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Separation Method

IP.com Disclosure Number: IPCOM000126678D
Publication Date: 2005-Jul-28
Document File: 1 page(s) / 26K

Publishing Venue

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Abstract

A synthesis of 4-hydroxypipecolates from N-Cbz-allylglycine methyl ester which employs a nucleophile-induced Mannich cyclization reaction with formaldehyde and formic acid to give a mixture of diastereoisomeric formates of N-Cbz-4-hydroxypipecolic acid methyl ester. Separation of the diastereoisomers can be achieved by selective enzymatic hydrolysis of the trans-diastereoisomer followed by formation of the aqueous base-soluble hemiphthalate ester derivative of the trans-alcohol.

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Separation Method

Lloyd and coworkers have reported a synthesis of 4-hydroxypipecolates from N-Cbz-allylglycine methyl ester which employs a nucleophile-induced Mannich cyclization reaction with formaldehyde and formic acid to give a mixture of diastereoisomeric formates of N-Cbz-4-hydroxypipecolic acid methyl ester (Lloyd, RC.; Smith, M.E.B.; Brick, D.;

Taylor

, S.J.C.;. Chaplin, D.A.;. McCague, R., Org. Process. Res., 2002, 6, 762-766).  Separation of the diastereoisomers can be achieved by selective enzymatic hydrolysis of the trans-diastereoisomer followed by formation of the aqueous base-soluble hemiphthalate ester derivative of the trans-alcohol.

An alternative method has been investigated for achieving the separation of the trans-alcohol from the unreacted cis-formate ester, following the enzymatic hydrolysis. This involved conversion of the trans-alcohol to the hemisulfate ester derivative.  The trans-alcohol hemisulfate ester was found to be both readily formed and extracted into aqueous solution, allowing the cis-formate ester to be readily isolated.  The hemisulfate ester is more soluble in aqueous base than the hemiphthalate, making this extraction easier.

In order to further process the separated trans-hemisulfate ester, this compound was found to be cleavable by two methods.  In methanolic sulphuric acid, at room temperature the ester was cleaved cleanly with retention of stereochemical configuration, but too slowly to achieve complete reaction in a reasonab...