Process for the preparation of hydroxy substituted gamma butyrolactones

Abstract

Preparation of 4-hydroxy substituted butyrolactones is described. A process for the preparation of 3-hydroxybutyrolactone, 1,2,4-trihydroxybutane and 3,4-dihydroxy acid methyl ester from malic acid is particularly described. The preparation of 4-hydroxymethyl-4-hydroxybutyric acid -1-methyl ester and 4-hydroxymethyl butyrolactone is particularly described. The compounds are intermediates to various pharmaceutical and agricultural products.

I claim:  
     
       1. A process for producing a hydroxy substituted compound which comprises: reacting in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester wherein the diacid contains 4 to 8 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent to produce the hydroxy substituted compound. 
     
     
       2. A process for the preparation of a hydroxy substituted gamma butyrolactone which comprises: 
       reading in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester, wherein the diacid contains 4 in 5 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent at a temperature between about −10° and 60° C. to produce the hydroxy substituted gamma butyrolactone and an alcohol as a by-product.  
     
     
       3. The process of  claim 2  wherein the diester is 4-carboxymethyl-4-hydroxybutyric acid-1-methyl ester and wherein the hydroxy substituted gamma butyrolactone is 4-hydroxymethyl butyrolactone. 
     
     
       4. The process of any one of claims  2  or  3  wherein the ester and the hydroxy substituted gamma butyrolactone are isomers. 
     
     
       5. The process of any me of claims  2  or  3  wherein one ester and the hydroxy substituted gamma butyrolactone are isomers, and wherein the isomers are (S) isomers. 
     
     
       6. The process is any one of claims  2  or  3  wherein the ester and the hydroxy substituted gamma butyrolactone are isomers and wherein the isomer are (R) isomers. 
     
     
       7. The process of any one of claims  2  or  3  wherein as an additional step the reaction mixture is acidified and heated to volatilize the alcohol from the vendors mixture and the hydroxy substituted gamma, butyrolactone. 
     
     
       8. The process of  claim 2  wherein the hydroxy substituted gamma butyrolactone is extracted from the reaction mixture with ethyl acetate. 
     
     
       9. The process of  claim 2  wherein in the ester the lower alkyl is methyl, wherein the alkylene contains five carbon atoms and wherein the butyrolactone is 4-hydroxymethyl gamma butyrolactone. 
     
     
       10. A process for the preparation of a compound selected from the group consisting of 1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid -1-methyl ester and mixtures thereof which comprises: 
       (a) reacting in a reaction mixture malic acid with a molar excess of anhydrous methanol in the presence of a catalytic mount of hydrogen ion end at a temperature between about 40° and reflux to produce hydroxybutane dioic acid di methyl ester; and  
       (b) reducing the hydroxybutane dioic acid dimethyl ester with an alkali metal borohydride to produce the compound.  
     
     
       11. The process of claim  10   27 wherein about one equivalent of the alkali metal borohydride is reacted with the hydroxybutane dioic acid dimethyl ester andto produce wherein the compound is substantially  the 3.4-hydroxybutyric acid methyl ester. 
     
     
       12. The process of  claim 10  wherein about three equivalents of the alkali metal borohydride is reacted with the hydroxy butane dioic acid dimethyl ester and the compound is substantially the 1,2,4-trihydroxybutane. 
     
     
       13. The process of any one of claims  10 ,  11  or  12  wherein the malic acid is an isomer. 
     
     
       14. The process of any one of claims  11  or  12  wherein the malic acid is an isomer and the humid is the (S) isomer. 
     
     
       15. The process of any one of  claim 11  or  12  wherein the malic acid is an isomer and the isomer is the (R) isomer. 
     
     
       16. The process of  claim 10  wherein the 3.4-dihydroxybutyric acid methyl ester is extracted from the reaction mixture with ethylacetate. 
     
     
       17. The process of  claim 10  wherein the reaction mixture in step (a) is refluxed. 
     
     
       18. The process of  claim 11  wherein as an additional step the 3,4-dihydroxy butyric acid -1-methyl ester is acidified and heated to volatilize the methanol from the reaction mixture from step (a) and  to produce the hydroxylactone   4 -hydroxymethyl butyrolactone.  
     
     
       19. The process of  claim 18  wherein about one equivalent of the alkali metal borohydride which is lithium borohydride is reacted with the hydroxy butane dioic acid dimethyl ester to produce the 3,4-dihydroxybutyric acid -1-methyl ester. 
     
     
       20. The process of  claim 10  wherein the 1,2,4-trihydroxybutane is extracted from the reaction mixture using water. 
     
     
       21. The process of  claim 19  wherein the malic acid is as the (R) isomer and the compound   3 , 4  dihydroxybutyric acid-   1   - methyl ester  produced is the (R) isomer. 
     
     
       22. The process of  claim 19  wherein the malic acid is as the (S) isomer and the compound   3 , 4 -dihydroxy butyric acid-   1   - methyl ester  produced is the (S) isomer. 
     
     
       23. The process of  claim 10  wherein in addition the 3,4-hydroxy butyric acid -1-methyl ester is separated and reacted with an acid to form 3-hydroxy gamma butyrolactone. 
     
     
       24. The process of  claim 1  wherein the alkali metal borohydride is lithium borohydride. 
     
     
       25. The process of  claim 2  wherein the alkali metal borohydride is lithium borohydride. 
     
     
       26. The process of  claim 10  wherein the alkali metal borohydride is lithium borohydride. 
     
     
       27. A process for the preparation of  3 , 4 - dihydroxybutyric acid -   1   - methyl ester which comprises:    
       ( a )  reacting in a reaction mixture malic acid with a molar excess of anhydrous methanol in the presence of a catalytic amount of hydrogen ion and at a temperature between about  40 ° and reflux to produce hydroxybutane dioic acid dimethyl ester; and    
       ( b )  reducing the hydroxybutane dioic acid dimethyl ester with an alkali metal borohydride to produce the  3 , 4   - dihydroxybutyric acid -   1   - methyl ester.   
     
     
       28. The process of any one of claims  11  or  27  wherein the malic acid is an isomer. 
     
     
       29. The process of  claim 11  wherein the malic acid is an isomer and the isomer is the ( S )  isomer.   
     
     
       30. The process of  claim 11  wherein the malic acid is an isomer and the isomer is the ( R )  isomer.   
     
     
       31. The process of  claim 27  wherein the  3 , 4 - dihydroxybutyric acid methyl ester is extracted from the reaction mixture with ethylacetate.   
     
     
       32. The process of  claim 27  wherein the reaction mixture in step ( a )  is refluxed.   
     
     
       33. The process of  claim 27  wherein in addition the  3 , 4 - hydroxy butyric acid -   1   - methyl ester is separated and reacted with an acid to form  3   - hydioxy gamma butyrolactone.   
     
     
       34. The process of  claim 27  wherein the alkali metal borohydride is lithium borohydride.