CA1136138A - Cephalosporin analogs and methods for production thereof - Google Patents
Cephalosporin analogs and methods for production thereofInfo
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- CA1136138A CA1136138A CA000342597A CA342597A CA1136138A CA 1136138 A CA1136138 A CA 1136138A CA 000342597 A CA000342597 A CA 000342597A CA 342597 A CA342597 A CA 342597A CA 1136138 A CA1136138 A CA 1136138A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
- C07D463/16—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
- C07D463/16—Nitrogen atoms
- C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
- C07D463/16—Nitrogen atoms
- C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D463/22—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by nitrogen 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)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to a cephalo-sporin analog of the formula:
wherein X represents an amino group, an azido group or a protected amino group, Hal represents a halogen atom and R represents a carboxyl group or a protected carboxyl group, and the salts thereof.
These compounds are useful intermediates in the preparation of highly active cephalosporin derivatives.
The present invention relates to a cephalo-sporin analog of the formula:
wherein X represents an amino group, an azido group or a protected amino group, Hal represents a halogen atom and R represents a carboxyl group or a protected carboxyl group, and the salts thereof.
These compounds are useful intermediates in the preparation of highly active cephalosporin derivatives.
Description
~136138 TITLE OF THE INVENTIO~
CEPHALOSPORIN ANALOGS AND METHODS
FOR PRODUCTION TffEREOF
Background of the Invention -The present invention relates to novel cephalo-sporin analogs and more specifically to new carbacephem compounds which differ from the cephalosporins by having a carbon atom instead of a sulphur atom in the dihydrothiazine ring. In the Journal of the American Chemical Society, 96, 7584 (1974) and J. Med. Chem., 20, 551 (1977) certain carba-cephems with substituted methyl groups at the C-3 position such as (+)-l-carbacephalotin represented by the formula:
O
N ~ ~2 H ~ N ~ Ac COO~
are disclosed as having antibacterial activity. In addition some compounds which are encompassed in the definition of the present carbacephem compounds hereinafter described are named
CEPHALOSPORIN ANALOGS AND METHODS
FOR PRODUCTION TffEREOF
Background of the Invention -The present invention relates to novel cephalo-sporin analogs and more specifically to new carbacephem compounds which differ from the cephalosporins by having a carbon atom instead of a sulphur atom in the dihydrothiazine ring. In the Journal of the American Chemical Society, 96, 7584 (1974) and J. Med. Chem., 20, 551 (1977) certain carba-cephems with substituted methyl groups at the C-3 position such as (+)-l-carbacephalotin represented by the formula:
O
N ~ ~2 H ~ N ~ Ac COO~
are disclosed as having antibacterial activity. In addition some compounds which are encompassed in the definition of the present carbacephem compounds hereinafter described are named
2~ as starting materials in U.S. Patent No. 4,123,~23 issued Octo~er 31, 1378. There is, however, no physical ~ata re-garding these compounds given in this patent. Neverthe-113~i138 less as microorganism populations develop immunity toexisting antibiotics new antibacterial compounds are in demand. To this end, novel carbacephems with a hydrogen atom at the C-3 position have been synthesized which are useful as intermediates in the preparation of unexpect-edly high antibacterial compounds, and such compounds as well as methods for synthesis thereof are disclosed in German Offenlegungsschrift Nos. 2911786 and 2911787/1979.
It has now been found that novel carbacephems with a halogen atom at the C-3 position may be synthe-sized which are also useful as intermediates in the preparation of unexpectedly high antibacterial compounds.
Summary of the Invention In accordance with the present invention, novel carbacephem compounds, i.e. cephalosporin analogs, are synthesized. The numbering system shown in the following formula is used hereinafter.
Broadly, the present invention relates to cephalosporin analogs xepresented by the formula ~ ~:
H H
X~
0~ l\~Ha 1 wherein X represents an amino group, an azido group or a protected amino group, Hal represents a halogen atom and R represents a carboxyl group or a protected car~oxyl group. (Hereinafter compounds represented by the fore-going formula are sometimes referred to as Compound ~ ~.
This also applies to other foxmulae).
~escription of the Invention ~ore specifically, the present invention relates to novel cephalosporin analogs represented by the general formula ~- ~:
~2N~
~ N ~ Hal ~~ ~
wherein Hal and R have the same meaning as defined above; and also compounds represented by the general formula ~ - ~:
Xl~
~ N ~ Hal ~~ ~
wherein Xl represents an azido group or a protected amino group and Hal and R have the same meaning as defined above; and the salts thereof.
As the protecting groups for the "protected amino group" in X or Xl, a phthaloyl group, t-butyloxy-carbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2,2,2-trifluoroethyloxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyl-oxycarbonyl group, phenylacetyl group, phenoxyacetyl group, benzylidene group, salicylidene group and the like may be used.
Chlorine, bromine and iodine atoms are suita-ble as the halogen atom.
The "protected carboxyl group" in R is repre-sented by -COOR wherein R is a protecting group of a carboxyl group used usually in the synthesis of peni-cîllins and cephalosporins. As R , an alkyl group having ~-5 carhon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, etc., a halogenated a~yl group having 1 to 5 carbon atoms such as a chloromethyl group, 2,2,2-trichloroethyl group, 2,2,Z-trifluoroethyl group, etc., an aryllnethyl group having 7-2~ carbon .~ , ~3 1~3~i138 atoms such as a benzyl group, diphenylmethyl group, tri-phenylmethyl group, etc., an arylmethyl group having 8 to 20 carbon atoms and methoxy, nitro group~s), etc. on the phenyl ring, such as p-nitrophenylmethyl group, p-methoxyphenylmethyl group, etc., a substituted silyl group such as a trimethylsilyl group, triphenylsilyl group, etc., a group enzymatically or non-enzymatically readily eliminable in vivo such as -CHoCoR4 (wherein R3 represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R4 represents a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or a phenyl group), etc. may be used.
As the salts of Compound ~ ~ , salts of an inorganic acid such as hydrochloride, sulfate, phosphate, carbonate, etc., salts of an organic acid such as formate, acetate, trifluoroacetate, malate, tartarate, etc., and when R is a carboxyl group, salts with an inorganic base such as sodium salt, potassium salt, calcium salt, barium salt, etc. and salts with an organic base such as salt with triethylamine, etc. are appropriate.
Compound C ~ includes all the stereoisomers at 6- and 7-positions. A compound obtained by convert-ing X in the general formula C ~ of a cis isomer to an acylamino group exhibits stronger antibacterial activity than that obtained in the same manner as above from the corresponding trans isomer. Therefore, cis isomers which may be converted into more useful antibiotics are more applicable. Nevertheless, trans isomers are also useful as they may be converted into useful antibiotics by introducing an ~-methoxy group at the 7-position.
Compounds ~ - ~ wherein X in Compound ~ ~ is an amino ~roup may be prepared from Compounds ~ -2- ~
set forth below wherein Xl in Compound ~- ~ is an azido 113~138 group or phthaloylamino group according to the following reaction process I.
Reaction Process I
la ~ reduction orH2N ~
N ~ Hal . . . > O ~ ~ Hal ellmlnatlon of a phthaloyl group R
~-2- ~ ~~ ~
wherein Xla represents an azido group or phthaloylamino group and R and Hal have the same meaning as defined above.
The reduction of Compound ~-2- ~ wherein Xla is an azido group is carried out using conventional methods employed in the field of synthetic chemistry of penicillins or cephalosporins. In the reaction, Compound ~- ~ can be produced by selecting suitable conditions and reagents to avoid the decomposition of substituents or functional groups of the carbacephem molecule.
Suitable reduction methods include:
1) catalytic reduction; 2) reduction using hydrogen sulfide and a base; 3) reduction using sodium boro-hydride; 4) reduction using zinc-acid; and 5) reduction using chromous (II) chloride, as are set forth below.
1) Catalytic reduction Compound ~ -2- ~ is sub3ected to catalytic reduction in a stream of hydrogen gas in the presence of a catalyst in an inactive solvent to obtain Compound - ~. Any solvent which does not affect the reaction may be used. Preferably ethanol, water, tetrahydro-furan, dioxane, ethyl acetate, acetic acid, or a mixture thereof is employed. As the catalyst, palladium-carbon, platinum oxide, palladium-calcium carbonate and ~aney nickel are appropriate.
~13~8 The reaction is generally carried out at a temperature of -20 to loo&, preferably at room tempera-ture, and at a pressure of 1 to 50 atmospheres, prefer-ably at atmospheric pressure.
In this reaction, when a compound represented ~y the general formula ~ -2- ~ wherein R is a carboxyl group protected by a protecting group such as a substi-tuted arylmethyl group, for example, a benzyl group, paramethoxybenzyl group, paranitrobenzyl group, benz-hydryl group, trityl group, etc. is used as the starting material, a compound represented by the general formula - ~ wherein R is a carboxyl group may also be obtained.
2) Reduction using hydrogen sulfide-base Compound ~-2- ~ is reduced with hydrogen sulfide in the presence of a base in an inactive solvent to obtain Compound ~ - ~. As the solvent, methylene chloride, chloroform, benzene, tetrahydrofuran, and the like are used alone or in combination. As the base, triethylamine, pyridine, and the like are appropriate.
The reaction is carried out at a temperature of 0 to 50C, preferably at room temperature.
It has now been found that novel carbacephems with a halogen atom at the C-3 position may be synthe-sized which are also useful as intermediates in the preparation of unexpectedly high antibacterial compounds.
Summary of the Invention In accordance with the present invention, novel carbacephem compounds, i.e. cephalosporin analogs, are synthesized. The numbering system shown in the following formula is used hereinafter.
Broadly, the present invention relates to cephalosporin analogs xepresented by the formula ~ ~:
H H
X~
0~ l\~Ha 1 wherein X represents an amino group, an azido group or a protected amino group, Hal represents a halogen atom and R represents a carboxyl group or a protected car~oxyl group. (Hereinafter compounds represented by the fore-going formula are sometimes referred to as Compound ~ ~.
This also applies to other foxmulae).
~escription of the Invention ~ore specifically, the present invention relates to novel cephalosporin analogs represented by the general formula ~- ~:
~2N~
~ N ~ Hal ~~ ~
wherein Hal and R have the same meaning as defined above; and also compounds represented by the general formula ~ - ~:
Xl~
~ N ~ Hal ~~ ~
wherein Xl represents an azido group or a protected amino group and Hal and R have the same meaning as defined above; and the salts thereof.
As the protecting groups for the "protected amino group" in X or Xl, a phthaloyl group, t-butyloxy-carbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2,2,2-trifluoroethyloxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyl-oxycarbonyl group, phenylacetyl group, phenoxyacetyl group, benzylidene group, salicylidene group and the like may be used.
Chlorine, bromine and iodine atoms are suita-ble as the halogen atom.
The "protected carboxyl group" in R is repre-sented by -COOR wherein R is a protecting group of a carboxyl group used usually in the synthesis of peni-cîllins and cephalosporins. As R , an alkyl group having ~-5 carhon atoms such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, etc., a halogenated a~yl group having 1 to 5 carbon atoms such as a chloromethyl group, 2,2,2-trichloroethyl group, 2,2,Z-trifluoroethyl group, etc., an aryllnethyl group having 7-2~ carbon .~ , ~3 1~3~i138 atoms such as a benzyl group, diphenylmethyl group, tri-phenylmethyl group, etc., an arylmethyl group having 8 to 20 carbon atoms and methoxy, nitro group~s), etc. on the phenyl ring, such as p-nitrophenylmethyl group, p-methoxyphenylmethyl group, etc., a substituted silyl group such as a trimethylsilyl group, triphenylsilyl group, etc., a group enzymatically or non-enzymatically readily eliminable in vivo such as -CHoCoR4 (wherein R3 represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R4 represents a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or a phenyl group), etc. may be used.
As the salts of Compound ~ ~ , salts of an inorganic acid such as hydrochloride, sulfate, phosphate, carbonate, etc., salts of an organic acid such as formate, acetate, trifluoroacetate, malate, tartarate, etc., and when R is a carboxyl group, salts with an inorganic base such as sodium salt, potassium salt, calcium salt, barium salt, etc. and salts with an organic base such as salt with triethylamine, etc. are appropriate.
Compound C ~ includes all the stereoisomers at 6- and 7-positions. A compound obtained by convert-ing X in the general formula C ~ of a cis isomer to an acylamino group exhibits stronger antibacterial activity than that obtained in the same manner as above from the corresponding trans isomer. Therefore, cis isomers which may be converted into more useful antibiotics are more applicable. Nevertheless, trans isomers are also useful as they may be converted into useful antibiotics by introducing an ~-methoxy group at the 7-position.
Compounds ~ - ~ wherein X in Compound ~ ~ is an amino ~roup may be prepared from Compounds ~ -2- ~
set forth below wherein Xl in Compound ~- ~ is an azido 113~138 group or phthaloylamino group according to the following reaction process I.
Reaction Process I
la ~ reduction orH2N ~
N ~ Hal . . . > O ~ ~ Hal ellmlnatlon of a phthaloyl group R
~-2- ~ ~~ ~
wherein Xla represents an azido group or phthaloylamino group and R and Hal have the same meaning as defined above.
The reduction of Compound ~-2- ~ wherein Xla is an azido group is carried out using conventional methods employed in the field of synthetic chemistry of penicillins or cephalosporins. In the reaction, Compound ~- ~ can be produced by selecting suitable conditions and reagents to avoid the decomposition of substituents or functional groups of the carbacephem molecule.
Suitable reduction methods include:
1) catalytic reduction; 2) reduction using hydrogen sulfide and a base; 3) reduction using sodium boro-hydride; 4) reduction using zinc-acid; and 5) reduction using chromous (II) chloride, as are set forth below.
1) Catalytic reduction Compound ~ -2- ~ is sub3ected to catalytic reduction in a stream of hydrogen gas in the presence of a catalyst in an inactive solvent to obtain Compound - ~. Any solvent which does not affect the reaction may be used. Preferably ethanol, water, tetrahydro-furan, dioxane, ethyl acetate, acetic acid, or a mixture thereof is employed. As the catalyst, palladium-carbon, platinum oxide, palladium-calcium carbonate and ~aney nickel are appropriate.
~13~8 The reaction is generally carried out at a temperature of -20 to loo&, preferably at room tempera-ture, and at a pressure of 1 to 50 atmospheres, prefer-ably at atmospheric pressure.
In this reaction, when a compound represented ~y the general formula ~ -2- ~ wherein R is a carboxyl group protected by a protecting group such as a substi-tuted arylmethyl group, for example, a benzyl group, paramethoxybenzyl group, paranitrobenzyl group, benz-hydryl group, trityl group, etc. is used as the starting material, a compound represented by the general formula - ~ wherein R is a carboxyl group may also be obtained.
2) Reduction using hydrogen sulfide-base Compound ~-2- ~ is reduced with hydrogen sulfide in the presence of a base in an inactive solvent to obtain Compound ~ - ~. As the solvent, methylene chloride, chloroform, benzene, tetrahydrofuran, and the like are used alone or in combination. As the base, triethylamine, pyridine, and the like are appropriate.
The reaction is carried out at a temperature of 0 to 50C, preferably at room temperature.
3) Reduction using sodium borohydride Compound ~ -2- ~ is reduced with sodium boro-hydride in an inactive solvent to obtain Compound ~- ~ .
As the solvent, methanol, ethanol, d~oxane, tetrahydro-furan are used alone or in combination. Sodium boro-hydride is used in an amount of one equivalent or excess to Compound ~ -2- ~.
The reaction is carried out at a temperature of 0 to 100C, preferably 10 to 50C.
As the solvent, methanol, ethanol, d~oxane, tetrahydro-furan are used alone or in combination. Sodium boro-hydride is used in an amount of one equivalent or excess to Compound ~ -2- ~.
The reaction is carried out at a temperature of 0 to 100C, preferably 10 to 50C.
4) Reduction using zinc-acid Compound ~-2- ~ is reduced with zinc-acid in an inactive solvent to obtain Compound r-~. As the solvent, acetone, water, dioxane, tetrahydrofuran, ethanol, acetic acid, etc. are used alone or in combi-nation. As the acid, hydrochloric acid or acetic acid 1~L3~i~38 iS suitable. Zinc and the acid are used in an amount of one equivalent or eXceSS to Compound ~ -2- ~.
The reaction iS carried oUt at a temperature of O to 100C, usually room temperature to 60C.
The reaction iS carried oUt at a temperature of O to 100C, usually room temperature to 60C.
5) Reduction using chromous (II) chloride Compound ~ -2- ~ iS reduced with chromous (II) chloride in the presence of an acid in an inactive solvent. The acid, solvents, and reaction conditions are the same as in zinc-acid method.
0 The elimination of a phthaloyl group from Compound ~-~- ~ iS carried oUt according to a con-ventional method for elimination of a phthaloyl group.
AS agents for the elimination, hydrazine, hydroxylamine, ethylamine, dimethylaminopropylamine, sodium sulfide-methylhydrazine, etc. may be used. The reaction may be carried out at -20 to 30C in an alcohol such as methanol, ethanol, and the like but other conventional conditions may also be applicable.
Compound ~- ~ iS prepared from compounds represented by the general formula ~ ~:
O ~ ~al ~ ~
wherein Xl~ Hal and R have the Same meaning as defined above, Y represents a sulfur atom or selenium atom, and R1 represents a substituted or unsubstituted al~yl group, aralkyl groUp or aryl groUp, or a heterocyclic group according to the following reaCtion process II.
113~138 Reaction Process II
1 ~ _ Rl- Y0~ al 1~
This reaction is the elimination of Rl-Y-OH
and is carried out usually in a solvent. The reaction temperature is 0 to 200C. As solvents preferably used, inert solvents such as aliphatic hydrocarbon (hexane, heptane, etc.), halogenated hydrocarbon (chloroform, methylene chloride, carbon tetrachloride, etc.), aromatic hydrocarbon (benzene, toluene, xylene, etc.), ether (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), ester (ethyl acetate, etc.), amide (dimethyl-formamide, dimethylacetamide, etc.), sulfoxide (dimethyl-sulfoxide, etc.) and so on may be used.
In case of the sul~oxide (Y=S), the reaction proceeds with heating. Reaction temperature is prefera-bly 50 to 200C. In case of elimination of a phenyl-sulfinyl group, most preferable results are obtained by heating with reflux temperature.
In case of the selenoxide (Y=Se), the reaction proceeds at a lower temperature compared with the case of the sulfoxide, and is preferably 0 to 30C.
In the definition of Rl in the general formula (II), as an alkyl group, an alkyl group having 1 to 5 carbon atoms such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl group, etc.; as an aralkyl group, a phenylalkyl group having 7 to 2~ carbon atoms such as a benzyl, phenethyl group, etc.; and as an aryl group, a phenyl group are illustrative. As the substit-uent(s) of the alkyl, aralkyl or aryl group, a halogen atom such as chlorine, bromine, etc., a nitro group, a 113~138 g lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms are illustrative.
Furthermore, as the heterocyclic group, a tetrazolyl group or thiazolyl group are-illustrative.
Preferably, a phenyl group as R1, a sulfur atom as Y and a chlorine atom as Hal are used.
Compound (II) includes all the stereoisomers at 2-, 3-, 6- and 7-positions and mixtures thereof.
Compound ~ ~ wherein the 6- and 7-positions are cis configuration is more useful as a starting compound for the more useful Compound ~ ~ in cis configuration.
Nevertheless, Compound ~ ~ with trans configuration is useful as a starting compound of Compound ~ ~ with trans configuration.
Compound ~ ~ is also a new compound and is prepared from a compound represented by the general formula ~I ~:
Xl\~ >
~ N ~ Y- Rl ~I ~
wherein Xl, Y, Rl and R have the same meaning as defined above according to reaction process III.
Reaction Process III
X~, ~ Xl~, I halogenation O ~ I ~ _ Rl > ~ ~ R ~Ha This reaction is an introduction of a halogen atom in ~-carbon of the sulfinyl or seleninyl group.
For example, for ~-chlorination of the sulfoxide, the reaction is carried out using a halogenating agent such 1il3~38 as tosyl chloride, nitrosyl chloride, dichloroiodophenyl, t-butyl hypochlorite, sulfuryl chloride, most preferably sulfuryl chloride, if necessary in the presence of a base such as pyridine, or the like.
The reaction is carried out at -78 to 20C, preferably under cooling conditions in an inert solvent, without water. The reaction time is usually within 30 minutes. As an example of a preferred embodiment, the reaction proceeds very mildly and rapidly by using sulfuryl chloride as a halogenating agent and a halogen-ated hydrocarbon such as dichloromethane as a solvent to obtain the desired compound in good yield.
Addition of calcium oxide to the reaction system for catching hydrogen chloride formed according to the progress of the reaction sometimes results in good effect. When an excess amount of sulfuryl chloride is used, dichloro compounds sometimes are formed as by-products. The reaction of alkylphenyl sulfoxide or dialkyl sulfoxide with sulfuryl chloride has been reported ~.C. Tin et. al. Tetrahedron-letter, 4643 (1970 ~ but there has been no report on such reaction applied to a ~-lactam compound.
Compound ~ I ~ is also a new compound and is prepared from a compound represented by the general formula ~V~:
Xl\r~/~
N ~ Y- Rl ~ V~
R
wherein Xl, Y, R and Rl have the same meaning as def~ned above according to reaction process IV.
`` 113~138 Reaction Process IV
Xl ~ oxidation 1 ~
N ~ Y - R ~ N ~ Y- R
R R
~V~ ~I ~
This reaction is an oxidation reaction of sulfide or selenide, and conventional oxidation reactions of such compounds to a sulfinyl compound or seleninyl compound are applicable. As oxidizing agents, various oxidizing agents such as manganese dioxide, chromic acid, lead tetraacetate, ruthenium tetroxide, N-halocarbonamide, oxygen, ozone, and the like may be used. As especially preferable oxidizing agents, anodic oxidation, periodic acid, hydrogen peroxide, organic peracid such as m-chloroperbenzoic acid are used.
The solvent is selected according to the oxi-dizing agent. Water, alcohol, acetic acid and a mixture thereof, or a halogenated hydrocarbon such as chloroform, and the like are preferred.
The reaction is usually carried out at -50 to 100C. When an excess amount of the oxidizing agent is used and the temperature is raised, sulfone is sometimes formed.
Compound rv~ is a new compound and is pre-pared from a compound represented by the general formula ~V~:
~ ~V~
O ~
wherein Xl and R have the same meaning as defined above according to reaction process V.
Reaction Process V
1 ~ R YH Xl ~ ~y _ Rl R R
~v7 ~v~
This reaction is the addition reaction of thiol or selenol represented by Rl-Y-H. The reaction is usually carried out at -50 to 100C in a solvent, and if necessary in the presence of a base.
As the base, organic bases such as piperidine, diethylamine, triethylamine, etc., metal hydride such as sodium hydride, potassium hydride, etc., alkyllithium such as n-butyllithium, etc., sodium hydroxide, potassium hydroxide, etc. may be used. When a strong base is used, it is preferred, for avoiding cleavage of the ~-lactam ring, that the compound Rl-Y-H is first treated with one or less equivalent amount of the base and then reacted with Compound V. More preferable results are obtained with the use of a weak base than with the use of a strong base. For example, better results are obtained with the use of piperidine when thiophenol is used as Rl-Y-H.
As a solvent, solvents inactive to the addition reaction are used. Aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydro-carbons such as chloroform, methylene chloride, carbon tetrachloride, ethers such as ethyl ether, tetrahydro-furan, dimethoxyethane, etc., esters such as ethyl acetate, etc., alcohols such as methanol, ethanol, etc., amides such as dimethylformamide, dimethylacetamide, etc , sulfoxides such as dimethylsul~oxide, etc., aceto-nitr~le and so on are employed.
Compound ~ ~ wherein ~ is a carboxyl group, ~36~38 may be produced by the following reaCtion proCess VI
using a compound represented by the general formula ~- ~ as the starting compound.
Reaction Process VI
O ~ Hal O ~ Hal COOR COOH
In the compounds of the foregoing reaction, X, Hal and R2 have the same meaning as defined above.
The reaction can be carried out by convention-al means employed in the field of the synthetic chemis-try of penicillins or cephalosporins. In the reaction, Compound ~- ~ can be produced by selecting suitable conditions and reagents to avoid the decomposition of substituents or functional groups of the carbacephem molecule.
Suitable reactions which convert the -COOR2 group to a -COOH group include: 1) catalytic reduction;
2) acidolysis; 3) cleavage reaction using a Lewis acid;
4) hydrolysis; 5) reduction other than catalytic reduction using reducing agents; and 6) a method using an esterase; each of which are described below.
1) Catalytic reduction In this reaction, the COOR2 group is converted to a COOH group in the presence of a catalyst in a hydrogen atmosphere and inactive solvent. As the solvent, any solvent which does not affect the reaction, and preferably ethanol, water, tetrahydrofuran, dioxane, ethyl acetate and acetic acid, may be used alone or in combination. As the catalyst, palladium-carbon, platinum oxide, palladium-calcium carbonate and Raney nic~el are suitable. The reaction is generally carried out at a pressure of 1 to 50 atmospheres and a tempera-ture of 0 to loo&, preferably at atmospheric pressure and room temperature.
This method is preferably employed when R2 is a benzyl group, p-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, p-methoxybenzyl group or the like.
When X is an azido group, the azido group may be reduced to an amino group when R2 is converted to H
by catalytic reduction. The resulting compound having an amino group is also a desired compound of the present invention.
2) Acidolysis In this reaction, the COOR2 is converted to a COOH group with an acid in an inactive solvent. As the acid, hydrogen chloride, p-toluenesulfonic acid, tri-fluoroacetic acid, etc. are suitable. As the solvent, any solvent which does not affect the reaction, and preferably ethyl acetate, benzene, ethanol, acetic acid, dioxane, methylene chloride and chloroform, may be used alone or in combination.
The reaction is generally carried out at a temperature of -15 to 50C, preferably 0 to 25C, for 10 minutes to 5 hours, preferably 30 minutes to 3 hours.
This method is preferably used when R2 is a t-butyl group, trityl group and so on.
3) Cleavage reaction using a Lewis acid Tn this reaction, the COOR2 group is converted to a COOH group by cleavage in the presence of a Lewis acid in an inactive solvent such as any solvent which does not affect the reaction, preferably a mixture of a nitroalkane such as nitromethane and a haloalkane such as methylene chloride. As the Lewis acid, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, and the like are used. The acid is used ~136i138 in an amount of 1.0 to 1.5 molar equivalents to Compound ~- ~. The reaction is preferably carried out in the presence of an agent such as anisole which uptakes any carbonium cation possibly formed. The reaction is carried out at a temperature of 0 to 50C, preferably at room temperature for 1 to 10 hours.
Addition of thiol compound such as ethane-thiol, ethanedithiol, etc. often enhances this type of reduction.
This method is preferably used when R is a benzyl, p-nitrobenzyl group and so on.
4) Hydrolysis In this reaction, the COOR2 group is converted to a COOH group by hydrolysis in the presence of an acid or alkali in an inactive solvent. Suitable acids include p-toluenesulfonic acid, hydrochloric acid, acetic acid, and the like. Any solvent which does not affect the reaction may be used and preferably aqueous methanol, N,N-dimethylformamide, acetic acid-water-tetrahydrofuran are employed. The reaction is generallycarried out at a temperature of 0 to 50C, preferably 15 to 25C for 10 minutes to 2 hours.
This method utilizing an acid is preferably used when R is a t-butyldimethylsilyl group.
As an alkali, calcium carbonate is preferably used in an amount of 1 to 6 molar equivalents to Compound ~- ~; and any solvent which does not affect the reaction and preferably tetrahydrofuran-water, dioxane-water or acetone-water are used. The reaction is generally carried out at a temperature of 0 to 30C
for 30 minutes to 24 hours.
This method utilizing an alkali is preferably employe~ when R2 is a methyl group, ethyl group and so on.
113Si~38 5) Reduction using reducing agents (other than cata-lytic reduction) In this reaction, the COOR group is converted to a COOH by reduction in an inactive solvent, for example using a zinc-acid method. For this reaction a solvent such as acetone, water, dioxane, tetrahydrofuran, ethanol, acetonitrile, N,N-dimethylformamide and acetic acid may be used alone or in combination. As the acid, hydrochloric acid and acetic acid are suitable. The reaction is carried out at a temperature of 0 to 100C, preferably 0 to 40C for 1 to 10 hours. The amount of zinc used for the reaction is usually 1 to 10 molar equivalents. 2 This method is preferably employed when R is 2,2,2-trichloroethyl and so on.
Compound ~V~ used as a starting material and the processes for preparation thereof are disclosed in German Offenlegungsschrift No. 2911786/197g. A repre-sentative example of the process steps is set forth below.
CHO ~ > ~
H2N y P(OEt)2 N ~ (OEt)2 C2 Bu 2 N3CH2COCl N ~
O ~ ~ P(OEt)2 >
3 C2 Bu o ~r o t)2 ~ ~ t ` 1136~38 For further reference, preparation of cephalo-sporins having a halogen substituent at the 3-position is carried out by the following reaction steps. ~.V.
Kaiser, et. al., J.O. Chem. 35, 2430 (1970), R.R.
Chauvette et. al., J. Am. Chem. ~oc., 96, 4986 (1974 ~ ~ reduction ~ ~
ozone ~ S ~ halogenation ~ S
~ O ~ ~ OH
As apparent from the foregoing, the process of the present invention is carried out according to 4 steps, i.e., 1) addition of thiol or selenol, 2) oxidation, 3) halo-genation and 4) elimination reaction; and, if necessary, additional steps such as 5) conversion of an azido or phthaloylamino group to an amino group at the 7-position and/or 6) conversion of a protected carboxyl group to a carboxyl group at the 2-position, using a 3~-carbacephem compound (for example, Compound 5) as the starting compound. Thus, the present invention offers new and useful 3-halogen substituted carbacephem structures and new processes for preparation thereof quite different from prior processes for the preparation of cephalo-sporin analogs.
Certain specific embodi~ents of the invention are illustrated by the following represented examples.
Preparation of (+)-cis-7-azido-3-chloro-2-t-butyloxycarbonyl-l-aæabicyclo ~ ,2, ~oct-2-en-8-one:
~13ti138 H H
N ~
COO Bu In this example, the compound is prepared according to the following processes a), b), c) and d).
Cis means the stereoisomerism at the 3- or 4-position of the 2-azetidinone ring or at the 6- or 7-position of the l-a2abicyclo ~,2, ~ octane rinq, which designation is applied as well hereinafter.
a) Preparation of (+)-cis-7-azido-3-phenylthio-2-t-butyloxycarbonyl-l-azabicyclo ~ ,2, ~ octane-8-one:
H H H H
3 ~ N
~ N ~ O ~ ~ SPh C02tBu C02tBu In this step, 528 mg (2 m mole) of (+)-cis-7-azido-2-t-butyloxycarbonyl-l-azabicyclo ~ ,2, ~oct-2-en-8-one is dissolved in lS ml of anhydrous benzene. Then, 0.2 ml (2 m mole) of thiophenol and 0.2 ml (2 m mole) of piperidine are added to the solution and the mixture is stirred at room temperature for 2 hours. After the reaction, the reaction mixture is washed with 10% citric acid and saturated aqueous sodium chloride, anddried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resultant oily residue is purified ~y silica gel column chromatography ~ilica gel: Wako-gel , C-200, product of Wa~o ~unyaku Co , 1td.
(the same silica gel is used hereinafter~, eluent: ethyl acetate: n-hexane = l : 4 (in volume, the same herein-after ~ to obtain 720 mg (yield: 96.3%) of the desired compound having the following physical properties.
- 1~36138 - 18a -Melting point: 77.5-78.0 &
IR(KBr)vmamx : 2110, 1765, 1745 NMR(CDC13~(ppm): 7.28-7.60(5H,m), 4.78(1H,d, J=5 Hz), 4.33(1H,s), 3.78-3.98(1H,m), 3.81(1H,s), 1.50-2.34(4H,m), 1.42(9H,s) ~) Preparation of (+)-cis-7-azido-3-phenylsulfinyl-2-t-butyloxycarbonyl-l-azabicyclo ~,2, ~octane-8-one:
H H H H
SPh N3 ~ SPh C2 Bu C2 Bu In this step, 480 mg (1.28 m mole) of the 3-phenylthio compound obtained in the foregoing step a) is ~ dissolved in 50 ml of anhydrous chloroform. Then 240 mg ; (1.41 m mole) of m-chloroperbenzoic acid is added to the solution under ice cooling. The reaction is carried out with stirring for 30 minutes and the reaction mixture is washed wiih saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried with an-hydrous sodium sulfate. The solvent is distilled off under reduced pressure to o~tain 500 mg (99.9~) of the desired compound having the following physical proper-ties.
~elting polnt: 95.5-96.5C
IR(KBr)vmax : 2120, 2100, 1780, 1735, 1035 NMR(CDC13)~(ppm): 7.55-7.91(5H,m), 4.87(1H,d, J=4.6 ~z), 4.05(1~,s), 3.90-4.10 (lH,m), 3.10(lH,s), 1.70-2.84 (4H,m), 1.30(9H,s) c) Preparation of (+)-cis-7-azido-3-chloro-3-phenyl-sulfinyl-2-t-butyloxycarbonyl-1-azabicyclo ~,2, ~-octane-8-one:
-,~
H H H ~
O ~ t ~ h CO~tBU BU02c Ir. this step, 109 mg of the sulfoxide compound obtained in the prece~ing step b) is dissolved in 1 ml of methylene chloride. Then, 23.5 mg (0.42 m mole) of calci~m oxide is added to the solution. Thereafter, 27 ~1 (0.34 m mole~
of sulfinyl chloride is added to the mixture under ice coolin~.
The reaction is carried out with stirring under ice cooling for one hour.
The reaction mix~ure is then washed with 10~ ci~ric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resultant oily resi~ue is purified by silica gel chroma~ography (silica gel; 5 g, eluent; ethyl acetate : n-hexane = 1 : 5~ to obtain 66.5 mg (56.1%) of the desired compound as an oily product having the ~ollowing properties. -1 IR(CHC13)vmax: 2120, 1770, 1735, 1055 NMR(CDC13~(ppm~: 7.53-8.00(5H,ml, 4.90(lH,d, J=SHz), 4.43(1H,s), 4.15-4.35 (lH,m~, 1.83- 85(4~,m), 1.38 (9H,s~
d~ Preparation of (~-cis-7-azido-3-chloro-2-t-butyloxy-carbonyl-1-azabicyclo~4,2,03Oc~-2-en-~-one:
' ' X ~ ~ ~
~Cl . ~ CL
~u~2C
1136~38 In this step, 1.3 g (3.06 m mole) of the 3-chloro-3-phenylsulfinyl compound obtained in the same manner as described in the preceding step c) is dis-solved in 100 ml of carbon tetrachloride and the solution is refluxed with heating for 6 hours.
After the reaction is completed, the solvent is distilled off under reduced pressure, and the re-sultant residue is purified by silica gel chromatography ~silica gel; 100 g eluent; ethyl acetate : n-hexane =
1 : 5) to obtain 596 mg (65.2~) of the desired compound having the following physical properties.
Melting point: 96-97&
IR(KBr)vCmax : 2120, 1765, 1735, 1630 PMR(CDC13)~(ppm): 4.93(1H,d, J=5 Hz), 3.72-3.92 (lH,m), 2.56-2.70(2H,m), 1.86-2.32(2H,m), 1.55(9H,s) CMR(CDC13)~(ppm): 127.7, 125.0 Preparation of (+)-cis-7-amino-3-chloro-2-t-butyloxycarbonyl-l-azabicyclo ~,2, ~ oct-2-en-8-one:
H H H H
N' 2 ~
N ~ O ~ ~ Cl C2 Bu C2 Bu In this example, 350 mg (1.17 m mole) of the azido compound obtained in step d) of Example 1 is dis-solved in 20 ml of ethanol. Then, 1.2 ml of 1~ hydro-chloric acid and 70 mg of 10~ palladium-carbon are added to the solution. Hydrogen gas is introduced into the mixture at room temperature and at atmospheric pressure for 3 hours. The palladium-carbon is then filtered off and the filtrate is concentrated under reduced pressure.
The resu7tant solid is dissolved in water and the .~ .~--1~3~38 solution is washed with ether. The water layer is rendered weakly alkaline by adding sodium bicarbonate and is then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium chloride and dried with anhydrous sodium sulfate. The solvent is thoroughly distilled off under reduced pressure to obtain 218.4 mg (68.4%) of the desired compound as a powder having the following properties.
Melting point: 102.5-104.5C
IR(KBr)vmax : 1770, 1720, 1620 NMR(CDC13)~(ppm): 4.43(lH,d, J=5 Hz), 3.52-3.90 (lH,m), 2.52-2.72(2H,m), 2.22(2H, br), 1.82-2.17(2H,m), 1.55(9H,s) EXAMP~E 3 Preparation of trifluoroacetate of (+)-cis-7-amino-3-chloro-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylic acid:
H H H H
H2N~ H 2N\H/~
O ~ ~ Cl ~ N ~ Cl C 3CO2 C2 Bu CO2H
In this example, 1 ml of trifluoroacetic acid is added to 102.2 mg (0.31 m mole) of the amino-ester compound obtained in Example 2 under ice cooling and the mixture is stirred at room temperature for 30 minutes.
The solvent is distilled off unde~ reduced pressure and ethex is added to the resultant oily residue to render it powdery. The residue is collected by suction filtration and dried ~n v~euo to obtain 75.5 mg (60.g%) of the desired compound having the ~ollowing properties.
30Melting point:208-220 C (decomposition) 113~}8 tKBr)vmmax : 1795, 1630 Preparation of (+)-cis-7-azido-3-chloro-1-azabicyclo ~ ,2, ~ oct-2-en-8-on-2-carboxylic acid:
N ~ ~ N
C2 Bu CO2H
In this example, 2 ml of trifluoroacetic acid is added to 83.9 mg (0.28 m mole) of the azido-ester compound obtained in step d) of Example 1 and the mixture is stirred at room temperature for 30 minutes.
The solvent is distilled off under reduced pressure and ether is added to the resultant oily residue to render it powdery. The residue is collected by suction filtration and dried in vacuo to o~tain 25.0 mg (36.7%) of the desired compound having the following properties.
Melting point: 147.5-148.5C
IR(KBr)vmamx : 2130, 1770, 1715, 1605 NMR(CD3OD)~(ppm): 5.16(1H,d, J=5 Hz), 3.82-4.02 (lH,m), 2.63-2.77(2H,m), 1.73-2.21(2H,m) In the following reference examples processes for preparing end products from the intermediates of the present invention are further illustrated.
Reference ~xample 1 Preparation of (~)-cis-7- ~ -(2-chloroacet-amidothiazole-4-yl)-2-syn-methoxyiminoacetylamin ~ -3-chloro-l-azahicyclo ~,2, ~ oct-2-en-8-on-2-car~oxylic acid:
~ 113~138 H2N~C1 3C2 >
ClCH2CONH-<~ 3 N CCONH ~
C 3 ~ N ~ Cl In this reference example, 122.6 mg (0.44 m mole) of 2-(2-chloroacetamidothiazole-4-yl)-2-syn-methoxyiminoacetic acid is dissolved in 2.5 ml of an-hydrous methylene chloride. Then, 68 ~1 (0.49 m mole) of triethylamine is dissolved therein and 92.0 mg (0.44 m mole) of phosphorus pentachloride is added under cooling with an ice - salt bath. The mixture is stirred at that temperature for one hour after which 5 ml of n-hexane is added thereto. The mixture is stirred under ice cooling for an additional 15 minutes. A separated oily material is obtained by removing n-hexane ~y decan-tation. The oily material is dissolved in 4 ml of tetrahydrofuran to prepare an acid chloride solution.
In a separate vessel, 121.7 mg (0.37 m mole) of the trifluoroacetate of (+)-7-amino-3-chloro-1-azabicyclo-~,2, ~oct-2-en-8-one-2-car~oxylic acid obtained in the same manner as described in Example 3 is dissolved in 5 ml of 50% aqueous tetrahydrofuran and 0.2 ml (1.47 m mole) of triethylamine. To this solution, the a~ove-prepared acid chloride solution in tetrahydrofuran is added with stirring under ice cooling. The mixture is stirred at that temperature for one hour and ad3usted to p~ 3 with lN hydrochloric acid. Water is then added and the mixture i5 extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride -` 1136138 and dried with anhydrous sodium sulfate. The solvent is distilled off to obtain 53.9 mg (30.5%) of the desired compound as a powder having the following properties.
IR(KBr)v : 1770, 1680, 1555, 1045 max NMR(DMSO-d6)~(ppm): 9.38(lH,d, J=8 Hz), 7.37 (lH,s), 5.45(lH,q, J=5, 8Hz), 4.35(2H,s) Reference Example 2 Preparation of (+)-cis-7- ~-(2-aminothiazole-4-yl)-2-syn-methoxyiminoacetamid ~-3-chloro-1-azabicyclo-~,2, ~ oct-2-en-8-on-2-carboxylic acid:
C lcH
N CCONH ~
NOCH3 O ~ N ~ Cl N ~ CCON~
NOCH3 ~ Cl In this reference example, 51.2 mg (0.11 m mole) of the chloro-acetamido compound obtained in the foregoing Reference Example 2 is dissolved in 1 ml of dimethylacetamide and 16.3 mg (0.22 m mole) of thiourea is added thereto. ~eaction is carried out by stirring the mixture at room temperature for 14 hours.
Then, 7 ml of ether is added to the reaction mixture and the stirring is continued for an additional 10 minutes. A separated oily material is obtained by removing the ether by decantation. The oily material is dissolved in a small amount of dimethylsulfoxide, absorbed on 10 ml of HP-10 resin in a column and eluated ~36138 with dimethylsulfoxide. The eluate is twice treated with HP-10 resin ~ luent: water-methanol (amount of methanol is gradually increased and finally elution is carried out with water : methanol = 1 : 1 ~ to obtain 15.2 mg (35.4~) of the desired compound having the following properties.
Melting point: 185.0-188.0C (decomposed) IR(KBr)vmm : 1765, 1670, 1630, 1540, 1040 NMR(DMSO-d6)~(ppm): 9.28(lH,d, J=8.8 Hz), 7.17 (2H,s), 6.75(1H,s), 5.44 (lH,q, J=5.3, 8.8 Hz), 3.84(3H,s), 1.24-2.52(4H,m) The antibacterial activity of the compound obtained in Reference Example 2 is set forth in the following table. The activity is determined by the Heart Infusion Agar Dilution Method (pH 7.2), and Cefazolin is used as a reference.
'~
Compound of Strain Cefazolin Reference Example 2 Staphylococcus aureus 209-P<0.05 50 Staphylococcus aureus Smith 0.4 50 Staphylococcus epidermidis0.78 50 Escherichia coli NIHJC-2 1.56 0.78 Escherichia coli Juhl 1.56 0.4 Klebsiella pneumoniae 80450.78 <o.05 Klebsiella pneumoniae Y-603.12 0.78 Serratia marcescens T-55 50 1.56 Proteus mirabilis 1287 12.5 0.1 Proteus vulgaris 6897 12.5 0.4 Proteus morgnii KY4298 >100 0.4 Proteus rettgeri KY4289 25 0.1 Pseudomonas putida F264 >100 3.12 113~:i138 SUPPLEMENTARY DISCLOSURE
The following Examples are added to illustrate the preparation of the starting compounds where Xla is phthaloylamino and the conversion of this latter sub-stituent to the amino group.
Preparation of tert-butyl (+)-cis-3-chloro-7-phthalylimino-l-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate:
H H
PhtN ~
C2 Bu The compound is prepared according to the following processes a) and b).
a) Preparation of tert-butyl (+)-cis-7-phthalyl-imino-3-phenylthio-1-azabicyclo ~ ,2, ~ octane-8-on-2-carboxylate H H H H
PhtN ~ Pht N
In this example, 9.20 g (25 m moles) of tert-butyl (+~-cis-7-phthalylimino-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate is dissolved in 100 ml of chloro-form. Then, 2.83 ml (27.5 m moles~ of thiophenol and 0.5 ml of piperazine are added to the solution and the mixture is stirred at room temperature for 3 hours. The solvent is distilled off and the resultant pale yellow oily residue is purified by silica gel chromatography 113ti13~3 (200 g of silica gel, eluent: n-hexane : ethyl acetate = 2 : 1) to o~tain 9.26 g (yield: 77.5%) of the desired compound as white granular crystals.
IR(KBr)vmmax : 1800, 1785, 1775, 1770, 1750, 1740, 1730, 1400, 1150 NMR(CDC13)~(ppm): 7.2-7.8(9H,m), 5.50(lH,d, J=5 Hz), 4.53(1H,s), 3.80-4.12 (lH,m), 3.82(lH, bs), 1.50-2.34 (~H,m), 1.47(9H,s) b) Preparation of tert-butyl (+)-cis-3-chloro-7-phthalylimino-l-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate H H ~ H H H H ~
PhtN ~ _ PhtN ~ PhtN ~ Cl_ _ ~ ~ Sph ~ ~ ~ph C2 Bu C2 Bu CO2tBu H H
PhtN ~
0~ _----N ~ C1 t C2 Bu In this example, 4.78 g (10 m moles) of tert-butyl (+)-cis-7-phthalylimino-3-phenylthio-1-azabicyclo-~,2, ~octane-8-on-2-carboxylate is dissolved in 100 ml of chloroform. Then, 2.37 g of m-chloroperbenzoic acid (purity: 80%) is added to the solution under ice cooling and the mixture is stirred for 30 minutes under the same condition. Thereafter, 1 ml of 10% aqueous sodium thio-sulfate is added to the reaction mixture and the mixture is washed with saturated aqueous sodium bicarhonate and saturated aqueous sodium chloride. The chloroform layer is separated and dried with anhydrous sodium sulfate.
The solvent is distilled off under reduced pressure.
The resultant white powder (520 mg) is dis-solved in 50 ml of methylene chloride. Then, 1.45 ml (18 m moles) of sulfuryl chloride is added dropwise to the solution under ice cooling and the mixture is stirred for one hour under the same condition. There-after, 50 ml of methylene chloride is added to the reaction mixture and the mixture is washed with 10%
aqueous citric acid, saturated aqueous sodium bi-carbonate and saturated aqueous sodium chloride in this order. The methylene chloride layer is separated and dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure.
Then, 80 ml of toluene is added to the re-sultant white powder (510 mg) and the mixture is gently refluxed with heating for one hour and 40 minutes. The reaction mixtuxe is concentrated under reduced pressure and the pale yellow oily residue is purified by silica gel chromatography (80 g of silica gel, eluent :
n-hexane : ethyl acetate = 1 : 1) to obtain 3.50 g (yield: 87~) of the desired compound as white crystals.
IR(KBr)vmmax : 1795, 1785, 1760, 1750, 1730, 1715, 1605, 1395, 905 NMR(CDC13)~(ppm): 7.7-7.9(4H,m), 5.58(lH,d, J=6 Hz), 3.85-4~1(1H,m), 2.5-2.7(2H,m), 1.8-2.4(2H,m) 1.52(9H,s) EX~PLE 6 Preparation of (+)-cis-3-chloro-7-phthalyl-imino-l-azabicyclo ~ ,2, ~oct-2-en-8-on-2-carboxylic acid:
1~3~i138 H H
PhtN L ~^~
~ N
In this example, 8 ml of trifluoroacetic acid is added to 1.7 g (4.22 m moles) of tert-butyl (+)-cis-3-chloro-7-phthalylimino-1-azabicyclo ~ ,2, ~oct-2-en-8-on-2-carboxylate under ice cooling and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and 30 ml of chloroform is added to the residue. The resulting solution is concentrated under reduced pressure to obtain white powder. Then, 30 ml of ether is added to the powder and the mixture is adequately stirred and ~iltered. The resultant powder is washed with 30 ml of ether to obtain 1.1 g (yield: 71.8%) of the desired compound.
NMR(DMSO-d6)~(ppm~: 7.92(4H, bs), 5.70(1H,d, J=5 Hz), 3.95-4.2(lH,m), 2.5-2.75(2H,m), 1.8-2.15(2H,m) Preparation of (+)-cis-7-amino-3-chloro-1-azabicyclo~ ,2, ~ oct-2-en-8-on-2-carboxylic acid:
H H
H2 ~
Y' In this example, 730 mg ~2 m moles) of (+)-cis-3-chloro-7-phthalylimino-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylic acid is dissolved in 10 ml o~ 0.2 N
aqueous sodium bicarbonate and 0.175 ml ~3.6 m moles) of .,~
. .
~3~138 hydrazine hydrate is added dropwise to the solution under ice cooling. The mixture is stirred at room temperature for 2 hours, adjusted to pH 1.2 with 1 N
hydrochloric acid and stirred at 30C for one hour and 50 minutes. The deposited insoluble material is filtered off. The filtrate is adjusted to pH 3.5 with saturated aqueous sodium bicarbonate and concentrated until the amount of the solution is about 5 ml. The concentrate is adsorbed on 100 ml of Diaion HP-10 in a column and eluted with water. The solvent is distilled off from the eluate under reduced pressure to obtain 560 mg (yield: 58.0~) of the desired compound as a white powder.
0 The elimination of a phthaloyl group from Compound ~-~- ~ iS carried oUt according to a con-ventional method for elimination of a phthaloyl group.
AS agents for the elimination, hydrazine, hydroxylamine, ethylamine, dimethylaminopropylamine, sodium sulfide-methylhydrazine, etc. may be used. The reaction may be carried out at -20 to 30C in an alcohol such as methanol, ethanol, and the like but other conventional conditions may also be applicable.
Compound ~- ~ iS prepared from compounds represented by the general formula ~ ~:
O ~ ~al ~ ~
wherein Xl~ Hal and R have the Same meaning as defined above, Y represents a sulfur atom or selenium atom, and R1 represents a substituted or unsubstituted al~yl group, aralkyl groUp or aryl groUp, or a heterocyclic group according to the following reaCtion process II.
113~138 Reaction Process II
1 ~ _ Rl- Y0~ al 1~
This reaction is the elimination of Rl-Y-OH
and is carried out usually in a solvent. The reaction temperature is 0 to 200C. As solvents preferably used, inert solvents such as aliphatic hydrocarbon (hexane, heptane, etc.), halogenated hydrocarbon (chloroform, methylene chloride, carbon tetrachloride, etc.), aromatic hydrocarbon (benzene, toluene, xylene, etc.), ether (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), ester (ethyl acetate, etc.), amide (dimethyl-formamide, dimethylacetamide, etc.), sulfoxide (dimethyl-sulfoxide, etc.) and so on may be used.
In case of the sul~oxide (Y=S), the reaction proceeds with heating. Reaction temperature is prefera-bly 50 to 200C. In case of elimination of a phenyl-sulfinyl group, most preferable results are obtained by heating with reflux temperature.
In case of the selenoxide (Y=Se), the reaction proceeds at a lower temperature compared with the case of the sulfoxide, and is preferably 0 to 30C.
In the definition of Rl in the general formula (II), as an alkyl group, an alkyl group having 1 to 5 carbon atoms such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl group, etc.; as an aralkyl group, a phenylalkyl group having 7 to 2~ carbon atoms such as a benzyl, phenethyl group, etc.; and as an aryl group, a phenyl group are illustrative. As the substit-uent(s) of the alkyl, aralkyl or aryl group, a halogen atom such as chlorine, bromine, etc., a nitro group, a 113~138 g lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms are illustrative.
Furthermore, as the heterocyclic group, a tetrazolyl group or thiazolyl group are-illustrative.
Preferably, a phenyl group as R1, a sulfur atom as Y and a chlorine atom as Hal are used.
Compound (II) includes all the stereoisomers at 2-, 3-, 6- and 7-positions and mixtures thereof.
Compound ~ ~ wherein the 6- and 7-positions are cis configuration is more useful as a starting compound for the more useful Compound ~ ~ in cis configuration.
Nevertheless, Compound ~ ~ with trans configuration is useful as a starting compound of Compound ~ ~ with trans configuration.
Compound ~ ~ is also a new compound and is prepared from a compound represented by the general formula ~I ~:
Xl\~ >
~ N ~ Y- Rl ~I ~
wherein Xl, Y, Rl and R have the same meaning as defined above according to reaction process III.
Reaction Process III
X~, ~ Xl~, I halogenation O ~ I ~ _ Rl > ~ ~ R ~Ha This reaction is an introduction of a halogen atom in ~-carbon of the sulfinyl or seleninyl group.
For example, for ~-chlorination of the sulfoxide, the reaction is carried out using a halogenating agent such 1il3~38 as tosyl chloride, nitrosyl chloride, dichloroiodophenyl, t-butyl hypochlorite, sulfuryl chloride, most preferably sulfuryl chloride, if necessary in the presence of a base such as pyridine, or the like.
The reaction is carried out at -78 to 20C, preferably under cooling conditions in an inert solvent, without water. The reaction time is usually within 30 minutes. As an example of a preferred embodiment, the reaction proceeds very mildly and rapidly by using sulfuryl chloride as a halogenating agent and a halogen-ated hydrocarbon such as dichloromethane as a solvent to obtain the desired compound in good yield.
Addition of calcium oxide to the reaction system for catching hydrogen chloride formed according to the progress of the reaction sometimes results in good effect. When an excess amount of sulfuryl chloride is used, dichloro compounds sometimes are formed as by-products. The reaction of alkylphenyl sulfoxide or dialkyl sulfoxide with sulfuryl chloride has been reported ~.C. Tin et. al. Tetrahedron-letter, 4643 (1970 ~ but there has been no report on such reaction applied to a ~-lactam compound.
Compound ~ I ~ is also a new compound and is prepared from a compound represented by the general formula ~V~:
Xl\r~/~
N ~ Y- Rl ~ V~
R
wherein Xl, Y, R and Rl have the same meaning as def~ned above according to reaction process IV.
`` 113~138 Reaction Process IV
Xl ~ oxidation 1 ~
N ~ Y - R ~ N ~ Y- R
R R
~V~ ~I ~
This reaction is an oxidation reaction of sulfide or selenide, and conventional oxidation reactions of such compounds to a sulfinyl compound or seleninyl compound are applicable. As oxidizing agents, various oxidizing agents such as manganese dioxide, chromic acid, lead tetraacetate, ruthenium tetroxide, N-halocarbonamide, oxygen, ozone, and the like may be used. As especially preferable oxidizing agents, anodic oxidation, periodic acid, hydrogen peroxide, organic peracid such as m-chloroperbenzoic acid are used.
The solvent is selected according to the oxi-dizing agent. Water, alcohol, acetic acid and a mixture thereof, or a halogenated hydrocarbon such as chloroform, and the like are preferred.
The reaction is usually carried out at -50 to 100C. When an excess amount of the oxidizing agent is used and the temperature is raised, sulfone is sometimes formed.
Compound rv~ is a new compound and is pre-pared from a compound represented by the general formula ~V~:
~ ~V~
O ~
wherein Xl and R have the same meaning as defined above according to reaction process V.
Reaction Process V
1 ~ R YH Xl ~ ~y _ Rl R R
~v7 ~v~
This reaction is the addition reaction of thiol or selenol represented by Rl-Y-H. The reaction is usually carried out at -50 to 100C in a solvent, and if necessary in the presence of a base.
As the base, organic bases such as piperidine, diethylamine, triethylamine, etc., metal hydride such as sodium hydride, potassium hydride, etc., alkyllithium such as n-butyllithium, etc., sodium hydroxide, potassium hydroxide, etc. may be used. When a strong base is used, it is preferred, for avoiding cleavage of the ~-lactam ring, that the compound Rl-Y-H is first treated with one or less equivalent amount of the base and then reacted with Compound V. More preferable results are obtained with the use of a weak base than with the use of a strong base. For example, better results are obtained with the use of piperidine when thiophenol is used as Rl-Y-H.
As a solvent, solvents inactive to the addition reaction are used. Aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydro-carbons such as chloroform, methylene chloride, carbon tetrachloride, ethers such as ethyl ether, tetrahydro-furan, dimethoxyethane, etc., esters such as ethyl acetate, etc., alcohols such as methanol, ethanol, etc., amides such as dimethylformamide, dimethylacetamide, etc , sulfoxides such as dimethylsul~oxide, etc., aceto-nitr~le and so on are employed.
Compound ~ ~ wherein ~ is a carboxyl group, ~36~38 may be produced by the following reaCtion proCess VI
using a compound represented by the general formula ~- ~ as the starting compound.
Reaction Process VI
O ~ Hal O ~ Hal COOR COOH
In the compounds of the foregoing reaction, X, Hal and R2 have the same meaning as defined above.
The reaction can be carried out by convention-al means employed in the field of the synthetic chemis-try of penicillins or cephalosporins. In the reaction, Compound ~- ~ can be produced by selecting suitable conditions and reagents to avoid the decomposition of substituents or functional groups of the carbacephem molecule.
Suitable reactions which convert the -COOR2 group to a -COOH group include: 1) catalytic reduction;
2) acidolysis; 3) cleavage reaction using a Lewis acid;
4) hydrolysis; 5) reduction other than catalytic reduction using reducing agents; and 6) a method using an esterase; each of which are described below.
1) Catalytic reduction In this reaction, the COOR2 group is converted to a COOH group in the presence of a catalyst in a hydrogen atmosphere and inactive solvent. As the solvent, any solvent which does not affect the reaction, and preferably ethanol, water, tetrahydrofuran, dioxane, ethyl acetate and acetic acid, may be used alone or in combination. As the catalyst, palladium-carbon, platinum oxide, palladium-calcium carbonate and Raney nic~el are suitable. The reaction is generally carried out at a pressure of 1 to 50 atmospheres and a tempera-ture of 0 to loo&, preferably at atmospheric pressure and room temperature.
This method is preferably employed when R2 is a benzyl group, p-nitrobenzyl group, diphenylmethyl group, triphenylmethyl group, p-methoxybenzyl group or the like.
When X is an azido group, the azido group may be reduced to an amino group when R2 is converted to H
by catalytic reduction. The resulting compound having an amino group is also a desired compound of the present invention.
2) Acidolysis In this reaction, the COOR2 is converted to a COOH group with an acid in an inactive solvent. As the acid, hydrogen chloride, p-toluenesulfonic acid, tri-fluoroacetic acid, etc. are suitable. As the solvent, any solvent which does not affect the reaction, and preferably ethyl acetate, benzene, ethanol, acetic acid, dioxane, methylene chloride and chloroform, may be used alone or in combination.
The reaction is generally carried out at a temperature of -15 to 50C, preferably 0 to 25C, for 10 minutes to 5 hours, preferably 30 minutes to 3 hours.
This method is preferably used when R2 is a t-butyl group, trityl group and so on.
3) Cleavage reaction using a Lewis acid Tn this reaction, the COOR2 group is converted to a COOH group by cleavage in the presence of a Lewis acid in an inactive solvent such as any solvent which does not affect the reaction, preferably a mixture of a nitroalkane such as nitromethane and a haloalkane such as methylene chloride. As the Lewis acid, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, and the like are used. The acid is used ~136i138 in an amount of 1.0 to 1.5 molar equivalents to Compound ~- ~. The reaction is preferably carried out in the presence of an agent such as anisole which uptakes any carbonium cation possibly formed. The reaction is carried out at a temperature of 0 to 50C, preferably at room temperature for 1 to 10 hours.
Addition of thiol compound such as ethane-thiol, ethanedithiol, etc. often enhances this type of reduction.
This method is preferably used when R is a benzyl, p-nitrobenzyl group and so on.
4) Hydrolysis In this reaction, the COOR2 group is converted to a COOH group by hydrolysis in the presence of an acid or alkali in an inactive solvent. Suitable acids include p-toluenesulfonic acid, hydrochloric acid, acetic acid, and the like. Any solvent which does not affect the reaction may be used and preferably aqueous methanol, N,N-dimethylformamide, acetic acid-water-tetrahydrofuran are employed. The reaction is generallycarried out at a temperature of 0 to 50C, preferably 15 to 25C for 10 minutes to 2 hours.
This method utilizing an acid is preferably used when R is a t-butyldimethylsilyl group.
As an alkali, calcium carbonate is preferably used in an amount of 1 to 6 molar equivalents to Compound ~- ~; and any solvent which does not affect the reaction and preferably tetrahydrofuran-water, dioxane-water or acetone-water are used. The reaction is generally carried out at a temperature of 0 to 30C
for 30 minutes to 24 hours.
This method utilizing an alkali is preferably employe~ when R2 is a methyl group, ethyl group and so on.
113Si~38 5) Reduction using reducing agents (other than cata-lytic reduction) In this reaction, the COOR group is converted to a COOH by reduction in an inactive solvent, for example using a zinc-acid method. For this reaction a solvent such as acetone, water, dioxane, tetrahydrofuran, ethanol, acetonitrile, N,N-dimethylformamide and acetic acid may be used alone or in combination. As the acid, hydrochloric acid and acetic acid are suitable. The reaction is carried out at a temperature of 0 to 100C, preferably 0 to 40C for 1 to 10 hours. The amount of zinc used for the reaction is usually 1 to 10 molar equivalents. 2 This method is preferably employed when R is 2,2,2-trichloroethyl and so on.
Compound ~V~ used as a starting material and the processes for preparation thereof are disclosed in German Offenlegungsschrift No. 2911786/197g. A repre-sentative example of the process steps is set forth below.
CHO ~ > ~
H2N y P(OEt)2 N ~ (OEt)2 C2 Bu 2 N3CH2COCl N ~
O ~ ~ P(OEt)2 >
3 C2 Bu o ~r o t)2 ~ ~ t ` 1136~38 For further reference, preparation of cephalo-sporins having a halogen substituent at the 3-position is carried out by the following reaction steps. ~.V.
Kaiser, et. al., J.O. Chem. 35, 2430 (1970), R.R.
Chauvette et. al., J. Am. Chem. ~oc., 96, 4986 (1974 ~ ~ reduction ~ ~
ozone ~ S ~ halogenation ~ S
~ O ~ ~ OH
As apparent from the foregoing, the process of the present invention is carried out according to 4 steps, i.e., 1) addition of thiol or selenol, 2) oxidation, 3) halo-genation and 4) elimination reaction; and, if necessary, additional steps such as 5) conversion of an azido or phthaloylamino group to an amino group at the 7-position and/or 6) conversion of a protected carboxyl group to a carboxyl group at the 2-position, using a 3~-carbacephem compound (for example, Compound 5) as the starting compound. Thus, the present invention offers new and useful 3-halogen substituted carbacephem structures and new processes for preparation thereof quite different from prior processes for the preparation of cephalo-sporin analogs.
Certain specific embodi~ents of the invention are illustrated by the following represented examples.
Preparation of (+)-cis-7-azido-3-chloro-2-t-butyloxycarbonyl-l-aæabicyclo ~ ,2, ~oct-2-en-8-one:
~13ti138 H H
N ~
COO Bu In this example, the compound is prepared according to the following processes a), b), c) and d).
Cis means the stereoisomerism at the 3- or 4-position of the 2-azetidinone ring or at the 6- or 7-position of the l-a2abicyclo ~,2, ~ octane rinq, which designation is applied as well hereinafter.
a) Preparation of (+)-cis-7-azido-3-phenylthio-2-t-butyloxycarbonyl-l-azabicyclo ~ ,2, ~ octane-8-one:
H H H H
3 ~ N
~ N ~ O ~ ~ SPh C02tBu C02tBu In this step, 528 mg (2 m mole) of (+)-cis-7-azido-2-t-butyloxycarbonyl-l-azabicyclo ~ ,2, ~oct-2-en-8-one is dissolved in lS ml of anhydrous benzene. Then, 0.2 ml (2 m mole) of thiophenol and 0.2 ml (2 m mole) of piperidine are added to the solution and the mixture is stirred at room temperature for 2 hours. After the reaction, the reaction mixture is washed with 10% citric acid and saturated aqueous sodium chloride, anddried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resultant oily residue is purified ~y silica gel column chromatography ~ilica gel: Wako-gel , C-200, product of Wa~o ~unyaku Co , 1td.
(the same silica gel is used hereinafter~, eluent: ethyl acetate: n-hexane = l : 4 (in volume, the same herein-after ~ to obtain 720 mg (yield: 96.3%) of the desired compound having the following physical properties.
- 1~36138 - 18a -Melting point: 77.5-78.0 &
IR(KBr)vmamx : 2110, 1765, 1745 NMR(CDC13~(ppm): 7.28-7.60(5H,m), 4.78(1H,d, J=5 Hz), 4.33(1H,s), 3.78-3.98(1H,m), 3.81(1H,s), 1.50-2.34(4H,m), 1.42(9H,s) ~) Preparation of (+)-cis-7-azido-3-phenylsulfinyl-2-t-butyloxycarbonyl-l-azabicyclo ~,2, ~octane-8-one:
H H H H
SPh N3 ~ SPh C2 Bu C2 Bu In this step, 480 mg (1.28 m mole) of the 3-phenylthio compound obtained in the foregoing step a) is ~ dissolved in 50 ml of anhydrous chloroform. Then 240 mg ; (1.41 m mole) of m-chloroperbenzoic acid is added to the solution under ice cooling. The reaction is carried out with stirring for 30 minutes and the reaction mixture is washed wiih saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried with an-hydrous sodium sulfate. The solvent is distilled off under reduced pressure to o~tain 500 mg (99.9~) of the desired compound having the following physical proper-ties.
~elting polnt: 95.5-96.5C
IR(KBr)vmax : 2120, 2100, 1780, 1735, 1035 NMR(CDC13)~(ppm): 7.55-7.91(5H,m), 4.87(1H,d, J=4.6 ~z), 4.05(1~,s), 3.90-4.10 (lH,m), 3.10(lH,s), 1.70-2.84 (4H,m), 1.30(9H,s) c) Preparation of (+)-cis-7-azido-3-chloro-3-phenyl-sulfinyl-2-t-butyloxycarbonyl-1-azabicyclo ~,2, ~-octane-8-one:
-,~
H H H ~
O ~ t ~ h CO~tBU BU02c Ir. this step, 109 mg of the sulfoxide compound obtained in the prece~ing step b) is dissolved in 1 ml of methylene chloride. Then, 23.5 mg (0.42 m mole) of calci~m oxide is added to the solution. Thereafter, 27 ~1 (0.34 m mole~
of sulfinyl chloride is added to the mixture under ice coolin~.
The reaction is carried out with stirring under ice cooling for one hour.
The reaction mix~ure is then washed with 10~ ci~ric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resultant oily resi~ue is purified by silica gel chroma~ography (silica gel; 5 g, eluent; ethyl acetate : n-hexane = 1 : 5~ to obtain 66.5 mg (56.1%) of the desired compound as an oily product having the ~ollowing properties. -1 IR(CHC13)vmax: 2120, 1770, 1735, 1055 NMR(CDC13~(ppm~: 7.53-8.00(5H,ml, 4.90(lH,d, J=SHz), 4.43(1H,s), 4.15-4.35 (lH,m~, 1.83- 85(4~,m), 1.38 (9H,s~
d~ Preparation of (~-cis-7-azido-3-chloro-2-t-butyloxy-carbonyl-1-azabicyclo~4,2,03Oc~-2-en-~-one:
' ' X ~ ~ ~
~Cl . ~ CL
~u~2C
1136~38 In this step, 1.3 g (3.06 m mole) of the 3-chloro-3-phenylsulfinyl compound obtained in the same manner as described in the preceding step c) is dis-solved in 100 ml of carbon tetrachloride and the solution is refluxed with heating for 6 hours.
After the reaction is completed, the solvent is distilled off under reduced pressure, and the re-sultant residue is purified by silica gel chromatography ~silica gel; 100 g eluent; ethyl acetate : n-hexane =
1 : 5) to obtain 596 mg (65.2~) of the desired compound having the following physical properties.
Melting point: 96-97&
IR(KBr)vCmax : 2120, 1765, 1735, 1630 PMR(CDC13)~(ppm): 4.93(1H,d, J=5 Hz), 3.72-3.92 (lH,m), 2.56-2.70(2H,m), 1.86-2.32(2H,m), 1.55(9H,s) CMR(CDC13)~(ppm): 127.7, 125.0 Preparation of (+)-cis-7-amino-3-chloro-2-t-butyloxycarbonyl-l-azabicyclo ~,2, ~ oct-2-en-8-one:
H H H H
N' 2 ~
N ~ O ~ ~ Cl C2 Bu C2 Bu In this example, 350 mg (1.17 m mole) of the azido compound obtained in step d) of Example 1 is dis-solved in 20 ml of ethanol. Then, 1.2 ml of 1~ hydro-chloric acid and 70 mg of 10~ palladium-carbon are added to the solution. Hydrogen gas is introduced into the mixture at room temperature and at atmospheric pressure for 3 hours. The palladium-carbon is then filtered off and the filtrate is concentrated under reduced pressure.
The resu7tant solid is dissolved in water and the .~ .~--1~3~38 solution is washed with ether. The water layer is rendered weakly alkaline by adding sodium bicarbonate and is then extracted with ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium chloride and dried with anhydrous sodium sulfate. The solvent is thoroughly distilled off under reduced pressure to obtain 218.4 mg (68.4%) of the desired compound as a powder having the following properties.
Melting point: 102.5-104.5C
IR(KBr)vmax : 1770, 1720, 1620 NMR(CDC13)~(ppm): 4.43(lH,d, J=5 Hz), 3.52-3.90 (lH,m), 2.52-2.72(2H,m), 2.22(2H, br), 1.82-2.17(2H,m), 1.55(9H,s) EXAMP~E 3 Preparation of trifluoroacetate of (+)-cis-7-amino-3-chloro-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylic acid:
H H H H
H2N~ H 2N\H/~
O ~ ~ Cl ~ N ~ Cl C 3CO2 C2 Bu CO2H
In this example, 1 ml of trifluoroacetic acid is added to 102.2 mg (0.31 m mole) of the amino-ester compound obtained in Example 2 under ice cooling and the mixture is stirred at room temperature for 30 minutes.
The solvent is distilled off unde~ reduced pressure and ethex is added to the resultant oily residue to render it powdery. The residue is collected by suction filtration and dried ~n v~euo to obtain 75.5 mg (60.g%) of the desired compound having the ~ollowing properties.
30Melting point:208-220 C (decomposition) 113~}8 tKBr)vmmax : 1795, 1630 Preparation of (+)-cis-7-azido-3-chloro-1-azabicyclo ~ ,2, ~ oct-2-en-8-on-2-carboxylic acid:
N ~ ~ N
C2 Bu CO2H
In this example, 2 ml of trifluoroacetic acid is added to 83.9 mg (0.28 m mole) of the azido-ester compound obtained in step d) of Example 1 and the mixture is stirred at room temperature for 30 minutes.
The solvent is distilled off under reduced pressure and ether is added to the resultant oily residue to render it powdery. The residue is collected by suction filtration and dried in vacuo to o~tain 25.0 mg (36.7%) of the desired compound having the following properties.
Melting point: 147.5-148.5C
IR(KBr)vmamx : 2130, 1770, 1715, 1605 NMR(CD3OD)~(ppm): 5.16(1H,d, J=5 Hz), 3.82-4.02 (lH,m), 2.63-2.77(2H,m), 1.73-2.21(2H,m) In the following reference examples processes for preparing end products from the intermediates of the present invention are further illustrated.
Reference ~xample 1 Preparation of (~)-cis-7- ~ -(2-chloroacet-amidothiazole-4-yl)-2-syn-methoxyiminoacetylamin ~ -3-chloro-l-azahicyclo ~,2, ~ oct-2-en-8-on-2-car~oxylic acid:
~ 113~138 H2N~C1 3C2 >
ClCH2CONH-<~ 3 N CCONH ~
C 3 ~ N ~ Cl In this reference example, 122.6 mg (0.44 m mole) of 2-(2-chloroacetamidothiazole-4-yl)-2-syn-methoxyiminoacetic acid is dissolved in 2.5 ml of an-hydrous methylene chloride. Then, 68 ~1 (0.49 m mole) of triethylamine is dissolved therein and 92.0 mg (0.44 m mole) of phosphorus pentachloride is added under cooling with an ice - salt bath. The mixture is stirred at that temperature for one hour after which 5 ml of n-hexane is added thereto. The mixture is stirred under ice cooling for an additional 15 minutes. A separated oily material is obtained by removing n-hexane ~y decan-tation. The oily material is dissolved in 4 ml of tetrahydrofuran to prepare an acid chloride solution.
In a separate vessel, 121.7 mg (0.37 m mole) of the trifluoroacetate of (+)-7-amino-3-chloro-1-azabicyclo-~,2, ~oct-2-en-8-one-2-car~oxylic acid obtained in the same manner as described in Example 3 is dissolved in 5 ml of 50% aqueous tetrahydrofuran and 0.2 ml (1.47 m mole) of triethylamine. To this solution, the a~ove-prepared acid chloride solution in tetrahydrofuran is added with stirring under ice cooling. The mixture is stirred at that temperature for one hour and ad3usted to p~ 3 with lN hydrochloric acid. Water is then added and the mixture i5 extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride -` 1136138 and dried with anhydrous sodium sulfate. The solvent is distilled off to obtain 53.9 mg (30.5%) of the desired compound as a powder having the following properties.
IR(KBr)v : 1770, 1680, 1555, 1045 max NMR(DMSO-d6)~(ppm): 9.38(lH,d, J=8 Hz), 7.37 (lH,s), 5.45(lH,q, J=5, 8Hz), 4.35(2H,s) Reference Example 2 Preparation of (+)-cis-7- ~-(2-aminothiazole-4-yl)-2-syn-methoxyiminoacetamid ~-3-chloro-1-azabicyclo-~,2, ~ oct-2-en-8-on-2-carboxylic acid:
C lcH
N CCONH ~
NOCH3 O ~ N ~ Cl N ~ CCON~
NOCH3 ~ Cl In this reference example, 51.2 mg (0.11 m mole) of the chloro-acetamido compound obtained in the foregoing Reference Example 2 is dissolved in 1 ml of dimethylacetamide and 16.3 mg (0.22 m mole) of thiourea is added thereto. ~eaction is carried out by stirring the mixture at room temperature for 14 hours.
Then, 7 ml of ether is added to the reaction mixture and the stirring is continued for an additional 10 minutes. A separated oily material is obtained by removing the ether by decantation. The oily material is dissolved in a small amount of dimethylsulfoxide, absorbed on 10 ml of HP-10 resin in a column and eluated ~36138 with dimethylsulfoxide. The eluate is twice treated with HP-10 resin ~ luent: water-methanol (amount of methanol is gradually increased and finally elution is carried out with water : methanol = 1 : 1 ~ to obtain 15.2 mg (35.4~) of the desired compound having the following properties.
Melting point: 185.0-188.0C (decomposed) IR(KBr)vmm : 1765, 1670, 1630, 1540, 1040 NMR(DMSO-d6)~(ppm): 9.28(lH,d, J=8.8 Hz), 7.17 (2H,s), 6.75(1H,s), 5.44 (lH,q, J=5.3, 8.8 Hz), 3.84(3H,s), 1.24-2.52(4H,m) The antibacterial activity of the compound obtained in Reference Example 2 is set forth in the following table. The activity is determined by the Heart Infusion Agar Dilution Method (pH 7.2), and Cefazolin is used as a reference.
'~
Compound of Strain Cefazolin Reference Example 2 Staphylococcus aureus 209-P<0.05 50 Staphylococcus aureus Smith 0.4 50 Staphylococcus epidermidis0.78 50 Escherichia coli NIHJC-2 1.56 0.78 Escherichia coli Juhl 1.56 0.4 Klebsiella pneumoniae 80450.78 <o.05 Klebsiella pneumoniae Y-603.12 0.78 Serratia marcescens T-55 50 1.56 Proteus mirabilis 1287 12.5 0.1 Proteus vulgaris 6897 12.5 0.4 Proteus morgnii KY4298 >100 0.4 Proteus rettgeri KY4289 25 0.1 Pseudomonas putida F264 >100 3.12 113~:i138 SUPPLEMENTARY DISCLOSURE
The following Examples are added to illustrate the preparation of the starting compounds where Xla is phthaloylamino and the conversion of this latter sub-stituent to the amino group.
Preparation of tert-butyl (+)-cis-3-chloro-7-phthalylimino-l-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate:
H H
PhtN ~
C2 Bu The compound is prepared according to the following processes a) and b).
a) Preparation of tert-butyl (+)-cis-7-phthalyl-imino-3-phenylthio-1-azabicyclo ~ ,2, ~ octane-8-on-2-carboxylate H H H H
PhtN ~ Pht N
In this example, 9.20 g (25 m moles) of tert-butyl (+~-cis-7-phthalylimino-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate is dissolved in 100 ml of chloro-form. Then, 2.83 ml (27.5 m moles~ of thiophenol and 0.5 ml of piperazine are added to the solution and the mixture is stirred at room temperature for 3 hours. The solvent is distilled off and the resultant pale yellow oily residue is purified by silica gel chromatography 113ti13~3 (200 g of silica gel, eluent: n-hexane : ethyl acetate = 2 : 1) to o~tain 9.26 g (yield: 77.5%) of the desired compound as white granular crystals.
IR(KBr)vmmax : 1800, 1785, 1775, 1770, 1750, 1740, 1730, 1400, 1150 NMR(CDC13)~(ppm): 7.2-7.8(9H,m), 5.50(lH,d, J=5 Hz), 4.53(1H,s), 3.80-4.12 (lH,m), 3.82(lH, bs), 1.50-2.34 (~H,m), 1.47(9H,s) b) Preparation of tert-butyl (+)-cis-3-chloro-7-phthalylimino-l-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylate H H ~ H H H H ~
PhtN ~ _ PhtN ~ PhtN ~ Cl_ _ ~ ~ Sph ~ ~ ~ph C2 Bu C2 Bu CO2tBu H H
PhtN ~
0~ _----N ~ C1 t C2 Bu In this example, 4.78 g (10 m moles) of tert-butyl (+)-cis-7-phthalylimino-3-phenylthio-1-azabicyclo-~,2, ~octane-8-on-2-carboxylate is dissolved in 100 ml of chloroform. Then, 2.37 g of m-chloroperbenzoic acid (purity: 80%) is added to the solution under ice cooling and the mixture is stirred for 30 minutes under the same condition. Thereafter, 1 ml of 10% aqueous sodium thio-sulfate is added to the reaction mixture and the mixture is washed with saturated aqueous sodium bicarhonate and saturated aqueous sodium chloride. The chloroform layer is separated and dried with anhydrous sodium sulfate.
The solvent is distilled off under reduced pressure.
The resultant white powder (520 mg) is dis-solved in 50 ml of methylene chloride. Then, 1.45 ml (18 m moles) of sulfuryl chloride is added dropwise to the solution under ice cooling and the mixture is stirred for one hour under the same condition. There-after, 50 ml of methylene chloride is added to the reaction mixture and the mixture is washed with 10%
aqueous citric acid, saturated aqueous sodium bi-carbonate and saturated aqueous sodium chloride in this order. The methylene chloride layer is separated and dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure.
Then, 80 ml of toluene is added to the re-sultant white powder (510 mg) and the mixture is gently refluxed with heating for one hour and 40 minutes. The reaction mixtuxe is concentrated under reduced pressure and the pale yellow oily residue is purified by silica gel chromatography (80 g of silica gel, eluent :
n-hexane : ethyl acetate = 1 : 1) to obtain 3.50 g (yield: 87~) of the desired compound as white crystals.
IR(KBr)vmmax : 1795, 1785, 1760, 1750, 1730, 1715, 1605, 1395, 905 NMR(CDC13)~(ppm): 7.7-7.9(4H,m), 5.58(lH,d, J=6 Hz), 3.85-4~1(1H,m), 2.5-2.7(2H,m), 1.8-2.4(2H,m) 1.52(9H,s) EX~PLE 6 Preparation of (+)-cis-3-chloro-7-phthalyl-imino-l-azabicyclo ~ ,2, ~oct-2-en-8-on-2-carboxylic acid:
1~3~i138 H H
PhtN L ~^~
~ N
In this example, 8 ml of trifluoroacetic acid is added to 1.7 g (4.22 m moles) of tert-butyl (+)-cis-3-chloro-7-phthalylimino-1-azabicyclo ~ ,2, ~oct-2-en-8-on-2-carboxylate under ice cooling and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and 30 ml of chloroform is added to the residue. The resulting solution is concentrated under reduced pressure to obtain white powder. Then, 30 ml of ether is added to the powder and the mixture is adequately stirred and ~iltered. The resultant powder is washed with 30 ml of ether to obtain 1.1 g (yield: 71.8%) of the desired compound.
NMR(DMSO-d6)~(ppm~: 7.92(4H, bs), 5.70(1H,d, J=5 Hz), 3.95-4.2(lH,m), 2.5-2.75(2H,m), 1.8-2.15(2H,m) Preparation of (+)-cis-7-amino-3-chloro-1-azabicyclo~ ,2, ~ oct-2-en-8-on-2-carboxylic acid:
H H
H2 ~
Y' In this example, 730 mg ~2 m moles) of (+)-cis-3-chloro-7-phthalylimino-1-azabicyclo ~,2, ~ oct-2-en-8-on-2-carboxylic acid is dissolved in 10 ml o~ 0.2 N
aqueous sodium bicarbonate and 0.175 ml ~3.6 m moles) of .,~
. .
~3~138 hydrazine hydrate is added dropwise to the solution under ice cooling. The mixture is stirred at room temperature for 2 hours, adjusted to pH 1.2 with 1 N
hydrochloric acid and stirred at 30C for one hour and 50 minutes. The deposited insoluble material is filtered off. The filtrate is adjusted to pH 3.5 with saturated aqueous sodium bicarbonate and concentrated until the amount of the solution is about 5 ml. The concentrate is adsorbed on 100 ml of Diaion HP-10 in a column and eluted with water. The solvent is distilled off from the eluate under reduced pressure to obtain 560 mg (yield: 58.0~) of the desired compound as a white powder.
Claims (17)
1. A process for producing a compound of the formula:
wherein Hal represents a halogen atom and R represents a carboxyl group or a protected carboxyl group represented by the formula -COOR2 wherein R2 represents an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, an arylmethyl group having 7 to 20 carbon atoms, an arylmethyl group having 8 to 20 carbon atoms and methoxy or nitro group(s) on the phenyl ring, a trimethylsilyl group, a triphenyl-silyl group, or a group (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R4 represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group), which comprises reducing or dephthal-oylating a compound represented by the formula:
wherein X1a represents an azide group or a phthaloyl-amino group, and Hal and R have the same meaning as defined above.
wherein Hal represents a halogen atom and R represents a carboxyl group or a protected carboxyl group represented by the formula -COOR2 wherein R2 represents an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, an arylmethyl group having 7 to 20 carbon atoms, an arylmethyl group having 8 to 20 carbon atoms and methoxy or nitro group(s) on the phenyl ring, a trimethylsilyl group, a triphenyl-silyl group, or a group (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R4 represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group), which comprises reducing or dephthal-oylating a compound represented by the formula:
wherein X1a represents an azide group or a phthaloyl-amino group, and Hal and R have the same meaning as defined above.
2. A process according to Claim 1, wherein R2 represents a t-butyl group, a benzyl group, a diphenyl-methyl group, a p-nitrophenylmethyl group or a p-methoxy-phenylmethyl group.
3. A process according to Claim 1, wherein the reduction is a catalytic reduction.
4. A process according to Claim 1, wherein hydrogen sulfide and a base are used as a reducing agent in the reduction.
5. A process according to Claim 1, wherein sodium borohydride is used in the reduction.
6. A process according to Claim 1, wherein zinc and an acid are used in the reduction.
7. A process according to Claim 1, wherein the reduction is carried out with chromous (II) chloride in the presence of an acid.
8. A process according to Claim 3, wherein R
in the starting compound is a protected carboxyl group and the protected group is converted to a carboxyl group.
in the starting compound is a protected carboxyl group and the protected group is converted to a carboxyl group.
9. A process according to Claim 8, wherein said protected group is a benzyl group, a p-methoxy-benzyl group, a p-nitrobenzyl group, a benzhydryl group or a trityl group.
10. A process according to Claim 1, wherein Hal is a chlorine atom.
11. A process according to Claim 10, wherein R
is a t-butyloxycarbonyl group.
is a t-butyloxycarbonyl group.
12. A process according to Claim 11, wherein R
is a carboxyl group.
is a carboxyl group.
13. A process wherein (?)-cis-7-azido-3-chloro-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0]oct-2-en-8-one is subjected to catalytic reduction and there is recovered (?)-cis-7-amino-3-chloro-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one.
14. A compound of the formula:
wherein Hal represents a halogen atom, and R represents a carboxyl group or a protected carboxyl group repre-sented by the general formula -COOR2 wherein R2 repre-sents an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, an arylmethyl group having 7 to 20 carbon atoms, an aryl-methyl group having 8 to 20 carbon atoms and methoxy or nitro group(s) on the phenyl ring, a trimethylsilyl group, a triphenylsilyl group, or a group (wherein R3 represents a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, and R4 represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group), when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
wherein Hal represents a halogen atom, and R represents a carboxyl group or a protected carboxyl group repre-sented by the general formula -COOR2 wherein R2 repre-sents an alkyl group having 1 to 5 carbon atoms, a halogenated alkyl group having 1 to 5 carbon atoms, an arylmethyl group having 7 to 20 carbon atoms, an aryl-methyl group having 8 to 20 carbon atoms and methoxy or nitro group(s) on the phenyl ring, a trimethylsilyl group, a triphenylsilyl group, or a group (wherein R3 represents a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms, and R4 represents an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a phenyl group), when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
15. The (?)-cis-7-amino-3-chloro-2-t-butyloxy-carbonyl-1-azabicyclo[4,2,0] oct-2-en-one, when prepared by the process defined in Claim 13 or by an obvious chemical equivalent.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
16. A process wherein (?)-cis-3-chloro-7-phthalylimino-l-azabicyclo[4,2,0] oct-2-en-8-on-2-carboxylic acid is subjected to hydrazine hydrate to remove the phthaloyl group and there is recovered the (?)-cis-7-amino-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-on-2-carboxylic acid.
17. The (?)-cis-7-amino-3-chloro-1-azabicyclo-[4,2,0]oct-2-en-8-on-2-carboxylic acid, when prepared by the process defined in Claim 16 or by an obvious chemi-cal equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP53162008A JPS6058920B2 (en) | 1978-12-26 | 1978-12-26 | Cephalosporin analogs |
| JP162,008/78 | 1978-12-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1136138A true CA1136138A (en) | 1982-11-23 |
Family
ID=15746283
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000342597A Expired CA1136138A (en) | 1978-12-26 | 1979-12-21 | Cephalosporin analogs and methods for production thereof |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS6058920B2 (en) |
| CA (1) | CA1136138A (en) |
| CH (1) | CH642968A5 (en) |
| DE (1) | DE2952413C2 (en) |
| DK (1) | DK549479A (en) |
| FR (1) | FR2445327A1 (en) |
| GB (1) | GB2041923B (en) |
| IT (1) | IT1192795B (en) |
| NO (1) | NO794177L (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0653739B2 (en) * | 1984-11-15 | 1994-07-20 | 協和醗酵工業株式会社 | 3-position substituted carbacephem compound |
| US4673737A (en) * | 1985-08-02 | 1987-06-16 | Harvard University | 7-acylamino-(or 7-amino)-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylic acids and esters thereof |
| JPS63184229U (en) * | 1987-05-19 | 1988-11-28 | ||
| US4885291A (en) * | 1988-01-14 | 1989-12-05 | Eli Lilly And Company | 1-carba(dethia)-3-cephem derivatives |
| US4977257A (en) * | 1988-11-14 | 1990-12-11 | Eli Lilly And Company | DMF solvates of a β-lactam antibiotic |
| US5077287A (en) * | 1991-01-18 | 1991-12-31 | Eli Lilly And Company | 3-thiazolylthio carbacephem antibacterial agents |
| CS133392A3 (en) * | 1991-05-10 | 1992-11-18 | Lilly Co Eli | Process for preparing twice blocked1-carba(1-dithia)-3-cephem-4-carboxylic acids |
| DE4331391A1 (en) * | 1993-09-15 | 1995-03-16 | Josef Dr Kemmer | Semiconductor (detector) structure |
| AU2003298513A1 (en) * | 2002-05-14 | 2004-05-13 | Northwestern University | STERICALLY-AWKWARD Beta-LACTAMASE INHIBITORS |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2714880A1 (en) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
-
1978
- 1978-12-26 JP JP53162008A patent/JPS6058920B2/en not_active Expired
-
1979
- 1979-12-19 NO NO794177A patent/NO794177L/en unknown
- 1979-12-20 CH CH1134579A patent/CH642968A5/en not_active IP Right Cessation
- 1979-12-21 CA CA000342597A patent/CA1136138A/en not_active Expired
- 1979-12-21 FR FR7931527A patent/FR2445327A1/en active Granted
- 1979-12-21 GB GB7944080A patent/GB2041923B/en not_active Expired
- 1979-12-21 DK DK549479A patent/DK549479A/en not_active Application Discontinuation
- 1979-12-24 IT IT69476/79A patent/IT1192795B/en active
- 1979-12-27 DE DE2952413A patent/DE2952413C2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2041923A (en) | 1980-09-17 |
| JPS5587791A (en) | 1980-07-02 |
| FR2445327B1 (en) | 1983-05-06 |
| IT7969476A0 (en) | 1979-12-24 |
| GB2041923B (en) | 1983-07-20 |
| NO794177L (en) | 1980-06-27 |
| JPS6058920B2 (en) | 1985-12-23 |
| IT1192795B (en) | 1988-05-04 |
| DE2952413A1 (en) | 1980-07-17 |
| FR2445327A1 (en) | 1980-07-25 |
| DK549479A (en) | 1980-06-27 |
| DE2952413C2 (en) | 1986-12-11 |
| CH642968A5 (en) | 1984-05-15 |
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