Enzymatic Resolution of trans-4-(4‘-Fluorophenyl)-3-hydroxymethylpiperidines, Key Intermediates in the Synthesis of (−)-Paroxetine

Abstract

Two Candida antarctica lipases catalyze the enantioselective acylation of N-substituted trans-4-(4'-fluorophenyl)-3-hydroxymethylpiperidines in organic solvents. These two lipases show opposite stereochemical preference in these processes. Both enantiomers can be obtained in their optically pure forms. The (3S,4R) isomer, is an intermediate for the synthesis of (-)-Paroxetine.

Molecular cloning of enantioselective ester hydrolase fromBacillus pumilusDBRL-191

“…The rate of reaction as well as selectivity was poor for propionate and butyrate derivatives (ee < 10%). It should be mentioned here that only a few enzymes have reportedly displayed the capability of resolution of paroxetine intermediate 7 [36–38]. BPE also displayed the capacity to resolve racemic 8 (Table 1), displaying moderate selectivity for S ‐isomer leaving the required R ‐ester of 70–72% ee after 71–72% conversion.…”

Developing a Commercially Viable Process for an Active Pharmaceutical Ingredient, Challenges, Myths and Reality in the Art of Process Chemistry

“…This was then condensed with sesame in the next step of to obtain Nmethyl paroxetine, using the novel solvent sulpholane and polar solvents like DMSO, N-methyl pyrrolidone, dimethyl acetamide, 2-ethoxy ethanol or methanol. N-methyl paroxetine obtained by this method was far more superior in quality than obtained by using prior art methods [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and the overall yield was in the range of 80% to 85% with respect to the starting (-) carbinol.…”

Biocatalysis Applied to the Synthesis of Nucleoside Analogs

“…A short and convenient synthesis of 3 ′ -and 5 ′ -O -levulinyl -2 ′ -deoxynucleosides [17] has been developed in Scheme 10.4 from the corresponding 3 ′ ,5 ′ -di -O -levulinyl derivatives by regioselective enzymatic hydrolysis, avoiding several tedious chemical protection/deprotection steps. Candida antarctica lipase A ( CALA ) has been identifi ed as an ideal biocatalyst for the resolution of sterically hindered compounds [18] and in some cases has shown an opposite enantioselectivity to CALB [19] . In addition, the regioselective acylation of 2 ′ -deoxynucleosides showed opposite regioselectivity using either CALA or CALB.…”