GB2171697A - 7-amino-cephem intermediates - Google Patents

7-amino-cephem intermediates Download PDF

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GB2171697A
GB2171697A GB08603333A GB8603333A GB2171697A GB 2171697 A GB2171697 A GB 2171697A GB 08603333 A GB08603333 A GB 08603333A GB 8603333 A GB8603333 A GB 8603333A GB 2171697 A GB2171697 A GB 2171697A
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Prior art keywords
group
substituted
salt
formula
acid
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GB08603333A
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GB2171697B (en
GB8603333D0 (en
Inventor
Hiroshi Sadaki
Hiroyuki Imaizumi
Takashi Nagai
Kenji Takeda
Isao Myokan
Takihiro Inaba
Yasuo Watanabe
Yoshikazu Fukuoka
Shinzaburo Minami
Isamu Saikawa
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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Priority claimed from JP57200382A external-priority patent/JPS5993085A/en
Priority claimed from JP58067871A external-priority patent/JPS59193893A/en
Priority claimed from JP58199945A external-priority patent/JPS6092293A/en
Application filed by Toyama Chemical Co Ltd filed Critical Toyama Chemical Co Ltd
Publication of GB8603333D0 publication Critical patent/GB8603333D0/en
Publication of GB2171697A publication Critical patent/GB2171697A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to novel 7-(optionally protected amino)-3-substituted methyl- DELTA 3-cephem-4-carboxylic acids which are useful intermediates for producing various novel cephalosporins, and a process for producing the said compounds. The 3-substituent is of formula: <IMAGE> where R<6> to R<9> are optional substituents.u

Description

1
SPECIFICATION
GB 2 171 697 A 1 7-(Substituted or unsubstituted amino)-3-substituted rnethylcephem-4- carboxylic acids and process for producing the same This invention relates to novel cephalosporins, processes for producing said cephalosporins, an anti-bacterial agent containing said cephalosporins, intermediates for the production of said cephalosporins and a process for producing said intermediates The present inventors have conducted studies with the aim of discovering compounds having a broad antibacterial spectrum, exhibiting an excellent anti-bacterial activity against gram-positive and gram-neg- 10 ative bacteria, being stable to p-lactamase produced by bacteria, having a low toxicity, being at the same time well absorbable upon oral or parenteral administration and having an excellent therapeutic effect on the diseases of human beings and animals. As a result, it has been found that novel cephalosporins char acterized in that a substituted or unsubstitued 2,3-dioxo-1,2,3,4- tetrahydropyrazinyl, 2-oxo-1,2-di hydro pyr- azinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyI or 6-oxo-1,6- dihydropyridazinyl group is attached to the 15 exomethylene group at the 3-position of the cephem ring through a carbon- nitrogen bond and the foilowing group is attached to the amino group at the 7-position, have the above-mentioned excellent properties:
R5-J/ N A 4 CO- 20 0 R wherein A, R4 and R5 are as defined below.
It is an object of this invention to provide novel cephalosporins having the above-mentioned chemical structural characteristic features, having a broad antibacterial spectrum, being stable against P-lactamase 25 produced by bacteria, having a low toxicity, being well absorbed upon oral or parenteral administration, and having an excellent therapeutic effect on the diseases of human beings and animals.
It is another object of this invention to provide a process for producing said novel cephalosporins.
It is a further object of this invention to provide an antibacterial agent containing said cephalosporins.
It is a still: further object of this invention to provide intermediates for the production of said novel cephalosporins and to_ provide a process for producing said intermediates.
The objects and advantages of this invention will become apparent from the following description.
According to this invention, there is provided a novel cephalosporin, particularly a cephalosporin represented by the following formula, or a salt thereof:
R3 N _k J, 4 2 R S R CH R 2 40 wherein R' represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of the formula, 8 0 0 R 7 R 10 0 R 11 45 6 N -N N R 9 0 r R 12 R 13 14 50 1 R N 1 N 0 XR15 55 in which R6 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocar bamoyl group, a sulfamoyl group or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cy cloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsul- 60 fonyl, arylsulfonyl, heterocyclic suffonyl, alkylcarbamoyl, dial kylca rba moyl, alkylthiocarbamoyl, dialkyl thiocarbarnoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylearbamoyl, arylsuifonylcarbamoyl, alkyl sulfonylthiocarbarnoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino, or het erocyclic group, or a group of the formula, 2 GB 2 171 697 A 2 - -N RIG "' R17 (each of R16 and R17,which may be the same or different, represents a hydrogen atom or an alkyl group or RIG and R17 together with their adjacent nitrogen atom may form a ring); each of R7, R8, R9, Rio, Rii, 1311, R14 and 1315, which may be the same or different, represents a hydrogen atom, a halogen atom or a sub- stituted or unsubstituted alkyl, aralkyl or aryl group; R13 represents a hydrogen atom, a halogen atom, a 10 carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy', alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dial kylcarbamoyl, alkylthiocarbarnoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfony[carbamoyl, aryisulfony[carbamoyl, alkylsulfonylthiocarbarnoyl or arylsulfonylthiocarbamoyl group; 133-represents a hydrogen atom or an alkoxy group; R4 represents a hydrogen atom or a halogen atom; R5 represents a hydrogen atom or a protected or unprotected amino group; and A represents a group of the formula, -CH,- or a group of the formula, -C11 N OR18 in which Ris represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl,. cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl-protecting group; or a group of the formula, 0 11 1_1 Rig -p 1.1 -25 R20 35 (each of R19 and R20, which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, al koxy, aralkyloxy, or aryloxy group), and the bond - means that the compound may be a syh-isomer or an anti-isomer or a mixture thereof.
This invention also provides a process for producing said cephalosporins and salts thereof and an anti bacterial agent containing said cephalosporins.
This invention will be further illustrated in detail below.
Herein, unless otherwise specified, the term "alkyl" means a straight or branched chain C1-14alkyl and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -sec.-butyl, tert.-butyl, pentyl, 45 hexyl, heptyl, octyl, doclecyl and lauryl; the term -alkoxy" means -0alkyl in which the alkyl is as defined above; the term "lower alkyl- means a straight or branched chain C,. Galkyl and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.- butyl and pentyl; the term "lower al koxy" means -0-lower alkyl in which the lower alkyl is as defined above, the term "acyl" means a formyl group; a C,,alkanoyl group which includes, for example, acetyl, propionyl, Isovaleryl, pivaloyl, and pen- 50 tanecarbonyl; a C,Gcycloalkanecarbonyl group which includes, for example, cyclopenty1carbonyl, and cy clohexylcarbonyl an aroyl group which incl, udes, for example, benzoyl, toluoyl; and 2-naphthoyl and a heterocyclic carbonyl group which includes, for example, thenoyl, 3- furoyl and nicotinoyl, the term "acy loxy- means -0-acyl in which the acyl is as defined above; the term "alkylthio" means -S-alkyl in which the alkyl is as defined above; the term "alkenyl" means C,oalkenyl and includes for example, vinyl, allyl, 55 isopropenyl, 2-pentenyl and butenyl; the term "alkynyl" mearis C,_, oalkynyl and includes, for example, ethynyl and 2-propynyl; the term "cycloalkyl" means C,,cycloalkyl and includes, for example, cyclopro pyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; the term "alkadienyl" means C,,,alkadienyl and includes, for example, 1,3-butadienyl and 1,4-hexadienyl; the term "cycloalkenyl" means CS-7CYCloalkenyl _60 and includes, for example, cyclopentenyl and cyclohexenyl'; the term "cycloalkadienyl" means C, cycloalkadienyl and includes, for example, cyclopentadienyl and cyclohexadienyl; the term "aryl" in cludes, for example, phenyl, naphthyl and indanyl; the term "aralkyl" includes, for example, benzyl, phenethyl, 4-methylbenzyl, and naphthylmethyl; the term "heterocyclic group" means a heterocyclic group containing at least one hetero atom selected from oxygen, nitrogen and sulfur and includes, for example, fury[, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadi- 65 3 GB 2 171 697 A 3 azolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4-(5-metyl-2-pyrrolinyl), 4-(2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl and cournarinyl; the term "heterocyclic alkyl" means a group consisting of the above-defined heterocyclic group and the above-defined alkyl group; and the term "hal5 ogen atom" includes, for example, fluorine, chlorine, bromine and iodine. The symbol R1 in the formulas in this specification represents a hydrogen atom or a carboxyl-protecting group, and the carboxyl-protecting group includes those which are conventionally used in the fields of penicillins and cephalosporins, for example, an ester-forming group which can be removed by a catalytic hydrogenation, a chemical reduction, or a treatment under other mild conditions; an ester-forming group which can be easily removed in a living body; or an organic silyl- containing group, an organic phosphorus-containing group, or an organic tin-containing group, which can easily be, removed upon treating with water or an alcohol; and other various well-known ester-forming groups. Among these protecting groups, preferable groups are as follows: (a) alkyl groups, for example, C,-,alkyl, (b) substituted lower alkyl groups wherein at least one of the substituents is selected from a halogen atom, or a nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yi, 1-indanyl, 2-indanyl, fury[, pyridyl, 4-imidazolyl, phthalimido, succinimido, azetidino, aziridino, pyrroliclino, piperidino, morpholino, thiomorpholino, N-lower-alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazo- 20 lyl, cournarinyl, 2,5- dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 2, 6-dimethylpiperidino, 4-(5-methyl-2-pyrrolinyl), 4-(2-pyrrolinyl), N- methyl-piperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, ary- loxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclic oxy, alkoxycarbonyloxy, alkenyloxycarbony25 loxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclic oxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclic oxycarbony[ or alkylanilino group or an alkylanilino group substituted by a halogen atom, a lower alkyl or lower alkoxy group, (c) cycloalkyl group; lower alkyl-substituted cycloalkyl group; or (2,2- di-lower-alkyl-1,3-dioxol-430 yl)methyl groups, (d) alkenyl groups, (e) alkynyl groups, (f) phenyl group; substituted phenyl groups wherein at least one of the substituents are selected from the substituents specifically mentioned in above (b); or aryl groups such as groups represented by the formula: 1 35 --<úY.
wherein -YI- is -CH=CH-0-, -CH=CH-S-, -CH,CH,S-, -CH=N-CH=W, -CH=CH-CH=CH, -CO-CH=CH-CO-, or -CO-CO-CH=CH-, or a substituted derivative thereof wherein the substituents are 40 selected from those specifically mentioned in above (b), or groups represented by the formula:
/--\ Y 2 wherein _Y2- is a lower alkylene group such as -(CH2)3- or -(CH2)4-1 or a substituted derivative thereof wherein the substituents are selected from those specifically mentioned in above (b), (g) aralkyl groups such as benzyl or substituted benzyl groups wherein at least one of the substituents are selected from those specifically mentioned in above (b), (h) heterocyclic group or substituted heterocyclic groups wherein at least one of the substituents are 50 selected from those specifically mentioned in above (b), (i) indanyl or phthalidyl groups or substituted derivatives thereof wherein the substituents are methyls or halogens; tetra hydro na phthyl groups or substituted derivatives thereof wherein the substituents are methyls or halogens; trityl, cholesteryl or bicyclo [4,4,01decyl; (j) phthalidylidene-lower-alkyl groups or substituted derivatives thereof wherein the substituents are halogens or lower alkyl groups.
The above-mentioned carboxyl-protecting groups are typical examples, and the carboxyl-protecting group may also be selected from the other protecting groups described in the following literature: U.S.
Patent Nos. 3,499,909, 3,573,296 and 3,641,018; DT-OS Nos. 2,301,014, 2, 253,287 and 2,337,105.
Among these carboxyl-protecting groups, preferable are diphenylmethyl, 6lower alkyl-2-oxo-1,3-dioxol- 60 4-yHower alkyl groups, acyloxyalkyl groups, acylthioalkyl (:)ups, phthalidyl group, indanyl group, phenyl group, substituted or unsubstituted phthalidylidene lower alkyl roups or those groups which can easily be removed in a living body such as groups represented by the following formulas:
4 GB 2 171 697 A -CH(CH,),OR21, -CH0C001321, and -CH(CH.).COOR21 1 R27 4 1 R- i R23 wherein R21 represents a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; Rrepresents a hydrogen atom or a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R23 represents,a hydrogen atom, a halogen atom or a known substituted or unsubstituted alk-yl, cycloalkyl, aryl or heterocyclic group, or -(CHIC001321 (1321 has the same meaning as defined above, and n represents 0, 1 or 2); and m represents 0, 1 or 2.
More specifically, there may be used 5-lower alkyl-2-oxo-1,3-dioxol-4-ylmethyI groups such as 5- 10 methyl-2-oxo-1,3-dioxol-4-yi-methyl, 5-ethyl-2-oxo-1,3-dioxoi-4-yl-methyl, 5-propyl-2-oxo-1 and 3-dioxol-4yi-methyl; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, va I eryloxym ethyl, 1-acetoxyethyl, 1-acetoxy-npropyl, 11-pivaloyloxyethyl and 1-pivaloyloxy-n-propyl; acylthioalkyl groups such as acetylthiomethyl, pivaloylthiomethyl, benzoyl- thiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1- pivaloylthioethyl, 1-benzoylthioethyl and 1-(pchlorobenzoylthio) ethyl; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl and n-butyloxymethyl; alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxyme-_ thy[, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbony loxymethyl, nbutoxycarbonyloxymethyl, tert..-butoxycarbonyloxymethyl, 1methoxycarbonyloxyethyl, 1-ethoxycarbonyl- oxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-tert. -butoxycarbonyloxyethyl and 20 1-n-butoxycarbonyloxyethyl; alkoxycarbonylmethyl groups such as methoxyca rbo nyl m ethyl and_ethokycarbony(methyi; phthalidyl group; indanyl group; phenyl group; phthalidilidene-alkyl groups such as 2(phthal idyl idene) ethyl, 2-(5-fl uorophthal idyl idene)ethyl, 2-(6-chlorophthalidylidene)-ethyI and 2-(6methoxyphtha lidyli den e)ethyl. 25 R2 represents a group of the formula:
0 0 R 7 R R 10 0 R 11 13 14 6 N -N N-R -N 30 R 9 N R12 N, XR is 1 1 R 0 0 0 in which R6 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocar bamoyl group, a sulfamoyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cy cloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, araikyloxycarbonyl, alkylsuffonyl, cycloalkylsul fonyl, arylsulfonyl, heterocyclic suffonyl, alkylcarbamoyl, dialky[carbamoyl, alkylthioc6rbamoyl, dialkyl thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfony[carbamoyl, arylsuffonylcarbamoyl, 40, alkylsulfonylthiocarbarnoyl, arylsulfonylthiocarbarnoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocar- 40 bonyl, alkylideneaminol cycloalky1methylenearnino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group; a group of the formula, R16 45 -N/ R17 (each of R1r, and R17, which may be the same or different, represents a hydrogen atom or an alkyl group, or RI6 and-1317 together with their adjacent nitrogen atom may form a ring), each of R7, R", R9, RIO, R", R12, R14 and R-1 which may be the same or different, represents a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl, aralkyl or aryl group; RI3 represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl group, a thiocarbarnoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dial kylcarbamoyl, alkylthiocarbarnoyl, dial kylthiocarbarnoyl, acylcarbamoyl, acYlthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbarnoyl or arylsulfonylthiocarbarnoyl group. In each of the groups for Rr, and R13 mentioned above, the term "cycloalkyloxy" means -0-cycloalkyl, the term "aryloxy" means -0-aryl, the term "alkoxycarbonyl" means GB 2 171697 A -C-O-alkyl, 11 U the term "cycloalkyloxycarbonyi" means -C-0-eycloalkyi, 11 U the term "acyloxycarbonyV' means -C-0-acy], 11 15 U the term "aralkyloxycarbonyi" means -C-O-aralkyl, 20 11 0 the term "alkylsulfonyl" means -S02-alkyl, the term "cycloalkylsulfonyl" means _S02_CYCloalkyl, the term "aryisulfonyl" means -S02-aryl, the term "heterocyclic sulfonyl" means -SO,.-heterocyclic ring, the term "alky[carbamoyl" means -C-NH-alkyl, 11 U the term "dialkyl carbamoyl- means alkyl -C-N / 11 \ 0 alkyl the term "alkylthiocarbamoyi" means -C-N / 11 \ S alkyl the term "dialkyithiocarbamoyi" means alkyl the term "acylcarbamoyl" means -C-NH-acyi, 11 U -60 the term "acyithiocarbamoyl" means -C-NH-acyi, 11 6 GB 2 171697 A 6 the term "alky[suifonylcarbamoyl" means -C-NH-SO,-alkyl, 0 the term "aryisuifonylcarbamoyi" means -C-NH-S0,7ary], 10 11 0 the term "alkylsuifonylthiocarbamoyi" means -C-NH-SO,-alkyl, 11 O_ the term "aryisuifonyithiocarbamoyi" means -C-NH-SO,-aryl, 11 S the term "alkvisulfamoyi" means -S0,7NH-alkyi, the term "dial kyl su Ifamoy]- means alkyl -SO,-N / alkyl the term "alkoxythiocarbonyi" means -C-0-alkyl, the term "alkylideneamino" means -N=CH-alkyl, the term "cycloalkylmethylamino" means -N=CH-cycloalkyl, the term "arylmethyleneamino" means -N=CH-aryl, and the term "heterocyclic 40 methyleneamino" means -N=CH- heterocyclic ring.
The groups of the formula, RIG R17 wherein RIG and R17 have the same meanings as defined above include amino group, alkylamino groups represented by -NH-alk-VI, dialkylamino groups represented by aikyl -N/ 55- alkyl and groups represented by the formulas 60- 7 -N, -MO, GB 2 171 697 A 7 -N N-alkyl, -N -N NH, (1 ' N 1==\ r-\- / j IN=N -N Of -N 0, -N S, -N so -N -N or 2' j 10 - IN=N -N 1 - \-- N The substituents for the various groups mentioned above include halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups represented by -NH-alkyi, dialkylamino groups represented by / alkyl \alkyl acylamino groups represented by -NH-acyi, alkoxycarbonyl groups represented by -C-0-alkyi, 11 U acylalkyl groups such as acetyimethyl and propionyl methyl, aminoalkyl groups such as aminomethyl, and aminoethyl, Walkylaminoalkyl groups such as N-methylaminomethyl and Wmethylaminoethyl, N,N dialkylaminoalkyl groups such as N,N-dimethylarninomethyl and N,N- dimethylarninoethyl hydroxyalkyl 35 groups such as hydroxymethyl, and hydroxyethyl, hydroxyiminoalkyl groups such as hydroxyiminome thyl and hydroxyiminoethyl, alkoxyalkyl groups such as methoxymethy], methoxyethy], ethoxymethyl and ethoxyethyl, carboxyalkyl groups such as carboxymethyl and carboxyethyl, alkoxycarbonylalkyl groups such as methoxycarbonyl methyl, meth oxyca rbonyl ethyl, ethoxyca rbo nyl methyl and ethoxycar bonylethyt, araikyloxycarbonylaikyl groups such as benzyloxycarbonyl methyl and benzyl oxyca rbonyl ethyl 40 sulfoalkyl groups such as sulfomethyl and sulfoethyl, sulfamoylalkyl groups such as sulfamoyimethyl and sulfamoylethyl, carbamoylalkyl groups such as carbamoyimethyl and carbamoylethyl, carbamoylalkenyl groups such as carbamoylallyl, Whydroxycarbamoylalkyl groups such as Whydroxycarbamoyl methyl and Whyd roxyca rba m oyl ethyl, a group of the formula -C = C-R1 0 T 0 0 50 in which R24 represents a lower alkyl group. The above-mentioned various groups as to R6, R7, W, Rg, RIO, W,, R12, R13, R14 and R15 may be substituted by at least one of the above- mentioned substituents. Among the above substituents, the hydroxyl group, the amino group and the carboxyl group may be protected by a suitable protecting group usually available in the art. The hydroxyl- protecting groups include all hydroxyl-protecting groups which can be usually used, such as easily removable acyl groups, for exam ple, benzyioxycarbony], 4-nitrobenzy[oxycarbonyi, 4- bromobenzyioxycarbonyi, 4-methoxybenzyloxycar bonyl, 3,4-dimethoxybenzyioxycarbonyi, 4-(phenylazo)benzyioxycarbonyi, 4(4 methoxyphenylazo)benzyioxycarbonyl, tert.-butoxycarbonyl. 1, 1 -dim ethyl p ropoxyca rbony], isopropoxy carbonyl, di phenyl methoxycarbony.1, 2,2,2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyi, 1-cyclopropylethoxycarbonyl, 8quinolyloxycarbonyl, formyi, acety], chloroacetyl, benzoyl and trifluoroacetyl; alky[sulfonyl groups, for example, methanesulfonyl and ethanesulfonyl; aryisuifonyl groups. for example, phenyisuifonyl and toluenesulfonyl; benzyl group; di phenyimethyl group; trityl group; methoxymethyl group; tetra hyd ropyra nyl group; tetrahydrofuranyl group; 2-nitrophenylthio group; or a 2,4-dinitrophenyithio group.
8 GB 2 171697 A 8 In addition, the amino-protecting groups include all usually.usable amino- protecting groups such as easily removable acyl groups, for example, 2,2,2-trichloroethoxycarbonyi, 2,2,2-tribromoethoxycarbonyi, benzyloxycarbonyl, p-toluenesulfonyl, 4nitrobenzyloxy-carbonyi, 2-bromobenzy[oxycarbony], acetyl, (mono-, di-, tri-)chioroacety], trifluoroacetyl, formyi, tert.-amyioxy-carbonyl, tert.butoxycarbonyl, 4-meth- oxybenzyloxycarbonyl, 3,4-dimethoxybenzyioxycarbonyl, 4-(phenyiazo.)- benzyloxycarbony], 4-(4-methoxyphenyl azo)benzyl oxyca rbonyi, pyridine-loxide-2-yi-methoxycarbonyi, 2-furyloxycarbonyl, diphenyimethoxycarbony], 1,1 -dirn ethyl propoxycarbo ny], isopropoxycarbonyl, 1cyclopropylethoxycarbony], phthaloVI, succiny], ladamantyloxycarbonyl and 8-quinolyloxycarbonyi; further easily removable groups, for example, trity], o-nitrophenyisuifonyl, 2,4-dinitrophenyithio, 2hydroxybenzyiidene, 2-hydroxy- 5-chlorobenzylidene, 2-hydroxy-1 -naphthyl methyl en e, 3-hydroxy-4- pyridyl methylene, 1-methoxycarbonyl2-propylidene, 1-ethoxycarbony]-2-propylidene, 3-ethoxycarbonyi-2butylidene, 1-acetyl-2-propylidene, 1 benzoyl-2-propylidene, 1-[N-(2-methoxyphenyi)carbamoyll-2-propylidene, 1- [N-(4-methoxy phenyi)carbamoyll-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2ethoxycarbonylcyclopentylidene, 2 acetylcyclohexylidene, 3,3-dimethyi-5-oxocyclohexylidene, and 4- nitrofurfurylidene; di- or tri-alkylsilyl group. Then, the carboxyl-protecting groups include all usually usable carboxyl-protecting groups, and there are cases where the carboxyl group is protected by such a group as methyl, ethyl, n-propy], isopro pyI, tert.-buty], n-butyi, benzyl, diphenyimethyl, trily], 4-nitrobenzy], 4-methoxybenzy], benzoyimethyi, ace tylmethyl, 4-nitrobenzoyl methyl, p-bro mobenzoyl methyl, 4-m ethanesu Ifo nyl benzoyl methyl, phthalimidomethy], 2,2,2-trichloroethyl, 1,1-dimethy]-2-propenyi, 1,1- dimethylpropyi, acetoxymethy], pro pionyloxymethyl, pivaloyloxymethyi, 3-methyi-3-butynyi, succi ni m idom ethyl, 1-cyclopropylethyl, methyl- 20, thiomethyl, phenylthiomethy], dimethylaminomethyl, q uinol i ne-1 -oxide- yi methyl, pyridine-l-oxide-2 yimethyl and bis(p-m ethoxyphenyi) methyl, where the carboxyl group is protected by a non-metal com pound such as titanium tetrachloride, and where the carboxyl group is protected by a silyl compound such as dimethylch[orosilane as described in Japanese Patent Application Kokai (laid-Open) No. 7073/71 and Dutch Patent Application No. 7105259 (Laid-Open).
R5 represents a hydrogen atom or a protected or unprotected amino group, and such amino-protecting groups include many groups usually employed in the fields of penicillins and cephalosporins, specifically all the amino-protecting groups mentioned above as to R2.
A represents a group of the formula, -CH27 or a group of the formula, -COR" 35 in which R's represents a hydrogen atom; a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl-protecting group, or a group of the formula, 0 R19 40 li/ - - -p \ R20 (each of R's and R-, which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, ak koxyl aralkyloxy or aryloxy group) and the bond - means that the compound may be a synisomer or an anti-isomer or a mixture thereof. The, said hydroxyl-protecting group includes the hydroxyl-protecting groups mentioned as to R2. In addition, the above-mentioned various groups for R18 may be substituted by at least one substituent selected from halogen atoms, oxo group, cyano group, hydroxyl group, al- 50 koxy groups, amino groups, alkylamino groups, dialkylamino groups, heterocyclic groups and groups of the formulas:
R25 0 - OR25 - 55 @__,- R25 11 / -COOR1, -CON -N R26 -NI-ICOR25 and -P \R26 R-, \OR26 60 wherein R, has the same meaning as defined above, and each of R251 R21; and R27, which may be the same or different, represents a, hydrogen atom, an alkyl group, an aralkyl group of an aryl group. Among these substituents, the hydroxyl group, the amino group, and the carboxyl group may be protected respectively by the hydroxyl-protecting group and the amino-protecting group mentioned as tol R2 and the carboxyl protecting group mentioned as to W.
65- 9 The oximes of the formula, include syn- and anti-isomers and mixtures thereof. 10 In the -C- 11 N OR111 N R -s - 4 R GB 2 171697 A 9 group of each formula in this invention, there are tautomers as shown by the following equilibrium for- 15 mulas where R5 is a protected or unprotected amino group, and such tautomers are included in this invention:
R 4 H N 5 N ---] R S <. S R 4 wherein R4 and R5 have the same meanings as defined above, and R5. represents a protected or unpro tected imino group. In the above formulas, the imino-protecting group for R5. includes those groups used in the fields of penicillins and cephalosporins, and specifically, same groups as the monovalent groups 25 among the amino-protecting groups mentioned above as to R2.
When the -CH,R2 group in the formula [11 is a group of the formula:
00 6 -CH 2 -N N-R or R 1 -N 0 R 11 1 - CH 2 -N 1 (R 12 0 wherein R6, RIO, R" and R12 have the same meanings as defined above, there are tautomers as shown in 35 the following equilibrium formulas when each of R6 and RIO is a hydrogen atom, and the tautomers are also included in this invention:
0 0 0 OH -CH 2 -N NH -CH 2 -NN 0 R HN 1 -CH 12 2 R 0 OH R N 1 -CH 2 -N R 12 0 The salts of the compounds of the formula [1] include salts at the basic group and the acidic group which are well-known in the fields of penicillins and cephalosporins. The salts at the basic group include salts with mineral acids such as hydrochloric acid, nitric acid and sulfuric acid salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, tol- uene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2, 4,6-tri m ethyl benzenesu Ifon ic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, phenylmethanesulfonic acid, benzene-1, 3disulfonic acid, toluene-3,5-disulfoniG acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid and naphthalene-1,3,5-trisulfonic acid. The salts at the acidic group include salts with alkali metals such as so- dium and potassium; salts withalkaline earth metals such as calcium and magnesium; ammonium salts; 60 and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-p-phenethylamine, 1- ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N- methylmorpholine, diethylamine and dicyclohexylamine.
GB 2 171 697 A This invention includes all optical isomers and the racemic compounds of cephalosphorins of the formula [11 and their salts, and also all crystal formS and hydrates of the said compounds. More specifically, preferable examples of the compounds represented by the formula [11 are oximes in which A is a group of the formula, -C- li N, ORI8 particularly syn-isomers thereof, in which Wa is preferably an alkyl group, especially methyl, ethyl; or a substituted alkyl group, especially -CHCOOR, or CH 15 C-COOR1 CH 20- 20 (R, has the same meaning as defined above).
Preferable examples of R2 are groups of the formula, 6 -N N-R 2 3U in which R6 is a hydrogen at9m1 a substituted or unsubstituted lower alkyl group or a group of the formula, -N/ R16 R17 (R16 and R17 have the same meanings as defined above); groups of the formula, 7 R 8 - R 1 40 R 9 0 in which each of R7, W and R9, which may be the same or different, represents a hydrogen atom or an 45 alkyl group; groups of the formula, R 10 0. R11 N 1 -N R 12 50 0 in which each of RIO, R,' and R12, which may be the same or different, represents a hydrogen atom, a 55 halogen atom or an alkyl group, and groups of the formula, R% R14 N 1 -N 1 Xa 15 0 in which each of R13, R14and R15, which may be the same or different, represents a hydrogen atom or an alkyl group.
Next, pharmacological effects are shown on some typical compounds represented by the formula [11.65 11 GB 2 171 697 A 11 1)Antibacterial activity (Table 1) According to the standard method of Japan Society of Chemotherapy [- CHEMOTHERAPY% Vol. 23, pp. 1-2 (1975)1, a bacterial solution obtained by culturing in Heart Infusion broth (manufactured by Eiken Kagaku) at 37'C for 20 hours was inoculated onto a Heart Infusion agar containing a drug and cultured at 37'C for 20 hours, after which the growth of the bacterial was observed, to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC (Kg/mi). The amount of the inoculated bacteria was 104 cells/plate (106 cells/mi). The MIC values of the following test compounds are as shown in Table 1:
(A) - trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(2-,3dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3-cephem-4-carboxylic acid, (B) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4methyl -2,3-d ioxo-1,2,3,4-tetra hyd ropyrazi nyi)l m ethyl}_A3-ceph em-4-ca rboxyl ic acid, (C) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4-ethyi2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyl}-A3-cephem-4-carboxylic acid, (D) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4-isopropyi-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)lmethyi}-A3-cephem-4-carboxylic acid, (E) trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4-dimethylamino-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)l-methyi{-A3-cephem-4-carboxyl ic acid, (F) 7-[2-(2-aminothiazol-4-yi)-2-(syn)-carboxy-methoxyiminoacetamidol-3{[1-(2,3 -dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3-cephem-4carboxylic acid, (G) trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)carboxymethoxyiminoacetamidol-3-{[1(4-methyl-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)l-methyi}-A3-cephem-4-carbox yiic acid, (H) trifluoroacetic acid salt of 742-(2-a m in oth iazo 1 -4-yi)-2-(syn)- ca rboxymethoxyi m i noacetam idol -3-{[1 (4-ethyi-2,3-dioxo-1,2,3,4-t6trahydropyrazinyi)l-methyi}-A3-cephem-4carboxy lic acid, (1) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yi)-2-(syn)carboxymethoxyiminoacetamidol-3-{[l(4-d i methyl am in o-2,3-d ioxo-1,2,3, 4-tetra hyd ro-pyrazi nyi)l m ethyl}_A3-ceph em-4-carboxyl ic acid, (J) trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(2-oxo1,2-dihydropyrazinyi)lmethyi}-A3cephem-4-carboxylic acid, (K) trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(3,6dioxo-l- ' 2,3,6tetrahydropyridazinyi)lmethyi}-A3-cephem-4-carboxylic acid, (L) formic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)carboxymethoxyiminoacetamidol-3-{[1-(3,6dioxo-1,2 3,6tetrahydropyridazinyi)lmethyi}-A3-cephem-4-carboxylic acid, (M) trif;uoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(3methyi-6-oxo-1,6-dihydropyridazinyi)lmethy 1}-A3-cephem-4-carboxylic acid, and (N) formic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-(syn)carboxymethoxyiminoacetamidol-3-{[1-(3methyi-6-oxo-1,6dihydropyridazinyl)lmethyi}-A3-cephem-4-carboxylic acid.
TABLE 1
Antibacterial activity 40 MIC (jjg1M1) Organism 45 Compound A 8 C D E F G H 1 j K L M N E.Coli N1W:50.1:50.1 Z--0.1:50.1 250.1:50.1 _0.1:50.1:50.1:50.1.50.1 50. 1:50.1:50.1 E. Coli TK-3:50.1 --50.1:550.1:50.1 -:0A:_50.1 0.2:_50.1 _:50.1 0.2 0.2 0. 78 0.2 0.2 K1. pneumoniae Y-50 --0.1:_50.1:-5-0.1:_50.1 --50.1 z_50.1 0.2 0.2 0. 2:_50.1:50.1 0.78 0.2 0.39 50 K1. pneumoniae Y-41 2-50.1 =50.1 ---50,1 --0.1 ---:50.1 0.39 ---50.1 --0. 1:_50.1 G.2 K1. pneumoniae Y-4 -:!50.1 0.2:_50.1 0.39:_50.1 0.2 0.2 0.2 0,39 - Ser. marcescens W-134 ---50.1 --'M:_50.1:_50.1 -- 0. 1 -5 0. 1 -- 0. 1 2- 50.1 ---250.1 0.39 0. 1 ---:50.1 0.78 --50.1 55 Ser. marcescens 11D620:_50.1:_50.1:_50.1 50.1 250.1:_50.1:_50.1:_50.1:_50. 1:_50.1 ---50.1 1.56 0.2:_5 0. 1 Pro. morganii T-216 -50.1:_50.1 --0.1:_50.1 t-50.1 --50.1:_50.1 5-0.1:_50. 1:_50.1 -50.1:_50.1 0.2 5-0.1 Pro. mirabilis T-111:-0.1 --0.1 -::0.1 0.2 Z-50.1 2-E0.1 2_50.1 --0.1:_50. 1 0.2:_50.1 _:50.1 0.2 -::: 0. 1 60 Pro. vulgaris GN76:_50.1 0.2 1.56 0.39 1.56:_50.1:_50.1:_50.1:_50.1 0. 78:_50.1:_50.1 0.2 --50.1 Cit. freundii N-7 0.39 1.56 0.78 1.56 0.78 0.78 1.56 1.56 1.56 0.78 0.78 3.13 0.78 0.78 Ps. aeruginosa GN918 12.5 25 6.25 - - - - 6.25 12.5 - - - - - 65 12 GB 2 171 697 A Note: Penicillinase-producing strain Cephalosporinase-producing strain 12 2) Urinary recovery - q A test compound was orally administered to mice (ICR, male, 4 weeks old) in an amount of 1 mg/ -5 mouse, and a urinary recovery was determined. The results obtained are shown in Table 2.
In the test compounds (No. 1 and No.- 2), the ester group is easily removed in a living body, whereby the compounds are converted into the corresponding free carboxylic acids. Therefore, the urinary recovery was determined. by quantitatively measuring the free carboxylic acids excreted into urine.
Administration method: A test compound suspended in 0.5% CIVIC (Carboxy Methyl Cellulose) was or- ally administered. 10 Quantitative measurement method: The amount of free carboxylic acid was measured by bioassay (a paper-disc method) using the test organism mentioned in Table 2.
TABLE 2
N C-CONH-1 H N 2 S N OR18 COOR 113---NIf' CH 2 R 2 (syn-isomer) Compound Test Urinary NO. R1 R2 organism Recovery Xl. pneumoniae 15.9 1.6 1 -CH 3 -CH 20COC (CH 3) 3 -N - ATCC 10031 0 N 2 -CH 3 -CH 2 OCOC(CH 3)3 1 11 20.4 3.7 -N 0 COOH -H CH 3 11 - 3 -CH N 10.4 1.1 1 -N 0 (mean:kS.E.) Note: 0 6 hours, one group; 5 mice 45. 3Acute toxicity LID,, values of the following test compounds were 3 g/kg or more when the compounds were intravenously administered to mice (ICR, male, body weight 20-24 g).
Tes t c o mp o, un ds..
0 Sodium 7-[2-(2-a m inothiazol-4-yi)-2-(syn)-m eth oxyim i noaceta m idol -3-{[1 -(2,3-dioxo-1,2,3,4-te- 50 trahydropyrazinyi)lmethy I}_A3-cephern-4-carboxyl ate, 0 sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-{[1(4-methyi-2, 3-dioxo1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3-cephem-4-carboxyi.ate, 0 sodium 7-[2-(2-aminothiazol-4-yi)-2-(syn)-methoxyiminoacetamido]-3-{[1(3,6-dioxo-1,2,3,6-te- trahydropyridazinyl)l methyl}-A3-cephem-4-carboxyl ate, and 0 sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-{[1(3-methyi-6-o xo-1,6- dihydropyridazinyi)lmethyi}-A3-Cephem-4-carboxyfate.
Next, an explanation is made below of production processes.
The compound of this invention can be prepared by the following processes:
13 GB 2 171697 A 13 Production Route 1 R 3 R.
0 w CH 2 R 29. [111 COOR 1 or a"salt thereof I), -bl 2) [III-a] [III 3) 4) -cl (III-dl or a salt thereof (conversion XCH2COCH2COOH IVII at 3 position) or a salt thereof or /areactive R 3 28 R 2 0 N CH 2 R COOR1 [IV] or a salt thereof, or a reactive derivative at amino group thereof Production Route 1 (Cont'd) XCH 2 COCCOOH [VIII 11 N U., or a salt thereof, or a reactive derivative /,, [VIIII thereo 1 CH2COCCOOH R3 28: S R - - -C or a salt thereof, or a reactive derivative at amino group thereof N A-COOH R -/ S 1 R 4 (v] or a salt thereof, or a reactive derivative thereof (acylation) derivative R 3 S thereof XCH 2 COCH 2 CON:; 2 N (acylation) 0 N, CH 2 R [IX3 COOR or a salt thereof (nitrosa- R---1\ S A tion) Y3 S XCH COCCONH ' ' ji N CH R 2 N 0 P ' 2 [X] (acylation) L COORI or a salt thereof (etherification or phosphorylation) N 18a OR R) f S R f-CON 1 ', S R 4 0:XN,ICH 2 R- COOR 1 11) or a salt thereof R 5 [M1 (ring closure) R 3 S --r 2 0,;-N, CH 2 R COOR1 [1a) or a salt thereof H 2 NCR 5 (XIII 11 H NCR5 2 (ring S closure) (XIII R3 p3 S b N CCONH '- - R'--/,' 11 1 Or a salt there- XCH 2 (ring CH2R2 of, or a reactive N TN "rj" CH2R2 closure) COOR1 derivative thereof 0 [IV] (acylation) 18a [XII COOR1 or a salt thereof R 5 N COCOOH S1R 4 [M11 or a reactive or a salt thereof R3 derivative N COCONH S thereof R JR 4 2 j:?'CH R (acylation) 1 0, COORI 2 IXIV1 or a salt thereof S R41 0 J CH 2 R2 OR1 8 COOR1 or a salt [Ibl the f oximination) - H 2 NOR is [XV3 or a salt thereof 14 GB 2 171697 A O4 6 Note: 1) Formula (Ill-a] is HN N-R R 7 R \ - N HN Y"R 9 0 2) Formula [III-bl is 3) Formula [III-cl is 4)- Formula [III-di is Production Route 2 3 R 30-CONH S / NT CH X 0 2 COOR1 or a salt thereof R3 1 R 3 O-CONH Nf 0 0 -m N CH N NR6 COOR 1 [XVII (conversion at 3-position) R3 R 30-CONH S 0 0 -CH N NR6 0 ? 1 2 COOR or salts thereof R 10 0 HN ykRl_2 0 R13 R 14 W 1 HN. Rl'S 0 W1 6 HN NR [III-al 11 or a salt thereof 3 R30-CONH S W 6 3;1:N,CH N NR [XVIIII 2 COOR1 [XVII 1 (conversion into A 3 -cephem) (Cont' d) 14 is GB 2 171 697 A 15 Production Route 2 (Cont'd) or a salt thereof (deacylation) 10 R 3 H 2 N f ' S 1. 6 15 f If / N,,,- CH N NR [XIXI 0 / 1 1 2 COOR or a salt thereof 20 in the above formulas, W, R2, R3f R4, R5, R6, R7, R8, Rs, RIO, R% R12, R13, R14, R15, Ris, A and the bond - have the same meanings as defined above; R's. represents the groups for R's except a hydrogen atom; R28 represents an amino group, or a group of the formula, R31 _\C=C-NI-1- ,-, 1 R32 hi in which each of R31-, R32 and R33,which may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a group of the formula, R34 "I R31 \\C=W in which each of R-- and R35, which may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction; R29 represents a substituted or unsubstituted acyloxy or carbamoyloxy group; R30 represents benzyi, phenoxymethyl or a group of the formula, n- N S:ZR 4 in which R4, R5 and A have the same meanings as defined above; X represents a halogen atom; >Z represents >S or >S--->0; and the dotted line in the ring represents a double bond between the 2and 3positions or the 3- and 4-positions.
A further detailed explanation is made below. R28 represents an amino group, a group of the formula, R31 C=C-NI-1- --, 1 R32 h33 60 or a group of the formula, 16 GB 2 171 697 A 16 R- "C=N-, 1..I R35 5 - and the group of the formula, R31 C=C-NI-1- 10 R32 R33 includes the group of the formula, - R31 CH-C=W 1 20 R32 R33 which is its isomer. The organic residues not participating in the reaction for R31, R32, R33, R- and R3s include those well-known in the art, specifically substituted or unsubstituted aliphatic residues, alicyclic residues, aromatic residues, aromatic-aliphatic residues, heterocyclic residues, acyl groups-and the like. 25 More specifically, the following groups are included:
(1) aliphatic residues: alkyl groups; alkenyl groups, (2) alicyclic residues: cycloalkyl groups; cycloalkenyl groups, (3) aromatic residues: aryl groups, (4) aromatic-aliphatic residues: aralkyl groups, (5) heterocyclic residues: heterocyclic groups, (6) acyl groups: acyl groups which can be derived from organic carboxylic acids which include aliphatic carboxylic acids, alicyclic carboxylic acids and alicyclo-aliphatic carboxylic acids; and also include aro matiG aliphatic carboxylic acids, aromatic-oxyaliphatic carboxyliG acids, aromatic-thioaliphatic carboxylic acids, heterocyclic aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids, and heterocyclic- 35 thioal.iphatic carboxylic acids, in which an aromatic residue or a heterocyclic group is bonded, directly or through an oxygen or sulfur atom, to an aliphatic carboxylic acid; organic carboxyliG acids wherein an aromatic residue, an aliphatic group or an alicycliG group is bonded to the carbonyl group through an oxygen, nitrogen or sulfur atom; aromatic carboxylic acids and heterocyclic carboxylic acids.
The above aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, iso- 40 butanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid a nd crotonic acid, the above alicyclic carboxylic acids include cyclohexanoic acid and the above alicycloaliphatic carboxylic acids include cyclopentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, and cyclohex adieneacetic acid.
Also, the aromatic residues in the above-mentioned organic carboxylic acids include phenyl, and naph- 45 thyl.
Each of the groups constituting these organic carboxylic acids may be further substituted by a substi tuent such as a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, a nitro group, an amino group, a protected amino group, a carboxyl group, or a protected carboxyl group.
Also, the substituted or unsubstituted acyloxy and carbarnoyloxy groups for R29 include alkanoyloxy groups such as acetoxy, propionyloxy and butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy and naphthoyloxy; and carbarnoyloxy group. These groups may be substi tuted by one or more substituents such as halogen atoms, nitro group, amino group, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl group, carboxyl group, sulfamoyl 55 group, carbamoyl group, alkoxycarbonylcarbamoyl groups, aroylcarbamoyl groups, alkoxycarbonylsulfa moyl groups, aryl groups and carbarnoyloxy group.
In the above-mentioned substituents for R29, hydroxyl group, amino group and carboxyl group may be protected with protecting groups which are usually employed, and the protecting groups include, specifi cally the hydroxyl-protecting groups, amino-protecting groups and carboxyl-protecting groups which 60 have been mentioned above as to R2.
a) Conversion reaction at 3-position 7-Substituted or unsubstituted amino-3-substituted methyl cephem carboxylic acid of the formula [IVI or a salt thereof can be produced in a high yield with a high purity using an industrially easy procedure 65 17 GB 2 171 697 A 17 by reacting a 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [111-a], a 2-oxo-1,2-dihydropyrazine of the formula [111-bl, a 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [III-c], or a 6-oxo-1,6-dihydropyrida zine of the formula [111-dj, or a salt thereof with a cephalosporanic acid represented by the formula [IQ or a salt thereof in the presence of an acid or a complex compound of an acid, then if desired, removing the protecting group, protecting the carboxyl group or converting the obtained compound to a salt thereof.
Further, the above-mentioned 2,3-dioxo-1,2,3,4-tetrahydropyrazine can be prepared by the method de scribed in the Journal of Chemical Society, Perkin 1, pp. 1888-1890 (1975).
Furthermore, if necessary, the substituent on the amino group at the 7position can be removed in a conventional manner to form a 7-unsubstituted amino compound. According to this procedure, not only A3-cephem compounds but also A2-cephem compounds can be used as the starting compounds, and where the A2-cephem compounds are used as the starting compounds, the reaction product L2-cephem compounds are further converted to A3-cephem compounds.
Also, not only compounds where >Z is >S but also compounds where >Z is >S->O can be used as the starting materials, and in the latter case >S--->O can be converted to >S during the reaction or in an after-treatment step.
If the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [111-al, the 2oxo-1,2-dihydropyridazine of the formula [111-bl, the 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [111-cl or the 6-oxo-1,6-dihydropyr idazine of the formula [111-d] which is used as a reactant in the reaction, has a basic or acidic group as the substituent, these compounds may, if necessary, be applied in the form of the corresponding salt to the reaction. In this case, the salts at the basic groups and the salts at the acidic groups include those men- 20 tioned as to the salts of the compounds of the formula [1].
Also, the salts of the compounds of the formulas DO and [IV] include salts at the basic groups and at the acidic groups, and these salts include those mentioned about the salts of the compounds of the for mula [1]. The salts of the compounds of the formula [III may be previously isolated and then used, or may be prepared in situ.
As the acids or the complex compounds of acids used in the reaction, there are mentioned, for exam ple, protonic acids, Lewis acids or complex compounds of Lewis acids. The protonic acids include sul furic acids, sulfonic acids and super acids (super acids means acids stronger than 100% sulfuric acid and includes some of the above-mentioned sulfuric acids and sulfonic acids). More specifically, the protonic acids include sulfuric acids such as sulfuric acid, chlorosulfuric acid, and fluorosulfuric acid, sulfonic acids, for example, alkyl (mon- or di-)sulfonic acids such as methanesulfonic acid and trifluoromethane sulfonic acid, aryl(mono-, dior tri-)sulfonic acids such as p- toluenesulfonic acid, super acids, such as perchloric acid, magic acid (FS03H-SbF,), FSO,,H-AsF,, CFSOH-SbF,, HF-BF., and H,SO,-SO,.
The Lewis acids include, for example, boron trifluoride, and the complex compounds of Lewis acids include complex compounds of boron trifluoricle with dialkyl ethers such as diethyl ether, di-n-propyl ether, and di-n-butyl ether; with amines such as ethylamine, n- propylamine, n-butylamine, and trietha nolamine; with esters such as ethyl formate and ethyl acetate; with aliphatic acids such as acetic acid and propionic acid; and with nitriles such as acetonitrile and propionitrile.
The reaction is preferably conducted in the presence of an organic solvent. The organic solvents used include all organic solvents inert to the reaction, for example, nitroalkanes such as nitromethane, nitroethane, and nitropropane; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid and propionic acid; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethyleneglycol climethyl ether, anisole and dimethyl Cellosolve; esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate and butyl acetate; nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane. These solvents may be used in admixture of two or more. In addition, com plex compounds formed from these organic solvents and Lewis acids can be used as the solvent. It is sufficient that the amount of the acid or the complex compound of the acid used is at least equimolar to the amount of the compound represented by the formula [111 or a salt thereof, and the amount may be varied depending on the respective cases. In particular, the use in a proportion of 2-10 moles per mole of 50 the compound of the formula [111 or a salt thereof is preferred. Where the complex compound of the acid is used, it can be used per se as a solvent, and two or more of the complex compounds may be used in admixture.
It is sufficient that the amount of the 2,3-dioxo-1,2,3,4tetrahydropyrazine of the formula [III-a], the 2 oxo-1,2-dihydropyrazine of the formula [111-bl, the 3,6-dioxo-1,2,3,6- tetrahydropyridazine of the formula [III-c] or the 6-oxo-1,6-dihydropyridazine of the formula [111-dl or a salt thereof is at least equimolar to the amount of the compound represented by the formula [111 or a salt thereof, and particularly, the use in an amount of about 1.0-5.0 moles per mole is preferred.
This reaction is usually carried out at 0-800C, and completes in ten minutes to thirty hours. The pres ence of water in the reaction system may cause undesirable side reactions such as lactonization of the 60 starting material or products and cleavage of P-lactam ring, so that it is desirable to keep the system under the anhydrous conditions. In order to fulfull this requirement, it is sufficient to add, to the reaction system, a suitable dehydrating agent, for example, a phosphorus compound such as phosphorus pentox ide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloricle, or phosphorus oxychloricle, an organic silylating agent such as N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylch- 65 is GB 2 171 697 A 18 lorosilane or dimethyldichlorosilane; an organic acid chloride such as acetyl chloride or p-toluenesulfonyl chlorider an acid anhydride such as acetic anhydride or trifluoroacetic anhydride; an inorganic dehydrat ing agent such as anhydrous magnesium sulfate, anhydrous calcium chloride, a molecular sieve or cal cium carbide.
If a compound represented by the formula [111 wherein RI represents a carboxyl-protecting group is 5 used as the starting material, a compound represented by the formula [IV] wherein R1 represents a hy drogen atom can, in some cases, be directly obtained by the reaction, or can be obtained by removing the protecting group in a conventional manner.
Next, conversion reaction at 3-position, which is described in Production Route 2, is explained.
The halogenated compound represented by the formula [XVII can be prepared according to the 10 method described in Tetrahedron Letters, No. 46, pp. 3991-3994 (1974) and Tetrahedron Letters No. 40, pp. 3915-3918 (1981).
The compound represented by the formula [XVIII or a salt thereof can be prepared by the reaction of a halogenated compound represented by the formula [XVI] or a salt thereof with a 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [111-al or a salt thereof in the presence of a base. The base includes alkali metal carbonates (for example, sodium carbonate or potassium carbonate; alkali metal hydrogencarbon ates (for example, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrox ides (for example, sodium hydroxide and potassium hydroxide; nitrogen- containing organic bases, for example, triethylamine, pyridine and N,N-dimethylaniline.
The conversion at 3-position is generally carried out in a suitable solvent. The solvent includes halo- 20 genated hydrocarbons such as chloroform and methylene chloride; ethers such as tetrahydrofuran, diox ane and the like; N,N-dimethylformamide; N,N-dimethylacetamide; acetone; water; and mixtures thereof.
In this case, the compound represented by the formula [111-a] or a salt thereof is preferably used in an amount of 1.0-2.0 moles per mole of the compound represented by the formula [XVII or a salt thereof.
The reaction is generally carried out at a temperature of 0-50C for 30 minutes to 10 hours.
The mixture of a A2- and A3-cephem compound thus obtained, that is,.a compound represented by the formula VVIII or a salt thereof, can be easily converted into the A3- cephem compound, to prepare-the compound of the formula [XVIIII or a salt thereof, which is then converted into the compound of the formula [XIX] or a salt thereof by the deacylation. Said conversion reaction and deacylation are known -in the fields of penicillins and cephalosporins and are specifically described in the Journal of Organic
Chemistry, Vol. 35, No. 7, pp. 2430-2433 (1970) and "Cephalosporins and Penicillins" (by Flynn, Academic Press), pp. 56-64.
If the substituents of the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [111-al, the 2-oxO-1,2-dihy dropyrazine of the formula the 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [111-c], or the 6 oxo-1,6-dihydropyridazine of the formula [III-dl or the salt thereof, which are used as the reactants in the 35 reaction, are substituted by a hydroxyl group, an amino group or a carboxyl group, these groups may be protected by the above-mentioned protecting groups prior to the reaction and subjected to a conven tional removal reaction after the completion of,the reaction to obtain a desired compound.
Also, the compound represented by the formula [IV] or [XIX] can, if necessary, be protected at the - carboxyl group or converted into the salt according to a conventional method, to obtain the objective 40 compound. Also, the -compound represented by the formula [IV] wherein R28 represents an amino group can be converted into a reactive derivative at the amino group or the compound represented by the for mula VIXI as mentioned hereinafter by a conventional method.
(b) Acylation When the compound represented by the formula [V], [V11, [Vill, [VIII1 or [X1111, or a salt thereof, or a reactive derivative thereof Is reacted with a compound represented by the formula [IV] or a salt thereof or a reactive derivative at the amino group, a compound represented by the formula [11, [IXI, [X], [X11 or NVI, or a salt thereof is obtained.
The salts of the compound represented by the formula [V], [V11, [VH], [VIII1 or [X1111 include salts at the 50 basic group or the acidic group, which specifically include those mentioned as to-the salts of the com pound represented by the formula [11.
The reactive derivatives at the amino group of the compound represented by the formula [1V1 include all derivatives which are often used in acylation, for example, an isocyanate; a. Schiff base produced by the reaction of the compound represented by the formula [1V1 or a salt thereof with a carbonyl compound 55 such as an aldehyde or a ketone, (ketimine type or its isomer, namely, enamine type); a s - ilyl derivative, a phosphorus derivative or a tin derivative, produced by the reaction of a compound represented by the formula [1V1 or a salt thereof with a silyl compound such as bis(trimethyisiiyi)acetamide, trimethylsilyla cetamide, or trimethylsilyl chloride, a phosphorus compound such as phosphorus trichloride, \ PC1, PC1, 10/ CH 3 F0/ 19 GB 2 171 697 A 19 C0\ 0/ PC11 (C11 3 CH 2 0) 2 Pcl,(CH 3 CH 2)2 PC1 or the like, or a tin (CH,CH,O),PCI, (CH,,Cl-1j,1PC1 or the like, or a tin compound such as (C,, H,),SnCl.
The reactive derivatives of the compounds represented by the formulas [V], [V11, [Vil], [VIIII and [X1111 include specifically acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active es ters, reactive derivatives obtained by reaction of the compounds represented by the formulas [V], [Vil, Will, [VIII] and [X1111 with a Vilsmeier reagent. The mixed acid anhyride includes a mixed acid anhydride with a. monoalkyl carbonate such as monoethyi carbonate and monoisobutyi carbonate, a mixed acid anhydride with a lower alkanoic acid which may be substituted by a halogen, such as pivalic acid or trichloroacetic acid. The active acid amide includes Wacylsaccharin, N- acylimidazole, N-acyibenzoylam ide, N,N'-dicyclohexyi-N-acylurea and Wacylsulfonamide. The active esterincludes cyanomethyl ester, substituted phenyl esters, substituted benzyl esters and substituted thienyl esters.
The reactive derivatives obtained by reaction with a Vilsmeier reagent include those obtained by reac- 15 tion with a Vilsmeier reagent obtained by reacting an acid amide such as N,N-dimethyitormamide or N, N-di methyl aceta m ide with a halogenating agent such as phosgene, thionyl chloride, phosphorus tri chloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate or oxalylchloride.
If each of the compounds represented by the formulas [V], [V]], [Vill, [V1111 and [X1111 is used in the form 20 of a free acid or a salt, a suitable condensing agent is used. The condensing agent includes N,W-disubsti tuted carbodiimides such as N,N'-dicyclohexylcarbodiimide; azolide compounds such as N,N'-thionyidiii dazole; dehydrating agents such as N-ethoxycarbony]-2-ethoxy-1,2- dihydroquinoline, phosphorus oxychloride and alkoxyacetylenes; 2-halo-genopyridinium salts such as 2- ch loropyridinium methyl iodide and 2-fluoropyridiniummethyl iodide.
This acylation reaction is usually carried out in a suitable solvent in the presence or absence of a base.
As the solvent, there may be used a solvent inert to the reaction, for example, a halogenated hydrocar bon such as chloroform, methylene chloride or the like; an ether such as tetrahydrofuran, dioxane or the like; N,N-dimethyiformamide; N,N-dimethylacetamide; acetone; water; or a mixture thereof. As the base, 3U there may be used an inorganic base such as an alkali metal hydroxide, an alkali metal hydrogencarbon- 30 ate, an alkali metal carbonate or an alkali metal acetate; a tertiary amine such as trimethylamine, triethy lamine, tributylamine pyridine, N-methylpiperidine, N-methyimorpholine, lutidine or collidine; or a secondary amine such as dicyclohexylamine or diethylamine.
The compound represented by the formula [IX] or a salt thereof which can be converted into the corn pound represented by the formula []a] or [Ibl or a salt thereof can be produced by the following proce- 35 dure:
In order to obtain the compound represented by the formula [[X] or a salt thereof using the compound represented by the formula []V] or a salt thereof, a 4-ha log en o-3-oxo- butyryl halide which is obtained by the reaction of a diketene with a halogen such as chlorine or bromine [Journal of the Chemical Society, 97, 1987 (1910)l may be reacted with the compound represented by the formula [IVI or a salt thereof according to a usual method. Reaction conditions and procedures which are known in the art can be applied to this reaction. And the salt of the compound represented by the formula [IX] can easily be prepared according to a usual method, and the salt includes the same salts as mentioned above as to the salts of the compound represented by the formula [11. Although the compound represented by the for mula [IXI or a salt thereof may be isolated and purified, it can be used for the subsequent reaction with- 45 out isolation.
In addition, the compound represented by the formura [V], [Vil, [Vill, [VIIII or [XIII] or a salt thereof or a reactive derivative thereof is preferably used in an amount of about one mole to several moles per mole of the compound represented by the formula [IVI or a salt thereof or its reactive derivative at the amino group. The reaction is usually carried out at a temperature ranging from - 50' to 40'C. The reaction time 50 is usually 10 minutes to 48 hours.
Furthermore, the compounds represented by the formulas [11, []X], [X], [Xl] and [XIV] wherein R1 is a carboxyl-protecting group can be converted to the compounds represented by the formulas [11, []X], [X], [M] and [XIVI wherein R, is a hydrogen atom, or their salts according to the usual method; and similarly the compounds represented by the general formulas [11, [IXI, [X], [Xl] and [XIV] wherein R' is a hydrogen 55 atom can be converted to the compounds represented by the formulas [1], [IX], [X], [Xl] and [XIV] wherein R' is a carboxyl-protecting group or salts thereof; and the salts of the compounds represented by the formulas [1], [[X], [X], [M] and [XIV] can be converted to the corresponding free acid forms, re spectively.
Also, in this acylation reaction, if W, R2 and R5 contain groups active to the reaction, these groups can 60 suitably be protected with conventional protecting groups prior to the reaction, and the protecting groups can also be removed by a usual method after the reaction.
The compound represented by the formula [11 or a salt thereof of this invention obtained by the above mentioned method can be isolated by a conventional method.
GB 2 171697 A (c) Nitrosation Subsequently, in order to obtain the compound represented by the formula [XI or a salt thereof from the compound represented by the formula [IX1 or a salt thereof, a nitrosating agent is reacted with the - compound represented by the formula [IX] or a salt thereof. The reaction is usually carried ou, t in a sol vent, and as the solvent, there may be used a solvent inert to the reaction such as water, acetic acid, benzene, methanol, ethanol or tetrahydrofuran. Preferable examples of the nitrosating agent include ni tric acid and derivatives thereof, for example, nitrosyl halides such as nitrosyl chloride and nitrosyl'bro mide, alkali metal nitrites such as sodium nitrite and potassium nitrite, alkyl nitrites such as butyl nitrite and pentyl nitrite. If a nitrous acid salt is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic 10 acid or acetic acid. If an alkyl nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide. The reaction is usually carried out at a temperature ranging from - 1 50C to 30'C, and-the reaction time is usually 10 minutes to 10 hours. The salt of the compound represented by the formula [X] can easily be prepared according to a usual method, and the salt includes the same salts as mentioned above as to the salts of the compound 15 represented by the formula [1]. Although the compound represented by the formula [XI or a salt thereof thus obtained can be isolated and purified by a well-known method, it can be used for the subsequent reaction without isolation.
(d) Etherification and phosphorylation In order to obtain the compound represented by the formula [M] or a salt thereof from the compound represented by the formula [X] or a salt thereof, the compound represented by the formula -[X] or a sa-it thereof is subjected to etherification reaction or phosphorylation reaction.
The etherification reaction and the phosphorylation reaction can be carried out by a usual method such as described in Japanese Patent Application Kokai (Laid-Open) Nos. 137, 988/78, 105,68918Or 149,295/80 25 and the like.
For example, alkylation can be carried out according.to a usual method. The reaction is generally car ried out at a temperature of -200 to 6M and completes in 5 minutes to 10 hours.
As the solvent, there may be used a solvent inert to the reaction, for example, tetra hyd rofu ran, diox ane, methanol, ethanol, chloroform. methylene chloride, ethyl acetate, butyl acetate, N,N-dimethylfor mamide, N,N-dinlethylacetamide, water, or a mixture thereof.
As the alkylating agent, there may be used, for example, a lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide or ethyl bromide, dfmethyl sulfate, diethyl sulfate, diazomethane, diazo ethane or methyl p-toluenesulfonate. If an alkylating agent other than diazomethaneand diazoethane is used, the reaction is carried out in the presence of an alkali metal carbonate such as sodium carbonate, 35 or potassium carbonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; or an organic base such as triethylamine, pyridine or N,N-dimethylaniline.
Also, the salt of the compound represented by the formula [M] can easily be obtained according to a usual method, and the salt includes the same salts as mentioned above as the salts of the compound represented by the formula [11.
In addition, a protecting group can be introduced and removed according to a usual method, whereby a compound can be changed into a corresponding objective compound.
Although the compound represented by the formula [M] or a salt thereof thus obtained may be iso lated and purified by a usual method-, they can be used for the subsequent reaction without isolation.
(e) Ring closure reaction The compound represented by the formula [lal or [lb]. or a salt thereof of this invention can be ob- tained by the reaction of the compound represented by the formula [IX1, [XI or [XII or a salt thereof with the thioformamide or thiourea represented by the formula [XII]. This reaction is usually carried out in a solvent. As the solventr there may be used a solvent inert to the reaction, for example, water, methanol, 50 ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N - dim ethyl acetamide, N-methyl pyridone, alone or in admixture of two or more. Although it is not essential to add an acid-removing agent, the reaction sometimes proceeds smoothly by adding an acid- removing agent in such an amount that the cephalosporin skeleton will not be influenced. The acid-removing agent used for the reaction includes inorganic and organic bases such as alkali metal hydroxides, alkali metal hydrog encarbonates, - 55 triethylamine, pyridine and N,N-dimethylaniline. The reaction is usually carried out at a temperature of 0 100'C. Thioformamide or thiourea is usually used in an amount of about one mole to several motes per mole of the compound represented by the formula [IX], [X] or [XII or- a salt t hereof. The reaction time is 1-48 hours, preferably 1-10 hours. Furthermore, in the compound represented by the formula [[a] or [lb], the protection of the carboxyl group and removal of the carboxyl protecting group or conversion of the 60 product to a salt can be carried out according to a usual method to convert the compound to the corre sponding objective compound. If R1, R2, and R5 in the formula [lal or [lb] contain groups active to the reaction, these groups can be suitably protected by a conventional protecting group prior to the reaction and the protecting group can be removed by a usual method after the reaction. The objective compound represented by the formula [lal or [lb] or its salt thus obtained can be isolated by a usual method. - 65 21 GB 2 171 697 A 21 (f) Oximination The compound represented by the formula [lb] or a salt thereof is obtained by reacting the compound represented by the formula [XIVI or a salt thereof with the compound represented by the formula [XV] or a salt thereof. The salt of the compound represented by the formula [XV1 includes hydrochlorides, hy drobromides, and sulfates. This reaction is usually carried out not only in a solvent such as water, an alcohol, N,N-dimethylacetamide or the like but also in other solvents inert to the reaction or a mixed solvent thereof. The reaction is carried out at a temperature of 00 to 100'C, preferably in a range of 100 to 500C. The reaction time is usually 10 minutes to 48 hours. The compound represented by the formula [XV] or a salt thereof is used in an amount of one mole to several moles per mole of the compound represented by the formula VIVI or a salt thereof. Although the salt of the compound represented by the 10 formula [XV] can be used per se for the reaction, it can also be reacted in the presence of a base, for example, an inorganic base such as an alkali metal hydroxide (for example, sodium hydroxide, potas sium hydroxide or the like), an alkaline earth metal hydroxide (for example, magnesium hydroxide or calcium hydroxide, an alkali metal carbonate (for example, sodium carbonate or potassium carbonate), an alkaline earth metal carbonate (for example, magnesium carbonate or calcium carbonate, an alkali metal hydrogencarbonate (for example, sodium hydrogencarbonate or potassium hydrogencarbonate), an alkaline earth metal phosphate (for example, magnesium phosphate or calcium phosphate), an alkali metal hydrogen phosphate (for example, disodium hydrogenphosphate, or dipotassium hydrogenphos phate) or an alkali metal acetate (for example, sodium acetate or potassium acetate), an organic base such as a trialkylamine (for example, trimethylamine or triethylamine), picoline, N-methylpyrrolidine, N- 20 methylmorpholine, 1,5-diazabicyclo-[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2, 21octane or 1,5-diazabicy clo[5,4,01-7-undecene. The compound represented by the formula [lb] or a salt thereof of this invention thus obtained can undergo conversion of R1 in a conventional manner, and can also be isolated by a usual method.
(g) Alkoxylation The compound represented by the formula [IV] wherein R3 is an alkoxy group can be synthesized from the compound represented by the formula [IV] wherein R3 is a hydrogen atom by a method known per se, for example, the method described in the Journal of Synthetic Organic Chemistry, Japan, 35, (7), 563 574 (1977).
Furthermore, the compound represented by the formula [11, [lal, [Ibl, [IX1, [XI, [XII or [XIVI wherein R3 is an alkoxy group can be synethesized from the respective compound represented by the formula [11, [1a], [lb], [IX], [XI, [XII or [XIV] wherein R3 is a hydrogen atom in a manner known per se, for example, the method described in Japanese Patent Application Kokai (Laid-Open) Nos. 24, 888/79 and 103,889/79.
The compound represented by the formula [1] or a salt thereof thus obtained can be administered to 35 human beings and animals in the form of a free acid or in the form of a pharmaceutically acceptable salt or ester for the purpose of the treatment of and protection against bacterial infections. It is preferable to parenterally administer the compound in the form of a free acid or a pharmaceutically acceptable salt or orally administer the compound in the form of a pharmaceutically acceptable ester. In that case, it is sufficient that the compound is formed into a dosage form usually used in cephalosporin medicines, for 40 example, tablet, capsule, powder, fine granule, granule, syrup, injection (including drip) or suppository.
When the above-mentioned medicine is formed into a dosage form, there may be used diluents and/or additives, for example, vehicles such as starch, lactose, sugar, calcium phosphate or calcium carbonate; bonding agents such as gum arabic, starch, micro-crystalline cellulose, carboxymethyl cellulose or hy droxypropyl cellulose; lubricants such as talc or magnesium stearate; disintegrating agents such as car- 45 boxymethyl calcium or talc.
When the compound represented by the formula [1) or a salt thereof is administered, the dosage, the administration time and the administration method can be varied depending on the symptoms of patient, and generally it is sufficient to administer orally or parenterally to an adult in a dose of 50-5000 mg in 1 to 4 portions a day.
This invention is explained below with reference to Referential Examples and Examples which are.
merely by way of illustration and not by way of limitation.
Referential 6(ample 1 (1) To a solution of 20.0 g of ethyl N-(2,2-di-ethoxyethyl)oxamate in 60 ml of ethanol was added 6.1 ml 55 of 70% by weight aqueous ethylamine solution, and the mixture was subjected to reaction at room tem perature for 1 hour. After the completion of the reaction, the precipitated crystals were collected by filtra tion and recrystallized from ethanol to obtain 17.0 g (yield: 85.1%) of Nethyl-N'-(2,2 diethoxyethyl)oxamide having a melting point of 131-132C.
IR (KBr) cm-1 v,.,)1650 In a similar manner, the compounds shown in Table 3 were obtained.
22 GB 2 171 697 A TABLE 3 (CH 3CH2 0) 2 CHCH 2 MCOCONHRC - 22 Compound Solvent for M.P. IR Mr) cm-1:
recrystal- (IC) V C=O R6 lization -H Ethyl 141-142 1650, 1635 acetate -CH 3 Ethanol 135-136 1645 - -(CH 2)2 CH 3 Acetone 84-85 1645 -CH / CH 3 Acetone 145-146 1650, 1635 "'CH n-Hexane 3 (CH 2)3 C H 3 n-Hexane 111-112 1645 -(CH 2)4 CH 3 n-Hexane 92-93 1650 -(CH 2)5 C11 3 n-Hexane 87-88 1650 -(CH 2)7 CH 3 n-Hexane 110-111 1645 -(CH) CH n-Hexane 83-84 1645 2 11 3 Ethanol 154-155 16 40 -CH -- 0 n-Hexane 113-114 1655 a 0.
-CH 2CH20H Ethanol 118-119 - ",,,CH3 -N Ethanol 157-158 1645 "'CH3 OCH3 128-129 1655 -CH _b -OCH3 I (2) To a solution of the 17.0 g of N-ethyl-N'-(2,2-diethoxyethyl)oxamide obtained in above (1) in 85 ml of 50 acetiG.acid was added 0.05 ml of concentrated hydrochloric acid. The mixture was refluxed for 30 min utes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 70 ml of acetone was added to the residue, and crystals were collected by filtration. The crystals were recrystallized from methanol to obtain 6.8 g (yield: 61.8%) of 4- ethyl-2,3-dioxo-1,2,3,4-tetrahydropyr- F,5 azine having a melting point of 173-1740C.
IR (KBr) cm-1: v,,1680-1620 In a similar manner, the compounds shown in Table 4 were obtained.
23 TABLE 4
1 ' HN N-RO Compound Solvent for m.p IR Mr) cm- I R 6 recrystal- ( " C) V lization C=O -H - >280 1680-1640 -CH 3 Ethanol 220-231 1690-1635 -(CH 2)2 CH 3 Acetone 182-183 1680-1640 _C,,_-CH3 Acetone 215-219 1680, 1625 'CH 3 -(CH 2)3 CU 3 Acetone 149-150 1680, 1640 -(CH 2)4 CH 3 Acetone 171-172 1685 ' 1660, 1620 -(CH) CH Acetone 141-142 1685 ' 1660, 2 5 3 1620 -(CH 2)7 CH 3 Acetone 145-146 1670, 1635 _(CH 2)11 CH 3 Ethanol 145-146 1660, 1625 _(D Acetone 254-255 1670, 1635 -CH2,.--g Acetic acid 225 1665, 1635 -CH CH OCOCH Methanol 178-180 1720, 1675, 2 2 3 1625 -N"' CH 3 Ethanol 229-230 1700-1625 CH3 OCH3 175-176 1740-1620 -CH 2,&OCH 3 (3) To a suspension of 5.2 g of the 4-(2,4-dimethoxybenzyl)-2,3-dioxo-1,2, 3,4-tetrahydropyrazine obtained in above (2) in 26 ml of N,Ndimethylformamide was added 4.1 g of potassium carbonate, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 5.8 g of 4bromomethyl-5-methyl1,3-dioxol-2-one was added thereto, and the mixture was subjected to reaction at 50-60'C for 3 hours. The reaction mixture was introduced into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, after which the organic layer was separated, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform) to obtain 4.9 g (yield, 66.0%, of 1-(2,4-dimethoxybenzyl)-4-(5-methyl-2-oxo1,3-dioxol-4-yl)-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 154-156'C.
IR (KBO cm-1: v,=01820, 1675, 1630 In a similar manner, the compounds shown in Table 5 were obtained.
GB 2 171 697 A 23 24 GB 2 171 697 A TABLE 5
1 10 24 OCH3 0 0 CH 3 0 - CH 2 -17--R6 11=11 Compound M.P. (OC) IR (KBr) cM- 1 V R6 C=O 0 188-190 -1775i 1700, 1650 -CH 2 OCOC(CH 3)3 100-101 1750, 1690, 1660, 1640 -CH 2 COOC(CH 3)3 105-106 1740, 1690, 1650 (4) In a mixed solvent of 37 m[ of trifluoroacetic acid and 10.8 g of anisole was dissolved 3.7 g of 1-(2,4 dimethoxybenzyi)-4-(5-methyi-2-oxo-1,3-dioxol-4-yi)methyi-2,3-dioxo-1,2,3, 4-t etrahydropyrazine obtained 30 in above (3) and the mixture was reacted at WC to WC for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure. To the residue was added 30 mi of diethyl ether and crystals were collected by filtration to obtain 2.0 9 (yield, 90.9%) of 4- (5-methy]-2-oxo-1,3-dioxol-4-yi)methyi-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 225226'C.
[R (KBr) cm-l: v,=, 1825, 1805, 1725, 1690, 1670 In a similar manner, the compounds shown in Table 6 were obtained.
TABLE 6
O-HN N R6 Compound ('C) IR (KBr) cm-l:
m.p. v c=0 45 - R6 0 >270 1790, 1775, 1730, -9=0 1690 - 50 -CH 166-167 1740, 1700, 1660 OCOC(CH 3)3 2 55 -CH COOH 282 1730,-1670-1630 2 (decomp.) 60 (5) To a solution of 2.6 g of 1-carboxymethyi-2,3-dioxo-1,2,3,4tetrahydropyrazine in 13 mI of N,N-clime- thylacetamide was added 3.9 g of diphenyidiazomethane at room temperature, and the mixture was sub- jected to reaction for for 10 minutes. The reaction mixture was introduced into a mixed solvent of 25 m] 65 GB 2 171697 A 25 of ethyl acetate and 25 m] of water, and the mixture was stirred for 15 minutes. Precipitated crystals were collected by filtration, and washed with 10 mi of ethyl acetate and 10 mi of diethyl ether in this order to obtain 2.9 g (yield, 80.4%) of 1 -di phenyl methyl oxyca rbo nyl m ethyl- 2,3-dioxo- 1,2,3,4-tetra hyd ropyrazi ne having a melting point of 97- 98'C. 5 IRKI3r)cm-l: vc =, 1750, 1675, 1645 Example 1 (1) To a solution of 10 mi of ethyl acetate containing 2.71 g of boron trifluoride were added 2.72 g of 7aminocephalosporanic acid (hereinafter referred to as 7-ACA) and 1.54 g of 4-ethyl-2,3-dioxo-1,2,3, 4-te- trahydropyrazine, and the mixture was subjected to reaction at room temperature for 16 hours. After completion of the reaction, the reaction mixture was introduced into 50 mi of methanol with cooling, and then 3.16 g of pyridine was added dropwise thereto. Precipitated crystals were collected by filtration, washed sufficiently with 30 mi of methanol, and thereafter dried to obtain 3.10 g (yield, 88.1%) of 7amino-3-{[1-(4-ethyi2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyl}-A3-ceph em-4-carboxylic acid having a melting point of 191-195'C (decomp.).
IR (KBr) cm-l: v,.0 1795, 1670, 1620 NIVIR (CF3COOD) 8 values:
1.44 (3H, t, J= 7Hz, NCH,CH3), 3.69 (2H, bs, C,.-H), 4.08 (2H, q, J=71-1z, NCH2CH.), 5.14, 5.51 (2H, ABq, J = 1 5Hz, S S 5.48 (2H, s, C,,-H, CM), 6.74, 7.00 (2H, ABq, J-6Hz,) H H /CH 2_ (2) The conversion reaction at 3-position mentioned in above (1) was carried out under the reaction 30 conditions shown in Table 7 to obtain 7amino-3-{[1-(4-ethyi-2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3cephem-4-carboxylic acid in the yields shown in Table 7.
TABLE 7
Starting material Acid or Reaction Amount No. Solvent condi- 7-ACA complex tions (Yield) 0 0 compound HN N-CH 2 CH 3 of acid 1 2.72 g 1.54 g Sulfo- Boron Room 2.6 g lane tri- tempera- (73.9%) ml fluoride ture 2.71 g 2 hours 2 2.72 g 1.54 g Nitro- Boron Room 2.85 g methane tri- tempera(81.0%) 14 ml fluoride- ture diethyl 16 hours ether complex 5.7 g 1 (3) In a similar manner to that in above (1), the compounds shown in Table 8 were obtained. (in this case, the objective compounds were obtained by pouring into ice-water the reaction mixture after com- 55 pletion of the conversion at 3-position and adjusting to pH 3.5 with 28% by weight aqueous ammonia solution with ice-cooling.) 26 GB 2 171 697 A 26 Table fl
H2N S r- CH -R 7N 2 0 7 2 COOH No. Compound PC) IR (KBr) CM- NMR (d 6-DMSO) 6 values: - M.P. 'V R2 c=o 0.87 (3H, t, J=6liz, N (CH 2)5C113), 0 1800, 1.05-1.49 (BH, m, '-NCII 1 1 2 (C112) 4C113 1 -N N (CH CH 189.5-191.0 1680 - 2)5 3 \C==/ (decomp.) 5 3.44 (2H, bs, C 2T1), 3.553.88 1620 (2H, m, >NCII 2 (CH 2)4 CH 3), 4.44, 5.05 (211, ABq, J=15liz, SCH 4.88 (1H, d, J=511z, CCHY' 5.06 (1H, d, J=SPIz, C 7-11), 6.71 (211, - 1 S,) 0.87 OH, t, J=Gliz, >N(CH 2) 7C113) 0 0 1.03-1.50 (1211, M," NCII 2 (CH 2) 6C113)' 2 -N N (CH 2)7 CH 3 191.5-192.5 1800, 3.40 (2H, bs, C 2-17), 3.52-3.86 \=Y (decomp.) 1680 (2H, _m, /NCH 2 (Cif 2)6 CH 3), 4.43, 1620 S 5.04 (211, ABq, J=151i:t, 2- 4.86 (1H, d J=6liz, C 6-11), 5.04 (111, d, J=6liz, C 7-H), 6.69 (211, t S, -,/) 1 0 0.91 OH, t, J=7Hz, 'N(CII) CH 2 4 3 3 -N N(CH) CII 196-199 1800, 1.16-1.95 (6H, m, 'NCH (CH) CH), 2 4 3 2 2 3 3 (decomp.) 1678, 1630 3.63 (211, bs, C 27H), 3.77 (2H, t, J=7Hz, >NCH 2 (CH 2)3 CH 3 4.34, 4.82 (2H, ABq, J=15Hz, CH 2- 5.32 (2H, bs, C 6 -H, C 7 -H), 6.76 (2H, bs, 3.72 (211, bs, C 2 H), 5.41, 1790, 5.72 (2H, ABq, J=15Hz, S Icif 4 HN >200 1655, 1 1630, 2- -N 1609 5.47 (2H, s, C 6 -H, C 7 -H), 7.59 (2H, S, h) X - - LI Measured in W 3 COOH 27 GB 2 171 697 A 27 (4) The conversion reaction at 3-position mentioned in above (1) was carried out under the reaction conditions shown in Table 9 to obtain 7amino-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)lmethyi}-A3cephem-4carboxylic acid in the yields shown in Table 9.
TABLE 9 5
Starting Acid or Reaction Amount No. material sol- complex condi- (Yield) !i vent compound tions 7-ACA Maleic of acid hydra zide Tri- Boron triRoom 1.72 g fluoro- fluoride- temper- (72.3%) 1 2.0 g 0.91 g acetic diethyl ature, acid ether complex 16 hours.
M1 4.17 g Sul Boron tri- Room 2.75 g 2 2.72 g 1.23 g folane fluoride temper- (84.9%) M1 2.71 g rature 3 hours (5) In a similar manner to that in above (1), the crude crystals shown in Table 10 were obtained.
TABLE 10
H 2 "O- CH 2 R 2 COOH No. - Compound R 2 o--1 1 -N N-H C==/ Q 0 2 -N N-CH \.==:71 0 0 3 -N N-CH CH CH 3 11==/ 4 0 0 CH 3 -N N-CH CH 3 -N N(CH) 3 CH 3 - Cont I d - 28 GB 2 171 697 A 28 Table 10 (ContIcl)- - H 2 N tl CH 2 R2 0 COOH 6 O- - -N N -OH -N ==Z/ N (CH 2)11 CH 3 0 0 -N N-CH CH OCOCH' \=./ 2 2 3 0 0 -N N-CH - 2 0 O- CH 3 -N N-N-"' \.==1 -,-CH 3 CH 3 -N 1 -R 1 CH 2 CH 3 N i -N 0 0 HN cl i -N 3 0 JL ' C113 2 0 3 HN + 1 -N i CH 3 n - Cont 1 d - 45, 65.
29 GB 2 171 697 A 29 Table 10 (Contld) 9 M 2 L OTNC,CH 2 R 2 COOH r', N -N 0 CH 3 CH 3 N -N. 1 16 0 Note: The compounds in Nos. 10, 11, 12, 13, 14 and 15 were obtained by the reaction using sulfolane as a solvent.
11: This compound was obtained by the procedure of introduction into methanol, filtration of insolu- 30 bles and addition of pyridine into the filtrate.
2: The representation was taken because it was not confirmed whether the chlorine atom was placed at 4- or 5-position, and whether the product.was composed of a single compound or a mixture. (Such representations in Tables appearing hereinafter have the same meaning.) 3: The representation means that the product was a mixture of a 4- substituted compound and a 5- 35 substituted compound. (Such representations in Tables appearing hereinafter have the same meaning.) Example 2
To a suspension of 3.0 g of the 7,amino-3-}[1-(4-ethyi-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)]methyi{-A3- cephem-4-carboxylic acid obtained in Example 1-(1) in 30 mi of methanol was added 1.62 9 of a p-toluene-sulfonic acid monohydrate to form a solution, and then 5.0 g of diphenyidiazomethane was slowly added to the solution, after which the resulting mixture was subjected to reaction at room temperature for 15 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent of 20 mi of ethyl acetate and 20 mi of water. The solution was adjusted to pH 7.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Sil ica Gel C-200, eluent; benzene:ethyl acetate = 1:4 by volume) to obtain 3. 1 g (yield, 70.3%) of diphenyl methyl 7-amino-3-{[1-(4-ethyi-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)lmethyi}-A3-cep hem-4-.carboxylate having a melting point of 183-1860C (decomp.).
IR (KBr) cm-l: vc =,, 1765, 1730, 1680, 1630 In a similar manner, the compounds shown in Table 11 were obtained.
GB 2 171 697 A Table 11
112N S 0 -PfN ell 2 R 2 COOCH (00) 2 Compound m-p- (0c) IR (KBr) cm -1: ve=o R2 0 0 -N NH 129-130 1765, 1725, (decamp.) 1690, 1630 0 0 -N N-CII 127-128 1770, 1725, 3 (decamp.) 1G90, 1640 0 169-171 1765, 1730, -N N(CH 2 2 CH 3 (decomp.) 1685, 1635 0 0 179-180.5 1760, 1720, CH 3 -N NCH (decamp.) 1685, 1635 CH 3 0 0 180-189 1760, 1725 -N N(CH CH (decamp.) 1680, 1630 2 3 3 0 0 185-194 1765, 1'730, -N N(CH CH (decamp.) 1685, 1630 2 4 3 0 0 170-174 1765, 1730, 5\---/< -N N(CH (decamp.)-- 1685, 1635 2)5CH3 0 0 186-188 1765, 1730, -N N(CH) CH (decamp.) 1685, 1635 2 7 3 0 0 164-172 1765, 1730, -N N(CH 2) 11C113 (decamp.) 16.95, 1635 - Cont'd - 31 Table 11 (Cont'd)' Compound M.P. Pc) R2 IR (KBr) cm -1: v C=0 0 0 -N N-(5 "C==:
165-168 (decomp.) 0 0 -N N-CH 2-( \=:y 1765, 1725, 1680, 1625 1551601770, 1725, (decomp.) 1680, 1630 0 0 -N NCH CH OCOCH \==-j 2 2 3 146-148 1770, 1725, (decomp.) 1678, 1623 172-175 1760, 1720, 1680, 1630 0 0 CH 3 -N N-N -,, \=:e CH 3 N -N 0 82-85 (decomp.) 1775, 1720, 1650 CH 3 CH 3 Il- N N -",) 0 HN 1 -N 0 H - -cl 0 0 HI, - CH 3 HN CH 3 0 0 108-114 (decomp.) 132-135 (decomp.) 1765, 1725, 1650 1780, 1730, 1665 178-181 (decomp.) CH 1 3 NI:
1 -N 0 GB 2 171697 A 31 1780, 1730, 1660 137-139 (decomp.) 1780, 1730, 1660 90-93 (decomp.) 1770, 1720, 1660 - Cont'd - 32 GB 2 171697 A 32 Table 11 (Cont'd) IR (KBr) cm- 1: V C=o CH 2 CH 3 N -1 0 138-143 (decomp.) 1770, 1720, 1660 S Example 3
In a mixed solvent of 25 mi of trifluoroacetic acid and 10 mi of anisole was dissolved 4.9 g of diphenVImethyl 7-amino-3-[1-(2,3-dioxo-1,2,3,4tetra-hydropyrazinyi)methyij-AS-cephem-4-car boxyI ate and the solution was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 50 rTi of diethyi ether was added to the 20 residue, after which crystals were collected by filtration. The crystals were sufficiently washed with 40 mi of diethyl ethe and then dried td obtain 4.25 g (yield, 97.0%) of trifluoroacetic acid salt of 7-amino-3-{[1(2,3-dioxo-1,2,3,4tetrahydropyrazinyi)l-mdthyi}-A3-cephem-4-ca rboxylic acid having a melting point of 105-106'C (decomp.) IR (KBr) cm-l: v, =, 1780, 1700-1630 NIVIR (CF.,COOD) -8 values:
3.72 (2H, bs, C,-H), 5.14,5.52(2H,ABq,J=15Hz, S CH2- 5.44 (2H, s, C,-H, CM), 6.78, 6.98 (2H, ABq, J=6Hz, IH> H In a similar manner, the compounds shown in Table 12 were obtained.
33 GB 2 171 697 A 33 Table 12
CF 3 COOHH 2N; CH 2-R 2 0 COOH Compound IR (Kbr) cm-1. (d COOD) 1 6-DMSO+W 3 ((d 3) NMR (CP3COOD ) 2 6 values:
- M.P. (c) v R 2 C=0 6-DMSO+D 2 0) 0 0 109-110 1795, 3.36 (3H, s, >NCH)l 3.50 (211, bs, C 2 -H), 3 1680, -N (decomp.) 16315 4.53, 5.11 (2H, ABq, J=15HZ, S N- CH3)ICH l==/ 2- 5.06 (1H, d, J=SHz, CCF), 5.17 (1H, d, J=SHz, C 7-H), 6.73 (2H, bs, ≥= 3 0.91 (311, t, J=7Fz, >N (CH2)2 c1), -N N(CM1CH3 152-155 1780, 1.35. 2.08 (2H, m,_7,rNCH 2 CH 2 CH 3)' 1675, (decomp.) 2 1635 - 3.52 (2H, bs, C 211), 3.77 (211, t, J=7liz, /NCH2C112 CH 3 S 4.31, 4.86 (2H, ABq, J=15Hz, 1 CH2- 5.35 (2H, bs, C 6 -H, C 7 -H), 6.73 (2H, bs, H H 1 0 0 1,46 (6H, d, J=7Hz,NCH -CH 3 CH CS 3 L59.5-161.5 1780, -N N-CH \C==/ \CH (decomp.) 1680 3.70 (2H, bs, C -H), 3 2 CH S 1620,NCHI 3 4.77-5.60 OH, M, i \CH CH 2 3 5.46 (2H, bs, C CH, c 7-H)' 6.82, 7.04 (2H, ABq, J=6Hz, 2 Cont'd 34 - GB 2 171 697 A 0 0 N- (CH) CH IC= 2 3 3 O5- -N ===1 N---e 0 0 A - -N l-(CH2)11CH3 0 0 -MCH CH OCOCII 2 2 3 34 Table 12 (Cont'd) 158-162 1780, (decomp.) 1675, 1635 167-169 (decomp.) 1780, 1680 1620 ) CH 0.92 OH, t, J=7Hz, N (CH2 3 3)' 1.10-1.90(411, M, \NCH 2 (CZ) 2 CH 3) ' 3.62 (2H, bs, C 2-H)' 3.75 (2H, t, i=7HZ, ,NCH 2(CH2) 2 CH 3 4.56, 5.18 (2 H, ABC1. J=15Hz, S 1 C112- 5.29 (2H, S, C 6 -H, C 7 -H), 6.70 (2H, bs, ?==) H H 1 H -r 1.15-2.35 klulf, m, 'r!E-H Hff H - 11 H) 1 3.69 (211, - bs, C2-11 4.47-5.07 (1H, M, 70), H S 5.21-5.54 (2H, m, 1 CH 2), 5.47 (2H, s, C,.-H, C 7 -H), 6.81-6.98 (2H, ABqI J=6Hz, H H 2 0.
1.
) 1 138143 (decomp.) 86-91 (decomp.) 1775, 1675, 1635 1780, 1725, 1675, 1635 89 (3H, t, J=7Hz, /NCII 2 (CH 2 10 CH 3) 02-1.85 (20H, m,.NCH 2 (CH 2)10 CH 3)' 11 -- 3. 63 (211, bs, C 2-H)' 3.76 (2H, t, J=7Hz, 'NCH 2 (CH 2)10 CH 3)' 1.1 - 4.57, 5.21 (2H, ABq, J=15Hz, S cZ7 5.32 (2H, bs, C 6 -H, C 7 -H), 6.67 (211, bs,) H H 1 2.03 (3H, S' -OCOCH3), 3.59 (2H, bs, 1 C 2-H)' 3.86-4.54(4H, m, 'NCH CH 0), :2---2 4.57, 5.16 (2H, ABq, J-15HZ, S ICH 2_ 5.28 (2H, bs, C CH' C7-,')' 6.81 (2H, bs,) H H 1 1 -- - Cont'd - GB 2 171 697 A 35 Table 12 (Cont'dl 0 0 3.34 (6H, s, -NI c2), CH 1780, '_'CH 3 3 -N N-NI \ 158-160 1680 CH 3 (decomp.) 5 3.72 (2H, be, C -H), 1630 2 5.12, 5.50 (2H, ABq, J=15Hz, S1 ), CH 2_ 5.49 (2H, s, C 6 -H, C 7-H)' 7.15 (2H, bs, 2 3.89 (2H, bs, C 2-H), 5.26, 5.62 (2H, ABq, N 119-122 1780, J=15HZ, S), 5 -52 (211, s, C H, C H), (decomp.) 16 7 S' ICH 6_ -N 11 1640 2_ 0 7.93, 8.69 (211, ABq, j-,Fz, 'I 8.88 (1H, S, >--H) 2 2.58 (3H, s, -CH 3), 3.73(2H, bs, c 2_ H), CH 3 241 - 243 1800, 5.50 (2H, bs, C 2 -H), 5.51, 5.93 (211, ZtBq, 1660, N (decomp.) 1600 1 S J15HZ, CH -N 2 0 7.52, 7.79 (2H, ABq, J=10Hz, H 2 1.36 (3H, t, J=7HZ, -CH 2 CH 3), 2.90 (2H, - q, J=7Hz, -CH 2CH 3), 3.69 (2H, bs, C2-H), C112CH 219-222 1800, 3 (decomp.) 1660, 5.47 RH, bs,-c H, C -H), 5.48, 5.90 (2H, 6 7 1600 N ABq, J=15Hz, S 7.48, 7.76 (211, ABq, -N CH2 H J=10HZ, H 2 3.70 (2H, bs, C2-H), 5.34, 5.79 (211, ABq, 0 1795, J=16Hz, S), 5.47 (2H, s, C -H, C -H), 6 7 1640, HN >200 1600 CH 2_ cl 7.59 (1H, 0 2 - Cont'd - 36 GB 2171697 A 36 Table 12 (Cont'd) 0 1IN CH 3 1 -N 0 0 HN 1 -N 11 0 1,CH 3 0 0 m -N \===11 NH 0 0 54 -N %c==/ N-CH 3 2.42 (1.5H, S, -CR 3 X 0.5), 2.50 (I.SH, 5, -CH 3 x 0.5), 3.73 (2H, bs, C 2 -H), 5.52 RH, s,-C 6 -H, C 5.63 (2H, bs, S 7 cHi 7.38 (0.5H, s, s, '5-H x 0.
2 >200 139-140 (decomp.) 1795, 1640, 1600 5-H x 0.5), 7.60 (0.5H, 1780, 1710, 1690 1620 3.46 PH, bs, C 2 -H), 4.47, 5.07 (2H, ABq, J=ISHZ, S), 5.04 (IH, d, J=SHz, )-CH 2_ C6-H), 5.20 (1H, d, J=5Hz, C -H), 6.34, 6 7 6.59 (2H, ABq, J=6HZ, H H 3 152-155 (decomp.) 1780, 1690, 1660, 1620 3.35 (3H, S,::7NCH 3), 3.48 (2H, bs, C 2-11) ' 4.50, 5.12 (2H, ABq, J=151Iz, S -)CH 2_ 4.87 (1H, d, J=5liz, C CH)' 5.03 (1H, d' J=SHZ, C 7 -H), 6.70 (2H, bs,) H H 3 (Note) Free compound; Objective compounds were obtained by reacting in a mixed solvent of trifl,4oroacetic acid and anisole, then removing the solvent, dissolving th residue in water and adjusting the pH to 3.5 with 28% aqueous-ammonia solution.
=.Free Compound, obtained by treating the trifluoroacetic acid salt with 45 pyridine in methanol.
Example 4
To a suspension of 5.0 g of 7-amino-3-{[l-(3-methyl-6-oxo-1,6dihYdropyridazinyl)lmethyll-A3-cephem-4- carboxylic acid in 15 ml of acetone were added 2.36 g of 1,8-diazabicyclo [5,4,0]-7-undecene and 4.51 g of 50 pivaloyloxymethyl iodide at 10-150C, and the mixture was subjected to reaction for 30 minutes. After completion of the reaction, the reaction mixture was introduced into a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, and the organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. Subsequently, 10 ml of an ethyl acetate solution containing 1.40 g of ox alic acid was added thereto, and the precipitated crystals were collected by filtration and washed with 55 ethyl acetate to obtain 4.59 g (yield, 56.2%) of oxalic acid salt of pivaloyloxymethyl 7-amino-3-J[143 methyl-6-oxo-1,6-dihydropyridazinyl)lmethyl}-,L3-cephem-4-carboxylate having a melting point of 145 147'C (decomp.).
IR (KBr) cm-1: Pc - 1790, 1750, 1660 _0 NMR (deDMSO) 8 values:
1.21 (9H, s, -CHx3).
2.29 (3H, s, >-CHJ, 3.52 (2H, bs, C,-H), 37 GB 2 171697 A -37 4.94,5.33(2H,ABq,J=15Hz, S 1CH2-), 5.14 (1 H, cl, J = 5Hz, C6-H), 5.76-6.23 (3H, M, C7-H, -OCH,O-), 5 7.01, 7.53 (2H, ABq, J=MHz, 7.44 (3H, bs, -NH,O) Example 5 (1) To a solution of 2.69 g of 1-(5-methyi-2-oxo-1,3-dioxol-4-yi)methy]-2, 3-dioxo-1,2,3,4-tetrahydropyrazine in 27 mi of N,N-dimethylformarniele was added 1.52 9 of potassium carbonate, and the resulting mixture was stirred at room temperature for 20 minutes. Subsequently, 4.67 9 of tertAutyl 7phenylacetamido-3-bromomethyi-A2-cephem-4-carboxylate was added thereto with ice-cooling, and the mixture was subjected to reaction at room temperature for 2 hours. The reaction mixture was introduced into a mixed solvent of 200 m] of ethyl acetate and 150 mi of water, and the organic layer was separated, washed with 150 mi of water, and then dried over anhydrous magnesium sulfate. Subsequently, the sol vent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 100 20 mi of chloroform. To the solution was added 2.45 g (purity, 70%) of m- chioroperbenzoic acid, and the mixture was subjected to reaction at room temperature for 1 hour. The solvent was removed by distilla tion under reduced pressure, and to the residue were added 100 m] of ethyl acetate and 100 mi of water.
The organic layer was separated, washed with 100 m] of water, and then dried over anhydrous magne- sium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue 25 was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform) to obtain 2.70 g (yield, 43.2% of tertAutyl 7-phenylacetamido-3-{[1-[4-(5-methyi-2-oxo-1,3dioxol-4-yi)methyi-2,3-dioxo- 1,2,3,4-tetra hyd ro-pyrazi nyll] m ethyl}_A3-cep hem-4-ca rboxyl ate- 1 - oxide having a melting point of 135 13WC (decomp.).
IR (KBr) cm-l: v,., 1820, 1790, 1720, 1685, 1650 (2) In a mixed solvent of 12 m] of N,N-climethyl-formamide and 6 mi of acetonitrile was dissolved 3.0 g of tertAutyl 7-phenylacetamido-3-{[1-[4-(5-methyi-2-oxo-1,3-dioxol-4yi)methyi-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinylllmethyi}-A3-cephem-4-carboxylate-1 -oxide. To the solution were added 1.0 g of stannous chloride and 1.58 g of acetyl chloride in this order with ice-cooling, and the mixture was subjected to reaction at room temperature for 30 minutes. The solvent was removed by distillation under reduced pressure, and to the residue were added 50 mi of ethyl acetate and 50 m] of water, after which the result ing mixture was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated, washed with 50 m] of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chroma tography (Wako Silica Gel C-200, eluent; toluene:ethyl acetate = 3:2 by volume) to obtain 2.12 g (yield, 40 72.4%) of tertAutyl 7-p henyiaceta m ido-3-{[ 1 -[4-(5-m ethyl-2-oxo-1,3- d ioxo 1-4-y1) methyl -2,3-d i oxo1,2,3,4 tertra hydro pyrazi nyll 1 methyl}_A3-cep h em-4-ca rboxyl ate having a melting point of 120-122'C (decomp.).
IR (KBr) cm-l: vc=, 1820, 1775, 1715, 1685, 1645 NMR (CDC'3) 8 values:
1.58 (9H_s, -C(CH,),,), 2.28 (3H, s, -CH.) 3.17, 3.61 (2H, ABq, J=MHz, C,-H), 3,77 (2 H,. s, &0 CH2_) 1 4.53, 5.13 (2H, A13q, J=15Hz,S'I 4.71 (2H, s, >NCHA, 5.03 (1 H, cl, J=51-1z, C,,-H), 5,93 (1H, dd, J=51-1z, J=8Hz, C7-H), cli- ) 1 6.53, 6.89 (2H, ABq, J=6Hz, 11-) 1 H H 60 7.32-7.51 (5H, m, -()) 1 7.57 (1 H, d, J=81-1z, -CONW) In a similar manner to that in above (1) and (2), the compounds shown in Table 13 were obtained. 65 38 GB 2 171697 A Table 13
CH 2 CONH S H-R6 3 - CH 2 0 COOC(CH 3)3 Compound CC) IR (KBr) dG-DM50 M.P. cm-l) 6 values NMR ( R6: V C=0 CDC1 3 1.52 (9H, S, -C(CH 3)3), 3.57 (4H, bs, 1780, c 2 -H, &CH--), 4.30, 5.12 (2H, ABq, 2 0 V, 0 180-183 1710, (decomp.) 1700, J=15Hz, S 5.12 (1H, cl, J=SHi, 680, -CH2 11645 c CH) ' 5.75 (1H,-dd, J=SHZ, j=8HZ, C7-H), 6.07, 6.54 (2H, ABq, J=6Hz, =<), H H 7.12-7.45 (SH, m,), 7.57-8-14 (SH,-- H M' dc 1 S<0 9.14 (1H, d, J=8Hz,-CONH-) 1.21 (9H, s, -C(CH 3)3 1.56 (9H, s, 1780, -C(CH 3)3), 3.22, 3.61 (2H, ABq, J=18Hz, 105-108 1740, -CH 2 OCOC(CH 3)3 (decomp.) 1730, C2 -H), 3.71 (2H, s, CH 2_), 4.58, 1660 5.11 (2H, ABq, J=ISHz, 5.03(1H, 2- d, J=SHz, C -H), 5.81 (2H, s, - 6 NCH 2_) 5.93 (1H, dd, J=5HZ,-J=9Hz, C 7-H)' -6.55, 6.88 (2H, ABq, J=7Hz, 7.14 (1H, H H d, J=9Hz, -CONH-), 7.43 (SH, s, 1.53 (9H, s, -C(CH 3)3), -3.27 (211, bs, 1770, C 2 -H), 3.61 (2a, s, (0)-CH 2_), 4.54 (2H, c -CH COOCH()2 124-129 1730, - 2 (decomp.) 1685, s, >NCH 2 -), 4.91 (2H, bs, S 1650)'CH 2 5,18-(1H, d, J=SHZ, c 6 -H), 5.86 1H, dd,, J=SHZ, J=8HZ, C 7 -H), 6.12, 6.59 (2H, ABq, J=6liz,, 6.88 (1H, s, -CHZ-), H 11 6-967.47 (1511 x 3), 7.95 (1H, d, J=8Hz, -CONH-) 38 39 GB 2 171 697 A 39 (3) In 30 mi of anhydrous methylene chloride was dissolved 2.0 9 of tert.- butyl 7-phenylacetamido-3-{[1[4-(5-methyf-2-oxo- 1,3-d ioxo-4-y1)m ethyl - 2,3-d ioxo- 1,2,3,4-tetra hydro pyrazi nyl 1 methyl}-L,3-cephem-4-ca rboxylate. To this solution were added 1.59 g of N,N-dimethylaniline and 0.57 9 of trimethylsilyi chloride in this order, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -40'C, and 0.89 g of phosphorus pentachloride was added thereto, and the mixture was subjected to reaction at -300 to -20'C for 2. 5 hours. Subsequently, the reaction mixture was cooled to -WC, and 5.2 g of anhydrous methanol was added thereto, after which the reaction was continued with ice-cooling for 1 hour. To the reaction mixture was added 20 mi of water and stirring was continued for a further 30 minutes. Subsequently, the reaction mixture was adjusted to pH 0.5 with 6 N hydrochloric acid, and then the aqueous layer was separated. To this aqueous layer was added 50 mi of ethyl acetate, and the mixture was adjusted to pH 6.5 with sodium hydrogencarbonate. The organic layer was separated, washed with 50 mi of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 50 mi of diethyl ether. The crystals were collected by filtration to obtain 1.05 g (yield, 64.8%) of tert.-butyl 7-amino-3-{[1- [4-(5-methyi2-oxo-1,3-dioxol-4-yi)methyi-2,3-dioxo-1,2,3,4tetrahydropyrazinylllmethyi}-A 3 -cephem-4-ca rboxyl ate hav- 15 ing a melting point of 185-188'C (decomp.).
IR (KBr) cm-l: 1820,1765,1705,1690,1635 NMR (CDCI,+d,-DMSO) 8 values:
1.52 (9H, s, -C(CH3)3), 2.24 (3H, s, -CH3), 3,46 (2H, bs, C,,-H), 4.35, 5. 08 (2H, A13q, J=151t, s ICH 2_ 1 4.76-5.09 (4H, m,. NCH2-, C,-1-1,C7-H), 6.74 (2H, s, ≥ll) In a similar manner, the compounds shown in Table 14 were obtained.
TABLE 14
S 0 0 2 N CH 2 N NR6 0;::c- \==::I COOC(C1r3)3 Compound IR (KBr) d -DMSO.....
M.P. ('C) -1 6 6 values NMR ( R6 CM CDC1 3) : V C=0 1.50 (9H, s, -C(CH 3)3), 3.48 (2H,'bs, C 2-H)' 0 0 111-113 1780, 4.28, 5.07 (2H, ABq, J=15Hz, S 8o' (decomp.) 1710, 1690, CH - 2 1650 - 4.82 (1H, d, J=SHz, C 6 -H), 5.03 (1H, d, J=SHz, C 7-H), 6.08, 6.55 (2H, ABq, J=6Hz, 7.58-8.12 (5H, m, h 0 H H 132134 1775, 1.17 (9H, s, -C(CH 3) 3), 1.53 (9H, S, -CH OCOC(CH (decomp.) 1740, 2 3)3 1715, -C(CH 3)3), 3.67 (2H, bs, C 2 -H), 4.41, 1695, (Hydrochloride) 1640 5.13 (2H, ABq, J=15Hz, S - Cont'd - 2 -5 40- GB 2 171697 A Table 14 (Cont'd) Note:
5.30 (2R, s,-->NCH2 - 5.75 (2H, bs, C 6 -H, C 7 -H), 6.80 (2H, bs, 1.54 (9H, S, -C(CH 3)-3 1.74 (2H, bs, -NH 2)' -CH 2CO0CH(@)2 160-163 1780, 3.05, 1.48 (2H, A.Bq, J=18Hz, C -H), 1760, 2 i(decomp.) 1715, 4.40-, 4.99 (2H, ABq, J=15Hz, S 1690, 1650 CH 2- 4.55 (2H, s, ',NCH 4.65 -(1H, d, J=SHz, 2_) C 6 -H), 4.84 (IH, d, J=SHz, C 7 -H), 6.09-, 6.62 (2H, ABq, J=6Hz, 6.85 (1H, s, -CH<), 7.17-7.31 (10H, m, -C x 2) A Iminoether compound was poured into water, and the deposited hydrochloride was isolated.
Example 6 (1) In 2.29 m[ of N,N-di methyl aceta m ide and 4.58 m] of acetonitrile was dissolved 2.29 g of 2-(2-for mamido-thiazol-4-yi)-2-(syn)-methoxyiminoacetic acid, and to the resulting solution was added dropwise 30 1.62 of phosphorus oxychlorlde, after which the mixture was subjected to reaction at -50 to O'C for 1 hour. Subsequently, 5.18 g of diphenyimethyl 7-amino-3-{[!-(4-ethyl-2,3dioxo-1,2,3,4-tetrahydropyra- zi nyl)l methyl}-A3-cephem-4-carboxyl ate was added to the reaction mixture, and the mixture was sub jected to reaction at -5' to O'C for 1 hour, After completion of the reaction, the reaction mixture was poured into a mixed solvent of 80 m[ of water and 80 m[ of ethyl acetate, and the resulting solution Was 35 adjusted to pH 6.5 with sodium hydrogencarbonate. Subsequently, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pres sure, and to the residue was added 60 mI of diethyl ether. Then, the crystals were collected by filtration to obtain 6.05 g (yield, 83.0%) of diphenyImethyl 7-[2-(2formamidothiazol-4-yi)-2-(syn)-methoxyiminoa_cetamidol-3-{[1-(4-ethyi-2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)lmethy Q_A3cephern-4-carboxyl ate having a melting point of 165-168'C.
1 IR (KBr) cm-l: vc=,, 1780, 1720, 1680, 1640 NMR (d,-DMSO) 8 values.
1.18 (3H, t, J=71-1z, N-CH,CH.), 3.59 (2H, bs, C,.M), 3.72 (2H, q, J=7Hz, N-CH2CH3), 3.97 (3H, s, -OCHJ, 4.42, 5.04 (2H, ABq, J=15Hz, S J1,- CH 25.30 (1 H, d, J = 5Hz, C,,M), 50 6.02 (1 H, dd, J =5Hz, J =8Hz, (:7H), 6.50, 6.62 (2H, ABq, J=6Hz,) 1 - 55. H 55 7.04 (1 H, s, -CH::::), N 7.17-7.82 (11 H, m, --5 X 2, S H) ' 1 - 60 8.63 (.1 H, s, HCO-), 9.89 (1 H, cl, J =8Hz, -CON W), 12.68 0H, bs, HCON) In a similar manner, the compounds shown in Tables 15, 16 and 17 were obtained.
41 GB 2 171697 A 41 Table 15
S f1CONH- N - C CONH CH R 2 0 S j, 4 11 2 R N OCH 3 COOCH()2 (syn-isomer) Compound R2 0 -N N-CH,==v 3 R4 M.P. PC) IR (KBr) cm- 1:
vr=o H 120-125 1780, 1720, (decomp.) 1680-1640 H 154-156 1785, 1720, (decomp.) 1685, 1645 131-136 1783, 1725, (decomp.) 1680, 1645 180-182 1780, 1720, (decomp.) 1680-1640 158-166 1780, 1725, (decomp.) 1675, 1640 126-138 1785, 1725, 1685, 1650 Br 142 1780, 1720, (decomp.) 1675, 1640 H 171-173 1780, 1720, (decomp.) 1690-1650 H 148-151 1780, 1730, (decomp.) 1690, 1660 0 0 -N N- (CH) CH \C 2 4 3 0 K (CH) CH -N \-- 2 5 3 0 0 -N'(CH) CH lt==Y 2 7 3 0 0 m -N N-(CH) CH 2 11 3 0j,) -N N-CH t==e 2-- 0 0 m -N N-CH CH ==Y 2 3 0 HN. -N 0 CH 3 N 1 -N 0 - Contd - 42 GB 2 171 697 A Table 15 (Cont'd) 191-195 1775,-1720, (decamp.) 1670 CH 3 CH 3 IN -N 0 Table 16
CH3 S 1 N C CONH ' CH CH -C-OCONH 2 3 2 N -CH 2 R OR COOCH( (syn-isomer) kon 5 N 3 Compound IR (KBr) cm-1:
R2 R18 M.P. "7-=o 0 --CH3 176-179 1780, 1720, P N NH (decamp.) 1680, 1640 0 0 -CH 152-155 1780, 1720, 1680, -4 3 (decamp.) 1640 N N-(CH CH 2 2 3 0 0 -CH 158-160 1780, 1720, 3 1680, 1640 t-CH (decamp.) - 3 N NCR CH 3 0 0 -CH 166-167 -1780, 1720, 3 1685, >-4 (decamp.) 1645 N N-(CH) CH 2 3 3 It==If -CH 162-165 1780, 1720, 3 1680, 04 (decamp.) 1640 -N N -0 0 -CH 3 145-147 1780, 1720, 1682, P (decamp.) 1640 -N N-CH CH OCOCH 3 2 - Cont'd - 42 43 GB 2 171 697 A 43 Table 16 (ContId) 0 0.
-N N- (CH) CH 1== 2 7 3 -CH 3 -CH 3 138-144 (decomp.) 1780, 1715, 1690, 1620 0 4 / CH 3 -N N-N = \11 CH 0 0 -N N-CH CH == 2 3 88-90 1780, 1720, 1690-1620 J -CH CH 131 2 3 (decomp.) -CH 3 -dH 3 -CH 3 -CH 3 1786, 1723, 1684, 1645 CH 2 CH 3 1 N 1 3 -N Ii 0 118-120 (decomp.) 1780, 1720, 1660 190-192 (decomp.) 183-185. (decomp.) 0 HN + I -N CH 3 0 1780, 1720, 1665 1780, 1720, 1670 N -N 0 128-131 (decomp.) 1780, 1720, 1680, 1660 44 GB 2.171697 A Table 17
CH 3 N C - CONHEI 11 E 5 R 2 CH 3 CH 2 C-OCONH-- SIN CH2 1- 0 CH 3 \ OCH3 COOC(CH 3)3 (syn-isomer) Compound - -1 IR Mr) cm 2 M.P. (OC) R Vr =O 0 0 4 141-143 1815, 1775, -N N_ CH - (decomp.) 1710, 1680, 2 7=_ C" 3 0 0 1640 Y 0 154-156 1775, 1710, 0 0 (decomp.) 1700, 1680, Y0 1650 -N N 0 0 85-88 1785, 1730, (decomp.) 1715, 1660 -N N-CH OCOC(CR 2 3 3 144-146 1775, 1745, 0 0 (decomp.) 1715, 1690, t_ 1650 -N N-CH COOCH( g)2 2 44 (2) To a solution of 6.05 g of diphenylmethyl 7-[2-(2-formamidothiazol-4yi)-2-(syn)-methoxyiminoacetamidol-3-1[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)I methyi}-A3-cephem-4-carboxylate in 31 ml of methanol was added 0.5 ml of concentrated hydrochloric acid, and the mixture was subjected to reaction at 35'C for 2 hours. After completion of the reaction, the solvent was removed by distillation under re duced pressure. To the residue were added 100 ml of ethyl acetate and 100 ml of water, and the resulting 45 solution was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation, under reduced pressure, and to the residue was added 50 ml of diethyl ether. The crystals were collected by filtration to obtain 5.1 g (yield, 87.7%) of diphenylmethyl 7-[2-(2aminothiazol-4-yi)-2-(syn)-methoxyiminoacetamidol-3-{[l-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazinyl)lmethyl)-A 3-cephem-4-carboxylate having 50 a melting point of 165-167'C.
IR (KBr) cm-1: -v,:=,, 1780, 1720, 1680, 1640 NIVIR (dcDMSO) 8 values:
1.18 (3H, t, J=7Hz, >N-CHCHJ, 3.55 (2H, bs, CrH), 3.75 (2H, q, J=7Hz, >N-CHCH3)I 3.90 (3H, s, -OCH.), 4. 41, 5.02 (2H, ABq, J = 1 5Hz, S 5.26 (1 H, cl, J =5Hz, C6-H), 6.01 (1'H, dd, J-5Hz, J=8Hz, C,-H), 6.52, 6.65 (2H, ABq, J=6Hz, HK CH 2_ ) 1 GB 2 171697 A 45 6.88 (1 H, s, N-i, S H 57.07 (1 H, s, -CH '), ) 1 7.15-7.84(10H,m,--nO x2), 9.81 (1 H, d, J =8Hz, -CON W) 10. In a similar manner, the compounds shown in Table 18 were obtained.
TABLE 18
N C-CONH S H N-"I 11 7 2;LN R2 R N ?CH2 COOCH ()) 2 OCH3 n0 (syn-isomer) Compound IR (KBr) cml.
* R2 R4 m 'Jz=o - P. PC) 0) 158-166 1780, 1720, 54 N N-CH H (decomp.) 1680, 1640 3 0 0 H 151156 1.780,.1720, m (decoirp.) 1680, 1640 N N-(CH CH 2 4 3 0 0 H 150-156 1780, 1720, (decomp.) 1680, 1640 N N-(CH CH 2 5 3 0 0 H 168-175 1775, 1723, m (decomp.) 1685, 1640 N N-(CH CH 2 11 3 \C=-d 0 0 H 161-166 1780, 1720, m 1680, 1640 N NCH2,--D 0 Br 146 1780, 1720, (decomp.) 1680, 1640 N NCH CH l== 2 3 I- - - Cont 46 GB 2 171 697 A 46 Table 18 (Cont'd) 0 HN 1 -N 0 175-178 (decomp.) 1780, 1720, 1685 -1660 CH 3 N 1 -N 0 146-14.8 (decomp.) 1780, 1720, 1660 (3) In a mixed solvent of 25.5 m] of trifluoroacetic acid and 7.86 g of anisole was dissolved 5.1 g of diphenyimethyl 7-[2-(2- - aminothiazol-4yf)-2-(syn)-methoxyiminoacetamidol-a-{[1-(4-ethyi-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)lmethyl}-A3-cephem-4-carboxylate, and the solution was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue was added 40 mi of diethyl ether and the crystals were collected by filtration to obtain 4.3 9 (yield, 91.1%) of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yl)-2(syn)methoxyiminoacetamidol-3-{11-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazinyl) lmethyl}-A3-cephem-4-car- 3() boxylic acid having a melting point of 155-157'C (decomp.).
IR (KBr) cm-l: vc=. 1775, 1710-1630 NMR (dcDIVISO) 8 values:
1.21 (3H, t, J=7Hz,>N-CH,Cl-1J, 3.52 (2H, bs, CM), 3.73 (2H, q, J=7Hz, >N-CHCHJ, 3.96 (3H, s, -OCHJ, 4.44, 5.12 (2H, ABq, J=15Hz, S 1 CH 405.21 (1 H, d, J =5Hz, C,-H), 5.83 (1 H, dd, J =5Hz, J =8Hz, CrH), 5.86 (3H, bs, -NHO), 6.71 (2H, bs, 6.95 (1 H, s, N'T), S H 9.90(1H,d,J=8Hz,-CONH-) In a similar manner, the compounds shown in Tables 19 and 20 were obtained.
-30 47 GB 2 171 697 A 47 Table 19
CP COOH.H N N Z_ C -CONH S 11 3 2 S R 4 N CH 2-R2 OCH COOH (syn-isomer) Cotupound IR (KBr) -1 M.P. (OC) cm NMR (d 6 -DMSO) 6 values:
: v R2 R4 c=o 3.34 (3H, si>N-CH 3), 3.51 (2H, bs, C 2 H) 0 0 1773, 4.00 (3H, s, -OCH 3), 4.52f 4.90 (2H 1670, -_J4-CH 3 H 95-102 1660, ABq,'J=15Hz, S 5.25 (1H, d, (decomp.) 1640 ICH 2- J=SHz, C 6 -H), 5.90 (1H, dd, J=SHZ, J=8liz, C 7 -H), N 6.6d (2H, bs, 6. 9 9 (1H, s, S H 9.85 (1H, d, J=8Hz, -CONH-) 0.86 (3H, t, J=7Hz, >N-(CH 2)4 CH 3), 1.05 - 1770, 1.85 (6H, m, >N-CH 2 (CH 2)3 CH 3), 3.53 (2H, 0 0 H 115-125 1670, m. (decomp.) 1660r bs, C 2-H), 3.73 (2H, t. J=7Hz, -N NCH) CH 1635 2 4 3 >N-CH 2 (CH 2)3 CH 3), 3.93 (3H, S, -OCH 3)l 4.40, 5.05 (2H, ABq, J=15Hz, S ICH 2- 5.20 (1H, d, J=SHz, C 6 -H), 5. 86 (1H, dd., J=SH2, J_=8Hz, C 7 -H), 6.68 (2H, bs,)-K), 6.95 (1H, 5, Nx) 1 S H 9.85 (1H, d, J=8Hz, -CONH-) 0.87 (3H, t, J=7Hz, >N-(CH 2)5 CH 3), 1.04- 0 0 1770, (CH CH), 3.53 (2H, 1.85 (8H, m, >NCH 2 2)4 3 m 155-160 1670, -DL.,N (CH 2)5 CH H (decomp.) 1655, bs, C 2-H), 3.77 (2H, t, J=7HZ, 1630 >NCH 2 (CH 2)4 CH 3), 3.97 (3H, s, -OCH 3)' 4.47, 5.13 (2H, ABa, J=15Hz, S ICH 2- 5.23 (IH, d, i=5HZ, C6 -H), 5.82 (1H, dd, H), 6.44 (3H, bs, J=5Hzg. j=SHz, C 7 -NH 3 @), 6.70 (2H, bs,)c=), 6.95 (1H, 5, H H 9.85 (1H, d, J=8Hz, -CONH-) S H - ContId 48 GB 2 171697 A Table 19 (Cont'd) 48 0.87 (3H, t, J=7Hz$ >N-(CH 2)11 CH 3), 1.04 1.84 (20H, m,>NCH 2 (CH 2)10 CH 3), 3.51 (2H, 0 0 H 140-147 1770, bs, C 2-11) s 3.72 (2H, t, J=7Hz, - -M-(CH CH (decomp.) 1675 1635 2 11 3 >NCH 2 (CH 2)10CH 3), 3.92 (3H, s, -OCH 3)' 4.45, 5.05 (2H, ABq, J=15HZ, S ICH 2_ 5.20 (1H, d, J=5Hz, C CH)' 5-80 (1H, dd, J=SHz.' J=8Hz", C 77H)l 6-15 (3H, bs, -NH 3 6.67 (2H, bs,)-), 6.88 (1H, H H s, lZ 9.75 UM, d, J=BHz, -CONH-) S H 3.52 (2H, bs, C,-H), 3.91 13H1 s -OCH 3)' 0 0. 1770, 4.41, 4.98 (2H, ABq, J=15Hz, S 1 -N N-CH H 130-135 1670, 2_ (decomp.) 1635 4. 95 (2H, s, -Cz -D), 5. 19 UR, d, J=5Hz, C 6 -H), 5.82 (1R, dd, J=SHz, J=SHz, C 7-H) ' 6-15 (3H, bs, -NH 3 0 6. 6 8 (211, bs, 6.90 (1H, s, N 7.35 (5H, R H bs, 9.75 (1H, d, J=EHZ, -CONH-) 1.21 (3H, t, J=7Hz, >NCH 2 CH 3), 3.50 (2H, 0 0 1775, bs 9 C -H), 3. 81 (2H, 9, J=7Hz, >NCH CH), 1680, 2 2 3 -bL NCH CH Br 147 1640 3.91 2 (decomp.) 3 OR, s, -OCH 3), 4.42, 5.10 (2H, ABq, j J=15HZ, S), 5.19 (!H, d, J=5Hz, ICH 2_ C CH)l 5-95 (1H, dd, J=SUZ' J=SHZ1-C7 -H),, 6.67 (2H, bs,)C=:), 9.64 (1H, d, J=BHz, H -CONH-) - Contd - 49 1 GB 2 171697 A 49 Table 19 (contld) 3.34 (2H, bs, C 2 -H), 3. 89 (3H, 5, -OCH 3)' 1775, 4.99 (2H, b), 5.12 (1H, d, J=5HZ, S ' 1H 1710, - 1690.
2- HN H 195-198 ? r- (deconip.) 1630 C CH) ' 5.75 (1H, - dd, J=SHz, J=8Hz, C 7-H)t 6.84 (1H, s, N 6.99, 7.10 (2H, ABq, T 0 S H H i=10Hz, 9.70 (1H, d, J=SHz, -CONH) 2.31 (3H, s,)_ CH3), 3.44 (2H, bs, C 2-H)' 1770, 3.96 (3H, S, -OCH 3)# 4.98, 5.40 (2H, ABq, CH 1710, J=1 SHZ, S 5.23 (1H, d, J=5Hz, 3 H 188-189 1680 1CH2 (decomp.) 1630 N C 6- H), 5.88 (1s, dd, J=SHz, J=BHz, C 7-H)' 0 (D), 6. 95 (1H, s, Ny 6.17 (311, bs, -NH 3 S H H 7.00; 7.50 (2H, ABq, J=lQHz, 9.87 (IH, d, J=SHZ, -CONH-) 2.22 (3H, s, -CH 3 3.46 (2H, bs, C 2 -H), i 0 0 1 1820, 3.90 (3H, 5, -OCH 3), 4.42, 5.05 (2H, ABq, -4 N 151-154 1775, 5 -N NCH=CH 1685. i=15HZ,), 4.78 (2H, S, >NCH 2-), 3 (decomp.) 1640 ICH 2 0 0 ir 0 5.18 (1H, d, J=5HZ, C -H), 5.80 (1!-., dd, 6 J=5Hz, J=8Hz, C 7 -H), 6.64 (H, S.
H H 6.84 (IH, s, X), 9.78 (1H, d, J=8HZ, S -CONH-) - contId - GB 2 171697 A Table 19 (Contrd) 3.59 (2H, bs, C 2-H), 3.99 (3H, 5, ' -OCH 3), 1770, 4.48, 5.19 (2H, ABq, i=15Hz, S 0 0 1700 ICH 0 ? 2 0 H 175-180 1630 (decornp.) 5.27 (1H, d, J=SHZ, C 6 -H), 5.94 (1H, dd, J=SHZ, J=SHZ, C -H), 6.15, 6.68 (2H, ABq.
7 J=6Hz, 6.99, (1H, s, N S 'H 7.66-8.19 (SH, m, 9 f. -\< 0) 1 9.92 (1H, d, J=8HzI -CONH-) 1.18 (9H, S, -C(CH 3)3), 3.54 (2H, bs, C), H 108-110 1780, 0 0 (decomp.) 1730, 3.98 (3H, s, -OCH), 4.49, 5.17 (2H, ABq, 3 1690, S -N N-CH OCOC(C 3 3 1650 J=15Hz 5.29 (IR, d, J--5Hz 2 1CH2 C 6 -H), 5.77 (2H, s,> NCH 2-), 5.90 (IH, dcl, J=SHZ, J=SHZ, C 7 -H), 6.79 (2H, bs,)c::5(), 7.02 (1HP 5,. N T H H S H 9.99 (1H, d, J=SHZ, -CONR-) 3.51 (2H, bs, C 2 -H), 3.96 (3H, s, -OCH 3), 0 0 1770, 4.52, 5.15 (2H, ABq, J=ISHZ, S Y H 161-166 1680, - -CH --CH 1640 - 2 COO (decomp.) -N H 4 2 4.54.(2H, s, >NCH 2-), 5.2 7 (IH, d, J=SHz, C 6 -H), 5.88 (1H, dd, J=SHz, J=8HZ, C7-H), N 6. 75- (2H, s,)C:D), 6. 98 (1H, 5 g X)' S H 9.92 (1H, d, J=BHz, -CONR) 51 GB 2 171 697 A 51 Table 20
CP 3 COOH.H 2 W j 11 S N N C -CONH S \ OR is -Nt CH 2 -R 2 COOH (syn-isomer) dompound IR (KBr) NMR (cl 6_ DMSO) 6 values:
M.P. PC) cm-1 R 2 R18-. V C=0 0.90 (3H, t, J=711z,>N-CH 2 CH 2 CH 3), 1.32- 1770, 2.01 (211, m, >NCH 2 CH 2 CH 3), 3.53 (211, bs, 0 0 165-167 1710 - m H),. 3. 73 -.(2H, t, J=7Hz, >N-CH CH CH), C2- 2 2 3 -N N- (C11 CH -CH (decomp.) 1630 - 2 2 3 3 3.96 (311, s, -OCH 3), 4.48, 5.14 (211, ABq, j=15HZ, 5); 5.14 (111, d, J=5Hz, ICH 2_ C CH)' 5-91 (111, dd, J=5Hz, J=SHz, C 7 -11), 6.24 (311, bs, -NH 6. 69 (2H, bs,)C:), 3 H H 6.92 (111, s, NX), 9.82 (1H, d, J=BHz, S H -CONH-) 1.25 (611, d, J=7Hz, >N-CH(CH 3)2),. 3.48 (211 0 0 1770, bs, C 2 -11), 3.93 (311, s, -OCH 3), 4.44, 5.08 M " CH 3 1710 S ? J=15Hz, 4.64-5.12 N -CH -CH 160-162 1630 (111, P 3 (211, A13q, ICH - (decomp.) 2_ CH 3 m, >N-CH(CH 3)2), 5.21 (111, d, J=SHz, C 6 -11), 5.86 (111, dd, J=SHZ, J=SHZ, C 7-H), 6.36 (D X::) (311, bs, -NH ), 6. 72 (211, bs, 3 H H N 9.79 (111, d, J=8HZ, 6.91 (111, s,:TI- S H -CONH-) 0.89 (311, t, J=7Hz, >N(CH) CH, 1.03 2 3 3).
1775, 1.93 (411, M, >N-CH 2 (CH 2)2 CH 3), 3.49. (211, 0 0 -Cif 3 155-157 1710, bs, C 2 -11), 3.74 (211, t, J.=7Hz, 1680 (CH) CH (decomp.) ? >NCH (CH) 2 3 3 CH 3), 3.92 (311, S, -OCH 1630 2 2 2 3 4.41, 5.11 (2H, ABq, J-15Hz, S Cl2 5.21 (111, d, J=SHz, C,-11), 5.81 (111, dd, J=5Hz, J=SHz, C -11) - 6. 65 (211, bs, 7 H H 6.87 (111, 5, N 7.26 (311, bs, -NH T 3 E) S H 9.81 (111, d, J=SHz, -CONH-) - Cont'd 52 GB 2 171697 A Table 20 (Cont'd) 52 H 9 H H H H H 0.86-2.06 (10H, M, >N!!), 3.45 HH H H 0 0 - -CH 3 175-177 1770, (2H, bs, C -H)-, 3-87 OH, S, -OCH), (decamp.) 1710 2 3 \-.i 16304.20-4.71 (1. H, m, >N 70),-4.36, 5.11- H ), 5.14 (3H, bs, (2H, ABq, J=IsfIZ, S -CH 2- -NH 3 E)J, 5. 23 (1H, d, J-5Hz, CCH), 5. 76 (111, dd, J=SHZ, J=SHZ, C 7 -H), 6.62 (2H, bs,)C::), 6,80 (IH, s, N), - h ii X S H 9. 66 (IH, d, J=SHz, -CONH-) 1.97 (3H, s, -OCOCH 3), 3.44 (2H, bs, C 2-H) 3.80-4.42 (4H, M, 5NCH 2CH20-), 3.91. (3H, 0 0 ' -CH 3 105-107 1770, Y(decamp.) 1720, S, OCH 3), 4.41, 5.04 (2H, ABq, J=15Hz, 1710 -N-J (CH) oco 3 ? 2 2 1630 1H 2 j, 5.13 (1H, d,J=5Hz, C CH), 5.79 (1H, dd, J=SHZ,J=8Hz, C 7 -H), 6.59 (2H, bs )c:) 6. 88 (1R, s, X), 7.38 (3H, bs, H H S H -NH 3 ED 9.75 (1H, d, J=BUZ, -CONH-) 0.88 (3H, t, J=7Hz,>N(CH 2) 7 CH 3 1.05- 0 0 1. 85 (12M. m, >NCH 2 (CH H (2H, jC 2) 6C 3), 3.53 CH -CH 131-135 1775 bs, C 2-H), 3.73 (2H, t, J=7HZ, 3 (CH) (decamp.) 1670 %=-/ 2 7 3 1660, >NCH (CH) CH'), 3.96 (3H, -5, -OCH),.
1640 2 2 6 3 3 4.48, 5.13- QU, ABq, J=ISHz, S ICH 2- 5.25 (IH, d, J=SHz, C CH)' 5-88 (1H, dd, J=Sliz, i=8HZ, C7-H), 6.72 (2H, bs,.
6. 9 8 (1 H, s, NT), 7.21 (3H, bs, ii h S H 1. - - - -NH 3(D), 9. 9 3 (1H, d, J=BlIZ, --CONH-) 1 I - cant, a - 53 GB 2 171697 A 53 Table 20 (Cont'd) 0 0 CH _CH 179-181 1770, 2.86 (6H, s, -N' CH 3 3 (decomp.) 1710, 113J, 3.51 (2H, bs, C -H), -N N-N 1680 CH 3 2 CH 1620 3.93 (3H, s, -OCH), 4.42, 5.07 (2H, AB9, 3 S 3 J=ISHZ, 5.22 (1H, d, i=5HZ, ICH 2 CG-H), 5.96 (1H, dd, J5Hz, J8HZ, C7-H), 6.57, 6.72 (2H, ABq, J=6HZ, 6.90(111 H H N 0) st 13), 7.44 (3H, bs, -NH 3), 9.80 (1H, S H d, J=8Hz, -CONH-) 1.20 (3H, t, J=7HZ,>NCH 2 CH 3), 1. 29 (3H, t, 169-174 1775, J=7Hz, -OCH 2 CH 3), 3.52 (2H, bs, C 2-H)l 0 0' -CH 2 cl (decomp.) 1645 3.47 (2H, q, J=7Hz, >N-CH 2 CH 3), 4.26 (2H, 3 -N N-CII CH q, J=7Hz, -OC,CH 3), 4.45, 5.13 (2H, ABq, -=i 2 3 L, J=15Hz, S), 5.26 (1H, d, J=SHz, ICH 2- C CH)' 5'90 (1H, dd, J=SHz, J=8Hz, C 7-H)' 6. 70 (2H, bs,)Z:3), 6. 95 (JH, S, N H H S H 9.86 (1H, d, J=8Hz, -CONH-) CH 2 CH 3 1.17 (3H, t, J=7Hz, CH 3 CH 2-), 2.64 (2H, N 153156 1780, q, J=7Hz, CH 3 CH 2_), 3.46 (2H, bs, C 2- H), -CH 3 (decomp.) 1720, 1690 3.96 OH, S, -OCH 3), 4.96, 5.40 (2H, ABq, 0 1630 J=15Hz, S 5.23 (1H, d, J=SHZ, ICH 2- C 6 -H), 5.88 (1H, dd, J=SHZ, J=SHz, C 7-H)l 6..95, 7.19 (2H, ABq, J=10Hz, lp ' - 1H 6.97 (1H, s, N S H 7.59 (3H, bs, -NH 3 0), 9.9G (1H, d, J=8liz, -CONH-) - Cont'd - 54 GB 2 171 697 A 54 Table 20 (ContId) 0 2.05 (1.5H, s, -CH 3 xO 5), 2.07 (1.5H, s, HN CH 3 -CH 3 xO.5), 3.34 (2H, bs, C2-H) (3H, 1 -CH 3 >200 1770, - S -N -OCH 3), 4.97 (2H, bs, 1710, lc 1 0 1665 + 5.09 (1H, d, J=5Hz, C CH)' 5.73 (1H, dd, 0 J=SHz, J=SHz, C7 -H), 6.77 (0.5H, s, -H H14 X 0.5), 6.80 (IH, NX 6.94 (0.5H, 1 -N CH 3 S H 0 s, -HXO.S), 7.75 (3H, bs, -NH 3 ED 9.67 (1H, d, J=8HZ, -CONH-) 3.43 (2H, bs, C 2 -H), 3.871(3H, s, OCH 3 S 4.51, 5.65 (2H, ABq, J=15Hz, ICHi 1770, N -CH - 1680 5.14 (1H, d,-J=SHZ, C CH), 5.78 (1H, dd, 144-147 5 -N 3 idecomp.) 1640 J=SHZ, J8HZ, C -H), 6.80 (1H, s, N -), -1 7 TI 0 S H 7-31, 7.57 (2H, ABq, J=5Hz, H 7.98 (1H, s, YH), 9.66 (1H, d, J=8Hz, -CONH-) 3.40 (2H, bs, C 2 -H), 3.90 (3H, s, -OCH 3)' 0. 1775, 4.87, 5.24 (2H, ABq, J=ISHz, S ICH N -CH 3 >200 1710,:l H 1665 -C, 1 -14 1630 5.06 (1H,d, J=SHz, C -H), 5.78 (1H, dd, 6 0 N J=SHZ, J=8HZ, C7-H), 6.84 (IH, s, X), S 11 7.44 (1H, s, -H), 9.69 (1H, d, J=8HZ, -CONfi-) 3.50 (2H, bs, C2m-li), 3.95 (3H, s, -OCH3) 4.47, 5.15 (2H, ABq, J=15Hz, S 0 0 m 1770, ICH 2- -N NH -CH 168170 1710 - 3 j (decomp.) 5.24 (1H, d, J=SHz, C -H), 5.85 (IH, dd, 1630 6 JSHZ, J8HZ, C7-H) 6.46, 6.62,(2H, ABC1, J=6Hz,)==(), 6.94 (1H, s, N 7.03 -L S H - (3H, bst -NH(D) 9.85 (.1H, d, J=8Hz, -CONH-) 3 1 GB 2 171697 A 55 (4) In 30 mi of water was dissolved 6.35 g of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yi)-2-(syn)meth oxyi m in oaceta m idol -3[ 1 (2,3-dioxo- 1,2,3,4-tetra hyd ropyrazi nyi)l methyl}-A3-cephem-4-ca rboxyl ic acid, and the resulting solution was adjusted to pH 7.4 with sodium hydrogencarbonate. Subsequently, this solution was purified by passing through an Amberlite XAD-2 column to obtain 4.7 g (yield, 86.6%) of sodium 7-[2-(2-a m in oth iazol -4-yi)-2-(syn)-methoxyi m i noaceta m idol -3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)l-methyi}-A3-cephem-4carboxyiate having a melting point of 200'C or more.
iR (KBO cm-l: v,=, 1763, 1670, 1650-1620 In a similar manner, the following compounds were obtained:
Sodium 7-[2-(2-aminothiazol-4-yi)-2-(syn)-methoxyiminoacetamidol-3-{[1-(4methyi-2, 3-dioxo-1,2,3,4-tetrahydropyrazi nyi)l methyl}-A3-cephem-4-ca rboxyl ate.
m.p.: 190-195'C (decomp.).
]R (KBr) cm-l: v,=0 1760, 1670, 1650, 1630 Sodium 7-[2-(2-aminothiazoi-4, yi)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6tetrahydropyrazi nyi)l methyl}-A3-cephem-4-ca rboxyl ate Sodium 7[2-(2-am inoth iazo 1-4-yi)-2-(syn)-methoxyi m in oaceta m idol- 3-{[ 1 -(3-methyi-6-oxo-1,6-di hydropyridazinyi)jmethyi}-A3-cephem-4-carboxylate.
Example 7 (1) To a solution of 3 g of 2-(2-tritylaminothiazol-4-y])-2-(syn)-tert.butoxycarbonyimethoxyiminoacetic ac 1 id in 15 m] of N,N-climethylacetamide was added dropwise 0.93 g of phosphorus oxychloride at -100C, 20 and the mixture was subjected to reaction at -5' to O'C for 1 hour. This solution was added dropwise to a solution of 19.4 mi of anhydrous methylene chloride containing 1.94 g of 7-amino-3-{[1-(4-ethyi-2,3 dioxo-1,2,3,4-tetrahydropyrazinyi)lmethy I}_A3-cephern-4-carboxylic acid and 2.25 g of bis (trimethylsilyl) acetamide at -Y to O'C. After completion of th dropwise addition, the mixture was subjected to reaction at the same temperature for 30 minutes and then at 00 to WC for 30 minutes. After completion of the 25 reaction, methylene chloride was removed by distillation under reduced pressure, and to the residue was added a mixed solvent of 100 mi of saturated aqueous sodium chloride solution and 100 mi of acetoni trile. Subsequently, the organic layer was separated and washed twice with 50-mi portions of saturated aqueous sodium chloride solution, and then the solvent was removed by distillation under reduced pres sure. The resulting residue was dissolved in 50 mi of methanol, after which 1 g of diphenyidiazomethane was added to the solution at 5Q to WC, and the mixture was subjected to reaction at the same tempera ture for 30 minutes. After completion of the reaction, the solvent was removed by distillation under re duced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; benzene: ethyl acetate=3:1) to obtain 1.6 g (yield, 27.8%) of diphenyImethyl 7-[2-(2-tritylaminothiazol-4 yl)-2-(syn)-tert.butoxycarbonyimethoxyiminoacetamidol-3-{[1-(4-ethy]-2,3dio xo-1,2,3,4-tetrahydropyra- 35 zinyi)lmethy I}_A3-ceph em-4-ca rboxyl ate having a melting point of 98- 100'C (decomp.).
M (KBr) cm-l: vc=,, 1780, 1720, 1680, 1630 NMR (d,,-DMSO) 8 values:
1.17 (3H, t, J=71-1z, >NCH,CH3), 1.44 (9H, s, -C(CH3)3), 3.62 (2H, bs, C2-H), 3.74 (2H, q, J=7Hz, >N-CHCH,), 0 4.55 (2H, 4.51, 5.16 (2H, ABq, J=15Hz, S) 1 -JICH 2_ - 50 5.27 (1 H, d, J =5Hz, C,,-H), 5.87 (1 H, dd, J = 5Hz, J = 8Hz, QM), 6.55 (2H, bs,)=), H H 6.80 (1 H, s, -CH <), 'N 6.97 (1 H, s,) 1 S H 7.05-7.67 (25H, m, -D X 5), 56 GB 2 171697 A 8.86 (1 H, bs, ()CNH-), 9.54 (1 H, d, J=8Hz, -CONW) In a similar manner, the compounds shown in Tables 21 and 22 were obtained.
Tabla 21 N CCONH 3 C-N // 9 3: 2 - P-S N 0 CH'21- \ 18 COOCH( @)2 OR (syn-isomer) Compound M-P- CC) IR (KBr) CM- 1: V R2 R18 - c=0 0 0 CH m 3 118-120 1780, 1720, 1690-1640 1 N N-CH CH -C-COOC(CH (decomp.) 2 3 1 3 3 3 0 0 -N N-H -CH COOC(CH 155-15& 1780, 1720-, 1680, 1640 2 3 3 (decomp-.) 0 0 -N N-CH -CH COOC(CR 125-127 1785, 1725, 1690, 1645 3 2 3 3 (decomp.) 0 0 - 1.1 CH 3 -CH COOC(CH) 151-15. 4 1780, 1725, 1685, 1640 -N N N 2 3 3 CH 3 (decomp.) 0 H -CH 2 COOC (C111 3J3 126-130 1780, 1725, 1690-1660 -N (decomp.) 0 CH 3 N -CH 2 COOC(CH 3)3 118-120 1780, 1720,-1660 1 -N (decomp.) 0 56 57 GB 2 171 697 A 57 Table 22
Q) 3-N 1 2 S:rWONH H N 7P C11 2 R 0 COOC(CH 3)3 OCH2COOC(CH3)3 compound R2 M.P. Pc) IR (KBr) cm- V C=0 10 0 133135 1820, 1780, 1720, 1690, 1650 -N N-CH CH (decomp'.) 2 3 Y 15 0 M 0 164-167 1785, 1730, 1710, 1690, 1660 -N - N 11- (decomp.) 20 0 135-138 1785, 1740, 1730, 1710, 1680, -N N-CH 2 OCOC(CH 3)3 (decomp.) 1660 25 0 0 30 -N N-CH 2 COOCH( &2 152-154 1785, 1750, 1720, 1690, 1655 (decomp.) 1 35 (2) In a mixed solvent of 8 mi of trifluoroacetic acid and 3 mi of anisole was dissolved 1.6 9 of diphenyimethyl 7-[2-(2-tritylaminothiazol4-yi)-2-(syn)-tert.-butoxycarbonyimethoxyiminoace tamidol-3-{[1-(4-ethyi2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl)lmethyi}-A3-cephem-4-carboxylate, and the solution was subjected to reaction at room temperature for 1 hour. After completion of the reaction, the solvent was removed by 40 distillation under resuced pressure. To the residue was added 10 m] of diethyl ether and the crystals were collected by filtration. Then, the crystals obtained were dissolved in 20 mi of 50% by weight aqueous formic acid solution, and the solution was subjected to reaction at 45o to 550C for 1 hour. After completion of the reaction, the precipitated crystals were separated by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 10 mi of ethyl acetate and the 45 crystals were collected by filtration. Subsequently, the crystals were sufficiently washed with 10 m] of ethyl acetate and dried to obtain 0.7 g (yield, 80.7%) of 7-[2-(2-aminothiazol-4-yi)-2-(syn)carboxymethoxyiminoacetamidol-3-{[1-(4-ethy]-2,3-dioxo-1,2,3,4tetrahydropyrazinyi)lmethyl}-A3-cephem-4-carboxylic acid having a melting point of 139-140'C (decomp.). 50 IR (KBr) cm-l: vc=. 1775, 1695, 1680, 1635 NIVIR (deDMSO) 8 values: 1.22 (3H, t, J=71-1z, >NCH2CHJ, 3.53 (2H, bs, C2-H), 3.74 (2H, q, J=71-1z, >NCH2C1-1J, 4.70 (2H, s. -OCH2CO-), 4.45, 5,10 (2H, ABq, J=151-1z, S - CH 2 - 5.23 (1 H, d - J = 5Hz, C,,M), 5.90(1H,d,J=5Hz,J=8Hz,C7-H), 6.69(2H,bs,), H H 58 GB 2 171697 A 6.94 (1 H, z,;), S R 58 9.70(1H,d,J=8Hz,-CONH-) In a similar manner, the compqpnds shown in Tabel 23 were obtained.
Table 23
C -CONH - f S H N S N -R 2 2 liCH2 OR 1 a COOH (syn-isom6r) 1 Compound IR (KBr) M.P. CC)) 6 values:
NMR (d -DMSO =_1: v 6 R2 R18 C=0.
1 1.22 (3H, t, J=7HZ, "-NCH 2CH3.) ' 0 0 CH 3 165-166 1775, 1.53 (6H, a, CH -M 1 (decomp.) 1705. 1---3 - -C-Coon 1690 -C-COOH -N NCH 2 CH 5 j 3 . 1 CH 3 1620 CH3 - - - 3_.54.(2a, bs, 3.75 (2H, C2-H) q, J=7Hz, >NCH2CH3), 4.49, 5.16 (2H, ABq, J=15Hz, S ICH 2_ 5.27 UR, d, J=5Hz, C CH)', 6.01 (1H, dd, J=SHz, J=8Hz, C 7 -H), 6.72 (2H, bs, 6.96 (1H, S, N), 9.64 (IH,.d, S H J=8HZ, -COM,-) 3.44 (2H, bs, C 2-H) 4.42, 0 0 1770, 5.00 (2H, Anq, J=15HZ, S m -N NH -Cl 1 COOH 182-183 1690, 2 (decomp.) 1670, CH 2_ 1640 4.60 (2K, bs, -OCH2COOH)r 5.19 (1H ' d, J=SHz, C CH)' 5.84 (1H. dd, J=SHZ, J=BHZ, C -H), 6.52 (2H, AB9, J=6Hz,.
7 ≥=<), 6.82 (11i, 5, N) 1 H H S H 9-56 (1H, d, J=8HZ, -CONH-) cont,d 59 Table 23 (Cont'd) GB 2 171 697 A 59 1 3.34-PH, s, >NCH 3), 3.41 (2H, 0 0 m 1770, bs, C 2-H), 4.45, 5.02 (2H, ABq, -N N-CH -CH COOH 88-91 1680, 3 2 (decomp.) 1660, J=15Hz, S 4.67 (2H, 1630 CH 2- bs, -OCH 2 COOH), 5.16 (1H, d, J=5Hz,.C CH)' 5.84 (1H, dd, J=SHz, J=8Hz, C 7 -H), 6.60 (2H, bs,)c:), 6.97 (1H, s, N- S H 9.75 (1H, d, J=SHz, -CONH-) 1 0 0 1770, 3 3 M- /CH 3 2.85 (6H, s, -N<C" 3.49 (IH, -N N N -CH 2 COOH 155-158 1710, CH 3 CH 3 (decomp.) 1670, 1630 bs, C 2 -H), 4. 4 3', 4.98 (2H, AB9, J=15Hz, S), 4.65 (2H, S, CH 2- 3.75 (2H, bs, C 2-H), 4.47, 0 0 0 0 1785, 5.13 (2H, ABq, J=15Hz, S COOH 137-140 1720, N CH Nr 2 TO, (decomp.) 1690, CH 2 1640 4.74 (2H, s, -OCH CO-), 5.13 (IH, 2 d, J=SHz, C 6 -H), 5.97 (1H, dd, J=5Hz, J=BHz, C 7-H), 6.12, 6.66 (2"H, ABq, J=6Hz, '=<), 7.05 H H N (1H, S, S H), 7.61-8.25 (SH, m, o O), 8.84 (1H, d, J=SHz, -CONH-) 1790, 1.17 (911, S, -C(CH 3)3), 3.72 -CH 2 COOH 178-183 1730, 0 0 (decomp.) 1690, (2H, bs, C 2 -H), 4.46, 5.20 (2.H, 1650 m 3 3 ABq, J=15Hz, S 4.70 (2H, -N N-CH20COC(C11 CH 2- 5, -OCH 2 CO-), 5.03 (1H, d, J=SHZ, C 6 -H), 5.73 (2H, s, >NCH 2_)' 6.06 (IH, dd, J=5Hz, J=8Hz, C 7-H), 6.73 (2H, bs, N 7.05 (IH, s, S1H 8.87 (IH, d, J=SHz, -CONH-) - Cont'd - GB 2 171 697 A la Table 23 (Cont'd) 0 0 -CH 2 COOH 135-142 1780, 3.73 (2H, bs, C 2-11), 4.48, 5.28 H. (decomp.) 1720, (2H, ABg, J=lSHz, S 4 ' 54 -N N-CH COOH 1680,. ICH2_ 2 1635 (2H, s, >NCH2-), 4.73 PH, s, -OCH2 CO-), 5.10 (1H, d, J=5HZ, C6 -H), 6.07 (IH, dd, J=5Hzf J=BHz, C7 -H), 6 ' 74 PH, bs, ), 7.05 (1H, S, N_), I H H S H 8.89 (1H, d, J=8Hz, -CONH-) 2 3.34 (2H, bs, C2-H)' 4.63 (2H, s, -OCH2CO-), 4.98 (2H, bs, 0 HN _CH 190-193 1770, s COOH 1710, a)t 5.10 1H, d, J=5Hz, I 2 (decomp.) 1660, CH 2 - N 1630 CG-H), 5.77 (IH, dd, J=5HZ, 0 J=8HZ' C 7 -H), 6.83 (IH, s, N-), 6.85, 7.11 (2H, ABq; SIH H J=10HZ,, 9. 51 (IH, d, J=BHz, -CONH-) 2 2.28 (3H, S,!>-CH 3), 3.43 (2H, CH 1770, bs' C 2 -H), 4.73 (2H, S, 3 194-197 1710, N _CH 2 COOH (decomp.) 1690 _OCH 2 CO-)f 5.14 UH, d, J=SHZ, 1 5 _N 1630 C 6 -H), 5.23 (2H', bs, SACH 0 2s.aa (IH, dd, J=5Hz, J=SHZ, C 7-H), 6.96, 7.46 (2H, ABq, J=10liz, 11) 7 01 (IH, s, X_ I I - H Nj-[H), 7.80 (3H, bs, -NHCt) 3 s 9.76 (IH, d, J=8HZ, -CONH-1 Note: 1 Trifluoroacetic acid salt (For the purpose of purifying the product - 55 obtained by the above-mentioned procedure, it was converted to a diphenyImethyl ester in a conventional manner, followed by de-esterif ication with trifluoroacatic acid to obtain a trifluoroacetic acid salt.) 2 Formate Example 8 (1) To a solution of 1.68 g of diketene in 8.40 mI of anhydrous methylene chloride was added dropwise a solution of 2.08 g of bromine in 6.25 mi of anhydrous methylene chloride with stirring at -30'C, and the mixture was subjected to reaction at -30' to -20'C for 30 minutes. The thus obtained reaction mix- ture was added dropwiseat -300C or less to a solution of 50 mi of anhydrous methylene chloride con- '65- 61 GB 2 171 697 A 61 taining 5.20 g of diphenylmethyl 7-amino-3-{[l-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazinyl)lmethyll.A3cephem-4-carboxylate and 4.08 g of bis(trimethylsilyl)acetamide.
After completion of the dropwise addition, the mixture was subjected to reaction at -300 to -20oC for 30 minutes and then at 0' to 10C for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue-thus obtained was dissolved in 50 ml of ethyl acetate and 40 ml of water. Then the organic layer was separated, washed with 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue was added 50 ml of diisopropyl ether, and the thus obtained crystals were collected by filtration to obtain 5.85 g (yield, 85.6%) of diphenylrnethyl 7-(4-bromo-3-oxobutyramido)-3-f[l-(4-ethyl-2,3dioxo-1,2,3,4-tetrahydropyra- 10 zinyl)] m ethyll-A3-cephem-4-ca rboxyl ate having a melting point of 138- 142oC (decomp.). IR (KBr) cm-1: vc=o 1778, 1720, 1680,1640 NIVIR (deDIVISO) 8 values:
1.22 (3H, t, J=7Hz, NCH2CH3).
3.40 (2H, bs, C2-H), 3.85 (2H, q, J=7Hz, NCH2CH.), 3.87 (2H, bs, BrCH2COCH2_)1 4.18 (2H, bs, BrCHCO-), 4.47, 4.96 (2H, ABq, J=15Hz, S 5.04 (1 H, d, J=51-1z, C,-H), 5.90 (1 H, dd, J=51-1z, J=81-1z, C7-H), -CH 2_ 6.15, M0 (2H, A13q, J=61-1z,) o H H 6.98 (1 H, s, -CH <), ) 1 7.40 (10H, bs, X 2), 8.55 (1 H, cl, J=8Hz, -CONW) In a similar manner, the following compound was obtained:
4.09 g (yield, 62.6%) of diphenyimethyl 7-(4-bromo-3-oxo-butyiramido)-3{[1-(3,6-dioxo-1,2,3,6-tetrahyd ropyridazi nyi)l m ethyl}-A3-cephem-4-ca rboxyl ate having a melting point of 124-126'C (decomp.). 35 IR (KBr) cml: vc =, 1780, 1725, 1660 NIVIR (d.,-DMSO) 8 values:
0 0 11 11 403.49 (4H, bs, 12-rl, 0 4.52 (2H, s, 5.06 (1 H, bs, S) 1 J_ CH 2_ 5.26 (1 H, d, J=51-iz, C,,M), 5.90 (1 H, dd, J=51-1z, J=.8Hz, C.,-H), 7.01, 7.25 (2H, ABq, J=10Hz, 7.09 (1 H, s, -CH), 7.24-7.91 (10H, m -e x 2), 9.34 (1 H, cl, J = 1 0Hz, -CONW) (2) To a solution of 5.50 g of diphenyimethyl 7-(4-bromo-3-oxobutyramido)- 3-{[1-(4-ethyi-2,3-dioxo1,2,3,4-tetra hyd ropyrazinyl)l m ethyl}-A3-cephem-4-ca rboxyl ate in 30 m] of acetic acid was added dropwise a solution of 5 mI of water containing 0.74 g of sodium nitrite with ice- cooling over a period of 1 hour, 65 62 GB 2 171697 A 62 and the resulting mixture was subjected to reaction at-room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 500 mi of water to precipitate crystals. The crystals were collected by filtration, washed sufficiently with water, and dried. Then, the crystals were dissolved in 10 mi of chloroform and then purified by a column chromatrography (Wako Silica Gel C-200, eluent; benzene: ethyl acetate=-2:1 by volume), to obtain 3.15 g (yield, 54.9%) of diphenyimethyl 7-(4-bromo-2hydroxyimino--3-oxobutylamido)-3-{[1-(4ethyi-2,3-dioxo-1,2,3,4-t otrahydropyrazi yi)l methyl}-A3-cephem4carboxylate having a melting point of 127-132'C (decomp.). [R (KBr) cm-l: vc - 1778, 1720, 1680, 1635 ---0 NIVIR (CDCI,) 8 values:
1.26 (3H, t, J=71-1z, >NCHWJ, 10 3.47 (2H, bs, C,-H), 3.81 (2H, q, J-7Hz, >NCHCH,), 4.52 (2H, s, BrCHCO-), - 4.53, 4.78 (2H, Abq, J =1 5Hz, S) ' - - ICH 2_ 15 5.11 (1 H, d, J=51-1z, C6-H), 5.80-6.15 (1 H, rn, C,-H), 6.13, 6.52 (2H, ABq, J=61-1z, H H 20 7.02 (1 H, s, -CH <), 7.41 (10H, bs, -C x 2), 9.20 (1 H, d, J=8Hz, -CONH-) In a similar manner, the following compound was obtained:
4.71 g (V ield, 75.1%) of diphenyimethyl 7-(4-bromo-2-hydroxyimino-3oxobutyramido)-3-{[1-(3,6-dioxo1,2,3,6-tetrahydropyridazinyl)lmethyi}-A3-cephem-4-carboxylate having a melting point of 138-1410C (de comp.) 3U [R (KBO em-': Y,=0 1780, 1720,1660 NIVIR (d,-DIVISO) 8 values:
3.46 (2H, bs, C,-H), 4.62 (2H, s, BrCH2C0_) 4.96 (2H, bs, S ICH 2 5.18 (1 H, d, J=5Hz, C6-H), 5.93 (1 H, dd,-J=5Hz, J=SHz, P,-H), 6.89, 7.13 (21-1 ABq, J=MHz, 6.96 (1 H, s, -CH<), 7.13-7.72 (1 OH, rn, -@ x 2), 9.45 (1 H, d, J=8Hz, -CON W), 13.36 (1 H, s, =N-OH) (3) In 12 ml of N,N-dimethylacetamide were dissolved 3.00 g of the diphenylmethyl 7-(4-brom - o-2-hy- 50 droxyimino-3-oxobutyramido)-3-1[1-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyraz inyl)lmethyl}-&3-cephem-4- carboxylate obtained in above (2) and 0.42 g of thiourea, and the resulting solution was subjected to reaction at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent of 120 ml of water and 240 ml of ethyl acetate. Subsequently, the mixture was adjusted to pH 7.0 with sodium hydrogencarbonate, after which the organic layer was separated, 156 and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order.
After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distil lation under reduced pressure. To the residue was added 20 ml of diethyl ether and the crystals were collected by filtration to obtain 2.10 g (yield, 72.3%) of diphenylmethyl 7-[2-(2-aminoihiazol-4-yi)-2-(syn)hydroxyiminoacetamidol-34[1-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazinyl)l methyll-A3-cephem-4-car- 60 boxy-late having a melting point of 137-140'C (decomp.).
63 GB 2 171697 A 63 IR (KBr) cml: v,,, 1778, 1720, 1680, 1640 NMR (d.-DMSO) 8 values:
1.19 (3H, t, J=71-1z, >NCHWJ, 3.48 (2H, bs, C,-H), 3.68 (2H, q, J=71-1z, > NCHCH,), 4.46, 5.04 (2H, ABq, J = 1 5Hz, S -LCH 2_ 5,28 (1 H, cl, J =5Hz, C,-H), 5.97 (1 H, dd, J=5Hz, J=8Hz, C,-H), 6.57, 6.75 (2H, ABq, J=61-1z, >i--) 1 H H 6.79 (1 H, s, N-.) ', ST 11 7.07 (1 H, s, -CH<), 7.53 (1 OH, bs, -5 x 2), 9.70 0HA, J=8Hz, -CONW) (4) in a mixed solvent of 10.0 mi of trifluoroacetic acid and 2.0 mi of anisole was dissolved 2.00 g of the 25 diphenyimethyl 7-[2-(2-aminothiazol-4-yi)-2-(syn)-hydroxyiminoacetamidol3-{[1-(4-ethyl-2,3 -dioxo-1,2,3,4- tetra hyd ropyrazinyi)j methyl}-A3cephem-4-carboxylate obtained in above (3), and the resulting solution was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and to the residue was added 15 mi of diethyl ether, after which the crystals were sufficiently washed with 10 m] of diethyl ether and then dried to obtain 1.62 30 g (yield, 87.6%) of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4- yi)-2-(syn)-hydroxyiminoacetamido]-3{[1-(4-ethyi-2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)jmethyl}-A3-cephem-4carb oxylic acid having a melting point of 112-118'C (decomp.).
iR (KBr) em-': v.
=, 1780, 1680, 1620 NMR (d,-DMSO) 8 values:
1.19 (3H, t, J=7Hz, >N-CH,WJ, 3.47 (2R, bs, C2-H), 3.72 (2H, cl, J=71-1z, >NCHCHJ, 4.45-6.70 (4H, m, S CcH, C,-H), -CH2- ' 6.59-6.83 (3H, m, / 0 R 11 N S _ H Example 9 (1) To a solution of 7.1 g of diphenyimethyl 7-(4-broma-2-hydroxyimino-3- oxobutyramido)-3-{[1-(4-ethyi2,3-dioxo-1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3-cephern-4-carboxylate in 70 m] of anhydrous methylene chloride was slowly added a solution of diazomethane in diethyl ether at - 5' to O'C, and the resulting solution was subjected to reaction at the same temperature for 30 minutes. After confirming the disap- 50 pearance of diazomethane, the solvent was removed by distillation under reduced pressure. Then, the obtained residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; benzene:
ethyi acetate=3:1 by volume) to obtain 2.32 g (yield, 32.0%) of diphenyimethyl 7-[4-bromo-2-(syn)-meth oxyimino-3oxobutyramidol-3-{[1-(4-ethyi-2,3-dioxo-1,2,3,4tetrahydropyrazin yi)lmethyi}-A3-cephem-4-car- boxylate having a melting point of 135-14M (decomp.).
IR (KBr) em-': v.
---0 1778, 1720, 1682, 1638 NMR (CDC'3) 8 Values:
1.25 (3H, t, J=7Hz, >NCH2CH,), 3.48 (2H, bs, C2-H), 3.84 (2H, q, J=71-1z, >NCHCH.), 4.00 (3H, s, -OCH3), 4.10 (2H, s, BrCHCO-), 4 1.48, 4.67 (2H, ABq, J=115Hz, S),-CH2 1 64 GB 2 171 697 A 5.10 OH, d, J=5Hz, C,-H), 6.05 (1 H, dd, J =5Hz, J =8Hz, C, H), 6.38, 6.73 (2H, ABq, J=ISHz, H H 6,98 (1 H, s, -CH <), 7.32 (1 OH, bs, -( x 2), 9.18 (1 H, d, J=81-1z, -CONW) In a similar manner, the following compound was obtained:
1.70 g (yield, 24.5%) of diphenyimethyl 7-[4-bromo-2-(syn)-methoxyimino-3oxobutyramidol-3-{[1-(3,6- dioxo-1,2,3,4-tetrahydro pyridazinyi)lmet_hyl}-A3-cephem-4-carboxyI ate having a melting point of 145-14M (dec.).
IR (KBr) cm-l: v,=, 1780,1730,1660 NMR (d.,-DMSO) 8 values 3.49 (2H, bs, C,-H), 4.03 (3H, s, -OCH3), 4.60 (2H, s, BrCH,.M), 5.02 (2H, bs,S)CH25.30 (1 H, cl, J = 5Hz, CcH), 6.02(1H,dd,J=5HzJ=8Hz,C.,-H), H 6.92, 7.16 (2H, ABq, J=MHz, 6.99 (1 H, s, -CH-z), 7.17-7.78 (1 OH, m -( x 2), 10.16 OH, d, J=8Hz, -CONW) 64 (2) In 14 ml of N,N-dimethylacetamide were dissolved 2.3 g of diphenylmethyl 7-[4-bromo-2-(syn)-methoxyimino-3-oxobutyramidol-3-i[l-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazin yi)lmethyll-A3-cephem-4-car- boxylate and 0.32 g of thiourea, and the resulting solution was subjected to reaction at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent of-50 ml of water and 150 ml of ethyl acetate. Then, sodium hydrogencarbonate was added thereto adjust the mixture to pH 6.7, and then the organic layer was separated. The aqueous layer was further extracted 40 twice with 100-ml portions of ethyl acetate. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. To the residue was added 20 ml of diethyl ether, and the crystals were collected by filtration to obtain 1.92 g (yield, 86.3%) of diphenylmethyl 7-[2-(2-am i nothiazol-4yi)-2-(syn)-methoxyiminoaceta m idol 3-1[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)I methyll-A-3-cephem4-carboxyl ate having a melting point of 165-167"C.
IR(KBr)cm-1: v,,, 1780, 1720, 1680, 1640 In a similar manner, the following compound was obtained:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yi-2-(syn)-methoxyiminoacetamidol-31[l-(,6-dioxo-1, 2,3,6-te- trahydropyridazinyl)lmethy ll-A3-cephem-4-carboxylate, m.p., 175-178'C (decomp.) IR (KBr) cm-1: v,=o 1780, 1720, 1685-1660 The same ring-closure reaction as above was conducted and then the reaction mentioned in Example 643) or Example 7-(2) was conducted, to obtain the compounds shown in Tables 24, 25 and 26.
Table 24
S N c- CONR W Coolf-H N- Ill 1 3 2 N R2 N 0^ C112 OCH, COOH R2 R2 R2 0 CH 0 -N N-CH -N N-CH COOH 3 2 -N 0 0 0 CH 3 0 0 CH -N \=/ N- (CH 2 4 CH3 3 N -N N (CH 2)2 CH 3 N 0 (syn-isomer) R 2 1 0 -NKCH CH OCOCH \-/ 2 2 3 0 0 N N- (CH 2)7 cH 3 X_/ R2 0 HN CH 3 HN 1 + 1 -N -N 3 0 0 - Cont'd - (3) (D 'i a) in (7) 0) Table 24 (Cont'd) 0 0 -N - (CH) CH \==1 2 5 3 C 0 7-- -N NCH C=C-CH 2 \ 3.
0 1 0 Y 0 0 Y- CH -N N-CH 3 \==/ - CH 3 0 0 (CH 2) 11 CH 3 0 0 o 0 / \1 -N- 00, 0 0 -M (CH) CH \==/ 2 3 3 0 0 Y-K -N N-CH \==/ 2_@ 0 0 -N -CH OCOC(CH 2 3 3 0 0 j-- -,(:
-N O-_ CH3 -N N N ==/ "CH3 0 0 -N NCH 2 CH 3 CH CH 3 N 1 -N HN cl 1 - N 0 0 0 -NH 0 H 0 0 Contld - Note: Hydrochloride 0) G) 67 Table 25
N C CONH - S CH 2 R 2 0 'P'N ' OR18 COOH (syn-isomer) R 2 R 5 Ris 0 5 NH -CH COOH -N NCH2CH 3 2- 2 0 0 CH 3 - N NCH CH CF3COOH.NH -C-COOH 2 3 2- 1 Al 3 0 0 NH - -CH COOH - N NH 2 2 0 0 - N,_NCH 3 CF3COOH.NH 2- -CH COOH 2 00 NN-N,,CH 3 \\CH W COOH.M2 -CH COOH 3 2 3 0 UN 1 HCOOH-NH - -CH COOH 2 2 NI 0 CH 3 N HCOOH-NH 2- -CH 2 COOH 1 N 0 0 - 0 -bN?" WH2C=C-CH, NH -CH COOH 2- 2 0 GB 2 171 697 A 67 68 GB 2 171697 A 68 Table 25 (ContId) 0 0 NH 2- -CH 2 COOH 0 -N \===/ N 0 0 NH 2- COOH .N,CH -CH OCOC(CH 2 3)3 2 0 0 N NCH 2 COOH NH 2- -CH 2 COOH 0 0 - N NCH CH HCOOH-NH - -CH COO-<0_) 2 3 2 2 0 0 -N HCOOR-NH - -CH \=YCH2CH3 2 2C00 0 0 -DMNCH CH HCOOH.NH -CH COOCH CH 2 3 2 2 2 3 Table 26
N- C- CON - r "S -CH2R 2 H ' 11 -TN H2N N 11 OCH 0 3 COOR (syn-isomer) R R2 -CHOCOC(CH -N NCH 2 CH 3 3)3 CH 3 0 0 H -CH0COC (CH3) 3 -N NCH3 1 kon 3 - cont'd - 39 GB 2 171697 A 69 Table26 (Contld)' 0 0 -CHOCOC(CH 3)3 -1 N-(CH 2) 4 CH 3 3 0 -CHOCOC(CH 3)3 r 1 -N -(CH 2)5 CH 3 l CH 3 0 -CHOCOC(CH 3)3 -1 IC== N(CE 2)7 CH 3 1 3 0 -THOCOC(CH 3)3 -N \--/ N(CH CH 3 CH 3 -0 0 m -CH OCOC(CH -N PC11,CH, 2 3 3 0 -CHOCOOC(CH 3)3 -N NCH CH 1 \==/ 2 3 3 Q 0 /11 -N NCH2 CH 3 -(CH) CH -N NCH CH 2 3 3 2 3 -CH C-C-CH 0 \ 0 -N NCH CH 2 3 H3 -CH OCOC(CH 1 2 3 3 N -N 0 - Contld - - GB 2 171697 A Table 26 (Cont'd) -CH20COC(CH 3)3 1 C 3 c - H 3 N N Y1 0 -CH 2 OCOC(CH 33 -CH 2 OCOC(CH 3)3 -CHOCOC(CH 3)3 1 _n 3 0 . HN 1 -N N -N 0 N 1 -N 0 -CH 2 OCOC(CH 3) 3 0 0 0 -N 1 Note: Hydrochloride Physical properties (m.p., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 6, 7, 11 and 12.
Example 10 (1) To a suspension of 2.2 g of 2-(2-formamidothiazol-4-yi)giyoxylic acid in 11 ml of N,N-di methyl ace tamide was added dropwise 1.8 g of phosphorus oxychloride at -200C, and the resulting mixture was subjected to reaction at the same temperature for 2 hours. Then, to this reaction mixture was added a solution of 26 m[ of methylene chloride containing 5.2 g of diphenyimethyl 7-amino-3-{[1-(4-ethyl-2,3- - dioxo-1,2,3,4-tetra hydro pyrazinyi)l methyl}-A3-cephem-4-carboxylate at - 300 to -20'C. After completion Of 45 the dropwise addition, the mixture was subjected to reaction at same temperature for one hour. After completion of the reaction, 70 m] of water and 50 mi of methylene chloride were added to the reaction mixture. Then, sodium hydrogencarbonate was added thereto to adjust the mixture to pH 6.5, and the insolubles were removed by filtration. The organic layer was thereafter separated, washed with 100 mi of water and 10 mi of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous 5C magnesium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloro form: methanol=20:1 by volume) to obtain 1.4 g (yield, 20.0%) of diphenyimethyl 7-[2-(2-formamidothia zol-4-yi)giyoxylamidol-3-{[1-ethyi-2,3-dioxo-1,2,3,.4tetrahydropyrazinyi)lm ethyi}A3-cephem-4-carboxylate having a melting point of 140-145'C (decomp.).
IR (KBO cm-l: v,,=. 1780, 1720, 1680, 1670, 1640 NIVIR (d&-DMSO) 8 values:
1.20 (3H, t, J=7Hz, -' NCH,WJ, 3.50 (2H, bs, C,-H), 3.96(2H,q,J=7Hz, '--NCHCH.,), 4.401 5.00 (2H, ABq, J =1 5Hz, S 1 CH 2_ 5.30 (1 H, d, J=5Hz, C,)-H), 6.00(1H,dd,J=5Hz,J=9Hz,C,,-H), 413 5E 6! 71 6.50, 6.62 (2H, ABq, J=5Hz,)=K), H. H 7.04 (1 H, s, -CH ---), 7.30 (10H, bs, '-@ x 2), 8.64 (1H, s, N T), S - 8,81 (1 H, s, HCO N W), 10.20 (1H, cl, J=9Hz, -CONW),.
12.90 (1 H, bs, HCO N) In a similar manner, the following compound was obtained: 0.09 g (yield, 19.2%) of diphenyimethyl 7 [2-(2-formamidothiazol-4-yi)giyoxylamido]-3-{[1-(3,6-dioxo-l,2,3,6tetrahydr opyridazinyl)lmethyi}-Aa-ce- phem-4-carboxylate, m.p.: 153-154'C (decomp.).
IR (KBr) cm-l: vc=. 1780, 1725, 1690, 1665 NMR (CDC6+d,,-DMSO) 8 values:
3.42 (2H, bs, C2-H), 4.96-5.40 (3H, m, S, CrH), - CH 2_ 5.95 (1 H, dd, J=51-1z, J=8Hz, C,-H), 11 _) X 2), 6.72-7.78 (13k, m, -CH H, -\/b 8.66 (1 H, S, M 3:) 1 S H 8.73 (1 H, s, HCO-), 9.86 (1 H, cl, J=81-1z, -CONW) GB 2 171 697 A 71 (2) To a solution of 7.0 g of diphenylmethyl 7-[2-(2-formamidothiazol-4- yi)glyoxylamidol-3-1[1-(4-ethyl2,3-d ioxo-1,2,3,4-tetrahyd ropyrazi nyl)]- methyll-,L3-cephem-4-carboxyI ate in 35 ml of N,N-dimethylacetam- ide.was added 1.7 g of methoxyamine hydrochloride with ice-cooling, and the resulting mixture was subjected to reaction at 15-200C for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate, and the organic layer was separated, washed with 250 ml of water and 250 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure. To the residue was added 50 ml of diethyl ether, and the resulting crystals were 45 collected by filtration to obtain 6.1 g (yield, 83.7%) of diphenylmethyl 7-[2-(2-formamidothiazol-4-yi)-2(syn)-methoxyiminoacetamidol-3-f[l-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyra zinyl)lmethyi}-A3-cephem-4- carboxylate having a melting point of 165-168'C.
IR(KBr) cm-1: vc=,, 1780, 1720, 1680, 1640 In a similar manner, the following compound was obtained:
Diphenylmethyl 7-[2-(2-formamidothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-1[1-(3,6-dio xo-1,2,3,6- tetra hyd ro pyriclazi nyl)] methyll-A3-cephem-4-ca rboxylate, m.p. 171-173"C (decomp.).
The same oximination reaction as above was conducted, and then, the reaction mentioned in Example 6-(2), (3) and/or Example 7-(2) was conducted, to obtain the following compound and the compounds 55 shown in Tables 27, 28 and 29:
Trifluoroacetic acid salt of 7-[2-(2-amino-5-bromothiazol-4-yl)-2-(syn)methoxyiminoacetamido]-3-{[l-(4ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyll-,L3-cephem-4carboxyli c acid, m.p.: 1470C (decomp.) 60IR(KBr) cm-1: vc=, 1775, 1680, 1640 Table 27
N. N]r c S cp COOH-H CONII:TI N, 3 -s N \ 0 ?-_CH2R 2 OCH 3 COOH 1 (3Yn-isoiner) R 0 - N N-CH \==1 3 3 N 0 CH 3 H 0 p _ m N N-CH2COOH \==11 0 0 - N \-/ N- (C11 23 4C113 j 0 0 0 -M (CH \==1 2) 2CH3 0 0 -N _ (CH) CH =1 2 5 3 0 0 -N NCH C-C-CH 21 \ 3 0 0 y 0 ), _ CH 3 -N N CH ==1 -CH 3 0 0 (CII) CH 2 11 3 0 0 0 -N -J4 0 0 -N N (CH) CH -./ 2 33 o 0 -N N-CH 2-G 0 0 -N -CH 0COC(CR ,-J 2 1 3 3 O -N 1 N -i -G 0 0 --X WCH CH OCOCH 2 2 3 0 HN CH 3 1 + -N UN 1 - N H 3 0 0 -H N-(CH 2)7 CH 3 \==1 N -N O ICH3 -N N-N '-=/ '-CH3 HN cl N 1 - N 0 0 m -N NCH CH \-/ 2 3 -N NH \==1 cit 2 CH 3 Q 1 -N HYdrochlorijc 0 HN l1 _N 0 - Cont'd - _i r') 73 GB 2 171697 A 73 Table 28
R Ni- C -CONH S S N \11 0 N 2 CH 2 R OR18 COOH (syn-isomer) R 2 R 5 ll 8 p > - NB 2_ -CH 2 COOH NCH 2 CH 3 \=71 0 0 CH - 3 N NCH 2 CH. 3 CF3C:00H.MI 2_ -C-COOH Cl3 0 0 NB -CH COOH - Nr "NB \==1 2 2 0 0 -CH COOR -CH 3 -NB 2 CF3COOH 2_ 0 0 W COOH.M -CH COOH NMN-N,-CH 3 \\CH 3 2 2 3 0 IIN 1 HCOOH-NH 2_ -CH 2 COOH N 0 CH 3 N HCOOH:NH 2_ -CH 2 COOH 0 0 " 0 -N NCH CC-CH NB LCH COOH 2 2 2 ly 0 - Cont'd 74 GB 2 171697 A Table 28 (Contd) 0 0 NE 2- -CH 2 COOH 0 -N N 0 0 NH -CH COOH -N) CH 0COC (CH 2 3 22 \-./ 3 0 0 m -N NCE 2 COOH Nil 2- -CH 2 COOH 0 0 -N NCH CIT HCOOH.NH -CH COO 2 3 2- 2 0 0 -N H CH -HCOOH.NH -CH coo \_JC 2 3 2- 2 0 0 NCH CH HCOOH.NH -CH COOCH CH 3 2 3 2 2 2 Table 29,
N - CONH - S -7N 2 R N-- -C H 2 S j N CH 2 R OCH 3 0 1 COOR (syn-isomer) R R2 0 -CHOCOC(CH 3)3 -N NCH CH 1 2 3 I-rl 3 0 -CHOCOC(CH -N NCH 1 3)3 3 CH 3 - ContId - 74 Table' 29 (Contld) 0 a -CHOCOC(CH -N N-(CH) CH 1 3 3 2 4 3 CH -CHOCOC(CH 3) 3 -N N-(CH2)5CH3 3 0 -CHOCOC(CH 3) 3 N(CE 2)7 CH3 CH 3 0 -CHOCOC(CH 3)3 -N N(CH 2)11Cn 3 CH 3 0 0 -CH OCOC(CH -N NCH CH 2 3 3 2 3 0 0 -CHOCOOC(CH -N NCH CH 1 3 3 2 3 3 0. 0 N NCH CH 2 3 -(CH CH -N NCH CH 2 3 3 2 3 - Contld - GB 2 171 697 A 75 76 GB 2 171697 A Table 29 XCon:t'd) -CH C=C-CH \ 3 Y 0 v 0 0 -N NCH CH \=1 2 3 -Cif 0COC (CH) 2 1 3 3 H3 N 1 _t15 1 0 -CH 2 ocor, CCH 3)3 - C11 3 C_3 N- N 1 0 -CH 2 0COC (CH 3)3 0 EN 1 -N -CH 2 OCOC (CH 3)3 N -N 0 CE3 N i -N 0 -CHOCOC(CH 3)3 1 CR 3 -CH 2 0COC (CH 3)3 O- 0 - ' 0 -N N-1 V/ 0 Note: Hydrochloride Physical properties (m.p., IR and NIVIR spectra) of the above compounds were the same as those obtained in Examples 6, 7, 11 and 12.
76 Example 11 (1) In a mixed solvent of 37 mi of trifluoroacetic acid and 10.8 g of anisole was dissolved 7.29 g of diphenyimethyl 7-[2-(2-formamidothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4-ethyi -2,3-dioxo1,2,3,4-tetrahydropyrazinyi)lmethyi}-A3-cephem-4-carboxylate, and the resulting solution was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the resulting residue was added 50 mi of diethyl ether, and the 60 crystals were collected by filtration, wclshed sufficiently with 50 rril of diethyl ether and dried to obtain 5.2 g (yield, 92.4%) of 7-[2-(2-formamidothiazol-4-yi)-2-(syn)methoxyiminoacetamidol-3-{[1-(4-ethyi -2,3-dioxo1,2,3,4-tetrahydropyrazinyl)lmethyi}-A3-cephem-4-carboxylic acid having-a melting point of 155-158T (de comp.).
65IR(KBr)cm-,:-vc=01775,1710,1675,1640 77 5.21 (1 H, d, J = 5Hz, C,,-H), GB 2 171 697 A 77 NIVIR (dc,-DMSO) 8 values:
1.20 (3H, t, J=7Hz, NCH2CH3), 3.49 (2H, bs, C2-H), 3.73 (2H, q, J=7Hz, NCHCHJ, 3.91 (3H, s, -OCHJ, 4.42, 4.95 (2H, ABq, J=15Hz, S CH 2_ 5.89 (1 H, dd, J =t 5Hz, J =8Hz, C.M), 6.65 (2H, bs, IF-:K), H H li 7.46 (1 H, s, S:H) 0 8.59 (1 H, s, HCON W), 9.77 (1 H, d, J = 8Hz, -CON W), 12.58 (1 H, bs, HCOM-) ) 1 In a similar manner, the compounds shown in Table 30 were obtained.
Table 30
HCONH - j J1 $ N N C - CONH::;:-NT N CH R 0 2 COOH OCH 3 (syn-isomer) compound IR (KBr) PC) m. P.
R2 cm-1: Vc=o 0 0 195-198 1775, 1720, (decamp.) 1680-1640 -N N-CH 3 \==-/ 0 -N N- (CH 2)4 CH 3 122-125 1775, 1680, (decamp.) 1640 -N N-(CH) CH 165-170 1775, 1680, 2 5 3 (decamp.) 1640 0 q -N N 0 195-198 1775, 1685, \C=: (decamp.) 1650 0 -N N(CH CH 155-158 1780, 1720, -===/ 2 7 3 (decamp.) - 1680-1640 - Cont'd 78 GB 2 171 697 A 78 Table 30 (Cont'd) 0 0 144-147 1778, 1685, -N N-(CH CH (decomp.) 1660, 1645 2 11 3 CH 1 3 N 1 186-188 1775, 1710, -N (decomp.) 1690, 1650 0 CH 3 CH 3 - N 218-221 1775, 1670, -N (decomp.) 1650 0 (2) To a solution of 5.63 g of 7-[2-(2-formamidothiazol-4-yl)-2-(syn)- m6thoxyiminoacetamidol-3-1[1-(4ethyl-2,8-dioxo-1,2,3,4-tetrahydropyrazinyl)lmethyll-A3- cephem-4carboxylic acid in 25 ml of N,N-dime thylacetamide were added 1.52 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide with ice-cooling, and the resulting mixture was subjected to reaction for 30 minutes. After comple- 30 tion of the reaction, the reaction mixture was poured into a mixed solvent of 100 ml of water and 100 ml of ethyl acetate. Subsequently, the organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue was added 50 ml of diethyl ether, and the crystals were collected by filtration to obtain 5.5 g (yield, 79.6%) of 1-pivaloyloxyethyl 7-[2-(2-formamidothiazol-4-yl)-2- (syn)-methoxyiminoacetamido]-3-{[l(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)lmethyl}-A3-cephem-4carboxyl ic having a melting point of 140-1420C.
IR (KBr) cm-1: -vc=, 1780, 1740,1680, 1640 In a similar manner, the compounds shown in Table 31 were obtained. In this case, the compounds shown in Table 31 can also be obtained by the same method as in Example 6(1), except that the corre- 40 sponding esters were substituted for the diphenylmethyl esters.
Table 31
N C-CONH HCONH -s r 2 pla CH R OCH 3 COOR1 - (syn-isomer) Compound Rl R2 M.P. (,C) IR (KBr) cm- 1: v C=0 0 0 -CHOCOC(CH 3)3 m 1 -N N-CH 182-189 1780, 1740, 1680-1640 3 CH 3 (decomp.) -CHOCOC(CH 3)3 0 0 1 m CH 3 -N N(CH 2)4 CH 3 120-122 1783, 1740, 1680, 1640 (decomp.) - Contd - GB 2 171697 A 79 Table 31 (Contld) -CHOCOC(CH 3)3 1 CH 3 0 0 -h (CH 2)5 CH - 3 108-115 1782, 1740, 1680, 1640 -CHOCOC(C11 3)3 1 _n 3 0 0 m -N N (CH) CH 2 3 166-168 (decQmp.) 1780, 1740, 1680-1640 -CHOCOC(CH 3)3 O -122 1785, 1745, 1685, 1645 1 117 CH -N N CH 3 '(CH2) 11 3 0 0 CH 2 OCOC(CH 3)3 158-160 1780, 1742, 1680, 1640 -N N-CH CH 2 3 -CHOCOOCH2 CH 0 0 3 150-152 1780, 1760, 1680, 1640 CH -N NCH CH 3 1 2 3 1 0 0 0 -N N CH 160-162 1780, 1680-1630 CH2 3 0 0 CH 2)3 CH 3 m 136-141 1780, 1720, 1680, 1640 -N NCH CH (decornp.) 2 3 -C112,C -C\C113 0 0 165-168 1910, 1775, 1720, 1670, m 0 0 -N N-CII CH (decomp.) 1640 2 3 c 0 0 M 0 -CH OCOC(CH -N N 0 193-195 1775, 1745, 1685,1650 2 3 3 (decomp.) CH 3 -CH N 0COC(C11 3)3 2 1 138-140 1780, 1750, 1690, 1660 -N (decomp.) 0 CH 3 CH 3 CH 0COC(CH H 158-164 1780, 1740o 1680-1640 2 3 3 N -1 (decomp.) 0 Note: 1 Diastereomer GB 2 171697 A (3) To a solution of the 5.5 g of 1-pivaloyloxy-ethyl 7[2-(2formamidothiazol-4-yi)-2-(syn)-methoxyiminoacetamidol-3-f[l-(4-ethyl-2,3dioxo-1,2,3,4-tetrahydropyrazinyl)lmethyl}-A 3-cephem-4-carboxylate obtained in above (2) in 27.5 ml of methanol was added 1.13 ml of concentrated hydrochloric acid, and the resulting mixture was subjected to reaction at 350C for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue were added 50 ml of ethyl acetate and 50 ml of water, and the mixture was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. To the residue was added 45 ml of diethyl ether, and the crystals were collected by filtration to obtain 4.65 g (yield, 88. 1%) of 1-pivaloyloxyethyl 1() 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-f[l-(4ethyl-2,3 -dioxo-1,2,3,4-tetrahydropyrazinyl)jmethyl}-A3-cephem-4-carboxylate having a melting point of 1481500C. IR (KBr) cm-1: vc=,, 1780, 1740, 1680, 1640 NMR (dr,-DMSO) 8 values: 0.90-1.39 (12H, m, -C(CH3)3, >NCH2CH,,), 1.52 (311, d, J=5Hz, -OCHO-), 1 14 ' '3 3.52 (2H, bs, CrH), NCHCH 3.76 (211, q, J=7Hz, 3), 3.88 (3H, s, -OCH3), 4.38, 5.04 (2H, ABq, J=15Hz, S ICH 2 5.21 (1 H, d, J =5Hz, C,-H), 5.87 (111, dd, J=51Az, J=8Hz, C,-H), 6.61 (2H, bs,),=:), H H 6.78 (1 H, s, N) 1 35 S H 7.04 (1 H, q, J=5Hz, -OCHO-), 1 - - - - Uti, 40 7.22 (2H, bs, -NH2), 9.67 (1 H, d, J=8Hz, -CONW) In a similar manner, the compounds shown in Table 32 were obtained.
81 GB 2 171 697 A 81 Table 32
N 3_ C CON S H 2 W< 0 - S N -N 2 O ?- CH2-R "OCH 3 COOR 1 (syn-isomer) Compound IR Mr) (C) M.P. cm-1: V NMR (d 6-DMSO) 6 values:
Rl R2 C=O 0 0 198-201 1780, 1.19 (9H, s, -C(CH 3Y' -CHOCOC(CH Y_(decomp.) 1740, 1.54 (3H, d, J=5Hz, -OCHO-), 3 3 -N N-CH 1680 3 1 1 CH 3 1640 1 n 3 3.30 (3H, s,>N-CH 3), 3.54 (2H, bs, C2-H), 3.88 (3H,. s, -OCH 3)' 4.40, 5.06 (2H, ABq, J=lSHz, ), 5.24 (1H, d, J=5Hz, S CH 2 - C6 -H), 5.91 (lH,' dd, J=5Hz, J-8Hz, C 7 -H), 6.46, 6.60 (2H, ABq, J=6Hz, ≥;), 6. 80 UH, s, H H LN 7.07 (1H, q, J=5HZ, -CH-), SJCH I- CH 3 7.26 (2H, bs, -NH2), 9.74 (1H, d, J=BHz, -CONH-) 0.87 OH, t, J=7HZ, >N(CH 2)4 CH 3)' -CHOCOC(CH 139-141' 1783, 1.18 (9H, s, -C(CH3)3), 1.53 3 3 1 V (decomp.) 1740, U1 -N N-(CH CH 3 1680, (3H, d, J=5Hz, -CHO-), 3 2 4 1640 CH 3 1.04-1.85 (6H, M, >NCH2 (CH 2)3 CH 3)' 3.59 (2H, bs, C2_H), 3.72 (2H, t, J=7Hz, >NCH 2 (CH 2)3 CH 3)' 3.91 (3H, s, -OCH 3), 4.45, 5.08 (2H, ABq, J=lSHz, S )_CH 25.28 UH, d, J=5HZ, C 6-H) 5.92 (lH, dd, J=5Hz, J-8HZ, C7 -H), 6.65 (2H, bs, 6.85 (1H, s, 7.00 UH, q, J=5Hz, S H -OCHO- 9.82 (1H, d, J=8HZ, CH 3 -CONH-) - cont, a - 82 GB 2 171 697 A 82 -Table 32 (Cont'd) 0.87 (3H, t, J=7Hz, >N(CH 2)s CH 3)' -CHOCOC(CH 0 0 145-150 1780, 1.18 (9H, S, -C(CH)), ) 3 3 3 m - (decomp.) 1740, - 1.03-1.79 (8H, m,>NCH (CH) CH)r 3 1685, 2 1 3 CH 3 -N = N (CH 2) 5 CH3 2__4 1645 1.53 (3H, d, J=5fiz, OCHO-),_ CH 3 3.60 (2H, bs, C 2 H), 3.72 (2H, t, J=7Hz, >NCH 2 (CH 2) 4 CH 3 3.90 (3H, s, -OCH 3), 4.41, 5.09 (2H, ABq, J=15HZ, S ICH 2_ 5.25 (1H, d, J=5Hz, C 6 -H), 5.90 (1H, dd, J=SHz, J=M, C 7 -H), 6.63 (2H, bs, 6.82 (1H, st 1-), 6.98 (IH, q, J=SHz, S if.
-OCHO-), 9.75 (1H, d, J=M, 1 CH 3 -CONH-) CHOCOC(CH 3)3 0 0 170-172 1780, 0.88 OH t, J=BHZ,>N(CH 2)7 CH 3)' 1 -i< (decomp.) 1740,.
CH -N N (CH) CH 1680, 1.02-1.43 (21H, m, -C(CH 3 2 7 3 3 3' 1640 ::NCH 2 (CH 2)6CH 3), 1.56 (3H, d, J=SHz, -OCHO-), 3.38-3.83 (4H, 1 CH 3 M, > NCH 2 (CH 2)6 CH 3 ' C 2-H), 3.90 (3H, s, -OCH 3), 4.43, 5.11 (2H,_ 5.28 ABq, J=. 15Hz, S ICH 2_ (1H, d, J=5HZ, C CH) 5.94 (IH, dcl,-J=5.Hz, J=8Hz, C 7-fl), 6.65 (2H, bs,)=K), 6.83 (1H., s, H H N X), 7.02 (1H, q, J=5Hz, S H -OCHO-), 7.15 (2H, bs, -NH 2)' CH 3 9.70 (IH, d, J=SHZ, -CONH-) - ContId 13 GB 2 171697 A 83 Table 32 (Cont'd) -CHOCOC(CH 3)3 1 k-n 3 0 0 153-158 (CH) CH (decomp.) 2 11 1780, 1745, 1675, 1640 1780, 1740, 1675, 1640 0.86 OH, t, J=7Hz, >N(CH2)1P3)' 1.18 (9H, s, -C(CH 3)3)' 1 1.02-1.87 (20H, m, >XCH 2 (CH 2)10 CH 3), 1.52 OH, d, J=SHz, -OCHO-), 3. 53 (2H, bs, 1 CH3 c 2-H), 3.70 (2H, t, J=7Hz, >NCH (CH) CH) 3.87 OH, S, 2-, 2 10 3 ' - OCH 3), 4.38, 5.03 (2H, A13q, J=15Hz, S 5.20 (111, d, ICH 2J=5Hz, CCH), 5.85 (1H, dd, J=SHz, J=BHz, C 7 -H), 6.58 (2H, bs, >:<), 6.75 (1H, S, N icH H S H 7.01 (1H, q, J=5Hz, -OCHO- 1 CH 3 9.65 (1H, d, J=8HZ, -CONH-) -CH 2 OCOC. (CH 3)3 0 0 m -N N-CH 2 CH r_ 3 145-147 1.01-1.35 (12H, m, C(CH 3)3' > NCH 2CH 3), 3.47 (2H, hs, C2 -H), 3.70 (2H, q, J=7Hz,>NCH 2 CH 3)' 3.78 (3H, s' -OCH3), 4.30, 5.01 (2H, Atq, J=15HZ, S ICH 2- 5.14 (1H, d, J=SHz, C 6-11) ' 5.67- 6.06 (3H, M, -OCH 2 0-, c 7-B)' 6.55 (2H, bs, 6.70 (1H, H H NS, c) ' 7.12 (iH, bs, -NH 2)' S H 9.52(1H.cl.J=SHz.-CON11-1 -CHOCOOCH 2 CH 3 1 torl 3 0 0 -N --CH 2 CH 3 155-157 1780, 1760, 1680, 1640 1.23 (6H, t, J=7Hz, >NCH 2 CH 3' -OCH 2 CH 3), 1.55 (3H, d, J=SHz, -OCHO- ), 3.53 (2H, bs, C 2 -H), 1 CH 3 3.76 (2H, q, J=7Hz, >NCH 2 CH 3)' 3.86 (3H, sp -OCH 3), 4.19 (2H, g, J=7Hz, -OCH 2 CH 3), 4.40, 5.05 (2H, ABq, J=15Hz, S 1H 2- - Cont 1 d - 84 GB 2 171 697 A Table 32 (Cont'd) 5.21 (1H, d, J=5Hz, C CH)' 5.86 (1H, dd, J=5Hz, J=M, C 7-H), 6.52, 6.65 (2H, ABq, J=6Hz, N ≥<), 6. 7 4 (1H, 5,!)C-), H H S H 6.87 (1H, q, J=SHZ, -OCHO-), CH 3 7.02 (2H, bs, -NH 2), 9.65 (1H, d, J=8Hz, -CONH-) 1 1 0 84 2 0 0 -NMCH CH 2 3 >200 1780 ' 1680 ' 1640 1.21 OH, t, J=7Hz,>NCH 2 CH 3)r 3.67(2H, bs, C 2 -H), 3.81 (2H, t, J=7Hz, >NCH 2 CH 3), 3.99 (3H, s-, S -OCH 3), 4.17-5.13 (SH, M,1 CH7-, 1 -NHO-), 5 22 (1H, d, J=SHZ, C H), 3 '1 6- 5.83 (1H, dd, J=SHz, J=M, C 7 -H), 6.95, 6.77 (2H, ABq, J=7Hz,)=<), 6. 95 (0. SH, S, E Ai N - N "C), X7), 7.00 (0.5H, S,, S ff S h 9.87 (1H, d, J=8Hz, -CONH-) 0.63-1.95 (10H, m, - -COOCH 2 CH 2 CH 2 CH 3' >NCH 2 CH 3)' 0 0 139-144 1780, - (decomp.) 1720, 3.55 (2H, bs, C 2 -H), 3.76 (2Hy -(CH CH -N NCH CH 1680, 2)3 3 2 3 1640 q, J=7Hz,>NCH 2 CH 3), 3.89 (3H, S, -OCH 3), 4.30 (2H, t, J=7Hz, -COOCH 2 CH 2 CH 2 CH 3), 4.39, 5.12 (2H, ABq, J=15Hz, S ICH 2 5.25 (1H, d, J=SHZ, C 6 H), 5.92 UR, dcl, J=SHZ, J=8HZ, C 7-H), 6.68 (2H, bsi), 6.82 (1H, H H 5, 7.28 (2H, bs, -NV' S H 9.79 (1H,d, J=M, CONH-) Contd - GB 2 171 697 A 85 Table 32 (Cont'd) 1.19 OH, t, J=7HZ,>-NCH2 CH 3)' 2.20 (3H, s, -C=C-CH), 3.53 1 1 2 -CH 2 C=CCH 3 0 0 173-175 1820 (2H, bs, C H), 3.73 (2H, q, 1780, 2 (decomp.) 0 0 -N N-CH CH 1730, J=7Hz,>NCH 2 CH3), 3.84 (3H, s, 2 3 1680, C 1640 -OCH 3), 4.34, 5.06 (2H, ABq, 11 0 ), 5.09-5.30 J=15Hz, S 1 CH2- OH, m.'CCR, -OCH,9=), 5.87 (1H, dd, J=SHz, J=8Hz, C 7 -H), 6.59 (2H, bs, '=<), 6.74 (1H, H H S, 1), 7.17 (2 H, bs, -NH 2) S, H 9.62 (111, d, J=8.Hz, -CONH-) 1.24 (9H, s, -C(CH 3)3), 2.31 (3H, CH 3 s, -CH 3), 3.40 (2H, bs, C2-H).
CH OCOC(CH N 141-142 1775, _3.99 (3H, S' -OCH3), 5.01, 5.33 3)3 2 1 (decomp.) 1740, -N 1650 (2H, ABq, J=15Hz, S 0 ICH 2- 5.09 (IH, d, J=SHz, C 6 -H), 5.61-6.14 OH, m, -OCH 2 0-, C 7 -H), 6.71 (2H, bs, -NH2), 6.77 (1H, s, N X-), 6.86, 11 7.24 (2H, ABq, J=10Hz, 9.34 (1H, d, J=8HZ, -CONH-) 1.19 (9H, S, -C(CH 3)3), 2.27 (6H, CH S, CH), 3.35 (2H, bs, C -H), CH 3 3 f, 3 2 -CH 2 OCOC(CH 3)3 i- 156-159 1775, CH 3 N (decomp.) 1740, N 1670 3.86 (3H, s, -OCH 3), 5.02, 5.40 1640 (2H, ABq, J=15Hz, S 1 CH 2- 5.20 (1H, d, J=5HZ, C 6 -H), 5.70 6.14 (3H, M' C7 -H, -OCH 2 o-), 6.81 (1H, s, N 7.26 (2H, S H m, -NH 2)l 7. 98 (1H, s, '5-H) - cont,d - 86 GB 2 171 697 A 86- Table 32 (ContId) -CH 2 OCOC(CH 3) 3 0 HN 1 N 0 151-153 (decomp.) 1780,. n45, 11660 1.17 OH, s, -C(CH 3) 3), 3.43 (4H, bs, C -R, -NH), 3.85 2 2 OH, S, -OCH 3), 4.75, 5.01 (2H, ABq, J=15HZ, S ICH 2-), 5.16 (1H, d, J=5HZ, C CH)' 5.60-6.08 (3H, M, C 7-H' -OC112 0-), 6.77 (1H, N JE-)l 6.89# 7.12 (2H, S H ABq, J=10Hz, H), 9.62 (1H, InH' d, J-8Hz, -CONH-) 3 -CH 2 OCOC(CH 3)3 f N -N Q 134-137 (decomp.) 1780, 1750, 1680 1650 1. 24 (9H, s, -C (CH 3) 3), 3.53 (2H, bs, C 2 -H), 4.06 'M, s, -OCH 3)' 4. 70, 5.35 (2F ABq, J=15HZ, S 5.2 (1H,.d, J=SHz, ICH 2C CH),, 5.98-6.48 (SH, m, -OCH 20_# C-7-H, -NH 2 6.88 (1H,.5, N) 7 54 7.70 (2H, u 1 - 1 S H ABq, J=SHz, 8.33 (1H, s H ->-H), 8.59 (1H, d, J=BHz, -CONH_) (measured in CDC1,1) 1 1 3 -CHOCOC(CH 3)3. 1 CH 3 CH 3 N 1 -N 143-145 (decomp.) 1780, 1740,. 1655 1.1Q (9H, s, -C(CH 3)3), 1.53 OH, d, J=6Hz, -OCHO-), 2.28 (3H, s, 1 CH 3 7CH), 3:,47 (4H, bs, (2-9, - 3 -NH 2 1, 3.89 OH, S, -OCII 3), 4.91, 5.29 (2H, ABq, J=15HZ, S ICH 2- 5.22 (1H, d, J=SHz, CCH)' 5.88 (IH, dd, J=5Hi, J=BHz, C 7 -H 6.92 (1H, s, N3E) S H 6.93, 7.41 (2H, ABq, J=10HZ, - Cont' d - 87 Table 31 (Cont!d) GB 2 171 697 A 87 6.96 (1H,' q, J=6HZ, -OCHO-), CH 3 9.74 (111, a, J=8Hz, -CONH-) 1.21 (9H, S, -C(CH 3)3' 3.65 (2H, bs, C2-H), 3.93 (3H, s, -OCH 3), 0 0 4.44, 5.14 (2H, ABq, J=15Hz, 0 -CH 2 OCOC(CH 3)3 -N-0 154-160 1775, S 5.28 (1H, d, J=5HZ, (decomp.) 1750, CH2 1700, 1650 C 6-H)' 5.78-6.76 (5H, m, C 7-H' -OCH2 0-, 6.89 (1H, s, N ]E-) -_7. 36 (2H, bs, NH -) 2 S H H (SH, m, "k), 7.72-8.27 9.91 (1H, d, J=BHz, -CONH-) Note: 1 Diastereomer 2 Hydrochloride (The salt was prepared in a conventional manner.) 3 The Objective compound was produced by reacting trifluoroac etic acid salt with a halide in the presence of.1,8-diazabicyclo[5,4,0]-7-undecene at -5-0C.
(4) To a solution of 1.05 g of the 7-[2-(2-formamido-thiazol-4-yi)-2(syn)-methoxyiminoacetamidol-3-{[1- 35 (2,3-d i methyl -6-oxo-1,6-di hyd ropyrazi nyi)l methyl}-A3-cephem-4-ca rboxyi ic acid obtained in above (1) in 10 m] of methanol was added 0.38 mi of concentrated hydrochloric acid, and the resulting mixture was sub jected to reaction at 350 for 2 hours. After completion of the reaction, the solvent was removed by distil lation under reduced pressure. To the residue was added 10 m[ of diethyl ether, and the crystals were collected by filtration to obtain 0.43 g (yield, 84.8%) of hydrochloride of 7-[2-(2-arriinothiazol-4-yi)-2-(syn)methoxyiminoacetamdo]-3-{[1-(2,3-dimethyi-6-oxo-1,6dihydropyrazinyi)lmethyi}-A3-cephem-4-carboxylic acid having a melting point of 25WIC or more.
IR(KBr) cm-l: vc=, 1765, 1660, 1620 NMR(d,-DMSO) 8 values:
2.20 (6H, bs, -CH, x 2), 3.18 (2H, bs, C2-H), 3.90 (3H, s, -OCH), S 4.94, 5.24 (2H, ABq, J = 1 5Hz, --- C H 2_ 505.10 (1 H, cl, J = 5Hz, C,-H), 5.78 (1 H, dd, J=5Hz, J =8Hz, C7-H), 6.89 (1 H, S, N 1,-H) ' S - 7.82 (1 H, s, 'l-H), 9.79 (1 H, dd, J=8Hz, -CONW) Example 12 (1) In a similar manner to that in E ' xample 7-0), the compounds shown in Table 33 were obtained from 60 the starting materials shown below.
88 GB 2 171697 A - 88 - C-COOH J 11 3C H N OCH 2 COOR.
(Ctarting material, syn-4!omer) C NN2 0 N N 0, N, CH2 \==/ -CH2CH3 COOCH Q)) 2 S 0 N-P-CONH r_ 1 J J 95) 3CN- 7EN1 CH N._N-CH CH 15- H S 2 2 3 (objec - tive coMpoUndo syn-isomer) OCII 2 COOR 1 OOCH (9) 2 TABLE 33 20
Objective compound IR (KBr) M.P. (QC) cm- 1: V R1 C=O_ 127-136 1780, 1720, (decomp.
1685, 1645 127-130, 1780, 1720,- (decomp;) 1685, 1635 E 150-152 1.780, 1720, _CH CH (decomp.) 2 3 1680, 1645 (2) The compounds shown in Table 34 were obtained by reacting the above- mentioned compounds in a 40 similar manner as in Example 7-(2).
Table 34
N C CONH S a 0 HCOOH-H N- If- c 2 S N 2\== 23 -N-CH N N-CH CH 1 COOH OCH2COOR (syn-isomer) Compound IR (KBr).
Rl M.P. CC) cm71: vc=o -DMSO) 6 values:
NMR (d 6 50 1.25 (3H, t, J=7Hz, >NCH 2CH3)l 3.50 (2H, bs, C 2 -H), 3.76 (2H, 123-125 1770,), 5.03 (2H, - 1680, q, J=7Hz,>NCH 2CH (decomp.) 3 1670, a, -OCH 2 CO-), 4.50-5.00 (2H,-m, 55 1630 ), 5.20 (1H, d, J=SHz, SICH 2_ c -H), 5.90 (1H, dd, J=5Hz, J.911z, 6 60 C7-H), 6.70 (2H, 6.98 (1H,, 7.3 0 (SH, bs, Cont'd 65 89 GB 2 171 697 A 89 Table 34 (Contld) L_ "t,2u -CH 2 CH 3 125-128 (decomp.) 122-123 (decomp.) 1770, 1680, 1670, 1635 1770, 1720 ' 1670, 1640 8.27-(1H, 5, HCOOH), 9.80 (1H, d, J=9Hz, -CONH-) i 1.25 OH, t, J=7Hz, >NCH 2 CH 3 2.00 (2H, m, H), 2.80 (4H, M, EX -H H H 3.50 (2H, bs, C 2 -H), 3.75 (2H, q, J=7Hz, >NCH 2 CH 3)' 5.00 (2H, 5, -OCH 2 CO-), 4.50-5.00 (2H, m, S ICH 2_), 5.25-(1H, d, J=5HZ, C CH)' 5-95 (1H, dd, J=5HZ, J=9HZ, C 7-H), 6.70 (2H, s, r=), 6.96 (1H, S, h ii 7. 30 OH, m, H H H N-) 1 1 _ S H ) 1 8.27 (1H, S, HCOOH), 9.80 (1H, d, J=9Hz, -CONH-) 1.22 (6H, t, J=7Hz, \,NCH 2 CH 3' -OCH 2 CH 3 3.51 (2H, bs, C 2 -H) 3.76 (2H,.. q, J--7Hz, NCH 2 CH 3)' 4.18 (2H, q, J=7Hz, -OCH2 CH 3)' 4.77 (2H, S, -OCH 2 CO-), 4.50-5.00 (2H, m, S JCH 2_), 5.24 (1H, d, J=5BZ' C6 -H), 5.91 (IH, dd, J=SHz, J=9Hz, C7- H), 6.69 (2H, S, ), 6.96 (1H, s, N H H SXH.
8.27 (1H, s, HCOOH), 9.84 (1H, d, J=9Hz, -CONH-) Example 13 (1) To a solution of 2.72 g of 2-(2-tert.-amyioxy-carboxamidothlazol-4- yl)acetic acid in 40 mI of anhy drous methylene chloride was added 1.06 9 of N-methyimorpholine, and the mixture was cooled to -WC. Subsequently, 1.12 9 of ethyl chlorocarbonate was added thereto, and the mixture was subjected to reaction at -3,50 to -250C for 1.5 hours, after which 5.18 9 of diphenyimethyl 7-amino-34[1-(4-ethyi 2,3-dioxo-1,2,.3,4-tetra hydro pyrazi nyi)l-methyi}-A3-cephem-4-carboxyl ate was added thereto, and the mix-65 GB 2 171697 A ture was subjected to reaction at -30' to -2M for 1 hour and then at -10' to WC for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 40 mi of ethyl acetate and 30 mi of water. The organic layer was separated, and 30 mi of water was added again thereto. The mixture was adjusted to pH 7.0 with sodium hydrogencarbonate with ice-cooling. The organic layer was separated, washed with 30 m[ of water and 30 mi of a saturated aqueous-sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue was added 35 m[ of diethyl ether, and the crystals were collected by filtration to obtain 3.62 g (yield, 90.5%) of diphenyimethyl 7-[2(2-tert.amyioxycarboxamidothiazol-4-yi)acetamido]-3-{[1-(4-ethyi-2,3-di oxo-1,2,3, 4-tetrahydropyra10 zinyllmethyi}-A3-cephem-4-carboxylate having a melting point of 152-154pc (decomp.). IR (KBr) cm-1.. v,=0 1780, 1720, 1685, 1640 In a similar manner, the following compound was obtained: 6.15 g (yield, 82.7%) of diphenyimethyl 7[2-(2-tert.-amyioxycarboxamidothiazol-4yl)acetamidol-3-{[1-(3,6-dioxo-1,2, 3,6-tetrahydropyridazinyi)methyi}-A3cephem-4-carboxylate, m.p.: 136-139'C (decomp.) [R (KBr) cm-l: vc =,, 1780, 1720, 1665 (2) The compounds shown in Table 35 were obtained by subjecting the compounds obtained in above (1) to reaction in the same manner as in Example 6-(3).
Table 35
CF 3 COOH.H 2 N N_Ca 2 CONH 5 2 S.: ?- CH 2 R COOH Compound IR (KBr) M.P. (.C) NMR (d -DMSO) 6 values X2 cm-l: V C=0 6 1.20 (3H, t, J=7Hz, 'NCH 2CH), 3.50 (2H, 3 109-115 1775, bs' C2-H), 3.61-3.81 (4H, m,,NCH2CH 3' (decomp.) 1690, -N R-CH 2C1T3 1630 N-F CH 2_), 4 47, S.17 (2Hr ABq, J=15HZ, S.' S I-CH 5.21 (1H, d, J=SHZ, C CH)' 5.60-6.02 OH, m, C -He.5) 6.81 (1H, 7 H H s, N), 9.24 (1H, d, J=SHz, -CONH-) JH 3.43 (2H, bs, C2H) 3.67 (2H, bSt N CH 2_)e 0 HN >200- 1770, S 1 1710, 5.08 (2H, bs, 5.16 (JH,-d, J=5HZ, 1670,;CH - -N - 1630 2 0 Jr=Slfz, J=8HZ, C7 -H), C6 -H), 5.78 (1H, dd, N 6.76 (1H, S, N;-), 7.01, 7.14 (2H, ABq, S H H n J=10Hz,:CnH 9.29 (IH, d, J=M, -CONH-) Example 14
In 48 ml of N,N-dimethylacetamide were dissolved 6.82 g of diphenylmethyl 7-(4-bromo-3-oxobutyramido)-34[1-(4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazi nyl)lmethyl}-A3-cephem-4-carboxylate and 1 g of thiourea, and the mixture was subjected to reaction at room temperature for 2 hours. After completion of 65 the reaction, the reaction mixture was poured into a mixed solvent of 500 ml of water and.500 ml of 25, -50 55- 60.
91 GB 2 171 697 A 91 ethyl acetate, and the mixture was adjusted to pH 6.7 with sodium hydrogencarbonate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was removed by dis tillation under reduced pressure. Subsequently, the residue was dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole, and the mixture was subjected to reaction at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the resi- 5 due was added 40 ml of diethyl ether, and the crystals were collected by filtration to obtain 4.50 g (yield, 74.1%) of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4yl)acetamidol-3-1[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyll-A3-cephem-4-carboxylic acid having a melting point of 109-1150C (dec.).
In a similar manner, the following compound was obtained: Trifluoroacetic acid salt of 7-[2-(2-amino thiazol-4-yl)acetamidol-3-1[1-(3,6-dioxo-1,2,3,6tetrahydropyridazinyl)lmeth yl}-A3,cephem-4-carboxylic acid, 10 m.p.: 200'C or more.
Physical properties (IR, NMR values) of this compound were identical with those in Example 13-(2).
Preparation Example 1 An aqueous sodium salt solution of 7-[2-(2-aminothiazol-4-yi)-2-(syn)- methoxyiminoacetamidol-3-{[1-(2,3-dioxo-l,2,3,4-tetrahydropyrazinyi)lmethyi}-Aacep hem-4-carboxylic acid was treated in a conventional -manner to obtain a freeze-dried and sterilized sodium salt. One gram (potency) of the sodium salt was dissolved in 20 mi of physiological saline solution to obtain an injection.
Preparation Example 2 One gram (potency) of the freeze-dried product obtained in Preparation Example 1 was dissolved in 4 mi of 0.5% (W/V) aqueous lidocaine hydrochloride solution to obtain a dilutable injection.
Preparation Example 3 25 One gram (potency) of the freeze-dried product obtained in Preparation Example 1 was dissolved in 20 25 mi of 5% glucose solution to obtain an injection. Moreover, the other compounds of the formula [11 can also be formed into the corresponding freeze_dried products (sodium salts) or injections by processing them in the same manner as in Preparation Examples 1 to 3.

Claims (24)

1. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid represented by the following formula or a salt thereof:
4 3 S R' 1- 40 wherein R' represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of the formula: 0 0 61 7 0 10 51 R R q 45 -N N-R R -N N Or -N 11 RR 50 R N 1 -N R 5 0 in which R5 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocar -60 bamoyl group, a sulfamoyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cy- 60 cloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsul fonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylearbamoyl, alkylthiocarbamoyl,, dialkyl thiocarbarnoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbarnoyl, aryisulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocar- 65 92 GB 2 171697 A bonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group or a group of the formula, 92 R's -N - 5 \ R's - (each of R's and R161which may be the same or different, represents a hydrogen atom or an alkyl group - or R and R together with their adjacent nitrogen atom may from a_ ring); each - of R6, R7, R8, R9, Rio, 1311, R13 10 and R14, which may be the same or different, represents a hydrogen atom, a halogen atom or a substituted or unsubstituted alkVI, aralkyl or aryl group; R12 represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl group, a thiocarbarnoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthlocarbamoyl, dialkylthiocarbarnoyl, acylcarbamoyl, acylthiocarbarnoyl, alkylsul- fony[carbamoyl, aryisulfonylcarbamoyl, alkylsulfonyltbiocarbarnoyl or arylsulfonylthiocarbarnoyl group; R3 represents a hydrogen atom or an alkoxy group; R represents an amino group,- a group of the formula, R7 ""\ C=C-NH 1 R8 RI.9 in which each of R17, RI8 and R19, which may be the same or different, represents a hydrogen atom or an organic residue or a group of the formula, R20 I\\ C=W 30 1..1, R21 in which each of R20 and R21, which may be the same or different, represen - ts a hydrogen atom or an 35 organic residue.
2. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 1, wherein R3 is a hydrogen atom.
3. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 2, wherein R4 is an amino group.
4. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 3, wherein R2 is a group of the formula, 0 d - - \v - -N N-R.. 45 \=i - in which R5 has the same meaning as defined in Claim 1.
5. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 4, wherein R5 is a hydrogen atom, a heterocyclic group or a substituted or 50 unsubstituted alkVI, aralkVI or cycloalkyl group or a group of the formula, R15 -N., - R's in which R's and R16 have the same meanings as defined in Claim 1,
6. A 74substituted or unsubstituted amino)-3-substituted methyl-A3-cephem- 4-carboxylic acid or a 60 salt thereof according to Claim 5, wherein R5 is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl group which may optionally be substituted by an. alkanoyloxy or_ a carboxyl group or a group of the formula, J 1 93 GB 2 171697 A 93 -C=C-R 1 0 v 0 0 (wherein R30 represents a lower alkyl group).
7. A 7-(substituted or unsubstituted amino)-3-substituted methyl -A3cephem-4-ca rboxyl ic acid or a salt thereof according to Claim 4, wherein Rs is a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl or cycloalkyl group or a group of the formula, -N \ R15 R 16 - 15 in which Rs and R16 have the same meanings as defined in Claim 1.
8. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 7, wherein Rs is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl group which may optionally be substituted by acyloxy.
9. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt 20 thereof according to Claim 3, wherein R2 is a group of the formula, 4 -r R -R- - N N -AR' 0 in which R6, R7 and R8 have the same meanings as defined in Claim 1.
10. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a 30 salt thereof according to Claim 9, wherein each of R6, R7 and R8, which may be the same or different, is a hydrogen atom or an alkyl group.
11. A7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 3, wherein R2 is a group of the formula, q 0 to - R -N R 1 1 11 - N \R r 0 in which Rg, RIO and W, have the same meanings as defined in Claim 1.
12. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 11, wherein each of R9, Rio and R", which may be the same of different, is 45 a hydrogen atom, a halogen atom or an alkyl group.
13. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 3, wherein R2 is a group of the formula, - R' ka N R 1 Id' -N R 0 in which R12, R13 and R14 have the same meanings as defined in Claim 1.
14. A 7-(substituted or unsubstituted amino)-3-substituted methyl-A3cephem-4-carboxylic acid or a salt thereof according to Claim 13 wherein each of R12, R13 and R14, which may be the same of different, is 60 a hydrogen atom or an alkyl group.
15. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem4-carboxylic acid represented by the following formula or a salt thereof:
1 94 GB 2 171 697 A 94 + R 3 R S -CH 2 R 2 0OR1 wherein R' represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of the formula:
6. rt" - in- 0 0 R P. 0 -N N-I \\e': 1 '-N R -N R 0 R- -N - 0 R or ]C t.-:1 R 1,4 - -N - 1 R 0 in which R5 represents a hydrogen atom, a hydroxyl group,.a nitro group, a -carbamoyl groupI a thiocar bamoyl group, a sulfamoyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cy cloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxyl alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkylOXYGarbonyli alkylsulfonyl, cycloalkylsul- 201 fonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoYl, alkylthiocarbamoyl, dialkyl thlocarbamoyl, acylcarbamoyl, acylthiocarbarnoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbarnoyl, aryisulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocar bonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group, or a group of the formula, -N/ RI5 R16 (each of RI5 and RirI which may be the same or different, represents a hydrogen atom or an alkyl group, or RI5 and 1316 together with their adjacent nitrogen atom may from a ring); each of R6 ' R7, R8, R9, Rio, Rii, R13 and R14, which may be the same or different, represents a hydrogen atom, a halogen atom or a sub stituted or unsubstituted alkyl, aralkyl or aryl group; R12 represents a hydrogen atom, a halogen atom, a 35 carboxyl group, a-sulfo group, a carbamoyl group, a thiocarbarnoyl group, or a substituted or unsubsti tuted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbarnoyl, dialkVIthiocarbamoyl, acylcarbamoyl, acylthiocarbarnoyl, alkylsul fonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbarnoyl or arylsulfonylthiocarbamoyl group; 40, R3 represents a hydrogen atom or an alkoxy group; R4 represents an amino group, a group of the for mula, R17 "I C=C-NW 1 1. h 1.
in which each of R17, R's and Rig, which may be the same or different, represents a hydrogen atom or an 50 organic residue not participating in the reaction or a group of the formula, R20 R21 I C=W 1.11 in which each of R20 and R21, which may be the same or different, represents a hydrogen atom or -an organic residue not participating in the reaction, which comprises reacting a cephalosporanic acid repre60 sented by the following formula, or a salt thereof - 50 GB 2 171 697 A g? 3 z 0 2 1 R' coo wherein W, 133 and R4 have the same meanings as defined above; Rrepresents a substituted or unsub- stituted acyloxy or carbamoylo.XY group; and Z represents S or S-0, with a compound of the 10 formula z T R 0 0 R;N HIMR R 0 [G R 13 91., R 1 R N--l R -N is or.. 1,7 1 1 1 1 -R HN rR HN - - 1 il.
0 in which R5, Re, R7, Re, R9, RIO, RII, R12, R13 and R14 have the same meanings as defined above or a salt 20 thereof in the presence of an acid or a complex compound of the acid and then, if desired, converting the reaction product 42-cephern compounds to 43-cephem compounds, removing the protecting group, pro tecting the carboxyl group or convert ' ing the product to a salt thereof.
16. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem 4-carboxylic acid or a salt thereof according to Claim 15, wherein R3 is a hydrogen atom.
17. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem 4-carboxylic acid or a salt thereof according to Claim 16, wherein said acid or complex compound of acid is a Lewis acid or a complex compound of a Lewis acid.
18. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-,L3-cephem 4-carboxylic acid or a salt thereof according to Claim 17, wherein said Lewis acid or the complex compound of the Lewis acid is boron trifluoride or a complex compound thereof.
19. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem 4-carboxylic acid or a salt thereof according to any one of Claims 15 to 18, wherein the reaction is ef fected in the presence of an organic solvent.
20. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem- 35 4-carboxylic acid or a salt thereof according to Claim 19, wherein said organic solvent is an organic car boxylic acid, an ester, a nitroalkane or a sulfolane.
21. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem 4-carboxylic acid or a salt thereof according to any one of Claims 15 to 20 wherein R34 is an axetoxy group.
22. A process for producing a 7-(substituted or unsubstituted amino)-3substituted methyl-A3-cephem 4-carboxylic acid or a salt thereof according to any one of Claims 15 to 21 wherein the reaction is ef fected at a temperature of OC to 800C.
23. A process according to Claim 15 and substantially as hereinbefore set forth with reference to the foregoing Examples.
24. A carboxylic acid derivative according to Claim 1 and substantially as hereinbefore set forth with reference to- the foregoing Examples.
Printed In the UK for HMSO, D8816935, 7186, 7102.
Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.
GB08603333A 1982-11-17 1983-11-16 7-amino-cephem intermediates Expired GB2171697B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP57200382A JPS5993085A (en) 1982-11-17 1982-11-17 Novel cephalosporin compound
JP58067871A JPS59193893A (en) 1983-04-19 1983-04-19 Novel cephalosporins
JP58199945A JPS6092293A (en) 1983-10-27 1983-10-27 Novel cephalosporin compound

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GB8603333D0 GB8603333D0 (en) 1986-03-19
GB2171697A true GB2171697A (en) 1986-09-03
GB2171697B GB2171697B (en) 1987-07-01

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JPS6064986A (en) * 1983-09-20 1985-04-13 Toyama Chem Co Ltd Production of cephalosporin
AT397086B (en) * 1984-05-25 1994-01-25 Toyama Chemical Co Ltd Process for the preparation of novel 2-(2-aminothiazol-4- yl)-2-(syn)-alkoxyiminoacetamides
GB2161476B (en) * 1984-05-25 1988-01-27 Toyama Chemical Co Ltd 2-aminothiazolyl-2-methoxyimino acetamides and their use in preparing cephalosporins

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JPS53119885A (en) * 1977-03-29 1978-10-19 Takeda Chem Ind Ltd Cephalosporin derivatives
DE2714880A1 (en) * 1977-04-02 1978-10-26 Hoechst Ag CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
JPS5492986A (en) * 1977-12-28 1979-07-23 Takeda Chem Ind Ltd Cephalosporin derivative
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FR2536074A1 (en) 1984-05-18
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ES8607320A1 (en) 1986-05-16
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FI75827B (en) 1988-04-29
NL8303955A (en) 1984-06-18
NL192792C (en) 1998-02-03
DK521883D0 (en) 1983-11-15
DK521883A (en) 1984-05-18
ES8607321A1 (en) 1986-05-16
CA1276139C (en) 1990-11-13
AU565648B2 (en) 1987-09-24
FI834183A (en) 1984-05-18
CA1253486A (en) 1989-05-02
BE898249A (en) 1984-05-17
AU549861B2 (en) 1986-02-20
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DE3341591A1 (en) 1984-05-17
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AU4742185A (en) 1986-01-02
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KR870000611B1 (en) 1987-03-25
GB8603333D0 (en) 1986-03-19
ES527333A0 (en) 1985-12-01
GB8330599D0 (en) 1983-12-21
GB2131800A (en) 1984-06-27
GB2131800B (en) 1986-07-09
ES8602815A1 (en) 1985-12-01
AU2142983A (en) 1985-05-23
DE3347928C2 (en) 1993-05-06
DE3341591C2 (en) 1988-04-07
CH657135A5 (en) 1986-08-15
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ES544723A0 (en) 1986-05-16
FR2536074B1 (en) 1986-09-05

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