Subsequent Chemical Steps to Pregabalin

Pathway A employed a reductive cyclization [21] to form 3-carboxy-4-alkyl-pyrrolidin-2-one (17), which could then be converted to pregabalin under acidic conditions pathway B employed a hydro lysis/reduction/decarboxylation analogous to the one used in the first-generahon route via intermediate 18 [7], and pathway C involving a heat-mediated decarboxylation to intermediate 19 followed by a hydrolysis/reduchon sequence to yield pregabalin. In pathway A, the hydro-genahon of 13 was performed in predominantly aqueous medium at neutral pH, with catalyhc amounts of Raney nickel, and afforded 17 in 95% isolated yield. The reduction could be performed at relatively high substrate loads (0.5-1.OM), 

Pathway B utilized conditions from the classical resolution route [7] which used 4 as the starting material instead of 13. Less exploratory work was done on this pathway, mainly because of the higher risk of epimerization of the C3 center under highly alkaline conditions as well as the difficult isolation of 18, which imphed carrying enzyme (as well as enzyme by-products) to the API isolation step. The poisoning of the Raney nickel by the enzyme found in pathway A also made this an undesirable option. 

The improvements in the route can be appreciated by examining the ratio of the kg of total waste to kg of pregabalin product (E factor) [8]. The classical resolution 

40-45% overall isolated yield (after recycling 4 once), 99.5% purity and 99.75% ee 

The examination of the total reagent usage in the two processes (last row in Table 8.3) clearly shows that the new enzymatic route (with recycling of 4) utilizes 7 times less input of chemicals. This includes 12 times less input of solvents as compared to the first-generation route. Moreover, in the optimized process, every chemical reaction is run in water with minimal solvents used for work-up. Some of the process water can be sent directly to the wastewater treatment plant, and the solvent from the hydrolysis/decarboxylation process is recovered. Further improvements from pilot plant and production scale runs have been demonstrated and will be implemented in the future. 

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