JPH0357106B2 - - Google Patents

Description

[Detailed description of the invention] Summary of the invention This application is based on the formula (In the formula, R¹and R²is as specified in the text.
and −N≡Q is the fourth term as specified in the text.
class ammonio group) 7-[2-(5-amino-1,2,4-thiadias)
zol-3-yl)-2-(substituted)iminoaceto
mido]-3-[3-(quaternary ammonio)-1-pro
pen-1-yl]-3-cephem-4-carboxy
For the production of sylate and its salts and esters
related to intermediates and their production. Background and prior art A Tsutomu, Teraji published on June 28, 1983
U.S. Pat. No. 4,390,534 to et al. In the formula, R¹is an amino or protected amino
and R²is hydrogen, acyl, optionally substituted
aryl, substituted alkyl, alkenyl,
Alkynyl, optionally substituted cycloal
substituted with a kyl, cycloalkenyl or oxo group.
is a substituted O- or S-containing 5-membered heterocycle.
ri；R³is hydrogen or alkyl; R^Fouris water
base, acyloxyalkyl, acylthioalkyl
optionally substituted pyridinioalkyl
optionally substituted heterocyclyl thioyl
oalkyl, alkyl, halogen, hydroxy
or optionally substituted thiazolioalkyl
R^Fiveis carboxy or protected
carboxy, but R^Fourdepending on the case
Substituted pyridinioalkyl or
is a thiazolioalkyl substituted with
R^Fiveis COO^-and dotted lines indicate single or double bonds.
cefam and cefam compounds have been developed.
shown. European Patent Application No. published on August 6, 1980
No. 13762 is consistent therewith and has a similar disclosure. U.S. Patent No. 4,381,299 (issued April 26, 1983)
), No. 4331665 (May 25, 1982) and No.
No. 4332798 (issued June 1, 1982) is
Appears in the parent application of U.S. Patent No. 4,390,534 and similar
has the disclosure. B European Patent Application No. published on October 13, 1982
No. 62321 has the formula, (In the formula, R¹is an amino or protected amino
R²is an optionally substituted lower fat
aliphatic hydrocarbon group or cycloalkenyl
ri, expression, The group may contain more than one nitrogen atom.
is a substituted heterocyclic cationic group) cefem compounds and their pharmaceutically acceptable
Salt is disclosed. Also, the expression (In the formula, R¹and R²is as described above,
R^Fouris a protected carboxyl group, and X^-teeth
acid residue) Intermediates of are disclosed. C European patent application published on March 23, 1983
No. 74653 has the formula, (In the formula, R¹is an amino or protected amino; R²is optionally substituted lower aliphatic carbonization
Hydrogen, cyclo(lower)alkyl or cyclo
(lower) alkenyl, R³is (lower) alkylamino, N-protected
(lower)alkylamino, di(lower)alkyl
Amino, sulfo (lower) alkylamino, hydro
Roxy (lower) alkylamino, N-protected hydride
Roxy (lower) alkylamino, acyloxy
(lower) alkyl, (lower) alkoxy (lower)
Alkoxy(lower)alkyl, di(lower)alkyl
Kylamino (lower) alkyl, (lower) alkyl
ruthio (lower) alkyl, (lower) alkylthi
E, (lower) alkoxy, (lower) alkoxy
(lower) alkoxy, hydroxy (lower) alkoxy
koxy, acyl (lower) alkyl, hydroxy
(lower)alkylthio, di(lower)alkylua
Mino (lower) alkylthio, N-containing unsaturated 5-membered
Heterocyclic group, N-containing unsaturated heterocyclic group
or N-containing that can be substituted with an appropriate substituent
unsaturated 5- or 6-membered heterocycle
(lower) alkyl, R^Fouris hydrogen or (lower) alkyl) A cefem compound or a salt thereof is disclosed.
Ru. D Tsutomu, Teraji published on June 1, 1982
U.S. Pat. No. 4,332,800 to et al.
ceremony, (In the formula, R¹is an amino or protected amino
R²is (lower) alkyl, and
is hydrogen or carbamoyl) are disclosed. E European Patent Application No. published on March 24, 1982
No. 47977 has the formula, [In the formula, m is 0 or 1, and Am is
and T is thiadiazine.
Zolyl component (with its two carbon atoms
) and R₂is hydrogen, optionally
Substituted alkyl, cycloalkyl, or
carbamoyl substituted by R₁
is optionally substituted thiazolio, optionally
Pyrazolio, tri(lower)alkyl substituted
Luammonio or ceremony, (R in the formula^ais substituted (lower) alkyl [substituent
is cycloalkyl, phenyl, hydroxy, a
Lucoxy, halogen, cyano, carbamoyl,
carboxyl or sulfo], (lower) a
alkenyl or carboxy-substituted (lower) alke
Nyl, (lower) alkylthio or carboxy
Substituted (lower) alkylthio, amino or -substituted
Replaced amino [substituents are (lower) alkyl, (lower)
Alkanoyl or aminobenzenesulfonyl
], di(lower) alkylamino, substituted carbon
Rubamoyl [substituents are (lower) alkyl, hydro]
Roxy (lower) alkyl, (lower) alkoxy,
hydroxy or cyano], di(lower)
Alkyl carbamoyl, thiocarbamoyl,
Chloalkyl, phenyl, hydroxy, (lower)
Alkoxy, halogen, (lower) alkoxyca
Rubonyl, (lower) alkanoyloxy, (lower)
class) alkanoyl, carboxyl, sulfo,
Ano, nitro or hydroxysulfo (lower)
is alkyl and R^bis hydrogen or carbamoy
or R^ahas the same meaning as R^c
is hydrogen or R^ahas the same meaning as
) pyridinio group] Cefem compounds and salts thereof are disclosed.
Ru. Although formally unrelated, March 11, 1981
European Patent Application No. 25017 published on the same day
has the disclosure. F European Patent Application No. published on June 24, 1981
No. 30630 has a formula, [In the formula, R¹may contain halogens.
optionally protected amino-substituted complex
ring group or formula, (In the formula, R³is (lower) alkyl) is the group of R²is carboxy or protected
carboxy, A is amino, protected
Amino, hydroxy, oxo and formula=N~
OR^Four(In the formula, R^Fouris hydrogen, cyclo(lower) alke
Nyl, (lower) alkynyl, (lower) alkenyl
[Optionally carboxy or protected carboxy]
], (lower) alkyl substituted by boxyl
[optionally carboxy, protected carboxy
Cy, amino, protected amino, cyano, phos
hono, protected phosphono, and per se
substituted with a heterocyclic group that can be substituted with
It has a substituent selected from the group
It is a lower alkylene that can be The 3-vinyl cephem compound and its salt are
be disclosed. This application includes the formula (In the formula, OR^Fouris methoxy, carboxymethoxy
cy, t-butoxycarbonylmethoxy or 1
-t-butoxycarbonylethoxy) Specifically disclosed are compounds of G British patent specification published on June 25, 1975
No. 1399086 includes the formula, (In the formula, R is hydrogen or an organic group, and R^a
is an etherification bonded to oxygen through a carbon atom
is a monovalent organic group, B is or S→O
(P is an organic group) Comprehensive development encompassing numerous cephalosporins
Includes instructions. In one embodiment, P is inter alia
formula, (In the formula, R³and R^Fourare independently hydrogen and nitric
(lower) alkoxycarbonyl, or
Substituted or unsubstituted aliphatic, cycloaliphatic, aromatic fats
(can be aromatic or aromatic) can be a vinyl group. However, 5-
Amino-1,2,4-thiadiazol-3-y
group is not identified as a possible R substituent, and
P is a quaternary ammonio-substituted propenyl group
It is not disclosed or implied that it may be possible.
U.S. Pat. No. 3,971,778 and its divisions, no.
No. 4024133, No. 4024137, No. 4064346, No.
No. 4033950, No. 4079178, No. 4091209, No.
Nos. 4092477 and 4093803 have similar disclosures.
do. H European Patent Application No. published on September 14, 1983
No. 88385 has the formula, (In the formula, R¹is (unsubstituted) thiadiazolyl
Yes, R²is carboxy (lower) alkyl or
is a protected carboxy(lower)alkyl
R, R³is hydrogen, halogen or (lower) alkali
Kenyl and R^Fouris carboxy or protected
carboxylic acid) are disclosed. 1-propenyl is R³
It is mentioned as one of the possible meanings of
Hey, that application is just R³is hydrogen, chloro or
is merely illustrative of compounds that are vinyl. I Daniel Earge published December 22, 1981
U.S. Pat. No. 4,307,233 to et al.
ceremony, [In the formula, R^Fiveare especially alkyl, vinyl,
Cyanomethyl or 2-methoxyprop-2-
can be a protecting group such as R³oh
and R^Fouris an alkyl group (possibly hydroxy,
Alkoxy, amino, alkylamino or di
substituted by alkylamino), or
is an enyl group or R³and R^FourThat's it
together with the nitrogen to which they are bound, in some cases
Other heterogens selected from N, O and S
and optionally substituted by an alkyl group.
to form a 5- or 6-membered saturated heterocycle
) 3-vinylcephalosporin derivatives of
It will be done. These compounds are 3-thiovinylcephala
Useful as an intermediate in the production of rosporin derivatives
be. 2-aminothiazol-4-yl substituent
5-amino-1,2,4-thiadiazole instead of
3-3-yl moiety or 3-substituent
Disclosure of quaternary ammonio-substituted propenyl components and
There is no suggestion. Published UK Patent No. 2051062
The issue matches it and has a similar disclosure. J European Patent Application No. published on June 9, 1982
No. 53537 inter alia, formula [In the formula, R^a _Fiveand R^b _Fiveare the same or different
hydrogen or alkyl, or
together contain 2 or 3 carbon atoms
Forms an alkylene group, R^c _Fiveis an acid protecting group,
R₂is an acid protecting group such as an ester, and R₃oh
and R_Fourare the same or different, hydrogen,
Alkyl (possibly hydroxy, alkoxy)
amino, alkylamino or dialkyl
substituted by amino), or phenyl group
or R₃and R_Fourmeans they are combined
In some cases, the nitrogen atom is
Other heteroatoms selected from N, O and S
containing and optionally substituted by an alkyl group
to form a 5- or 6-membered saturated heterocycle.
can be done] 3-vinylcephalosporin derivatives of
It will be done. These compounds are 3-thiovinylcephala
As an intermediate in the production of rosporin derivatives
Useful. 2-aminothiazol-4-yl
5-amino-1,2,4-thiazidi in place of substituent
azol-3-yl moiety or 3-substituent
Opening of the quaternary ammonio-substituted propenyl group
No indication or suggestion. U.S. Patent No. 4,423,214 matches and similarly
has the disclosure. K European Patent Application No. published on June 2, 1982
No. 53074 has a formula, [In the formula, R^o _1a(one example among several aspects) {In the formula, R_Fiveis inter alia hydrogen, alkyl,
such as vinyl, cyanomethyl, trityl, etc.
oxime protecting group, or formula, (In the formula, R^a _Fiveand R^b _Fiveare the same or different
hydrogen, alkyl, or together
an alkylene group of 2 or 3 carbon atoms
There can be R^c _Fiveis a hydrogen or acid protecting group
be) can be the basis of} can be R^o _2ais hydrogen or methoxy
An acid protecting group such as methyl, R^ois (number aspect
) a 5- or 6-membered member containing a single heteroatom
aromatic heterocycles, such as 2- or 3-pyridi
2- or 3-thienyl;
is a methyl group substituted by 3-furyl.
R, R³is the expression, R_FourS.O.₂O- (R_Fouris alkyl, trihalomethyl, or
phenyl substituted by
) ] A large number of 3-vinylcephalosporin derivatives are included.
Disclosed comprehensively. These compounds are said to have antibacterial activity
3 - The substituent has the formula, It is an intermediate in the production of compounds that are the basis of
It has been stated. This patent applies to both intermediates and final products.
R^ois a methyl group substituted with an N-containing heterocycle
(thus giving a heterocyclic-substituted propenyl moiety)
), but it is possible that the heterocycle
Teach only that it is bonded through one of the carbon atoms
do. Therefore, quaternary ammonio-substituted propenyl
Does not suggest a base. The literature covers intermediates and final products.
R in the composition^ois shown simply as methyl. moreover,
Both the intermediate and the final product have a propenyl group.
The second substituent (each -O₃S.R.^Fouror −SR)
must be included. Also, 2-aminothiazole-
5-amino-1,2,4- in place of 4-yl substituent
Disclosed or suggested for thiadiazol-3-yl component
There is no. L European Patent Application No. published on June 9, 1982
No. 53538 contains, inter alia, the formula; (where n is 0 or 1, R^Fiveis hydrogen,
alkyl, vinyl, cyanomethyl or oxy
is a protective group and R³is a halogen) A 3-vinylcephalosporin intermediate of
It will be done. 2-aminothiazol-4-yl substituent
5-amino-1,2,4-thiadiazole instead of
disclosure or suggestion of a l-3-yl moiety, and 3
3-halo-1-propene-1- in the -position
No disclosure or suggestion of file. full disclosure This application is a novel cephalosporin, a powerful antibacterial agent.
This invention relates to intermediates in the production of phosphorus derivatives. Than
For details, this application uses the formula, [In the formula, R¹is hydrogen or the usual amino protecting group
and R²contains hydrogen, 1 to 4 carbon atoms
Straight or branched chain alkyl group, 3 to 6 carbons
Cycloalkyl or cycloalke containing elementary atoms
Nyl ring or formula, [formula] [expression] [expression] or 【formula】 (In the formula, R³is hydrogen, (lower) alkyl or carbon.
ruboxyl, and X is halogen, hydroxy or
or (lower) alkoxy, R^Fourand R^Fiveteeth
each independently hydrogen, methyl or ethyl
or R^Fourand R^Fiveis that they are combined
containing 3 to 5 carbon atoms together with carbon atoms
(can be a cycloalkylidene ring) is the basis of −N≡Q is a quaternary ammonio group) compounds and their non-toxic, pharmaceutically acceptable
Preparation of salts and chemically hydrolyzable esters
Concerning intermediates in construction. As shown in the structural formula, the compound of formula
“Syn” or “Z” coordination with respect to the ximino group
has. Compounds are geometric isomers, so
Some of the ``inch'' isomers can also exist.
Ru. The compound of formula is at least 90% “syn” isomer
May include the body. Preferably the compound of formula
"Syn" substantially free of "anti" isomer
It is an isomer. Possible geometric isomers of alkoxyimino groups
In addition to the compound of the formula (and the formula and the formula
intermediate) is also related to the double bond of the propenyl group.
(cis (“Z”) and trans (“T”))
form a sexual body. A non-toxic, pharmaceutically acceptable salt of a compound of formula
Mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and
Salts with sulfuric acid or organic carboxylic acids or sulfuric acids
Phonic acids such as acetic acid, trifluoroacetic acid, citric acid
acids, formic acid, maleic acid, oxalic acid, succinic acid,
Zozoic acid, tartaric acid, fumaric acid, mandelic acid, asco
Rubic acid, malic acid, methanesulfonic acid, benzene
sulfonic acid, p-toluenesulfonic acid and
Known to the technology of Nisilin and Cephalosporin
and salts with other acids used. these
The acid addition salts of are prepared by conventional methods. Examples of physiologically hydrolyzable esters of formula
Indanyl, phthalidyl, methoxymethyl,
Acetoxymethyl, pivaloyloxymethyl, glycol
Lysyloxymethyl, phenylglycyloxime
Chil, 5-methyl-2-oxo-1,3-dioxy
solen-4-ylmethyl and penicillin and
Other known and used cephalosporin techniques
Contains physiologically hydrolyzable esters of
Ru. Such esters are conventionally known in the art.
Manufactured by law. R¹Compounds with the formula where is hydrogen have various grams
High antibacterial activity against positive and gram-negative bacteria
for the treatment of bacterial infections in animals including humans.
Useful. Compounds of formula are known pharmaceutical carriers.
It can be formulated for parenteral use by conventional methods using
can be prepared in single-dose form or in multi-dose containers.
can be present in the vessel. Their composition is
solutions, suspensions or
Can be in the form of an emulsion and can also be used as a regular liquid
Dispersing, suspending or stabilizing agents may be included. composition
Also, e.g. sterile, pyrogen-free water
Can be in dry powder form to be reconstituted before use
can. The compound of formula also contains cocoa butter or
Using a regular suppository base like other glycerides
It can be formulated as a suppository. compound of formula
Penicillin or other cephalosporins if desired
When given in combination with other antibiotics such as Sporin
can be done. The composition is preferably provided in a single dosage form.
Contains about 50 to about 1500 mg of the active ingredient of formula
Ru. The dose of the compound of formula depends on the patient's weight, age,
as well as factors such as the individual nature and extent of the disease.
Accordingly, it is within the discretion of the physician. But for adults
The dosage is usually about 100% per day depending on the frequency and route of administration.
It will be in the range of 500 to about 5000 mg. intramuscularly in adults
Or when administered intravenously, approximately 1 day in divided doses.
Although a total dose of 750 to about 3000 mg will usually be sufficient,
However, higher daily doses of some compounds are
Recommended in case of Pseudomonas infection
Maybe. formula, −N≡Q The quaternary ammonio group of is acyclic, cyclic or two
can be a combination of nitrogen, sulfur and acid
one or more additional hetero
Can contain atoms. An example of an acyclic quaternary ammonio group is the formula, [In the formula, R⁶,R⁷and R⁸are the same or different
For example, (lower) alkyl or substituted
Substituted (lower) alkyl {the substituent is e.g. halogen
amino, amino (however, the amino group is on the α-carbon)
Hydroxy (however, hydro
xy group cannot be on the α-carbon), (low
class) alkoxy (however, the alkoxy group is α-carbon
}, (lower) a
Lukylthio, (lower) alkylamino, di(lower)
Alkylamino, carbamoyl, (lower) alke
Nyl, phenyl (lower) alkyl, phenyl or
is a substituted phenyl (the substituents are e.g. halogen,
hydroxy, amino, (lower) alkylamino,
Di(lower) alkylamino, acylamino, (lower)
(lower) alkyl, (lower) alkylthio, (lower) a
can be lucoxy etc.)
can〕 It is the basis of An example of a cyclic quaternary ammonio group is a fully unsaturated monocyclic ring.
a heterocyclic ring system of the formula, and at least one N-containing ring is
It is a bicyclic heterocyclic ring system that is completely unsaturated. suitable
Cyclic quaternary ammonio ring systems include, for example, the formula,
[Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] 【formula】 [Formula] [Formula] [In the formula, R⁹and R^Tenare the same or different
For example, hydrogen, halogen, amino, (lower)
Alkyl, (lower) alkenyl, (lower) alkyl
Thio, carboxy, hydroxy, (lower) alco
xy, (lower) alkoxy (lower) alkyl, ha
(lower) alkyl, hydroxy (lower) alkyl
amino(lower) alkyl, (lower) alkyl
Amino (lower) alkyl, di (lower) alkyl
Mino (lower) alkyl, (lower) alkylamino,
Di(lower) alkylamino, carboxy(lower)
Alkyl, carboxy (lower) alkylamino,
Carboxy (lower) alkylthio, carbamoy
N-(lower)alkylcarbamoyl, formyl
ruamino, acylamino, acyloxy, feni
Ru, pyridyl, amidino, guanidino, etc.
be able to〕 It includes things like. Heterocyclic structure allows
If R⁹and R^Tentogether with 3 to 5 carbons
alkylene groups containing atoms, e.g. propylene
can be done. Examples of combined acyclic/cyclic quaternary ammonio groups
For example, the expression, [expression] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] 【formula】 [In the formula, R¹¹For example, (lower) alkyl, (lower)
(class) alkoxy (lower) alkyl, hydroxy
(lower) alkyl (however, the hydroxy group is α-
cannot be on carbon), carboxy (low
(class) alkyl, amino (lower) alkyl (only)
However, the amino group cannot be on the α-carbon.
), (lower) alkenyl, halo (lower) alkyl
R can be allyl, allyl, etc.¹²For example,
Hydrogen, hydroxy, halogen, (lower) alkyl,
Hydroxy (lower) alkyl, (lower) alkoxy
Shi (lower) alkyl, halo (lower) alkyl, a
Mino (lower) alkyl, (lower) alkoxy, (lower)
(class) alkylthio, (lower) alkenyl, amino,
(lower) alkylamino, di(lower) alkylua
Mino, acylamino, acyloxy, carbamoy
, amidino (lower) alkyl, phenyl, pyryl
Can be Jill, Amidino, Guanidino, etc.
Wear〕 It includes things like. Preferred quaternary ammonio groups have the formula:
[Formula] [Formula] [Formula] [Formula] 【formula】 During the ceremony, R¹³,R¹⁴and R¹⁵are the same or different
(lower) alkyl, (lower) alkenyl, amino
(lower) alkyl (however, the amino group is α-carbon
or hydroxy
(lower) alkyl (however, the hydroxy group is α-
cannot be on carbon), and R¹⁶Hydrogen, (lower)alkyl, (lower)alkoxy
(lower) alkylthio, amino, (lower) alkylthio, (lower) alkylthio,
Kylamino, di(lower) alkylamino, formi
Ruamino, (lower) alkanoylamino, carbo
xy, hydroxy, carboxy (lower) alkyl
carboxy (lower) alkyl, hydroxy
Shi (lower) alkyl, halo (lower) alkyl, a
Mino (lower) alkyl, (lower) alkoxy (lower)
alkyl, carbamoyl or N- (lower)
Alkyl cabamoyl or R¹⁶is 3~
represents a divalent alkylene group having 5 carbon atoms
can be done, R¹⁷is (lower) alkyl, (lower) alkoxy
(lower) alkyl, halo (lower) alkyl, ant
hydroxy (lower) alkyl (however, hydroxy
(roxy group is not on the α-carbon), amino (lower)
Alkyl (however, the amino group is not on the α-carbon
), or phenyl (lower) alkyl, R¹⁸is hydrogen, (lower)alkyl, (lower)alco
xy, (lower) alkoxy (lower) alkyl, (lower)
(class) alkylthio, amino, (lower) alkylua
Mino, di(lower) alkylamino, carboxy,
Hydroxy, carboxy (lower) alkyl, hydro
Roxy (lower) alkyl, amino (lower) alkyl
, formylamino, (lower) alkanoylamine
carbamoyl or N-(lower) alkyl carboxycarbohydrate
Rubamoil, n is an integer from 1 to 3 (inclusive), Z is CH₂or when n is 2
Z can also be S, O or N-R¹⁹(In the formula, R¹⁹is water
or (lower) alkyl)
I can, R²⁰and R^{twenty one}are the same or different,
Hydrogen, (lower) alkyl, (lower) alkoxy,
(lower) alkylthio, amino, (lower) alkyl
Amino, di(lower) alkylamino, carboxy
cy, hydroxy, hydroxy (lower) alkyl,
Amino (lower) alkyl, (lower) alkoxy
(lower) alkyl, carboxy (lower) alkyl,
Carboxy (lower) alkylamino, (lower) a
Lucanoylamino, carboxy (lower) alkano
ylamino, carbamoyl or N-(lower) a
It is Lukil carbamoyl. belongs to. A particularly preferred quaternary ammonio group is N-(lower)
Alkylpyrrolidinio (especially N-methylpyrrolidinio)
io), tri(lower)alkylammonio(especially
trimethylammonio), pyridinio, aminopi
Rizinio, Formylaminopyridinio, Carbamo
Ilpyridinio, amino (lower) alkylpyridi
Nio, carboxypyridinio, hydroxy (low
class) alkylpyridinio, N-(lower) alkyl
Carbamoylpyridinio, (lower) alkylenepy
Rizinio, 2-methylthiazolio and 2-amino
Not-5-thiazolo[4,5-c]pyridinio
Ru. In the compound of formula R²particularly favorable meaning of
Taste: (lower) alkyl (especially methyl), 3-5
cycloalkyl containing 3 to 5 carbon atoms
1-carboxycycloalk-1- containing elementary atoms
yl, allyl, propargyl and carboxy
(lower) alkyl (especially 2-carboxypropyl)
2-yl). The most preferred compound of formula
The new compound is (1) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-(trimethylammoni
e)-1-propen-1-yl]-3-cephem
-4-carboxylate, (2) 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-1-methylpyrrolidini
e)-1-propen-1-yl]-3-cephem
-4-carboxylate, (3) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-pyridinio-1-pro
pen-1-yl]-3-cephem-4-carbo
xylate, (4) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(3-aminopyridiny)
e)-1-propen-1-yl]-3-cephem
-4-carboxylate, (5) 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(3-formylamino
pyridinio)-1-propen-1-yl]-3-
cefem-4-carboxylate, (6) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-aminomethylpi
lysinio)-1-propen-1-yl]-3-ce
fem-4-carboxylate, (7) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-carbamoylpi
lysinio)-1-propen-1-yl]-3-ce
fem-4-carboxylate, (8) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(4-carbamoylpi
lysinio)-1-propen-1-yl]-3-ce
fem-4-carboxylate, (9) 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(2-methylthiazoli
e)-1-propen-1-yl]-3-cephem
-4-carboxylate, (10) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(2-amino-5-thi
Azolo[4,5-c)pyridinio)-1-pro
pen-1-yl]-3-cephem-4-carbo
xylate, (11) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(4-hydroxymeth)
tylpyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate, (12) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(3-hydroxythi
melpyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate, (13) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
acetamide]-3-[3-(4-{N-methylcarbonate)
Rubamoyl}pyridinio)-1-propene-1
-yl]-3-cephem-4-carboxylene
to, (14) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(2,3-propylene
pyridinio)-1-propen-1-yl]-3
- cefem-4-carboxylate, (15) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-ethoxyimino
Acetamide]-3-[3-(4-carbamoyl
pyridinio)-1-propen-1-yl]-3-
cefem-4-carboxylate, (16) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-cyclopentyl
Oxyiminoacetamide]-3-[3-(4-
carbamoylpyridinio)-1-propene-1
-yl]-3-cephem-4-carboxylene
to, (17) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-allyloxy
Minoacetamide]-3-[3-(4-carbamo
ylpyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate, (18) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-propargylo
xyiminoacetamide]-3-[3-(4-ka)
Rubamoylpyridinio)-1-propene-1-
]-3-cephem-4-carboxylate, (19) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(4-carboxypyl)
lysinio)-1-propen-1-yl]-3-ce
fem-4-carboxylate, (20) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-ethoxyimino
Acetamide]-3-[3-(4-carboxypyl)
lysinio)-2-propen-1-yl]-3-ce
fem-4-carboxylate, (21) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-tomeximino
Acetamide]-3-[3-(3-carboxyme
tylpyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate, (22) 7-[2-(5-amino-1,2,4-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(4-carboxyme
tylpyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate, It is. Used for various reactants, intermediates and final products
The code system is as follows: ｜Roman numerals｜-｜Arabic numerals (where applicable)
)｜｜Character (if applicable)｜ Roman numerals indicate that the compound is the final product [1]
or intermediates or other reactants (all other
Roman numerals). arabic numerals
and the letters mean the entire class (genus) of the compound
Not used when Arabic numerals are substituents R²indicates a specific meaning of
specific R²group is protected by a conventional carboxylic acid protecting group.
If it contains a protected carboxyl group, this fact
A prime mark after an Arabic numeral to indicate
'(') is used. carboxyl group is protected
If not, "prime code" will not be used.
stomach. "Prime code" is also a protected carboxy
R containing syl group²Inclusive when referring to groups inclusively
R²used for substituents (e.g. R²'). The letter at the end of the compound number is a quaternary ammonio group. −N≡Q indicates a specific meaning of For convenience, preferred R²radicals and quaternary ammonium
The Arabic numerals and letters shown below the
is shown.arabic numerals ^R2 1 = methyl 2 = ethyl 3 = allyl 4 = Propargyl 5 = cyclopentylA −N≡Q A = 1-methylpyrrolidinio B = pyridinio C = 2-amino-5-thiazolo[4,5-c]
Pyridinio D = trimethylammonio E = 3-aminopyridinio F = 3-formylaminopyridinio G = 3-carbamoylpyridinio H = 4-carbamoylpyridinio I = 3-aminomethylpyridinio J = 2-methylthiazolio K = 3-hydroxymethylpyridinio L = 4-hydroxymethylpyridinio M = 4-(N-methylcarbamoyl)pyridiny
O N = 4-carboxypyridinio O = 2,3-propylenepyridinio P = 3-carboxymethylpyridinio Q = 4-carboxymethylthiopyridinio In the primary evaluation of the compound of formula
Small inhibitory concentration (MIC) of 32 test microorganisms in 6 groups
Muller Hinton (Muller−
Hinton) Measured by the multiple agar dilution method in agar.
Ta. Geometric mean of MICs measured in these studies
is shown in Table 1. 【table】 【table】 Table 2 shows selected microorganisms for various compounds of formula
50% protection against organisms in mice
(PD₅₀) is shown. Table 3 shows the dosage of 20mg/Kg.
The test compound was administered intramuscularly to mice.
Shows blood concentrations of various compounds. 【table】 【table】 The method for producing the compound of the formula will be explained. preferable
The procedure is shown in Reaction Schemes 1a, 1b and 1c, and the
One procedure is shown in Reaction Scheme 2. Abbreviation "Ph"
represents a phenyl group. Therefore −CH(Ph)₂component
is a benzhydryl group, which is a preferred carboxyl group.
It is a bonic acid protecting group. R²contains a carboxyl group
When removing the carboxyl group, like the t-butyl component,
It is preferable to protect with a common carboxylic acid protecting group.
Delicious. Y represents chloro, bromo or iodine
vinegar. Reaction scheme 1a shows the progression from compound to compound.
Two selection methods are shown. Tertiary amine (
) is the direct route using
Applicable to manufacturing. Indirect route via compounds
uses a secondary amine as a reactant and in the next step
Quaternize. Secondary amine RR′NH is acyclic
(e.g. dimethylamine) or cyclic (e.g. pipi)
loridine) and therefore this indirect hand
The order is that the quaternary ammonio group is acyclic or acyclic/
Suitable for the preparation of compounds of the formula which are cyclic hybrids.
This indirect route allows the quaternary nitrogen to be completely unsaturated.
Bare rings (e.g. pyridinio, thiazolyl, 2-amino)
No-5-thiazolo[4,5-c]pyridinio
etc.) is not suitable for the production of compounds of the formula. Reaction scheme 1b shows the starting material () 7-amino
The group is protected as a Schiff base during many reaction steps.
and the desired 7-side chain acid is added late during production.
This is a modification of reaction scheme 1a in that one other
The general procedure is the same. Reaction scheme 1c is a further variation of reaction scheme 1b.
In schemes 1a and 1b, the fourth of the 3-side chain
Grading is the last step, but in reaction scheme 1c
The last step is acylation of the 7-amino group.
The relationship between reaction schemes 1a, 1b and 1c is shown in the following flow.
- shown on the chart. In reaction schemes 1a, 1b and 1c, benzene
Dryl group is indicated as the preferred carboxylic acid protecting group.
It was. Other carboxylic acid carriers well known in the art
It will be understood by those skilled in the art that protecting groups can be used.
cormorant. Acylated acids are in the form of derivatives, e.g.
chlorides, activated esters, mixed acid anhydrides, etc.
All of them can be used as
The technique is well known. it in its acid chloride form
It is preferable to use it in this state. Acylated acid
In addition, its common amino protecting groups, such as N-trithi
Amino acids protected by
can have a group. Phosphonium iodide
(or) to convert phosphorylide (or) into phosphorylide (or).
The base used to produce
NaOH, Na₂C.O.₃, IRA−410(OH^-) Resin, IRA
(C.O.₃ ⁼) or a mixture thereof.
be able to. Phosphorylide to 3-chloropropylene
penyl-3-cephem compound (or compound
(to a compound)
Roacetaldehyde is commercially available at 40-50
% aqueous solution, distilled solution (e.g. 70%) or nothing
It can be an aldehyde of water. The compound (Scheme 1a) prepared from the compound
Typically about 2:1 at the propenyl double bond
It was found to have a Z:E ratio. On the other hand, compound
Compounds prepared from compounds (Scheme 1b) are typical
It was almost exclusively the Z isomer. The difference
The difference is not the route used, but the Wittig reaction.
The terms used to respond to (to, or to)
It may be in the matter. Bitzteich again
(Wittig) reaction (from to in scheme 1a, and
(from to) in Scheme 1b)
Ryl reagents, e.g. N,O-bis(trimethylsilyl)
) The use of acetamide reduces the yield and
It was observed that an improvement in purity and purity occurred. the
The reaction is preferably carried out with 2 to 5 equivalents of silyl reagent.
Yes. Chloropropenyl cefem () aceto
iodopropenylcef when reacted with NaI in a
Em () is formed, and the double bond in the propenyl group is
Z was regenerated to E during iodination. short anti
The reaction time largely preserves the configuration of the parent compound.
However, long reaction times produce mainly the E isomer of the compound.
It was. However, excessive reaction time at high temperatures is
This results in compounds of lower purity. Approximately 10 minutes at 25℃
and 2 hours at 5°C to produce pure in good yield.
was discovered. When using reaction scheme 1c, the compound
When iodinated with NaI, the iodination is substantially
When finished, convert the acetone solution to CCl_FourDilute with
The isomerization part of the reaction is acetone-CCl_FourIf you do it with
It has been found that purer compounds are obtained.
Chloropropenil cefem () iodopro
Iodination to penilcefuem () in DMF,
When done with KI, the difference in double bond from Z to E
Sexualization progressed as quickly as iodization. The total reaction is
Complete within 45 minutes at room temperature, during the course of the reaction
CCl_FourThis resulted in a pure product without dilution. The compound is usually debrodzkin without purification.
The final product () is a Waters Assoc.
Waters' Associates PrepPAK−
500/C₁₈Insert the fill material transferred from the cartridge.
Reversed phase column chromatography using a glass column
Purified by phytochemistry. Reaction scheme 2 shown in simple schematic form above is:
Compound (equivalent to the compound in Scheme 1a)
is converted to its S-oxide before quaternization.
It is the same as reaction scheme 1a except for. Compound
is then reduced, and the rest of reaction scheme 2 is the reaction scheme
As shown in equation 1a. In reaction scheme 2, 7
- The side chain amino group is a known amino group such as trityl group.
It is preferable to protect with a protecting group. The acylated acid of the formula is a known compound or
is easily manufactured by published procedures. 1983
European Patent Specification No. 7470 published on October 12th
(The application was published (February 6, 1980) with R²is methyl,
Formulas that are ethyl, propyl and isopropyl
An example is the production of a compound. Description of conventional technology
No. 4,390,534 referred to in R.²
For example, cyclopentyl, 2-cyclopentene
-1-yl, allyl, 2-propynyl, 1-t-
Butyloxycarbonyl-1-methylethyl, 1
-t-butyloxycarbonyl-1-cyclopene
Chil, 1-ethoxycarbonyl-1-methylethyl
L, t-butyloxycarbonylmethyl, 1-t
-butyloxycarbonyl-2-methylpropyl
Preparation of compounds with a wide range of formulas such as trityl, trityl, etc.
structure is shown. used as starting material in Reaction Schemes 1a, 1b and 1c.
The compound used, (7-amino-3-chloromethane)
Chil-3-cephem-4-carboxylate) is
It is a known compound. Used in the production of quaternary ammonio compounds of the formula
Tertiary amines (and secondary amines of the formula
RR′NH) is a known compound or
Easily manufactured by commercial vendors. Many of the aminos are in the city
It's on sale. A compound of the formula [In the formula, R²′ is R²is the same as or the expression
[expression] or [expression] (In the formula, X, R^Fourand R^Fiveis as described above.
) is the basis of B¹is a normal carboxyl protecting group.
Yes, B²is hydrogen or the usual amino protecting group.
, Z is chloro, bromo or iodo, m
is 0 or 1] compound with tertiary amine Q≡R (or in sequence
) Reaction with compounds of secondary amines PR′NH and R″Z
and if m is 1, sulfoxide is removed by a conventional method.
reduction and then remove all protecting groups by conventional methods.
Manufactured by a method including: A compound of the formula is also a compound of the formula The compound with the formula, [In the formula, R²′ is R²is the same as or
expression, [expression] or [expression] (In the formula, X, R^Fourand R^Fiveis as described above.
R, B¹is the usual carboxyl protecting group) is the basis of B²is hydrogen or normal amino protected
is the basis] or acylated derivatives of said acids.
It can also be produced by a method including: The reaction takes place with dimethyl sulfoxide and hexamethyl phosphatide.
sphoramide, methylene chloride, chloroform,
Thyl ether, hexane, ethyl acetate, tetrahedron
Non-aqueous like Dorofuran, Acetonitrile etc.
carried out in organic solvents or mixtures of such solvents.
be exposed. The reaction is conveniently carried out at a temperature of about -10°C to about +50°C.
It is usually preferable to carry out the reaction at room temperature.
stomach. During the quaternization step, at least 1 mole of tertiary atom
Min is a compound, or one of
Should be used about per mole, usually about 25
It is preferred to use ~100% excess tertiary amine.
Yes. In the above reaction, B¹suitable for use as
Carboxyl protecting groups are well known to those skilled in the art and
Ralkyl groups such as benzyl, p-methoxybenzi
p-nitrobenzyl and phenylmethyl
(benzhydryl); alkyl group e.g. t-buty
haloalkyl group e.g. 2,2,2-trichloro
Loethyl, and the literature, e.g. British Patent No.
1399086, other carboxyl protections described in
Contains groups. Easily removed by treatment with acid.
It is preferable to use a carboxylic acid protecting group that is removed.
stomach. A particularly preferred carboxylic acid protecting group is benzhydride.
Lyle and t-butyl components. B²Amino protecting groups suitable for use as
Also well known in the art, trityl groups and
Syl groups such as chloroacetyl, formyl and to
Contains dichloroethoxycarbonyl. treated with acid
Amino protection that is easily removed by
Groups such as trityl groups are preferred. Cephalosporin nucleus is 1-oxide (m=1)
When used in the form of m-oxide, 1-oxide
Loroperbenzoic acid, peracetic acid, sodium tungstate
Manufactured by known procedures such as oxidation with
be done. The 1-oxide is then treated using known procedures, e.g.
The corresponding alco due to iodide ion in the sexual medium
reduction by reduction of xysulfonium salts;
I can do it. The alkoxysulfonium salt itself is 1
- treatment of the oxide with e.g. acetyl chloride
easily generated by The present invention is based on the formula: (In the formula, R^{twenty two}is hydrogen or normal carboxyl
Protecting group, R^{twenty three},R^{twenty four}and R^{twenty five}are the same or
are different: hydrogen, hydroxy, (lower) a
alkyl or (lower) alkoxy) new intermediates, or their salts, solvates, and hydrates
relating to things or esters. The terms acylamino and acyloxy used
The acyl moiety is a (lower) alkanoyl (e.g.
lumyl, acetyl, propionyl, butyryl, i
sobutyryl, isovaleryl, etc.), aroyl (e.g.
(e.g. bayzoyl), (lower) alkanesulfony
(e.g. mesyl, ethanesulfonyl, etc.),
or arylsulfonyl (e.g. benzenesulfonyl)
Acylated amino acids such as nyl, tosyl, etc.
or represents an acylated hydroxy group. The terms “(lower) alkyl” and “(lower) alkyl” used
``rukoxy'', ``(lower) alkylthio'' (etc.) are 1
Straight or branched chain atom containing ~6 carbon atoms
means alkyl, alkoxy, alkylthio (etc.)
Taste. Similarly the terms (lower) alkenyl and
(lower)alkynyl contains 2 to 6 carbon atoms
means an alkenyl or alkynyl group. Reference example 1 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(1-methylpyrrolidini
e)-1-propen-1-yl]-3-cephem
-4-carboxylate (-1A) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl (-1) (Z/E=2/1, 150 mg,
0.21 mmol) in ethyl acetate (2 ml)
1-Methylpyrrolidine (36 mg, 0.42 mmol)
Stir the solution in ethyl acetate (1 ml) at once.
I added a lot. Stir the mixture for 15 minutes, add isopro
When diluted with pyl ether (10 ml), a precipitate formed,
It was collected by filtration. The solid (130mg),
A mixture of formic acid (1 ml) and concentrated HCl (0.1 ml) was added to the room.
Stir warm. After 1 hour, the reaction mixture was removed under reduced pressure.
It was concentrated, diluted with water (20ml) and filtered. water soluble
Transfer the liquid to a reverse phase column (Prep PAK-500/C₁₈Cartori
Azalea filling, 100ml), water and 10%
CH₃Eluted with OH. Collect the desired fraction
When concentrated in vacuo to a small volume and lyophilized, the title
Compound (I-1A) (Z/E=1/1/), 13 mg
(12%) was obtained, melting point >280°C (decomposition). IR:ν^KBr _naxcm^-13400, 1760, 1660, 1610. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 236
(372), 288(322). NMR: δ^D2O _ppn 2.31 (4H, m, [formula]), 3.12 (3H, s, N-CH₃), 3.6 (5H, m, 2-H)
and [formula]), 3.79 (1H, s, 2-H), 4.1 (2H, d, J=8, C- _H2 N), 4.2
(3H,s,OCH₃), 5.356 (1H, d, J=
4.5, 6-H), 5.95 (3H, m, 7-H and
and 3-CH=CH), 6.66 (1/2H, d, J
=10,3-CHcis), 7.0(1/2H,d,
J=16,3-CH trans). Reference example 2 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-pyridinio-1-prope
-1-yl]-3-cephem-4-carboxy
Sylate (-1B) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl(-1) (E, 716 mg, 1 mmol),
Dimethyls with pyridine (158 mg, 2 mmol)
The mixture in sulfoxide (DMSO) (1 ml) was prepared at room temperature.
I stirred it for an hour. Ethyl acetate (20
ml) to precipitate a solid (620 mg), which was
Formic acid (60mg) containing sodium bisulfite (60mg)
ml). Stir the mixture at 40°C for 30 minutes,
It was concentrated to dryness. H the residue₂Dissolved in O (40 ml),
Some insoluble matter was removed. Reversed phase column for aqueous solution
(Prep PAK-500/C₁₈, 100ml) and
H₂O (300ml) and 5% aqueous CH₃In OH (800ml)
The eluent was purified by UV (254 nm) and HPLC.
I monitored it. fraction containing the desired product
(5% aqueous CH₃OH) and concentrated to a small volume.
and when lyophilized, the title compound (-1B)40
mg (8%) was obtained, melting point >200°C (decomposed). IR:ν^KBr _naxcm^-13350, 1760, 1660, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 240
(352), 258 (366), 267 (279), 290 (469). NMR: δ^D2O+DMSO-d6 _ppn 3.74 (2H, rb-s, 2-H), 4.20 (3H,
s, OCH₃), 5.92 (1H, d, J = 4.5, 7
-H), 6.15 (1H, m, 3-CH=CH),
7.04 (1H, d, J = 16, 3-CH tran
), 8.2 (2H, m.Py−_3,5), 8.62 (1H, m,
Py−H_Four), 8.97 (2H, m, Py−_2,6). Reference example 3 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-pyridinio)-1-pro
pen-1-yl]-3-cephem-4-carbo
Xylate (I-1B) Chloropropenyl compound, 7-[2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)-
2-methoxyiminoacetamide]-3-(3-k
Rolo-1-propen-1-yl)-3-cephem
-4-Diphenylmethyl carboxylate (-1)
(Z, 937 mg, 1.5 mmol), NaI (11 mg, 0.075 mmol)
pyridine in DMSO (3 ml) containing
(237 mg, 3 mmol) in a stirred solution. mixture
Things were left overnight at room temperature in the dark. mixture
Dilution with ethyl acetate (30 ml) liberates the precipitate;
It was then collected by filtration and ethyl acetate (10
Protected product when washed and dried with 350 ml)
mg was produced. Contains sodium bisulfite (34mg)
The precipitate was treated with formic acid (3.4 ml) at 40°C for 30 minutes.
After removal of formic acid, the residue was subjected to reverse phase column chromatography.
Fee (Prep PAK500/C₁₈filling the cartridge
5% aqueous CH₃Elute with OH
It was purified by Fold containing the desired product
Combined based on lactation HPLC analysis and under hydraulic pressure
Evaporation and lyophilization yields the title compound (−1B)
(Z/E=4/1), 41 mg (5.5%) was obtained.
Melting point, >200°C (decomposition). IR:ν^KBr _naxcm^-13300, 1760, 1660, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 237 (386), 250 (377), 258 (369), 265
(347), 280(311). NMR: δ^D2O _ppn 3.45 and 3.76 (1H, d, J = 16, 2-
H), 4.18 (3H, s, OCH₃), 5.34 (3H,
m, CH=CH−CH₂and 6-H), 5.92
(1H, d, J = 4.5, 7-H), 6.58 (4/
5H, d, J = 11, 3-CH cis), 7.03
(1/5H, d, J = 16, 3-CH tran
), 8.12 (2H, m, Py−H_3,5), 8.56 (1H,
m, Py−H_Four), 8.82 (2H, m, Py−H_2,6). Reference example 4 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(2-amino-5-thia
Zoro[4,5-c]pyridinio)-1-prope
-1-yl]-3-cephem-4-carboxy
Sylate (I-1C) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl (-1) (E isomer, 714 mg, 1 mmol
), 2-aminothiazolo[4,5-c]pyridi
[T. Takahashi et al., Pharm.Bull (Japan),2，
34 (1954)] and dried.
A solution of DMSO (1 ml) was stirred at room temperature for 1 hour.
When ethyl acetate (20ml) is added to the reaction mixture, it turns yellow.
A powder (710 mg) resulted. Formic acid (7ml) and
Sodium hydrogen sulfate (70mg) to powder (700mg)
and the mixture was stirred for 30 minutes at 40-45°C. steaming
H the residue after firing₂Triturated with O (40 ml). insoluble matter
Filter the filtrate, H₂O and 10% CH₃Dissolve OH
A reverse phase column (Prep PAK-500/C) was used as a release agent.₁₈,
100ml). desired
Combine the fractions containing the product and remove the solvent under vacuum.
Removed below. Lyophilization yields the desired product (
-1C) was obtained as a colorless amorphous powder of the E isomer.
It was. Yield 110 mg (19%). Melting point, >200°C (decomposition). IR:ν^KBr _naxcm^-13300, 1760, 1660, 1630, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 245
(499), 285(286). NMR: δ^DMSO-d6+D2O _ppn 3.86 (3H,s,OC _H3 ), 4.98 (1H, d, J
=4.5,6-H),5.2(2H,m,CH=CH
-C _H2 ), 5.57 (1H, m, 3-CH=CH),
5.96 (1H, m, 7-H), 7.16 (1H, d, J
= 16, 3-CH transformer), 8.36 and 8.45
(each 1H, d, J=7, Py-H), 8.92 (1H,
s, Py-H). Reference example 5 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-trimethylammonio-
1-propen-1-yl]-3-cephem-4
-carboxylate (ID) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
Lumenyl (-1) (Z/E=2/1, 490 mg,
0.68 mmol) in ethyl acetate (14 ml)
to 0.1 M trimethylalcohol in ether (13.6 ml).
Min solution was added in one portion. Stir the mixture for 10 minutes.
Then, evaporate to dryness and dissolve the residue in ether (20 ml).
I crushed it. The resulting solid (490 mg) was treated with anisole.
1 drop of trifluoroacetic acid (0.2 ml) was added.
After stirring for 1.5 h, the mixture was evaporated to dryness under reduced pressure.
Dry and triturate the residual oil in ether (20 ml).
Ta. The resulting precipitate was collected by filtration and₂O(20
ml). Remove some insoluble matter and make an aqueous solution
, using water as eluent₁₈reversed phase column
(Prep PAK-500/C₁₈cartridge filling,
Waters, 30 ml). desired compound
The fractions containing substances are combined and concentrated into a small volume,
Upon lyophilization, the title compound (-1D) (Z/E=
1/1) 30mg (9.2%) as colorless amorphous powder
Obtained. Melting point, >150°C (decomposition). IR:ν^KBr _naxcm^-13300, 1770, 1670, 1605. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 236
(389), 287(343). NMR: δ^D2O _ppn 3.45 and 3.7 (1H, d, J = 16, 2-H),
3.18 (1H, s, 2-H), 4.1 (2H, d, J
=8,-C _H2 N), 4.21 (3H, s, OCH₃),
5.39 (1H, d, J = 4.5, 6-H), 5.95
(2H,m,3-CH=CHand 7-H),
6.61 (1/2H, d, J = 11, 3-CH series
), 7.05 (1/2H, d, J = 16, 3-CH
Trance). Reference example 6 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-aminopyridinio)
-1-propen-1-yl]-3-cephem-
4-carboxylate (I-1E) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
Lumenyl (-1) (E, 716 mg, 1 mmol)
3-aminopyridine (188 mg,
2 mmol) was added to the stirred solution. mixture at 1 o'clock
Stir briefly and dilute with ethyl acetate (20ml). Living
Collect the precipitate by filtration and wash with ethyl acetate.
When dried, 520 mg of yellow powder was obtained. powder
(500mg), formic acid (5ml) and sodium bisulfite
(50 mg) was stirred at 40°C for 30 min.
Ta. Concentrate the mixture in vacuo and add H₂Dissolved in O (40ml)
and filtered to remove insoluble matter. 7.5% aqueous solution
Aqueous CH₃Reversed phase column (Prep PAK−
500/C₁₈, 100ml) for chromatography.
I got it. Evaporate the fraction containing the desired compound
and lyophilized to give the title compound (-1E) (7
mg, 1.4%). Melting point, >185°C (decomposition). IR:ν^KBr _naxcm^-13400, 1765, 1675, 1620, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 246
(403), 290(468). NMR: δ^D2O _ppn 3.72 (2H, m, 2-H), 4.14 (3H, s,
OCH₃), 5.35 (3H, m, 6-H and CH
=CH−C _H2 ), 5.9 (1H, d, J = 4.5, 7
-H), 6.1 (1H, m, 3-CH=CH),
7.05 (1H, d, J = 16, 3-CH, Tran
), 8.1 (1H, m, PY−H_Five), 8.54 (1H,
br-s,PY-H₆), 8.68 (1H, m, PY-
H_Four), 9.4 (1H, m, PY−H₂). -1 (716 mg, 1 mmol) in the same manner as above.
3-t-butoxycarbonylaminopyri depending on the order
Treatment with gin (324 mg, 2 mmol) resulted in -
1E, 12 mg (2.3%) was obtained. Reference example 7 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-amino-1-pyri
Zinio)-1-propen-1-yl]-3-cef
Em-4-carboxylate (I-1E) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl (-1) (Z/E=2/1, 500 mg,
0.7 mmol) and 3-aminopyridine (66 mg, 0.7
mmol) in dimethyl sulfoxide (1 ml)
The mixture was stirred at room temperature for 20 minutes. vinegar mixture
diluted with ethyl acid (10ml) and ether (10ml)
The resulting precipitate was collected by filtration and dissolved in ether.
(10ml) and dried. Quaternized salt,
Dissolved in phosphoric acid (3 ml) containing concentrated HCl (0.3 ml)
and stirred for 1.5 h at room temperature. Mixture under reduced pressure
It was concentrated and dried. Dissolve the residue in 2% HCl (10 ml).
It was dissolved and filtered. Transfer the aqueous layer to a reverse phase column (Prep PAK)
-500/C₁₈, 100ml) for chromatography.
I put it on. After washing with water (500 ml), rinse the column with 5% aqueous
CH₃Eluted with OH. Flux containing the title compound
When combined, concentrated in vacuo, and lyophilized, the title
Compound (-1E) (Z/E=1/1) 15 mg (4.2
%) was obtained as a colorless amorphous powder. MP, >160°C (decomposed). IR:ν^KBr _naxcm^-13400, 1765, 1675, 1620, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 244
(434), 287(333). NMR: δ^DMSO-d6+D2O _ppn 3.73 (2H, m), 4.14 (3H, s, OCH₃),
5.35 (2H, m, 6-H and CH=CH-C
H₂), 6.0 (2H, m, 7-H and 3-CH
=CH), 6.6 (1/2H, d, J = 11, 3-
CH cis), 7.05 (1/2H, d, J = 16, 3
-CH transformer), 8.08 (1H, m, Py-
H_Five), 8.6 (2H, m, Py−_4,6), 9.4 (1H,
m, Py−H₂) Reference example 8 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-formylaminopi
lysinio)-1-propen-1-yl]-3-
Cefem-4-carboxylate (I-1F) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
Lumenyl (-1) (E, 716 mg, 1 mmol) and
3-Formylaminopyridine [N. Enomoto et al.
Bull.Chem.Soc.Japan,45, 2665 (1972) procedure
(244 mg, 2 mmol) and DMSO
(2 ml) of the mixture was stirred at room temperature for 1 hour, and the vinegar
Poured into ethyl acid (200ml). Filter the precipitate
collected, thoroughly washed with ethyl acetate, and dried.
Ta. Quaternized salt (500mg) and sodium bisulfite
A mixture of HCOOH (5 ml) and HCOOH (50 mg)
Stir at ~50°C for 80 min and evaporate to dryness in vacuo.
Dissolve the residue in water (40ml) and dilute with NaHCO₃Neutralize with
and then filtered to remove insoluble material. transparent
Transfer the filtrate to a reverse phase column, Prep PAK-500/C₁₈, (100
ml) above, water and 5% CH₃OH, 10%CH₃Oh,
20%CH₃OH and 30% CH₃Chromatograph with OH
I put it on the fee. fraction containing the desired compound
Concentrate in vacuo and lyophilize to form a title.
Compound (-1F) (E), 16 mg (2.9%) is a yellowish brown powder
obtained as the end. Melting point, >170°C (decomposition). IR:ν^KBr _naxcm^-13340 (br), 1760, 1670, 1620 (br)
，
1590. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 218
(428), 248 (362), 290 (474). NMR: δ^D2O+NaHCO3 _ppn 3.68 (2H, br, 2-H), 4.15 (3H, s,
OCH₃), 5.91 (1H, d, J = 4.5, 7-
H), 6.25 (1H, m, CH=CH−CH2),
6.98 (1H, d, J = 16, 3-CH tran
), 8.8-7.9 (4H, m, Py-H), 9.38
(1H,br,NHCH.O.). Reference example 9 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-carbamoylpyri
Zinio)-1-propen-1-yl]-3-ceph
Em-4-carboxylate (I-1G) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
of lumenyl (-1) (E, 716 mg, 1 mmol)
Nicotinamide (24
mg, 2 mmol) and the mixture was kept at room temperature for 1.5 h.
Stir briefly and stir into ethyl acetate (200ml).
I added while doing so. Collect the resulting precipitate by filtration.
Ta. Quaternization salt (500ml) with sodium bisulfite
Dissolved in HCOOH (5 ml) in the presence of HCOOH (50 mg)
and heat the mixture for 40 minutes at 40-50°C with stirring.
Heat and evaporate to dryness. Dissolve the residue in water (40ml)
The undissolved solids were filtered and washed with a small amount of water.
Combine the filtration and washing solutions into a reverse phase column, Prep PAK−
500/C₁₈, 100ml) for chromatography.
I got it. Water and 5%, 10% and 20% aqueous CH₃
Fractions sequentially eluted with OH and containing the desired substance
were combined, concentrated in vacuo, and lyophilized to yield the title compound.
(-1G) (E), 21mg (3.8%) as yellow powder
Obtained by doing. Melting point, >175°C (decomposition). IR:ν^KBr _naxcm^-13340 (br), 1760, 1670, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 235
(326), 274 (sh, 405), 290 (446). NMR: δ^D2O _ppn 3.68 (2H, br, 2-H), 4.15 (3H, s,
OHC₃), 5.32 (1H, d, J = 4.5, 6-
H), 5.45 (1H, d, J=7, CH=CH−
C _H2 ), 5.88 (1H, d, J = 4.5, 7-H),
6.15 (1H, d-t, J=16 and 7,3-
CH＝CH), 7.00 (1H, d, J = 16, 3-
CH transformer), 8.23 (1H, m, Py−H_Five),
9.03 (2H, m, Py−H_Fourand₆), 9.34
(1H, s, Py−H₂). Reference example 10 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-carbamoylpyri
Zinio)-1-propen-1-yl]-3-cef
Em-4-carboxylate (I-1H) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
of lumenyl (-1) (E, 716 mg, 1 mmol)
Isonicotine in a stirred solution in dry DMSO (2 ml)
Amide (244 mg, 2 mmol) was added. blend
Stir at room temperature for 1 hour, then add ethyl acetate
(200 ml). The resulting precipitate is filtered
It was collected, thoroughly washed with ethyl acetate, and dried.
Quaternized substance (400mg) and sodium bisulfite
(40 mg) and a stirred mixture in HCOOH (4 ml).
Heated at ~50°C for 1 hour and evaporated to dryness under reduced pressure.
The crude solid was dissolved in water (40ml). Filter out undissolved substances
After filtering, the filtration was performed using a reverse phase column (Prep PAK/C₁₈,
100ml) with water and 5%, 10%, 20% and 30%
aqueous CH₃Chromatography using OH as eluent
It's rough. fraction containing the desired compound
The combined components were evaporated and lyophilized to yield the title compound.
(-1H) (E), 21mg (3.8%) as light yellow powder
Obtained by doing. Melting point, >180°C (decomposition). IR:ν^KBr _naxcm^-13340 (br), 1760, 1670, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 222
(362), 285(452). NMR: δ^D2O+NaHCO3 _ppn 3.68 (2H, br, 2-H), 4.15 (3H, s,
OCH₃), 5.33 (1H, d, J = 4.5, 6-
H), 5.46 (2H, d, J=7, CH=CH−
C _H2 ), 5.90 (1H, d, J = 4.5, 7-H),
6.17 (1H, d-t, J=16 and 7,3-
CH＝CH), 7.02 (1H, d, J = 16, 3-
CH, transformer), 8.43 and 9.09 (2H each,
d, J=7, Py−H). Reference example 11 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-aminomethylpyri
Zinio)-1-propen-1-yl]-3-ceph
Em-4-carboxylate (I-1I) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
Lumenyl (-1) (E, 716 mg, 1 mmol) and
3-(t-butyloxycarbonylaminomethyl)
DMSO (2 mmol) with pyridine (516 mg, 2 mmol)
ml) was stirred for 30 min at room temperature. mixture
Pour the mixture into ethyl acetate (200ml) and filter the precipitate.
Collected by filtration, thoroughly washed with ethyl acetate and dried.
did. Quaternized salt (500mg), sodium bisulfite
A mixture of HCOOH (5 ml) and HCOOH (50 mg)
Stir at ~50°C for 80 min and evaporate to dryness under reduced pressure.
Ta. Dissolve the residual solid in water (40ml) and add the mixture to
NaHCO₃It was neutralized. Filter out undissolved materials
Transfer the liquid to a reverse phase column (Prep PAK-500/C₁₈,cart
Chromatograph on Ritsuji packing, 100ml)
Add water sequentially to 5%, 10%, 20% and 30%
% aqueous CH₃OH eluted. Contains the desired compound
The combined fractions are evaporated and freeze-dried.
and the title compound (-1I) (E), 10 mg (1.8%)
was obtained as a tan powder. IR:ν^KBr _naxcm^-13380 (br), 1760, 1650 (sh), 1620
(sh). UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 235
(sh, 260), 286 (370). NMR: δ^D2O+NaHCO3 _ppn 3.68 (2H, br, 2-H), 4.16 (3H, s,
OCH₃), 6.98 (1H, d, J = 16, 3-CH
transformer), 8.05 (1H, m, Py−H_Five), 8.50
(1H, m, Py−H_Four), 8.80 (2H, m, Py−
_2,6). Reference example 12 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-carbamoylpyri
Zinio)-1-propen-1-yl]-3-ceph
Em-4-carboxylate (I-1H) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl (-1) (E isomer, 4.1 g, 5.7 mm
mol) and isonicotinamide (1.4 g, 11 mmol) and isonicotinamide (1.4 g, 11 mmol)
TLC the mixture in dry DMSO (6 ml) with
(Silica gel plate, CHCl₃:CH₃OH=3:
Stir at room temperature for 2 hours while monitoring according to step 1).
Zeta. Dilute the reaction mixture with ethyl acetate (100ml)
A yellow gum-like substance is then released, which is treated with formic acid (40
ml) and sodium bisulfite (390mg)
℃ for 10 minutes. The resulting solution was concentrated and dried.
Ta. H the residue₂Dissolve in O (100ml) and remove insoluble matter.
Removed by filtration. Combine the filtrate and washings and reverse phase
Filling material (Prep PAK-500/C₁₈, 120ml).
The solution was packed on top of the column. H column₂At O
eluted. Collect the eluent with a 300ml fraction,
UV (254nm) and HPLC [Licrosolve
(Lichrosorb) RP-18, 4 x 300nm, 0.01M phosphorus
Acid ammonium buffer, PH7.2, 20% CH₃Contains OH
Monitored by: Fraction No.4 and
and No. 5 were combined and concentrated to a small volume. freeze dry
and the title compound -1H, 250 mg (8.1%) were obtained.
Ta. Melting point, >180°C (decomposition). The spectrum is the product obtained in Reference Example 10.
It was shown that there was a match. Production of hydrochloride CH of compound −1H (98 mg, 0.18 mmol)₃
Add 10% HCl (0.1 ml) to the suspension in OH (1 ml).
Well, stir the mixture for 5 minutes. The resulting yellow solution
When acetone (100ml) is added to the solution, a precipitate is formed.
was collected by filtration and diluted with acetone (2 x 10ml).
After washing and drying in vacuum, -1H hydrochloride is removed.
Obtained as a colored powder. Yield 88 mg (79%). melting point,
>190℃ (decomposition). IR:ν^KBr _naxcm^-13300, 1770, 1680, 1620. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 227
(385), 286(374). NMR: δ^D2O _ppn 2.32 (2H, s, acetone-H), 3.79 (2H,
br-s, 2-H), 4.17 (3H, s, OCH₃),
5.34 (1H, d, J = 4.5, 6-H), 5.49)
(2H, d, J=7, CH=CH-C _H2 ),
5.93 (1H, d, J = 4.5, 7-H), 6.28
(1H, d-t, J = 168.43 and 9.1 (each
2H, d, J = 7, Py-H). Reference example 13 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(methylthiazolio)-1
-propen-1-yl]-3-cephem-4-
Carboxylate (I-1J) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl(-1) (E, 714 mg, 1 mmol) and
2-Methylthiadiazole [R.P.Kurkjy, E.V.
Brown, J.Am.Chem.Soc.74, 5778 (1952)
[produced according to the procedure] (198 mg, 2 mmol)
Dry CH₂Cl₂AgBF to the mixture in (10ml)_Four(90% pure
217 mg, 1 mmol) was added at -20°C. Mixed
The mixture was stirred at room temperature for 30 minutes and filtered. precipitation
10%CH₃OH−CHCl₃(3 x 20ml).
The combined extracts were washed with brine (2 x 5 ml) and
MgSO_FourDry on top and evaporate to dryness leaving a yellow residue
is produced, which is triturated in isopropyl ether.
and filtration yielded 350 mg of quaternized product.
Ta. This solid, sodium bisulfite (35 mg)
and formic acid (3.5 ml) at 40°C for 30 minutes.
Mixed. The mixture was concentrated to remove the formic acid and the residue
H₂Diluted with O (40ml). Filter some insoluble matter
It was removed by The filtrate was transferred to a reverse phase column (Prep PAK
-500/C₁₈, 100 ml). column
H₂O (200ml), 5% aqueous CH₃OH (400ml) and
10% aqueous CH₃Fraction HPLC analysis containing OH
(Licrosolve RP-18, 4 x 300mm, 0.01M phosphorus
Acid ammonium buffer PH7.2, 20% CH₃(contains OH)
Pooled based on. Concentrate the combined solution to a small volume
and freeze-drying gives the title compound (-1J) (E),
40 mg (7.7%) was obtained. Melting point, >195°C (min
solution). IR:ν^KBr _naxcm^-13300, 1760, 1660, 1600. UV: λ phosphate buffer (pH7) maxnm(E1% 1cm) 238
(442), 292(421). NMR: δ^D2O+DMSO-d6 _ppn 3.06(3H,s,thiazole-C _H3 ), 3.74
(2H, br-s, 2-H), 4.19 (3H, s,
OCH₃), 5.92 (1H, d, J = 4.5, 7-
H), 6.1 (1H, m, 3-CH=CH), 6.8
(1H, d, J = 16, 3-CH transformer),
8.04 and 8.23 (each 1H, d, J = 4, cheer
Sol-H). Reference example 14 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-hydroxymethyl
pyridinio)-1-propen-1-yl]-3-
Cefem-4-carboxylate (I-1L) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propene-1-
yl)-3-cephem-4-carboxylic acid diphenyl
methyl (-1) (E isomer, 1.07 g, 1.5 mm
mole), CH₃4-Hydroxymethy in CN (4.5ml)
Lupyridine (818 mg, 7.5 mmol) and CH₃
A mixture of OH (3 ml) was diluted with N₂1 hour at room temperature under atmosphere
I stirred it up for a while. After removing the solvent by evaporation, the residue
Tritify the distillate in isopropyl ether and filter
Collected by isopropyl ether and methanol
The fourth is washed with a mixture of water and water (3:1, 10ml).
1.28g of graded cefemester was produced as a yellow powder.
It was. 1.25g of quaternized ester) and sodium bisulfite
in 85% HCOOH (10ml) with thorium (600mg)
solution in H₂Stir for 1 hour at room temperature under atmosphere.
After adding 85% HCOOH (5 ml), the mixture was
I stirred for another hour under the condition. toluene
In addition, the reaction mixture was evaporated under reduced pressure to the azeotropic point.
Ta. Trituration of the residue with acetone yields the title compound.
1.17 g of crude formate was obtained. This compound (1.15g)
Filter the suspension in water (100 ml) to remove insoluble matter.
and washed with water (10 ml x 2). filtrate and washing liquid
combined and subjected to reversed phase column chromatography.
Ta. Prep PAK500/C₁₈Cartridge column (U)
Fill with the filling (60ml) from the
The sampled column was soaked in water, 5% methanol and 10% methanol.
It was developed sequentially with tanol. Fold containing the desired compound
The combined lactones were concentrated under reduced pressure and diluted with acetone.
The title compound (−1L) is precipitated by addition of
100 mg was obtained as a pale yellow powder. Powder (90mg)
of CH in methanol (9 ml)₃During OH
of 1M HCl (0.5 ml) was added and the mixture was allowed to cool at room temperature.
Mix and concentrate in vacuo. Isopropa in concentrate
77 mg of the title compound dihydrochloride precipitated when nol was added.
did. Light yellow powder. Melting point, >190°C (decomposition). IR:ν^KBr _naxcm^-11775, 1670, 1635, 1530. UV: λ phosphate buffer (pH7) maxnm(ε), 230
(22600), 264 (sh, 16300) NMR: δ^D2O _ppn 3.83 (2H, br.2−CH), 4.17 (3H, s,
OCH₃), 5.06 (2H, s,
[Formula]), 5.36 (1H, d, J=4.5Hz, 6-H), 5.41(2H, d, J=
7, Hz, CH=CH-C _H2 ), 5.94 (1H,
d, J = 4.5Hz, 7-H), 6.36 (1H, d,
t, J=16 and 7Hz, CH=CH.C.H₂),
7.13 (1H, d, J=16Hz, CH=CH-
CH₂), 8.08 and 8.83 (each 2H, d, J = 7
Hz, Py−H). Reference example 15 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-ethoxyiminoacetate
toamide]-3-[3-(4-carbamoylpyri
Zinio)-1-propen-1-yl]-3-cef
Em-4-carboxylate (I-2H) 7-Amino-3-[3-(4-carbamoylpyri)
Zinio)-1-propen-1-yl]-3-cefe
Mu-4-carboxylate hydrochloride (E isomer)
A solution of 200 mg of 2-
Ethoxyimino-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetyl chloride
Hydrochloride [Japanese Patent Application (Publication) No. 57-24389
(Produced according to the procedure described on 2/8/82)] 190mg
One part at a time, the mixture was diluted with 2N−Na₂C.O.₃(about 1
ml) to adjust the pH to 6.5-7.0. Reaction mixture at 10℃
Stir for 1 hour, adjust pH to 2 with 1N-HCl, and adjust to true
Evaporated in the sky. Filter the residue and transfer the filtrate to HP-
Chromatography on a column of 20
with 500 ml of water and 25% aqueous isopropanol.
Then eluted. fraction containing the desired product.
The mixture was evaporated under reduced pressure. Isop removes oily residue
Treatment with lopanol (20 ml) produced the title compound (
−2H) 263 mg (93%), melting point, 170°C (min.
solution). 225 mg (0.40 mmol) of the above zwitterionic meth
CH to a stirred suspension in 10 ml of alcohol₃1N− in OH
Add 1 ml of HCl and stir the mixture for 30 min at room temperature.
Ta. The solution was filtered and concentrated under reduced pressure. to the residue
Add 15 ml of isopropyl alcohol and the resulting precipitate
is collected by filtration and dried in vacuo to yield the title compound.
was obtained as its hydrochloride. Yield 146 mg (57
%). Melting point, 160°C (decomposed). Estimated purity 65%. IR:ν^KBr _naxcm^-13300, 1780, 1680, 1620. UV: λ phosphate buffer (pH7) maxnm(ε)227
(22300), 288 (22800). NMR: δ^D2O _ppn 1.44 (3H, t, J-7Hz, OCH₂-CH3),
3.74 (2H, br.s, 2-H) 4.45 (2H, q, J
=7Hz,OC _H2 −CH₃), 5.36 (1H, d, J
=4.5Hz, 6-H), 5.46(2H, d, J=7
Hz, 3-CH=CH-C _H2 ), 5.92 (1H,
d, J = 4.5Hz, 7-H), 6.20 (1H, m,
3-CH=CH), 7.04 (1H, d, J=16
Hz, 3-CH= CH), 8.43 (2H, d, J =
7Hz, Py−H_A), 9.10 (2H, d, J=7
Hz, Py−H_B). Reference example 16 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-carbamoylpyri
Zinio)-1-propen-1-yl]-3-ceph
Em-4-carboxylate (I-1H) (E
gender) This reference example shows the intermediate, 7-[2-(5-amino
-1,2,4-thiadiazol-3-yl)-2
-methoxyiminoacetamide]-3-[3-(4
-carbamoylpyridinio)-1-propene-1
-yl]-3-cephem-4-carboxylic acid benzene
The reaction in which hydryl formate (−1H) is isolated
Compounds that go through the latter few steps of scheme 1a or 1b
The production of Product-1H is illustrated. A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(4-carbamoyl-
1-pyridinio)-1-propen-1-yl]-
Benzhydryl 3-cephem-4-carboxylate
Formate (E isomer) (-1H) -1H (Y-I, E isomer) (34 g, 75% pure
degree) of acetone and CH₃Mixture with OH (1/1,
Amberlite solution in 200ml)
Place on a column of IRA−410 (formate form, 340 ml).
there was. The column was eluted with the same solvent system. first frame
Evaporate Luxion (1) to a volume of approximately 100ml.
and remove the brown residue with isopropyl ether (400ml).
I ground it up. Collect the resulting powder by filtration,
Drying under vacuum yields the title compound −1H (isomer
29g (75% purity by HPLC) of brown powder
Obtained by doing. Melting point, >150°C (decomposition). IR:ν^KBr _naxcm^-13300, 1780, 1680, 1630, 1600. UV:λ^EtOH _naxnm (E1% 1cm) 282 (186). NMR: δacetone d6/CH3OH-d4 (1/1) ppm 4.0(3H,s,OCH₃), 5.26 (1H, d, J=
4.5, Hz, 6-H), 5.43 (2H, d, J=7
HzC _H2 N⁺), 5.99 (1H, d, J = 4.5, Hz,
7-H), 6.5 (1H, m, 3-CH=CH),
6.92 (1H, s, CHPh₂), 7.1 (1H, d, J
=16Hz, 3-CH), 7.35 (10H, m, Ph−
H), 8.36 (1H, s,H.C.OO), 8.46 and
9.12 (2H each, d, J = 8Hz, Ph-H). B 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(4-carbamoyl-
1-pyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylate (I-
1H) (E isomer) -1H (E isomer) from Step A (29 g,
75% purity) and 85% formic acid (290 ml) in a chamber.
Stir for 2 hours at a warm temperature. Evaporate the mixture and it will turn brown.
A colored oil results, which is triturated with acetone (500ml).
there was. The powder was collected by filtration and mixed with acetone (2x
Washing with 100 ml of water and drying in vacuum yields the title compound.
24 g of crude compound (50% purity by HPLC) was obtained.
It was. The brown solid was washed with 2N-HCl twice (1 or 2 times).
and 0.5). Combine the aqueous extract
Filled with Diaion HP-20 (1.5)
placed on the column. Wash the column with water (8)
Purified, 30% CH₃Eluted with OH (5). desired
Evaporate the fraction containing the product to approximately 30 ml.
Ta. Treatment of the concentrate with acetone (200ml) results in precipitation.
A sludge forms, which is collected by filtration and dried in a vacuum.
The title compound (zwitterionic form) is then 10.1 g (85
% purity) was obtained as a yellow powder. this product
CH of₃CH to suspension in OH (100ml)₃1N in OH
- Add HCl (55 ml) at room temperature and let the mixture stand for 30 minutes.
I mixed it up. Filter the resulting clear solution to remove insoluble matter.
Remove, concentrate to a volume of approximately 50 ml, and add isopropanol.
(200 ml). The resulting powder is collected and
Wash with sopropanol (50 ml) and dry in vacuum.
and the title compound I-1H (E isomer) (HCl salt),
10.5g (85% purity) was obtained. Melting point, >180°C (min
solution). Pale yellow powder. Reference example 17 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(4-carbamoylpi
lysinio)-1-propen-1-yl]-3-ce
Fem-4-carboxylate (I-1H) (E
isomer) This reference example shows the intermediate −1H (formate) as a simple
The latter few steps of reaction scheme 1a or 1b without separating
The preparation of compound 1-1H is shown. -1 (E isomer) (27.6 g, 38.5 mmol)
and isonicotinamide (22.8 g, 187 mmol)
of, CH₃CN (120ml) and CH₃Mix with OH (100ml)
The solution in the compound was stirred at room temperature under nitrogen atmosphere for 1 hour.
Mixed. After evaporating the organic solvent, the oily residue is
When triturated with propyl ether, the quaternized salt and iso
50.5 g of a mixture with nicotinamide resulted. the
mixture (50.3g) and sodium bisulfite (16
g) N solution in 85% HCOOH (160 ml)₂under
The mixture was stirred at room temperature for 40 minutes and then at 40°C for 1 hour.
The mixture was evaporated in vacuo. Remove residual oil from toluene
(50ml) and evaporate azeotropically, acetone
(400ml) yields 27.8g of the title crude compound.
It was. This material was diluted twice with 2N HCl (1 and
0.5) Processed. HP-20 resin with acid extract
(1.5) was placed on the column. Fill the column with water (9
) and 30% methanol (10).
Combine and concentrate fractions containing the desired compound
and a yellow oil will result, it is acetone (300ml)
When crushed, 9.35 g of the title compound in zwitterionic form is produced.
It was. CH of product (9.35g)₃Suspension in OH (180ml)
CH in liquid₃Addition of 1N HCl in OH (55 ml)
A clear solution was obtained. Concentrate the solution to approximately 100ml,
Dilution with isopropanol gives the title compound I-
9.50g (purity 75%) of 1H (E isomer) is its hydrochloride
It was precipitated as Pale yellow amorphous powder. Melting point, >195
°C (decomposition). Reference example 18 7-[-2-(5-amino-1,2,4,-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(4-carbamoyl
pyridinio)-1-propen-1-yl]-3-
Cefem-4-carboxylate (I-1H)
(E isomer) This reference example is the last step of reaction scheme 1c (7-N
-acylation) to produce compound 1-1H.
show. 7-Amino-cefem hydrochloride-H (E
- isomer) (5.0 g, 12.6 mmol) in 50% aqueous solution
Sodium bicarbonate in ice-cold suspension in setone (100ml)
Lium was added little by little. The PH of the mixture is the PH during the reaction
It was monitored by a meter. Cold neutralized solution (PH approx. 7)
2-(5-amino-1,2,4,-thiadiazole)
(3-yl)-2-methoxyiminoacetyl
A small amount of loride hydrochloride (4.02 g, 15.6 mmol)
and sodium bicarbonate over 1 hour.
Adjust the pH of the reaction mixture by occasionally adding
It was maintained within the range of 6.8-7.5. The reaction also depends on tlc
I monitored it. All of compound-H disappears.
After cooling, the mixture was adjusted to pH 3 by the addition of 2N hydrochloric acid.
I made it. Filter the mixture and concentrate the filtrate under reduced pressure.
Ta. Diluting the residue with acetone (400ml) causes precipitation.
The title is that lees are released and collected by filtration.
9.59 g of compound resulted as a pale yellow powder. to HPLC
Estimated purity is 40%. Crude product (9.5g) in 2N hydrochloric acid
Filter the suspension in (150 ml) and use the filtrate as HP-20 resin.
It was adsorbed onto a column of oil (500 ml). Water (1.5
), then wash the column with 25% aqueous isopropylene.
Elute with alcohol and transfer the eluent to 100ml flux.
It was collected in Yong. Pool the desired fraction
The mixture was acidified with 2N hydrochloric acid (10 ml) and concentrated. Residue
Grind the distillate with isopropyl alcohol (200ml)
It was crushed and the precipitate was collected by filtration. on phosphorus pentoxide
After drying the title compound I-1H (E isomer) in hydrochloric acid
5.18 g of salt were obtained as a yellow amorphous powder. Melt
point, >190°C (decomposition). Estimated purity 75%. Reference example 19 Purification and crystallization of compound I-H (E isomer) Compound IH hydrochloride obtained in Reference Example 16
was a pale yellow amorphous powder with 85% purity. Step 1 6g of 85% purity hydrochloride in H₂O, dissolved in 20 ml,
Filtered through a pad of Celite. amber filtrate
(PH2) using a reverse phase column (Prep PAK-500/C)₁₈mosquito
120ml filling
and eluted with water. The eluent was purified by HOLC
It was collected with a 120ml fraction while being monitored.
The total of fraction No. 3 to fraction No. 5 is approx.
Concentrate to 10 ml and precipitate with acetone (100 ml)
When soaked, the zwitterionic form of I-H (light yellow amorphous powder)
Finally, 3.3 g (estimated purity 95%) was obtained. 95% purity powder (3.2g) CH₃In OH (32ml)
CH to a suspension of₃Add 1N HCl in OH (18 ml),
Stir the mixture at room temperature until a clear solution is obtained.
Ta. The solution was filtered and the filtrate was concentrated to approximately 10 ml. dark
Adding isopropanol (100ml) to the condensate makes it pale.
A yellow precipitate is liberated, which is collected by filtration and
Wash with sopropanol (5 ml) and dry.
2.6 g of HCl salt (amorphous powder, estimated purity 95%) was obtained.
It was done. Solution of 95% pure hydrochloride (1 g) in water (4 ml)
NaHCO₃(200mg) to adjust the pH to 6.5 for 30 minutes.
I mixed it up. Capture the crystals released during stirring by filtration.
Collect, wash with water (2 x 5 ml) and dry in vacuo.
and I-H (zwitterionic form) 710mg as pale yellow columnar crystals.
Obtained as crystal. Melting point, >185°C (decomposition). Very small amount
Analysis showed it to be trihydrate. IR:ν^KBr _naxcm^-11780, 1695, 1660, 1630, 1610. UV: λ phosphate buffer (pH7) maxnm(ε)227
(22000), 290 (23000). NMR: δ^DMSO-d6+D2O _ppn 3.45 (2H, br, s, 2-H), 3.9 (3H, s,
O.C. _H3 ), 4.99 (1H, d, J = 4.5Hz, 6-
H), 5.16 (2H, d, J=7Hz, C _H2 N⁺),
5.61 (1H, d, J = 4.5Hz, 7-H), 5.8
(1H, d-t, J=16 and 7Hz, 3-
CH＝CH), 6.93 (1H, d, J = 16Hz, 3
-CH), 8.18 and 8.89 (each 2H, d, J =
7Hz, Py-H). Elemental analysis: C_{twenty one}H₂₀N₈O₆S₂・3H₂against O Calculated value: C, 42.14; H, 4.38; N, 18.72; S, 10.71. Measured value: C, 42.41; H, 4.35; N, 18.86; S, 11.00. 〓Column, Licrosolve RP-18, 4 x 300mm:
Mobile phase, 0.01M phosphate buffer (PH7.2)/CH₃
OH=85/15: Detection, UV (254nm). Step 2 After crystalline I-1H is obtained from step 1, pure
By seeding crystal pieces of I-1H, crude I-
The crystalline zwitterionic form of I- directly from 1H hydrochloride
It was possible to obtain 1H. Dissolution of 85% pure hydrochloride (250 mg) in water (1 ml)
The liquid was treated with activated carbon. Add the solution to NaHCO₃(60
mg) to adjust the pH to 6.5 and decolorize with activated carbon. filtrate
Seed with the crystal pieces obtained in step 1 and leave to stand at room temperature.
Stirred at night. Collect the liberated crystals by filtration.
Wash with water (2 x 2 ml) and dry under reduced pressure.
Light yellow columnar crystals of I-1H (zwitterionic form) 170
mg (80% recovery), melting point, >185°C (decomposition), was obtained.
, which was consistent with that obtained by step 1.
(as shown by IR, UV, NMR). The crystalline zwitterionic form of compound I-1H in water
Somewhat dissolved (6 mg/ml at 23°C in saline). Reference example 20 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-hydroxymethylene
lupyridinio)-1-propenyl]-3-ceph
Em-4-carboxylate (I-1K) (E
gender) A 7-[2-(5-amino-1,2,4,-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(3-hydroxymeth)
tylpyridinio)-1-propenyl]-3-cef
Em-4-carboxylic acid diphenylmethyl iodine
Do (E isomer) (XII-1K) -1 (E-isomer, 1.79 g, 2.5 mmol)
CH₃OH2.5ml and CH₃3- in solution in 7.5 ml of CN
Hydroxymethylpyridine (545 mg, 5 mmol)
was added and the mixture was stirred at room temperature for 3 hours. reaction
Stir the mixture vigorously into ethyl acetate (100ml).
I added it without hesitation. Collect the resulting precipitate by filtration
Then, wash with a small amount of ethyl acetate and dry to obtain the title.
Compound - 1K, 2.06g (100%) yellowish brown
Obtained as a powder. Melting point, 170-180°C (decomposition). IR:ν_nax(KBr)cm^-11780, 1725, 1675, 1615,
1530, 1385, 1225, 1040, 750, 700. UV:λ_nax(C₂H_FiveOH)nm(E1% 1cm) 290 (196). NMR: δ(DMSO+D₂0) ppm 3.7 (2H, br, s, 2-H), 3.91 (3H, s,
O.C. _H3 ), 4.70 (2H, s, Py-C- _H2 −
OH), 5.28 (2H, m, C _H2 −N⁺), 5.23
(1H, d, J = 5Hz, 6-H), 5.90 (1H,
d, J = 5Hz, 7-H), 6.34 (1H, m,
3-CH=CH), 6.86 (1H, d, J=16
Hz, 3-CH), 6.89 (1H, s, CHPb₂),
7.35 (10H, m, Ph-H), 7.9-8.9 (4H,
m, Py-H). B 7-[2-(5-amino-1,2,4,-thia
diazol-3-yl)-2-methoxyimino
Acetamide]-3-[3-(Hydroxymethyl
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (I-1K) (E isomer
body) -1K (E isomer, 2.0 g, 2.4 mmol)
and 85% of sodium bisulfite (1g)
Stir the mixture in HCOOH (10ml) at room temperature for 2 hours.
Mixed. The reaction mixture was concentrated under reduced pressure to approximately 5 ml.
Ta. Vigorously remove the oily residue into acetone (100ml).
I added it while stirring. Collect the precipitate by filtration
However, when washed with a small amount of acetone and dried, it becomes yellowish brown.
1.1g of powder was obtained, which was subjected to column chromatography.
Fee [Prep PAK-500/C₁₈Cartridge (U)
Purify by using fillings of
and I-1K, 283 mg (22%) were obtained as amorphous powder.
It was done. 4N−H powder₂S0_Fourand from acetone
When crystallized, 144 mg of the title compound I-1K was obtained as colorless needles.
Obtained as solid crystals. Melting point, 185-188°C (decomposed). IR:ν_nax(KBr) cm^-11775, 1680sh, 1660,
1630, 1225, 1045, 850. UV:λ_nax(phosphate buffer, PH7) nm (E1% 1cm)
236.5 (283), 275sh (280), 292.5 (330). NMR: δ(D₂0) ppm 3.75 (2H, s, 2-H), 4.18 (3H, s,
O.C. _H3 ), 4.97 (2H, s, Py-C _H2 −OH),
5.35 (1H, d, J=4Hz, 6-H), 5.43
(2H, d, J=6.5Hz, CH₂−N⁺), 5.92
(1H, d, J = 4Hz, 7-H), 6.18 (1H,
d-t, J=16Hz, J=6.5Hz, 3-CH=
CH-), 6.97 (1H, d, J = 16Hz, 3-
CH), 8.13 (1H, dd, J=8Hz, J=
6Hz, Py-H) 8.60 (1H, d, J=8Hz,
Ph−H), 8.84 (1H, d, J=6Hz, Py−
H), 8.90 (1H, s, Py-H). Reference example 21 7-[2-(5-amino-1,2,4,-thiadi
azol-3-yl)-2-(Z)-methoxyi
Minoacetamide]-3-[3-(4-N-methy
(carbamoylpyridinio)-1-propenyl]
-3-cefem-4-carboxylate (I-
1M) (E isomer) 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-methoxyiminoacetate
toamide]-3-(3-iodo-propenyl)-3
-Cefem-4-carboxylic acid diphenylmethyl
(-1) (E isomer, 450 mg, 0.62 mmol) and
4-N-methylcarbamoylpyridine (M. shark
Jima, Pharmaceutical Journal80, 1706 (1960)
Production] (215 mg, 158 mmol) and acetonitrile
The mixture in a bottle (2 ml) was heated at room temperature under a nitrogen atmosphere.
I stirred the time. The mixture was evaporated under reduced pressure to remove the residue.
When the distillate is triturated with ether, 530 mg of quaternized salt is obtained.
Obtained. Its solid and sodium hydrogen sulfite
(150 mg) in 85% formic acid (2 ml).
Stir briefly and then heat at 40°C for 30 minutes. mixture
The material was evaporated under reduced pressure. The residue is acetone
The crude product was collected by filtration. crude production
Chromatograph the material on a HP-20 (1.5 x 18 cm) column.
The column was washed with water and a 30% aqueous solution.
Eluted with tanol. Reduce pressure of methanolic eluent
Evaporate down and freeze dry the residue to form an amorphous powder
140 mg of powder was obtained, which was further subjected to HPLC (column:
Licrosolve RP-18, solvent: 15% CH₃OH) to
After further purification and lyophilization of the HPLC eluent, the table
This yielded 60 mg (18%) of the title compound I-1M. melting point,
180-183℃ (decomposition). Estimated purity: 80%. IR:ν_nax(KBr)cm^-11760, 1660, 1600. UV:λ_nax(phosphate buffer, PH7) nm (ε) 230
(22100), 286 (22100). NMR: δ(D₂0) ppm 3.08(3H,s,CONHC _H3 ), 3.72 (2H,
s, 2-H), 4.16 (3H, s, OCH₃),
5.35 (1H, d, J=4.5Hz, 6-H), 5.95
(1H, d, J = 4.5Hz, 7-H), 7.00 (1H,
d, J = 16Hz, 3-H), 8.35 (2H, d,
J = 6 Hz, pyridine-H), 9.05 (2H, d,
J=6Hz, pyridine-H). Reference example 22 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(carboxypyridiny
e)-1-propenyl]-3-cephem-4-ka
Ruboxylate (I-1N) Drying of isonicotinic acid (340 mg, 2.8 mmol)
Stir suspension in DMF (3.5 ml) under nitrogen atmosphere.
N,O-bis(trimethylsilyl)acetamide
(0.7 ml, 2.8 mmol) was added. The resulting transparent solution
7-[2-(5-amino-1,2,4,-thia)
diazol-3-yl)-2-methoxyiminoa
Cetamido]-3-(3-iodo-1-propenyi)
diphenyl)-3-cephem-4-carboxylate
Methyl(-1) (E isomer, 720 mg, 1 mmol
Add the red solution at room temperature for 1.5 hours.
I mixed it up. The reaction mixture was treated with sodium thiosulfate
(150 ml) of a stirred saturated solution of sodium chloride (50
ml) dropwise. Collect the yellow precipitate by filtration.
Wash with water and dry to obtain 722 mg of pale yellow powder.
It was. Its powder (700mg) and sodium bisulfite
(70 mg) in 85% formic acid (5 ml) and make a solution.
was left at room temperature for 1.5 hours. toluene mixture
(50ml) and concentrated. Acetate the residue
(70 ml) and isolate the precipitate by filtration.
421 mg of yellow powder was produced. This coarse powder (400
mg) in water (2 ml), and the suspension
Added sodium. Prep the resulting dark solution
PAK-500/C₁₈Cart cartridge (Water cartridge)
500) packed onto the column (50 ml).
The column was eluted with water (200ml).
The eluent was fractionated into 10 fractions (20 ml each) and
Combine the desired fractions (fractions No. 4 to 7).
The pH was adjusted to 3 with 2N hydrochloric acid, and the mixture was concentrated. residue
Grind with acetone (30ml) and filter the precipitate.
When collected, 201 mg (37%) of the title compound I-1N was obtained.
Obtained as a yellow powder. E/Z=7/1; 80%
purity. Melting point, >189°C (decomposed). IR:ν_nax(KBr)cm^-11770, 1665, 1600. UV:λ_nax(phosphate buffer, PH7) nm (ε) 227
(22500), 290 (22100). NMR: δ(D₂0+NaHCO₃) ppm 3.7 (2H, br, s), 4.15 (3H, s), 5.32
(1H, d, J = 4.5Hz), 5.39 (2H, d, J
= 6Hz), 6.14 (1H, d-t, J = 15.5 and
and 6Hz), 7.03 (1H, d, J = 15.5Hz),
8.31 (2H, d, J=7Hz), 8.94 (2H, d,
J=7Hz). Reference example 23 7-[2-(5-amino-1,2,4,-thiadi
azol-3-yl)-2-(Z)-methoxyi
Minoacetamide]-3-[3-(2,3-cyc
lopentenopyridinio)-1-propenyl]-3
-Cefem-4-carboxylate (I-1O)
(E isomer) 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-methoxyiminoacetate
toamide]-3-(3-iodo-1-propenyl)
-3-cephem-4-carboxylic acid diphenylmethylate
(-1) (E isomer, 450 mg, 0.62 mmol)
and 2,3-cyclopentenopyridine (217 mg,
1.83 mmol) in acetonitrile (2 ml)
Stir the mixture for 4 hours at room temperature under nitrogen atmosphere.
Ta. After evaporation under reduced pressure, the mixture was dissolved in ether.
When ground, 560 mg of quaternary salt was obtained. the
A mixture of the solid and 85% formic acid (2 ml) was heated under nitrogen for 3 hours.
Stir for an hour and then heat at 40°C for 30 minutes. Mixed
The mixture is evaporated under reduced pressure and the residue is triturated to give a coarse
391 mg of product was obtained, which was purified by HP-20 (1.5×
Purified by chromatography on a 18cm) column.
Manufactured. Wash the column with water and 30% aqueous methanol.
eluted. Evaporate the methanolic eluent under reduced pressure
and then lyophilized to obtain 160 mg of amorphous powder.
and then further HPLC (column: Licrosol
Solvent: 10% CH₃OH).
Lyophilization of the HPLC eluent yields the title compound I-
1O, 50mg (15%) was obtained. Melting point, >190℃
(Disassembly). Estimated purity 75%. IR: νmax (KBr) cm^-11765, 1670, 1600. UV:λ_nax(phosphate buffer, PH7) nm (ε) 235
(20000), 283 (25000). NMR: δ(D₂0+NaHCO₃) ppm 2.2−2.6 (2H, m, −CH₂−), 3.1−3.6
(4H, m-CH₂-), 3.72 (2H, s, 2-
H), 4.17 (3H, OCH₃), 5.33 (1H, d, J
= 4.5Hz, 6-H), 5.90 (1H, d, J = 4.5
Hz, 7-H), 6.75 (1H, d, J=16Hz,
3-CH), 7.65-8.2 (3H, m, pyridine-
H). Reference example 24 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-(Z)-ethoxy
Minoacetamide]-3-[3-(4-carboxylic acid)
Cypyridinio)-1-propenyl]-3-cefe
Mu-4-carboxylate (I-2N, E isomer
body) and 7-[2-(5-amino-1,2,4,-thiadi
Azol-3-yl)-2-(Z)-ethoxy
Minoacetamide]-3-[3-(4-carboxylic acid)
Cypyridinio)-1-propenyl]-3-cefe
Mu-4-carboxylate (I-1N, Z isomer
body) BSA (1.0ml, 4.12mmol) and isonicotinic acid
IX-2 in a cooled mixture with (506 mg, 4.12 mmol)
(from production No. 21) (1.0 g, 1.37 mmol) was added,
The mixture was stirred at room temperature under nitrogen for 2 hours. mixture
10% Na₂S₂0₃(20ml) When poured into the liquid, it becomes quaternary.
1.3g of salt precipitated and was collected by filtration and water
Washed and dried. Its solids and sodium bisulfite
mixture of formic acid (98%, 5 ml) with
The mixture was heated at 40 °C for 1 h and evaporated under reduced pressure.
Ta. Triturate the residue with acetone and filter to obtain a coarse
Product (E-propenyl isomer: Z-propenyl
900 mg of isomer=2:1) was obtained. isomer fraction
Separation is HPLC (Column: Lichrosolve, Solvent: 15%
CH₃This was done by OH). HPLC fast transfer flow
The lactyone was collected, evaporated under reduced pressure, and freeze-dried.
When dried, the E-propenyl isomer of I-2N (44 mg,
A yield of 6%) was obtained. slower moving flux
is the Z-propenyl isomer of I-2N (32 mg, yield
4%) was given using the same procedure. I-2N, E isomer Melting point: >200℃ (decomposition) IR:ν_nax(KBr)cm^-11765, 1660, 1620, 1380. UV:λ_nax(water), nm (ε) 228 (22200), 291
(23600). NMR: δ(D₂O) ppm 1.45 (3H, t, j=6Hz, CH₂C _H3 ),
3.72 (2H, s, 2-H), 4.45 (2H, q, C
H ₂ CH ₃ ), 5.40 (1H, d, J = 4Hz, 6-
H), 5.90 (1H, d, J = 4Hz, 7-H),
7.05 (1H, d, J=15Hz, 3-CH), 8.30
(2H, d, J = 6Hz, Py-H), 8.95 (2H,
d, J=6Hz, Py-H). I-2N, Z isomer melting point: >200°C (decomposed). IR: ν _nax (KBr) cm ^-1 1760, 1660 (sh), 1620,
1370. UV: λ _nax (phosphate buffer, PH7) nm (ε) 225
(22400), 275 (sh, 16000). _NMR : δ( _D20 )ppm 1.45 (3H, t, j=7Hz, _CH2CH3 ),
3.50 (1H, d, J=17Hz, 2-H), 3.75
(1H, d, J = 17Hz, 2-H), 5.38 (1H,
d, J=4Hz, 6-H), 5.95(1H, d,
J = 4Hz, 7-H), 6.62 (1H, d, J =
11Hz, 3-CH), 8.35 (2H, d, J=6
Hz, Py−H), 8.92 (2H, d, J=6Hz,
Py-H). Reference example 25 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyimino)-acetamide]-3-[3-
(4-Carbamoylpyridinio)-1-propenyl]-3-cephem-4-carboxylate (I-3H) (E isomer) 7-amino-3-[3-(4-carbamoylpyridinio)- 1-(E)-propenyl]-3-cephem 4-carboxylate hydrochloride 35 mg (0.08 mol)
2-(5-amino-1,2,4,-thiadiazol-3-yl) in solution in 2 ml of 50% aqueous acetone.
52 mg of -2-(propen-3-yloxyimino)-acetyl chloride hydrochloride (from Preparation No. 25) was added and the mixture was adjusted to PH _6.5-7.0 with 2N- _Na2CO3 . The mixture was stirred at room temperature for 1 hour and then diluted with 1N HCl.
The pH was adjusted to 2, and the residue was concentrated under reduced pressure.
Chromatography was carried out using a column of 20 resin, eluting with 300 ml of water and 30% _CH3OH - _H2O . The product containing fractions were combined and evaporated under reduced pressure. Residue, 73mg, Prep PAK−
A column purified by a reverse phase carrier column taken from a 500/C ₁₈ cartridge (Waters, 30ml) was mixed with water, 5% CH ₃ OH, 10% CH ₃ OH and
Eluted sequentially with 20% CH ₃ OH. The product-containing fractions are combined and lyophilized to yield the title product I-
3H, 26 mg (62%) was obtained. Melting point, 160°C (decomposition). IR: ν _nax (KBr) cm ^-1 3400, 1765, 1680, 1605,
1400. UV: λ _nax (phosphate buffer, PH7) nm (ε) 226
(24600), 288 (22800) NMR: δ (D ₂ 0) ppm 3.75 (2H, s, 2-H), 5.41 (1H, d, J
=5Hz, 6-H), 5.50(4H, m, CH ₂ N ⁺
and CH=C H ₂ ), 5.98 (1H, d, J=5
Hz, 7-H), 6.20 (1H, m, 3-CH=C
H), 7.09 (1H, d, J = 17Hz, 3-CH),
8.50 (2H, d, J=7Hz, Py-H), 9.16
(2H, d, J = 7Hz, Py-H). Reference example 26 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-propargyloxyiminoacetamide]-3-[3-(4-carbamoylpyridinio)-1-propenyl] -3-
Cefem-4-carboxylate (1-4H)
(E isomer) 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem-4-carboxylate hydrochloride (-H) 86
mg (0.19 mmol) of 2-propargyloxyimino-2-(5) in 2 ml of 50% aqueous acetone.
-amino-1,2,4,-thiadiazole-3-
yl)-acetyl chloride hydrochloride (from production No. 26)
Added 63 mg. The suspension was adjusted to pH6.5 with 2N−Na ₂ CO ₃
7.0 and then stirred for 1 hour at room temperature.
The reaction mixture was brought to PH2 with 1N HCl and concentrated in vacuo. The residue was diluted with 30 ml of water, neutralized with NaHCO ₃ and filtered. Filter the filtrate using Prep PAK-500/
Reverse phase carrier (30 ml) from a C ₁₈ cartridge (Waters) was transferred to the top of the packed column. Fill the column with water, 5% _CH3OH , 10% _CH3
Eluted sequentially with OH and 20% _CH3OH . The product-containing fractions were combined and lyophilized to yield the title product I-4H, 13 mg (12%). Estimated purity 70%, melting point, 160°C. IR: ν _nax (KBr) cm ^-1 3400, 2120, 1765, 1680,
1610. UV: λ _nax (phosphate buffer, PH7) nm (ε) 229
(24000), 288 (21200). NMR: δ (D ₂ 0) ppm 3.78 (2H, s, 2-H), 5.15 (2H, d, J
= 1Hz, -C H ₂ -C≡CH), 5.40 (1H, d,
J = 5Hz, 6-H), 5.50 (2H, m, C H
−N ⁺ ), 5.98 (1H, d, J=5Hz, 7−
H), 6.20 (1H, m, 3-CH= CH ), 7.05
(1H, d, J=7Hz, 3- CH ), 8.50
(2H, d, J = 7Hz, Py-H), 9.16 (2H,
d, J = 7Hz, Py-H). Reference example 27 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3-[3-(4-carbamoylpyridinio)-1-propenyl] -3
-Cefem-4-carboxylate (1-5H)
(E isomer) 50% of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propenyl]-3-cephem 4-carboxylate hydrochloride 139 mg (0.31 mmol) in an ice bath. 2-(5-Amino-1,2,4,-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27) 120 in a stirred solution in 3.5 ml of aqueous acetone.
mg (0.44 mmol) was added in portions. mixture
Adjust the pH to 6.5-7.0 with 2N−Na ₂ C0 ₃ (0.9 ml), and add 10
Stir at ℃ for 1 hour. The reaction mixture was diluted with 1N HCl.
to pH 2 and evaporated under reduced pressure. residue
Chromatographed on a column of HP-20 resin (20 ml), 300 ml of water and 30% CH ₃ OH-H ₂
0 and sequentially eluted. The product containing fractions were combined and concentrated in vacuo. Treatment of the residue with 60 ml of acetone gave the title product I-5H, 111 mg (83%). Melting point, 160°C (decomposed). Estimated purity 70%. IR: ν _nax (KBr) cm ^-1 3400, 1770, 1680, 1605,
1530. UV: λ _nax (phosphate buffer, PH7) nm (ε) 224
(23300), 286 (24600). NMR: δ (DnSO-d ₆ ) ppm 1.70 (8H, br.s, [formula]), 4.68 (1H, br.s, [formula]), 5.05 (1H, d, J=5Hz, 6-H) 5.30 (2H, m,
CH ₂ N ⁺ ), 5.67 (1H, dd, J=5Hz,
and 7Hz, 7-H), 6.20 (1H, m, 3
-CH= CH ), 7.08 (1H, d, J=17Hz,
3-CH), 8.34 (2H, d, J=7Hz, Py-
H), 9.11 (2H, d, J=7Hz, Py-H),
9.38 (1H, d, J = 7Hz, 7-NH). Reference example 28 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(3-carboxymethylpyridinio)-1-propenyl]- 3-cephem-4-carboxylate (1-1p) (E isomer) A 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]- 3-[3-(3-carboxymethylpyridinio)-1-propenyl]-3-cephem-4-carboxylic acid diphenylmethyl (
-1P, iodide, E isomer) 3-carboxymethylpyridine hydrochloride (0.89
N, 5 mmol) in 10 ml of CH ₂ Cl ₂
O-bis(trimethylsilyl)acetamide (4.97ml, 18mmol) was added and the mixture was stirred at room temperature until a clear solution was obtained. in solution-
1 (1.79 g, 2.5 mmol) was added and the mixture was left at room temperature. After 3 hours, add CH ₃ OH3 to the cooled mixture.
ml and the solution was evaporated in vacuo to give an oil which was triturated with ethyl acetate to give the title compound-1P, 2.28 g as a tan powder. Melting point: 161℃ (decomposition). IR: ν _nax (KBr) cm ^-1 1780, 1720, 1675, 1630,
1530, 1385, 1225, 1045, 755, 700. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1 cm) 295 (188). NMR: δ (DMSO + D ₂ 0) ppm 3.70 (2H, br, s, 2-H), 3.90 (5H,
s, OCH ₃ and Py-CH ₂ CO), 5.25 (3H,
m, -CH ₂ N ⁺ and 6-H), 5.92 (1H,
d, J = 4.5Hz, 7-H), 6.35 (1H, m,
3-CH= CH- ), 6.90 (1H, d, J=16
Hz, 3-CH), 6.92 (1H, s, CHPh ₂ ),
7.35 (10H, m, Ph-H), 8.8-9.0 (4H,
m, Ph-H). B 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(3-carboxymethylpyridinio)-1-propenyl ]-3-Cefem-4-carboxylate (1-1P) (E isomer) A mixture of -1P (iodide) (2.28 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was heated at room temperature. I stirred it for 2 hours. The reaction mixture was concentrated under reduced pressure to approximately 5 ml. Trituration of the oily residue with acetone (100 ml) yielded 1.22 g of crude product,
Column chromatography (HP-20,
420 ml) to give the title compound I-1P,
533 mg (38%, from -1) was obtained as a pale yellow amorphous powder. Melting point: 161℃ (decomposition). IR: ν _nax (KBr) cm ^-1 1770, 1670, 1600, 1530,
1385, 1140, 1040. UV: λ _nax (phosphate buffer, PH6.2) nm (E1% 1cm)
234 (374), 277sh (390), 290 (402). NMR: δ (D ₂ 0 + NaHCO ₃ ) ppm 3.78 (2H, s, 2-H), 3.92 (5H, s,
Py−CH ₂ CO), 4.22 (3H, s, 0CH ₃ ),
5.40 (1H, d, J=4Hz, 6-H), 5.44
(2H, d, J=6.5Hz, −CH ₂ −N ⁺ ), 5.97
(1H, d, J = 4Hz, 7-H), 6.20 (1H,
d-t, J=16 and 3-CH=C H ),
7.08 (1H, d, J=16Hz, 3-CH), 8.11
(1H, dd, J=8 and 7Hz, Py−
H ₅ ), 8.53 (1H, d, J=8Hz, Py−H ₄ ),
8.82 (1H, d, J=8Hz, Py−H ₆ ), 8.86
(1H, S, Py−H ₂ ). Reference example 29 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(4-carboxymethylthiopyridinio)-1-propenyl]- 3-cephem-4-carboxylate (1-1Q) (E isomer) A 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]- 3-[3-(4-carboxymethylpyridinio)-1-propenyl]-3-cephem-4-carboxylic acid diphenylmethyl (
-1Q, iodide, E isomer) 4-carboxymethylthiopyridine (0.88g,
5 mmol) in 10 ml of CH ₂ Cl ₂ , N,
O-bis(trimethylsilyl)acetonamide (5 ml, 18 mmol) was added and the mixture was stirred at room temperature until a clear solution was obtained. -1 in solution
(E isomer, 1.79 g, 2.5 mmol) was added and the mixture was left at room temperature. After 3 hours, add _CH3 to the cold mixture.
3 ml of OH was added and the solution was evaporated in vacuo to give an oily residue which was triturated with ethyl acetate to give 2.43 g of the title compound-1Q (iodide) as a tan powder. Melting point 155℃ (decomposition). IR: ν _nax (KBr) cm ^-1 1780, 1720, 1670, 1625,
1525, 1385, 1225, 1115, 1040, 755,
700. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1 cm) 312 (299). NMR: δ (DMSO-d ₆ + D ₂ O) ppm 3.70 (2H, br, s, 2-H), 3.93 (3H,
s, OCH ₃ ), 5.07 (2H, m, CH ₂ −N ⁺ ),
5.23 (1H, d, J=5Hz, 6-H), 5.90
(1H, d, J = 5Hz, 7-H), 6.29 (1H,
m, 3-CH= CH ), 6.87 (1H, d, J=
16Hz, 3-CH), 6.91 (1H, s, CHPh ₂ ),
7.35 (10H, m, Ph-H), 7.88 and 8.58
(Each 2H, d, J = 6Hz, Py-H). B 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(4-carboxymethylpyridinio)-1-propenyl ]-3-Cefem-4-carboxylate (1-1Q) (E isomer) A mixture of -1Q (iodide) (2.43 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was heated at room temperature. I stirred it for 2 hours. The reaction mixture was concentrated under reduced pressure to approximately 5 ml. The oily residue was triturated with acetone (100 ml), filtered and dried to yield the crude product (1.39 g), which was purified by column chromatography (HP-20, 20 ml) to yield the title compound I-1Q, 577 mg. (-1 to 39%)
was obtained as a pale yellow amorphous powder. Melting point 188℃
(Disassembly). IR: ν _nax (KBr) cm ^-1 1765, 1670, 1625, 1530,
1380, 1110, 1035. UV: λ _nax (phosphate buffer, PH6.2) nm (E1% 1cm)
234 (459), 310 (678). NMR: δ (D ₂ 0 + NaHCO ₃ ) ppm 3.79 (2H, br.s, 2-H), 4.10 (2H, s,
S-CH ₂ ), 4.23 (3H, s, OCH ₃ ), 5.25
(2H, d, J=6.5Hz, CH ₂ −N ⁺ ), 5.39
(1H, d, J = 4.0Hz, 6-H), 5.97 (1H,
d, J = 4Hz, 7-H), 6.18 (1H, d-
t, J=15.5Hz and 6.5Hz, 3-CH=C
H), 7.05 (1H, d, J = 15.5Hz, 3-
CH), 7.84 and 8.55 (each 2H, d, J = 7
Hz, Py−H). Reference example 30 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(1-methylpyrrolidinio)-1-propenyl]- 3-CEFEM-4-
Carboxylate sulfate (-1A, sulfate) A 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(1 -methylpyrrolidinio)-1-propenyl]-3-cephem-4
-diphenylmethyl carboxylate (-1A,
Iodide, E isomer) 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(3-iodopropenyl)-3-
Diphenylmethyl cefem-4-carboxylate (
-1) (from Preparation No. 14) (21.5 g, 30 mmol) in ethyl acetate (300 ml) cooled 1-methylpyropyridine) 2.25 g, 30 mmol of ethyl acetate (30 mmol)
ml) was added dropwise over 1 hour with stirring at -5 to 0°C. After stirring for an additional 10 minutes, the resulting precipitate was collected by filtration and washed with chloroform (200 ml) to yield the title compound (-
1A, iodide) 23.0 g (95.8%) were obtained, melting point >175°C (decomposition). IR: ν _nax (KBr) cm ^-1 3300, 1780, 1730, 1685,
1615. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1cm) 218 (435),
295 (188). B 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(1-methylpyropyridinio)-1-propenyl] -3-Cefm-
Diphenylmethyl 4-carboxylate (-1A,
Amberlite IRA-410 (chloride form,
230ml) column. The column was developed with a solvent and the fractions containing the desired compound were combined and concentrated to an oily residue, which was diluted with ethyl acetate).
300 ml) to give the title compound (-1A, chloride), 17.9 g (87.7%), mp.
190℃ (decomposition). IR: ν _nax (KBr) cm ^-1 3380, 1780, 1680, 1620. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1cm) 220 (369),
290 (232). C 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(1-methylpyrrolidinio)-1-propenyl] -3-CEFM-4
-Carboxylate sulfate (-1A, sulfate) A mixture of compound (-1A, chloride) (17.8 g, 25 mmol) in 85% formic acid (178 ml) was stirred at room temperature under nitrogen atmosphere for 2 hours. The mixture was evaporated in vacuo and the oily residue was triturated with acetone to yield 9.80 g of crude-1A. Concentrate the filtrate;
When washed with acetone, even more crude -1A, 2.95g
was gotten. The combined crude products were extracted with 2N HCl (1 and 0.5). The combined extracts were adsorbed onto Diaion HP-20 resin (1.5 columns) and it was eluted with water and 30% aqueous methanol. Collect the desired fraction and evaporate it in vacuo to an oily residue, which is dissolved in isopropanol (200
ml) and acetone (200 ml) yielding 7.09 g of a pale yellow powder. This substance (6.80g)
was dissolved in water (20ml), then Prep PAK-
Column chromatography was performed on a packed 500/C ₁₈ cartridge (90 ml) using water and 10% aqueous methanol as eluents. eluent
HPLC [Column, Nucleocil SSC
-ODS-262, 8 x 100 mm; mobile phase, 0.01M phosphate buffer (PH7.2)/CH ₃ OH = 90:10; detection,
The mixture was collected in a 20 ml fraction while being monitored by UV (254 nm). Fraction No. 4 to Fraction No. 10 are combined and evaporated under reduced pressure, and freeze-dried to yield a yellow powder (E/Z=7/1, 70% purity).
2.28 g was obtained (harvest 1). Fraction No.11
~ Fraction No. 85 was treated as above to yield 3.27 g of yellow powder (E/Z=5/1, 70% purity) (Harvest 2). Prep part of Harvest 1 (1.0mg)
PAK-500C ₁₈ cartridge filling (90ml)
The above was purified again by chromatography. The column was eluted sequentially with water and 5% aqueous methanol. The eluate containing the desired compound was concentrated and lyophilized to yield 638 mg of yellow powder (E/Z=7/1, 80%
purity) was obtained. Remaining part of Harvest 1 (1.14
If g) is finished in the same way, 880 mg of yellow powder (E/Z
=7/1, 80% purity) was obtained. Combine the two pure samples and add one part (1.45 g) to 1N sulfuric acid (5 ml).
dissolved in The solution was diluted with acetone (315ml) with stirring. A cream colored precipitate was collected by filtration to yield the title compound (-1A, sulfate) (E/
Z=7/1, 80% purity) 1.48 g were obtained, melting point >185°C (decomposition). IR: ν _nax (KBr) cm ^-1 3380, 3000, 1765, 1675,
1630, 1535, 1390, 1115. UV: λ _nax (phosphate buffer, PH7) nm (ε) 236
(19900), 291.5 (22500). NMR: δ (D ₂ 0 + NaHCO ₃ ) ppm 2.36 (4H, br., [Formula]), 3.15 (3H, s, [Formula]), 3.62 (5H, br., 2-H, and [Formula]), 3.83 (1H, br., 2-H), 4.13 (2H, d,
J = 8Hz, CH ₂ N ⁺ ), 4.22 (3H, s,
OCH ₃ ), 5.39 (1H, d, J = 4.5Hz, 6-
H), 5.96 (1H, d, J = 4.5Hz, 7-H),
6.00 (1H, m, 3-CH=C H ), 6.67 (1/
8H, d, J = 10Hz, 3-CH, cis), 7.04
(7/8H, d, J = 16Hz, 3-ch, transformer). Reference example 31 7-[2-(5-Amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-trimethylammonio-1-propenyl]-3-cephem-4 -carboxylate (1-1D) A 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-trimethylammonio-1- propenyl]-3-cephem-4-carboxylic acid diphenylmethyl (-1D, iodide) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3- (3-iodopropenyl)-3-cephem-4-carboxylic acid diphenylmethyl (-
1. To a solution of 13.0 g (19 mmol) (from production No. 10) in 38 ml of dry ethyl acetate,
1.75 ml (19.1 mmol) of 1.1N trimethylamine was added at -5°C and the mixture was stirred at -5°C for 1 hour. The resulting precipitate was filtered, thoroughly washed with CHCl ₃ and dried to give 12.5 g (88
%) was obtained as iodide. IR: ν _nax (KBr) cm ^-1 3300, 1765, 1720, 1665. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 300 (18400). B 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-trimethylammonio-1-propenyl]-3-cephem-4 - Diphenylmethyl carboxylate (-1D, chloride) Dissolve iodide (-1D, 12.5 g) in 60 ml of CH ₃ OH-acetone (1:1) and apply it to a column of ion exchange resin [IRA-410 (Cl ^- ), 125 ml]. passed through.
The column was eluted with 300 ml of CH ₃ OH-acetone (1:1), the eluate was concentrated in vacuo and triturated with 300 ml of isopropyl ether to give the quaternary salt (-1D,
10.4 g (91%) of chloride) were obtained. IR: ν _nax (KBr) cm ^-1 3300, 1765, 1710, 1665, UV: λ _nax (C ₂ H ₅ OH) nm (ε) 298 (15100). C 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-trimethylammonio-1-propenyl]-3-cephem-4 -Carboxylate (-1D, sulfate, E isomer) -1D (chloride) 10.4 g (16.0 mmol)
A solution of in 20.8 ml of 85% formic acid was left at room temperature for 3 hours and concentrated in vacuo. Isopropanol the residue
210ml and filtered the precipitate. Solid (10.1g)
was ground with 210 ml of water and neutralized with sodium bicarbonate. Filter the suspension and transfer the filtrate to HP-20 (300
ml) column, which was eluted sequentially with water (1000 ml), 10% CH ₃ OH (200 ml) and 30% CH ₃ OH (150 ml). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was filled with a packing obtained from a Prep PAK-500/C ₁₈ cartridge (Waters, 200ml). Water (600ml) and 30% _CH3OH
(200 ml) and then concentration of the fractions containing the desired product yielded 2.52 g of the title compound.
(18%) was obtained. Zwitterionic products (1.5
g) in 1N-H ₂ SO ₄ (5 ml) was dissolved in acetone.
One portion was added to 300 ml, and the resulting precipitate was filtered and dried. −1D sulfate yield is 1.42g (80%)
It was hot. The E/Z ratio is approximately 10/based on HPLC.
It was 1. IR: ν _nax (KBr) cm ^-1 3380, 1765, 1665. UV: λ _nax (phosphate buffer, PH7) nm (ε) 237
(19500), 293 (22400). NMR: δ(D ₂ 0) ppm 3.25 (9H, s, N ⁺ -CH ₃ ), 3.94 (2H, s,
2-H), 4.14 (2H, d, J=7Hz, CH ₂
N ⁺ ), 4.23 (3H, s, O-CH ₃ ), 5.42
(1H, d, J = 4.5Hz, 6-H), 6.00 (1H,
d, J = 4.5Hz, 7-H), 6.23 (1H, d-
t, J=7 and 16Hz, 3-CH= CH ),
7.23 (1H, d, J = 16Hz, 3-CH). Reference example 32 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(4-carbamoylpyridinio)-1-propenyl]- 3-Cefm-
4-Carboxylate (-1E) (E isomer) 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem 4-carboxylate hydrochloride ( -H, 397
benzotriazol _- 1-yl-2-
(5-amino-1,2,4-thiadiazole-3
-yl)-2-methoxyiminoacetate (479
mg, 1.5 mmol) (from Preparation No. 28) was added. The mixture was stirred at room temperature for 3.5 hours. reaction mixture
The pH was adjusted to 3-4 with 3N-HCl and diluted with 200 ml of acetone to form a precipitate, which was collected by filtration. The crude product was dissolved in a small amount of aqueous THF and the solution was adjusted to PH 6.8 with NaHCl ₃ , treated with decolorizing charcoal, concentrated to about 1 ml and seeded with a few pieces of crystal-1H.
After stirring overnight, the crystalline precipitate was collected by filtration to yield the title compound -1H (zwitterionic form). Yield 83 mg (16%). Melting point, >185°C (decomposition).
The physicochemical data of this product matched those of the compound of Reference Example 10. Reference example 33 Production No. 1 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid Diphenylmethyl (-1) 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetic acid (-
1) (2.1 g, 10 mmol) in dry CH ₂ Cl ₂ (50 ml)
PCl ₅ (2.09 g, 10 mmol) was added to the stirred suspension at −30° C. and the mixture was stirred at −15 to −20° C. for 20 minutes. Add 7-amino-3- to the above acid chloride solution.
CH ₂ Cl ₂ (50
ml) was added at -30°C. After stirring at -10<0>C for 1 hour, the mixture was concentrated _to remove _CH2Cl2 and diluted with ethyl acetate (200ml). mixture
10% aqueous _NaHCO3 (2 x 40ml), _H20 (2 x 20ml)
and _MgSO4 with sequential washes with brine (10 ml).
It was dried. The solvent was evaporated in vacuo and the resulting oily residue (10 g) was dissolved in CHCl ₃ (20 ml) and added to silica gel [Wako gel C-200, 100
g, containing 10ml of 1/1.5M PH7 phosphate buffer)
Chromatography was performed using 1/3% CH ₃ OH-CHCl ₃ as above. Evaporation of the fractions containing the title compound gave 5.7 g (95%) of -1 as a yellow amorphous powder. Melting point, >140°C (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1720, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 245 (1800), 280 (9900). NMR: δ ^DMSO-d6 _ppn 3.53 (2H, ABq, 2-H), 3.94 (3H, s,
OC H ₃ ), 4.42 (2H, s, 3-CH ₂ ), 5.22
(1H, d, J = 4.5, 6-H), 5.92 (1H,
dd, J=4.5 and 6,7-H), 6.93
(1H, s, C HP h ₂ ), 7.36 (10H, m, Ph
-H), 8.1 (2H, br-s, NH ₂ ), 9.58
(1H, d, J = 6,7-NH). Production No. 2 Diphenylmethyl 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylate (-
1) -1 from production No. 1 (5.7 g, 9.5 mmol)
A mixture of and NaI (4.3 g, 29 mmol) in dry acetone (50 ml) was stirred at room temperature for 5 minutes.
The mixture was concentrated under reduced pressure and the resulting oil was triturated into a mixture of ethyl acetate (100ml) and _H2O (10ml). Separate the organic layer and add 10% w/v
Washed sequentially with sodium thiosulfate and brine. After drying, the ethyl acetate was removed in vacuo to give 6.1 g (93%) of the title compound (-1) as a yellow amorphous powder, melting point >120°C (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1725, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 245 (17000), 282 (12000). NMR: δ ^DMSO-d6 _ppn 3.72 (2H, ABq, 2-H), 3.94 (3H, s,
OCH ₃ ), 4.23 (2H, s, 3-CH ₂ ), 5.21
(1H, d, J = 4.5, 6-H), 5.89 (1H,
dd, J=4.5 and 6,7-H), 6.94
(1H, s, C HP h ₂ ), 7.35 (10H, m, Ph
-H), 8.12 (2H, br-s, NH ₂ ), 9.65
(1H, d, J = 6,7-NH). Production No. 3 7-[2-(5-Amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-triphenylphosphoniomethyl-3-cephem-carboxylic acid diphenyl Enylmethyliodide (-1) -1 from Preparation No. 2 (690 mg, 1 mmol) and triphenylphosphine (786 mg, 3 mmol)
A mixture of and in ethyl acetate (20ml) was stirred at room temperature overnight. The liberated solid was collected, washed with ethyl acetate (2 x 10ml) and dried to yield 950mg (100%) of phosphonium iodide-1. Melting point: 186℃ (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1710, 1680, 1610. UV: λ ^EtOH _nax nm (ε) 268 (15000), 275 (13000, 300
(7300). NMR: δ ^DMSO-d6 _ppn 3.52 (2H, br-s, 2H), 3.94 (3H, s,
OC H ₃ ), 5.34 (1H, d, J = 4.5, 6-
H), 5.9 (1H, m, 7-H), 6.3 (1H,
s), 7.3 (10H, m, Ph-H), 7.8 (15H,
m, Ph-H). Production No. 4 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[(triphenylphosphoranylidene)methyl]-3-cephem -4-Diphenylmethyl carboxylate (-1) -1 from Preparation No. 3 (952 mg, 1 mmol),
Amberlite IR-410 (OH ^- form, 500mg) and 1N
A mixture of -NaOH (4 ml) in CH ₂ Cl ₂ (10 ml) was stirred at room temperature for 1 hour. The mixture was filtered and the separated organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil was triturated with ethyl acetate and the resulting yellow precipitate was collected by filtration to yield the title compound,
-1, 740 mg (90%) was produced. Melting point, >180℃
(Disassembly). IR: ν ^KBr _nax cm ^-1 3400, 1750, 1630. UV: λ ^EtOH _nax nm (ε) 268 (12000), 276 (10000),
384 (23000). Production No. 5 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(3-chloro-1-propene-
Diphenylmethyl (-1)-3-cephem-4-carboxylate (-1) -1 from Preparation No. 4 (6.9 g, 8.4 mmol)
To a solution of MgSO ₄ (3 g) and 40% chloroacetaldehyde (810 mg, 8.4 mmol) in 84 ml of methylene chloride was added. The mixture was stirred at room temperature for 1.5 hours and then filtered. The filtrate was soaked in silica gel (Wakogel C-200, 100g 1/1.5M phosphate buffer).
eluted by using CHCl ₃ containing CHCl ₃ and CH ₃ OH on a column (containing 10 ml). The fraction containing the desired product (0.5-1% _CH3OH-
CHCl ₃ ) Evaporation in vacuo yields the title compound-1,
1.6 g (30%) was obtained as a yellow amorphous powder, which was a mixture of Z and isomers regarding the chloropropenyl moiety (Z/E=2/1, by nmr). Melting point, >130°C (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1725, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 240 (20000), 286 (12000). NMR: δ ^DMSO-d6+D2O _ppn 3.56 and 3.8 (m, 2-H), 3.94 (3H,
s, OCH ₃ ), 4.16 (d, J = 7.5, CH H ₂
Cl), 5.26 (1H, d, J = 4.5, 6-H),
5.87 (1H, d, J = 4.5, 7-H), 6.28
(2/3H, d, J=11,3-c Hcis-
H), 6.72 (1/3H, d, J = 16, 3-C
H, trans-H), 6.81 (2/3H, s,
C H Ph ₂ ), 6.92 (1/3H, s, C H Ph ₂ ),
7.4 (10H, m, Ph-H). Example 1 Production No. 6 7-benzylideneamino-3-[(triphenylphosphoranylidene)methyl]-3-cephem-
Diphenylmethyl 4-carboxylate () 7-benzylideneamino-3-[(triphenylphosphonio)methyl]-3-cephem-4-carboxylic acid diphenylmethyl iodide () [Japanese Patent Application (Publication) 1987-86187 No. (7/31/81)
[produced according to the procedure] (60 g, 70 mmol)
1N NaOH (140 ml) in solution in CH ₂ Cl ₂ (350 ml)
and Amberlite IRA-410 (OH ^- form, 35g)
was added at 5°C. The mixture was stirred at 5° C. for 1 hour and filtered. Separate the organic layer, dry with _MgSO4 ,
It was concentrated to a volume of approximately 100ml and precipitated with ethyl acetate (500ml). The resulting yellow solid was collected by filtration and dried in vacuo to yield the title compound, 48 g (94
%) was obtained, >195-8°C (decomposition). IR: ν ^KBr _nax cm ^-1 1770, 1620, Production No. 7 7-Benzylideneamino-3-(3-chloro-
1-propen-1-yl)-3-cephem-4
- diphenylmethyl carboxylate (2.9 g, 4 mmol) from Preparation No. 6
Anhydrous chloroacetaldehyde (800 mg) to a stirred solution in a mixture of CH ₂ Cl ₂ (40 ml) and H ₂ O (10 ml)
was added at room temperature. An additional 800 mg of chloroacetaldehyde was added to the mixture in three portions over 1 hour, during which time the PH of the mixture was maintained at 6-9 by addition of 1N NaOH. Remove the aqueous layer after 15 minutes,
The organic layer was dried over _MgSO4 . Evaporation of the solvent gave a red oil, which was dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml).
dissolved in The solution was washed sequentially with saturated aqueous _NaHCO3 (10ml) and _H20 (10ml).
Yellow oil upon removal of solvent after drying over _MgSO4
3.3g was obtained. The oil was dissolved in CH ₂ Cl ₂ (50 ml) and added with 1/1.5M phosphate buffer (1.2
ml, PH6.4) was added and filtered, and the silica gel was dissolved in CH ₂
Washed with _Cl2 (50ml). The filtrate and washings were evaporated to dryness. Trituration of the residue with n-hexane yielded 1.7 g (80%) of the title compound () as a yellow powder. In the nmr spectrum, the chloropropenyl component is Z
It was shown that it has coordination. Melting point, >50°C (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1775, 1720, 1630,. UV: λ ^EtOH _nax nm (ε) 253 (11000), 258 (11000),
265 (10000), 273 (8300), 281 (7000), 290
(6300). NMR: δ ^DMSO-d6 _ppn 3.63 (2H, br-s, 2H), 4.0 (2H, m, C
H ₂ −Cl), 5.42 (2H, m, 6-H and 3
-CH= CH ), 5.72 (1H, d, J=4.5, 7
-H), 6.27 (1H, d, J = 11, 3-CH),
6.85 (1H, s, C HP h ₂ ), 7.33 (10H, m,
Ph-H). Preparation of anhydrous chloroacetaldehyde Anhydrous calcium chloride was added with stirring to a cooled solution of 50% aqueous chloroacetaldehyde (50 ml) and the two layers were separated. The chloroacetaldehyde hydrate layer ⁽¹⁾ (upper layer) was separated, diluted with CHCl ₃ (100 ml), mixed with MgSO ₄ (20 g), heated to reflux for 5 minutes and filtered. Solvent and water azeotropically (boiling point 56
~64℃) ⁽²⁾ and distillation of the residue yields anhydrous chloroacetaldehyde ⁽³⁾ , boiling point 70~82℃/
760nm was obtained. IR: ν film maxcm ^-1 1720. (1) RPKurkjy, EVBrown, J.Am.Chem.
Soc., 74, 5778 (1952). (2) S.Trippett, DMWalker, J.Chem.Soc.,
1961, 1266. (3) HOHouse, VKJones, GAFrank, J.
Org, Chem., 29 , 3327 (1964). Reference Example 34 Production No. 8 Diphenylmethyl 7-amino-3-(3-chloro-1-propen-1-yl)-3-cephem-4-carboxylate () from Production No. 7 (180 mg, 0.34 mmol)
acetic acid (0.25 mL) in ethyl acetate (10 ml).
Girard's reagent T in CH ₃ OH (10 ml) containing
It was added to a solution of [(carboxymethyl)trimethylammonium chloride hydrazide] (251 mg, 1.5 mmol) at 5°C. After stirring at 5℃ for 30 minutes,
The mixture was concentrated to remove CH ₃ OH and then added to ethyl acetate (20ml). Ethyl acetate solution in _H2
0 (2 x 5 ml), saturated aqueous _NaHCO3 (5 ml) and brine (5 ml) and dried over _MgSO4 . Evaporation of the solvent yielded the title compound (Z
145 mg (97%) of the isomer) was obtained as a yellow powder. Melting point, >100°C (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1770, 1720. UV: λ ^EtOH _nax nm (ε) 252 (3700), 258 (3800), 260
(4000), 274 (4000), 285 (4000). Reference example 35 Production No. 9 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(-chloro-1-propene-1
-yl)-3-cephem-4-carboxylic acid diphenylmethyl (-1) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid (-
A mixture of 1) (10.1 g, 50 mmol) and _PCl5 (10.4 g, 50 mmol) in dry _CH2Cl2 ( ₁₀₀ ml) was stirred at -7 to -15<0>C for 2 hours. clear solution
- When poured into hexane (500 ml), a precipitate formed. The organic layer was discarded by decantation and the remaining solid was triturated with n-hexane (100ml).
The yellow precipitate was collected by filtration and dried in vacuo to yield the acid chloride, 12.5 g (99%), at 80° C. (decomposed). IR: νnujiol maxcm ^-1 1770. The acid chloride (25 mg, 0.1 mmol) was added to a solution of (Z isomer) (44 mg, 0.1 mmol) from Preparation No. 8 in dry CH ₂ Cl ₂ (5 ml) at room temperature with stirring. After 30 minutes, the mixture was concentrated under reduced pressure, treated with ethyl acetate (20 ml) and saturated aqueous NaHCO ₃ (5
ml). Saturate the organic layer with aqueous NaHCO ₃ (5
ml), brine (5 ml), 10% HCl (5 ml) and brine (5 ml). The solvent was dried over MgSO ₄ and then evaporated to dryness to yield the product as a yellow foam. The air bubbles were dissolved in silica gel (Wakogel C-200, 1g, 1/1.5M phosphate buffer PH).
6.4, containing 0.1 ml) purified by column chromatography eluting with _{CH2Cl2 - CH3OH} (100:1) to yield the title compound-1 (Z isomer).
31 mg (50%) resulted as a yellow powder. Melting point, >
150℃ (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1775, 1720, 1675, 1630. UV: λ ^EtOH _nax nm (ε) 240 (17000), 280 (10000). NMR: δ ^DMSO-d6 _ppn 3.6 (2H, m, 2-H), 3.92 (3H, s, O
-C H ₃ ), 4.0 (2H, m, C H ₂ Cl), 5.27
(2H, m, 6-H and 3-CH=C H ),
5.83 (1H, dd, J=4.5 and 10,7-
H), 6.25 (1H, d, J=11,3- CH ),
6.83 (1H, s, CH Ph ₂ ), 7.33 (10h, m,
Ph-H), 8.0 (2H, br-s, _NH2 ), 9.57
(1H, d, j = 10,7-NH). Reference example 36 Production No. 10 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-iodo-1-propene-
Diphenylmethyl (-1)-3-cephem-4-carboxylate (-1) from production No. 5 (Z/E=2/1, 480
mg, 0.77 mmol) NaI (346 mg, 2.3 mmol)
A solution in dry acetone (10ml) containing 30% at room temperature
Stir for a minute. The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between ethyl acetate (50ml) and water (10ml). 10%/w/v upper layer
Washed sequentially with aqueous sodium thiosulfate solution (10ml) and brine (10ml) and dried over _MgSO4 . Evaporation of the solvent yields the title compound-1
(Z/E=1/1) 540 mg (98%) obtained as a slightly red amorphous solid, >120°C (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1720, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 240 (21000), 290 (12000). NMR: δ ^DMSO+D2O _ppn 3.67 (2H, m, 2-H), 5.29 (1H, d, J
= 4.5, 6-H), 5.95 (1H, d, J = 4.5,
7-H), 6.27 (1/2H, d, J = 11, 3
-CH cis), 6.72 (1/2H, d, J=16,
3-CH, trans), 6.87 and 6.96 (each 1/2H, s, CH Ph ₂ ), 7.4 (10H, m,
Ph-H). Reference example 37 Production No. 11 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-iodo-1-propene-
Diphenylmethyl (-1)-1-yl)-3-cephem-4-carboxylate -1 (Z isomer) from Preparation No. 9 (5.6 g, 9
A mixture of NaI (4 g, 27 mmol) in dry acetone (100 ml) was stirred at room temperature for 1.5 hours. The mixture was evaporated and the residual oil was diluted with ethyl acetate (90ml). 10% w/ ethyl acetate layer
v Sodium thiosulfate aqueous solution (10ml) and _H2
0 (10 ml). Removal of the dry (MgSO ₄ ) solvent gave a yellow oil that was solidified by trituration with isopropyl ether. When the precipitate was filtered, the title compound-1, 4.3g (67%)
was obtained as the E isomer. Melting point, >165°C (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1780, 1725, 1680, 1610. UV: λ ^EtOH _nax nm (ε) 240 (18000), 297 (11000). NMR: δ ^DMSO-D6+2O _ppn 3.90 (3H, s, 0CH ₃ ), 5.25 (1H, m, 6
-H), 5.95 (1H, m, 7-H), 6.72 (d,
J = 16, 3-CH transformer), 6.96 (1H,
s, CH- Ph2 ), 7.4 ( _10H , m, Ph-H). Reference Example 38 Production No. 12 7-Amino-3-[3-chloro-1-propen-1-yl]-3-cephem-4-carboxylic acid benzhydryl (Z-isomer) () The compound is shown in reaction scheme 1b and It is a common intermediate used in 1c. A 7-benzylideneamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylic acid benzhydryl chloride () 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl hydrochloride (hydrochloric acid To a suspension of (200 g, 0.44 mol) in CH ₂ Cl ₂ (940 ml) was added 1N NaOH (440 ml) at room temperature.
The mixture was stirred for 10 minutes and the organic layer was separated. MgSO ₄ (75 g) and benzaldehyde (51 g, 0.48 mol) were added to the organic layer and the mixture was left for 3 hours. Filter the reaction mixture and remove insoluble material _{with CH2Cl2}
(200ml). Combine the filtrate and washing liquid and add triphenylphosphine (126 g, 0.48 mol).
added. The mixture was concentrated to approximately 400 ml and left for 4 days. The resulting viscous oil was dissolved in ethyl acetate (1
) and trituration liberated the title compound as a pale yellow crystalline product powder, which was collected by filtration and dried in vacuo. Yield 322g (96%).
Melting point, 185-190°C (decomposition). IR: ν ^KBr _nax cm ^-1 1780, 1720, 1630. UV: λ ^CH2Cl2 _nax nm (ε) 260 (24100). B 7-benzylideneamino-3-[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylic acid benzhydryl () (322 g, 0.42 mol) and 5N-Na ₂ CO ₃ (252
15 ml) in CH ₂ Cl ₂ (1.6 ml) at room temperature.
Stir vigorously for a minute. Separate the organic layer
Dry over MgSO ₄ and concentrate to a volume of approximately 500 ml.
Addition of the concentrate to acetone (1) with stirring produced a pale yellow crystalline powder, which was collected by filtration, yielding 237 g (78%), 195
~198℃ (decomposition). IR: ν ^KBr _nax cm ^-1 1770, 1620. UV: λ ^CH2Cl2 _nax nm (ε) 254 (23000), 389 (22000)
. NMR: δ ^CDCl3 _ppn 2.56 and 3.16 (2H, ABq), 5.00 (1H,
d, J = 4Hz), 5.23 (1H, d, J = 4
Hz, ), 5.47 (1H, d, J = 22Hz), 6.95
(1H, s), 7.2-7.8 (30H, m), 8.55 (1H,
s). C 7-amino-3-[chloro-1 propene-1
-yl]-3-cephem-4-carboxylic acid benzhydryl hydrochloride (Z isomer) (hydrochloride) (214 g, 0.294 mol) and N,O bis-(trimethylsilyl)acetamide (40 ml, 0.15 mol) in dry CH ₂ to a refluxing solution in Cl ₂ (2.9)
A 50% solution of chloroacetaldehyde (93 g, 0.59 mol) in CHCl ₃ was added dropwise with stirring over 15 minutes. After standing for 30 minutes, the mixture was concentrated to dryness. The residue was treated with CH ₂ Cl ₂ (1.5), Girard's reagent T (99 g, 0.59 mol) and 10% aqueous HCl (300
ml) was added and the mixture was stirred at room temperature for 1 hour.
The organic layer was dissolved in water (200 ml) and saturated NaCl solution (200 ml).
washed with activated charcoal (5 ml), dried over _MgSO4 and washed with activated carbon (5 ml).
g) and filtered. The filtrate was cooled to -10<0>C and treated with 1N HCl in _CH3OH (300ml).
The mixture was stirred at room temperature for 30 minutes and concentrated to approximately 300 ml. Dilute the concentrate with ethyl acetate (400ml) and
Seeded with a few crystals of hydrochloride. After 2 hours, the liberated crystals were collected by filtration, washed with ethyl acetate (200ml) and dried in vacuo to give the title compound, 74g (53%) as its hydrochloride salt, >185°C (decomposed). . Pale yellow needles. IR: ν ^KBr _nax cm ^-1 2830, 1780, 1720. UV: λ ^EtOH _nax nm (ε) 286 (8800). NMR: δ ^DMSO-d6 _ppn 3.73 (2H, br, s, 2-H), 3.97 (2H,
m, CH ₂ Cl), 5.22 (1H, d, J = 4.5Hz,
6-H), 5.37 (1H, d, J=4.5Hz, 7-
H), 5.77 (1H, m, 3-CH= CH ), 6.45
(1H, d, J=11Hz, 3- CH ), 6.88
(1H, s, CH Ph ₂ ), 7.33 (10H, br, s,
Ph-H). Elemental analysis, calculated values for C ₂₃ H ₂₁ N ₂ O ₃ SCl/HCl: C, 57.87; H, 4.65; N, 5.87; S,
6.72; Cl; 14.85. Measured value: C, 57.62; H, 4.53; N, 5.70; S,
6.64; CL; 14.89. Reference example 39 Production No. 13 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-chloro-1-propene-
1-yl]-3-cephem-4-carboxylic acid benzhydryl (Z-isomer) (-1) N,0- of Z isomer (20 g, 42 mmol)
Bis(trimethylsilyl)acetamide (34ml,
2-(5 _- amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride ( _15.2 g, 59 mmol) was added in three portions over 30 minutes at -10 to 0°C. The mixture was stirred at 0-5°C for 30 minutes and concentrated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (420 ml) and the solution was washed sequentially with saturated aqueous NaHCO ( ₃ x 15 ml), saturated aqueous NaCl (15 ml), 10% HCl (15 ml) and saturated aqueous NaCl (15%). , concentrated to a volume of approximately 50 ml. When n-heptane (200 ml) was added to the concentrate, 28.5 g (90 ml) of the title compound-1 (Z-isomer) was obtained.
% purity) was obtained as a colorless powder. Melting point, >150
°C (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1780, 1720, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 240 (20000), 283 (12000). NMR: δ acetone-d6 ppm 3.6 (2H, m, 2-H), 3.95 (3H, s, OC
H ₃ ), 4.0 (2H, m, CH ₂ Cl) 5.32 (1H, d,
J = 4.5Hz, 6-H), 5.62 (1H, m, 3-
CH= CH ), 6.03 (1H, d, J=4.5Hz, 7
-H), 6.32 (1H, d, J=11Hz, 3-
CH), 6.87 (1H, s, CH Ph ₂ ), 7.33
(10H, br, s, Ph-H). Reference example 40 Production No. 14 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-iodo-1-propene-
Benzhydryl [1-yl]-3-cephem-4-carboxylic acid (E-isomer) (-1) -1 (Z-isomer) (28.5 g, 90% purity) and sodium iodide (19 g) in dry acetone (420ml)
The mixture was stirred at room temperature for 10 minutes and left at 5°C for 2 hours. The mixture was concentrated under reduced pressure. Ethyl acetate (420ml) and 10% w/v aqueous sodium thiosulfate solution (30ml) were added to the residue and the mixture was triturated. Wash the organic layer with water (30ml) and
Dry over MgSO ₄ and concentrate to a volume of approximately 50 ml.
Diluting the concentrate with n-heptane (200 ml) yields 30.6 g (95% purity) of the title compound-1 (E isomer).
was obtained as a yellow powder, melting point >120°C (decomposition). IR: ν ^KBr _nax cm ^-1 3400, 1780, 1725, 1680, 1620. UV: λ ^EtOH _nax nm (ε) 306 (15000). NMR: δ acetone-d6 ppm 3.71 (2H, m, 2-H), 3.97 (3H, s,
OC H ₂ ), 4.0 (2H, d, J=8Hz, C H ₂
I), 5.26 (1H, d, J = 4.5Hz, 6-H),
6.03 (1H, dd, J=4.5 and 8Hz,
Double line J = 4.5Hz due to D ₂ O, 7-
H), 6.32 (1H, d-t, J=15 and 8
Hz, 3-CH= CH ), 6.79 (1H, d, J=
15Hz, 3-CH), 6.98 (1H, s, CH
Ph ₂ ), 7.35 (10H, m, Ph-H), 7.63
(N H ₂ annihilated by 2H, br, s, D ₂ O),
8.52 (1H, d, J=8Hz, annihilated by _D2O , 7- NH ). Reference example 41 Production No. 15 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[3-(4-carbamoyl-
1-pyridinio)-1-propen-1-yl]-
3-cephem-4-carboxylic acid benzhydryl iodide (E isomer) (-1H) -1 (E isomer) (30.5 g) and isonicotinamide (26 g, 212 mmol) in _CH3CN (120 ml) )
to the suspension in CH ₃ OH until the mixture becomes clear.
(100ml) was added. The solution was stirred at room temperature under a nitrogen atmosphere for 2 hours and concentrated under reduced pressure to approximately 100 ml.
The residual semi-solid was triturated with isopropyl ether (200ml). The solvent was removed by decantation and the remaining yellow powder was dissolved in isopropyl ether and _CH3.
Washed with a mixture with OH (3/1, 120ml).
The powder was collected by filtration and dried in vacuo to give 36 g (75% purity as estimated by HPLC) of the title compound -1H (E isomer) as a pale yellow powder, mp >150°C (decomposition). IR: ν ^KBr _nax cm ^-1 3300, 1780, 1720, 1680, 1620. UV: λ ^EtOH _nax nm (E1%H 1cm) 282 (170). NMR: δ ^DMSO-d6 _ppn 3.72 (2H, m, 2-H), 3.90 (3H, s,
OC H ₂ ), 5.25 (3H, m, 6-H and C
H ₂ N ⁺ ), 5.9 (1H, dd, J = 4.5 and 8 Hz, changes to doublet J = 4.5 Hz by addition of D ₂ O, 7-H), 6.35 (1H, m, 3-CH =
C H ), 6.89 (1H, s, C H Ph ₂ ), 6.9 (1H,
d, J = 18Hz, 3-C H ), 7.35 (10H,
m, Ph−H), 8.06 (2H, br, s, N H ₂ annihilated by D ₂ O) 8.21 (2H, br, s, D ₂ O
NH ₂ ), 8.36 and 9.07
(each 2H, d, J = 6Hz, Py- H ), 9.57
(1H, d, J = 8 Hz, annihilated by addition of D ₂ O, 7-NH). Example 2 Production No. 16 7-Benzylideneamino-3-[3-chloro-
1-propen-1-yl]-3-cephem-4
-Benzhydryl carboxylate () (Z isomer) 7-aminocephalic acid intermediate (Z isomer)
(13.4 g, 28 mmol) and benzaldehyde (3.3
g, 31 mmol) in ethyl acetate (150 ml) with 0.5N sodium hydroxide (56 ml, 28
(mmol) was added dropwise over 20 minutes so as to maintain the temperature of the reaction mixture below 10°C. The mixture was stirred for a further 15 min while cooling, the organic layer was separated and added to saturated aqueous sodium bicarbonate (100 ml x
2) and dried over magnesium sulfate.
A small amount of activated carbon was added to the dry solution and the mixture was filtered. The filtrate was concentrated to dryness. The residue was dissolved in carbon tetrachloride (50ml) and concentrated again. This step 3
the mixture was monitored by reverse phase TLC,
It was confirmed that the starting 7-aminocephalosporin had already been converted to Schiff's base. Removal of the solvent in vacuo yielded 16.45 g of the title compound (Z isomer) as a pale yellow powder (estimated purity 85%, melting point 74°C (decomposition)).
It was used for the next step without purification. IR: ν ^KBr _nax cm ^-1 1780, 1720, 1635. UV: λ ^CH2Cl2 _nax nm (E1%H 1cm) 257 (400). NMR: δ ^CDCl3 _ppn 6.18 (1H, d, J = 11Hz). Reference Example 42 Production No. 17 7-Benzylideneamino-3-[3-(4-carbamoyl-1-pyridinio)-1-propene-
1-yl]-3-cephem-4-carboxylic acid benzhydryl iodo (-H) (E isomer) A cooled mixture of 3-chloropropenylcepheme (Z isomer) (16.4 g) in acetone (5 ml) A solution of sodium iodide (6.3 g, 42 mmol) in acetone (30 ml) was added dropwise over 10 minutes under a nitrogen atmosphere and the mixture was stirred at room temperature.
The reaction is the ratio of UV absorption (E1% 1cm (255nm)/E1% 1cm
(320 nm)). When the ratio reached less than 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400ml) and left at room temperature. When the ratio was less than 1.10 (after 3 hours), the mixture was concentrated to one half of its volume. Add a small amount of activated charcoal to the concentrate,
and diatomaceous earth were added and filtered. The filter cake was washed with a 1:1 mixture of methylene chloride and carbon tetrachloride (100ml). Add isonicotinamide (3.5 g, 28.7 mmol) to the combined filtrate and washing solution.
A solution of 100% in dimethylformamide (20ml) was added and the mixture was concentrated under reduced pressure. Concentrate at room temperature
Leave it for 1.5 hours and add isopropyl ether (100ml x
3). The residual brown semi-solid was dissolved in methylene chloride (50ml) and the solution was added dropwise to ethyl acetate (1.5ml) with stirring. The resulting precipitate was collected by filtration and washed with ethyl acetate (200ml). The title compound after drying in vacuo over phosphorous pentoxide -
17 g of H (E isomer) was obtained. Yellow amorphous powder.
Melting point 150-155℃ (decomposition). Estimated purity by nmr 80
%. IR: ν ^KBr _nax cm ^-1 1775, 1725, 1690, 1635. UV: λ ^CH2Cl2 _nax nm (E1%H 1cm) 258 (355), 298 (255). NMR: δ ^DMSO-d6 _ppn 3.4−3.8 (2H, br.), 5.35 (2H, br.), 5.41
(1H, d, J = 4Hz), 5.73 (1H, d, J
=4Hz), 6.93 (1H, s,), 6.97 (1H, d,
J=16Hz), 7.3-7.5 (15H, dr.s), 8.40
(2H, d, J = 6.5Hz), 9.15 (2H, d, J
= 6.5Hz). Reference example 43 Production No. 18 7-amino-3-[3-(4-carbamoyl-1
-pyridinio)-1-propen-1-yl]-3
-Cefem-4-carboxylate (-
H) (E isomer) To a suspension of quaternized cefem-H (17 g) in 85% formic acid (250 ml) was added concentrated hydrochloric acid (5 ml) dropwise and the mixture was stirred at room temperature for 1.5 hours, leaving a small amount of Treated with activated carbon. Filter the mixture and add 85% formic acid (5
ml). The filtrate was combined with the washing liquid and poured into acetone (1) with stirring. The resulting precipitate was collected by filtration, yielding 9.52 g of a yellow crude product. A small amount of activated carbon was added to a suspension of the crude product (9.5g) in water (50ml) and the mixture was filtered.
The filtrate was added dropwise to isopropyl alcohol (700ml) with stirring. The resulting precipitate was collected by filtration, washed with a small amount of methanol (30 ml), and dried to give 7.58 g of the title compound -H (E isomer).
was obtained as the hydrochloride. Pale yellow powder. Estimated purity 85% by UV. Melting point 173-185°C (decomposition). IR: ν ^KBr _nax cm ^-1 1795, 1680, 1620, 1575, 1540. UV: λ phosphate buffer maxnm (PH7) (E1% 1cm) 294
(457). NMR: δ ^D2O+DCL _ppn 3.82 (2H, s,), 5.17 (1H, d, J=5
Hz), 5.33 (2H, d, J = 7Hz), 5.43 (1H,
d, J=5Hz), 6.37(1H, d-t, J=
16 and 7Hz), 7.23 (1H, d, J = 16
Hz), 8.34 (2H, d, J = 7Hz), 9.00 (2H,
d, J = 7Hz). Reference Example 44 Production No. 19 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (-1, as acid chloride hydrochloride) A 2- Cyano-2-methoxyiminoacetamide α-cyanoacetamide (252 g, 3 mol) and sodium sulfite (414 g, 6 mol) in water (600 ml)
Acetic acid (371 ml, 10 mol) was added to the stirred mixture in ml) over 1.5 hours at 5-10°C. The mixture was stirred for an additional 1.5 hours and the pH was adjusted to 8.5 with 6N-NaOH. Add dimethyl sulfate (568 ml, 6 moles) to the mixture.
was added at 15-20°C and the mixture was stirred at 45°C for 1.5 hours. The reaction mixture was adjusted to pH 8.5 with 6N NaOH and left overnight at 5°C to liberate a precipitate, which was collected by filtration, washed with cold water and air-dried, yielding 292 g (77%) of the title compound as brown needles. Obtained as crystals, melting at 170-172 °C. IR: ν ^KBr _nax cm ^-1 3400, 3180, 1720 (sh), 1715,
1690, 1615, 1570. UV: λ ^H2O _nax nm (ε) 238.5 (8290), 268 (sh, 3870)
. NMR: δ ^DMSO-d6 _ppn 4.20 (3H, s, OCH ₃ ), 7.85 (2H, br.
_NH2 ). Elemental analysis, calculated for _C4H5N3O2 : C, 37.80; H, 3.97; N, 33.06 Found: _C , 37.43; _H , 3.75; N, 32.51 _. B 2-Methoxyiminopropanedinitrile 2-cyano-2-methoxyiminoacetamide (88.9 g, 0.7 mol), sodium chloride (70 g) and phosphorine chloride (97 ml, 1.05 mol) in dry 1,2-dichloroethane (350 ml) The stirred mixture was refluxed for 16 hours. The insoluble material was filtered through a pad of dicalite and washed with dichloroethane. The filtrate was combined with the washing liquid and poured into stirred ice water (1.5) to decompose excess phosphoryl chloride. The organic phase was washed with 10% NaHCO ₃ (500 ml), water (500 ml x 3) and saturated NaCl solution (500 ml) and dried over MgSO ₄ . Distillation of the filtrate under reduced pressure yielded 61.6 g (81%) of the title compound.
Boiling point 62℃/24mmHg. (Literature, boiling point 47-48℃/12mm
Hg). IR: ν liquid film maxcm ^-1 3020, 2960, 2245,
2020, 1530, 1455, 1080. NMR: δ ^CDCl3 _ppn 4.35 (3H, s, _OCH3 ). C 2-Cyano-2-methoxyiminoacetamidinium acetate 28% of ammonium chloride (28.4 g, 0.53 mol)
Ammonia water (355ml) and ethanol (180ml)
2-methoxyiminopropanedinitrile (58.0 g, 0.53 mol) in a solution of ethanol (120 ml) in ethanol (120 ml).
ml) at -15 to -10°C while stirring.
Added dropwise over a period of minutes. The mixture was stirred at -10°C overnight and then at room temperature (20-25°C) for 1 day. The reaction mixture was partitioned between water (350ml) and _CH2Cl2 ( _350ml ), the aqueous layer was saturated with sodium chloride and again
Extracted with _CH2Cl2 ( _300ml ). The organic extracts were combined and dried over MgSO ₄ and evaporated in vacuo. A solution of the residue in ethyl acetate (1.6) with acetic acid to pH 3
-4, the title compound precipitated as crystals, which were collected by filtration and washed with ethyl acetate. Yield 67.6g (69%). Melting point 152-4°C (decomposition). [Literature, melting point 150-155°C (decomposition)]. IR: ν ^KBr _nax cm ^-1 3160, 2900, 2360, 2235, 2000,
1665, 1555, 1495, 1415. UV: λ ^EtOH _nax nm (ε) 243 (8500), 265 (sh, 5380)
,
305 (sh, 1400). NMR: δ ^DMSO-d6 _ppn 1.88 (3H, s, CH ₃ COOH), 4.15 (3H,
s, OCH ₃ ) 7.60 (4H, br.). Elemental analysis, calculated for _{C4H6N4O.CH3COOH} : C, 38,71; H, 5.41 _{; N} , 30.09 Measured: C _, 38.71; H, 5.59; N, 29.51. D 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetonitrile 2-cyano-2-methoxyiminoacetamidinium acetate (125 g, 0.672 mol) in _CH3
Triethylamine (234 ml, 1.68 mol) was added to a suspension in OH (1.25) at −10 °C, then Br ₂ (41.6
ml, 0.806 mol) was added dropwise over 20 minutes at −15 to −10° C. and the mixture was stirred for 20 minutes. into the mixture
KSCN (78.3g, 0.806mol) in _CH3OH (550ml)
The solution was added dropwise over 1 hour at -15 to -10°C. After stirring for 1 hour at 0-5°C, the mixture was poured into ice water (12), resulting in a crystalline precipitate, which was collected by filtration, washed with water and air-dried to yield 120 g (98%) of the title compound. was gotten. Melting point 263~
5°C (decomposition). The melting point of the compound prepared here is about 60 °C higher than that given by the literature [melting point 210-15 °C (decomposed)], but the spectral and microanalytical data support its structure well. IR: ν ^KBr _nax cm ^-1 3435, 3260, 3120, 2960, 2245,
2020, 1630, 1545, 1455, 1415. UV: λ ^EtOH _nax nm (ε) 248 (13300), 310 (3470). NMR: δ ^DMSO-d6 _ppn 4.21 (3H, s, OCH ₃ ), 8.30 (2H, br.
_NH2 ). Elemental analysis, calculated values for C ₅ H ₅ N ₅ OS: C, 32.78; H, 2.75; N, 38.23S,
17.50 Measured value: C, 32.76; H, 2.51; N, 38.02, S,
17.50. E 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetic acid (-1) 2-(5-amino-1,2,4,-thiadiazol-3-yl )-2-methoxyiminoacetonitrile (18.3 g, 0.1 mol) in 4N-NaOH (250 ml)
The mixture inside was heated at 50-55°C for 3 hours while stirring. The reaction mixture was adjusted to _PH1 with _H3PO4 ,
Washed with ethyl acetate (100ml), saturated with NaCl,
3 with a mixture of ethyl acetate and tetrahydrofuran
Extracted twice (3:1, 2 x 300 ml and 1 x 200 ml). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. Trituration of the residue with isopropyl ether gave pale yellow crystals of the title acid. yield
16.8g (83%). Melting point, 184-5°C (decomposition) [Literature*, melting point, 180-182°C (decomposition)]. IR: ν ^KBr _nax cm ^-1 3460, 3260, 3140, 1725, 1620,
1605, 1545. UV: λ ^H20 _nax nm (ε) 234 (13200), 288 (sh, 3620)
. F 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride 2-(5-amino-1,2,4,-thiadiazol-3-yl) -2-methoxyiminoacetic acid (-
1) PCl ₅ (41.6 g, 0.2 mol) was added to a suspension of (40.4 g, 0.2 mol) in dry CH ₂ Cl ₂ (400 ml) at -50°C.
Added in degrees. The mixture was stirred at -20 to -5°C for 4 hours and poured into a mixture of n-heptane and isopropyl ether (2:1,2). The yellow precipitate was collected by filtration and washed with the same solvent mixture;
The title hydrochloride oxide when dried over KOH under reduced pressure
46.0g (90%) was produced. IR: νnujiol maxcm ^-1 1775. JP-A-57-158769 (Fujisawa, September 1982)
Published on the 10th) (UK application 3/6/81) Reference example 45 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetamide]-3-[3-chloro-1-propenyl]-3-fuseem- Diphenylmethyl 4-carboxylate (-2, Z isomer) N,O-bis(trimethylsilyl)acetamide (2.3 ml, 9 mmol) and crystalline 7-amino-
3-[3-chloro-1-(Z)-propen-1-yl]-3-fuceem-4-carboxylic acid diphenylmethyl hydrochloride (1.388 g, 2.8 mmol)
2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetyl chloride hydrochloride (from Preparation No. 12) in methylene chloride (10 ml). 800mg, 2.95mmol)
was added portionwise at -10°C with stirring and the mixture was left at 0°C for 2 hours. The mixture was diluted with ethyl acetate (200ml), washed with water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave the title product-2 as an amorphous powder. Yield 1.70g (95%). Melting point, >150°C (decomposition). IR: ν _nax (KBr) cm ^-1 3300, 1780, 1720, 1690,
1380, 1220. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 285 (11000). NMR: δ ^DMSO-d6 _ppn 1.26 (3H, t, J=7Hz, CH ₂ CH ₂ CH ₃ ),
4.25 (2H, q, J=7Hz, CH ₂ CH ₃ ),
5.90 (1H, dd, J=4 and 8H, 7
-H), 6.26 (1H, d, J=11Hz, 3-
CH), 6.85 (1H, s, CHPh ₂ ), 9.53 (1H,
d, J = 8Hz, 7-NH). Reference example 46 7-[2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetamide]-3-[3-iodo-1-propenyl]-3-cephem- Diphenylmethyl 4-carboxylate (-2) -2 (1.90 g, 3 mmol) (from production No. 20)
and sodium iodide (1.4 g, 9 mmol) in acetone (20 ml) was stirred at room temperature for 10 minutes and then left at 5° C. for 3 hours. The mixture was evaporated under reduced pressure, diluted with ethyl acetate (100ml) and
Washed with 10% sodium thiosulfate and water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether yields the title product-2, 1.82 g (84%)
was obtained as a light brown amorphous powder. IR: ν _nax (KBr) cm ^-1 3290, 1770, 1720, 1670,
1530, 1370, 1220. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1 cm) 304 (199). Reference example 47 7-benzylideneamino-3-[(E)-3-
(carbamoylpyridinio)-1-propenyl]
-3-Cefem-4-carboxylic acid diphenylmethyl (-H iodide) (E isomer) 3-chloropropenyl cefem (, Z isomer, (42.8 g, 90 mmol) (from Preparation No. 16) in dry DMF ( KI (20 g, 120 mmol) was added in one portion to the cooled solution in 80 ml) and the mixture was stirred at room temperature.
1% 1 cm (320 nm)]. ratio is 1.10
When less than 100 mL (after 45 minutes), the mixture was diluted with 800 ml of methylene chloride, treated with activated charcoal (4 g) and filtered. The filter cake was washed with 100 portions of CH ₂ Cl ₂ . Isonicotinamide (14.64 g) was added to the combined filtrate and washing liquid, and the mixture was concentrated under reduced pressure. The concentrate was kept at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane (1:1, 600 ml). The residual brown semi-solid was dissolved in CH ₂ Cl ₂ (100 ml) and the solution was added dropwise to ethyl acetate (3) with vigorous stirring. Title compound -H _, quaternized after drying in vacuo over _P2O5 , 57.37
g (88%) was obtained as iodide. Yellow amorphous powder. Melting point, 150-155°C (decomposition). This product is
Obtained by iodination with No. (Manufacturing No.
17). Reference example 48 7-Amino-3-(3-chloro-1-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl hydrochloride (Z isomer) (, hydrochloride) 25% solution of chloroacetaldehyde in _CHCl3 (69 g, (80 g, 0.11 mol) in CH ₂ Cl ₂ (1.1) containing N,O-bis(trimethylsilyl)acetamide (16.2 ml, 0.06 mol)
solution in one portion at -10°C and the mixture was left at 5°C overnight. The mixture was concentrated to about 0.3% and mixed with a mixed solvent of ethyl acetate and isopropyl ether (1/
2,0.6), silica gel (Wako Gel C-100, 60 g) was added, and the mixture was filtered through a dicalite pad. The filter cake was washed with the same solvent system (0.2
). The total amount of filtrate and washing liquid is approximately 0.2
It was concentrated to 100 ml, treated with Giraldo's reagent T (60 g, 0.26 mol) and 4N HCl (220 ml), and seeded with a few crystals of the hydrochloride salt. After stirring for 3 hours, the resulting crystals were collected by filtration, washed with water (0.5) and ethyl acetate (0.5), and dried in vacuo to yield 37 g (70%) of the title compound hydrochloride.
Melting point, >185°C (decomposition). Pale yellow needles. This product corresponded to that obtained in Preparation No. 12. Reference example 49 7-Amino-3-(3-chloro-1-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl hydrochloride (Z isomer) (, hydrochloride) Chloroacetaldehyde (25% solvent in _CHCl3 ,
628 mg, ₂ mmol) of N,O- _bis (trimethylsilyl)acetamide (0.135 ml, 0.5 mmol) and (723 mg,
1 mmol) were added sequentially at 5°C. Mixture at 5℃
I left it there overnight. Evaporate the mixture and add a mixture of ethyl acetate and isopropyl ether (1/2, 10
ml). Insoluble matter was removed by filtration, and the filtrate was concentrated to about 5 ml. The concentrate was diluted with 4N-HCl (2
ml), seeded with hydrochloride, and incubated at room temperature for 1
I stirred the time. The crystals were collected by filtration, washed with ethyl acetate (10 ml) and water (10 ml), and dried in vacuo to give the title compound hydrochloride, 384 mg (80 ml).
%) occurred. >185℃ (decomposition). Pale yellow crystals. This product corresponded to that obtained in Preparation No. 12. Reference example 50 Production No. 25 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetyl chloride hydrochloride (-3,
(as acid chloride hydrochloride) A 2-(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2
-(propen-3-yloxyimino)ethyl acetate N-(propen-3-yloxy)phthalimide [E. Grochosaki and J. Jurczak,
Synthesis, 1976 , 682]
685 mg (3.37 mmol) and 175 mg of hydrazine hydrate
(3.35 mmol) in 5 ml of C ₂ H ₅ OH was stirred for 1 hour at room temperature. The resulting precipitate was filtered, and the filtrate and washing liquid were combined. Add 2-(5-t-
Methyl butoxycarbonylamino-1,2,4,-thiadiazol-3-yl)-2-oxoacetate
967 mg (3.37 mmol) were added and the mixture was left at room temperature for 1 hour and concentrated on a rotary concentrator. The residue was purified by silica gel chromatography. The column was washed with n-hexane/ethyl acetate (4:
The fractions eluted with 1) and containing the main product were combined and concentrated under reduced pressure. Yield 514 mg (46%). Melting point, 83-86°C. IR: ν _nax (KBr) cm ^-1 3100, 1745, 1710, 1610. UV: λ _nax (C ₂ H ₅ OH) nm (ε) 223 (9700), 242
(10000). NMR: δ (CDCl ₃ ) ppm 1.55 (9H, s, B0C-H), 4.40 (2H, d,
J = 5Hz, O-CH ₂ ), 5.21 (2H, m, C
H ₂ = CH), 5.90 (1H, m, -CH ), 9.50
(1H, br.s, NH). B 2-(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2
-(propen-3-yloxyimino)acetic acid ⁽¹⁾ 2-(5-t-butoxycarbonylamino-1,
Methyl 2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetate 770
mg (2.3 mmol) and 3.5 ml (7.0
(mmol) in 15 ml of CH ₃ OH was refluxed for 30 min. The reaction mixture was concentrated in vacuo and diluted with 10 ml of ethyl acetate- _H20 (1:1). The aqueous layer was separated, the pH was adjusted to 2 with 6N-NCl, and ethyl acetate (10ml) was added.
×2). The ethyl acetate solution was dried over MgSO ₄ and concentrated on a rotary concentrator to yield 596 mg (81%) of the title compound. Melting point, 134/135
°C (Reference ⁽¹⁾ , melting point 135-136 °C). IR: ν _nax cm ^-1 3150, 1745, 1710,
1550. UV: λ _nax (C ₂ H ₅ OH) nm (ε) 223 (11000), 242
(11300). NMR: δ (DMSO-d ₆ ) ppm 1.55 (9H, s, B0C-H), 4.77 (2H, d,
J = 5Hz, O-CH ₂ ), 5.22 (2H, m,
_CH2 =CH), 6.0 (1H, m, CH= _CH2 ). (1) I. Csendes et al., J. Antibiotics, 36 , 1020
(1983). C 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetic acid (-3) ⁽¹⁾ 2-(5-t-butoxycarbonyl Amino-1,
2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetic acid 570 mg
(1.74 mmol) in 6 ml of trifluoroacetic acid was left at room temperature for 1 hour. Evaporation and trituration with 30 ml of isopropyl ether gave 376 mg (95%) of the title compound. Melting point, 109°C (decomposed). IR: ν _nax cm ^-1 3180, 1710, 1545,
1460. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 245 (13500). NMR: δ(DMSO- _d6 ) ppm 4.77 (2H, d, J=5Hz, O- _CH2 ), 5.20
(2H, m, C H = CH), 6.0 (1H, m, C
H= _CH2 ). (1) JP-A-57-112396 (7/13/82), Fujisawa), British Application No. 7935538 (10/12/79). D 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propen-3-yloxyiminoacetyl chloride hydrochloride-3, 350 mg (1.54 mmol) and phosphorus pentachloride
410 mg (1.97 mmol) of dichloromethane (5
ml) was stirred at 25°C for 1 hour. The reaction mixture was poured into 60 ml of n-hexane, and the precipitate was filtered. Yield 323mg. IR: ν _nax cm ^-1 1765. Reference Example 51 Production No. 26 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propargyloxyiminoacetyl chloride hydrochloride (-4, as acid chloride hydrochloride) A 2-(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2
-(Methyl propargyloxyiminoacetate N-propargyloxyphthalimide ⁽¹⁾ 870mg
(4.32 mmol) and hydrazine hydrate 200 mg (4.0
mmol) in 5 ml of ethanol at 25 °C.
The mixture was stirred for 1 hour and filtered. The filtrate and washing liquid were combined, and 2-(5-t-butoxycarbonylamino-1,2,4,-thiadiazol-3-yl) was added to the mixture.
-Methyl 2-oxoacetate ⁽²⁾ 1.0g (3.86 mmol)
added. The solution was left for 1 hour and concentrated under reduced pressure. Purified by silica gel chromatography and then concentrated to yield 3.19 mg (27%) of the title product.
was gotten. Melting point, 72-75°C. IR: ν _nax cm ^-1 3200, 2380, 1745,
1710, 1610. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 355 (12200). NMR: δ (DMSO-d ₆ ) ppm 1.56 (9H, s, BOC-H), 3.55 (1H, t,
J = 2Hz, CH≡CH), 4.85 (2H, d, J
-2Hz, -C H ₂ -C≡CH), 8.9 (1H, br.
s, NH). (1) Commercially available, Aldrich. (2) I. Csendes et al., J. Antibiotics 36 , 1020 (1983). B 2-(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2
-propargyloxyiminoacetic acid 2-(5-t-butoxycarbonylamino-1,
490 mg (1.4 mmol) of methyl 2,4,-thiadiazol-3-yl)-2-propargyloxyiminoacetate and 2.2 ml (4.4 mmol) of 2N NaOH aqueous solution
A solution of and in 14 ml of CH ₃ OH was refluxed for 30 min. The reaction mixture was concentrated under reduced pressure, and the solution was diluted with ethyl acetate.
10 ml of H ₂ 0 (1:1) was added. The separated aqueous layer
6N-NCl to pH2, ethyl acetate (2 x 10ml)
Extracted with. Drying over MgSO ₄ and then concentration of the organic phase gave 149 mg (89%) of the title compound. Melting point, 135°C (decomposed). IR: ν _nax cm ^-1 3350, 1720, 1670,
1550. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 233 (11500). NMR: δ (DMSO-d ₆ ) ppm 1.55 (9H, s, BOC-H), 3.55 (1H, t,
J=2Hz, C≡CH), 4.89(2H, d, J=
2Hz, C H ₂ −C≡CH), 9.0 (1H, s,
NH). C 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propargyloxyiminoacetic acid (-4) ⁽³⁾ 2-(5-t-butoxycarbonylamino-1,
410 mg (1.26 mmol) of 2,4,-thiadiazol-3-yl)-2-propargyloxyiminoacetic acid
A solution of in 5 ml of trifluoroacetic acid was left at 25° C. for 1 hour. After concentration, the residue is diluted with isopropyl ether.
Trituration with 25 ml gave 204 mg (72%) of the title compound. Melting point, 156-158°C (decomposition). IR: ν _nax cm ^-1 3300, 2480, 1730,
1610. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 234 (12000). NMR: δ(DMSO- _d6 ) ppm 3.52 (1H, t, J=2Hz, C≡CH), 4.86
(2H, d, J=2Hz, C H ₂ −C≡CH),
8.10 (2H, br, s, NH). (3) JP-A-57-112396 (7/13/82), Fujisawa),
UK Application No. 7935538 (10/12/79). D 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-(propargyloxyiminoacetyl chloride hydrochloride-4, 175 mg (0.07 mmol) and phosphorus pentachloride
182 mg (0.88 mmol) of dichloromethane (2
ml) was stirred at -5°C for 1 hour. The reaction mixture was poured into 30 ml of n-hexane, and the precipitate was filtered. Yield 65 mg (34%). IR: ν _nax cm ^-1 1770. Reference Example 52 Production No. 27 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetyl chloride hydrochloride (-5, as acid chloride hydrochloride) A 2 -(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2
-Cyclopentyloxyimino)methyl acetate N-(cyclopentyloxy)phthalimide ⁽¹⁾
860 mg (3.7 mmol) and 185 mg of hydrazine hydrate
A suspension of (3.7 mmol) in 5 ml of C ₂ H ₅ OH was stirred for 1 hour at room temperature and filtered. The filtrate and washing liquid were combined, and 2-(5-t-butoxycarbonylamino-
1,2,4,-thiadiazol-3-yl)-2-
1.06 g (3.7 mmol) of methyl oxoacetate ⁽²⁾ was added. The solution was left at room temperature for 1 hour, concentrated in vacuo, and the residue was purified by silica gel chromatography. n-hexane-ethyl acetate (4:
Elution with 1) followed by evaporation gave the title compound. Yield 906 mg (81%). Melting point, 115-118℃
(Disassembly). IR: ν _nax (KBr) cm ^-1 3200, 1745, 1710, 1550. UV: λ _nax (C ₂ H ₅ OH) nm (ε) 217 (1800), 252
(7600). NMR: δ (CDCl ₃ ) ppm 1.51 (9H, s, BOC-H), 1.60 (8H, br.
s, [formula]), 3.88 (3H, s, OCH ₃ ), 4.90 (1H, br.s,
[Formula]), 8.70 (1H, br.s, NH). (1) U.S. Patent No. 3971778 (7/27/76,
Glaxo), UK Application No. 49255 (10/25/72). (2) I. Csendes et al., J. Antibiotocs 36 , 1020 (1983). B 2-(5-t-butoxycarbonylamino-
1,2,4-thiadiazol-3-yl)-2
-cyclopentyloxyiminoacetic acid 2-(5-t-butoxycarbonylamino-1,
Methyl 2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetate 500 mg (1.34
A solution of 2N NaOH solution (2 ml, 4 mmol) in 15 ml of CH ₃ OH was refluxed for 30 minutes. Concentrate the reaction mixture and add ethyl acetate to the solution.
10 ml of H ₂ 0 (1:1) was added. Separate the aquarium
Adjust the pH to 2 with 6N-HCl and use ethyl acetate (10ml x 2).
Extracted with. Wash the organic layer with brine,
Dry over MgSO ₄ and concentrate under reduced pressure to yield 377 mg (78%) of the title compound. Melting point, 185°C (decomposed). IR: ν _nax (KBr) cm ^-1 3160, 1710, 1550. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 238 (13300). NMR: δ (DMSO) ppm 1.51 (9H, s, BOC-H), 1.70 (8H, br.
s., [formula]), 4.82 (1H, m, [formula]). C2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetic acid (-5, ZE isomer) ⁽³⁾ 2-(5-t-butoxycarbonylamino-1,
A solution of 348 mg (0.97 mmol) of 2,4,-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetic acid in 2 ml of trifluoroacetic acid was prepared
I left it for a while. The reaction mixture was concentrated under reduced pressure.
The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the title compound. Melting point, 162-165°C (decomposed). [Reference ⁽³⁾ Melting point 160-165°C (decomposition)]. IR: ν _nax cm ^-1 3290, 3200, 1710,
1615, 1600. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 283 (13300). NMR: δ(DMSO- _d6 ) ppm 1.17-2.10 (8H, m), 4.60-4.98 (1H,
m), 8.22 (2H, s). (3) JP-A-57-158769 (9/30/82), Fujisawa),
UK Application No. 8107134 (3/6/81). D 2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetyl chloride hydrochloride-5, 190 mg (0.74 mmol) and phosphorus pentachloride
219 mg (1.0 mmol) of dichloromethane (2
ml) was stirred for 1 hour at room temperature. The reaction mixture was poured into 50 ml of n-hexane. The resulting precipitate was collected by filtration. Yield 122 mg (60%). IR: ν _nax cm ^-1 1760. Reference Example 53 Production No. 28 Benzotriazol-1-yl-2-(5-amino-1,2,4,-thiadiazol-3-yl)-2-methoxyiminoacetate 1-hydroxybenzotriazole (2.7g,
A mixture of dicyclohexylcarbodiimide (4.12 g, 20 mmol) in 65 ml DMF was stirred at room temperature. After 15 minutes, add to the stirred mixture -
1 (4.04 g, 20 mmol) was added at 0° C. and stirring was continued for 3 hours. The reaction mixture was filtered to remove insoluble urea and the filter cake was washed with a small amount of DMF.
The filtrate and washing liquid were combined and poured into 800 ml of ice water.
The precipitate was collected by filtration to yield 5.24 g (82%) of the title compound as a pale gray powder. Melting point, 189-192
°C (decomposition). IR: ν _nax (KBr) cm ^-1 1815, 1620, 1540, 1415,
1090, 1060, 1005, 945, 865, 740. UV: λ _nax (C ₂ H ₅ OH) nm (E1% 1 cm) 246 (580), 283 sh (228).

Claims (1)

[Claims] 1 formula, (wherein R ²² is hydrogen or a conventional carboxyl protecting group, R ²³ , R ²⁴ and R ²⁵ are the same or different and are hydrogen, hydroxy, (lower) alkyl or (lower) alkoxy, Z is chloro, bromo or iodo), or a salt, solvate, hydrate or ester thereof. 2. The compound according to claim 1, wherein R ²² is a benzhydryl group and Z is chloro or iodo. 3. The compound according to claim 2, wherein R ²³ , R ²⁴ and R ²⁵ are hydrogen. 4 7-benzylideneamino-3-[3-chloro-1-propen-1-yl]-3-cephem-4
- The compound according to claim 3, which is a benzhydryl carboxylate. 5 7-Benzylideneamino-3-[3-iodo-1-propen-1-yl]-3-cephem-4
- The compound according to claim 3, which is a benzhydryl carboxylate. 6 formula (wherein R ²² is hydrogen or a conventional carboxylic acid protecting group, R ²³ , R ²⁴ and R ²⁵ are the same or different and are hydrogen, hydroxy, (lower) alkyl or (lower) alkoxy. , Z is chloro, bromo or iodo), or a salt, solvate, hydrate or ester thereof, the method comprising: (In the formula, R ²³ , R ²⁴ and R ²⁵ are as described above) (wherein R ²² is a conventional carboxylic acid protecting group) by reacting with a compound of the formula, and then reacting the compound of formula with sodium iodide or potassium iodide to form a compound of formula, and then reacting the compound of formula with triphenylphosphine to give the formula, or reacting a compound of formula with triphenylphosphine to produce a compound of formula, and then reacting a compound of formula with a base to produce a compound of formula, and then convert the compound of formula into ZCH ₂
Reacting with CHO (wherein Z is chlorine, bromine or iodine) to give the formula, and finally, if desired, removing the carboxyl protecting group R ²² by conventional methods to produce the corresponding free acid, and converting the free acid into its salt or ester.