Chemo-enzymatic process for the preparation of homopropargylic alcohol

Patent metadata

Field	Value
Publication number	US-12247239-B2
Application number	US-202017621052-A
Country	US
Kind code	B2
Filing date	Jun 17, 2020
Priority date	Jun 21, 2019
Publication date	Mar 11, 2025
Grant date	Mar 11, 2025

Abstract

The present invention relates to an enzymatic process for preparation of optically pure enantiomers of homopropargylic alcohol compounds of formula I, which are useful intermediates for the synthesis of Halichondrin B and analogs. wherein, P is H or an alcohol protecting group, n is an integer ranging from 0-12.

First claim

The invention claimed is:

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):

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):

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);

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):

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

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):

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):

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).

2. The process according to claim 1 , wherein the alcohol protecting group is selected from the group consisting of methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether, p-methoxybenzyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetic acid ester, pivalic acid ester, and benzoic acid ester.

3. The process according to claim 1 , wherein the alcohol protecting group is t-butyldiphenylsilyl ether.

4. The process according to claim 1 , wherein the metal catalyst in (i) is zinc dust or indium.

5. The process according to claim 1 , wherein the acyl donor in step (ii) is isopropenyl acetate or vinyl acetate.

6. The process according to claim 1 , wherein the organic solvents in (ii) and (iv) are selected from the group consisting of tetrahydrofuran, methyl 1-butyl ether, dimethyl sulfoxide, dimethyl formamide, acetone, methyl ethyl ketone, acetonitrile, benzonitrile, methanol, ethanol, t-butanol, methyl tert-butyl ether, and toluene.

7. The process according to claim 1 , wherein the enzyme in (ii) is loaded at from 0.1 wt. % to 100 wt. % with respect to the weight of the racemic homopropargylic alcohol compound.

8. The process according to claim 1 , wherein the anhydride in (iii) is selected from the group consisting of phthalic anhydride, maleic anhydride, and succinic anhydride.

9. The process according to claim 1 , wherein the compounds of formula (Ia) and formula (Ib) are obtained in at least 95% enantiomeric excess.

10. The process according to claim 1 , wherein the enzyme in (ii) is packed in a column or in a fixed bed reactor, and wherein the reaction in (ii) is carried out as a continuous-flow process for 0.5 hours to 6 hours at steady state.

Assignees

• Council Scient Ind Res
• Council Scient Ind Res

Inventors

• Chandrasekhar Srivari
• Ghosh Subhash
• Krishna Avula Shiva
• Reddy Chada Raji
• Sudhakar Gangarajula
• Thenkrishnan Kumaraguru
• Pabbaraja Srihari
• Mainkar Prathama Satyendra
• Nasam Rajesh

Classifications

• C12Y301/01003

  Triacylglycerol lipase (3.1.1.3) · CPC title

• C12P41/002

  by oxidation/reduction reactions · CPC title

• C12P7/625

  Polyesters of hydroxy carboxylic acids · CPC title

• C12N9/20

  Triglyceride splitting, e.g. by means of lipase · CPC title

• C12P7/62

  Carboxylic acid esters · CPC title