Claims
- 1. The process of epimerizing a compound having the formula: ##STR11## wherein the symbol indicated as a curved broken line represents the following: ##STR12## wherein R.sub.1 is an easily removable ester blocking group; R' is hydrogen, halo, loweralkanoyloxy, carbamoyloxy, furyl, thienyl, thiazolyl, thiadiazolyl, pyrrolyl, or tetrazolyl; each of which can be substituted with a lower alkyl substituent of 1-6 carbon atoms; X is divalent radical, --0--, --CH.sub.2 --, or --NQ--, wherein Q is hydrogen, formyl, benzyl, or loweralkyl; which comprises the steps of:
- (a) reacting the compound above with an aromatic or aliphatic aldehyde or ketone to yield an intermediate of the formula: ##STR13## wherein the broken curved line is as defined above, and R.sup.2 is loweralkyl or phenyl and R.sup.3 is hydrogen, loweralkyl or phenyl;
- (b) and treating the latter intermediate with a base sufficiently strong to convert the aldimino compound to its anionic form said treatment conducted in the presence of an aprotic solvent and the optional presence of a dipolar aprotic co-solvent, followed by addition of a molecular excess of acid, a carboxylic acid having from 1-5 carbon atoms;
- (c) and reacting the compound thereby produced with acid in the optional presence of an amine, and recovering the product, ##STR14## wherein the curved broken line is as defined above.
- 2. The process of Step (A) of claim 1 wherein a solvent is employed.
- 3. The process of claim 2 wherein the solvent is methylene chloride.
- 4. The process of claim 2 wherein the reaction is conducted at ambient temperature.
- 5. The process of Step (A) of claim 1 wherein the reactants are employed in approximately equimolar amounts.
- 6. The process of Step (B) of claim 1 wherein the aprotic solvent is tetrahydrofuran.
- 7. The process of Step (B) of claim 1 wherein the dipolar aprotic solvent is dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, N-methyl pyrrolidone, or dimethylacetamide.
- 8. The process of Step (B) of claim 1 wherein the strong base is an organosodium, organopotassium or organolithium compound.
- 9. The process of claim 8 wherein the strong base is phenyl lithium, t-butyl lithium or n-butyl lithium.
- 10. The process of claim 1 in which the acid is acetic acid.
- 11. The process of Step (C) of claim 1 wherein the amine is aniline, phenylhydrazine, or 2,4-dinitrophenylhydrazine.
- 12. The process of Step (B) of claim 1 wherein the acid is hydrochloric acid or p-toluenesulfonic acid.
- 13. The process of Step (C) of claim 1 wherein aniline hydrochloride is used as the amine in the presence of acid.
- 14. The process of Step (C) of claim 1 wherein the amine is 2,4-dinitrophenylhydrazine and the acid is p-toluenesulfonic acid.
- 15. The process of Step (B) of claim 1 wherein an alcoholic solvent is used.
- 16. The process of Step (B) of claim 1 wherein the solvent is a lower alcohol having 1-5 carbon atoms.
- 17. The process of claim 1 wherein R.sub.1 is alkyl, of from 1-20 carbon atoms, phthalimidomethyl, succinimidomethyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, 2-methylthioethyl, 2-(p-methylphenyl)-ethyl, methoxymethyl, p-methoxyphenoxymethyl, benzyloxymethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dinitrobenzyl, 2,4,6-trimethylbenzyl or 3,5-dichloro-4-hydroxy-benzyl, benzhydryl, p-methoxybenzhydryl, or trimethylsilyl.
- 18. The process of claim 17 wherein R.sub.1 is methyl, tertiary butyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, p-methoxybenzyl, benzyl, benzhydryl, methoxymethyl, and p-methoxyphenoxymethyl.
- 19. The process of claim 1 wherein the heterocyclic thio substituent is 5-methyl-1,3,4-thiadiazolyl-2-yl or 1-methyl-tetrazol-5-yl.
- 20. The process of claim 1 wherein X is a divalent radical, --0--, --CH.sub.2 --, or --NQ-- wherein Q is hydrogen, formyl, benzyl, or loweralkyl of 1-6 carbon atoms.
- 21. The process of claim 1 wherein R"' is loweralkanoyl having 2-6 carbon atoms.
RELATIONSHIP TO OTHER APPLICATIONS
This application is a divisional application of U.S. Ser. No. 644,250, filed Dec. 24, 1975, now U.S. Pat. No. 4,051,132, issued Sept. 27, 1977, which was a continuation of U.S. application Ser. No. 436,014, filed Jan. 23, 1974, now abandoned, which was a continuation-in-part of U.S. application Ser. No. 350,543, filed Apr. 16, 1973, now abandoned, which was a continuation-in-part of U.S. application Ser. No. 267,858, filed June 30, 1972, now abandoned; this application is also a continuation-in-part of prior co-pending U.S. applications Ser. Nos. 303,906, filed Nov. 6, 1972, 306,066, filed Nov. 13, 1972, 314,484, filed Dec. 12, 1972, 319,945, filed Dec. 29, 1972 and 340,804, filed Mar. 13, 1973, all now abandoned.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
3719667 |
Gutowski |
Mar 1973 |
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Non-Patent Literature Citations (1)
Entry |
Morrison, et al., Organic Chemistry, Sec. Ed. 1966, Allyn and Bacon, Inc., Boston, pp. 989-994. |
Divisions (1)
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Number |
Date |
Country |
Parent |
644250 |
Dec 1975 |
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Continuations (1)
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Number |
Date |
Country |
Parent |
436014 |
Jan 1974 |
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Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
350543 |
Apr 1973 |
|
Parent |
267858 |
Jun 1972 |
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