Process for carbapenem synthesis

1. A process for synthesizing a compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently are H, C 1-10 alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula II:

by hydrogenolysis in the presence of a prereduced metal catalyst belonging to the group consisting of palladium, platinum and rhodium, and a base to give a solution of formula I, extracting a solution containing a compound of formula I or 3.

or a pharmaceutically acceptable salt thereof, wherein each X + is a charge-balancing group, and R 1 and R 2 are as described above with a C 4-10 alcohol in the presence of an ion-pairing reagent, while maintaining a pH of the aqueous phase between neutral and mildly basic, and isolating the compound of formula I or 3 from the resulting aqueous phase, wherein the metal catalyst is a salt or metal powder or supported on solid supports selected from the group consisting of alumina, silica, calcium carbonate, barium carbonate, barium sulfate, strontium carbonate, polymers, or carbon, P is a carboxyl protecting group which can removed by hydrogenolysis, P* is H, H 2 + , or a protecting group which can be removed by hydrogenolysis, wherein when P* is H 2 + a negatively charged counterion is present.

2. A process according to claim 1 wherein the extraction is conducted using a multi-stage extractor.

3. A process according to claim 2 wherein the extraction is conducted using a multi-stage countercurrent centrifugal extractor.

4. A process in accordance with claim 1 wherein the alcohol is iso-amyl alcohol, tert-amyl alcohol, 1-butanol, 2-butanol, 1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-menthyl-1-pentanol, 2-ethyl-1-butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol and the metal catalyst is prereduced palladium on carbon.

5. A process in accordance with claim 4 wherein the alcohol is iso-amyl alcohol or 1-butanol.

6. A process in accordance with claim 1 wherein the ion-pairing reagent comprises C 6-24 carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids or their salts.

7. A process in accordance with claim 5 wherein ion-pairing reagent is a sodium salt of diphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid.

8. A process according to claim 1 wherein the extracted solution contains a compound of formula 3.

9. A process for synthesizing a compound represented by formula Ia:

or a pharmaceutically acceptable salt thereof, is disclosed comprising deprotecting a compound of formula IIa:

by hydrogenolysis in the presence of a prereduceed metal ctalyst beloning to the group consisting of palladium, platinum and rhodium, and base to give a solution of formula Ia, extracting a solution containing a compound of formula Ia or 3a:

or a pharmaceutically acceptable salt thereof, wherein each X + is a charge-balancing group, with a C 4-10 alcohol in the presence of an ion-pairing reagent, while maintaing a pH of the aqueous phase between neutral and mildly basic, and isolating the compound of formula Ia from the resulting agueous phase, wherein the metal catalyst is a salt or metal powder or supported on solid supports selected from the group consisting of alumina, silica, calcium carbonate, barium carbonate, barium sulfate, strontium carbonate, polymers, or carbon, P is a carboxyl protecting group which can removed by hydrogenolysis, P* is H, H 2 + , or a protecting group which can be removed by hydrogenolysis, wherein when P* is H 2 + a negatively charged counterion is present.

10. A process according to claim 9 wherein the extraction is conducted using a multi-stage extractor.

11. A process according to claim 10 wherein the extraction is conducted using a multi-stage countercurrent centrifugal extractor.

12. A process in accordance with claim 9 wherein the alcohol is iso-amyl alcohol, tert-amyl alcohol, 1-butanol, 2-butanol, 1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-methyl-1-pentanol, 2-ethyl-1-butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol and the metal catalyst is prereduced palladium on carbon.

13. A process in accordance with claim 12 wherein the alcohol is iso-amyl alcohol or 1-butanol.

14. A process in accordance with claim 9 wherein the ion-pairing reagent comprises C 6-24 carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids or their salts.

15. A process in accordance with claim 14 wherein the ion-pairing reagent is a sodium salt of diphenyiphosphoric acid, stearic acid or dodecylbenzenesulfonic acid.

16. A process according to claim 9 wherein the extracted solution contains a compound of formula 3a: