Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin.
An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.
Gill
Iqbal
I
Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, One Squibb Drive, New Brunswick, NJ 08903, USA. iqba.gill@bms.com
Patel
Ramesh
R
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000641:Ammonia / Q000378:metabolism*; D001194:Asbestos / Q000494:pharmacology; D001709:Biotechnology; D002122:Calcium Chloride / Q000494:pharmacology; D002219:Carbamates / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002384:Catalysis; D003998:Dicarboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004952:Esters / Q000737:chemistry* / Q000494:pharmacology; D004980:Ethane / Q000031:analogs & derivatives; D000431:Ethanol / Q000378:metabolism; D005656:Fungal Proteins; D008049:Lipase / Q000378:metabolism; D015394:Molecular Structure; D009584:Nitrogen / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D012972:Sodium Hydroxide / Q000494:pharmacology; D013237:Stereoisomerism
C508948:1-(1,1-dimethylethyl)-5-ethyl ester; C508947:4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid; D002219:Carbamates; D003998:Dicarboxylic Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D004952:Esters; D005656:Fungal Proteins; D011758:Pyrroles; D001194:Asbestos; D002245:Carbon Dioxide; D000431:Ethanol; D012972:Sodium Hydroxide; D000641:Ammonia; C006638:ascarite; C502994:saxagliptin; D008049:Lipase; C431349:lipase B, Candida antarctica; D018819:Dipeptidyl Peptidase 4; D004980:Ethane; D002122:Calcium Chloride; D009584:Nitrogen; C070766:carbamic acid; D000218:Adamantane