Claims
- 1. A process for the production of clavulanic acid, a pharmaceutically acceptable salt thereof or an ester thereof of the sub-formula (a), (b), (c) or (d): ##STR4## wherein R.sup.1 is hydrogen or alkyl, alkenyl or alkynyl of up to 3 carbon atoms; R.sup.2 is hydrogen or methyl; R.sup.3 is phenyl unsubstituted or substituted by a fluorine, chlorine or bromine atom or by a nitro, methyl or methoxy moiety; R.sup.4 is hydrogen or phenyl unsubstituted or substituted by a fluorine, chlorine or bromine atom or by a nitro, methyl or methoxy moiety; R.sup.5 is hydrogen or methyl; R.sup.6 is alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; or R.sup.5 is joined to R.sup.6 to form together with --CH.OCO moiety a phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl moiety; and R.sup.7 is alkyl of 1 to 4 carbon atoms, chlorophenyl or nitrophenyl moiety; or CHR.sup.1 R.sup.2 is phenacyl or bromophenacyl, which comprises:
- (a) subjecting the tertiary-butylamine salt of clavulanic acid to ion-replacement to produce clavulanic acid or a pharmaceutically acceptable salt thereof;
- (b) esterifying the tertiary-butylamine salt of clavulanic acid to the desired ester; or
- (c) converting the tertiary-butylamine salt of clavulanic acid to the free acid or another salt and esterifying said acid or said other salt to the desired ester.
- 2. A process according to claim 1 wherein the process is ion-replacement and a solution of the tertiary-butylamine salt is passed through a bed of a cation exchange resin.
- 3. A process according to claim 2 for the production of the sodium, potassium or calcium salt of clavulanic acid, wherein the cation exchange resin is in the sodium, potassium or calcium form respectively.
- 4. A process according to claim 1 wherein the process is ion-replacement by metathesis of the tertiary-butylamine cation with a suitable base.
- 5. A process according to claim 4 wherein the base is a carbonate, bicarbonate or hydroxide of a pharmaceutically acceptable alkali or alkaline earth metal, or a salt of an alkanoic acid of a formula (III):
- R.sup.10 --CO.sub.2 H (III)
- wherein R.sup.10 is alkyl of 1-20 carbon atoms.
- 6. A process according to claim 5 wherein said alkanoate salt is used and the salt is the acetate, propionate or ethylhexanoate salt.
- 7. A process according to claim 5 for the preparation of the potassium or sodium salts of clavulanic acid wherein the alkanoate salt is potassium 2-ethylhexanoate or sodium 2-ethylhexanoate.
- 8. A process according to claim 1 for the production of an ester of clavulanic acid wherein the tertiary-butylamine salt of clavulanic acid is reacted with an alcohol or thiol in the presence of carbodi-imide.
- 9. A process according to claim 1 for the production of an ester of clavulanic acid wherein the tertiary-butylamine salt of clavulanic acid is reacted with a diazo compound.
- 10. A process for the purification of clavulanic acid, a pharmaceutically acceptable salt thereof or ester thereof of the sub-formula (a), (b), (c) or (d): ##STR5## wherein R.sup.1 is hydrogen or alkyl, alkenyl or alkynyl of up to 3 carbon atoms; R.sup.2 is hydrogen or methyl; R.sup.3 is phenyl unsubstituted or substituted by a fluorine, chlorine or bromine atom or by a nitro, methyl or methoxy moiety; R.sup.4 is hydrogen or phenyl unsubstituted or substituted by a fluorine, chlorine or bromine atom or by a nitro, methyl or methoxy moiety; R.sup.5 is hydrogen or methyl; R.sup.6 is alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbon atoms; or R.sup.5 is joined to R.sup.6 to form together with the --CHOCO moiety a phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl moiety; and R.sup.7 is alkyl of 1 to 4 carbon atoms, chlorophenyl or nitrophenyl moiety; or CHR.sup.1 R.sup.2 is phenacyl or bromophenacyl, which comprises:
- (a) contacting impure clavulanic acid in a suitable organic solvent with tertiary-butylamine;
- (b) isolating the tertiary-butylamine salt of clavulanic acid; and
- (c) converting the thus-formed tertiary-butylamine salt of clavulanic acid into clavulanic acid or a pharmaceutically acceptable salt or esterifying it to such an ester thereof.
- 11. A process according to claim 10 for the purification of the sodium, potassium, calcium or magnesium salt of clavulanic acid wherein the thus-formed tertiary-butylamine salt of clavulanic acid is converted to the sodium, potassium, calcium or magnesium salt thereof.
- 12. A process according to claim 11 for the purification of the sodium or potassium salt of clavulanic acid wherein the thus-formed tertiary-butylamine salt of clavulanic acid is converted into the sodium or potassium salt of clavulanic acid.
- 13. A process according to claim 10 wherein R.sup.1 is hydrogen, methyl, ethyl, vinyl or ethenyl; R.sup.2 is hydrogen; R.sup.3 is phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl; R.sup.4 is hydrogen; R.sup.6 is methyl, t-butyl or ethoxy; or is joined to R.sup.5 to form a phthalidyl, methoxyphthalidyl or dimethoxyphthalidyl moiety; and R.sup.7 is methyl.
- 14. A process according to claim 10 wherein the ester moiety of the sub-formula (a) is methyl or ethyl; the ester moiety of the sub-formula (b) is benzyl or p-nitrobenzyl; the ester moiety of the sub-formula (c) is acetoxymethyl, pivaloyloxymethyl, .alpha.-ethoxycarbonyloxymethyl or phthalidyl; and the ester moiety of the sub-formula (d) is methoxymethyl.
- 15. A process according to claim 10 wherein the organic solvent is ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, methyl ethyl ketone, acetone, methyl isobutyl ketone, tetrahydrofuran or a mixture thereof.
- 16. A process according to claim 15 wherein the solvent is ethyl acetate.
- 17. A process according to claim 1 wherein R.sup.1 is hydrogen, methyl, ethyl, vinyl or ethenyl; R.sup.2 is hydrogen; R.sup.3 is phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl; R.sup.4 is hydrogen; R.sup.6 is methyl, t-butyl or ethoxy; or is joined to R.sup.5 to form a phthalidyl, methoxyphthalidyl or dimethoxyphthalidyl moiety; and R.sup.7 is methyl.
Priority Claims (1)
Number |
Date |
Country |
Kind |
7927544 |
Aug 1979 |
GBX |
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CROSS-REFERENCE
This is a continuation of Ser. No. 179,760, filed Aug. 20, 1980, abandoned.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
4144242 |
Fleming et al. |
Mar 1979 |
|
4244965 |
Howorth et al. |
Jan 1981 |
|
Foreign Referenced Citations (1)
Number |
Date |
Country |
7502492 |
Apr 1976 |
ZAX |
Non-Patent Literature Citations (1)
Entry |
Beecham II, Chem. Abs. 90, 109963, (6-22-78). |
Continuations (1)
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Number |
Date |
Country |
Parent |
179760 |
Aug 1980 |
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