US 12,247,239 B2
Chemo-enzymatic process for the preparation of homopropargylic alcohol
Srivari Chandrasekhar, Telangana (IN); Subhash Ghosh, Telangana (IN); Avula Shiva Krishna, Telangana (IN); Chada Raji Reddy, Telangana (IN); Gangarajula Sudhakar, Telangana (IN); Kumaraguru Thenkrishnan, Telangana (IN); Srihari Pabbaraja, Telangana (IN); Prathama Satyendra Mainkar, Telangana (IN); and Rajesh Nasam, Telangana (IN)
Assigned to COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH, New Delhi (IN)
Appl. No. 17/621,052
Filed by Council of Scientific and Industrial Research, New Delhi (IN)
PCT Filed Jun. 17, 2020, PCT No. PCT/IN2020/050533
§ 371(c)(1), (2) Date Dec. 20, 2021,
PCT Pub. No. WO2020/255164, PCT Pub. Date Dec. 24, 2020.
Prior Publication US 2022/0333139 A1, Oct. 20, 2022
Int. Cl. C12P 7/02 (2006.01); C12N 9/20 (2006.01); C12P 7/04 (2006.01); C12P 7/625 (2022.01); C12P 41/00 (2006.01)
CPC C12P 7/04 (2013.01) [C12N 9/20 (2013.01); C12P 7/625 (2013.01); C12P 41/002 (2013.01); C12Y 301/01003 (2013.01)] 10 Claims
 
1. A chemo-enzymatic process for preparing optically pure enantiomers of a homopropargylic alcohol compound, the process comprising:
(i) reacting an aldehyde compound of formula (III):

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where:
P is hydrogen or an alcohol protecting group; and
n is an integer from 0 to 12,
with a propargyl halide compound of formula (IV):

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where X is Cl, Br, or I;
in an organic solvent in the presence of a metal catalyst to obtain a racemic homopropargylic alcohol compound of formula (I);

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where P and n are as defined in formula (III);
(ii) treating the racemic homopropargylic alcohol compound obtained in (i) with an enzyme, wherein the enzyme is a lipase from Pseudomonas fluorescens, Candida cylindracea, or Candida Antarctica, in the presence of an acyl donor and an organic solvent at temperature from 20° C. to 50° C. to obtain an enantiomerically enriched alcohol compound of formula (Ia):

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where P and n are as defined in formula (III),
and an optically pure acylated compound of formula (Ic):

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where P and n are as defined in formula (III);
(iii) isolating the enantiomerically enriched alcohol compound of formula (Ia) and the optically pure acylated compound of formula (Ic) with an anhydride to obtain semi-ester derivatives having formula (Id) from the enantiomerically enriched alcohol compound of formula (Ia):

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where P and n are as defined in formula (III),
while retaining the compound of formula (Ic);
(iv) washing the semi-ester derivatives of formula (Id) obtained from (iii) with an organic solvent to obtain an optically pure acetyl product having formula (Ic);
(v) hydrolysing the optically pure acylated compound of formula (Ic) in the presence of a base to obtain a compound of formula (Ib):

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where P and n are as defined in formula (III); and
(vi) hydrolysing the semi-ester derivative of formula (Id) of (iii) with a base to obtain an optically pure enantiomerically enriched alcohol product having formula (Ia).