Manufacture of cefalosporins and intermediates
AssigneeMiat S.p.A.
InventorGlordano Lesma
Life of this patent
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Abstract
There is described a process for the preparation of 3-disubstituted cepham-4-carboxylic acid derivatives of formula I 1 wherein R″ is 4-methoxybenzyl, X is the residue of a thioether and Z is a residue of a nucleophilic compound and the conversion of these novel intermediates into the corresponding 3-cephem derivatives by oxidative cleavage of the mercaptan X-SH. By suitable deprotection, these 3-cephem derivatives afford cephalosporins such as ceftiofur, cefotaxime and ceftriaxone.
Claims19
Process for the preparation of a 3-disubstituted cepham-4-carboxylic acid derivative of formula I
- 24
- wherein R″ is 4-methoxybenzyl, X is the residue of a thioether and Z is the residue of a nucleophilic compound selected from the group consisting of 2-furoylthio, acetoxy and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- 1,2,4-triazin-3-ylthio radicals, which comprises
- (i) reacting a functional derivative of the α-(2-chloroacetamido)thiazol-4-yl-α-methoxyiminoacetic acid of formula II
- 25
- with a 7β-amino-3-methylenecepham-4-carboxylic acid derivative of formula III
- 26
- wherein R″ is 4-methoxybenzyl, or with an addition salt thereof;
- (ii) treating the corresponding 4-methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-methylenecepham-4-carboxylate thus obtained of formula IV
- 27
- wherein R″ is 4-methoxybenzyl, with a S-chloromercaptan of formula X—S—Cl, in which X is as defined above;
- and
- (iii) reacting the corresponding 4-methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-thio-3-chloromethylcepham-4-carboxylate thus obtained of formula V
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- wherein R″ and X are as defined above, with a compound of formula M-Z, in which M is an alkaline metal or a hydrogen atom and Z is the residue of a nucleophilic compound selected from the group consisting of the 2-furoylthio, acetoxy and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- 1,2,4-triazin-3-ylthio radicals.
A process for preparing cefotaxime which comprises
- (a) reacting a functional derivative of the α-(2-chloroacetamido)thiazol-4-yl-α-methoxyiminoacetic acid of formula II
- 35
- with a 7β-amino-3-methylenecepham-4-carboxylic acid derivative of formula III
- 36
- wherein R″ is 4-methoxybenzyl, or with an addition salt thereof;
- (b) treating the corresponding 4-methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-methylenecepham-4-carboxylate thus obtained of formula IV
- 37
- wherein R″ is 4-methoxybenzyl, with a S-chloromercaptan of formula X—S—Cl, in which X is the residue of a thioether;
- and
- (c) reacting the corresponding 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-thio-3-chloromethyl-4-carboxylic acid derivative thus obtained of formula V
- 38
- wherein R″ and X are as defined above, with sodium or potassium acetate;
- (d) submitting the compound thus obtained of formula Ia
- 39
- wherein X and R″ are as defined above, to an oxidation with a peracid;
- (e) submitting the compound thus obtained of formula VII
- 40
- wherein R″ is as defined above, to a reduction with stannous chloride;
- and
- (f) deprotecting the compound thus obtained of formula VIIIa
- 41
- wherein R″ and Z are as defined above, to obtain cefotaxime.
4-Methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-methylenecepham-4-carboxylate of formula IV
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- wherein R″ is 4-methoxybenzyl.
3,3-Disubstituted cepham derivatives of formula I′
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- wherein R″ is 4-methoxybenzyl, Z′ is a chlorine atom or a radical selected from the group consisting of the 2-furoylthio, acetoxy, and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-ylthio radicals and X is the residue of a thioether.
4-Methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-chloromethyl-3-cephem-4-carboxylate of formula VI
- 45
- wherein R″ is 4-methoxybenzyl.
Dependencies are inferred from the claim text.