JPH0351716B2 - - 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.
Yes, -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
The present invention relates to intermediates and methods for 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
Yes, R³is hydrogen, acyl, optionally substituted
aryl, substituted alkyl, alkenyl, alkyl
Nyl, optionally substituted cycloalkyl,
O substituted with chloroalkenyl or oxo group
- or S-containing 5-membered heterocycle; R³is hydrogen
or alkyl; R^Fouris hydrogen, acyl
Sialkyl, acylthioalkyl, optionally substituted
substituted pyridinioalkyl, optionally substituted
Heterocyclylthioalkyl, alkyl,
rogene, hydroxy or optionally substituted
thiazolioalkyl, R^Fiveis carboxylic
or protected carboxy, but R^Four
is optionally substituted pyridinioalkyl or
is optionally substituted thiazolioalkyl
When R^Fiveis COO^-and the dotted line indicates a single bond or a double bond.
Cepham and cepham compounds (indicating a double bond)
be disclosed. 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 (issued May 25, 1982) and No.
No. 4332798 (issued June 1, 1982) is
Appears in the parent application of National Patent No. 4390534 and has a similar development.
have an indication. B European Patent Application No. published on October 13, 1982
No. 62321 has the formula, (In the formula, R¹is an amino or protected amino
and R²is an optionally substituted lower aliphatic
is a hydrocarbon group or cycloalkenyl,
formula, optionally contains more than one nitrogen atom
is a substituted heterocyclic cationic group) cefem compounds and their pharmaceutically acceptable salts
will be disclosed. Also, the expression (In the formula, R¹and R²is as described above,
R^Fouris a protected carboxyl group, and X^-is 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 an optionally substituted lower aliphatic hydrocarbon
radical, cyclo(lower) alkyl or cyclo(lower)
class) alkenyl, R³is (lower) alkylamino, N-protected (lower)
class) alkylamino, di(lower) alkylamino
-, sulfo (lower) alkylamino, hydroxy
(lower) alkylamino, N-protected hydroxy
(lower) alkylamino, acyloxy (lower)
Alkyl, (lower) alkoxy (lower) alkoxy
Di(lower)alkyl, di(lower)alkylamino
(lower) alkyl, (lower) alkylthio (lower)
Alkyl, (lower)alkylthio, (lower)alco
xy, (lower) alkoxy (lower) alkoxy,
Hydroxy (lower) alkoxy, acyl (lower)
Alkyl, hydroxy (lower) alkylthio, di
(lower) alkylamino (lower) alkylthio,
N-containing unsaturated 5-membered heterocyclic group, N-containing unsaturated heterocyclic group
Cyclicthio or substituted with appropriate substituents
N-containing unsaturated 5- or 6-membered heterocycles
cutio(lower) alkyl, R^Fouris hydrogen or (lower) alkyl) Disclosed are cefem compounds, or salts thereof. 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
and R²is (lower) alkyl and X is water
carbamoyl) Compounds 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
more substituted amino, T is thiadiazoli
element (bonded to other groups by its two carbon atoms)
) and R₂is hydrogen, optionally substituted
alkyl, cycloalkyl, or optionally
carbamoyl converted into R₁depends on the case
Substituted thiazolio, optionally substituted pi
Lasolio, tri(lower) alkylammonio also
is the expression, (R in the formula^ais substituted (lower) alkyl [substituent is
cycloalkyl, phenyl, hydroxy, alco
xy, halogen, cyano, carbamoyl, carbo
xyl or sulfo], (lower) alkenyl
or carboxy-substituted (lower) alkenyl, (lower)
alkylthio or carboxy substituted (lower)
alkylthio, amino or -substituted amino [substituted
The group is (lower) alkyl, (lower) alkanoyl or
or aminobenzenesulfonyl], di(low
class) alkylamino, substituted carbamoyl [substituent
is (lower) alkyl, hydroxy (lower) alkyl
(lower) alkoxy, hydroxy or sia
], di(lower) alkyl carbamoyl,
thiocarbamoyl, cycloalkyl, phenyl,
Hydroxy, (lower) alkoxy, halogen, (lower)
(class) alkoxycarbonyl, (lower) alkanoyl
ruoxy, (lower) alkanoyl, carboxyl,
Sulfo, cyano, nitro or hydroxysulfo
(lower) alkyl, R^bis hydrogen or carba
Moyle or R^ahas the same meaning as
R^cis hydrogen or R^ahas the same meaning as
) pyridinio group] Cefem compounds and salts thereof are disclosed. Although formally unrelated, March 11, 1981
European Patent Application No. 25017, published in
has an indication. F European Patent Application No. published on June 24, 1981
No. 30630 has a formula, [In the formula, R¹can also have halogen
optionally protected amino-substituted heterocycles
group or formula, (In the formula, R³is (lower) alkyl) is the group of R²is carboxy or protected
carboxy, A is amino, protected amino
ノ, hydroxy, oxo and formula=N~OR^Four (In the formula, R^Fouris hydrogen, cyclo(lower) alkeni
(lower) alkynyl, (lower) alkenyl
Carboxy or protected carboxy
substituted by], (lower) alkyl [in the case
More carboxy, protected carboxy, amino
No, protected amino, cyano, phosphono, protected
phosphono, and itself substituted
[substituted with a heterocyclic group that can be substituted]
may have a substituent selected from the groups
3-vinylcephene, which is a lower alkylene
Compounds and salts thereof are disclosed. This application includes the formula (In the formula, OR^Fouris methoxy, carboxymethoxy
cy, t-butoxycarbonylmethoxy or 1-
t-butoxycarbonylethoxy) compound
The thing is specifically disclosed. 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^ateeth
Etherified monovalent bonded to oxygen through a carbon atom
is an organic group, B is S or S→O,
P is an organic group) Comprehensive disclosure encompassing numerous cephalosporins of
is included. In one embodiment, P is inter alia of the formula, (In the formula, R³and R^Fourare independently hydrogen, nitrile,
(lower)alkoxycarbonyl or substituted or
or unsubstituted aliphatic, cycloaliphatic, araliphatic or
can be aromatic) can be a vinyl group. However, 5-A
Mino-1,2,4-thiadiazol-3-yl group
is not identified as a possible R substituent, and P is not identified as a possible R substituent.
Can be a quaternary ammonio-substituted propenyl group
It is not disclosed or implied that it can be done. US Patent No.
No. 3971778 and its division, No. 4024133, No.
No. 4024137, No. 4064346, No. 4033950, No.
No. 4079178, No. 4091209, No. 4092477 and No.
No. 4093803 has a similar disclosure. H European Patent Application No. published on September 14, 1983
No. 88385 has the formula, (In the formula, R¹is (unsubstituted) thiadiazolyl
R, R²is carboxy (lower) alkyl or
protected carboxy (lower) alkyl,
R³is hydrogen, halogen or (lower) alkenyl
and R^Fouris carboxy or protected carboxy
boxy) Compounds are disclosed. 1-propenyl is R³of
Although it is mentioned as one of the possible meanings
Also, that application is simply R³is hydrogen, chloro or bicarbonate.
are merely illustrative of compounds that are I Daniel Farge Published December 22, 1981
U.S. Pat. No. 4,307,233 to et al.
ceremony, [In the formula, R^Fiveare especially alkyl, vinyl,
Anomethyl or 2-methoxyprop-2-yl
can be a protecting group such as R³and R^Four
is an alkyl group (sometimes hydroxy, alkoxy)
amino, alkylamino or dialkylamino
phenyl group) or phenyl group.
or R³and R^Fourmeans that they are combined
together with nitrogen, possibly N, O and
Contains other heteroatoms selected from S, and if
5- or 6-membered alkyl group substituted by
(can form a saturated heterocycle with members) 3-vinylcephalosporin derivatives of
Ru. Those compounds are 3-thiovinylcephalos
Useful as an intermediate in the production of porin derivatives.
5 in place of 2-aminothiazol-4-yl substituent
-amino-1,2,4-thiadiazole-3-y
Quaternary ammonia on the 3-substituent or 3-substituent
There is no disclosure or suggestion of an o-substituted propenyl moiety.
Published UK Patent Application No. 2051062 is one of the
and have similar disclosures. 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;
Alkyl containing together 2 or 3 carbon atoms
Forming a ren group, R^c _Fiveis an acid protecting group and R₂Hae
It is an acid protecting group such as stellate, and R₃and R_Fourteeth
Same or different, hydrogen, alkyl (in place)
Depending on the combination, hydroxy, alkoxy, amino, alkyl
Substituted by kylamino or dialkylamino
), or phenyl group, or R₃and
R_Fourtogether with the nitrogen atoms to which they are bonded.
selected from N, O and S depending on the case
Contains other heteroatoms and optionally alkyl
5- or 6-membered saturated heterocycle substituted with groups
] 3-vinylcephalosporin derivatives of
Ru. Those compounds are 3-thiovinylcephalos
Useful as an intermediate in the production of porin derivatives
be. 2-aminothiazol-4-yl substituent
Alternative 5-amino-1,2,4-thiadiazole-
3-yl moiety, or quaternary on a 3-substituent
Disclosure or suggestion of ammonio-substituted propenyl group
do not have. U.S. Patent No. 4,423,214 matches and has similar
Have a 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_Fiveare hydrogen, alkyl, bicarbonate, etc.
oxidants such as nil, cyanomethyl, trityl, etc.
sim protecting group, or formula, (In the formula, R^a _Fiveand R^b _Fiveare the same or different
hydrogen, alkyl, or together
It is an alkylene group of 2 or 3 carbon atoms.
can be done, R^c _Fiveis a hydrogen or acid protecting group) can be the basis of} can be R^o _2ais hydrogen or methoxy
An acid protecting group such as methyl, R^ois (number aspect
) 5- or 6-membered containing a single heteroatom
aromatic heterocycles, such as 2- or 3-pyridi
2- or 3-thienyl, or 2- or
is a methyl group substituted by 3-furyl.
R, R³is the expression, R_FourS.O.₂O- (R_Fouris alkyl, trihalomethyl, or
(can be 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
Disclosure or suggestion of 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 oxime
Protecting group, R³is a halogen) A 3-vinylcephalosporin intermediate of
Ru. 2-aminothiazol-4-yl substituent
5-amino-1,2,4-thiadiazole-3
- disclosure or suggestion of an yl moiety, and in the 3-position
Disclosure of 3-halo-1-propen-1-yl in
Or no suggestion. full disclosure This application is a novel cephalosporin, a powerful antibacterial agent.
This invention relates to intermediates for phosphorus derivatives. For more details, please refer to Honde
The wish is a ceremony, [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
a cycloalkyl ring containing elementary atoms, or a formula,
[expression] or [expression] (In the formula, R³is hydrogen and R^Fourand R^FiveThat's it
each independently hydrogen, methyl or ethyl;
Or R^Fourand R^Fiveis the carbon to which they are bonded
A system containing 3 to 5 carbon atoms together with atoms
(can be a chloroalkylidene ring)
can be, -N ≡Q is a quaternary ammonio group) compounds and their non-toxic, pharmaceutically acceptable
Among salts and chemically hydrolyzable esters
Concerning the interbody. 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 regarding alkoxyimino groups
In addition to the compound of formula (and
intermediate) also relates to the double bond of the propenyl group
Forms geometric (cis and trans) isomers.
Cis (“Z”) and trans of these compounds
(“E”) isomers are both specifically within the scope of this invention.
include. 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 administered 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)
(cannot be used), hydroxy (however,
the roxy group cannot be on the α-carbon),
(lower) alkoxy (however, the alkoxy group is
(cannot be on the α-carbon)}, (low
(class) alkylthio, (lower) alkylamino, di
(lower) alkylamino, carbamoyl, (lower)
alkenyl, phenyl (lower) alkyl, phenyl
phenyl or substituted phenyl, whose substituents are e.g.
Gen, hydroxy, amino, (lower) alkyla
mino, di(lower) alkylamino, acylamino
ノ, (lower) alkyl, (lower) alkylthio,
(lower) alkoxy etc.)
can be done] It is the basis of An example of a cyclic quaternary ammonio group is a fully unsaturated monocyclic ring.
heterocyclic ring system, and at least one N-containing ring is complete.
It is a bicyclic ring system that is completely unsaturated. suitable ring
The formula quaternary ammonio ring system includes, for example, the 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】 [In the formula, R¹¹For example, (lower) alkyl group,
(lower) alkoxy (lower) alkyl, hydroxy
(lower) alkyl (however, the hydroxy group is α
- cannot be on carbon), carboxy
(lower) alkyl, amino (lower) alkyl
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: and 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)
is alkylcarbamoyl 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 do it, 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-carboxylerate, (10) 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-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-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamido]-3-[3-(4-hydroxymethylene)
lupyridinio)-1-propen-1-yl]-3
- cefem-4-carboxylate, (12) 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-hydroxymethylene
lupyridinio)-1-propen-1-yl]-3
- cefem-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-methoxyimino
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
methylthiopyridinio)-1-propene-1-y
]-3-cephem-4-carboxylate, It is. Used for various reactants, intermediates and final products
The code system is as follows: ｜Roman numerals｜-Arabic numerals (if applicable)｜｜text
Character (if applicable) | Roman numerals are the final product of a compound.
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 = cyclopentylletter −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-pyropyrenepyridinio 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 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】 【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, One procedure is shown in Reaction Scheme 2. Abbreviation
"Ph" represents a phenyl group. accordingly −CH(Ph)₂The component is a benzhydryl group,
It is a preferred carboxylic acid protecting group. R²but
When containing a carboxyl group, the carboxyl group is
- with common carboxylic acid protecting groups such as butyl moieties.
Preferably protected. Y is chloro, bromo
or iodine. In reaction scheme 1a, proceed from compound to compound XII.
Two selection methods are shown. Tertiary amine (XI)
The direct route using produces all compounds of formula
Applicable to The indirect route via the compound is the
A secondary amine is used as a reactant and the quaternary amine is used in the next step.
to grade. Secondary amines RR′NH are acyclic (e.g.
dimethylamine) or cyclic (e.g. pyrrolidine)
), so this indirect procedure
Quaternary ammonio group is acyclic or acyclic/cyclic
Suitable for preparing compounds of formulas that are hybrids. During this time
A tangential path is a heterocycle in which the quaternary nitrogen is completely unsaturated (e.g.
For example, pyridinio, thiazolio, 2-amino-5-
thiazolo[4,5-c]pyridinio, etc.)
Not suitable for the preparation of compounds of 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) is converted into phosphorylide (also
The base used to produce ) is
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 double bond from Z to E
Isomerization proceeded as quickly as iodination. full reaction
is completed within 45 minutes at room temperature, and 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 Prep PAK−
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-amyl-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 of formula XI (and secondary amines,
RR′NH) is a known compound or one skilled in the art
easily manufactured by Many of the amines are commercially available.
It is. 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
secondary amines PR′NH and compounds of formula R″Z)
If m is 1, sulfoxide is prepared by a conventional method.
and then remove all protecting groups by standard methods.
manufactured by a method comprising: Compounds of the formula also include 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 base and B²is hydrogen or the usual amino protecting group
] 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
compound, or one mole of
Should be used about 25 to
Preferably, 100% excess of tertiary amine is used.
stomach. 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: [wherein Z is chloro, bromo or iodo]
R, R²is hydrogen, a straight chain containing 1 to 4 carbon atoms
or a branched chain alkyl group, 3 to 6 carbon atoms
a cycloalkyl group containing a child, or a formula,
[expression] or [expression] (In the formula, R³is hydrogen and R^Fourand R^FiveThat's it
each independently hydrogen, methyl or ethyl;
Or R^Fourand R^Fiveis the carbon to which they are bonded
A system containing 3 to 5 carbon atoms together with atoms
(can be a chloroalkylidene ring)
be〕 new intermediates, and their salts and esters
do. amino and/or carboxyl groups
For common amino or carboxyl protecting groups
Also included are compounds of more protected formulas. 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. benzoyl), (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 term "(lower) alkyl" used refers to 1 to 6
Straight or branched chain alkyl containing carbon atoms
means. 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
1- mmol) in ethyl acetate (2 ml)
Methylpyrrolidine (36mg, 0.42mmol) in acetic acid
Stir the solution in ethyl (1 ml) at once.
added. Stir the mixture for 15 minutes, add isopropyl
Dilution with ether (10 ml) produces a precipitate, which
was collected by filtration. Its solid (130mg), formic acid
(1 ml) and concentrated HCl (0.1 ml) at room temperature.
Stirred. After 1 hour, the reaction mixture was concentrated under reduced pressure.
The mixture was concentrated, diluted with water (20ml) and filtered. aqueous solution
Reversed phase column (Prep PAK-500/C₁₈Cartridge
of water and 10%
CH₃Eluted with OH. Collect the desired fraction
When concentrated in vacuo to a small volume and lyophilized, the title
Compound (-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), 5.36 (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-CH cis), 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, br-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，_Five), 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-prope
-1-yl]-3-cephem-4-carboxy
Sylate (-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 PAK 500/C₁₈Filling the cartridge
5% aqueous CH₃Dissolved in OH
Purified by separation. Contains the desired product
Combined based on fraction HPLC analysis, under hydraulic pressure
The title compound (−
1B) (Z/E=4/1), 41mg (5.5%) was gotten. 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−H₃，_Five), 8.56
(1H, m, Py−H_Four), 8.82 (2H, m, Py−
H₂，₆). 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 (-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]pyridine
[T. Takahashi et al., Pharm・Bull (Japan),2,34
(1954)] and dried DMSO
(1 ml) solution was stirred at room temperature for 1 hour. reaction mixture
When ethyl acetate (20ml) is added to the mixture, a yellow powder is formed.
(710 mg) was produced. Formic acid (7ml) and sulfite water
Add base sodium (70mg) to the powder (700mg),
The mixture was stirred at 40-45 °C for 30 minutes. residue after evaporation
H₂Triturated with O (40 ml). Filter insoluble matter
and the filtrate, H₂O and 10% CH₃OH as eluent
and reversed phase column (Prep PAK-500/C₁₈, 100ml)
Chromatography was carried out above. desired product
Combine the fractions containing and remove the solvent under reduced pressure.
did. Lyophilization yields the desired product (−1C)
was obtained as a colorless amorphous powder of the E isomer. Collection
Amount 110mg (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 (-D) 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).
0.1M trimethylamine solution in ether (13.6ml)
The liquid was added in one go. Stir and steam the mixture for 10 minutes.
Dry and triturate the residue with ether (20 ml).
Ta. Add 1 drop of anisole to the resulting solid (490 mg).
of trifluoroacetic acid (0.2 ml). 1.5 o'clock
After stirring briefly, the mixture was evaporated to dryness under reduced pressure.
The residual oil was triturated in ether (20ml). arising
The precipitate was collected by filtration and₂Dissolved in O (20ml)
did. Remove some insoluble materials and dissolve the aqueous solution in water.
C used as a release agent₁₈Reversed phase column (Prep PAK-
500/C₁₈Cartridge filling, water
30 ml). Fold containing the desired compound
Combine the lactones, concentrate to a small volume, and lyophilize.
and the title compound (-1D) (Z/E=1/1) 30mg
(9.2%) was obtained as a colorless amorphous powder. Melt
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),
3.81 (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 cis), 7.05 (1/2H, d, J = 16, 3-
CH transformer). 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 (-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) in a 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
The title compound (I-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 (-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 mi
limole) and 3-aminopyridine (66mg, 0.7ml)
mol) in dimethyl sulfoxide (1 ml).
The mixture was stirred at room temperature for 20 minutes. The mixture was diluted with acetic acid.
diluted with chill (10 ml) and ether (10 ml),
The resulting precipitate was collected by filtration and mixed with ether (10
ml) and dried. The quaternized salt is
Dissolved in formic acid (3 ml) containing condensed HCl (0.3 ml),
Stir for 1.5 hours at room temperature. Concentrate the mixture under reduced pressure.
It was condensed to dryness. Dissolve the residue in 2% HCl (10 ml)
and filtered. Transfer the aqueous layer to a reversed phase column (Prep PAK−).
500/C₁₈, 100ml) for chromatography.
I got it. 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) 15mg (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-d ₆ ^+D2O _ppn 3.73 (2H, m), 4.14 (3H, s, OCH₃),
5.35 (3H, 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−H_Four，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-ce
Fem-4-carbosylate (-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
methyl(-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%) as a yellowish brown powder
obtained as. 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, NHCHO). 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 (-1G) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-[3-(3-iodo-1-propene
-1-yl)-3-cephem-4-carboxylic acid di
Phenylmethyl (-1) (E, 716 mg, 1 mmol
nicotinamide in DMSO (2 ml).
(24 mg, 2 mmol) was added and the mixture was kept at room temperature for 1.5
Stir for an hour and stir into ethyl acetate (200ml).
I added it slowly. Collect the resulting precipitate by filtration
did. Quaternized salt (500mg) with sodium bisulfite
dissolved in HCOOH (5 ml) in the presence of HCOOH (50 mg).
Stir the mixture at 40-50℃ for 40 minutes.
Heat and evaporate to dryness. Dissolve the residue in water (40ml)
Dissolve, filter undissolved solids and wash with a small amount of water.
Ta. Combine the filtrate and washing solution and apply to reverse phase column, Prep
PAK-500/C₁₈Chromatography on (100ml)
- I put it on. water and 5%, 10% and 20% water
Sex CH₃The flux containing the desired substance was eluted with OH.
When concentrated in vacuo and freeze-dried, the title
Compound (-1G) (E), 21 mg (3.8%) as yellow powder
obtained as. Melting point, >175°C (decomposition). IR:ν^KBr _naxcm^-13340 (br), 1760, 1670, 1660. UV: λ phosphate buffer (pH7) maxnm (E1%1cm) 235 (326), 274 (sh, 405), 290 (446). NMR: δ^D2O+NaHCO3 _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−
CH₂), 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 (-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). Filter the resulting precipitate
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 filtrate was applied to a reverse phase column (Prep PAK/C₁₈,
100ml) with water and 5%, 10%, 20% and 30%
aqueous CH₃Chromatography using OH as eluent
I put it on Roughy. Fluxi containing the desired compound
The title compound is obtained by evaporation and freeze-drying of the
(-1H) (E), 21 mg (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 (1H, d, J=7, CH=CH=
CH₂), 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, trans), 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-cef
Em-4-carboxylate (-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/C₁₈Cartori
Chromatography on Azalea packing, 100 ml)
water, 5%, 10%, 20% and 30%
aqueous CH₃Eluted with OH. Contains the desired compound
By combining the fractions, steaming them, and freeze-drying them,
Title compound (-1I) (E), 10 mg (1.8%) yellowish brown
Obtained as a colored powder. IR:ν^KBr _naxcm^-13380 (br), 1760, 1650 (sh), 16
20
(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−H₂，₆). 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-cef
M)-1-carboxylate (-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 Compound −1H (98 mg, 0.18 mmol)
CH₃Add 10% HCl (0.1 ml) to the suspension in OH (1 ml).
was added and the mixture was stirred for 5 minutes. The resulting yellow solution
When acetone (100ml) is added to the solution, a precipitate is formed,
Collect it by filtration and add acetone (2 x 10ml)
-1H hydrochloride is washed with water and dried in vacuum.
Obtained as a colorless powder. Yield 88 mg (79%). Melt
point, >190°C (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 (1H, 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−CH₂),
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-(2-methylthiazolio)
-1-propen-1-yl]-3-cephem-
4-carboxylate (-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. 10 precipitation
%CH₃OH−CHCl₃(3 x 20ml). Lottery
Combine the extracts and wash with brine (2 x 5 ml),
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 CH₃HPLC analysis of fractions 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.
When compressed and lyophilized, 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-CH₃), 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 (-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
CH₃A mixture of OH (3 ml) was diluted with N₂at room temperature under atmosphere
I stirred it for an hour. Solvent removed by evaporation
After that, triturate the residual oil in isopropyl ether.
collected by filtration, and isopropyl ether.
Wash with a mixture of methanol (3:1, 10 ml).
Then, 1.28 g of quaternized cefem ester becomes a yellow powder.
Arose as. 1.25g of quaternized ester) and sulfur
85% HCOOH (10
ml) solution in H₂Stir for 1 hour at room temperature under atmosphere.
Mixed. Add 85% HCOOH (5 ml), then mix
The material was stirred for another hour under the same conditions. to
Luene is added and the reaction mixture is azeotropically evaporated under reduced pressure.
I let it emanate. Grind the residue with acetone and title
1.17 g of compound formate was obtained. this compound
(1.15 g) in water (100 ml) was filtered to remove the
The solution was removed and washed with water (10 ml x 2). With filtrate
Combine with washing solution and perform reverse phase column chromatography.
I put it on. Prep PAK500/C₁₈cartridge column
Filling (60ml) from (Waters)
The packed column was diluted with water, 5% methanol and 10%
% methanol. Contains the desired compound
The combined fractions were concentrated under reduced pressure, and the acetate
The title compound (−
1L) 100mg was obtained as a pale yellow powder. Powder (90
mg) in methanol (9 ml),
CH₃Add 1M HCl in OH (0.5ml) and the mixture
Stir at room temperature and concentrate in vacuo. Add to concentrate
Addition of sopropanol produces the hydrochloride salt of the title compound77
mg was precipitated. Light yellow powder. Melting point, >190°C (min
solution). 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−CH₂), 5.94 (1H, d, J
=4.5Hz, 7-H), 6.36(1H, d, t, J
=16 and 7Hz, CH=CHCH₂), 7.13
(1H, d, J=16Hz, CH=CH−CH₂),
8.08 and 8.83 (each 2H, d, J = 7Hz, 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 (-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 (I
−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 (decomposition). 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, 0CH₂−CH₃), 5.36 (1H, d, J
=4.5Hz, 6-H), 5.46(2H, d, J=7
Hz, 3-CH=CH-CH₂), 5.92 (1H, d,
J = 4.5Hz, 7-H), 6.20 (1H, m, 3-
CH=CH), 7.04 (1H, d, J=16Hz, 3
-CH=CH), 8.43 (2H, d, J=7Hz,
py−H_A), 9.10 (2H, d, J=7Hz, 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-cef
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 (XXVII−1H) is isolated
Conversion through the latter few stages of diagram 1a or 1b
The preparation of compound I-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) (XXVII-1H) XII−1H(Y =I , E isomer) (34g, 75%
purity) of acetone and CH₃Mixture with OH (1/
1. Amberlite solution in 200ml)
(Amberlite) IRA−410 (formate form, 340ml)
placed on the column. Elute the column with the same solvent system.
Ta. Dissolve the first fraction (1) in approximately 100 ml.
Evaporate until dry and remove brown residue with isopropyl ether.
Grind with tel (400 ml). Filter the resulting powder
Collected by and dried under vacuum to give the title compound
XXVII-1H (isomer) 29g (75% by HPLC)
purity) was obtained as a brown powder. Melting point, >150℃
(Disassembly). IR:ν^KBr _naxcm^-13300, 1780, 1680, 1630, 1600. UV:λ^EtOH _naxnm (E1% 1cm) 282 (186). NMR: δacetone d6/CH3OH-d(1/1) ppm 4.0 (3H, s, 0CH₃), 5.26 (1H, d, J=
4.5Hz, 6-H), 5.43 (2H, d, J=7Hz,
H₂N⁺), 5.99 (1H, d, J = 4.5Hz, 7-
H), 6.5 (1H, m, 3-CH=CH₂), 6.92
(1H, s, CHPh₂), 7.1 (1H, d, J = 16
Hz, 3-CH), 7.35 (10H, m, Ph-H),
8.36 (1H, s, HCOO), 8.46 and 9.12
(1H each, d, J = 8Hz, Py-H). B 7-[2-(5-amino-1,2,4-thiadi
azol-3-yl)methoxyiminoacetoacetate
mido]-3-[3-(4-carbamoyl-1-pi
lysinio)-1-propen-1-yl]-3-ce
Fem-4-carboxylate (I-1H) (E
isomer) XXVII-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 product-containing fraction 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)₃N 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),
10.5 g (85% purity) was obtained. Melting point, >180℃
(Disassembly). Pale yellow powder. Reference example 17 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) (E
gender) This reference example uses intermediate XXVII-1H (formate).
The latter few steps of scheme 1a or 1b without isolation
The preparation of compound 1-1H via IX-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 (9.3g)₃Suspension in OH (180ml)
to CH₃Clear when adding 1N HCl in OH (55 ml)
A solution was obtained. Concentrate the solution to approximately 100 ml and
Dilution with sopropanol yields the title compound I-1H
(E isomer) 9.50g (purity 75%) is its hydrochloride
and precipitated. Pale yellow amorphous powder. Melting point, >195℃
(Disassembly). Reference example 18 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 is the last step (7-N
-acylation) to produce compound I-1H.
show. 7-amino-cefem hydrochloride XXII-H (E-different
(5.0 g, 12.6 mmol) in 50% aqueous acetate
(100 ml) of sodium bicarbonate to an ice-cold suspension in
Added the mucilage little by little. The PH of the mixture is measured using a PH meter during the reaction.
I monitored it more. 2 in cold neutralized solution (PH approx. 7)
-(5-amino-1,2,4-thiadiazole-
3-yl)-2-methoxyiminoacetyl chloride
Hydrochloride (4.02 g, 15.6 mmol) little by little
Add the sodium bicarbonate over a period of time.
Adjust the pH of the reaction mixture to 6.8 by adding
Maintained within 7.5. The reaction can also be monitored by tlc.
I watched it. All of compound XXII-H is consumed.
After that, the mixture was brought to pH 3 by the addition of 2N hydrochloric acid.
Ta. The mixture was filtered and the filtrate was concentrated under reduced pressure.
Diluting the residue with acetone (400ml) resulted in a precipitate.
The title compound is liberated and collected by filtration.
9.59g resulted as a pale yellow powder. by HPLC
Estimated purity 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 Yon. 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 pentachloride
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-1H (E isomer) Compound I-1H hydrochloric acid obtained in Reference Example 16
The salt 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. HOLC eluent^*by
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)
I-1H in the zwitterionic form (light yellow amorphous powder)
Finally, 3.3 g (estimated purity 95%) was obtained. 95% purity powder (3.2g) of 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-1H (zwitterionic form) 710mg in pale yellow columnar form
Obtained as crystals. Melting point, >185°C (decomposition). slight
Quantitative 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-d ₆ ^+D ₂ ^O _ppn 3.45 (2H, br, s, 2-H), 3.9 (3H, s,
OCH₃), 4.99 (1H, d, J = 4.5Hz, 6-
H), 5.16 (2H, d, J=7Hz, CH₂N⁺),
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, 4.338; N, 18.72; S, 10.71. Measured value: C, 42.41; H, 4.35; N, 18.86; S, 11.00. *Column, Lichrosolve RP-18, 4 x 300mm: Transfer
Motion phase, 0.01M phosphate buffer (PH7.2)/CH₃OH
=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-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-hydroxymethyl
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (I-1K) (E isomer
body) A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-hydroxymethylene
lupyridinio)-1-propenyl]-3-cefe
Mu-4-carboxylic acid diphenylmethyl iodide
(E isomer) (XII-1K) IX-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 XII-1K, 2.06g (100%) as a tan powder
obtained as. Melting point, 170-180°C (decomposition). IR:ν_nax(KBr)cm^-1 1780, 1725, 1675, 1615, 1530, 1385, 1225, 1040, 750, 700. UV:λ_nax(C₂H_FiveOH)nm(E1% 1cm) 290 (196). NMR: δ(DMSO+D₂O)ppm 3.7 (2H, br, s, 2-H), 3.91 (3H, s,
OCH₃), 4.70 (2H, s, Py-CH₂−OH),
5.28 (2H, m, CH₂−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 = 16Hz, 3-
CH), 6.89 (1H, s, CHPh₂), 7.35
(10H, m, Ph-H), 7.9-8.9 (4H, m,
Py-H). B 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-(Hydroxymethylpi
lysinio)-1-propenyl]-3-cephem-
4-carboxylate (I-1K) (E isomer) XII-1K (E isomer, 2.0 g, 2.4 mmol) and
85% HCOOH with sodium hydrogen sulfate (1 g)
(10 ml) was stirred at room temperature for 2 hours.
The reaction mixture was concentrated under reduced pressure to approximately 5 ml. oily residue
Stir the distillate vigorously in acetone (100 ml).
I added a lot. Collect the precipitate by filtration and remove a small amount of
Washed with acetone and dried to give 1.1g yellowish brown powder.
is obtained, and it is subjected to column chromatography.
[Prep PAK-500/C₁₈Cartridge (water)
I-
1K, 283mg (22%) obtained as amorphous powder
Ta. Powder 4N−H₂S.O._Fourand crystallized from acetone
Upon conversion, 144 mg of the title compound I-1K was obtained as colorless needle-like crystals.
obtained as. Melting point, 185-188°C (decomposed). IR:ν_nax(KBr)cm^-1 1775, 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(D₂O) ppm 3.75 (2H, s, 2-H), 4.18 (3H, s,
OCH₃), 4.97 (2H, s, Py-CH₂−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=16
Hz, 3-CH), 8.13 (1H, dd, J=8
Hz, J = 6Hz, Py-H), 8.60 (1H, d,
J=8Hz, Py−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-thiadias)
sol-3-yl)-2-(Z)-methoxyimi
noacetamide]-3-[3-(4-N-methyl
carbamoylpyridinio)-1-propenyl]-
3-cephem-4-carboxylate (I-
1M) (E isomer) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propenyl)-
Diphenylmethyl 3-cephem-4-carboxylate
(-1) (E isomer, 450 mg, 0.62 mmol) and
4-N-methylcarbamoylpyridine (M. shark
Following the procedure of Jima, Pharmaceutical Journal 80, 1706 (1960)
Production] (215 mg, 1.58 mmol) and acetonitrile
(2 ml) 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 bisulfite
(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 30% aqueous meth.
Eluted with nol. Methanolic eluent under reduced pressure
Evaporate to lyophilize the residue to form an amorphous powder
140 mg was obtained, which was further subjected to HPLC (column: refill).
Closolve RP-18, solvent: 15% CH₃OH)
When the HPLC eluate is lyophilized, the title
Product I-1M, 60 mg (18%) was produced. 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(D₂O) ppm 3.08(3H,s,CONHCH₃), 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-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(carboxypyridinio)
-1-propenyl]-3-cephem-4-cal
Boxylate (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,thiazidi)
Azol-3-yl)-2-methoxyiminoacetate
toamide]-3-(3-iodo-1-propenyl)
-3-cephem-4-carboxylic acid diphenylmethylate
(IX-1) (E isomer, 720 mg, 1 mmol)
was added in one portion and the red solution was stirred at room temperature for 1.5 hours.
Zeta. The reaction mixture was diluted with sodium thiosulfate (150
mg) in a stirred saturated solution of sodium chloride (50 ml)
was added dropwise. Collect the yellow precipitate by filtration and add water.
After washing and drying, 722 mg of pale yellow powder was obtained.
Its powder (700mg) and sodium bisulfite (70mg)
mg) in 85% formic acid (5 ml), and the solution was stirred at room temperature.
I left it for 1.5 hours. Mixture with toluene (50ml)
and concentrated. Dissolve the residue in acetone (70%
ml) and the precipitate is isolated by filtration, resulting in a yellow
421 mg of colored powder resulted. Add this coarse powder (400mg) to water.
(2 ml) and add sodium bicarbonate to the suspension.
added. Prep PAK−
500/C₁₈Cartridge (Waters System)
500) on a column packed with (50 ml),
The column was eluted with water (200ml). eluent
Fractionate into 10 fractions (20ml each) and add the desired fraction.
Combine the fractions (fractions No. 4 to 7), 2N
The pH was adjusted to 3 with hydrochloric acid and concentrated. Acetone the residue
(30ml) and collect the precipitate by filtration.
and the title compound I-1N, 201 mg (37%) as a yellow powder.
obtained as. E/Z=7/1; 80% purity. Melt
point, >189°C (decomposition). IR:ν_nax(KBr)cm^-11770, 1665, 1600. UV:λ_nax(phosphate buffer, PH7) nm (ε) 227 (22500), 290 (22100). NMR: δ(D₂O＋NaHCO₃) ppm 3.7 (2H, br, s), 4.15 (3H, s), 5.32
(1H, d, J = 4Hz), 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-thiadias)
sol-3-yl)-2-(Z)-methoxyimi
noacetamide]-3-[3-(2,3-cyclo
pentenopyridinio)-1-propenyl]-3-
Cefem-4-carboxylate (I-1O(E
isomer) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
amide]-3-(3-iodo-1-propenyl)-
Diphenylmethyl 3-cephem-4-carboxylate
(IX-1) (E isomer, 450 mg, 0.62 mmol) and
2,3-cyclopentenopyridine (217 mg, 1.83
mmol) in acetonitrile (2 ml)
The mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. decrease
After evaporation under pressure, the mixture was triturated in ether.
Upon crushing, 560 mg of quaternary salt was obtained. with that solid
A mixture of 85% formic acid (2 ml) was added at room temperature under nitrogen.
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 transferred to HP-20 (1.5×18
Purified by chromatography on a column of
Ta. Elute the column with water and 30% aqueous methanol
did. The methanolic eluent was evaporated under reduced pressure;
Then freeze-drying yields 160 mg of amorphous powder;
Further, HPLC (column: Lichrosolve, Solvent
Medium: 10% CH₃Purified by OH). HPLC solution
Lyophilization of the syneresis yields the title compound I-1O, 50 mg.
(15%) was obtained. Melting point, >190°C (decomposition). Estimation
75% purity. IR:ν_nax(KBr)cm^-11765, 1670, 1600. UV:λ_nax(phosphate buffer, PH7) nm (ε) 235 (20000), 283 (25000). NMR: δ(D₂O＋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-thiadias)
sol-3-yl)-2-(Z)-ethoxyimi
Noacetamide]-3-[3-(4-carboxy
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (I-2N, E isomer) and 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-(Z)-ethoxyimi
Noacetamide]-3-[3-(4-carboxy
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (I-1N, Z isomer) BSA (1.0ml, 4.12mmol) and isonicotinic acid
(506 mg, 4.12 mmol) in a cooled mixture with −2
(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% Na₂S₂O₃(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, CH₂CH₃), 3.72
(2H, s, 2-H), 4.45 (2H, q,
CH₂CH₃), 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 (decomposition). IR:ν_nax(KBr)cm^-11760, 1600 (sh), 1620, 1370. UV:λ_nax(phosphate buffer, PH7) nm (ε) 225 (22400), 275 (sh, 16000). NMR: δ(D₂O)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=6Hz, Py-
H), 8.92 (2H, d, J = 6Hz, Py-H). Reference example 25 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-(propen-3-yl
oxyimino)-acetamide]-3-[3-(4
-carbamoylpyridinio)-1-propenyl]
-3-cefem-4-carboxylate (1-
3H) (E isomer) 7-Amino-3-[3-(4-carbamoylpyri)
Zinio)-1-(E)-propenyl]-3-cephem
4-carboxylate hydrochloride 35mg (0.08mol)
2-(5-
Amino-1,2,4-thiadiazol-3-y
)-2-(propen-3-yloxyimino)-
Acetyl chloride hydrochloride (from production No. 25) 52mg
Add the mixture to 2N−Na₂C.O.₃Adjust to PH6.5~7.0 with
did. The mixture was stirred at room temperature for 1 hour, then 1N−
The pH was adjusted to 2 with HCl and concentrated under reduced pressure. residue
Chromatography using HP-20 resin column
- and add 300ml of water and 30% CH₃OH-H₂O
It was eluted with Combine the fractions containing the product
Evaporated under reduced pressure. Prep Residue, 73mg
PAK-500/C₁₈Cartridge (Waters,
30 ml) by a column of reversed phase carrier.
The purified column was soaked in water, 5% CH₃OH, 10%
CH₃OH and 20% CH₃Eluted sequentially with OH. Living
When the fractions containing the compound are combined and freeze-dried,
26 mg (62%) of the title product I-3H was obtained. melting point,
160℃ (decomposition). IR:ν_nax(KBr)cm^-13400, 1765, 1680, 1605, 1400. UV:λ_nax(phosphate buffer, PH7) nm (ε) 226 (24600), 288 (22800) NMR: δ(D₂O)ppm 3.75 (2H, s, 2-H), 5.41 (1H, d, J
=5Hz, 6-H), 5.50 (4H, m, CH₂N⁺
and CH=CH₂), 5.98 (1H, d, J=5
Hz, 7-H), 6.20 (1H, m, 3-CH=
CH), 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-thiadias)
sol-3-yl)-2-propargyloxy
iminoacetamide]-3-[3-(4-carba
moylpyridinio)-1-propenyl]-3-ce
Fem-4-carboxylate (1-4H) (E
isomer) 7-Amino-3-[3-(4-carbamoylpyri)
Zinio)-1-(E)-propenyl]-3-cephem
4-carboxylate hydrochloride (XX-H) 86mg
(0.19 mmol) dissolved in 2 ml of 50% aqueous acetone
2-propargyloxyimino-2-(5-
Amino-1,2,4-thiadiazol-3-y
) - Acetyl chloride hydrochloride (from production No. 26)
Added 63 mg. The suspension was diluted with 2N−Na₂C.O.₃at PH6.5~
7.0 and then stirred for 1 hour at room temperature.
The reaction mixture was brought to pH 2 with 1N HCl and concentrated in vacuo.
Shrunk. Dilute the residue with 30 ml of water and NaHCO₃in
Neutralized and filtered. Filter the filtrate using Prep PAK-500/
C₁₈Reverse taken from Cartridge (Waters)
Top of column filled with phase carrier (30ml)
Moved to. Fill the column with water, 5% CH₃OH, 10%
CH₃OH and 20% CH₃Eluted sequentially with OH. Living
When the fractions containing the compound are combined and freeze-dried,
13 mg (12%) of the title product I-4H was produced. recommendation
Constant purity 70%, melting point, 160℃. IR:ν_nax(KBr)cm^-13400, 2120, 1765, 1680,
1610. UV:λ_nax(phosphate buffer, PH7) nm (ε) 229 (24000), 288 (21200). NMR: δ(D₂O)ppm 3.8 (2H, s, 2-H), 5.15 (2H, d, J
=1Hz, -CH₂-C≡CH), 5.40 (1H, d,
J = 5Hz, 6-H), 5.50 (2H, m, CH-
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-thiadias)
sol-3-yl)-2-cyclopentyloxy
shiiminoacetamide]-3-[3-(4-cal
Bamoylpyridinio)-1-propenyl]-3-
Cefem-4-carboxylate (1-5H)
(E isomer) 7-Amino-3-[3-(4-carba) in an ice-cold bath
moylpyridinio)-1-propenyl]-3-ceph
Em-4-carboxylate hydrochloride 139mg (0.31mg)
Stirred solution of (Limol) in 3.5 ml of 50% aqueous acetone
2-(5-amino-1,2,4-thiadiazole)
(3-yl)-2-cyclopentyloxyimide
Noacetyl chloride hydrochloride (from production No. 27) 120
mg (0.44 mmol) was added in portions. mixture
2N−Na₂C.O.₃(0.9ml) to adjust the pH to 6.5-7.0, 10
Stir at ℃ for 1 hour. The reaction mixture was diluted with 1N HCl.
to pH 2 and evaporated under reduced pressure. residue
Chromatography on a column of HP-20 resin (20ml)
Add 300ml of water and 30% CH₃OH-
H₂It was eluted sequentially with O. fraction containing the product
The combined contents were concentrated in vacuo. Acetone 60% of the residue
The title product I-5H, 111 mg (83
%)was gotten. Melting point, 160°C (decomposition). Estimated purity
70%. IR:ν_nax(KBr)cm^-13400, 1770, 1680, 1605,
1530. UV:λ_nax(phosphate buffer, PH7) nm (ε) 224 (23300), 286 (24600). NMR: δ(DnSO−d₆) 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,
CH₂N⁺), 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-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(3-carboxymethyl
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (1-1P) (E isomer
body) A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-carboxymethylene
lupyridinio)-1-propenyl]-3-cefe
Diphenylmethyl mu-4-carboxylate (XII-
1P, iodide, E isomer) 3-Carboxymethylpyridine hydrochloride (0.89
g, 5 mmol) of CH₂Cl₂N to the suspension in 10 ml,
O-bis(trimethylsilyl)acetamide
(4.97 ml, 18 mmol) and stir the mixture into a clear solution.
Stir at room temperature until a liquid is obtained. In solution-
1 (1.79 g, 2.5 mmol) and the mixture was brought to room temperature.
I left it there. After 3 hours, add CH to the cooled mixture.₃OH3
ml and evaporate the solution in vacuo to form an oily substance.
triturated with ethyl acetate to give the title compound
2.28 g of product XII-1P was obtained 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(C₂H_FiveOH)nm(E1% 1cm) 295 (188). NMR: δ(DMSO+D₂O)ppm 3.70 (2H, br, s, 2-H), 3.90 (5H,
s, OCH₃and Py−CH₂CO), 5.25 (3H,
m, -CH₂N⁺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, CHPh₂),
7.35 (10H, m, Ph-H), 8.8-9.0 (4H,
m, Ph-H). B 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(3-carboxymethylene
lupyridinio)-1-propenyl]-3-cefe
Mu-4-carboxylate (I-1P) (E isomer
body) XII-1P (Gigid) (2.28g) and sodium bisulfite
(1.1 g) in 85% HCOOH (10 ml).
The mixture was stirred at room temperature for 2 hours. Reduce reaction mixture
Concentrate to approximately 5 ml under pressure. Acetone the oily residue
(100ml) yields 1.22g of crude product;
Column chromatography (HP-20, 420
ml) to yield the title compound I-1P, 533 mg.
(38%, from -1) as a pale yellow amorphous powder
Obtained. 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(D₂O＋NaHCO₃) ppm 3.78 (2H, s, 2-H), 3.92 (5H, s,
Py−CH₂CO), 4.22 (3H, s, OCH₃),
5.40 (1H, d, J=4Hz, 6-H), 5.44
(2H, d, J=6.5Hz, -CH₂−N⁺), 5.97
(1H, d, J = 4Hz, 7-H), 6.20 (1H,
d-t, J=16 and 3-CH=CH),
7.08 (1H, d, J=16Hz, 3-CH), 8.11
(1H, dd, J=8 and 7Hz, Py−
H_Five), 8.53 (1H, d, J = 8Hz, Py−H_Four),
8.82 (1H, d, J=8Hz, Py−H₆), 8.86
(1H, s, Py, H₂). Reference example 29 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-carboxymethyl
pyridinio)-1-propenyl]-3-cephem
-4-carboxylate (1-1Q) (E isomer
body) A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-(4-carboxymethylene)
ruthiopyridinio)-1-propenyl]-3-ce
Diphenylmethyl fem-4-carboxylate (XII
-1Q, iodide, E isomer) 4-Carboxymethylthiopyridine (0.88g,
5 mmol) of CH₂Cl₂To the suspension in 10 ml, N,
O-bis(trimethylsilyl)acetamide (5
ml, 18 mmol) and the mixture obtained a clear solution.
Stir at room temperature until mixed. −1(E
isomer, 1.79 g, 2.5 mmol) and the mixture
was left at room temperature. After 3 hours, add to the cold mixture.
CH₃Add 3ml of OH and evaporate the solution in vacuo.
An oily residue was obtained, which was triturated with ethyl acetate.
2.43g of the title compound XII-1Q (iodide) is yellowish brown.
Obtained as a colored powder. Melting point 155℃ (decomposition). IR:ν_nax(KBr)cm^-11780, 1720, 1670, 1625,
1525, 1385, 1225, 1115, 1040, 755,
700. UV:λ_nax(C₂H_FiveOH) nm (E1% 1 cm) 312 (299). NMR: δ(DMSO−d₆+D₂O)ppm 3.70 (2H, br, s, 2-H), 3.93 (3H,
s, OCH₃), 5.07 (2H, m, CH₂−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, CHPh₂),
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-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-(4-carboxymethylene)
lupyridinio)-1-propenyl]-3-cefe
Mu-4-carboxylate (I-Q) (E isomer
body) XII-1Q (iodide) (2.43g) and bisulfite sodium
in 85% HCOOH (10ml) with thorium (1.1g)
The mixture was stirred at room temperature for 2 hours. reaction mixture
Concentrate to approximately 5 ml under reduced pressure. Aceto oily residue
(100ml), filtered and dried to form a coarse
The product (1.39 g) was generated and was subjected to column chromatography.
When purified by Graphi (HP-20, 20ml)
The title compound I-1Q, 577 mg (-1 to 39%)
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(D₂O＋NaHCO₃) ppm 3.79 (2H, br, s, 2-H), 4.10 (2H,
s,S-CH₂), 4.23 (3H, s, OCH₃),
5.25 (2H, d, J = 6.5Hz, CH₂−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
= CH), 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-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(1-methylpyrrolidini
e)-1-propenyl]-3-cephem-4-ka
Ruboxylate sulfate (I-1A, sulfate) A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(1-methylpyrrolidi
nio)-1-propenyl]-3-cephem-4-
Diphenylmethyl carboxylate (XII-1A, iodine)
Dido, E isomer) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
Amido]-3-(3-iodopropenyl)-3-se
Diphenylmethyl fem-4-carboxylate (-
1) Vinegar (from production No. 14) (21.5 g, 30 mmol)
1-Methylpyro in the coolant in ethyl chloride (300ml)
Lysine (2.25 g, 30 mmol) in ethyl acetate (30
ml) for 1 hour while stirring at -5 to 0°C.
It was added dropwise over a period of time. Stir for another 10 minutes
After that, the resulting precipitate is collected by filtration and treated with chlorophore.
The title compound (−
1A, iodide) 23.0g (95.8%) was obtained.
point, >175°C (decomposition). IR:ν_nax(KBr)cm^-1 3300, 1780, 1730, 1685, 1615. UV:λ_nax(C₂H_FiveOH)nm (E1% ) 218(435), 295(188). B 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(1-methylpyrrolidi
nio)-1-propenyl]-3-cephem-4-
Diphenylmethyl carboxylate (XII-1A, chloro
Lido) Compound (XII-1A, iodide) 23g, 28.7ml
mol) to a mixture of acetone and methanol (1:
1, 230ml) and pre-treated with the same mixed solvent.
Amberlite IRA−410 (chloride form, 230
ml) column. Expand the column with solvent.
and combine the fractions containing the desired compound.
to an oily residue and dilute it with ethyl acetate (300
ml) to give the title compound (XII-1A, chloride).
), 17.9g (87.7%) was obtained, melting point, 190℃
(Disassembly). IR:ν_nax(KBr)cm^-1 3380, 1780, 1680, 1620. UV:λ_nax(C₂H_FiveOH)nm(E1% 1cm) 220 (369), 290 (232). C 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
cetamide]-3-[3-(1-methylpyrrolidi
nio)-1-propenyl]-3-cephem-4-
Carboxylate sulfate (I-1A, sulfate) Compound (XII-1A, chloride), (17.8g, 25ml
nitrogen mixture in 85% formic acid (178 ml)
Stir for 2 hours at room temperature under atmosphere. True mixture
Evaporate in the air and triturate the oily residue with acetone.
and crude I-1A, 9.80 g. Concentrate the filtrate;
When washed with acetone, additional crude I-1A, 2.95 g
was gotten. Combine the crude products and add 2N-HCl (and
and 0.5). Combine the extracts and make a diamond
Adsorbed onto HP-20 resin (1.5 columns),
It was eluted with water and 30% aqueous methanol.
Collect the desired fraction and remove the oily residue in vacuo.
Evaporate it into isopropanol (200ml)
and a pale yellow color when triturated with acetone (200 ml).
7.09 g of colored powder resulted. Add this substance (6.80g) to water.
(20ml), then Prep PAK-500/C₁₈
Fill the cartridge (90ml) with water and 10
% aqueous methanol as eluent.
It was subjected to romatography. Transfer the eluent to HPLC
Lamb, Nucleocil SSC-ODS-
262, 8 x 100 mm; mobile phase, 0.01M phosphate buffer
(PH7.2)/CH₃OH=90:10; detection, UV
(254nm)] while monitoring the 2ml flux.
It was collected in Yon. Fraction No. 4 ~ Fraction
evaporate under reduced pressure and freeze-dry.
and 2.28 g of yellow powder (E/Z=7/1, 70% purity)
was obtained (Harvest 1). Furakuyon No.11~Furaku
When Shion No. 85 is treated in the same manner as above, it becomes a yellow powder.
(E/Z=5/1, 70% purity) 3.27g was produced
(Harvest 2). Part of Harvest 1 (1.0g) is Prep PAK
−500C₁₈Refill the cartridge (90ml)
It was purified by chromatography. column
Eluted sequentially with water and 5% aqueous methanol. place
Concentrate and lyophilize the eluate containing the desired compound
and 638 mg of yellow powder (E/Z=7/1, 80% purity)
was gotten. The remaining part of Harvest 1 (1.14g) was
880mg of yellow powder (E/Z=7/1,
80% purity) was obtained. Combine two pure samples
Dissolve 1 part (1.45g) in 1N sulfuric acid (5ml).
Ta. While stirring the solution with acetone (315 ml)
Diluted. Collect the cream-colored precipitate by filtration.
and the title compound (I-1A, sulfate) (E/Z=7/
1.80% purity) 1.48g was obtained, melting point, >185℃
(Disassembly). 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(D₂O＋NaHCO₃) 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, CH₂N⁺), 4.22 (3H, s,
OCH₃), 5.39 (1H, d, J = 4.5Hz, 6-
H), 5.96 (1H, d, J = 4.5Hz, 7-H),
6.00 (1H, m, 3-CH=CH), 6.67 (1/8
H, d, J = 10Hz, 3-CH, cis), 7.04
(7/8H, d, J = 16Hz, 3-CH, Tran
vinegar). Reference example 31 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-trimethylammonio-
1-propenyl]-3-cephem-4-carbo
Xylate (1-1D) A 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-trimethylammonio
-1-propenyl]-3-cephem-4-cal
Diphenylmethyl bonate (XII-1D, iodide) 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
Amido]-3-(3-iodopropenyl)-3-se
Diphenylmethyl fem-4-carboxylate (-
1. Manufacture, from No. 10) 13.0 g (19 mmol) dry
in ethyl acetate to a solution in 38 ml of dry ethyl acetate.
1.75 ml (19.1 mmol) of 1.1N trimethylamine
Add at -5°C and stir the mixture for 1 hour at -5°C.
Ta. The resulting precipitate was filtered and CHCl₃Wash thoroughly with
When dried, the title compound (XII-1D) 12.5 g (88%)
was obtained as iodide. IR:ν_nax(KBr)cm^-1 3300, 1765, 1720, 1665. UV:λ_nax(C₂H_FiveOH) nm(ε) 300 (18400). B 7-[2-(5-amino-1,2,4-thiadi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-trimethylammonio
-1-propenyl]-3-cephem-4-cal
Diphenylmethyl bonate (XII-1D, chloride Iodide (XII-1D, 12.5g) in CH₃OH-ace
ion exchange resin (1:1) dissolved in 60 ml
(IRA−410(Cl^-), 125ml] column. mosquito
CH rum₃Dissolved in 300ml of OH-acetone (1:1)
Remove, concentrate the eluent in vacuo and dilute with isopropyl ether.
Quaternary salt (XII-1D, black salt) is obtained by grinding with 300ml of
10.4 g (91%) of Lido) was obtained. IR:ν_nax(KBr)cm^-1 3300, 1765, 1710, 1665, UV:λ_nax(C₂H_FiveOH) nm(ε) 298 (15100). C 7-[2-(5-amino-1,2,4-thiazidi
Azol-3-yl)-2-methoxyiminoa
Cetamide]-3-[3-trimethylammonio
-1-propenyl]-3-cephem-4-cal
Boxylate (I-1D, sulfate, E isomer) XII-1D (chloride) 10.4 g (16.0 mmol)
The solution in 20.8 ml of 85% formic acid was left at room temperature for 3 hours,
Concentrated in vacuo. Isopropanol 210 residue
ml and filtered the precipitate. Solid (10.1g)
Grind with 210ml of water and neutralize with sodium bicarbonate.
did. Filter the suspension and transfer the filtration to HP-20 (300ml)
chromatography on a column of
Next water (1000ml), 10% CH₃OH (200ml) and 30
%CH₃Eluted with OH (150ml). desired product
The containing fractions were combined and concentrated under reduced pressure. Residue
The distillate was purified by reverse phase chromatography.
Column is Prep PAK-500/C₁₈Cartridge (U)
Fill the filling obtained from Oaters, 200 ml).
did. Water (600ml) and 30% CH₃OH (200ml)
and then the fraction containing the desired product
When concentrated, 2.52g (18%) of the title compound was obtained.
Obtained. 1N− of the zwitterionic product (1.5 g)
H₂S.O._Four(5 ml) to 300 ml of acetone.
The resulting precipitate was filtered and dried. I-
The yield of 1D sulfate was 1.42 g (80%).
The E/Z ratio is approximately 10/1 based on HPLC.
Ta. IR:ν_nax(KBr)cm^-1 3380, 1765, 1665. UV:λ_nax(phosphate buffer, PH7) nm (ε) 237 (19500), 293 (22400). NMR: δ(D₂O)ppm 3.25 (9H, s, N⁺−CH₃), 3・94 (2H,
s, 2-H), 4.14 (2H, d, J=7Hz,
CH₂N⁺), 4.23 (3H, s, O-CH₃), 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-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[3-(4-carbamoylpyri
Zinio)-1-propenyl]-3-cephem-4
-Carboxylate (I-1E) (E isomer) 7-Amino-3-[3-(4-carbamoylpyri)
Zinio)-1-(E)-propenyl]-3-cephem
4-carboxylate hydrochloride (XX-H, 397
mg, 1 mmol) and NaHCl₃(168 mg, 2 mm
in aqueous DMF (3.5 ml water and 7.5 ml DMF) with
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. Mixed
The mixture was stirred at room temperature for 3.5 hours. reaction mixture
Adjust the pH to 3-4 with 3N-HCl and add 200ml of acetone.
When diluted, a precipitate forms, which is collected by filtration.
Ta. Dissolve the crude product in a small amount of aqueous THF to make a solution.
NaHCl₃Adjust the pH to 6.8 and treat with decolorizing charcoal, approx.
It was concentrated to 1 ml and seeded with a few pieces of crystal I-1H.
After stirring overnight, the crystalline precipitate was collected by filtration.
Then the title compound I-1H (zwitterionic form) is formed.
It was. Yield 83 mg (16%). Melting point, >185°C (decomposition).
The physicochemical data of this product is the compound of Reference Example 10.
It matched that of the thing. Example 1 Manufacturing No.1 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-chloromethyl-3-cephem
-4-Diphenylmethyl carboxylate (-1) 2-(5-amino-1,2,4-thiadiazole
(-3-yl)-2-methoxyiminoacetic acid (-
1) (2.1 g, 10 mmol) of dry CH₂Cl₂(50ml)
PCL into a stirred suspension in_Five(2.09g, 10mmol)
Add at -30°C and heat the mixture at -15 to -20°C for 20 minutes.
I mixed it up. Add 7-amino-3- to the above acid chloride solution.
Chloromethyl-3-cephem-4-carboxylic acid di
Phenylmethyl hydrochloride () (4.5 g, 10 mmol)
), N,O-bis(trimethylsilyl)acetate
CH containing toamide (10g, 50mmol)₂Cl₂(50
ml) was added at -30°C. -10℃ for 1 hour
After stirring, the mixture is concentrated to CH₂Cl₂remove
and diluted with ethyl acetate (200ml). mixture
10% aqueous NaHCO₃(2 x 40ml), H₂O (2 x 20ml)
and MgSO with sequential washes with brine (10 ml)._Four
It was dried. Evaporate the solvent in vacuo and remove the resulting oily
The residue (10g) was dissolved in CHCl₃(20ml) and si
Kagel (Wako gel) C-200, 100
g, containing 10 ml of 1/1.5 MPH7 phosphate buffer)
1/3% CH on top₃OH−CHCl₃chromatograph using
I put it on Graphie. Flux containing the title compound
When Yon is evaporated, -1, 5.7g (95%) becomes yellow.
Obtained as a colored amorphous powder. Melting point, >140°C (min
solution). IR:ν^KBr _naxcm^-13300, 1780, 1720, 1680, 1620. UV:λ^EtOH _naxnm (ε) 245 (1800), 280 (9900). NMR: δ^DMSO-d6 _ppn 3.53 (2H, ABq, 2-H), 3.94 (3H, s,
OCH₃), 4.42 (2H, s, 3-CH₂), 5.22
(1H, d, J = 4.5, 6-H), 5.92 (1H,
dd, J=4.5 and 6,7-H), 6.93
(1H, s, CHPh₂), 7.36 (10H, m, Ph−
H), 8.1 (2H, br-s, NH₂), 9.58 (1H,
d, J = 6,7-NH). Manufacturing No.2 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-iodomethyl-3-cephem
-4-Diphenylmethyl carboxylate (-1) -1 from production No. 1 (5.7 g, 9.5 mmol)
and NaI (4.3g, 29mmol) in dry acetone
The mixture in (50ml) was stirred at room temperature for 5 minutes.
The mixture was concentrated under reduced pressure and the resulting oil was dissolved in acetic acid.
Ethyl (100ml) and H₂Add to the mixture with O (10ml)
I mixed it up. Separate the organic layer and add 10% w/v
Wash sequentially with sodium osulfate and brine.
Ta. After drying, remove the ethyl acetate in vacuo and the title
Compound (-1) 6.1g (93%) is a yellow amorphous powder
obtained as a powder, melting point >120°C (decomposition). IR:ν^KBr _naxcm^-13300, 1780, 1725, 1680, 1620. UV:λ^EtOH _naxnm (ε) 245 (17000), 282 (12000)
. NMR: δ^DMSO-d _6ppn 3.72 (2H, ABq, 2-H), 3.94 (3H, s,
OCH₃), 4.23 (2H, s, 3-CH₂), 5.21
(1H, d, J = 4.5, 6-H), 5.89 (1H,
dd, J=4.5 and 6.7-H), 6.94
(1H,s,CHPh₂), 7.35 (10H, m, Ph
-H), 8.12 (2H, br-s, NH₂), 9.65
(1H, d, J = 6.7−NH). Manufacturing No.3 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-triphenylphosphoniomethi
Diphenylmethylene-3-cephem-carboxylate
Ruiodide (-1) -1 (690 mg, 1 mmol) from production No. 2 and
Triphenylphosphine (786 mg, 3 mmol)
mixture in ethyl acetate (20 ml) at room temperature overnight.
Stirred. Collect the liberated solid and add it to ethyl acetate.
(2 x 10 ml) and drying produces phosphonium.
950 mg (100%) of iodide-1 was obtained. Melt
Point 186℃ (decomposition). IR:ν^KBr _naxcm^-13300, 1780, 1710, 1680, 1610. UV:λ^EtOH _naxnm (ε) 268 (15000), 275 (13000)
,
300 (7300). NMR: δ^DMSO-d _6ppn 3.52 (2H, br-s, 2H), 3.94 (3H, s,
OCH₃), 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). Manufacturing No.4 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-[(triphenylphosphoranili
den)methyl]-3-cephem-4-carvone
Diphenylmethyl acid (-1) -1 (952 mg, 1 mmol) from production No. 3,
Amberlite IR-410 (OH- form, 500mg) and 1N
-CH with NaOH (4 ml)₂Cl₂(10ml) mixture in
was stirred at room temperature for 1 hour. Filter the mixture and min.
The separated organic layer was treated with MgSO_Fourand concentrated under reduced pressure.
did. The resulting oil was triturated with ethyl acetate, resulting in
Collecting the yellow precipitate by filtration yields the title compound,
-1, 740 mg (90%) was produced. Melting point, >180℃
(Disassembly). IR:ν^KBr _naxcm^-13400, 1750, 1630. UV:λ^EtOH _naxnm (ε) 268 (12000), 276 (10000)
,
384 (23000). Manufacturing No.5 7-[2-(5-amino-1,2,4-thiadias)
sol-3-yl)-2-methoxyiminoacetate
toamide]-3-(3-chloro-1-propene-
1-yl)-3-cephem-4-carboxylic acid di
Phenylmethyl (-1) -1 from production No. 4 (6.9 g, 8.4 mmol)
MgSO in solution in 84 ml of methylene chloride_Four(3g)
and 40% chloroacetaldehyde (810mg, 8.4mg)
Rimol) was added. Stir the mixture at room temperature for 1.5 hours.
Mix and then filter. The filtrate was soaked in silica gel (
-Gel C-200, 100g 1/1.5M phosphate buffer
(containing 10 ml) CHCl on the column₃and CH₃Contains OH
MuCHCl₃It was eluted by using desired raw
fraction (0.5-1% CH₃OH-
CHCl₃) Evaporation in vacuo gives the title compound-1,
1.6 g (30%) was produced as a yellow amorphous powder;
is the Z and E isomerism with respect to the chloropropenyl moiety
(Z/E=2/1, nmr
). Melting point, >130°C (decomposition). IR:ν^KBr _naxcm^-13300, 1780, 1725, 1680, 1620. UV:λ^EtOH _naxnm (ε) 240 (20000), 286 (12000)
. NMR: δ^DMSO-d ₆ ^+D ₂ ^O _ppn 3.56 and 3.8 (m, 2-H), 3.94 (3H,
s, OCH₃), 4.16 (d, J = 7.5, CH
₂C1), 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-CHcis-
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). Reference Example 33 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)
[manufactured according to the order] (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,. Reference Example 34 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, while 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, 80ml). Saturate the solution with ₃ aqueous NaHCO (10
ml) and _H2O (10 ml). _MgSO4
After drying above and removing the solvent, 3.3 g of a yellow oil was obtained. Dissolve the oil in _CH2Cl2 ( _50ml ),
Add to this 1/1.5M phosphate buffer (1.2ml, PH6.4)
Silica gel (12g, Wakogel C-200) containing
was added and filtered, and the silica gel was washed with CH ₂ Cl ₂ (50 ml). The filtrate and washings were combined and evaporated to dryness. Trituration of the residue with n-hexane yields the title compound (
) 1.7 g (80%) resulted as a yellow powder.
The nmr spectrum showed that the chloropropenyl component had Z 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,
CH ₂ −C1), 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, CHPh 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 35 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 ethyl acetate (20ml) was added. Ethyl acetate solution in _H2O
(2 x 5 ml), washed successively with saturated aqueous NaHCO ₃ (5 ml) and brine (5 ml) and dried over MgSO ₄ . Evaporation of the solvent gave 145 mg (97%) of the title compound (Z isomer) 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), 620
(4000), 274 (4000), 285 (4000) Example 2 Production No. 9 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]- 3-(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 (-
1) (10.1 g, 50 mmol) and PCl ₅ (10.4 g), 50
(mmol) in dry CH ₂ Cl ₂ (100 ml) was stirred at -7 to -15°C for 2 hours. A precipitate formed when the clear solution was poured into n-hexane (500 ml). discard the organic layer by decantation;
The residual 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) was purified by column chromatography, eluting with _{CH2Cl2 - CH3OH} (100:1).31 mg (50%) of the title compound-1 (Z isomer) was yellow. Appeared as a powder. Melting point, >150°C (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
−CH ₃ ), 4.0 (2H, m, CH ₂ C1), 5.27
(2H, m, 6-H and 3-CH=CH),
5.83 (1H, dd, J=4.5 and 10,7-
H), 6.25 (1H, d, J = 11, 3-CH),
6.83 (1H, s, CHPh ₂ ), 7.33 (10H, m,
Ph-H), 8.0 (2H, br-s, _NH2 ), 9.57
(1H, d, J = 10,7-NH). Example 3 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). The upper layer was washed sequentially with 10% w/v aqueous sodium thiosulfate solution (10 ml) and brine (10 ml) and dried over _MgSO4 . Evaporation of the solvent gave the title compound-1 (Z/
E=1/1) 540 mg (98%) were 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, transformer), 6.87 and 6.96 (1/2 each
H, s, CHPh ₂ ), 7.4 (10H, m, Ph-
H). Reference example 36 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
vSodium thiosulfate aqueous solution (10ml) and
Washed with _H2O (10ml). Removal of the dried (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+D2O _ppn 3.90 (3H, s, OCH 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 37 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 powder, which was collected by filtration and dried in vacuo. Yield 322g (96%). Melting point, 185-190°C (decomposed). 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 residual oil 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, CHPh ₂ ), 7.33 (10H, br, s,
Ph-H). Elemental analysis, calculated values for _{C23H21N2O3SCl} / _HCl : C, 57.87; _H , 4.65; _N , 5.87; S, 6.72; Cl; 14.85. Measured values: C, 57.62; H, 4.53; N, 5.70; S, 6.64; Cl; 14.89. Example 4 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,O- 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,
OCH 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=4.5
Hz, 7-H), 6.32 (1H, d, J=11Hz,
3-CH), 6.87 (1H, s, CHPh ₂ ), 7.33
(10H, br, s, Ph-H). Example 5 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,
OCH ₂ ), 4.0 (2H, d, J=8Hz, CH ₂ I),
5.26 (1H, d, J=4.5Hz, 6-H), 6.03
(1H, dd, J=4.5 and 8Hz, D ₂ O
changes to double line J = 4.5Hz, 7-H),
6.32 (1H, d-t, J=15 and 8Hz, 3
−CH=CH), 6.79 (1H, d, J=15Hz,
3-CH), 6.98 (1H, s, CHPh ₂ ), 7.35
(10H, m, Ph-H), 7.63 (2H, br, s,
Disappeared by D ₂ O (NH ₂ ), 8.52 (1H, d, J
= 8 Hz, annihilated by D ₂ O, 7-NH). Reference example 38 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
-Cefem-4-carboxylic acid benzhydryl iodide (E isomer) (XII-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.
Washed with a mixture with CH ₃ OH (3/1, 120 ml). The powder was collected by filtration and dried in vacuo to give the title compound . IR: ν ^KBr _nax cm ^-1 3300, 1780, 1720, 1680, 1620. UV: λ ^EtOH _nax nm (E10%H 1cm) 282 (170). NMR: δ ^DMSO-d6 _ppn 3.72 (2H, m, 2-H), 3.90 (3H, s,
OCH ₂ ), 5.25 (3H, m, 6-H and
CH ₂ N ⁺ ), 5.9 (1H, dd, J = 4.5 and 8 Hz, doublet J = 4.5 Hz with addition of D ₂ O
change to, 7-H), 6.35 (1H, m, 3-CH
= CH), 6.89 (1H, s, CHPh ₂ ), 6.9
(1H, d, J = 18Hz, 3-CH), 7.35
(10H, Ph−H), 8.06 (2H, br, s, D ₂ O
annihilated by NH ₂ ), 8.21 (2H, br, s,
The addition of D ₂ O annihilates NH ₂ ), 8.36 and
9.07 (each 2H, d, J = 6Hz, Py-H),
9.57 (1H, d, J=8Hz, annihilated by addition of _D2O , 7-NH). Reference example 39 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)
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 minutes while cooling, the organic layer was separated and added to saturated aqueous sodium bicarbonate (100 ml).
x2) 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 procedure was repeated three times and 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 in the next step without purification. IR: ν ^KBr _nax cm ^-1 1780, 1725, 1635. UV: λ ^CH2Cl2 _nax nm (E10%H 1cm) 257 (400). NMR: δ ^CDCl _3ppn 6.18 (1H, d, J = 11Hz). Reference Example 40 Production No. 17 7-Benzylideneamino-3-[3-(4-carbamoyl-1-pyridinio)-1-propene-
Cooling of 3-chloropropenylcephem (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 to the mixture 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). Isonicotinic acid amide (3.5 g, 28.7 mmol) was added 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 for 1.5 hours, 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). After drying in vacuo over phosphorous pentoxide the title compound XI-H
(E isomer) 17 g was obtained. Yellow amorphous powder.
Melting point 150-155℃ (decomposition). Estimated purity by nmr 80
%. IR: ν ^KBr _nax cm ^-1 17751725, 1690, 1635. UV: λ ^CH2Cl2 _nax nm (E ¹ % ^H ₁ cm) 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 41 Production No. 18 7-amino-3-[3-(4-carbamoyl-1
-pyridinio)-1-propen-1-yl]-3
-Cefem-4-carboxylate (XII-
H) (E isomer) To a suspension of quaternized Cefem XI-H (17 g) in 85% formic acid (25 ml) was added concentrated hydrochloric acid (5 ml) dropwise;
The mixture was stirred at room temperature for 1.5 hours and treated with a small amount of activated carbon. Filter the mixture and add 85% formic acid (5 ml)
Washed with. Combine the filtrate with the washing liquid and add acetone (1
) and poured into the mixture while 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 yield 7.58 g of the title compound XII-H (E isomer) as a hydrochloride. Pale yellow powder. Estimated purity 85% by UV. Melting point 173-188°C (decomposition). IR: ν ^KBr _nax cm ^-1 1795, 1680, 1620, 1575, 1540. UV: λ phosphate buffer max (PH7) nm (E1% 1cm) 294 (457). NMR: δ ^D2O+DCL _ppn 3.82 (2H, s), 5.17 (1H, d, J=5Hz),
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 = 16Hz),
8.34 (2H, d, J = 7Hz), 9.00 (2H, d,
J=7Hz). Reference example 42 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 to yield 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 (H, s, _OCH3 ), 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 61.5 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 values _{for C4H6N4O.CH3COOH} : C, _38.71 ; H, 5.41; N, _30.09 Measured values: 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)
Triethylamine (234 ml, 1.68 mol) was added to a suspension in CH ₃ 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 for C5H5N5OS :} C, 32.78; H, 2.75; N, 38.23 _S , 17.50 Measured: C, 32.76; H, 2.51; N, 38.02, S, 17.50. B 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 ^H2O _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) A suspension of PCl 5 (40.4 g, 0.2 mol) in dry CH ₂ Cl ₂ (400 ml) with PCl ₅ (41.6 g, 0.2 mol)
mol) was added in one portion at -50°C. -20～
The mixture was stirred at -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, washed with the same solvent mixture, and dried over KOH under reduced pressure to yield 46.0 g (90%) of the title acid chloride. IR: νnujiol maxcm ^-1 1775. *Unexamined Japanese Patent Publication No. 57-158, 769 (Fujisawa, September 1982)
Published on the 10th) (UK application 3/6/81) Example 6 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetamide]-3-[3-chloro-1-propenyl]--3-cephem- Dienylmethyl 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-cephem-4-carboxylic acid diphenylmethyl hydrochloride (1.338 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 ₃ ), 4.25
(2H, q, J=7Hz, CH ₂ CH ₃ ), 5.90
(1H, dd, J=4 and 8Hz, 7-
H), 6.25 (1H, d, J = 11Hz, 3-CH),
6.85 (1H, s.CHPh ₂ ), 9.53 (1H, d, J=
8Hz, 7-NH). Example 7 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetamide]-3-[3-iodo-1-propenyl]-3-cephem-4 -Diphenylmethyl carboxylate (-2) -2 (1.90 g, 3 mmol) (from production No. 20)
A mixture of 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 43 7-Benzylideneamino-3-((E)-3-(4
-carbamoylpyridinio)-1-propenyl]
-3-Cefem-4-carboxylic acid diphenylmethyl (XI-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. The reaction is determined by the ratio of UV absorption [E1% 1cm (255nm)/E
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 ml of CH ₂ Cl ₂ . Isonicotinamide (14.64 g) was added to the combined filtrate and washing solution, 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. After drying in _vacuum over _P2O5 ,
Quaternized title compound XI-H, 57.37 g (88
%) was obtained as iodide. Yellow amorphous powder. Melting point, 150-155°C (decomposition). This product is No.
(Manufacturing No.
17). Reference example 44 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) and diluted with silica gel (Wakogel C-
100, 60g) was added and filtered through a pad of dicalite. filter cake in the same solvent system (0.2)
Washed with. The filtrate and washings were combined and concentrated to about 0.2, and Girald's reagent T (60 g, 0.26 mol) and
Treated with 4N HCl (220ml) and seeded with a few crystals of X hydrochloride. 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, mp. >185℃ (decomposition). Pale yellow needles. This product corresponded to that obtained in Preparation No. 12. Reference example 45 7-Amino-3-(3-chloro-1-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl hydrochloride (Z isomer) (, hydrochloride) Chloroacetaldehyde (25% solution in _CHCl3 ,
A solution 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, 10ml)
diluted with Insoluble matter was removed by filtration, and the filtrate was concentrated to about 5 ml. The concentrate was treated with 4N HCl (2 ml), seeded with hydrochloride salt and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with ethyl acetate (10ml) and water (10ml) and dried in vacuo to yield the title compound hydrochloride, 384mg (80%). >185℃ (decomposition). Pale yellow needles. This product corresponded to that obtained in Preparation No. 12. Reference example 46 Production No. 25 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(propen-3-yloximino)acetyl chloride hydrochloride (-3,
(as hydrochloride oxide hydrochloride) A 2-(5-t-butoxycarbonylamino-
1,2,4-thiadiazol-3-yl)-2
-(propen-3-yloxyimino)methyl acetate N-(propen-3-yloxy)phthalimide [E. Grochosaki and J. Jurczak, Synthesis,
A mixture of 685 mg (3.37 mmol) of hydrazine hydrate and 175 mg (3.35 mmol) of hydrazine hydrate in 5 ml of C ₂ H ₅ OH was stirred at room temperature for 1 hour. The resulting precipitate was filtered, and the filtrate and washing liquid were combined. To the solution was added 967 mg (3.37
(mmol) was added and the mixture was left at room temperature for 1 hour and concentrated using a rotary concentrator. The residue was purified by silica gel chromatography. The column was eluted with n-hexane/ethyl acetate (4:1) and the fractions containing the main product were combined and concentrated under reduced pressure. Yield 514 mg (46%). Melting point, 83-86
℃. 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, BOC-H), 4.40 (2H, d,
J=5Hz), O- _CH2 ), 5.21(2H, m,
CH ₂ = CH), 5.90 (1H, m, -CH = CH ₂ ),
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 770mg
(2.3 mmol) and 3.5 ml of 2N NaOH solution (7.0 mmol) in 15 ml of _CH3OH was refluxed for 30 min. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate.
Diluted with 10 ml H ₂ O (1:1). Separate the aqueous layer;
Adjust pH to 2 with 6N-HCl, ethyl acetate (10ml)
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℃
(Reference ⁽¹⁾ , melting point 135-136°C). IR: ν _nax cm ^-1 3150, 1745, 1710, 1550. UV: λ _{nax ( C2H5OH} ) nm (ε) 223 (11000), 242 (11300). NMR: δ (DMSO-d ₆ ) ppm 1.55 (9H, s, BOC-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-butoxycarbonylamino -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 then trituration with 30 ml of isopropyl ether gives the title compound
376 mg (95%) was obtained. 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, CH=CH), 6.0 (1H, m, CH
= _CH2 ). (1) Japanese Patent Application Laid-open No. 112396 (1982) (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 - 3350 mg (1.54 mmol) and phosphorus pentachloride 410
mg (1.97 mmol) of dichloromethane (5 ml)
The solution inside 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 47 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. Purification by silica gel chromatography and then concentration yielded 319 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 ) 235 (12200). NMR: δ (DMSO-d ₆ ) ppm 1.56 (9H, s, BOC-H), 3.55 (1H, t,
J = 2Hz, CK≡CH), 4.85 (2H, d, J
=2Hz, -CH 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 O (1:1) was added. The separated aqueous layer is heated to 6N
The pH was brought to 2 with -HCl and extracted with ethyl acetate (2x10ml). 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, CH 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,
2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetic acid 410 mg (1.26 mmol)
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
(1H, d, J=2Hz, CH 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 48 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 and concentrated in vacuo. The residue was purified by silica gel column chromatography. Elution with n-hexane-ethyl acetate (4:1) followed by evaporation gave the title compound. Yield 906 mg (81%). Melting point, 115~
118℃. 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 O (1:1) was added. Separate the aqueous layer and 6N
The pH was adjusted to 2 with -HCl and extracted with ethyl acetate (10 ml x 2). The organic layer is washed with brine, dried over _MgSO4 and concentrated under reduced pressure to yield 377 mg of the title compound.
(78%) occurred. 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]). C 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetic acid (-5, Z 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 160-65°C (decomposition)]. IR: ν _nax cm ^-1 3290, 3200, 1710, 1615, 1600. UV: λ _nax ( _C2H5OH ) nm ( _ε ) 283 (13300). NMR: δ(DMSO-d ₆ ) 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 -5190 mg (0.74 mmol) and phosphorus pentachloride 219
mg (1.0 mmol) of dichloromethane (2 ml)
The solution was stirred at room temperature for 1 hour. 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 49 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), 283ch (228).

Claims (1)

[Claims] 1 formula, [wherein R ¹ is hydrogen or a conventional amino protecting group, R ² is hydrogen, a straight or branched alkyl group containing 1 to 4 carbon atoms, or a straight chain or branched alkyl group containing 3 to 6 carbon atoms. A cycloalkyl group containing or formula,
[Formula] or [Formula] (wherein R ³ is hydrogen, R ⁴ and R ⁵ are each independently hydrogen, methyl or ethyl,
Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached can be a cycloalkylidene ring containing 3 to 5 carbon atoms), and B ¹ is a conventional carboxyl group. is a protecting group,
Z is chloro, bromo or iodo], or a salt, hydrate, solvate or ester thereof. 2 The compound according to claim 1, wherein Z is chloro or iodo, and R ² is (lower) alkyl, cycloalkyl of 3 to 5 carbon atoms, alkyl, propargyl, or a salt thereof, water hydrate, solvate or ester. 3. A compound according to claim 2, wherein ^R2 is methyl, ethyl, cyclopentyl, allyl or propargyl. 4 B ¹ is hydrogen or a benzhydryl group,
4. The compound according to claim 3, wherein R ¹ is hydrogen or a trityl group. 5 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(3-iodo-1-propene-1
The compound according to claim 4, which is diphenylmethyl-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 6 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-(3-iodo-1-propene-1
The compound according to claim 4, which is diphenylmethyl-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 7 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3-(3-iodo-1-
The compound according to claim 4, which is diphenylmethyl propen-1-yl)-3-cephem-4-carboxylate, or a salt or hydrate thereof;
solvate or ester. 8 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamide]-3-(3-iodo-1-propen-1-yl)-3- The compound according to claim 4, which is diphenylmethyl cefem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 9 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetamide]-3-(3-iodo-1-propen-1-yl)-3- The compound according to claim 4, which is diphenylmethyl cefem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 10 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(3-chloro-1-propene-
The compound according to claim 4, which is diphenylmethyl 1-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 11 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-(3-chloro-1-propene-
The compound according to claim 4, which is diphenylmethyl 1-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 12 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3-(3-chloro-1
The compound according to claim 4, which is diphenylmethyl -propen-1-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 13 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamide]-3-(3-chloro-1-propen-1-yl)-3- The compound according to claim 4, which is diphenylmethyl cefem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 14 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetamide]-3-(3-chloro-1-
The compound according to claim 4, which is diphenylmethyl propen-1-yl)-3-cephem-4carboxylate, or a salt, hydrate, solvate or ester thereof. 15 formula, [wherein R ¹ is hydrogen or a conventional amino protecting group, R ² is hydrogen, a straight or branched alkyl group containing 1 to 4 carbon atoms, or a straight chain or branched alkyl group containing 3 to 6 carbon atoms. A cycloalkyl group containing or formula,
[Formula] or [Formula] (wherein R ³ is hydrogen, R ⁴ and R ⁵ are each independently hydrogen, methyl or ethyl,
Alternatively, R ⁴ and R ⁵ together with the carbon atom to which they are attached can be a cycloalkylidene ring containing 3 to 5 carbon atoms), and B ¹ is a conventional carbon is an acid protecting group, and Z
is chloro, bromo or iodo], or a salt, hydrate, solvate or ester thereof; The compound with the formula, (In the formula, R ¹ , R ² and B ¹ are as described above) 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 form a compound of formula, and then reacting a compound of formula with a base to form a compound of formula, , and then a compound of formula
Reacting with ClCH ₂ CHO gives the formula, and then reacting a compound of formula with sodium or potassium iodide to produce a compound of formula, or reacting a compound of formula with sodium or potassium bromide to produce a compound of formula, and finally removing all protecting groups by conventional methods and converting the free acid compound to its salt or ester, if desired.