Claims
- 1. A process for preparing a cephalosporanic acid having the formula (V): ##STR7## wherein R.sub.6 CO represents a 2-thienylacetyl group; an .alpha.-substituted-.alpha.-(2-thienyl)acetyl group wherein the substituent is a substituted or unsubstituted benzoyloxy group, a substituted or unsubstituted benzyloxy group, or a substituted or unsubstituted alkoxycarbonyloxy group having 2-3 carbon atoms; an .alpha.-substituted-.alpha.-phenylacetyl group wherein the substituent is halo, azido, hydroxy, alkanoyloxy having 2 to 5 carbon atoms, alkoxycarbonyloxy having 2 to 6 carbon atoms, halogenoalkanoyl having 2 to 3 carbon atoms, benzyloxycarbonyloxy, alkyltio having 1 to 2 carbon atoms, or alkoxycarbonyl having 2 to 5 carbon atoms; a substituted or unsubstituted benzyloxycarbonylamino group; a substituted or unsubstituted alkoxycarbonylamino group having 2 to 6 carbon atoms; a (carbamylalken-2-yl)amino group wherein the alken moiety has 2 to 3 carbon atoms; .alpha.-(t-butyloxy)-.alpha.-(p-methoxyphenyl)acetyl; .alpha.-valeryloxy-.alpha.-(p-nitrophenyl)acetyl; pyridylmercaptoacetyl; tetrazolylacetyl; aminocyclohexanecarbonyl; aminocyclohexadienylacetyl; aminocyclohexenylacetyl and cyanoacetyl;
- which comprises
- contacting an esterifying agent having the formula (II): ##STR8## wherein R.sub.3, R.sub.4 and R.sub.5 may be the same or different, each represents a hydrogen atom, alkyl having from 1 to 4 carbon atoms, phenyl, nitrophenyl, methoxyphenyl, benzoyl, benzyloxy, benzylthio, (C.sub.1 -C.sub.4)alkanoyloxy, benzoxy or benzoyloxy, and X represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonoxy,
- in liquid sulfur dioxide in the presence of a secondary or tertiary amine selected from the group consisting of diethylamine, monomethylaniline, piperidine, pyrrolidine, N,N'-tetramethylguanidine, triethylamine, tripropylamine, tributylamine, pyridine, picoline, lutidine, collidine, quinoline, isoquinoline, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethylpyrrolidine, N,N-dimethylaniline and N,N-diethylaniline, at a temperature of from about -10.degree. to about -5.degree. C., with an N-protected-cephalosporin C having the formula (I): ##STR9## wherein R.sub.1 represents a group selected from the group consisting of C.sub.1 -C.sub.4 alkanoyl; benzoyl; nitrobenzoyl, halobenzoyl; C.sub.1 -C.sub.5 alkoxycarbonyl; C.sub.1 -C.sub.4 haloalkoxycarbonyl; (C.sub.1 -C.sub.4)alkoxy-(C.sub.1 -C.sub.4)alkoxycarbonyl; benzyloxycarbonyl; C.sub.1 -C.sub.2 alkoxybenzyloxycarbonyl; halobenzyloxycarbonyl; phenyl substituted with nitro, methoxy, cyano or carbomethoxy; benzene sulfonyl; tosyl and nitrophenylsulfenyl; R.sub.2 is hydrogen, or together with R.sub.1 forms a ring selected from the group consisting of phthaloyl and halophthaloyl,
- to form a diester having the formula (III): ##STR10## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above,
- contacting the diester (III) in an inert solvent with an iminohalide forming agent at a temperature of from about -10.degree. to about 0.degree. C. to form an iminohalide,
- contacting the iminohalide with a lower alcohol having from 1 to 4 carbon atoms to form an iminoether,
- contacting the iminoether with an active derivative of an organic acid having the formula (IV):
- R.sub.6 --COOH (IV)
- wherein R.sub.6 CO is as defined above;
- said active derivative being selected from the group consisting of an alkali metal salt of a mixed anhydride of said organic acid and sulfur trioxide; and a halide, an anhydride, an active ester, an azide, a cyanide, and an amide of said organic acid, to form a reaction product,
- hydrolyzing said reaction product, and
- converting the ester group at the 4-position of the ring to a carboxylic acid group.
- 2. The process of claim 1, wherein the group ##STR11## of said esterifying agent represents t-butyl, p-nitrophenylmethyl, benzhydryl, di-(p-nitro)benzhydryl, di-(p-methoxy)benzhydryl, benzyloxymethyl, benzylthiomethyl, phenacyl, acetoxymethyl, pivaloyloxymethyl, benzoxymethyl or .alpha.-benzoyloxyethyl.
- 3. The process of claim 1, wherein said ring formed of R.sub.1 and R.sub.2 is a phthaloyl group, a tetrachlorophthaloyl group or a tetrabromophthaloyl group.
- 4. The process of claim 1, wherein said iminohalide forming agent is a phosphorus halide or a phosphoryl halide.
- 5. The process of claim 1, wherein said lower alcohol is methyl alcohol.
- 6. The process of claim 1, wherein said material contacted with the iminoether is an alkali metal salt of a mixed anhydride of an organic acid and sulfur trioxide.
- 7. The process of claim 1, wherein said organic acid is a phenylacetic acid, thienylacetic acid, mandelic acid, pyridylmercaptoacetic acid, tetrazoylacetic acid, 1-amino-cyclohexanecarboxylic acid, .alpha.-aminocyclohexadienylacetic acid, .alpha.-amino-cyclohexenylacetic acid or cyanoacetic acid.
- 8. A process for preparing a cephalosporanic acid having the formula (V): ##STR12## wherein R.sub.6 CO is as defined above; which comprises contacting an N-protected-cephalosporin C diester having the formula (III): ##STR13## wherein R.sub.1 represents a group selected from the group consisting of C.sub.1 -C.sub.4 alkanoyl; benzoyl; nitrobenzoyl; halobenzoyl; C.sub.1 -C.sub.5 alkoxycarbonyl; C.sub.1 -C.sub.4 haloalkoxycarbonyl; (C.sub.1 -C.sub.4)alkoxy-(C.sub.1 -C.sub.4)alkoxycarbonyl; benzyloxycarbonyl; C.sub.1 -C.sub.2 alkoxybenzyloxycarbonyl; halobenzyloxycarbonyl; phenyl substituted with nitro, methoxy, cyano or carbomethoxy; benzene sulfonyl; tosyl and nitrophenylsulfenyl; R.sub.2 is hydrogen, or together with R.sub.1 forms a ring selected from the group consisting of phthaloyl and halophthaloyl,
- in an inert solvent with an iminohalide forming agent at a temperature of from about -10.degree. C. to about 0.degree. C. to form an iminohalide,
- contacting the iminohalide with a lower alcohol having from 1 to 4 carbon atoms to form an iminoether,
- contacting the iminoether with an active derivative of an organic acid having the formula (IV):
- R.sub.6 --COOH (IV)
- wherein R.sub.6 CO is as defined above;
- said active derivative being selected from the group consisting of an alkali metal salt of a mixed anhydride of said organic acid and sulfur trioxide; and a halide, an anhydride, an active ster, an azide, a cyanide, and an amide of said organic acid, to form a reaction product,
- hydrolyzing said reaction product, and
- converting the ester group at the 4-position of the ring to a carboxylic acid group.
- 9. The process of claim 8, wherein the group ##STR14## of said diethyl ester (III) represents t-butyl, p-nitrophenylmethyl, benzhydryl, di-(p-nitro)benzhydryl, di-(p-methoxy)benzhydryl, benzyloxymethyl, benzylthiomethyl, phenacyl, acetoxymethyl, pivaloyloxymethyl, benzoxymethyl, or .alpha.-benzoyloxyethyl.
- 10. The process of claim 8, wherein said ring formed of R.sub.1 and R.sub.2 is a phthaloyl group, a tetrachlorophthaloyl group or a tetrabromophthaloyl group.
- 11. The process of claim 8, wherein said iminohalide forming agent is a phosphorus halide or a phosphoryl halide.
- 12. The process of claim 8, wherein said lower alcohol is methyl alcohol.
- 13. The process of claim 8, wherein said material contacted with said iminoether is an alkali metal salt of a mixed anhydride of an organic acid and sulfur trioxide.
- 14. The process of claim 8, wherein said organic acid is a phenylacetic acid, thienylacetic acid, mandelic acid, pyridylmercaptoacetic acid, tetrazoylacetic acid, 1-aminocyclohexanecarboxylic acid, .alpha.-aminocyclohexadienylacetic acid, .alpha.-aminocyclohexenylacetic acid or cyanoacetic acid.
- 15. A process for preparing an N-protected-cephalosporin C diester having the formula (III): ##STR15## wherein R.sub.1 represents a group selected from the group consisting of C.sub.1 -C.sub.4 alkanoyl; benzoyl; nitrobenzoyl; halobenzoyl; C.sub.1 -C.sub.5 alkoxycarbonyl; C.sub.1 -C.sub.4 haloalkoxycarbonyl; (C.sub.1 -C.sub.4)alkoxy-(C.sub.1 -C.sub.4)alkoxycarbonyl; benzyloxycarbonyl; C.sub.1 -C.sub.2 alkoxybenzyloxycarbonyl; halobenzyloxycarbonyl; phenyl substituted with nitro, methoxy, cyano or carbomethoxy; benzene sulfonyl; tosyl and nitrophenylsulfenyl; R.sub.2 is hydrogen, or together with R.sub.1 forms a ring selected from the group consisting of phthaloyl and halophthaloyl; R.sub.3, R.sub.4 and R.sub.5 may be the same or different, each represents a hydrogen atom, alkyl having from 1 to 4 carbon atoms, phenyl, nitrophenyl, methoxyphenyl, benzoyl, benzyloxy, benzylthio, (C.sub.1 -C.sub.4)alkanoyloxy, benzoxy or benzoyloxy,
- which comprises contacting an N-protected-cephalosporin C having the formula (I): ##STR16## wherein R.sub.1 and R.sub.2 are as defined above, in liquid sulfur dioxide in the presence of a secondary amine or a tertiary amine selected from the group consisting of diethylamine, monomethylaniline, piperidine, pyrrolidine, N,N'-tetramethylguanidine, triethylamine, tripropylamine, tributylamine, pyridine, picoline, lutidine, collidine, quinoline, isoquinoline, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethylpyrrolidine, N,N-dimethylaniline and N,N-diethylaniline, at a temperature of from about -10.degree. C. to about -5.degree. C. with an esterifying agent having the formula (II): ##STR17## wherein R.sub.3, R.sub.4 and R.sub.5 are as defined above, and X represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.
- 16. The process of claim 15, wherein the group ##STR18## of said diester (III) represents t-butyl, p-nitrophenylmethyl, benzhydryl, di-(p-nitro)benzhydryl, di-(p-methoxy)benzhydryl, benzyloxymethyl, benzylthiomethyl, phenacyl, acetoxymethyl, pivaloyloxymethyl, benzoxymethyl, or .alpha.-benzoyloxyethyl.
Priority Claims (1)
Number |
Date |
Country |
Kind |
51/56645 |
May 1976 |
JPX |
|
RELATED APPLICATION
This application is a continuation-in-part of our application Ser. No. 792,799, filed May 2, 1977, and now abandoned.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4022773 |
Ishimaru |
May 1977 |
|
4074047 |
Foxtun et al. |
Feb 1978 |
|
4079180 |
Susuki et al. |
Mar 1978 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
792799 |
May 1977 |
|