Claims
- 1. A process for the preparation of 3-chloro-cefem compounds of formula I: ##STR20## in which R represents hydrogen, or a therapeutically acceptable salt or ester thereof, characterized in that it comprises the following stages:
- (1) condensation of the compound of formula VII ##STR21## with acetone in the presence of a base followed by nitrosylation in the presence of an acid to produce a compound of formula IX ##STR22## (2) in either order subjecting the product of formula (IX) obtained in the previous stage to esterification in the presence of a polar organic solvent with a halogen derivative of the formula R.sup.2 -Hal, in which Hal represents halogen and R.sup.2 is an ester-forming alkyl or aryl group, and to oxidation, to produce the sulphoxide of formula XI ##STR23## in which R.sup.2 has the value indicated above; (3) treatment of the sulphoxide of formula XI, obtained in the previous stage, first with a halogenating agent to obtain the intermediate sulfinyl chloride of formula XII ##STR24## in which R.sup.2 is as defined above and Hal is a halogen atom, and subsequently with an acidic compound in order finally to obtain the 3-exomethylcefam derivative of formula XIII ##STR25## in which R.sup.2 is as defined above; (4) submitting the exomethylene bond of compound XIII, obtained in the previous stage, to oxidative cleavage, to obtain the 3-hydroxycefem derivative of formula XIV ##STR26## in which R.sup.2 is as defined above; (5) performing the following three reactions: (i) substitution of the hydroxyl group in position 3 by a chlorine atom, (ii) reduction of the sulphoxide group, and (iii) reduction of the N-nitroso group in the lateral chain, by which a compound of formula XVI is obtained ##STR27## in which R.sup.2 is as defined above; and (6) de-protection of the side chain and the carboxyl group, finally separating the product of formula I.
- 2. The process of claim 1, in which the base used in Stage (1) is a tertiary amine.
- 3. The process of claim 2, in which the amine is triethylamine.
- 4. The process of claim 1, in which the agent used in the nitrosylation in Stage (1) is an alkali metal salt of nitrous acid.
- 5. The process of claim 4, in which the alkali metal salt is sodium nitrite.
- 6. The process of claim 1, in which the agent used in the esterification in Stage (2) is selected from the group consisting of alkyl halides, benzyl halides and derivatives thereof.
- 7. The process of claim 6, in which the agent is selected from the group consisting of methyl iodide, benzyl chloride or para-nitrobenzyl bromide.
- 8. The process of claim 1, in which the esterification which is performed in Stage (2) takes place in the presence of an acid acceptor.
- 9. The process of claim 8, in which the acid acceptor is selected from the group consisting of potassium bicarbonate or sodium bicarbonate.
- 10. The process of claim 1, in which the oxidation of the sulphide to sulphoxide in Stage (2) takes place using an ozone-saturated solution as an oxidizing agent in an anhydrous inert solvent at a temperature below 0.degree. C.
- 11. A process according to claim 1, characterized in that peracetic acid or metachlorobenzoic acid, are used as oxidizing agents in Stage (2).
- 12. The process of claim 1, in which the intermediate sulphenyl chloride is obtained in Stage (3) by treating the sulphoxide with a halogenating agent selected from the group consisting of N-haloamides and N-haloimides.
- 13. The process of claim 12, in which the halogenating agent is N-chlorosuccinimide or N-bromosuccinimide.
- 14. The process of claim 1, in which the solvent used in Stage (3) is selected from the group consisting of halogen derivatives and hydrocarbons.
- 15. The process of claim 14 in which the solvent is selected from the group consisting of chloroform, 1,2-dichloroethane, benzene and toluene.
- 16. The process of claim 1, in which the acid used to close the six-member ring in Stage (3) is a compound of the group called Lewis acids.
- 17. The process of claim 16, in which the Lewis acid is selected from the group consisting of aluminum chloride, tin (IV) chloride and zinc bromide.
- 18. The process of claim 1, in which the oxidative cleavage in Stage (4) is carried out by treatment with an ozone-saturated solution in an anhydrous inert solvent at a temperature below 0.degree. C.
- 19. The process of claim 1, in which Stage (5) is carried out by using the reagent formed in the reaction of dimethylformamide with phosphorus trichloride.
- 20. The process of claim 1, in which the three reactions which constitute Stage (5) are carried out in a single step.
- 21. The process of claim 1, in which the de-protection of the acetonylidene group of the side chain is carried out by hydrolysis in the presence of an acid.
- 22. The process of claim 21, in which the acid is trifluoroacetic acid.
- 23. The process of claim 1, in which the de-protection of the ester group is carried out when R is benzhydryl, trichloroethyl or trialkylsilyl by hydrolysis or by reduction, when R is benzhydryl, p-nitrobenzyl or benzyl.
- 24. The process of claim 1, in which the product of formula I in which R is H is separated in an aqueous medium with an isoelectric pH.
- 25. The process for the preparation of 3-chloro-cefem compounds of formula I ##STR28## in which R represents hydrogen, or a therapeutically acceptable salt or ester thereof, which comprises the following stages:
- (1) condensation of the compound of formula VII ##STR29## with acetone in the presence of a tertiary amine, followed by nitrosylation with an alkali metal nitrite in an acid medium, to produce a compound of formula IX ##STR30## (2) in either order subjecting the product of formula (IX) obtained in the previous stage to esterification with a halogen derivative of the formula R.sup.2 -Hal in which Hal represents halogen and R.sup.2 is an ester-forming alkyl or benzyl halide or a derivative thereof in the presence of a basic agent, and to oxidation, by ozone or by a peracid to produce the sulphoxide or formula XI ##STR31## in which R.sup.2 has the value indicated above; (3) treatment of the sulphoxide of formula XI, obtained in the previous stage, first with a chlorinating agent comprising an N-chloroamide or N-chloroimide in a solvent selected from the group consisting of chloroform, 1,2-dichloroethane, benzene and toluene to obtain the intermediate sulphenyl chloride of formula XII ##STR32## in which R.sup.2 is as defined above, and subsequently with a Lewis acid in order finally to obtain the 3-exomethylcefam derivative of formula XIII ##STR33## in which R.sup.2 is as defined above; (4) submitting the exomethylene bond of compound XIII, obtained in the previous stage, to oxidative cleavage by ozonolysis, to obtain the 3-hydroxycefem derivative of the formula XIV ##STR34## in which R.sup.2 is as defined above; (5) performing the following three reactions in a single step: (i) substitution of the hydroxyl group in position 3 by a chlorine atom using the reagent formed by reaction of dimethyl formamide with phosphorus trichloride, (ii) reduction of the sulphoxide group, and (iii) reduction of the N-nitroso group in the lateral chain, by which a compound of general formula XVI is obtained ##STR35## in which R.sup.2 is as defined above; and (6) de-protection of the acetonylidene group by hydrolysis in an acid medium and of the carboxyl group by hydrolysis or reduction, finally separating the product of formula I.
Priority Claims (1)
Number |
Date |
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8900071 |
Jan 1989 |
ESX |
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Parent Case Info
This application is a continuation of application Ser. No. 07/462,411, filed Jan. 9, 1990, now abandoned.
US Referenced Citations (6)
Non-Patent Literature Citations (4)
Entry |
Advanced Organic Chemistry by Jerry March pp. 382-384, 2nd edition McGraw Hill Book Company (1977). |
Pharmazeutische Wirkstoffe, von A. Kleeman, Georg Thieme Verlag, Stuttgart and New York, 1982. |
Biochemicals, Organic Compounds For Research and Diagnostic Reagents, Sigma Chemical Company, pp. 112 and 230 (1991). |
S. Kukolja, J. Chem. Soc. 28: 181 (1977). |
Continuations (1)
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462411 |
Jan 1990 |
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