Process for preparing an optically active cineole derivative

Patent metadata

Field	Value
Publication number	US-11639358-B2
Application number	US-201816614163-A
Country	US
Kind code	B2
Filing date	May 9, 2018
Priority date	May 19, 2017
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

The present invention relates to a process for preparing optically active 1,4-cineole derivatives by enzymatic resolution and enantiomerically pure optically active 1,4-cineole derivatives of purity greater than 99.9% that have been prepared by this process. The present invention further relates to a process for preparing 7-oxabicyclo[2.2.1]heptane derivatives from the enantiomerically pure optically active 1,4-cineole derivatives.

First claim

The invention claimed is:

1. A process for preparing an optically active compound of formula (II-R),

or an optically active compound of formula (II-S),

wherein
R 1 is selected from the group consisting of hydrogen and unsubstituted or substituted alkyl and
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted alkyl;

said process comprises at least the steps of:
(i) reacting a first mixture comprising a compound of formula (II)

with an acylating agent in the presence of a hydrolase to obtain a second mixture containing a first enantiomer of the compounds of formula (II) in acylated form and a second enantiomer of the compounds of formula (II) in unacylated form, wherein:
R 1 and R 2 in formula (II) are as defined above, and
the hydrolase is selected from the group consisting of lipases from bacteria of the Burkholderia genera, lipases from bacteria of the Pseudomonas genera, and lipases from fungal strains of Thermomyces ; and

(ii) isolating the second enantiomer of the compound of formula (II) in unacylated form from the second mixture of step (i) to obtain an optically active compound of formula (II-R) or an optically active compound of formula (II-S) and a third mixture containing the first enantiomer of the compounds of formula (II) in acylated form.

2. The process of claim 1 , further comprising the steps of
(iii) subjecting the third mixture of step (ii) to basic saponification to obtain a fourth mixture containing the first enantiomer of the compounds of formula (I) in unacylated form; and
(iv) isolating the first enantiomer of the compounds of formula (I) in unacylated form from the fourth mixture of step (iii) to obtain an optically active compound of formula (II-R) or an optically active compound of formula (II-S).

3. The process of claim 2 , further comprising the steps of
(v) providing a suspension comprising the optically active compound of formula (II-R) or formula (II-S) as obtained in step (iv) in at least one non-polar solvent;
(vi) stirring the suspension obtained in step (v) at temperature in the range of ≥10° C. to reflux temperature of the non-polar solvent; and
(vii) isolating crystals of the optically active enantiomer of formula (II-R) or formula (II-S) obtained in step (vi).

4. The process of claim 3 , further comprising adding seed crystals of a desired enantiomer of formula (I-R) or formula (I-S) in step (vi).

5. The process of claim 1 , wherein in the second mixture in step (i), the first enantiomer of the compounds of formula (II) in acylated form is the optically active compound of formula (II-S) and the second enantiomer of the compounds of formula (II) in unacylated form is the optically active compound of formula (II-R).

6. The process of claim 1 , wherein the acylating agent is selected from the group consisting of a vinyl or propenyl ester of a saturated aliphatic carboxylic acid; aliphatic alkyl ester of a saturated cycloaliphatic carboxylic acid; and saturated aliphatic carboxylic acid anhydride.

7. The process of claim 1 , wherein in step (i) the compound of formula (II) and the acylating agent is reacted for a period of ≥30 minutes to ≤100 hours at a temperature in the range of ≥0 to ≤70° C.

8. The process of claim 1 , wherein an excess of acylating agent is removed before step (ii).

9. The process of claim 1 , wherein in step (ii) the second enantiomer of the compound of formula (II) in unacylated form is isolated from the second mixture containing the first enantiomer of the compounds of formula (II) in acylated form and the second enantiomer of the compounds of formula (II) in unacylated form by subjecting the second mixture to a pressure in the range ≥10 to ≤500 Pa and a temperature in the range of ≥20 to ≤240° C.

10. A process for preparing an optically active compound of formula (I-R),

or optically active compounds of formula (I-S),

wherein
R 1 is selected from hydrogen and unsubstituted or substituted alkyl;
R 2 is selected from hydrogen and unsubstituted or substituted alkyl; and
R 4 is unsubstituted or substituted alkyl;

the method comprising:
preparing an optically active compound of formula (II-R),

or an optically active compound of formula (II-S),

wherein
R 1 is selected from the group consisting of hydrogen and unsubstituted or substituted alkyl and
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted alkyl;
said process comprises at least the steps of:
(i) reacting a first mixture comprising a compound of formula (II)

with an acylating agent in the presence of a hydrolase to obtain a second mixture containing a first enantiomer of the compounds of formula (II) in acylated form and a second enantiomer of the compounds of formula (II) in unacylated form, wherein:
R 1 and R 2 in formula (II) are as defined above, and
the hydrolase is selected from the group consisting of lipases from bacteria of the Burkholderia genera, lipases from bacteria of the Pseudomonas genera, and lipases from fungal strains of Thermomyces;
(ii) isolating the second enantiomer of the compound of formula (II) in unacylated form from the second mixture of step (i) to obtain an optically active compound of formula (II-R) or an optically active compound of formula (II-S) and a third mixture containing the first enantiomer of the compounds of formula (II) in acylated form; and
(iii) reacting the optically active compound of formula (II-R) or the optically active compound of formula (II-S) in the presence of a non-polar solvent and in the presence of a base with a compound of formula (III)

wherein X is a leaving group and R 4 is unsubstituted or substituted alkyl.

11. The process according to claim 10 , wherein the optically active compound of formula (I-R) and (I-S) is selected from the group consisting of (1R,2S,4S)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane and (1S,2R,4R)-4-isopropyl-1-methyl-2-(o-tolylmethoxy)-7-oxabicyclo[2.2.1]heptane.

12. The process of claim 2 , wherein the acylating agent is selected from the group consisting of a vinyl or propenyl ester of a saturated aliphatic carboxylic acid; aliphatic alkyl ester of a saturated cycloaliphatic carboxylic acid; and saturated aliphatic carboxylic acid anhydride.

13. The process of claim 3 , wherein the acylating agent is selected from the group consisting of a vinyl or propenyl ester of a saturated aliphatic carboxylic acid; aliphatic alkyl ester of a saturated cycloaliphatic carboxylic acid; and saturated aliphatic carboxylic acid anhydride.

Assignees

• Basf Agro Bv

Inventors

• Ditrich Klaus
• Rack Michael
• Benson Stefan
• Goetz Roland
• Kraus Helmut

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07D493/08 Primary

  Bridged systems · CPC title