IL42087A

IL42087A - The preparation of 7-aminocephalosporanic acid derivative

Info

Publication number: IL42087A
Application number: IL42087A
Authority: IL
Original assignee: Lilly Co Eli
Priority date: 1972-05-01
Filing date: 1973-04-20
Publication date: 1976-01-30
Also published as: JPS4947387A; RO62896A; NL7306068A; JPS5842194B2; IL42087A0; YU108273A; IE37562L; FR2183098A1; ES414153A1; GB1421199A; HU167595B; CH582184A5; SU587867A3; HU167444B; IE37562B1; FR2183098B1; AR203623A1; AU5468973A; DE2321234A1; DD105239A5

Claims

1. In a process for- cleaving a 7-carbox-amido group of a pephalosporin of the formula C00Rx wherein R is aminoadipoyl; an aminoadipoyl in which the amino group is protepted with to 03-,-alkanoyl, to C12-aroyl, to C^-alkylpxycarbonyl, Cg to C12^aryloxy-carbpnyl, or such a protecting group substituted with halogen, nitro or C to C^-alkyloxy groups; or R is a C2 to CQ alkanoyl, a to dihaloal-kanoyl, wherein Y is oxygen, sulfur or a carbon to carbon bond; n is an integer of from 0 to 3 andiis ;&t jleasjt 1 when Y is oxygen or sulfur; m is an integer of from 1 to 3; Q, is amino, hydroxy, carboxy; pr R is otherwise the acyl group derived from a penicillin used to prepare the cephalosporin; Cg-C^-thioalkanoyloxy C^-C12-thioaroyloxy hydroxy, mercaptp, hydrogen C^-C^-alkoxythlonocarboxylthio C-|_-C^-alkoxy, or C, -C,-alkylthio; and R is hydrogen, alkali metal, or a car oxyl esteri ing O group selected from 2,2, 2 tr'i

2. A process as defined in claim 1 wherein cephalosporin C, an alkali metal salt of cephalosporin C, or an N-acylated cephalosporin C compound is (1) suspended 0 or dissolved in tetrahydrofuran, and therein (2 ) treated with an C- Cg-alkanoyl halide in the presence of a base to block the carbo yls of the cephalosporin C molecule with anhydride groups, ( 3 ) the cephalosporin C anhydride product from step (2) is treated with base and phosphorus pentachloride at -25°C. to 30°C. to form the imino halide of the cephalosporin C molecule, (4) the imino halide from step (3) is treated with an alcohol to form' the cephalosporin C imino-ether, ( 5) the cephalosporin C imino-ether from step (4) is treated with water to cleave the cephalosporin C side chain, (6 ) the reaction product from step (5) is treated with base to adjust the pH of the mixture to the isoelectric point of 7-ACA to form 7-ACA, and (7 ) the 7-ACA is recovered from the reaction medium.

3. A process as defined in claim 2 wherein an N-chloroaqetyl cephalosporin C quinoline salt is suspended in tetrahydrofuran and treated with an N,N-bis-(C1 to With acetyl chloride' to block the carboxyl groups to mixed anhydride groups, the mixed anhydride is cooled to less than 0°C. and is treated with phosphorus pentachloride in the presence of base to form the imino chloride, the imino chloride is treated with a C1 to C^ alkanol to form the imino-ether, the imino-ether is treated with an aqueous medium to cleave the 7-acyl side chain aaad- to- form,'-7-am.inoce'ph"alo-sporanic acid therein, and the pH is adjusted with a base to a pH at which 7-aminpcephalosporanic acid precipitates therefrom.

4. A process as defined in claim 2 wherein an alkali metal salt of cephalosporin C is suspended or dissolved in tetrahydrofuran and treated with an N,N-bis C-L to C^-dialkyl)aniline and with acetyl chloride to block the carboxyl groups with mixed anhydride groups, the mixed anhydride is cooled to less than 0°C and is treated with phosphorus pentachloride in the presence of a base to form the iminOf-chlpride , the imino-chlo-ride is treated with an alcohol to form the imino-ether, the imino-ether is treated with an aqueous medium to cleave the 7-acyl side chain and to form 7-amino-cephalosporanic aoid therein, and the pH of the mixture is adjusted with a base to a pH at which 7-aminocep-halosporanic acid precipitates therefrom.

5. A process as defined in claim 1 whe'rein a 7-acylamidodesacetoxycephalosporanate ester is ^ljj suspended or dissolved in tetrahydrofuran , and therein (2 ) treated with a base and phosphorus pentachloride at -25° to 30°C. to form the ' iiiiino halide of the 7-acyl-amidodesacetoxycephalpspdririate ester, (3) the imino halide from step (2) is treated with an alcohol to form the imino-ether, ( the imino-ether from step (3) is treated with water to cleave the imino-ether, ( 5) the reaction product from step (^) is treated with base to adjust the pH of the mixture to precipitate the 7-amino desacetoxycephalosporinate ester w-ucleus , and (6) the 7-aminodesacetoxycephalosporinate ester nucleus is recovered from the reaction medium.

6. A process as defined in claim 5 wherein the 7-acylamldodesacetoxycephalosporanate ester starting material is p-nitrobenzyl 7-^phenpxyacetamidodesacetoxy- cephalosporinate to form as product pf the process the p-nitrobpnzyl 7-aminodesacetoxycephalosporinate .

7. A process as defined in claim 5 wherein the 7-acylamidodesacetoxycephalpsporahte ester starting material is 2,2,2-trichloroethyl 7-phenoxyacet-amidodesacetoxycephalosporanate to form as product of the process the 2,2,2-trichloroethyl ce'ph'alosporlnate ester.

8. A process as defined in claim 2 which comprises (l) mixing sodium cephalosporin C with tetrahy-drofuran, (2 ) treating the mixture from step (l) with quinoline, ( 3 ) treating the mixture from step (2) with acetyl chloride in the presence of a base to block the carboxyl groups of the cephalosporin C molecule with anhydride groups, (4) treating the anhydride product from, step (3) with phosphorus pentachloride in the presence of a base to form the imino halide, ( 5 ) treating the imino halide from step ( ) with methanol to form the methyl imino-ether, (6) treating the methyl imino^ ether from step 5 with water to form 7^aminocephalo-sporanic acid, in the reaction mixture, (7 ) treating the mixture from step 6 with sufficient ammonium hydroxide to raise the pfi of the mixtures at which the 7-aminocephal'osporanic acid precipitates from the reaction mixture, and ( 8) recovering the 7-aminocephalosporanic acid.

9. A propess as defined in any one of claims 1 to 8 which comprises incorporating quinoline, iso-quinoline, 3-picoline, ^-picoline, pyridine or an acid addition salt of one or more thereof or a complex thereof with a C2 to .alL'kanoyl halide' into the organic diluent.

10. A process as defined in claim 1 wherein R is' R2C(0)- where in R2-C(0)- is the carboxylic acyl group to be cleaved; X is hydrogen, to C^-alkanoyloxy Cl to C6 alky^oxv or cl to c6 alkylthio; and ^ is hydrogen or an, alkali metal cation, to form a 7-amino-, cephalosporin nucleus of the formula C00H or a solution, salt or solvated form thereof, which comprises incorporating a catalytic amount of quinoline, isoquinoline , 3-Picoline, -picoline, pyridine or an acid addition salt pf one or more of such bases, or a complex thereof with a to C^-alkanoyl halide into the tetrahydrofuran, bis (2-methoxyethyl )ether , 2-methoxyethyl acetate, ethylene gl-yool diaootato, 1, -dioxane or 1,3-dioxane containing medium prior to the addition of the halogenating agent,

11. A process as defined in claim 10 wherein an alkali metal salt of cephalosporin C is incorporated into tetrahydrofuran , and treated by the described process to form 7-aminocephalosporanic acid.

12. A process as defined in claim 11 wherein quinoline or an acid addition salt thereof is used as the catalyst.

13. A process as defined in claim 12 wherein the quinoline is added in a molar ratio from about 3 to 10 millimoles of quinoline per 20 milli-moles of alkali metal cephalosporin C.

14. 1 . A process as defined in olaim 10 wherein quinoline is added to a mixture of sodium cephalosporin C and tetrahydrofuran prior to or simultaneously with a C2 to C^-alkanoyl halide, blocking reagent.

15. A process as defined in claim 1 for cleaving the 7-(5'-aminoadipoyl) side chain for sodium cephalo sporin C to form 7-aminocephalosporanic acid by the steps of commingling sodium cephalosporin C with tetrahydrofuran and a hydrogen^ halide absorbing base, adding acetyl chloride to acylate the cephalosporin C carboxyl and amino groups, adding phosphorus pentachloride and a base to form the imino-chloride of the acylated cephalosporin C, adding methanol to form the imino-ether, and hydrolyz-ing the reaction product with water, which comprises incorporating quinoline, isoquinoline , 3-Picoline, -pico-line, pyridine or an acid addition salt or a complex of such a base with a to C -alkanoyl chloride, into the reaction mixture prior to or simultaneously with addition of acetyl chloride to the sodium cephalosporin C/tetra-hydrofuran mixture.

16. A process according to claim 9 wherein quinoline and acetyl chloride are incorporated.

17. A process according to claim 10 wherein the catalyst is isoquinoline, 3-picoline, picoline, pyridine or an acid addition salt or complex thereof.