Patent EA-002449-B1 (EA)
Title: Process for selective preparation of z-isomers of 3-(2-substituted vinyl)cephalosporins
Inventor: OKADA YUMIKO
IPC: C07D501/00
Filed: 1998-06-24
Abstract: 1. A process for the selective production of the Z-isomer of a 7-N-unsubstituted or substituted-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or an ester thereof represented by the following general formula (IV)   wherein R<1> denotes a hydrogen atom or a mono-valent amino-protecting group, or R<1> denotes a 2-(2-N-protected or unprotected-aminothiazol-4-yl)-2-alkoxyiminoacetyl group having the following formula (II)   where R<5> is a hydrogen atom or a mono-valent amino-protecting group and R<6> is a hydrogen atom, or R<5> and R<6> as taken together mean one di-valent amino-protecting group and R<7> is an alkyl group of 1 to 4 carbon atoms, and wherein R<2> denotes a hydrogen atom, or R<1> and R<2> as taken together mean one di-valent amino-protecting group and R<3> denotes a hydrogen atom, a pivaloyloxymethyl group or an ester-forming group as a carboxyl-protecting group, and R<8> denotes a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a trifluoromethyl group or a chloro group, characterized in that said process comprises reacting a 7-N-unsubstituted or substituted-amino-3-[(tri-substituted-phosphoranylidene)methyl]-3-cephem-4-carboxylic acid or an ester thereof represented by the following general formula (I)   where R<1>, R<2> and R<3> each have the same meanings as defined above and R<4> denotes an alkyl group of 1 to 6 carbon atoms or an aryl group, or a compound represented by the following general formula (I')   where R<1>, R<2>, R<3> and R<4> each have the same meanings as defined above, with a 4-substituted or unsubstituted-thiazol-5-carbaldehyde represented by the following formula (III)   where R<8> has the same meaning as defined above. 2. A process according to Claim 1, wherein the reaction of a compound of formula (I) with a compound of formula (III) is effected at a temperature of 0 degree C / -50 degree C. 3. A process according to Claim 1, wherein the mix ratio of the chlorinated hydrocarbon solvent(s) to the lower alkanol(s) present in the mixed solvent as used is in the range of 1:1 to 1:0.28, more preferably in the range of 1:0.5 to 1:0.4, and wherein the reaction of a compound of formula (I) with a compound of formula(III) is effected at a temperature in the range of -10 degree C / -30 degree C, preferably in the range of -10 degree C / -23 degree C. 4. A process according to Claim 1, wherein the chlorinated hydrocarbon solvent is a monochloro-, dichloro-or trichloro-(C1-C2)-alkane, preferably methylene chloride, chloroform or dichloroethane, or a mixture of two or more of them. 5. A process according to Claim 1, wherein the lower alkanol is an alkanol of 1 SIMILAR 6 carbon atoms, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, or a mixture of two or more of them. 6. A process according to Claim 1, wherein the reaction is effected in a mixed solvent consisting of a mixture of chloroform or methylene chloride with n-propanol as mixed at a mix ratio (by volume) in the range of 1:0.25 to 1:0.4, at a temperature in the range of -18 degree C / -23 degree C. 7. A process for the production of a highly pure Z-isomer of a 7-N-unsubstituted or substituted-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or an ester thereof having the following general formula (IV)   wherein R<1> denotes a hydrogen atom or a mono-valent amino-protecting group, or R<1> denotes a 2-(2-N-protected or unprotected-aminothiazol-4-yl)-2-alkoxyiminoacetyl group of the following formula (II)   where R<5> is a hydrogen atom or a mono-valent amino-protecting group and R<6> is a hydrogen atom, or R<5> and R<6> as taken together mean one di-valent amino-protecting group and R<7> is an alkyl group of 1 to 4 carbon atoms, and wherein R<2> denotes a hydrogen atom, or R<1> and R<2> as taken together mean one di-valent amino-protecting group and R<3> denotes a hydrogen atom, a pivaloyloxymethyl group or an ester-forming group as a carboxyl-protecting group, and R<8> denotes a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a trifluoromethyl group or a chloro group, which process comprises reacting in a mixed solvent consisting of a mixture of chloroform or methylene chloride with n-propanol as mixed at a mix ratio (by volume) in the range of 1:0.25 to 1:0.28, at a temperature in the range of -18 degree C / -23 degree C, a 7-N-unsubstituted or substituted-amino-3-[(tri-substituted-phosphoranylidene)methyl]-3-cephem-4-carboxylic acid or an ester thereof having the following general formula (I)   wherein R<1>, R<2> and <3> each have the same meanings as defined above and R<4> denotes an alkyl group of 1 to 6 carbon atoms or an aryl group, or a compound represented by the following general formula (I')   where R<1> , R<2> , R<3> and R<4> each have the same meanings as defined above, with a 4-substituted or unsubstituted-thiazol-5-carbaldehyde represented by the following formula (III)   where R<8> has the same meaning as defined above, thereby to obtain the reaction solution containing the Z-isomer of the 7-N-unsubstituted or substituted-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid or an ester thereof of the general formula (IV) above, then washing said reaction solution with an aqueous potassium pyrosulfite solution, thereafter concentrating the reaction solution, adding to the resulting concentrated solution methanol or butyl acetate or a mixture thereof so as to crystallize the Z-isomer of the compound of formula (IV) out of the solution.