4-(1H)-pyridone (2.330 grams, 10.13 add N-methyl-N-(trimethyl silyl in 60 milliliters of ethyl acetate suspension mmole)) trifluoroacetamide (3.76 milliliters, 20.26 mmoles).Stirred 30 minutes under the room temperature, be cooled to 0 ℃.Simultaneously; in (S)-3-(((phenyl methoxyl group) carbonyl)-amino)-2-azetidinone (2.228 grams; 10.13 stir on the limit in 60 milliliters of ethyl acetate suspension mmole), the limit adds chloro sulfonyl isocyanate (882 microlitres, 10.13 mmoles).Gained solution was stirred under room temperature 30 minutes, be cooled to 0 ℃, use triethylamine (4.23 milliliters, 30.39 mmoles) to handle at last, that continues uses the silylated 2-(amino methyl of chatting face to face and stating again)-5-(phenyl methoxyl group)-4(1H)-pyridone handles.This mixture was stirred under room temperature two days.
Concentrate under the vacuum, resistates is dissolved in CH 3In the CN-water (40～60), pH drops to and isolates heavy-gravity oily matter 2.9 this moments, and when being cooled to 5 ℃, this oily matter just solidifies.Separate this solid, wash with water four times, dry under the vacuum, obtain 3.4 gram crude products, dissolve this crude product and 1 liter the enterprising circumstances in which people get things ready for a trip of HP-20 resin column of packing into are composed purifying, carry out gradient elution with acetone-water with the dimethyl formamide of minimum volume, the material that desire is wanted is with about 65% acetone wash-out, merge relevant portion, lyophilize obtains title compound 2.69 grams.
F) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester (mixture of monopotassium salt and single triethylammonium salts)
Under an atmospheric nitrogen atmosphere, be stirred in 16 milliliters of dimethyl formamides (3S)-(1-((((((1; 4-dihydro-4-oxo-5-(phenyl methoxyl group)-and the 2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) (912 milligrams of carboxylamine benzene methyls; 1.64 mmole), the mixture of right-toluenesulphonic acids-hydrate (625 milligrams, 3.28 mmoles) and palladium-carbon (190 milligrams) of 10% is until exhausting 3.28 mmoles (73 milliliters) hydrogen (about 3 hours).To (Z)-2-amino-α of-20 ℃ that are stirring-((2-(phenylbenzene methoxy base)-1; 1-dimethyl-2-oxo oxyethyl group) imido grpup)-(846 milligrams of 4-thiazolyl acetic acids; 1.804 add diphenyl phosphate chloride (374 microlitres in 16 milliliters of dimethyl formamide solutions mmole); 1.804 mmole); that continues adds triethylamine (450 microlitres again; 3.28 mmole); stirred 1 hour down in-20 ℃; add above-mentioned hydrogenolysis subsequently (3S)-(1-((((((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl)-mixture of carboxylamine phenyl methyl esters.The gained mixture was stirred 1 hour down in-20 ℃, stir down in 5 ℃ again and spend the night, leach catalyzer, remove volatile matter under the vacuum.Gained oily matter be dissolved in minimum volume acetone-water (75～25, pH=5.2) in, be added drop-wise to 20 milliliters of Dowex50 * 2-400(K under stirring again +) be connected to-SO 3The styrene-divinylbenzene copolymer gel of-group is sold by The Dow Chemical Co. (US) 2030 Dow Center, Abbott Road, Midland, Michigan 48640, (DOW Chemical CO.)) acetone-water (35～65) suspension in.After 40 minutes, filter this mixture, filtrate is carried out lyophilize, obtain 2.1 gram solids.This solid is dissolved in the acetonitrile-water (40～60 of minimum, pH=5.6) in, and on the Hp-20 resin of packing into (800 milliliters) post, carry out gradient elution with acetonitrile-water, the product of wanting with about 30% acetonitrile wash-out desire, merge the wash-out component that contains product, lyophilize obtains 254 milligrams of impure title compounds.
G) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid.
Under 0 ℃ of stirring; trifluoroacetic acid (4.7 milliliters) is added drop-wise to above-mentioned impure (3S(Z))-(((1-(2-amino-4-thiazolyl)-((1-((((((1 for 2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl amino methyl)))))-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-3 milliliters of methylene dichloride of 2 Methylpropionic acid benzhydryl ester (mixture of monopotassium salt and single triethylammonium salts) (131 milligrams) and 0.3 milliliter of methyl-phenoxide suspension in; after stirring 45 minutes under 5 ℃, add 2 milliliters of toluene; remove volatile matter under the vacuum; gained oily matter hexane wash (3 * 4 milliliters); and grind the solid matter that obtains with 10 milliliters of ether; this solid matter with ether (10 milliliters) washing once, and is dry under the vacuum.With 166 milligrams (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester (mixture of monopotassium salt and single triethylammonium salts) repeats above-mentioned reaction and post-processing operation.Merge crude product, be dissolved in 2 milliliters of CH 3CN-water (40～60) (pH=2.5) in, go up with the acetonitrile-water gradient elution to carry out chromatographic separation in Hp-20 resin column (200 milliliters), use CH 3The product that CN-water (20～80) wash-out desire is wanted; merge relevant elutriant component; lyophilize obtains 103 milligrams of (3S(Z)-2-, and (((1-(2-amino-4-thiazolyl)-((1-((((((1 for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl amino methyl)))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, be white solid.
Embodiment 5
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxygen-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, 2-(((4-p-methoxy-phenyl) methoxyl group) carbonyl) hydrazides
Under room temperature, 25 milliliters of dry dimethyl formamide solutions of 4.54 gram (0.022 mole) dicyclohexyl carbodiimides are added to stir containing and 4.90 restrain (0.020 moles) 1 down, 4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, 4.50 gram (0.022 mole) carbazic acid 4-methoxy benzyl ester, 0.12 in the suspension of 25 milliliters of dry dimethyl formamides of gram (1.0 mmole) 4-dimethylamino-pyridine and 0.155 gram (1.0 mmole) I-hydroxybenzotriazole hydrate, continue to stir and spend the night, leach precipitation, filtrate is evaporated in a vacuum, its resistates is adding ether and sodium bicarbonate aqueous solution stirring after fixing, collect solid, wash with water, dry under vacuum at last, crude product (8.14 gram) in Soxhlet apparatus with 800 milliliters of CHCl 3Extracting 7 hours is directly from cold CHCl 3Pure product 1 are separated out in crystallization in the extracting solution, 4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 2-pyridine carboxylic acid, 2-(((4-p-methoxy-phenyl) methoxyl group) carbonyl) hydrazides 5.70 grams (67%) evaporate CHCl under the vacuum 3Solution has obtained impure title compound 1.5 grams (18%) again, 174.5～178 ℃ of fusing points.
B) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid hydrazides trifluoroacetic acid (1: 2) salt
38 milliliters of trifluoroacetic acid solution of 3.81 milliliters of (35.04 mmole) methyl-phenoxides of-10 ℃ are joined 3.71 ice-cooled gram (8.76 mmoles) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-and the 1-pyridine carboxylic acid, in 15 milliliters of dry methylene chloride suspension of 2-(((4-p-methoxy-phenyl) methoxyl group) carbonyl) hydrazides.Stirred 20 minutes down in 0 ℃, evaporate in the vacuum, its resistates then is a title compound, is solid shape, it and several milliliters of dry ethers are stirred together, and suction filtration, dry under the vacuum, get product and weigh 3.25 grams (99%), 173～175 ℃ of fusing points decompose.
C) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 2-Pyridinecarboxylic Acid hydrazides
With 3.84 milliliters of (19.64 mmole) N-methyl-N-(trimethyl silyls) trifluoroacetamide be added to 3.19 the gram (8.55 mmoles) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-35 milliliters of dry acetonitrile suspension of 2-Pyridinecarboxylic Acid hydrazides trifluoroacetic acid (1: 2) salt in, at room temperature continue to stir 30 minutes, after evaporation under the vacuum, resistates is dissolved in the ether, then drip 1 ml methanol again, the suction filtration collecting precipitation, use ether, petroleum ether, dry under the vacuum, obtain title compound 2.05 gram (92%) (204～208 ℃ of fusing points, (decomposition)).
D) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, 2-((2-(phenyl methoxyl group) carbonyl) diazanyl) carbonyl) hydrazides
Down 11.69 milliliters of (0.060 mole) N-methyl-N-trimethyl silyl trifluoroacetamides are added to 5.19 gram (0.020 moles) 1 in cooling, 4-dihydro-4-oxo-5-(phenyl methoxyl group)-20 milliliters of dry acetonitrile suspension of 2-Pyridinecarboxylic Acid hydrazides in, under room temperature, continue to stir 30 minutes, this clear solution of evaporation is dissolved in resistates in 30 milliliters of dry methylene chloride under the vacuum.Restrain (0.020 mole) under 0～5 ℃ this drips of solution being added to 4.57 under the stirring
Figure 86106980_IMG216
(J.Gante, Chem.Ber.97 volume, 2551 pages, (1964)) 60 milliliters of dichloromethane solutions in, after stirring 2.5 hours under this temperature, evaporate under vacuum, with the dissolving of 20 ml methanol, evaporation obtains the title compound of solid foam shape to this solid foam under the vacuum again, with dry ether stirring then becoming crystallization, these product weigh 8.87 grams (98%), fusing point＞120 ℃, (decomposition).
E) 1,4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid, 2-(diazanyl carbonyl) acyl group, dihydrochloride
Exist down in 0.4 gram (10%) palladium-carbon, with 4.02 gram (8.9 mmoles) 1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, 2-((2-(phenyl methoxyl group) carbonyl) diazanyl) carbonyl) the 50 ml methanol solution hydrogenations of 2.94 milliliters of (35.6 mmole) concentrated hydrochloric acids of hydrazides are 10 minutes, leach catalyzer, promptly obtain title compound after boiling off solvent under the vacuum, be solid (2.58 gram), stir with several milliliters of dry ethers, suction filtration is collected, and is dry under the vacuum, weighs 2.47 grams (92%), 235～236 ℃ of fusing points decompose.
F) (3S)-(1-((((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl
4.86 milliliters of (25.0 mmole) N-methyl-N-trimethyl silyl trifluoroacetamides are added to 1 of 1.5 grams (5.0 mmole), 4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid, 2-(diazanyl carbonyl) hydrazides, in 20 milliliters of dry acetonitrile suspension of dihydrochloride, stirred 45 minutes under the room temperature, with this clear solution vaporising under vacuum, resistates is dissolved in 20 milliliters of dry ethyl acetate (solution A)
In stir down 0.45 milliliter of (5.0 mmole) chloro sulfonyl isocyanate is joined 1.10 grams (5.0 mmole) (S)-40 milliliters of dry ethyl acetate suspension of 3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone in.Under room temperature, stirred 1 hour, be cooled to 0 ℃.After adding 10 milliliters of dry methylene chloride and 2.09 milliliters of (15.0 mmole) triethylamines, drip A solution down to this solution in 0 ℃ of stirring.After 0 ℃ stirring is spent the night down, this reaction mixture is poured in the frozen water, separated organic layer.To pH2, obtain thick throw out with 1N hcl acidifying water, suction filtration is collected water washing, and is dry under the vacuum, is title compound, weighs 1.76 grams (64%).
G) (3S)-3-amino-N-((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetic acid (1: 2) salt
Under 0 ℃; in the mixture of 5.13 milliliters of trifluoroacetic acids and 1.21 milliliters of thioanisoles, add (3S)-(1-((((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl of 1.73 grams (3.1 mmole).After stirring is spent the night under the room temperature, evaporate under the vacuum, resistates is stirred with dry methylene chloride, suction filtration collecting precipitation thing is used washed with dichloromethane, and is dry under the vacuum, gets title compound 1.78 grams (88%).
H) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
To-30 ℃ 1.10 the gram (2.5 mmole) (Z)-2-amino-α-((2-two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-and add 1.05 milliliters of (7.5 mmole) triethylamines in 22 milliliters of dry dimethyl formamide solutions of 4-thiazolyl acetic acid, then add diphenyl phosphate chloride 0.53 again and restrain (2.5 mmole).After stirring 1 hour under-30 ℃; drip 1.05 milliliters of (7.5 mmole) triethylamines; then add again 1.62 the gram (2.5 mmole) (3S)-3-amino-N-((2-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) carbonyl) diazanyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetate (1: 2) salt.Stirred 2 hours down in-10 ℃, stirred 1 hour down in 0 ℃ again.Remove under the vacuum and desolvate, resistates is extracted in several milliliters the ethyl acetate and frozen water.With dilute hydrochloric acid its pH is transferred to 2, suction filtration is collected insolubles, and stirs until crystallization with several milliliters ethyl acetate, after drying under the vacuum, obtains title compound 1.72 grams (82%).
I) (3S(Z))-((((((((((2-((1 for 2-for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl diazanyl carbonyl)))))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, disodium salt
Under-10 ℃, restrain (2.0 mmole) crude products (3S(Z) to 1.68)-((((((((((2-((1 for 2-for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl diazanyl carbonyl)))))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid; add 2.0 milliliters of methyl-phenoxides in 3 milliliters of dry methylene chloride suspension of benzhydryl ester, then add 20 milliliters of trifluoroacetic acids again.After stirring 10 minutes under 0 ℃, in 0 °～5 ℃ following solvent removed in vacuo, resistates is dissolved in frozen water and the ether and with dilute solution of sodium hydroxide (1%) and transfers pH to 6.0, organic phase and insoluble rerum natura (0.38 gram) are separated, water lyophilize (2.66 gram), the resistates that lyophilize is obtained is with XAD-2 resin (macroreticular styrene-divinyl benzene resin) purifying (water wash-out), lyophilize obtains colourless powder shape title compound 0.25 gram (17%), fusing point＞213 ℃, (decomposition).
Embodiment 6
(3S-(3 α (Z); 4 β))-((((((((2-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 4-methyl-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, disodium salt
A) (3S-is trans)-(1-((((2-((1,4-dihydro-4-oxo-5-hydroxyl-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-4-methyl-2-oxo-3-azelidinyl) carboxylamine, benzene methyl
In 2.34 gram (3S-is trans)-(4-methyl-2-oxo-3-azelidinyl) carboxylamines, add the 1.41g chloro sulfonyl isocyanate in 50 milliliters of dry ethyl acetate suspension of benzene methyl.Stir under the room temperature after 1 hour, form clear solution (A solution).
In 1.70 grams 1,4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid adds 6 gram N-methyl-N-(trimethyl silyls in 50 milliliters of dry ethyl acetate suspension of hydrazides) trifluoroacetamide.50 ℃ are stirred down after 1 hour, form clear solution (solution B).
After being cooled to-10 ℃, solution B is added in the solution A, stirs under the room temperature and spend the night, be cooled to-15 ℃, just, then add 150 milliliters of frozen water again to wherein adding 3 gram triethylamines.0 ℃ was stirred down after 1 hour, with 50 ml waters washing organic phase.Water pH to 2 after regulate merging with 1N hydrochloric acid, with 100 milliliters of ethyl acetate extractions three times, the dry organic phase that merges, evaporating solvent obtains title compound 3.64 and restrains.
B) (3S-is trans)-3-amino-N-((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl)-4-methyl-2-oxo-1-azetidine carboxylic acid amides, trifluoroacetate (1: 2)
Under room temperature; (3S-is trans)-(((((2-((1 for 1-to 3.5 grams; 4-dihydro-4-oxo-5-hydroxyl-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 4-methyl-2-oxo-3-azelidinyl) add 50 milliliters of trifluoroacetic acids in 20 milliliters of thioanisoles of carboxylamine benzene methyl, stirred 13 hours.Add crude product 3.2 grams that obtain precipitating behind 100 milliliters of ether.In 50 milliliters of Virahol/methylene dichloride (1: 1), stir this crude product 1 hour, obtain title compound 2.21 grams.
C) (3S-(3 α (Z); 4 β))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-4-methyl-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, benzhydryl ester
Under-30 ℃ to 1.8 gram (Z)-2-amino-α-((2-phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-s)-add 2.1 gram diphenyl phosphate chlorides in 30 milliliters of dimethyl formamide solutions of 4-thiazolyl acetic acid and 1.2 gram triethylamines.After stirring 45 minutes under-30 ℃; ((2-((1 to add 1.95 gram (3S-is trans)-3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) alkylsulfonyl diazanyl carbonyl)))-4-methyl-2-oxo-1-azetidin oxygen yl-carboxamides; 10 milliliters of dimethyl formamides of trifluoroacetate (1: 2) salt then add 0.8 gram triethylamine.Stirred 2 hours down in-10 ℃, after stirring 1 hour under 0 ℃, remove dimethyl formamide in the vacuum again.Resistates stirs in 250 milliliters of ethyl acetate and 400 milliliters of frozen water.Regulate water pH to 1.5 with 2N HCl, and extract secondary respectively with 200 milliliters of ethyl acetate, the organic phase dried over sodium sulfate, evaporation obtains title compound crude product 1.3 grams.
D) (3S-(3 α (Z); 4 β))-((((((((2-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 4-methyl-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, disodium salt
Under-5 ℃, 30 milliliters of trifluoroacetic acids are joined 1.2 and restrain (3S-(3 α (Z); 4 β))-((((((((2-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 4-methyl-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, benzhydryl ester is dissolved in 10 milliliters of methylene dichloride and the 15 milliliters of methyl-phenoxide mixed solvents in the gained solution.Stir after 30 minutes, add 100 milliliters of ether, obtain 0.8 gram throw out.This throw out is suspended in 20 ml waters, and regulates pH to 6.5 with sodium bicarbonate, then this clear solution is carried out chromatographic separation with XAD-2, water is made elutriant, obtains pure title compound 0.28 gram.
Embodiment 7
(3S(Z))-((((((((3-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 1-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen) ring penta carboxylic acid, disodium salt
A) (3S(Z))-((((((((3-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 1-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen) ring penta carboxylic acid, benzhydryl ester
With 3.5 milliliters of (25 mmole) triethylamines join 3.9 grams (8.3 mmole) (Z)-2-amino-α-(((1-(phenylbenzene methoxy base) carbonyl) cyclopentyl) oxygen) imino-)-100 milliliters of dry acetonitrile suspension of 4-thiazolyl acetic acid in and form clear solution.After being cooled to-30 ℃, add 1.8 milliliters of diphenyl phosphate chlorides (8.3 mmole), stir 1 hour (solution A) down in-30 ℃.
Simultaneously; with 4.5 the gram (8.3 mmole) (3S)-((3-(((1 for 3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides, trifluoroacetic acid (1: 2) salt suspension is in 100 milliliters of dry ethyl acetate.Then, under room temperature, add 7.2 milliliters of two (trimethyl silyl) ethanamides, obtain clear solution after 5 minutes.Stir after 1 hour, this solution is cooled to 0 ℃ (solution B).
Under-30 ℃ of stirrings, drip solution B, last 10 minutes to solution A.Stirred 1 hour down in-10 ℃, stirred 1.5 hours in 0 ℃ again.Boil off volatile matter, the development of resistates water is solidified the back and is collected solid, and it is suspended in the water of pH about 2, stirs after 30 minutes, collects solid, and drying obtains crude product title compound 12.0 grams.
B) (3S(Z))-((((((((3-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 1-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen) ring penta carboxylic acid, disodium salt
With crude product (3S(Z))-((((((((3-(((1 for 1-for (1-(2-amino-4-thiazolyl) 2-for 1-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen) ring penta carboxylic acid; benzhydryl ester (12 gram) is suspended in 20 milliliters of methyl-phenoxides; when it being cooled to-10 ℃, add 100 milliliters of trifluoroacetic acids.Stirred 1 hour down in-10 ℃, under-10 ℃, add 300 milliliters of ether, stir after 1 hour, leach precipitation, get 5.7 grams to precipitate.It is dissolved in the mixture of 30 ml waters and 60 milliliters of acetone.Add 0.1NNaOH down in 0 ℃ of stirring and regulate pH to 5.5.Boil off acetone under the vacuum.The aqueous solution obtains solid residue 5.7 grams through freeze-dried.Make elutriant with Hp-20(water) carry out chromatography, obtain pure product 1.69 grams (27%) of title compound.
1H-nucleus magnetic resonance (DMSO-d 6+ CF 3COOH): S=1.67(S, 4H); 2.07(α, 4H); 3.65(t, 2H); 3.75(dd, 1H); 3.97(dd, 1H); 4.07(t, 2H); 5.07(dd, 1H); 7.00(S, 1H); 7.67(S, 1H); 8.07(S, 1H); Ppm.
Embodiment 8
(3S(Z))-((((((((3-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, disodium salt
A) 2-(azido methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone
In 2.0 gram (6 mmole) 2-(chloromethyls)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-add 3.9 gram (60 mmole) sodiumazide and 0.1 gram 18-hat (ether)-6 in 20 milliliters of acetonitrile suspension of pyridone.Stream heating just 4 hours, suction leaches salt, evaporated filtrate under the vacuum.Resistates obtains title compound 1.86 grams, 120 ℃ of fusing points with silica gel chromatography column purification (ethyl acetate-methyl alcohol is made elutriant at 8: 2).
B) 2-(amino methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone
With the 2-(azido methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone (1.0 gram, 2.89 mmoles) is dissolved in 50 ml methanol, adds platinum oxide 0.10 gram.In this mixture, feed hydrogen foaming 30 minutes, leach catalyzer with Hai Fuluo (Hy+10) suction, evaporated filtrate under the vacuum, its oily resistates is developed with ether, obtains crystallization title compound (0.89 gram), 207 ℃ of fusing points.
C) 2-(((((2-chloroethyl) amino) carbonyl) amino) methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone
In 48.0 gram (0.15 mole) 2-(amino methyls)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-add 12.8 milliliters of (0.15 mole) 2-chloroethyl isocyanates in 1.5 liters of ethyl acetate suspension of pyridone.Under room temperature, stir and spend the night, the product suction filtration is dry under the vacuum with the ethyl acetate washing, obtain title compound 59.6 grams, 130 ℃ of fusing points.
D) 2-((2-oxo-1-imidazolidyl) methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone
Ethanol (500 milliliters) drips of solution of 7.29 gram (0.13 mole) potassium hydroxide are added to 60.8 gram (0.13 mole) 2-(((((2-chloroethyl) amino) carbonyl) amino) methyl)-5-(phenyl methoxyl groups)-the 1-(phenyl methyl)-4(1H)-pyridone and 1.3 liters of alcoholic acid mixtures in.Reflux 3 hours removes under the vacuum and desolvates the resistates silica gel chromatography, make elutriant with ethyl acetate and methyl alcohol (7: 3) mixture, get product 23.1 grams, be further purified with the acetonitrile recrystallization, obtain title compound 17.0 grams, 190 ℃ of fusing points decompose.
E) 5-hydroxyl-2-((2-oxo-1-imidazolidyl) methyl)-4(1H)-pyridone, tosilate
In 2-((2-oxo-1-imidazolidyl) methyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone (4.98 grams, 12.8 add right-toluenesulphonic acids-hydrate (4.86 grams in the solution of 90 milliliters of dimethyl formamides mmole), 25.6 mmole) and palladium-carbon (1.0 gram), feed hydrogen, foamed 30 minutes, suction leaches catalyzer, evaporated filtrate under the vacuum, resistates is developed with methylene dichloride and ether, suction leaches product, obtain title compound 4.12 grams, 195 ℃ of fusing points
F) 5-hydroxyl-2-((2-oxo-1-imidazolidyl) methyl-4(1H)-pyridone
With 5-hydroxyl-2-((2-oxo-1-imidazolidyl) methyl)-4(1H)-pyridone, right-tosylate (4.0 grams, 10.5 mmole) be dissolved in 50 ml waters, regulate pH to 6.5 with 2N NaOH, suction leaches precipitation, water washing, dry under the vacuum, obtain title compound 1.5 grams, 280 ℃ of fusing points, (decomposition).
G) (S)-(1-((((3-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine, benzene methyl
With 1.10 grams (5 mmole) (S)-3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone is suspended in 20 milliliters of dry ethyl acetate, adds 0.44 milliliter of (5 mmole) chloro sulfonyl isocyanate.Stirred the mixture under room temperature 1 hour, (solution a).
In 10 milliliters of dry ethyl acetate suspension of 1.04 gram (5 mmole) 5-hydroxyl-2-((2-oxo-1-imidazolidyl) methyl)-4(1H)-pyridones, add 3.70 milliliters of (20 mmole) N-methyl-N-(trimethyl silyls) trifluoroacetamide, with mixture heating up to 60 ℃, in 60 ℃ of these clear solutions of following vacuum-evaporation, resistates is dissolved in (solution b) in 10 milliliters of dry ethyl acetate.
Solution b is added in the solution a, stirs under room temperature and spend the night, remove under the vacuum and desolvate, resistates is developed with ether, obtains title compound 2.91 grams, and 180 ℃ of fusing points decompose.
H) (S)-and 3-amino-N-((3-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides, trifluoroacetate
(S)-(((((3-((1 for 1-in adding in the mixture of 0.5 milliliter of thioanisole and 2 milliliters of trifluoroacetic acids; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl (0.50 gram; 0.93 mmole); under room temperature, stir and spend the night; evaporate under the vacuum; resistates is developed with ether; suction filtration; dry in the vacuum; obtain title compound 0.49 gram, 155 ℃ of fusing points.
I) (3S(Z))-((((((((3-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, the phenylbenzene methyl esters
In 0.41 gram (0.93 mmole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imido grpup)-add 0.39 milliliter in 20 milliliters of dry acetonitrile suspension of 4-thiazolyl acetic acid
(2.8 mmole) triethylamine.Mixture is cooled to-30 ℃, and is added dropwise to 0.19 milliliter of (0.93 mmole) diphenyl phosphate chloride.(solution a) in 1 hour to stir this reaction mixture down in-30 ℃.
((3-((1 in (S)-3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides; add in the suspension of 20 milliliters of dry acetonitriles of trifluoroacetate (0.48 gram, 0.93 mmole) 0.78 milliliter (3.2 mmole) two-the trimethyl silyl ethanamide.After stirring 30 minutes under the room temperature, it is added among the solution a.
Stirred this reaction mixture 1 hour down in-10 ℃, stirred 1.5 hours down in 0 ℃ again.This clear solution of evaporation under vacuum; in this oily resistates, add 50 ml waters; regulate pH to 2 with 2N HCl; promptly from then in the solution crystallization separate out (3S(Z))-((((((((3-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid, disodium salt.Suction leaches this product, washes with water, and is dry under the vacuum, obtains title compound 0.7 gram.
J) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo-ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
With (3S(Z))-((((((((3-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester (0.7 gram, 0.85 mmole) is suspended in 1.4 milliliters of methyl-phenoxides and is cooled to-10 ℃.After adding trifluoroacetic acid, stirred 1 hour down in-10 ℃.Add 100 milliliters of ether, suction elimination throw out, the ether washing, dry under the vacuum.
This trifluoroacetate is dissolved in the mixture of first alcohol and water, and is adjusted to pH to 6.5, remove methyl alcohol under the vacuum with 2N NaOH, with aqueous solution lyophilize, obtain title compound 0.5 gram, with medium pressure liquid chromatography (MPLC) purifying, 250 ℃ of fusing points, (decomposition).
Embodiment 9
(3S(Z))-((((((((4-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2,3-dihydro-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 2-(chloromethyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-the pyridonium salt hydrochlorate
With 3.21 gram (10 mmole) 2-(hydroxymethyls)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-20 milliliters of chloroform suspension of pyridone are cooled to 0 ℃ and be added dropwise to 4.65 milliliters of (64 mmole) thionyl chlorides.0 ℃ is stirred down 10 minutes reflux 1 hour then, boils off solvent under the vacuum, and the resistates petroleum ether is dry under the vacuum, obtains title compound 3.66 and restrains 85 ℃ of fusing points, (decomposition).
B) 2-(chloromethyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone
With the 2-(chloromethyl)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridonium salt hydrochlorate (3.5 grams, 9.3 mmole) be dissolved in the mixture of water/ethyl acetate, layering washes organic phase with water twice, dried over mgso, evaporate under the vacuum, resistates is developed with sherwood oil, suction filtration, dry under the vacuum, obtain title compound 2.27 grams, 115～120 ℃ of fusing points, (decomposition).
C) N-(trityl group) piperazine-2, the 3-diketone
With 2,3-piperazinedione (11.4 grams, 100 mmoles), the two trimethyl silyl ethanamides (55.7 grams, 270 mmoles) and the mixture heating up of 150 milliliters of acetonitriles refluxed 1 hour.In 30 minutes, be added dropwise to trityl group chlorine 22.2 grams (80 mmole), reflux is 2 hours again, after stirring is spent the night under the room temperature, in this clear solution, add 21.6 ml waters, leach its throw out (3.13 gram), concentrated filtrate under the vacuum, the development of resistates water, drying obtains crude product title compound 25.5 grams, use ethyl alcohol recrystallization, pure product weigh 12.19 grams, 230～235 ℃ of fusing points.
D) methyl 1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-1-(phenyl methyl)-2-pyridyl))-and the 4-(trityl group)-2, the 3-piperazinedione
In the N-(trityl group) piperazine-2, add 0.35 gram (11.77 mmole) sodium hydride (80% oil) in 95 milliliters of dry dimethyl formamide solutions of 3-diketone (4.19 grams, 11.77 mmoles).Stop in this thick suspension, to add the 2-(chloromethyl after the release hydrogen)-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-4(1H)-pyridone (4.0 grams, 11.77 25 milliliters of dry dimethyl formamide solutions mmole), this muddiness liquid becomes clear solution.After stirring 1 hour under the room temperature, begin precipitation, leach drying under crystallization, washing, the vacuum after two hours, obtain title compound 5.13 grams, 165～168 ℃ of fusing points.
E) methyl 1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-1-(phenyl methyl)-2-pyridyl))-2, the 3-piperazinedione
Under room temperature to 1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-the 2-pyridyl) methyl)-the 4-(trityl group)-2, drip 65 milliliters of formic acid in 65 milliliters of dichloromethane solutions of 3-piperazinedione (8.77 grams, 13.23 mmoles).Stir after 3 days, volatile matter is removed in distillation under vacuum, and resistates is developed twice with ether, obtain 5.24 gram 1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-the 2-pyridyl) methyl)-2,3-piperazinedione, 260～265 ℃ of fusing points.
F) (S)-(((((4-((1 for 1-; 4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-the 2-pyridyl) methyl)-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) the carboxylamine benzene methyl
In (S)-3-(((phenyl methoxyl group)-carbonyl) amino)-2-azetidinone (0.44 gram; 2.0 add 0.28 gram (2.0 mmole) chloro sulfonyl isocyanate in 25 milliliters of dry ethyl acetate solutions mmole), under room temperature, stirred 30 minutes.In this solution, add 12 milliliters of methylene dichloride, 0.61 gram (6 mmole) triethylamine and give earlier stirred (3 hours) by 1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-the 2-pyridyl) methyl)-2,3-piperazinedione (0.83 gram, 2.0 mmoles) and N-methyl-N-(trimethyl silyl).The mixture in 25 milliliters of dry ethyl acetate that trifluoroacetamide (1.59 grams, 8.0 mmoles) is formed.After stirring 3 days under the room temperature, add frozen water, regulate pH to 1 with hydrochloric acid, the elimination insoluble residue, dry under the vacuum, obtain 1.15 gram title compounds, purity 72%.
G) (S)-and 3-amino-N-((4-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2,3-dioxo-1-piperazinyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides, the 4-toluenesulfonate
In (S)-(((((4-((1 for 1-; 4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 1-(phenyl methyl)-the 2-pyridyl) methyl)-2; 3-dioxy-1-piperazinyl) carbonyl amino alkylsulfonyl)))-and 2-oxo-3-azelidinyl) add right-toluenesulphonic acids 0.5 gram (2.64 mmole) in 20 milliliters of dimethyl formamide solutions of carboxylamine benzene methyl (0.98 gram, 1.32 mmoles) and (10%) palladium-carbon 0.5 restrains.Logical hydrogen foamed 1 hour in this mixture, leached catalyzer, boiled off solvent under the vacuum, and its resistates is developed with methylene dichloride, after the drying, obtained title compound 0.82 gram, and 160～185 ℃ of fusing points decompose.
H) (3S(Z))-((((((((4-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
Under-30 ℃, to (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-4-thiazolyl acetic acid (0.57 gram, 1.3 add triethylamine (0.39 gram in 30 milliliters of dimethyl formamide solutions mmole), 3.9 mmole) and chlorine phenyl-phosphate (0.31 gram, 1.3 mmoles).Stir after 1 hour; add triethylamine (0.39 gram; 3.9 mmole) and (S)-((4-((1 for 3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2; 3-dioxo-1-piperazinyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides; 4-toluenesulfonate (0.98 gram, 1.3 mmoles).Stirred 2 hours down in-10 ℃, stirred 1.5 hours down in 0 ℃ again.Add entry and ethyl acetate, pH is transferred to 1, leach throw out and wash with ethyl acetate with the HCl of 3N, dry under the vacuum, obtain title compound 0.86 gram, 130～190 ℃ of fusing points, (decomposition).
I) (3S(Z))-((((((((4-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
Under-10 ℃; 7 milliliters of trifluoroacetic acids are added to (3S(Z))-((((((((4-((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl)-2; 3-dioxo-1-piperazinyl) carbonyl amino alkylsulfonyl)))-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-1.4 milliliters of methyl-phenoxide suspension of 2 Methylpropionic acid benzhydryl ester (0.8 gram, 0.94 mmole) in.Stir after 1 hour, add 30 milliliters of ether, leach throw out, dry under the vacuum.This trifluoroacetate is suspended in the water, regulates pH to 6.5 with sodium hydroxide (2N).With the solution lyophilize, obtain 0.66 gram crude product with it with using second batch sample (totally 1.55 grams) on the macroreticular styrene-divinylbenzene copolymer, to carry out the medium pressure liquid chromatography chromatography with quadrat method preparation, obtain 0.34 gram title compound.Use macroreticular styrene-divinylbenzene copolymer chromatogram row chromatography for the second time again, obtain title compound 0.18 gram, 242～270 ℃ of fusing points.
Embodiment 10
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methylene radical) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2-first propionic acid disodium salt
A) 4, two (phenyl the methoxyl group)-2-Pyridinecarboxylic Acid benzene methyls of 5-
Adding 21.5 restrains (156 mmole) bricks acid potassium and stirred 1 hour under room temperature in 350 milliliters of dimethyl formamide suspension of 29.4 gram (120 mmole) neighbour-benzyl comenamic acids.Add 31 milliliters of (264 mmole) bromotoluenes,, kept 25 hours in stirring down heated mixt to 100 ℃.Behind the cool to room temperature, boil off dimethyl formamide under the vacuum.Resistates is developed with ethyl acetate, can heat (to 60 ℃) in short-term.Leach inorganic salt (40 gram), filtrate is concentrated to about 75 milliliters,, obtain title compound 35.5 grams, 116.7 ℃ of fusing points with silica gel chromatography column purification (ethyl acetate: sherwood oil (90: 10) is made elutriant).
B) 4, two (phenyl the methoxyl group)-2-piconols of 5-
Under 0 ℃, with 1.06 gram (25 mmoles) 4, two (phenyl the methoxyl group)-2-Pyridinecarboxylic Acid benzene methyls of 5-are divided in the suspension of three parts of 10 milliliters of ether that join 95 milligrams of (25 mmole) lithium aluminum hydrides and 10 milliliters of tetrahydrofuran (THF)s.After stirring 20 minutes under 0 ℃, add 0.2 milliliter of saturated sodium bicarbonate solution, 0.2 milliliter 10% potassium hydroxide solution adds saturated sodium bicarbonate solution up to inorganic throw out flocculation together again.Inclining transparent organic phase and vaporising under vacuum, obtains a kind of oil, and it can slowly separate out crystallization, weighs 0.6 gram, 96.6 ℃ of fusing points.
C) 4, two (phenyl the methoxyl group)-2-pyridylaldehydes of 5-
In 0.54 gram (1.7 mmole) 4, add 1.5 milligrams of (17 mmole) Manganse Dioxide in 15 milliliters of acetone solns of two (phenyl the methoxyl group)-2-piconols of 5-, under room temperature, stir and spend the night, mixture is filtered by silicagel column (70～250 order), with acetone wash-out aldehyde, evaporation of eluate, resistates is developed with sherwood oil, obtain title compound 0.3 gram, 104.3 ℃ of fusing points.
D) 1,4-dihydro-5-hydroxyl-4-oxo-2-pyridylaldehyde
In 4, two (phenyl the methoxyl group)-2-pyridylaldehydes of 5-(1.9 grams, 6.0 add 0.2 gram palladium carbon catalyst in 25 milliliters of dry dimethyl formamide solutions mmole), in this mixture, feed hydrogen foaming three hours, leach catalyzer, under vacuum, boil off solvent, resistates is developed with ether, obtain title compound 0.64 gram, 174～177 ℃ of fusing points decompose.
E) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methylene radical) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
In (3S(Z))-2-(((2-((1-((((3-amino-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-1-(2-amino-4-thiazolyl)-2-oxo ethylidene) amino) oxygen)-2-propionic acid-sodium salt (0.64 gram; 1.1 add 1 in 15 milliliters of dry dimethyl formamide solutions mmole); 4-dihydro-5-hydroxyl-4-oxo-2-pyridylaldehyde (0.18 gram; 1.3 mmole); stir after 4.5 hours; add 4 of 0.02 gram (0.14 mmole); under room temperature, stir and spend the night; boil off solvent under the vacuum; resistates is dissolved in 30 ml waters; filter; solution is through lyophilize; crude product (0.82 gram) is dissolved in 5 ml waters and also carries out chromatographic separation with macroreticular styrene-divinylbenzene copolymer resin; water is made elutriant; obtain pure product 0.22 gram, 248 ℃ of fusing points decompose.
Embodiment 11
((((((((4-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for (3S(Z)-2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-and amino)-2,3-dioxo-1-piperazinyl)-alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 4, two (the benzyloxy)-2-Pyridinecarboxylic Acids of 5-
To 11.8 gram (28 mmoles) 4, in the solution of 115 milliliters of tetrahydrofuran (THF)s of two (the benzyloxy)-2-Pyridinecarboxylic Acid benzene methyls of 5-, add 16 ml waters and 35 milliliters of 1N potassium hydroxide.Stir the back of spending the night under the room temperature and add 115 ml waters, regulate pH to 2.5 with 1N hydrochloric acid.Leach acid, washing, vacuum-drying gets 8.6 gram title compounds, 203.6 ℃ of fusing points.
B) N-(2,3-dioxo-1-piperazinyl)-4, two (the benzyloxy)-2-pyridine carboxamides of 5-
With 4, two (the benzyloxy)-2-Pyridinecarboxylic Acids of 5-(7.1 grams, 21.17 hydroxybenzotriazole (0.29 gram mmole),, 2.12 mmole) and N-aminopiperazine-2,3-diketone (2.73 grams, 21.17 the suspension of 140 milliliters of dry dimethyl formamides mmole) stirred 15 minutes, added 4.80 gram (23.3 mmole) dicyclohexyl carbodiimides then.Stir after 21 hours under the room temperature, leach dicyclohexylurea (DCU) (4.0 gram), vacuum evaporating solvent.Developed solid residues 40 minutes with 240 milliliters of tetrahydrofuran (THF)s, filter,, get 7.76 gram title compounds, 231.1 ℃ of fusing points with tetrahydrofuran (THF) washing, vacuum-drying.
C) (S)-(1-((((4-(((4,5-two (benzyloxy)-2-pyridyl) carbonyl) amino)-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl
To (S)-3-(((benzyloxy) carbonyl) amino)-2-azetidinone (2.02 grams; 9.18 in the suspension of 130 milliliters of ethyl acetate mmole); add chloro sulfonyl isocyanate (1.43 grams; 10 mmoles); stir after 1 hour; add triethylamine (2.79 grams, 27.54 mmoles) down in 0 ℃.With N-(2,3-dioxo-1-piperazinyl)-4, two (the benzyloxy)-2-pyridine carboxamides of 5-(4.10 grams, 9.18 mmole) and N-methyl-N-(trimethyl silyl) trifluoroacetamide (5.4 the gram, 27.54 the solution in 150 milliliters of ethyl acetate mmole), the pre-stirring after 1.5 hours joins in the said mixture.After stirring is spent the night under the room temperature, add 220 milliliters of frozen water, regulate pH to 2(from 10.3) with 3N hydrochloric acid.Organic phase with brine treatment is told is settled out title compound, filters, and washing and vacuum-drying get product 5.35 grams.With the mixture of 25 ml waters and 37.5 milliliters of acetone with the development 1 hour when the pH=6.3 of 2.5 these materials of gram, 2.12 gram title compounds.
D) (S)-and N-(4-((((3-amino-2-oxo-1-azelidinyl)-carbonyl) amino) alkylsulfonyl)-2,3-dioxo-1-piperazinyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides
In that (S)-(((((4-(((4 for 1-; two (the benzyloxy)-2-pyridyl of 5-) amino carbonyl))-2; 3-dioxo-1-piperazinyl) carbonyl amino alkylsulfonyl)))-and 2-oxo-3-azelidinyl) carboxylamine benzene methyl (1.54 grams; 2 mmoles) in 30 milliliters of dimethyl formamide solutions; add 0.77 gram palladium/carbon, this mixture of hydrogenolysis 45 minutes.Filtering catalyzer on Hyflo, the not good title compound of emanating out of resultant solution just can be directly used in next step.
E) (3S(Z))-((((((((4-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
To (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imido grpup)-4-thiazolyl acetic acid (0.88 gram, 2.0 add triethylamine (0.60 gram in 20 milliliters of dimethyl formamide solutions mmole), 6.0 mmole), and under-30 ℃ and nitrogen atmosphere, add chloro triphenylphosphate (0.54 gram, 2.0 mmoles).After stirring 1 hour under-30 ℃; drip triethylamine (0.20 gram; 2 mmoles) and (S)-N-(4-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-2; 3-dioxo-1-piperazinyl)-1, the dimethyl formamide solution of 4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides.This mixture was stirred 2 hours down at-10 ℃, then stirred 17 hours down at 0 ℃.Steam solvent in the vacuum, resistates is allocated in 40 milliliters of ethyl acetate and the 20 milliliters of frozen water.Transfer pH to 1.5 with dilute hydrochloric acid, separate the oily matter of from solvent, telling, dry under the vacuum, output 1.35 gram title compounds.
F) (3S(Z))-((((((((4-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-and carbonyl) amino)-2,3-dioxo-1-piperazinyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
In under-10 ℃ in the mixture of 2.6 milliliters of methyl-phenoxides and 13 milliliters of trifluoroacetic acids; add (3S(Z))-((((((((4-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-2; 3-dioxo-1-piperazinyl) carbonyl amino alkylsulfonyl)))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester (1.3 grams; 1.48 mmole), stirred this mixture 2 hours down in 0 ℃.Vacuum steams volatile matter, develops resistates with ether, draws 1.06 gram trifluoroacetates after the drying.This trifluoroacetate is suspended in 20 ml waters, uses 1N NaOH pH regulator to 6.5.This solution of lyophilize gets 1.10 gram crude products, on the macroreticular styrene-divinylbenzene copolymer this product is carried out medium pressure liquid chromatography and separates, and uses water as elutriant.Productive rate 0.48 gram.This material again with other sample of pressing the same manner preparation twice of circumstances in which people get things ready for a trip spectrum chromatography again.Column chromatography uses the whole styrene-divinylbenzene copolymer of macroreticular for the second time, and column chromatography uses Ou Gainuo root (Organogen) for the third time, all uses water as elutriant at every turn.Get product 0.10 gram at last, fusing point is greater than 300 ℃.
Embodiment 12
(3S(Z))-(((2-amino-4-thiazolyl) ((2-fluoro oxyethyl group) imido grpup) ethanoyl) amino)-((3-(((1 for N-for 3-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides, ethyl diisopropyl amine salt
To (Z)-2-amino-α-((2-fluoro oxyethyl group) imino-)-4-thiazolyl acetic acid (0.33 gram, 1.4 in the solution of 5 milliliters of dry dimethyl formamides mmole), add N-hydroxybenzotriazole (0.19 gram, 1.4 mmole) and N-ethyl diisopropyl amine (0.18 gram, 1.4 mmoles).Under 0 ℃, add dicyclohexyl carbodiimide (0.29 gram, 1.4 mmoles), stirred this mixture 1 hour.((3-(((1 to add (3S)-3-amino-N-, 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides trifluoroacetate (1: 2) (0.87 gram, 1.6 mmoles; See routine 1G) and 3 milliliters of dry dimethyl formamide solutions of N-ethyl diisopropyl amine (0.41 gram, 3.2 mmoles), stirred 2 hours down in 0 ℃, under the room temperature with this mixture restir 16 hours.Leach dicyclohexylurea (DCU), steam solvent in the vacuum, the remaining oily matter of water development is till complete crystallization.Solid collected by filtration (0.82 gram), pH is transferred to 6.1 with filtrate, lyophilize.This solid suspension in 40 ml waters, is transferred pH to 6.0 with 0.25N NaOH.Leach undissolved material, lyophilize filtrate.Merge these two parts of cryodesiccated materials (about 0.6 gram), separate in macroreticular styrene-divinylbenzene copolymer post ascending chromatography, with water and water: acetonitrile (95: 5) is made elutriant.After the lyophilize, get 0.22 gram title compound from suitable wash-out component, fusing point is 163～165 ℃.
Embodiment 13
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid trisodium salt
A) N, the vexed peace acyl chloride hydrochloride of O-dibenzyl-Kao
Under 0 °～5 ℃, 11.45 gram (55.0 mmole) phosphorus pentachlorides are joined 16.77 gram (50.0 mmole) N in batches, in the suspension of 360 milliliters of dry methylene chloride of O-dibenzyl comenamic acid, under room temperature, continue to stir 1 hour, suction filtration goes out precipitation, with 20 milliliters of exsiccant washed with dichloromethane, vacuum-drying gets 15.02 gram title compounds, 126～127 ℃ of fusing points (decomposition).
B) (2-((phenyl methoxyl group) carbonyl) diazanyl) acetate 1,1-dimethyl ethyl ester
In the solution of 40 milliliters of dimethyl formamides of 6.65 gram (0.040 mole) N-((phenyl methoxyl group) carbonyl) hydrazines that stirring, drip the solution of 8.58 gram (0.044 mole) bromo-acetic acid tert-butyls in 20 milliliters of dimethyl formamides, drip 8.2 milliliters of (0.048 mole) N then, the solution of N-diisopropylethylamine in 8 milliliters of dimethyl formamides.With after the mixture stirring 1 day, vacuum is steamed and is desolventized, and resistates is dissolved in ether and the water under the room temperature.Wash organic layer with water three times, dry (sal epsom), vacuum-evaporation stays oily matter (10.6 gram), carries out purifying with silica gel column chromatography, with ethyl acetate-toluene (1: 1) wash-out.Evaporate suitable wash-out component in a vacuum, resistates is stirred with sherwood oil, get 6.0 gram title compounds, 61～62 ℃ of fusing points.
C) acetate 1 (1-((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) carbonyl)-2-((phenyl methoxyl group) carbonyl) diazanyl), 1-dimethyl ethyl ester
15.6 milliliters of (80.0 mmole) N-methyl-N-trimethyl silyl trifluoroacetamides are joined contain 11.2 gram (40.0 mmole) (2-((phenyl methoxyl group) carbonyl) diazanyl) acetate 1, in 60 milliliters of dry acetonitrile solutions of 1-dimethyl ethyl ester.Stirred 30 minutes under the room temperature, the transparent liquid of vacuum-evaporation is dissolved in resistates in 45 milliliters of dry methylene chloride.Under room temperature this solution dripped to and contain 15.61 gram N, the O-dibenzyl is examined in 60 milliliters of dry methylene chloride suspension of vexed peace acyl chloride hydrochloride.After stirring was spent the night, this reaction mixture of vacuum-evaporation stirred resistates and the 10 milliliters of formic acid that stay jointly, and the silica gel chromatography purifying is carried out in vacuum-evaporation once more then, with ethyl acetate and ethyl acetate-methyl alcohol (10: 1) wash-out.After the vacuum-evaporation, obtain a kind of solid foam thing from suitable wash-out component, it becomes crystallization after ether stirs, and gets 12.7 grams, 177～178 ℃ of fusing points (decomposition)
D) (1-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) acetate 1,1-dimethyl ethyl ester
In the presence of 1.6 gram palladium charcoals (10%), (1-((1 with 7.17 grams (12.0 mmole), 4-dihydro-4-oxo-5-(phenyl methoxyl group)-and the 2-pyridyl) carbonyl)-2-((phenyl methoxyl group) carbonyl) diazanyl) acetate 1, the suspension hydrogenation of 1-dimethyl ethyl ester in 400 ml methanol 40 minutes.The product that leaches catalyzer and be settled out is with the product of 300 milliliters of exsiccant dimethyl formamide thorough washing with dissolution precipitation.By solvent removed in vacuo in the filtrate that merges, the resistates that stays is stirred with ether, separate out crystallization (1.68 grams, 221 ℃ of fusing points, (decomposition)).Recrystallization in methyl alcohol obtains pure compound 1.26 grams, 225 ℃ of fusing points, 229 ℃ of clinkerings (decomposition).
E) (3S)-(1-((1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-and 2-((((2-oxo-2-(((phenyl methoxyl group) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) diazanyl) acetate; 1,1-dimethyl ethyl ester
With 9.0 milliliters of (46.2 mmole) N-methyl-N-trimethyl silyl trifluoroacetamides join contain 3.2 the gram (11.0 mmole) (1-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) acetate 1 diazanyl carbonyl)) is in 120 milliliters of dry ethyl acetate suspension of 1-dimethyl ethyl ester.Continue under the room temperature to stir 1 hour, obtain clear liquid (solution A).
In stirring down, to 2.42 grams (11.0 mmole) (S)-3-(((phenyl methoxyl group) carbonyl) amino)-2-azetidinone adds 0.99 milliliter of (11.0 mmole) chloro sulfonyl isocyanate in the suspension of 80 milliliters of dry ethyl acetate.Under room temperature, stirred the mixture 1 hour, and be cooled to 0 ℃ then.Under 0 ℃, splash into solution A and continue at room temperature to stir and spend the night.After adding 4 milliliters of triethylamines, this mixture of vacuum-evaporation.Resistates is dissolved in 10 ml methanol-water mixture (4: 1).This solution is splashed in 30 ml methanol-water mixture, and keeping its pH is 2, and the residue that stays (10.25 gram) becomes crystallization when stirring with number ml water and methyl alcohol.Use Virahol-water (4: 1), methyl alcohol, methyl alcohol-ether (1: 1) and ether washing (and stirring) precipitation successively, make its purifying.Get 2.39 grams after the vacuum-drying.
F) (S)-3-amino-1-((((2-(carboxymethyl)-2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-azetidinone trifluoroacetate
Under 0 ℃; in the mixture of 7.0 milliliters of trifluoroacetic acids and 1.66 milliliters of thioanisoles; add 2.39 grams (3.9 mmole) (3S)-(1-((1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-and 2-((((2-oxo-3-(((phenyl methoxyl group) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) diazanyl) acetate 1,1-dimethyl ethyl ester.Stir under the room temperature and spend the night this solution of vacuum-evaporation.Resistates is used ethyl acetate, ethyl acetate-sherwood oil (1: 1), sherwood oil and washed with dichloromethane (and stirring) in succession.Vacuum-drying then.This crude product salt need not to be further purified and just is used for step down, gets 2.15 grams.
G) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid phenylbenzene methyl esters
0.70 milliliter of (3.24 mmole) chlorinated diphenyl phosphate is added dropwise to and is as cold as in the mixture under-30 ℃, this mixture be in 30 milliliters of dry acetonitriles, contain 1.42 the gram (3.24 mmole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-4-thiazolyl acetic acid and 1.81 milliliters of (12.96 mmole) triethylamines, (solution A).
Under room temperature, 3.27 milliliters of (12.96 mmole) two trimethyl silyl ethanamides are joined and contain 2.13 gram (～3.3 mmole) crude product (S)-3-amino-1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyls)-suspension of 30 milliliters of dry ethyl acetate of 2-azetidinone trifluoroacetate in.Stir after 1 hour, cool off this clear liquor and it is splashed in-30 ℃ of solution A.Down stirred these mixtures 1 hour in-10 ℃, 0 ℃ of following restir 1.5 hours, vacuum-evaporation then.This resistates is stirred with the number ml water, add dilute hydrochloric acid its pH regulator to 2.Leach precipitation, washing, at pH is that 5.5～6.0 times (adding dilute sodium hydroxide) makes in its water-soluble again-acetone, and on the macroreticular styrene-divinylbenzene copolymer, carry out the medium pressure liquid chromatography purifying, make the suitable elution fraction of gradient elution (0～100%) lyophilize with water-methanol, get 270 milligrams of pure product.It is suspended in several milliliters of cold water, and is acidified to pH2 with the precipitation free acid with dilute hydrochloric acid, suction strainer is collected it, and vacuum-drying gets 0.19 gram, fusing point＞180 ℃ (decomposition).
H) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid trifluoro-acetate
With 0.17 gram (0.2 mmole) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo-ethylidene) amino) oxygen)-2 Methylpropionic acid phenylbenzene methyl esters slowly joins and is cooled in-10 ℃ of 0.62 milliliter of stirring (8.0 mmole) trifluoroacetic acids and 0.087 milliliter of (0.8 mmole) thioanisole solution.Continue down to stir 15 minutes in 0 ℃.At 0～5 ℃ of this suspension of following vacuum-evaporation, resistates stirs with dry ether, and suction filtration is collected, and with dry ether washing, vacuum-drying, gets product 0.14 gram, fusing point＞230 ℃ (decomposition).
I) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid trisodium salt
With 115 milligrams (0.146 mmole) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(carboxymethyl)-2-((1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl diazanyl carbonyl)))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid trifluoroacetate is suspended in 15 ml waters, drips dilute sodium hydroxide with pH regulator to 5.5.Successively this solution is passed through macroreticular styrene-divinylbenzene copolymer (0.05～0.1 millimeter) post and crosslinked glycan gel (25～100 microns) post, water wash-out.Merge suitable elution fraction, lyophilize gets 100 milligrams of title compounds.
Embodiment 14
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 2-(cyanogen methyl)-the 5-(benzyloxy)-the 1-(phenmethyl)-4(1H)-pyridone
To 2.0 gram (6 mmole) 2-(chloromethyls)-the 5-(benzyloxy)-the 1-(phenmethyl)-4(1H)-and add 3.9 gram (60 mmole) potassium cyanide and 0.1 gram hexaoxacyclooctadecane-6-6 in the suspension of pyridone in 20 milliliters of acetonitriles, this mixture heating up was refluxed 2.5 hours.Suction filtration is told salt, vacuum-evaporation filtrate.With the resistates that the silica gel chromatography column purification obtains, make elutriant with ethyl acetate-methyl alcohol (8: 2), get 0.55 gram title compound, 175～180 ℃ of fusing points.
B) 1,4-dihydro-5-hydroxyl-4-oxo-1-(phenmethyl)-the 2-pyridylacetic acid(HPAC)
Under 70 ℃, with 2.45 gram (7.16 mmole) 2-(cyanogen methyl)-the 5-(benzyloxy)-the 1-(phenmethyl)-4(1H)-mixture of pyridone and 40 milliliters of concentrated hydrochloric acids (37%) stirred vacuum-evaporation then 4 hours.Resistates is suspended in 15 milliliters of icy waters, adds 5N sodium hydroxide and regulate pH to 2.0.Leach precipitation, with frozen water and ether washing, vacuum-drying (1.71 gram).This thick acid is dissolved among 20 milliliters of 0.5N NaOH, and (pH1.8) makes it to precipitate again with the 2N hcl acidifying, and suction strainer is collected, and washs with frozen water.Get 1.52 grams, 231～235 ℃ of fusing points.
C) 1,4-dihydro-5-hydroxyl-4-oxo-N-(2-oxo-1-imidazolidyl)-the 1-(phenmethyl)-2-pyridylacetic acid(HPAC) amine
4.99 milliliters of (35.83 mmole) triethylamines are joined in the suspension that contains following material: 9.29 gram (35.83 mmoles) 1,4-dihydro-5-hydroxyl-4-oxo-1-(phenmethyl)-and the 2-pyridylacetic acid(HPAC), 0.28 gram (1.79 mmole) N-hydroxybenzotriazole, 0.22 gram (1.79 mmole) N-Dimethylamino pyridine, 3.62 gram (35.83 mmole) N-aminooimidazole alkane ketone and 8.13 gram (39.41 mmole) dicyclohexyl carbodiimides are in 115 milliliters of exsiccant dimethyl formamides.Continue under the room temperature to stir to spend the night.Leach sedimentary dicyclohexylurea (DCU), with the dimethyl formamide washing, vacuum-evaporation filtrate stays resistates, becomes crystallization when it stirs with 110 milliliters of methylene dichloride.The suction filtration collecting precipitation, vacuum-drying.This crude product is suspended in 65 milliliters of dry acetonitriles, adds 14.0 milliliters of (71.6 mmole) N-methyl-N-trimethyl silyl trifluoroacetamides.Stir after 30 minutes under the room temperature, leach not molten dicyclohexylurea (DCU), vacuum-evaporation filtrate.The oily resistates was boiled 15 minutes cooling in 70 ml methanol.The suction strainer collecting precipitation.Use methyl alcohol, methyl alcohol-ether (1: 1) and ether washing successively, vacuum-drying.Get 8.7 grams.242 ℃ of clinkerings, 260～265 ℃ of fusing points (decomposition).
D) (S)-and (1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-1-(phenmethyl)-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) single sodium salt of carboxylamine benzene methyl
5.86 milliliters of (30.0 mmole) N-methyl-N-trimethyl silyl trifluoroacetamides are joined 1 of 3.42 grams (10.0 mmole), 4-dihydro-5-hydroxyl-4-oxo-N-(2-oxo-1-imidazolidyl)-the 1-(phenmethyl)-suspension of 50 milliliters of dry ethyl acetate of 2-pyridine ethanamide in, continue to stir 1 hour (solution A) under the room temperature.
In stirring down; 0.90 milliliter of (10.0 mmole) chloro sulfonyl isocyanate is joined in 50 milliliters of dry ethyl acetate solutions of (S)-3-(((benzyloxy) carbonyl) amino)-2-azetidinone of 2.20 grams (10.0 mmole); stir this mixture 1 hour under the room temperature, be cooled to 0 ℃ then.Under 0 ℃ of stirring, solution A is splashed into.After stirring under the room temperature is spent the night, this mixture of vacuum-evaporation, resistates is dissolved in several ml methanol and the water.Add dilute sodium hydroxide, pH is transferred to 5.5, the solution that lyophilize leaches.Carry out the medium pressure liquid chromatography purifying on the macroreticular styrene-divinylbenzene copolymer, water-acetone (8: 1) wash-out carries out lyophilize to relevant pure elution fraction, gets 0.40 gram title compound.With similarity condition pure component is not carried out the medium pressure liquid chromatography purifying second time, product 0.60 gram.
E) (S)-and N-(3-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-2-oxo-1-imidazolidyl)-1,4-dihydro-S-hydroxyl-4-oxo-2-pyridine ethanamide trifluoro-acetate
In the presence of 0.15 gram palladium carbon (10%); with 0.90 gram (1.3 mmole) (S)-(1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-1-(phenmethyl)-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) hydrogenation 20 minutes in 13 milliliters of dry dimethyl formamide solutions that contain 0.50 milliliter of (6.5 mmole) trifluoroacetic acid of carboxylamine benzene methyl list sodium salt.Filtration catalizer is with several milliliters of dimethyl formamide washings.Obtain the oily resistates after the vacuum-evaporation filtrate, after several milliliters of ethyl acetate stir, become crystallization.Get product 0.675 gram, fusing point＞150 ℃ (decomposition).
With this crude product title compound simple agitation 1 hour in dry ethyl acetate, filter then, with ethyl acetate washing, vacuum-drying, to improve purity.Productive rate 80%, fusing point＞165 ℃, (decomposition).
F) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
With 1.1 milliliters of (4.45 mmole) two trimethyl silyl ethanamides join 0.75 the gram (1.35 mmole) (S)-N-(3-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-2-oxo-1-imidazolidyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine ethanamide trifluoroacetate is in the suspension of 12 milliliters of dry ethyl acetate.After the stirring at room 1 hour, this clear liquor of vacuum-evaporation is dissolved in the oily resistates in 12 milliliters of dry ethyl acetate (solution A).
With 0.60 the gram (1.35 mmole) (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-suspension of 4-thiazolyl acetic acid in 12 milliliters of dry acetonitriles is cooled to-30 ℃, dropwise add 0.57 milliliter of (5.4 mmole) triethylamine therein, and then splash into 0.29 milliliter of (1.35 mmole) chlorinated diphenyl phosphate.After-30 ℃ continuation is stirred 1 hour down, stirred 1 hour down in 0 ℃ again.Solvent removed in vacuo, resistates stir with number ml water (0 ℃) and make it precipitation.The suction strainer collecting precipitation, cold water washing is suspended in the water of pH=2 (adding several dilute hydrochloric acid), filters water, methyl alcohol and ether washing successively, vacuum-drying.Get product 1.07 grams, fusing point＞180 ℃ (decomposition).This crude product can be used for next step and need not purifying.
G) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
In-10 ℃ solution of 2.0 milliliters of methyl-phenoxides in 10 milliliters of trifluoroacetic acids; add 1.01 gram (1.17 mmole) crude products (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) ethanoyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid phenylbenzene methyl esters.After stirring 20 minutes under-10 ℃, 10 ℃ of following solvent removed in vacuo.Resistates is stirred with several milliliters of methylene dichloride, filter, with several milliliters of methylene dichloride restir once, by suction strainer, hexane wash, product is collected in vacuum-drying.This crude product (1.06 gram) is suspended in several ml water-acetonitriles, adds 1N NaOH then and transfer pH to 6.0 to make it dissolving.Behind the vacuum concentration, this aqueous solution is carried out medium pressure liquid chromatography purifying, water wash-out on the macroreticular styrene-divinylbenzene copolymer.Merge suitable elution fraction, lyophilize.Product 0.10 gram, molten point＞255 ℃.
Embodiment 15
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-((3-(1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 2-((1-hydroxyl-1-methoxyl group) methyl)-5-(phenyl methoxyl group)-4(1H)-pyridone
Under the room temperature, with 9.0 gram 2-(methylols)-5-(phenyl methoxyl group)-4(1H)-pyridone and 26 gram Manganse Dioxide (activating) stir in 100 ml methanol and spend the night, generate the product crystallization, after reaction mixture boiled 10 minutes, by the filter of Hyflo heat, with 50 milliliters of boiling methanol wash filter cakes twice, the filtrate that evaporation merges, resistates stirs with 50 milliliters of ethyl acetate, forms the white products crystallization.Obtain 9.7 grams, 156 ℃ of fusing points (decomposition).
B) 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-the 2-ethyl propenoate
Under 70 ℃, with 0.5 gram tosic acid, 6.26 gram 2-(1-hydroxyl-1-methoxyl methyls)-5-(phenyl methoxyl group)-4(1H)-pyridone and 8.35 gram ethoxycarbonyl methylene tri phenyl phosphoranes stirred 3 hours in 100 milliliters of dioxs, formed transparent dark solution.Vacuum evaporating solvent, the oily resistates of title compound and triphenyl phosphine oxide, it is dissolved in 30 milliliters of Virahols, begin to separate out the product crystallization.After placement is spent the night in refrigerator, leach crystal,, use the Virahol recrystallization with the ether washing.Get 5.72 grams, 188 ℃ of fusing points.
C) 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-2-vinylformic acid
With 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-2-vinylformic acid (1.5 gram) and 0.29 gram potassium hydroxide in 30 milliliters of ethanol in 50 ℃ of stirrings 2 hours down.Behind the evaporating solvent, resistates is dissolved in 100 ml waters, filters.Adding 2N hydrochloric acid in the filtrate is 5.0 to pH, and title compound is separated out in crystallization from solution, with its filtration, washes with water, and vacuum-drying gets 1.14 grams, 236 ℃ of fusing points.
D) 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-N-(2-oxo-1-imidazolidyl)-the 2-acrylamide
With 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 2-pyridyl)-2-vinylformic acid (10.85 gram), 1 gram N-hydroxybenzotriazole, 0.01 gram N, N-dimethyl amine yl pyridines and 8.24 gram dicyclohexyl carbodiimides stirred 30 minutes in 100 milliliters of dimethyl formamides.After being cooled to 0 ℃, add 4 gram N-aminooimidazole alkane ketone, continue to stir 1 hour down in 0 ℃, and at room temperature continue to stir 10 hours, then the suspension that obtains is heated to 60 ℃, filter.It is suspended in 50 milliliters of dimethyl formamides again, is heated to 60 ℃, filter once more.40 ℃ (oil pump vacuum tightness) is the filtrate of evaporation merging down.The oily resistates is stirred with 50 ml waters that contain 2 gram sodium bicarbonates, filter back water, acetone and ether washing solid, obtain 12.3 gram solid matters after the drying.It was stirred 1 hour in 100 milliliters of methylene dichloride with 8 gram tosic acid.Filtration obtains 12.98 gram white solids, and it is suspended in water.Water-dimethyl formamide recrystallization gets 8.49 gram title compounds, 271 ℃ of fusing points.
E) (3S)-and (1-((((3-((3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) the carboxylamine benzene methyl
With 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 2-pyridyl)-N-(2-oxo-1-imidazolidyl)-2-acrylamide (3.55 gram) is suspended in 100 milliliters of ethyl acetate, adds 6.3 gram N-methyl-N-(trimethyl silyls) trifluoroacetamide.Stir and obtain clear solution after 1 hour.Within 10 minutes, this solution is joined in 3.3 gram (S)-1-(((chlorosulfonyl) amino) carbonyl)-3-(((benzyloxy) carbonyl) the amino)-cold solns (0 ℃) of 2-azetidinone in 50 milliliters of ethyl acetate then.Evaporating solvent after stirring is spent the night stirs the oily resistates 1 hour with 50 milliliters of Virahols.The precipitation that filtering separation generates with Virahol and ether washing, gets 5.91 grams.
F) (3S)-3-amino-N-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl)-1-azetidine carboxylic acid amides trifluoroacetate
Under room temperature; with (3S)-(1-((((3-((3-(1,4-dihydro-4-oxo-5-(benzyloxy)-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl (6.8 gram) stirs in 60 milliliters of trifluoroacetic acid-thioanisoles (3: 1) and spends the night.Resulting solution evaporation behind 1/3 volume, is added 50 milliliters of Virahols and 10 milliliters of ether.Obtain (3S)-3-amino-N-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) the alkylsulfonyl)-1-azetidine carboxylic acid amides trifluoroacetate of white precipitate shape.With the ether washing several times, drying.Get 4.30 grams.
G) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-((3-(1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
With (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-4-thiazolyl acetic acid (2.2 gram) and 1.5 restrains triethylamines and is dissolved in 150 milliliters of acetonitriles.Under-30 ℃, drip 1.4 gram chlorinated diphenyl phosphates, stirred the mixture 1 hour.
With 6 milliliters of N-methyl-N-(trimethyl silyls) trifluoroacetamide handles (the 3S)-3-amino-N-be suspended in 100 milliliters of ethyl acetate ((3-(((1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-and 1-oxo-2-propenyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl)-1-azetidine carboxylic acid amides 2.0 trifluoroacetates (3.3 gram), under room temperature, stirred 1 hour.Under-30 ℃, this drips of solution is added to (15 minutes) in the activatory acid.Stirred 1 hour down and stirred 30 minutes down at-10 ℃ then in 0 ℃.Vacuum evaporating solvent, remaining oily matter stirs with the frozen water (2N phosphoric acid) of pH2.Discard frozen water, resistates with the frozen water washing, is dissolved in 100 milliliters of tetrahydrofuran (THF)s more then.With this solution of dried over sodium sulfate, evaporated filtrate.Get phenylbenzene methyl esters 1.81 grams of the title compound of solid foam thing form.
Under 0 ℃, 1.5 these materials of gram were stirred 30 minutes in 30 milliliters of trifluoroacetic acid-methyl-phenoxides, add 100 milliliters of ether after-filtration and separate to such an extent that the trifluoroacetate 1.7 of title compound restrains.It is dissolved in 10 ml waters, and adding sodium bicarbonate is 5.5 up to pH.With this filtering solution,, use water as elutriant at the enterprising circumstances in which people get things ready for a trip spectrum purifying of macroreticular styrene-divinylbenzene copolymer (400 gram).Contain 0.64 gram product in the suitable eluant component.There is the bioactive by product of a kind of a spot of tool in the bioautography demonstration.With Merck Lobar C this material is carried out the chromatogram purification second time, use water as elutriant.In suitable eluant component, contain 0.17 gram title compound.
Embodiment 16
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(3-(1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-and 2-vinylformic acid, 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides
Under 0 ℃, with 1.36 gram 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-the 2-pyridyl)-2-vinylformic acid, 0.75 gram N-hydroxybenzotriazole, 0.01 gram N, N-Dimethylamino pyridine and 1.06 gram dicyclohexyl carbodiimides stirred 20 minutes in 20 milliliters of dimethyl formamides.Add 0.66 gram N-(tert-butoxycarbonyl) hydrazine.After stirring is spent the night, leach the dicyclohexylurea (DCU) of formation, with 10 milliliters of dimethyl formamide wash filtrates.With the filtrate evaporate to dryness, resistates is suspended in 30 ml waters, adds 1 gram sodium bicarbonate, stirs after-filtration and separates title compound.With obtaining white crystals behind dimethyl formamide-water recrystallization.Get product 1.47 grams, 141 ℃ of fusing points.
B) 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-2-propylene hydrazides.
Under 0～5 ℃, with 3.86 gram 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-2-vinylformic acid, 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides stirs half an hour in 30 milliliters of trifluoroacetic acids.Add 50 milliliters of ether postprecipitations and go out the trifluoroacetate of title compound.Salt suspension in 30 ml waters, was stirred 20 minutes behind the adding 2 gram sodium bicarbonates, leach title compound, washing, drying obtains a cream-coloured powder, output 2.75 grams.
C) (3S)-1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid, 2-((((2-oxo-3-(((phenyl methoxyl group) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides
With 2.86 gram 3-(1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl)-2-propylene hydrazides and 8.1 gram N-methyl-N-(trimethyl silyls) trifluoroacetamide stirred 1 hour in 50 milliliters of ethyl acetate.In in resulting settled solution, adding 3.27 gram (S)-1-(((chlorosulfonyl) amino) carbonyl)-3-(((phenyl methoxyl group) carbonyl) the amino)-solution (10 minute in finish) of 2-azetidinone in 30 milliliters of ethyl acetate under 0 ℃.After stirring is spent the night, evaporating solvent, resistates and 50 milliliters of Virahols and an acid are stirred together.Leach title compound, with Virahol and ether washing.Output 5.42 grams.
D) (3S)-and 3-(1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-2-vinylformic acid, 2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides trifluoroacetate
Under the room temperature; with 5.2 gram (3S)-1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-Pyridinecarboxylic Acid 2-((((2-oxo-3-(((phenyl methoxyl group) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides stirs in 50 milliliters of trifluoroacetic acid-thioanisoles (3: 1) and spends the night.In this clear liquid, add 100 milliliters of ether-isopropanol mixtures (8: 2).Leach the precipitation of generation,, get 4.01 grams after the drying with the ether washing.
E) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(3-(1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-1-oxo-2-propenyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
With (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-4-thiazolyl acetic acid (1.5 gram) and 1 restrains triethylamine and is dissolved in 100 milliliters of acetonitriles.Drip 1 down in-30 ℃ and restrain chlorinated diphenyl phosphate, stirred this mixture 1 hour.
Under room temperature; with (3S)-3-(1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-2-vinylformic acid; 2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides trifluoroacetate (2.0 gram) and 5.5 milliliters of N-methyl-N-(trimethyl silyls) trifluoroacetamide stirred 1 hour in 50 milliliters of ethyl acetate; form a kind of settled solution; the cooling back is added drop-wise to it in activatory acid under-30 ℃; under-30 ℃, mixture was stirred 1 hour; then stirred 30 minutes down in-10 ℃, 0 ℃ was stirred 1 hour down.This solvent of vacuum-evaporation then, resistates stirs with 50 milliliters of Virahols, forms a kind of solids, filters to make its separation and (phosphoric acid adjustings) and 100 milliliters of frozen water stirrings 20 minutes when pH2.Filtration obtains the phenylbenzene methyl esters of title compound, with frozen water washing three times, uses 50 milliliters at every turn, dry (1.78 gram).Under 0 ℃ this ester of 1.5 grams was stirred 30 minutes with 50 milliliters of trifluoroacetic acid-methyl-phenoxides (4: 1).After adding 150 milliliters of ether, trifluoroacetate 1.65 grams of filtering separation title compound free acid.
1 this material of gram is suspended in 5 ml waters, regulates pH to 6.0(sodium bicarbonate) then this clear liquid is composed purifying in the enterprising circumstances in which people get things ready for a trip of 400 gram macroreticular styrene-divinylbenzene copolymers, use water as elutriant, get 413 milligrams of title compounds.400 milligrams of these materials are carried out chromatogram purification once more on Merck Lobar C, use water as elutriant, get 160 milligrams.
Embodiment 17
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-(((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) N-(4-methoxybenzyl)-O-benzyl comenamic acid
10 gram O-benzyl comenamic acids and 10 milliliters of 4-methoxybenzylamines were refluxed 4 hours in 60 ml waters.Use this reaction mixture of 2N hcl acidifying to pH=2 under the room temperature, get 15 gram crystallizations.Yong the diox recrystallization, 12.3 gram title compounds, 175 ℃ of fusing points.
B) 1,4-dihydro-1-((4-p-methoxy-phenyl) methyl)-4-oxo-5-(phenyl methoxyl group)-N-(2-((phenmethyl) amino) ethyl)-2-pyridine carboxamides
In under the room temperature 3.69 gram N-((4-p-methoxy-phenyl) methyl)-O-benzyl comenamic acids, 1.50 gram N-hydroxybenzotriazoles and 2.05 gram dicyclohexyl carbodiimides being stirred 1 hour in 50 milliliters of dioxs.Drip the solution of 1.35 gram N-benzyl ethylene diamines in 5 milliliters of dioxs then.After spending the night, stirring leaches the dicyclohexylurea (DCU) of formation, De diox in the evaporated filtrate.Remaining oily matter is dissolved in 50 milliliters of methylene dichloride,, uses 50 milliliters at every turn, washing with 10% sodium bicarbonate extracting twice.Use the dried over sodium sulfate dichloromethane solution, evaporation with the solid of ethyl alcohol recrystallization remnants, obtains title compound crystallization 4.2 grams, 112 ℃ of fusing points.
C) N-(2-aminoethyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides tosilate
1,4-dihydro-1-((4-p-methoxy-phenyl) methyl)-4-oxo-5-(phenyl methoxyl group)-N-(2-((phenmethyl) amino) ethyl)-2-pyridine carboxamides (9.95 gram) and the mixture of 7.7 gram tosic acid in 100 ml methanol, handle with 3 gram palladium charcoals (10%), in this reaction mixture, leading to hydrogen 6 hours under 45～50 ℃.Led to argon gas 10 minutes then in this reaction mixture, filter, evaporated filtrate obtains cream-coloured title compound crystallization, and again with 50 milliliters of ether washings, output 10.5 restrains 271 ℃ of fusing points with 20 milliliters of cold methanols.
D) N-(2-aminoethyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides dihydrochloride
With 5.42 gram N-(2-aminoethyls)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides tosilate is dissolved in 50 milliliters of formic acid, add 7.5 milliliters of formic acid-hydrochloric acid gas (2.2 equivalent hydrochloric acid) and 150 milliliters of ether successively, obtain white crystals.Filtering separation also with after 200 milliliters of ether washings, gets 2.60 gram title compounds, 287 ℃ of fusing points.
E) (3S)-(1-(((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl
In in 4.38 gram (S)-3-(((phenyl methoxyl group) carbonyl) the amino)-suspension of 2-azetidinone in 50 milliliters of ethyl acetate, adding 2.83 gram chloro sulfonyl isocyanates under the room temperature, stir and obtain a settled solution after 30 minutes.
Under 50 ℃, with 5.40 gram N-(2-aminoethyls)-1, mixture and 24 gram (6 equivalent) N-methyl-N-(trimethyl silyls of 4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides dihydrochloride in 50 milliliters of acetonitriles) trifluoroacetamide stirred 1 hour jointly, under vacuum, evaporate volatile matter then, in the oily matter of remnants, add 50 milliliters of ethyl acetate.
The solution to 0 that cooling prepares above ℃ is added to second solution in first solution in stirring down.After stirring is spent the night, in 0 ℃ with stir down, adds 200 milliliters of Virahols, cream-coloured crystallization shape title compound 8.77 restrains 145 ℃ of fusing points.
F) (3S)-and N-(((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) amino) ethyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides, 2.0 trifluoroacetates
Under 0 ℃; in the mixture of 20 milliliters of thioanisole-40 milliliter trifluoroacetic acids; (3S)-(1-(((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl (2 gram) was stirred 12 hours.After adding 100 milliliters of ether, filter to isolate the white crystal (carefully) of title compound.After 50 milliliters of Virahols and the washing of 100 milliliters of ether, 2.12 gram title compounds, 136 ℃ of fusing points (decomposition).
G) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-(((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
Dissolving 4.40 gram (Z)-2-amino-α-((2-(phenylbenzene methoxy base)-1,1-dimethyl-2-oxo oxyethyl group) imino-s in 150 milliliters of acetonitriles)-4-thiazolyl acetic acid and 3 gram triethylamines.Drip 2.8 down in-30 ℃ and restrain chlorinated diphenyl phosphates, mixture was stirred 1 hour.
With (3S)-N-(((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) amino) ethyl)-1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides, 2.0 trifluoroacetates (6.13 gram) and 17 restrain N-methyl-N-(trimethyl silyls) trifluoroacetamide stirred 2 hours in 100 milliliters of ethyl acetate; vacuum distilling goes out the solvent in this clear liquid, again in the remaining oily matter of 30 ℃ of down evaporations (oil pump vacuum tightness＜0.01 millimeter) 2 hours.Resistates is dissolved in 100 milliliters of ethyl acetate and under-30 ℃ once more in 30 minutes, it splashed into to activatory acid.-10 ℃ and 0 ℃ mixture was stirred 1 hour respectively.Evaporating solvent is at pH3(2N phosphoric acid) under remaining oily matter is stirred with frozen water, discard frozen water, resistates washs with frozen water, drying, 7.8 grammeter look crystallizations.
H) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-(((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
In 30 milliliters of trifluoroacetic acid-methyl-phenoxides; (3S(Z) with 3 grams)-and 2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino) ethyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester stirred 30 minutes.Trifluoroacetate with separated free acid behind the ether sedimentation.7.9 these materials of gram are suspended in 20 ml waters, regulate pH to 6.0 with sodium bicarbonate.Stir after half an hour, filtering suspension liquid carries out chromatogram purification with the macroreticular styrene-divinylbenzene copolymer to this solution, uses water as elutriant, gets product 0.24 gram.With Merck Lobar C post this material is carried out chromatogram purification once more, get product 0.078 gram, 275 ℃ of fusing points (decomposition).
Embodiment 18
(2S (2 α; 3 β (Z)))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-methyl-4-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) carboxylamine benzene methyl (2S-is trans)-(1-((((3-(((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-methyl-4-oxo-3-azelidinyl)
2.35 gram (3S-is trans)-(4-methyl-2-oxo-3-azelidinyl) carboxylamine benzene methyls and 1.41 gram chloro sulfonyl isocyanates were stirred 1 hour down at 0 °～5 ℃ in 50 milliliters of ethyl acetate, obtain clear soln (solution A).Under 40 ℃, in 50 milliliters of ethyl acetate, with 3.28 grams 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidyl)-5-(phenyl methoxyl group)-2-pyridine carboxamides and 6 gram N-methyl-N-(trimethyl silyls) 1 hour (solution B) of trifluoroacetamide stirring.
In stirring in following 30 minutes, in the solution A of cold (0 ℃), add solution B.After continuously stirring was spent the night, evaporating solvent stirred resistates (oily) with 50 milliliters of Virahols and an acetate, generated cream-coloured title compound precipitation 4.3 grams, 163 ℃ of fusing points (decomposition).
B) (2S-is trans)-N-(3-((((3-amino-2-methyl-4-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-2-oxo-1-imidazolidyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides, two tosilate
Under the room temperature; in 50 milliliters of dimethyl formamides, 3.8 gram hydration tosic acid and 2.5 gram palladium charcoals (10%); with 5.9 gram (2S-is trans)-(1-((((3-(((1,4-dihydro-4-oxo-5-(phenyl methoxyl group)-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-methyl-4-oxo-3-azelidinyls) carboxylamine benzene methyl hydrogenation 1 hour.After the Hyflo filtration, vacuum is steamed and is removed dimethyl formamide.The oily resistates stirs with 100 milliliters of methylene dichloride, forms white crystals shape title compound (5.8 gram) immediately.
C) (2S-(2 α; 3 β (Z)))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-methyl-4-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
With (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-4-thiazolyl acetic acid (4.40 gram) and 3.0 restrains triethylamines and is dissolved in 150 milliliters of acetonitriles.Dropping 2.8 restrains chlorinated diphenyl phosphates and stirred 1 hour under-30 ℃.
In under-20 ℃ in 50 milliliters of dimethyl formamides; with 7.9 gram (2S-is trans)-N-(3-((((3-amino-2-methyl-4-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-2-oxo-1-imidazolidyl)-1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides, two tosilate and 2.02 gram triethylamines stirred 5 minutes.
Also stirred 1 hour down at-30 ℃ in-30 ℃ of suspension that prepare above merging down and solution, then stirred 1 hour down in-10 ℃, 0～10 ℃ is stirred down and spends the night.Vacuum is steamed and to be desolventized, resistates with 100 milliliters of frozen water at pH3(phosphoric acid) under stirring.Leach the benzhydryl ester of title compound, wash with water, get 6.13 grammeter toner ends.
In 30 milliliters of trifluoroacetic acid-methyl-phenoxides (4: 1), the above-mentioned ester of 2 grams was stirred 30 minutes under 0 ℃.Add 100 milliliters of ether, precipitation is separated out the trifluoroacetate of above-mentioned free acid.It is suspended in 10 ml waters, transfers pH to 6.0.After the filtration, make filtrate pass through macroreticular styrene-divinylbenzene copolymer post, use water as elutriant, get product 0.48 gram.
After carrying out the chromatogram purification second time (water is made elutriant) with Merck Lobar C post, obtain 0.17 gram title compound.
Embodiment 19
(3S(Z))-(((((3-(((1 for 1-for 2-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-miaow thiophene alkyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl)-α-(methoxyimino)-4-thiazole ethanamide, a sylvite
Under the room temperature, in the suspension of 0.6 gram (Z)-2-amino-α-(methoxyimino)-4-thiazolyl acetic acid (0.003 mole), add 2.14 milliliters of (0.009 mole) Tributylamines.This suspension is cooled to-30 ℃, under this temperature, adds 0.66 milliliter of chlorinated diphenyl phosphate (0.003 mole).Stir this reaction mixture 1 hour (mixture A) down in-30 ℃.
Under the room temperature; to 1.62 the gram (0.003 mole) (3S)-((3-(((1 for 3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides adds 2.6 milliliters of two-trimethyl silyl ethanamides in the suspension of 20 milliliters of ethyl acetate; form a kind of brown clear solution; under the room temperature it was stirred 1 hour, be cooled to 0 ℃ (solution B) then.
In stirring down, solution B is added dropwise among the mixture A, keep its temperature to be-30 ℃ (about 10 minutes) simultaneously.Under-10 ℃, this mixture was stirred 1 hour, stirred vacuum-evaporation 1.5 hours down in 0 ℃ again.Remaining syrup is dissolved in 50 milliliters of acetone.In this solution, add 6 milliliters 1 mole second caproic acid potassium, to precipitate 3 gram crude products.But in filtrate, add the ether redeposition and separate out 0.2 gram crude product.Crude product obtains 1.85 gram title compounds through macroreticular styrene-divinylbenzene copolymer column chromatography purifying.
Embodiment 20
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid
With (3S(Z))-((((((((3-(((1 for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid disodium salt (2.2 grams; see embodiment 1) be dissolved in 20 milliliters of acetone-waters (1: 1), transfer pH to 2 with 2N hydrochloric acid.Carry out chromatogram purification with the macroreticular styrene-divinylbenzene copolymer, get 0.7 gram title compound.
Embodiment 21
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-N-hydroxy-2-methyl propionic acid amide-sodium salt
(Z)-2-amino-α-((1,1-dimethyl-2-oxo-2-((three benzyloxies) amino) oxyethyl group) imino-)-4-thiazolyl acetic acid (4.72 gram) is suspended in 65 milliliters of acetonitriles, adds 3.72 milliliters of triethylamines down in-30 ℃.Stir after 10 minutes, splash into 1.97 milliliters of chlorinated diphenyl phosphates, continue to stir 90 minutes (solution A) then.
((3-(((1 with (3S)-3-amino-N-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) alkylsulfonyl)-2-oxo-1-azetidine carboxylic acid amides (8.9 milliliters) is suspended in 70 milliliters of acetonitriles, adds 7.7 milliliters of two trimethyl silyl ethanamides.After-10 ℃ of stirrings were stirred 1.5 hours down in 1 hour and 0 ℃, obtain settled solution.The trifluoroacetic acid trimethyl silyl ester of vacuum evaporating solvent and formation is dissolved in remaining oily matter in 70 milliliters of ethyl acetate (solution B).
Under-20 ℃, in 30 minutes, solution A is splashed in the solution B that is stirring then, stirred 1.5 hours and under 0 ℃, stirred and finished reaction in 1 hour in-10 ℃ of continuation.
Vacuum steams solvent then.The oily resistates is stirred with 300 milliliters of frozen water (its pH value transfers to 4.0 with 10% phosphoric acid).Leach the solid of formation, washing, vacuum-drying is spent the night, and gets 9 gram crude products.
4.5 gram crude products were stirred under 0 ℃ 1 hour with 45 milliliters of formic acid (98%) and 4.5 milliliters of methylene dichloride.Use ether sedimentation, obtain 2.3 gram title compounds.
Embodiment 22
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 2-(((benzyloxy) carbonyl) amino)-2-imidazolidone
1-amino-2-imidazolidone (26 grams, 0.257 mole) is dissolved in 200 ml waters.Make the solution layering with 200 milliliters of ethyl acetate and 43.8 gram chloroformic acids; Stir and in mixture, to splash into benzyl ester (0.257 mole) down and to add caesium simultaneously and sodium hydrogen carbonate solution is 8.5～9 to keep pH.After stirring is spent the night under the room temperature, leach title compound, wash with water earlier, with the ethyl acetate washing, get 46.7 grams, 140～144 ℃ of fusing points then.
B) 1-(((benzyloxy) carbonyl) amino)-3-(is chloroformyl)-the 2-imidazolidone
In the suspension of 1 liter of methylene dichloride, add the solution of 35 gram carbonyl chlorides in 200 milliliters of methylene dichloride to 69.9 gram (0.297 mole) 2-(((benzyloxy) carbonyl) amino)-2-imidazolidones.Stir the mixture under the room temperature and spend the night, form clear solution.Solvent removed in vacuo with the remaining soup compound of ether development, gets 76.0 grams, 102～105 ℃ of fusing points.
C) 3-(((benzyloxy) carbonyl) amino)-2-oxo-1-imidazolidine carboxylic acid, 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides
(((benzyloxy) carbonyl) amino)-3-(is chloroformyl with 76 gram (0.255 mole) 1-)-the 2-imidazolidone joins under room temperature in 1.5 liters of ethyl acetate.After being cooled to 0～5 ℃, in 30 minutes, splash into 39.6 gram (0.9 mole) N-(tertbutyloxycarbonyls) hydrazides and the solution of 41.8 milliliters of triethylamines (0.3 mole) in 150 milliliters of ethyl acetate.The mixture stirring is spent the night, leach precipitation, drying stirs to remove triethylamine hydrochloride with 800 ml waters, filters, and washing and dry gets product 71.2 and restrains 195～198 ℃ of fusing points.
D) hydrazine carboxylic acid 1 2-((3-(((1,4-dihydro-4-oxo-5-(benzyloxy)-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl), 1-dimethyl ethyl ester
With 31.5 gram (0.08 mole) 3-(((benzyloxy) carbonyl) amino)-2-oxo-1-imidazolidine carboxylic acids, 2-((1,1-dimethyl oxyethyl group) carbonyl) hydrazides is dissolved in 400 milliliters of dimethyl formamides, add 16 gram palladium charcoals (10%), make hydrogen pass through reaction mixture under stirring.After 1 hour, leach catalyzer.In filtrate, add 19.62 gram neighbour-benzyl comenamic acids (0.08 mole), 0.48 gram Dimethylamino pyridine and 0.64 gram N-hydroxybenzotriazole.Stirred this mixture 1 hour under the room temperature.Under room temperature, add 18.13 gram dicyclohexyl carbodiimide solution (0.088 mole), this mixture is stirred spend the night.Leach precipitation (dicyclohexylurea (DCU)), vacuum-evaporation filtrate, water development resistates adds sodium bicarbonate therein with pH regulator to 7.5.Leach precipitation, get 36 gram title compounds.
E) 3-(((1,4-dihydro-4-oxo-5-(benzyloxy)-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazoles alkanoic acid hydrazides
Following in-10 ℃ with stirring, ((3-(((1 with 36 gram 2-, 4-dihydro-4-oxo-5-(benzyloxy)-and the 2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) hydrazine carboxylic acid 1,1-dimethyl ethyl ester joins in 300 milliliters of trifluoroacetic acids.Mixture stirred 1 hour at 0 ℃, and vacuum is removed trifluoroacetic acid, develops resistates with ether, got the trifluoroacetate of 41 gram title compounds.Cooling is suspended in this trifluoroacetate in the water down, adds 2N sodium hydroxide and regulates pH to 7, leaches precipitation, gets 21.9 gram title compounds.
F) 3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl)-carbonyl) amino)-2-oxo-1-imidazolidine carboxylic acid hydrazides
With 21.9 gram 3-(((1,4-dihydro-4-oxo-5-(benzyloxy)-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidine carboxylic hydrazides is suspended in 250 milliliters of acetonitriles.In this suspension, add 75 milliliters of two trimethyl silyl ethanamides, stir this mixture to form solution.In this solution, add 10 gram palladium charcoals (10%), make hydrogen pass through mixture under the vigorous stirring.After 1 hour, debenzylation reaction is complete.After the filtration, add 15 ml methanol and 10 acetate, get 10.8 grams with the precipitation title compound.This crude product is stirred with 150 milliliters of ethanol, get 8.8 gram title compounds, fusing point＜205 ℃ (decomposition).
G) (S)-(1-((((2-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl
To 5.9 gram (0.02 mole) crude product 3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-suspension of 2-oxo-1-imidazolidine carboxylic hydrazides in, add 14.9 milliliters of (0.08 mole) N-methyl-N-(trimethyl silyls) trifluoroacetamide, and under 50 ℃, stir this mixture to form solution (solution A).
In the suspension that contains 4.4 gram (S)-3-(((benzyloxy) carbonyl) amino)-2-chlorine heterocycle butanones (0.02 mole) and 160 milliliters of ethyl acetate, under room temperature, add 1.76 milliliters of chloro sulfonyl isocyanates.Stir this mixture 1 hour (solution B).
Under ice-cooled, solution A is added in the solution B.Stir after 1 hour, in mixture, add 2.8 milliliters of (0.02 mole) triethylamines, at room temperature stir then and spend the night.Add 2.8 milliliters of (0.02 mole) triethylamines again, add frozen water then.Mixture was thoroughly stirred 1 hour the solution layering.Water layer is acidified to pH3, and the filtering separation precipitation gets 5.3 gram crude product title compounds.
This dissolving crude product in acetone-water, is added 2N sodium hydrate regulator solution pH to 6.5, after vacuum is removed acetone, filtering solution and lyophilize, the thick sodium salt of 5.5 gram title compounds.With the macroreticular styrene-divinylbenzene copolymer this thick sodium salt is carried out chromatogram purification, obtain 0.64 gram pure substance.It is soluble in water, and with the precipitation title compound, output 0.5 restrains with the 2N hcl acidifying.
H) (S)-and N-(3-((2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) diazanyl) carbonyl)-2-oxo-1-imidazolidyl)-1,4-dihydro-5-hydroxyl-4-oxo-2-pyridine carboxamides
0.5 gram (S)-(1-((((2-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) carboxylamine benzene methyl is joined in the mixture of 0.5 milliliter of thioanisole and 2 milliliters of trifluoroacetic acids.Under the room temperature vacuum-evaporation is spent the night in the mixture stirring.Develop resistates with ethyl acetate, obtain title compound with quantitative yield.
I) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid benzhydryl ester
To 0.35 gram (0.0008 mole) (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-10 milliliters of acetonitrile solutions of 4-thiazolyl acetic acid in, add 0.34 milliliter of triethylamine.Mixture is cooled to-30 ℃, adds 0.17 milliliter of chlorinated diphenyl phosphate.Reaction mixture stirs 1 hour (solution A) down in-30 ℃.
To 0.008 mole of (S)-N-(3-((2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl) diazanyl) carbonyl)-2-oxo-1-imidazolidyl)-1; in the 4-dihydro-5-hydroxyl-suspension of 4-oxo-2-pyridine carboxamides in 6 milliliters of ethyl acetate, add 0.7 milliliter of two trimethyl silyl ethanamide (solution B).
Under-30 ℃, solution B is added in the solution A.Successively mixture was stirred vacuum-evaporation respectively 2 and 1 hours-10 ℃ and 0 ℃.Resistates with water treatment after, obtain 0.7 gram crude product title compound, 155 ℃ of fusing points (decomposition).
J) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((3-(((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl) amino)-2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
Under-10 ℃; to 0.7 gram (3S(Z))-((((((((((3-(((1 for 2-for 1-for (1-(2-amino-4-thiazolyl)-2-for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) amino carbonyl))-and 2-oxo-1-imidazolidyl) carbonyl) diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid; benzhydryl ester (0.00077 mole) adds 6 milliliters of trifluoroacetic acids in the suspension of 1 milliliter of methyl-phenoxide.Mixture kept 1 hour at-10 ℃, added the trifluoroacetate of ether with precipitation raw material free acid down at-10 ℃, output 0.5 gram.
Under cooling, this precipitation is suspended in water, add 2N sodium hydroxide and transfer pH to 5.5.Obtain 0.55 gram crude product after the lyophilize.This thick product carries out chromatogram purification with the macroreticular styrene-divinylbenzene copolymer, gets pure title compound 0.1 gram.
Embodiment 23
(3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-2-methyl diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
A) 1,4-dihydro-4-oxo-5-(benzyloxy)-the 1-(phenmethyl)-2-Pyridinecarboxylic Acid 1-methylhydrazide
Under ice-cooled, with N, the O-dibenzyl is examined vexed peace acyl chlorides (0.15 mole) and is suspended in 150 milliliters of methylene dichloride.In this suspension, add 26.2 milliliters of (0.5 mole) methyl hydrazines, add 150 milliliters of acetonitriles then.This mixture at room temperature stirs and spends the night, and this turbid solution of vacuum-evaporation is developed with 300 ml waters.The solid matter that obtains gets 26.3 gram crude products after filtration after the drying.This crude product of water recrystallization obtains the pure title compound of 12.7 grams, 138～142 ℃ of fusing points.
B) (S)-1,4-dihydro-4-oxo-5-(benzyloxy)-the 1-(phenmethyl)-2-Pyridinecarboxylic Acid, 1-methyl-2-((((2-oxo-3-(((benzyloxy) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides
With 1,4-dihydro-4-oxo-5-(benzyloxy)-the 1-(phenmethyl)-2-Pyridinecarboxylic Acid 1-methylhydrazide (1.82 grams, 0.005 mole) is suspended in 20 milliliters of ethyl acetate.Adding total amount under the room temperature is the N-methyl-N-(trimethyl silyl of 1.85 milliliters (0.01 moles)) trifluoroacetamide, stir this mixture 4 hours (suspending liquid A) down in 60 ℃.
Under room temperature with 1.1 grams (0.005 mole) (S)-3-(((benzyloxy) carbonyl) amino)-2-azetidinone is suspended in 40 milliliters of ethyl acetate, adds 0.5 milliliter of chloro sulfonyl isocyanate.Under the room temperature mixture is stirred 1 hour to form solution (solution B).
In ice-cooled 1.2 milliliters of triethylamines, 20 milliliters of methylene dichloride and the suspending liquid A of in solution B, successively adding down.Under the room temperature this suspension stirred and spend the night, in this is muddy solution slightly, add 30 milliliters of methylene dichloride and 20 ml waters, and at room temperature stirred this mixture 1 hour.
This water pH is 6.5～7.Add 60 milliliters of ethyl acetate, tell organic layer, wash water twice with methylene dichloride-ethyl acetate mixture (1: 3).The organic phase MgSO that merges 4Drying, evaporation gets 4.5 gram syrups, separates out crystallization after placing weekend.After the ether processing, obtain 2.6 gram crude product title compounds.
C) 1,4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid 2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-1-methylhydrazide trifluoroacetate
To containing 2 gram (S)-1; 4-dihydro-4-oxo-5-(benzyloxy)-the 1-(phenmethyl)-60 milliliters of dimethyl formamide solutions of 2-Pyridinecarboxylic Acid 1-methyl-2-((((2-oxo-3-(((benzyloxy) carbonyl) amino)-1-azelidinyl) carbonyl) amino) alkylsulfonyl) hydrazides in, add 1.1 milliliters of trifluoroacetic acids and 1 gram palladium charcoal (10%) successively.Behind nitrogen wash, in solution, fed hydrogen 60 minutes in stirring down, filtration catalizer, vacuum-evaporation filtrate is developed resistates with ether, obtains 1.1 gram title compound crude products, productive rate 86.6%.
D) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-2-methyl diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
To contain 0.88 the gram (0.002 mole) (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-and add 0.7 milliliter of (0.005 mole) triethylamine in the suspension of 30 milliliters of acetonitriles of 4-thiazolyl acetic acid, add 0.44 milliliter of (0.002 mole) chlorinated diphenyl phosphate down at-30 ℃ then.Stir this mixture 1 hour (solution A) down in-30 ℃.
Under room temperature; to containing 1.2 gram (0.002 moles) 1; 4-dihydro-5-hydroxyl-4-oxo-2-Pyridinecarboxylic Acid; 2-((((3-amino-2-oxo-1-azelidinyl) carbonyl) amino) alkylsulfonyl)-1-methylhydrazide; in the suspension of 30 milliliters of ethyl acetate of trifluoroacetate; add 2 milliliters of two-trimethyl silyl ethanamides (about 0.008 mole), after 30 minutes, promptly form clear soln (solution B).
Under-30 ℃, solution B is splashed in (about 10 minutes) solution A.Be incubated 1 hour down at-10 ℃, kept 1 hour in 0 ℃ again.Evaporating solvent, the resistates water treatment after filtration and the drying, gets 2.4 gram title compound crude products.
E) (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-2-methyl diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid disodium salt
Under-10 ℃; with 2.4 gram crude products (3S(Z))-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((2-((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl)-2-methyl diazanyl) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester is added in the mixture of 20 milliliters of trifluoroacetic acids and 4 milliliters of methyl-phenoxides.Under-10 ℃, add ether down with the precipitin reaction product, get the trifluoroacetate crude product of 1.12 gram title compounds with mixture stirring 1 hour and at-10 ℃.
In the acetone-water suspension of this crude product, add 2N sodium hydroxide and lyophilize, can make this crude product be converted into sodium salt.On macroreticular styrene-divinylbenzene copolymer post, this sodium salt is carried out chromatogram purification, make elutriant, obtain 0.25 gram with water.
Embodiment 24
(3S)-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid
A) 2-(methylol)-the 5-(benzyloxy)-4H-pyrans-4-ketone
To include 56.8 gram (0.4 mole) 5-hydroxyl-2-(methylols)-400 ml methanol suspension of 4H-pyrans-4-ketone, earlier with being dissolved in the gram of 16 in 200 milliliters of warm methyl alcohol (0.4 mole) sodium-hydroxide treatment, handle with 50.6 gram (46 milliliters, 0.4 mole) benzyl chlorides then.Mixture heating up was refluxed 3.5 hours, pour into after the cooling in 1 premium on currency.Leach the solid that obtains and with about 1.5 premium on currency, 200 milliliters of ethanol and 400 milliliters of hexane wash.After the drying, product weighs 55.7 grams under the high vacuum.
B) 1,4-dihydro-2-(methylol)-the 5-(benzyloxy)-the 4-pyridone
With 9.65 gram (41.59 mmole) 2-methylol-5-(benzyloxies)-4H-pyrans-4-ketone, 95 milliliters of strong aquas and 20 milliliters of mixture heated overnight under refluxing that ethanol is formed.Add 75 milliliters of ammonium hydroxide again, with 2 hours postcooling of mixture backflow.Leach the brown solid thing of generation, wash elutant with water and be neutral.Crude product is suspended in the ethanol, filters, with ethanol and hexane wash, vacuum-drying.Get title compound 7.61 grams.
C) 1-(chloromethyl)-1,4-dihydro-5-(benzyloxy)-4-pyridonium salt hydrochlorate
Under argon atmospher, will include 1,4-dihydro-2-(methylol)-the 5-(benzyloxy)-chloroform (15 milliliters) suspension of 4-pyridone (3 gram, 12.99 mmoles) is cooled to 0 ℃, and handles with thionyl chloride (6.1 milliliters, 83.62 mmoles).In several minutes, obtain a kind of homogeneous solution.Behind the restir 5 minutes, precipitation is separated out the coloured solid of paste.Remove cryostat and with mixture reflux 45 minutes.Mixture is cooled to 0 ℃, leaches the white suspension material, with chloroform and hexane wash, vacuum-drying.Get title compound 3.65 grams.
D) 2-(azido-methyl)-1,4-dihydro-5-(Phenoxymethyl)-the 4-pyridone
Under room temperature and argon atmospher, with the 1-(chloromethyl)-1,4-dihydro-5-(benzyloxy)-4-pyridonium salt hydrochlorate (3.59 grams, 12.54 sodiumazide (4.08 grams mmole),, 62.7 mmole) and the mixture of diisopropylethylamine (2.19 milliliters, 12.54 mmoles) in 70 milliliters of dimethyl formamides stirred 3.5 days.Add 4.08 gram sodiumazide again, and mixture was heated 2 hours down at 45～50 ℃.After the cooling, in reactant impouring 500 ml waters, generate insoluble white solid.Make supernatant liquor pH be reduced to 7.5 from 8.5 with dilute hydrochloric acid, leach white solid.After water, acetone and the hexane wash, this solids of vacuum-drying, the output of title compound is 2.81 grams.
E) 2-(aminomethyl)-and 4-oxo-5-(benzyloxy) pyridine
Under room temperature and 1 atmospheric pressure hydrogen atmosphere, will include the 2-(azido-methyl)-1,4-dihydro-5-(Phenoxymethyl)-100 milliliters of dimethyl formamide suspension stirrings of 4-pyridone (2.030 gram, 7.93 mmoles) and platinum oxide (200 milligrams) 6 hours.Filtration catalizer, this solution of vacuum concentration obtains grey powdery title compound 1.5 grams.
F) (3S)-1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-(((benzyloxy) carbonyl) amino) azetidine
To including the 2-(aminomethyl)-4-oxo-5-(benzyloxy) pyridine (2.330 grams, 10.13 in 60 milliliters of ethyl acetate suspension mmole), under agitation add N-methyl-N-(trimethyl silyl) trifluoroacetamide (3.76 milliliters, 20.26 mmoles).Under the room temperature with the solution stirring that obtains 30 minutes, be cooled to 0 ℃ then, simultaneously, to including (S)-3-(((benzyloxy) carbonyl) amino)-2-azetidinone (2.228 grams, 10.13 in the suspension of 60 milliliters of ethyl acetate mmole), add Sulfuryl chloride isocyanate (882 microlitres, 10.13 mmoles) down in stirring.Under room temperature,, be cooled to 0 ℃ then, handle, use above-mentioned silylated 2-(aminomethyl then with triethylamine (4.23 milliliters, 30.39 mmoles) with the solution stirring that obtains 30 minutes)-4-oxo-5-(benzyloxy) pyridine handles.Under room temperature, this mixture was stirred 2 days.
This mixture of vacuum concentration is dissolved in resistates in acetonitrile-water (40: the 60) mixture, and pH reduces to and tells thick oily matter after 2.9.When being cooled to 5 ℃, this oily matter solidifies.Isolate this solid, wash with water four times, obtain 3.4 gram title compound crude products after the vacuum-drying.With this dissolving crude product in the dimethyl formamide of small volume as far as possible, and in the macroreticular styrene-divinylbenzene copolymer post (1 liter) of packing into.Acetone-water with ladder concentration is made gradient elution, with the required material of about 65% acetone wash-out.Merge relevant eluant component, obtain 2.69 gram title compounds after the lyophilize.
G) (3S)-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester
Under an atmospheric pressure hydrogen atmosphere; stirring is by (3S)-1-((((((1; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl amino methyl)))))-(912 milligrams of 2-oxo-3-(((benzyloxy) carbonyl) amino) azetidines; 1.64 mmole), tosic acid-hydrate is (625 milligrams; 3.28 mmole) and the mixture in 16 milliliters of dimethyl formamides, formed of 10% palladium charcoal (190 milligrams), up to consuming 3.28 mmoles (73 milliliters) hydrogen (about 3 hours).
Including (Z)-2-amino-α-((2-(two benzyloxies)-1,1-dimethyl-2-oxo oxyethyl group) imino-)-(846 milligrams of 4-thiazolyl acetic acids, 1.804 in the solution of 16 milliliters of dimethyl formamides mmole), add chlorinated diphenyl phosphate (374 microlitres in-20 ℃ down with stirring, 1.804 mmole), add triethylamine (450 microlitres, 3.28 mmoles) then.
Under-20 ℃ with this solution stirring 1 hour, add hydrogenolysis then the said mixture of compound.Then add triethylamine (921 microlitres, 6.6 mmoles).At-20 ℃ the mixture stirring that obtains was then spent the night 5 ℃ of stirrings in 1 hour.Filtration catalizer, vacuum is removed volatile matter, with the oily matter that obtains be dissolved in as far as possible the acetone-water of small volume (75: 25) (pH5.2) in, while stirring it is splashed into 20 milliliters of Dowex50 * 2-400(K +) in the suspension in acetone-water (35: 65).After 40 minutes, filter this mixture, filtrate obtains 2.1 gram solids after lyophilize.With this solid be dissolved in as far as possible the acetonitrile-water of small volume (40: 60) (pH5.6) in, pack in the macroreticular styrene-divinylbenzene copolymer post (800 milliliters), make gradient elution with ladder concentration acetonitrile-water.Required material is eluted by about 30% acetonitrile.Merge relevant elution fraction, obtain title compound after the lyophilize.
H) (3S)-2-(((1-(2-amino-4-thiazolyl)-2-((1-((((((1,4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) methyl) amino) alkylsulfonyl) amino) carbonyl)-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-2 Methylpropionic acid
Under 0 ℃ of stirring; trifluoroacetic acid (4.7 milliliters) is added drop-wise to includes (3S)-2-(((1-(2-amino-4-thiazolyl)-((1-((((((1 for 2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl amino methyl)))))-2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-3 milliliters of methylene dichloride of 2 Methylpropionic acid benzhydryl ester (131 milligrams, 0.113 mmole) and 0.3 milliliter of methyl-phenoxide suspension in.5 ℃ are stirred after 45 minutes down, add 2 milliliters of toluene, and vacuum is removed volatile matter.Oily matter with hexane (3 * 4 milliliters) washing generates with 10 milliliters of ether developments, makes it to become solid again.With 10 milliliters of ether once, vacuum-drying with this solids wash.(((1-(2-amino-4-thiazolyl)-((1-((((((1 for 2-with 0.166 mmole (3S)-2-; 4-dihydro-5-hydroxyl-4-oxo-2-pyridyl) carbonyl amino alkylsulfonyl amino methyl)))))-and 2-oxo-3-azelidinyl) amino)-2-oxo ethylidene) amino) oxygen)-the 2 Methylpropionic acid benzhydryl ester, repeat above-mentioned reaction and post-processing operation.Merge the gained solid crude product, with its be dissolved in 2 milliliters of acetonitrile-waters (40: 60) (pH2.5) in, carry out chromatogram purification with macroreticular styrene-divinylbenzene copolymer post (200 milliliters), carry out gradient elution with acetonitrile-water.When with acetonitrile-water (20: 80), but wash-out goes out required material.Merge relevant component, obtain 103 milligrams of title compounds after the lyophilize, white solid, 180 ℃ of fusing points (decomposition).
Figure 86106980_IMG217

Claims (1)

1, a kind of preparation has the method for the compound or pharmaceutically acceptable salt thereof of following formula (A),
Figure 86106980_IMG3
R is in the formula (A):
Figure 86106980_IMG4
R 1Be the acyl group that comes by carboxylic acid derivatives, R 2And R 3Identical or different, the phenyl of respectively do for oneself hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, replacement or 4,5,6 or 7 yuan of heterocycles, perhaps R 2And R 3In one be hydrogen, another be azido-, monochloromethyl, dihalomethyl, trihalogenmethyl, carbalkoxy, 2-styryl, 2-phenylacetylene base, carboxyl ,-CH 2X 1,-S-X 2,-O-X 2,
Figure 86106980_IMG5
X 1Be azido-, amino, hydroxyl, carboxyl, carbalkoxy, alkanoyl amino, phenylcarbonyl group amino, (phenyl of replacement) carbonyl amino amino, alkane sulfonyloxy, phenylsulfonyloxy, (phenyl of replacement) sulfonyloxy, phenyl, replacement phenyl, cyano group,
Figure 86106980_IMG6
X 2Be alkyl, the phenyl of alkyl, replacement, phenyl, benzene alkyl, (phenyl of replacement) alkyl, alkanoyl, phenyl alkanoyl, (phenyl of replacement) alkanoyl, phenylcarbamoyl, (phenyl of replacement) carbonyl or the heteroaryl carbonyl of replacement,
X 3And X 4In, one is hydrogen, another is a hydrogen or alkyl,
Perhaps X 3And X 4Form a cycloalkyl with the carbon atom that links to each other with them;
X 5Be formyl radical, alkanoyl, phenylcarbamoyl, (phenyl of replacement) carbonyl, benzene alkyl carbonyl, (phenyl of replacement) alkyl carbonyl, carboxyl, carbalkoxy, aminocarboxyl, (amino of replacement) carbonyl or cyano group;
X 6And X 7Identical or different, each is the phenyl of hydrogen, alkyl, phenyl or replacement, perhaps X naturally 6Be hydrogen and X 7Be amino, alkanoyl amino or alkoxyl group, perhaps X amino, that replace 6And X 7With 4,5,6 or 7 yuan of heterocycles of the common formation of the nitrogen-atoms that links to each other with them;
A is-CH=CH--(CH 2) m-,-(CH 2) m-O-,
-(CH 2) m-NH-or-CH 2-S-CH 2-;
M is 0,1 or 2;
A 1Be a singly-bound,
Figure 86106980_IMG7
A 2Be a singly-bound ,-NH-,-CH 2-CH 2-NH-, or
Figure 86106980_IMG8
A 3Be-(CH 2) p-,
Figure 86106980_IMG9
-NH-CH 2-，-O-CH 2-，
Figure 86106980_IMG10
A 4Be
Figure 86106980_IMG11
A 5Be a singly-bound ,-CH 2-,-NH-CH 2-,-N=CH-, or
A 6Be a singly-bound ,-CH=CH-or-(CH 2) t-;
P is 0 or 1;
Y is 2,3 or 4;
Q is 0 or 1;
T is 1,2,3 or 4; And
X is hydrogen, carboxyl or formamyl,
Present method is characterised in that:
(1) make following formula: compound with by R 1-carboxylic acid derivatives and a R coming 1Acyl group carries out acylation reaction,
Figure 86106980_IMG13
Perhaps
(2) in following formula: compound: introduce one-CO-NH-SO 2The R activating group.
CN198686106980A 1985-09-26 1986-09-26 The alkylsulfonyl that 2-oxo-1-{[(replaces)-and amino] carbonyl } azetidine-typed Pending CN86106980A (en)

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CN100467021C (en) * 2003-07-15 2009-03-11 韩国生命工学研究院 Novel 2-oxo-heterocyclic compounds and use of pharmaceutical compositions comprising said compounds
CN106986820A (en) * 2017-02-24 2017-07-28 浙江工商大学 The preparation method and purposes of multi-functional pyridone ketone derivatives and its hydrate

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CN106986820A (en) * 2017-02-24 2017-07-28 浙江工商大学 The preparation method and purposes of multi-functional pyridone ketone derivatives and its hydrate
CN106986820B (en) * 2017-02-24 2019-05-21 浙江工商大学 Preparation and use of multifunctional hydroxypyridone derivatives and their hydrates

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