IL44791A

IL44791A - Cephalosporin cleavage process

Info

Publication number: IL44791A
Application number: IL44791A
Authority: IL
Original assignee: Lilly Co Eli
Priority date: 1973-06-18
Filing date: 1974-05-09
Publication date: 1976-09-30
Also published as: GB1474544A; US3905966A; IE39253B1; IL44791A0; FR2233328A1; ES448016A1; NL7408170A; CH601313A5; JPS61352B2; FR2233328B1; CA1018155A; DE2429166A1; BE816408A; ES427388A1; JPS5036488A; IE39253L

Claims

■A: What we claim is :

1. A process for cleaving the amic acid function ΐ:ι of a 7- (amic acid) cephalosporin having the formula 0 COO R I in which R and R are hydrogen, or R and R taken together a a with the carbon atoms to which they are attached represent an ortho-phenylene ring; R^ is a carboxy protecting group; and 2 is hydrogen, acetoxy, methoxy, methylthio, (5-methyl-l , 3 , 4- thiadiazol-2-yl ) thio , or ( l-methyl-lH-tetrazol-5-yl ) thio ; which comprises (1) reacting said 7- (amic acid) cephalosporin with an alkyl chloroformate in the presence of a tertiary amine to form the corresponding mixed anhydride having the formula 0 in which R, is an alkyl group having from 1 to 4 carbon atoms; X- 3996 - 35 - (2) reacting the product mixture from the aforementioned chlorofprmate treatment with a hydrazine of the formula R3HNNHR4 in which ^ and R^ independently are hydrogen or methyl; and (3) a) reacting the reaction mixture from the aforementioned hydrazine treatment with an acyl halide to produce the corresponding 7-acylamido cephalosporin; or b) when at least one of R3 and ^ is methyl, recovering the corresponding 7-amino cephalosporin from the reaction 10 mixture of the aforementioned hydrazine treatment; or c) when R^ and R^ are hydrogen, heating the reaction mixture from the aforementioned hydrazine treatment to a temperature of from about 50 °C. to about 100 °C. to produce the corresponding 7-amino cephalosporin; or d) when R^ and R^ are hydrogen, reacting the reaction mixture from the aforementioned hydrazine treatment with acid to produce the corresponding 7-amino cephalosporin in the form of its acid addition salt.

2. Process of claim 1, in which the reaction 20 mixture from the hydrazine treatment is reacted with an acyl halide to produce the corresponding 7-acylamido cephalosporin.

3. Process of claim 1, in which the product mixture from the chloroformate treatment is reacted with a hydrazine in which at least one of R^ and R^ is methyl, and the 7-amino cephalosporin is recovered from the reaction mixture.

4. Process of claim 1, in which the product mixture from the chloroformate treatment is reacted with a hydrazine in which R_ and R. are hydrogen, and the resulting X-3996 -36- reaction mixture is heated to a temperature of from about 50°C. to about 100°C. to produce the 7-amino cephalosporin.

5. Process of claim 1, in which the product mixture from the chloroformate treatment is reacted with a hydrazine in which R3 and R4 are hydrogen, and the :■-,,->- resulting reaction mixture is reacted with acid to produce the 7-amino cephalosporin in the form of its acid addition sal .

6. Process of any of claims 1 to 5, in which the . 10 amic acid cephalosporin is reacted with an alkyl chloroformate in the presence of a tertiary amine at a temperature of from about -20°C. to about +5°C.

7. Process of any of claims .1 to 6, in which the alkyl chloroformate is ethyl chloroformate .

8. Process of claim 5, in which the product mixture from the chloroformate treatment is first reacted with up to 1 equivalent of a hydrazine in which and are hydrogen per equivalent of the amic acid at a temperature of from about -10 °C. to about room temperature for from about 1 to about 20 10 minutes, and the resulting reaction mixture is reacted with from about 1 to about 2 equivalents of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, and sulfuric acid per equivalent of the original amic ... acid for about 5 to about 10 minutes to produce the corresponding 7-amino cephalosporin in the form of its acid addition salt.. X-3996 -37-

9. Process of claim 3, in which the product mixture from the chloroformate treatment is first reacted with up to 1 equivalent of a hydrazine in which at least one of and R4 is methyl per equivalent of the amic acid at a temperature of from about -10 °C. to about room temperature for from about 1 to about 10 minutes to produce the corresponding 7-amino cephalosporin.

10. Process of any of claims 1 to 9 for cleaving the amic acid function of a compound of formula I in which R and R are hydrogen. el

11. Process of any of claims 1 to 9 for cleaving the amic acid function of a compound of formula I in which R and R¾ taken together with the carbon atoms to which they are attached represent an ortho-phenylene ring.

12. A process for cleaving the amic acid function of a 7- (amic acid) cephalosporin substantially as hereinbefore described with particular reference to the examples. S. HOROWITZ & CO. AGENTS FOR APPLICANTS X-3996 -38-