DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of alkyl (2S)-2-hydroxy butanoate of Formula I.
The present invention also relates to a cyclohexyl amine salt of (2S)-2-hydroxy butanoic acid of Formula II, and process for the preparation thereof.
BACKGROUND OF THE INVENTION:
Optically active alkyl (2S)-2-hydroxy butanoate of Formula I,

[Formula I]
“wherein R is branched or unbranched C1 to C4 alkyl group”
are useful compounds as reagents or raw materials in the manufacture of medicines, agrochemicals, and industrial products. For example, alkyl (2S)-2-hydroxy butanoate of Formula I, can be used as an important raw material for the preparation of Pemafibrate which is used for the treatment of hypertriglyceridemia, prevention of cardiovascular events in patients with elevated triglycerides levels.
These compounds are needed to be in their most pure form so as to obtain optically pure product which may be used in various pharmaceutical compositions. Therefore, the industrial process which can provide optically pure compound of Formula I is needed to be developed.
J. Org. Chem. 1988,53, 2589-2593 discloses preparation of various a-hydroxy esters by reduction of a-keto esters using Bakers’ Yeast.
Major drawback of this process is the esters such as ethyl 2-hydroxyhexanoate, ethyl 2-hydroxypentanoate, ethyl 2-hydroxybutanoate, ethyl lactate which are prepared by this method have lower yield. Additionally, 2-keto acid ester used in this method is chemically unstable and is expensive. Hence this method is not industrially suitable.

US patent number US 9682913, hereinafter referred to as US’913, discloses a method for improving optical purity of a hydroxycarboxylic acid by chemical methods. The method involves reacting the hydroxycarboxylic acid with an optically inactive base to get hydroxycarboxylic acid salt. This salt is finally esterified. One of the examples provided in US’913 discloses preparation of ester of 2-hydroxybutyric acid in which (S)-2-Aminobutyric acid was taken as a starting material to prepare (S)-2-Hydroxybutyric acid, which was further reacted with dicyclohexylamine to get hydroxycarboxylic acid salt. The said acid salt was reacted with n-butanol containing sulfuric acid to get optically pure (S)-butyl 2-hydroxybutanoate.
The process disclosed in US’913 suffers a problem of tedious work up as sulphate salt of dicyclohexylamine formed during esterification is not water soluble, which makes isolation of pure (S)-butyl 2-hydroxybutanoate difficult during the work up and may require additional purification. This affects the overall yield and purity of (S)-butyl 2-hydroxybutanoate. Therefore, this process is not commercially suitable.
Most of the prior arts discussed above suffer from many disadvantages like tedious work up process, requires expensive reagents, making the process costly. Additionally, complex work up process also affects the overall yield as well as the purity of the final product. Therefore, there is an urgent need for an improved process for the preparation of pure ester of 2S-hydroxycarboxylic acid.
The present inventors have developed a method for manufacturing optically pure esters of 2-hydroxycarboxylic acid which solves above problems.

OBJECT OF THE INVENTION:
The main object of the present invention is to provide simple, efficient and industrially advantageous process for the preparation of optically pure alkyl (2S)-2-hydroxy butanoate of Formula I,

[Formula I]
“wherein R is branched or unbranched C1 to C4 alkyl group”
Another object of the present invention is to provide process for the preparation of a cyclohexylamine salt of (2S)-2-hydroxybutyric acid of Formula II,

[Formula II].
Yet another object of the present invention is to provide an optically pure cyclohexylamine salt of (S)-2- hydroxybutyric acid of Formula II,

[Formula II].
SUMMARY OF THE INVENTION:
First aspect of the present invention is to provide process for the preparation of optically pure alkyl (2S)-2-hydroxy butanoate of Formula I,

[Formula I]
“wherein R is branched or unbranched C1 to C4 alkyl group”
comprising the steps of:
(a) reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II,

[Formula II]
; and
(b) reacting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with alcohol of formula IV,
R-OH
[Formula IV]
“wherein R is branched or unbranched C1 to C4 alkyl group”
to obtain optically pure alkyl (2S)-2-hydroxy butanoate of Formula I.
Second aspect of the present invention is to provide process for the preparation of the cyclohexylamine salt of (S)-2- hydroxybutyric acid of Formula II,

[Formula II]
comprising reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain the cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
Third aspect of the present invention is to provide optically pure cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.

[Formula II]
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of optically pure alkyl (2S)-2-hydroxy butanoate of Formula I.
According to first embodiment, the present invention provides the process for the preparation of optically pure alkyl (2S)-2-hydroxy butanoate of Formula I,

[Formula I]
comprising the steps of:
(a) reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II,

[Formula II]
; and
(b) reacting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with alcohol of Formula IV,
R-OH
[Formula IV]
“wherein R is branched or unbranched C1 to C4 alkyl group”
to obtain optically pure alkyl (2S)-2-hydroxy butanoate of Formula I.
(S)-2-hydroxybutyric acid of Formula III used as starting material for the preparation of alkyl (2S)-2-hydroxy butanoate of Formula I can be prepared by processes known in the prior-art.
In accordance with step (a) of the first embodiment, (S)-2-hydroxybutyric acid of Formula III can be reacted with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
In accordance with step (a) of the first embodiment, the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine can be carried out in presence of solvent selected from the group consisting of C1 to C4 alcohol, ethers such as, diethyl ether, methyl tert-butyl ether (MTBE), ethyl acetate, toluene, xylene. Preferably, the solvent is methyl tert-butyl ether (MTBE).
The volume of the solvent used during the reaction can be in the range of 5.0 volume to 21.0 volume, preferably 7.0 volume to 10.0 volume.
In accordance with step (a) of the first embodiment, cyclohexylamine can be used in the proportion of 1.0 to 1.5 molar equivalents with respect to (S)-2-hydroxybutyric acid of Formula III, preferably 1.0 to 1.1 equivalents.
In accordance with step (a) of the first embodiment, cyclohexylamine can be added dropwise to the solution of (S)-2-hydroxybutyric acid of Formula III, in a period of 1 hour to 2 hours. The reaction mixture can be further maintained at this temperature for 1 hour to 4 hours, preferably for 2 hours.
In accordance with step (a) of the first embodiment, the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine can be carried out at temperature of 20? to reflux temperature of solvent used, preferably at 20°C to 70°C.
After completion of reaction, the solids obtained can be filtered, washed with solvent used during the reaction to obtain wet cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II. Resulting wet cake can be dried in Vacuum Tray Dryer (VTD) at 40°C to 60°C for 8 hours to 10 hours.
The resulting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II may have chiral purity greater than 98% enantiomeric excess (e.e.) by High-Performance Liquid Chromatography (HPLC).
The resulting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II may have yield greater than 80.0%.
In accordance with step (b) of the first embodiment, cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II can be reacted with R-OH of Formula IV, wherein R is branched or unbranched C1 to C4 alkyl group.
In accordance with step (b) of the first embodiment, reaction of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with R-OH of Formula IV can be carried out in presence of acid.
Acid can be selected from hydrochloric acid, sulphuric acid; preferably the acid is sulphuric acid.
Reaction of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with R-OH of Formula IV and acid can be carried out with or without solvent. The solvent can be selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In accordance with step (b) of the first embodiment, R-OH of Formula IV can be used in the proportion of 0.5 volume to 6.0 volume with respect to cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
In accordance with step (b) of the first embodiment, acid can be used in the proportion of 0.5 to 3.0 molar equivalents with respect to cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II, preferably 0.5 to 2.0 equivalents.
In accordance with step (b) of the first embodiment, acid can be added slowly at 20°C to reflux temperature of solvent used.
In accordance with the step (b) of the first embodiment, reaction of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with R-OH of Formula IV can be carried out at 20°C to reflux temperature of solvent used.
In accordance with step (b) of the first embodiment, reaction of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with R-OH of Formula IV can be carried out for 03 hours to 15 hours.
After completion of reaction, the reaction mixture can be cooled to 30 to 50°C. The unreacted excess R-OH can be distilled out under reduced pressure at 20 to 50°C. The resulting concentrated mass can be cooled to 15 to 25°C. To this cooled mass, purified water and methylene dichloride (MDC) can be added. The resulting mixture can be stirred for 25 to 30 minutes. The organic and aqueous layers can be separated, followed by 3 to 4 times methylene dichloride extract given to aqueous layer. The combined organic layer can be washed with 6.5% aqueous sodium bicarbonate solution. All the organic layers can be combined and can be washed with purified water. Resulting organic layer can be distilled out completely to remove the solvent and to obtain an optically pure alkyl (2S)-2-hydroxy butanoate of Formula I.
The resulting alkyl (2S)-2-hydroxy butanoate of Formula I may have purity greater than 98% by Gas Chromatography (GC), preferably greater than 98.5% by GC.
The resulting alkyl (2S)-2-hydroxy butanoate of Formula I may have chiral purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC.
The resulting alkyl (2S)-2-hydroxy butanoate of Formula I may have yield greater than 80%, preferably greater than 82.0%.
According to second embodiment, the present invention provides process for the preparation of the cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II,

[Formula II]
comprising reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain the cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
In accordance with second embodiment, (S)-2-hydroxybutyric acid of Formula III can be reacted with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
In accordance with second embodiment, the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine can be carried out in presence of solvent selected from the group consisting of C1 to C4 alcohol, ethers such as, diethyl ether, methyl tert-butyl ether (MTBE), ethyl acetate, toluene, xylene. Preferably, the solvent is methyl tert-butyl ether (MTBE).
The volume of the solvent used during the reaction can be in the range of 5.0 volume to 21.0 volume, preferably 7.0 volume to 10.0 volume.
In accordance with second embodiment, cyclohexylamine can be used in the proportion of 1.0 to 1.5 molar equivalents with respect to (S)-2-hydroxybutyric acid of Formula III, preferably 1.0 to 1.1 equivalents.
In accordance with second embodiment, cyclohexylamine can be added dropwise to the solution of (S)-2-hydroxybutyric acid of Formula III, in a period of 1 hour to 2 hours. The reaction mixture can be further maintained at this temperature for 1 hour to 4 hours, preferably for 2 hours.
In accordance with second embodiment, the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine can be carried out at temperature of 20? to reflux temperature of solvent used, preferably at 20°C to 70°C.
After completion of reaction, the solids obtained can be filtered, washed with solvent used during the reaction to obtain wet cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II. Resulting wet cake can be dried in Vacuum Tray Dryer (VTD) at 40°C to 60°C for 8 hours to 10 hours.
The resulting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II may have chiral purity greater than 98% enantiomeric excess (e.e.) by HPLC.
The resulting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II may have yield greater than 80.0%
Accordingly to third embodiment, the present invention provides optically pure cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II,

[Formula II].

EXAMPLES
The following examples are given by way of illustration. It may be understood for the person skilled in the art that these examples are only typical embodiments of the invention and are not therefore considered to be limiting the scope of the present invention.
Example 1: Preparation of (S)-2-hydroxybutyric acid
To a stirred solution of purified water (4600 mL) and conc. Sulphuric acid (448 g), L-(+) 2-amino butyric acid (400 g) was added at 25°C to 35°C. The resulting mixture was cooled to 0 to -5°C and aqueous sodium nitrite solution [sodium nitrite (536.0 g) + purified water (1360 mL)] was slowly added at the same temperature and stirred for 1.0 hour. The resulting mixture was then further stirred for 15 hours at 25°C to 30°C. After completion of reaction, sodium chloride (2400.0 g) followed by ethyl acetate (1200 mL) was added to the reaction mixture at 25°C 30°C and stirred for 15 minutes at same temperature. Resulting mixture was allowed to separate the layers. Organic and aqueous layers were separated, and aqueous layer was extracted with ethyl acetate (14 X 1200 mL). All the organic layers were combined and distilled under vacuum at 50°C to 60°C followed by striping using toluene (3 x 400 mL) to remove the solvent. After removal of solvent resulting oil was cooled to 25°C to 35°C to get the title compound (241.0 g).
Example 2: Preparation of cyclohexylamine salt of (S)-2-hydroxybutyric acid
To a stirred solution of (S)-2-hydroxybutyric acid (241.0 g) obtained in example 1 and methyl tert-butyl ether (2200 mL), cyclohexylamine (230.0 g) was added at 25°C to 30°C. The resulting mixture was stirred for 2.0 hours at 25°C to 30°C. After completion of reaction, resulting mixture was filtered, washed with methyl tert-butyl ether (800.0 mL) to obtain a wet cake. Resulting wet cake was dried at 45°C to 50°C for 8 hours under vacuum to obtain title compound (377.0 g).
Example 3: Preparation of Ethyl (2S)-2-hydroxybutanoate
To a mixture of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II obtained in example 2 (377 g) and ethanol (1900 mL), conc. sulphuric acid (366 g) was added slowly) at 25°C to 35°C over a period of 2 hours. The resulting mixture was stirred for 15 hours at 75 °C to 80 °C. After completion of reaction, resulting reaction mixture was cooled to 30°C to 50°C and distilled under reduced pressure to obtain concentrated mass. To the concentrated mass, purified water (754 mL) and methylene dichloride (377 mL) was added at 15°C to 25°C. Purified water (754 mL) and methylene dichloride (377 mL) was added to the resulting mixture and further stirred for 15 minutes at same temperature. Resulting mixture was allowed to separate the layers. Resulting aqueous layer was extracted with methylene dichloride (2x 377 mL). All the organic layers were combined and washed with water (4 x 377 mL). Resulting organic layer was washed with 6.5 % aqueous sodium bicarbonate (377 mL). Resulting organic layer was washed with purified water (377 mL). Resulting organic layer were distilled under reduced pressure at 60°C to obtain title compound (201 g) having chiral purity of 99.5% e.e.
Example 4: Preparation of cyclohexylamine salt of (S)-2-hydroxybutyric acid
To a stirred solution of purified water (440 mL) and conc. sulphuric acid (42.76 g), L (+) 2-amino butyric acid (50 g) was added at 25°C to 35°C. The resulting mixture was cooled to 0 to -5°C and aqueous sodium nitrite solution [sodium nitrite (67 g) + purified water (100 mL)] was slowly added at the same temperature and stirred for 1.0 hour. The resulting mixture was heated to 25°C to 30°C and stirred for 8.0 hour. Sodium chloride (172 g) followed by methyl tertiary-butyl ether (150 mL) was added to the reaction mixture at 25°C to 30°C and stirred for 15 minutes at same temperature. Resulting mixture was allowed to separate the layers. Organic and aqueous layers were separated, and the aqueous layer was extracted with methyl tertiary-butyl ether (6 x 150 mL). Cyclohexyl amine (40 g) was added to combined organic layers and the mixture was heated to 50°C to 55°C. Resulting mixture was stirred for 30 minutes at same temperature. Resulting mixture was then cooled to 20°C to 30°C and stirred for 30 minutes. The resulting mixture was filtered, washed with methyl tert-butyl ether (100.0 mL) to obtain a wet cake. Retarder (25 mL), Methyl tertiary-butyl ether (25 mL) was added to the wet cake at 25°C to 30°C. The resulting mixture was heated to 50°C to 55°C and then stirred for 30.0 minutes. Methyl tertiary-butyl ether (150 mL) was slowly added at the same temperature and stirred for 30 minutes. The resulting mixture was cooled to 10°C to 15°C and stirred for 1 hour. The resulting mixture was filtered, washed with methyl tert-butyl ether (50.0 mL) to obtain a wet cake. The resulting wet cake was dried at 55°C to 60°C for 9 hours under vacuum to obtain title compound (62 g) having chiral purity of 99.80%
Example 5: Preparation of Ethyl (2S)-2-hydroxybutanoate
To a mixture of cyclohexylamine salt of (S)-2-hydroxybutyric acid (50 g) and methylene chloride (200 mL), retarder (36 mL) and conc. sulphuric acid (27.72 g) was added slowly at 25°C to 35°C. The resulting mixture was heated to 40°C to 45°C to get clear reaction mass and then stirred for 4 hours. The resulting mixture was cooled to 20°C to 25°C and slowly added purified water (50 mL) and stirred for 15 minutes at same temperature. Resulting mixture was allowed to separate the layers. Organic and aqueous layers were separated. Resulting organic layer washed with aqueous sodium bicarbonate solution (3 x 50 mL) [sodium bicarbonate (3 g) + purified water (50 mL)]. Purified water (50 mL) was added to organic layer at 20°C to 25°C and stirred for 15 minutes. Resulting mixture was allowed to separate the layers. Resulting organic layer were distilled completely under reduced pressure to obtain title compound (27.4 g) having chiral purity of 99.66%.
Advantages of the present invention:
1. Process provides highly pure alkyl (2S)-2-hydroxy butanoate of Formula I.
2. Simple work up process.
3. Product is easily isolated which is free from the sulphate formed in the reaction.
,CLAIMS:I / We Claim:
1. A process for the preparation of optically pure alkyl (2S)-2-hydroxy butanoate of Formula I,

[Formula I]
“wherein R is branched or unbranched C1 to C4 alkyl group”
comprising the steps of:
(a) reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II, and

[Formula II]

(b) reacting cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with alcohol of Formula IV,
R-OH
[Formula IV]
“wherein R is branched or unbranched C1 to C4 alkyl group”
to obtain optically pure alkyl (2S)-2-hydroxy butanoate of Formula I.
2. The process as claimed in claim 01; wherein in step (a), the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine is carried out in presence of solvent selected from the group consisting of C1 to C4 alcohol, diethyl ether, methyl tert-butyl ether, ethyl acetate, toluene, xylene or mixture thereof at 20? to 70°C.
3. The process as claimed in claim 01; wherein in step (a), molar equivalent of cyclohexylamine with respect to (S)-2-hydroxybutyric acid of Formula III is 1.0 to 1.5.
4. The process as claimed in claim 01; wherein in step (b), the reaction of cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II with R-OH of Formula IV is carried out in presence of acid such as hydrochloric acid or sulphuric acid at 20°C to 90°C.
5. A process for the preparation of the cyclohexylamine salt of (S)-2- hydroxybutyric acid of Formula II,

[Formula II]
comprising reacting (S)-2-hydroxybutyric acid of Formula III,

[Formula III]
with cyclohexylamine to obtain cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II.
6. The process as claimed in claim 05; wherein the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine is carried out in presence of solvent selected from the group consisting of C1 to C4 alcohol, diethyl ether, methyl tert-butyl ether, ethyl acetate, toluene, xylene or mixture thereof.
7. The process as claimed in claim 05; wherein molar equivalent of cyclohexylamine with respect to (S)-2-hydroxybutyric acid of Formula III is 1.0 to 1.5.
8. The process as claimed in claim 05; wherein the reaction of (S)-2-hydroxybutyric acid of Formula III with cyclohexylamine is carried out at temperature of 20? to 70°C.
9. Cyclohexylamine salt of (S)-2-hydroxybutyric acid of Formula II,

[Formula II]
having chiral purity greater than 99% enantiomeric excess (e.e.).

Dated this 08th November, 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd