DESC:Field of the Invention
The present invention relates to a process for preparing (3R)-hydroxy tetrahydrofuran.

Background of the Invention
(3R)-hydroxy tetrahydrofuran is an important building block used in the synthesis of various active pharmaceutical ingredients and agrochemicals.
(3R)-hydroxy tetrahydrofuran is represented by Formula I

(3R)-hydroxy tetrahydrofuran has been known to be prepared by various methods wherein in one of the prior art, i.e. Journal of Organic Chemistry, 48(16), 2767–2769 reports synthesis of (3R)-hydroxy tetrahydrofuran from (R)-dimethyl maleate as shown below in scheme 1.

(R)-dimethyl maleate is reduced to (R)-(+)-1,2,4-butanetriol using lithium aluminium hydride. The butane triol thus formed is cyclodehydrated with catalytic amount of p-toluenesulfonic acid monohydrate. The yield obtained is 85%. However it is to be understood that the starting material (R)-dimethyl maleate as used in the process is costly and it effects overall costing of (3R)-hydroxy tetrahydrofuran. Hence a cost effective route is needed for preparation of (3R)-hydroxy tetrahydrofuran.
US20030032818 discloses stereo-specific hydrolysis of optically active esters. In this process, (S)-3-hydroxy tetrahydrofuran is treated with mesyl chloride in presence of triethylamine. The mesyl ester formed is further treated with strong acid such as methane sulfonic acid. The reaction is carried out for 5 hours. The solution is eluted on strongly basic anion exchange resin Amberlyst IRA 410. In this process the enantiomeric excess (ee) obtained was about 88% ee.
Hence in order to overcome the drawbacks of the aforesaid processes, there exists a need for a cost effective process for preparation of compound of Formula (I) with higher yield, better purity and higher enantiomeric excess (ee).

Summary of the Invention
In a general aspect, the present invention provides a process of preparing (3R)-hydroxy tetrahydrofuran.
In an embodiment, the process of preparing (3R)-hydroxy tetrahydrofuran comprises
reacting (S)-sulfonyloxy derivative of tetrahydrofuran of Formula (II)

where, R1 is lower alkyl, phenyl and phenyl substituted by CH3, -NO2
with a primary alcohol, secondary alcohol or a benzoic acid derivative in presence of a base and a solvent forming a compound of Formula (III);

where R2 is:
,
where R3 and R4 is selected from H, lower alkyl (1-4C), and lower alkoxy (1-4C), R5 is H, -CH3;
and
deprotecting R2 group of compound of Formula (III).

In an embodiment, the process of deprotecting R2 group of the compound of Formula (III), where R2 is a benzyl derivative comprises hydrogenating in presence of metal catalyst selected from Palladium (Pd), Platinum (Pt), Rhodium (Rh) and Nickel (Ni) and a solvent.

In another embodiment, the process of deprotecting R2 group of the compound of Formula (III), where R2 is a benzoyl derivative comprises acid or alkali hydrolysis of compound of Formula (III) in the presence of a solvent.
The primary alcohol can be selected from of benzyl alcohol, p-methyl benzyl alcohol, p-methoxy benzyl alcohol and p-chlorobenzyl alcohol and the like and the secondary alcohol can be selected from alpha-methylbenzylalcohol, p-methyl alpha-methylbenzylalcohol, p-methoxy alpha-methylbenzylalcohol and p-chloro alpha-methylbenzylalcohol and the like.
The benzoic acid derivative can be selected from benzoic acid, sodium benzoate, potassium benzoate, 4-methyl benzoic acid, 4-methoxy benzoic acid and 4-chloro benzoic acid or salt thereof. The base can be selected from the group comprising of alkali metal hydroxides, alkali metal alkoxides, metal hydrides, alkali metal carbonates, alkali metal bicarbonates or like. The alkali metal hydroxide can be selected from hydroxide, potassium hydroxide; the alkali metal alkoxide can be selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide; the metal hydride can be selected sodium hydride, potassium hydride; the alkali metal carbonate can be selected from sodium carbonate, potassium carbonate, caesium carbonate; and the alkali metal bicarbonates can be selected from sodium bicarbonate, potassium bicarbonate. The reaction of compound of Formula (II) can be carried out in presence of a solvent selected from dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide. The deprotection reaction can be carried out in presence of a solvent selected from water and/or alcohol and etheral solvent.

In an embodiment, (3R)-hydroxy tetrahydrofuran prepared by the process has a purity of 97% to 99.5% HPLC purity.

Detailed Description of the invention
The present invention relates to a process for preparation of a (3R)-hydroxy tetrahydrofuran of Formula (I).

In an embodiment, a (S)-sulfonyloxy derivative of tetrahydrofuran of Formula (II)
where, R1 is lower alkyl, phenyl and phenyl substituted by CH3, -NO2 is reacted with a primary alcohol, secondary alcohol or a benzoic acid derivative in presence of a base and a solvent forming a compound of Formula (III);

where R2 is benzoyl or benzyl derivative as shown below
,
wherein R3 and R4 is selected from H, lower alkyl, and lower alkoxy, R5 is H, -CH3. Preferably, when R3 and R4 are lower alkyl group, the lower alkyl group is selected from (1-4C) alkyl; the lower alkoxy group is selected from -O-(1-4C)alkyl and halide preferably chloride.
The R2 group of Formula (III) is then deprotected to obtain compound of Formula (I). R2 can be removed from compound (III) by acid or alkali hydrolysis, hydrogenation or acidic or alkali cleavage.

In an embodiment, the deprotection of compound of Formula (III), where R2 is a benzyl derivative can proceed by hydrogenation.

In another embodiment, the deprotection of compound of Formula (III), where R2 is a benzoyl derivative, can be carried out by acid or alkali hydrolysis.
Typically, the deprotection of R2 group is carried out in the presence of a solvent.

In one embodiment, a process for preparing 3-hydroxy tetrahydrofuran comprising reacting (S)-sulfonyloxy derivative of tetrahydrofuran of Formula (II) with a benzoic acid derivative is provided. Compound of Formula (II) is reacted with the benzoic acid derivative in the presence of a base forming a benzoyl ester of compound of Formula (III):

where R2 is benzoyl derivative as shown below

wherein R3 is selected from H, lower alkyl, lower alkoxy and halo.
The benzoic acid derivative can be selected from benzoic acid, sodium benzoate, potassium benzoate, 4-methyl benzoic acid, 4-methoxy benzoic acid and 4-chloro benzoic acid or salt thereof.
The reaction of compound of Formula (II) and benzoic acid derivative is carried out in the presence of a base and a solvent. The base can be selected from the group comprising alkali metal hydroxides, alkali metal alkoxides, metal hydrides, alkali metal carbonates, alkali metal bicarbonates or like. The alkali metal hydroxide can be selected from the group comprising of sodium hydroxide, potassium hydroxide; the alkali metal alkoxide used can be selected from the group comprising of sodium methoxide, sodium ethoxide, potassium tert-butoxide; the metal hydride used can be selected from the group comprising of sodium hydride, potassium hydride; the alkali metal carbonate used can be selected from the group comprising of sodium carbonate, potassium carbonate, cesium carbonate; and the alkali metal bicarbonates can be selected from the group comprising of sodium bicarbonate, potassium bicarbonate. The solvent can be selected from the group comprising of dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like. The reaction can be carried out at a temperature from 44°C to 100°C, preferably 60°C to 90°C and more preferably 75°C to 80°C.
In an embodiment, the deprotection of compound of Formula (III), where R2 is a benzoyl derivative, can be carried out by acid or alkali hydrolysis. The acid hydrolysis can be carried out in the presence of a mineral acid selected from the group of hydrochloric acid, sulfuric acid, trifluoracetic acid or like. The alkali hydrolysis can be can be carried out in the presence of an alkali selected from a group of alkali metal hydroxide, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or like selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or like.

In another embodiment, a process for preparing 3(R)-hydroxy tetrahydrofuran comprising reacting (S)-sulfonyloxy derivative of tetrahydrofuran of Formula (II) with a primary alcohol or a secondary alcohol is provided. Compound of Formula (II) is reacted with the alcohol to form corresponding ether of compound of Formula (III):

where R2 is benzyl derivative as shown below

wherein R4 is selected from H, lower alkyl, lower alkoxy and halo, R5 is H, -CH3.
The primary alcohol can be selected from an aromatic alcohol selected from benzyl alcohol, p-methyl benzyl alcohol, p-methoxy benzyl alcohol and p-chlorobenzyl alcohol, and the like. The secondary alcohol can be selected from an aromatic alcohol selected from alpha-methylbenzylalcohol, p-methyl alpha-methylbenzylalcohol, p-methoxy alpha-methylbenzylalcohol and p-chloro alpha-methylbenzylalcohol, and the like.
The reaction is carried out in presence of a solvent. The solvent can be selected from the group comprising of dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like. The reaction can be carried out at a temperature from 44°C to 100°C, preferably 60°C to 90°C and more preferably 75°C to 80°C.

In another embodiment, the deprotection of compound of Formula (III), where R2 is a benzyl derivative can proceed by hydrogenation in presence of a catalyst selected from Pd, Pt, Rh or like.

In general, the deprotection reaction can be carried out in presence of a solvent. The solvent can be selected from water and/or alcohol and etheral solvent. The alcoholic solvent can be selected from (1-4C) alcohol selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol or like. The etheral solvent can be selected from tetrahydrofuran, cyclo pentyl methyl ether or like.
The process of the present invention produces the compound of Formula (I) having a purity of 97% to 99.5% HPLC purity.

In an embodiment, 3-hydroxy tetrahydrofuran having a purity of 97% to 99.5% HPLC purity is provided.

In context of the present invention, the inversion at stereocenter occurs in the reaction, as the reaction proceeds through Nucleophilic Substitution (SN2) mechanism. The benzoate or benzyloxide anion attacks from other side of the sulfonyloxy leaving group wherein the inversion at stereocenter occurs in the reaction. The process of present invention describes nucleophilic substitution reaction of tosyl with benzyl derivative or benzoic acid derivative which is the main step of inversion of hydroxy group. The reaction substantially takes place in an alkaline medium. (3R)-hydroxy tetrahydrofuran is used as an important intermediate for the synthesis of various active pharmaceutical products and agrochemicals. The process of the present invention is an eco-friendly and a cost effective process feasible for higher scale production. The process of the present invention does not require any excess or additional purifications steps and hence the reaction time is reduced and there is isolation of higher yield product. The process of the present invention provides high enantiomeric excess i.e. =95% enatimeric excess (ee) with better purity and without any strenuous work up.

EXAMPLES
Examples and implementations are provided herein below for the illustration of the invention and are not limiting thereof.
Example 1 - Preparation of [(3R)-tetrahydrofuran-3-yl] benzoate (III)
[(3S)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate (100 g) (II) was charged to mixture of benzoic acid (100 g) and potassium hydroxide (46 g) in dimethyl formamide (1 L). The reaction mixture was maintained at 75-80°C. After completion of the reaction, the mass was cooled to room temperature and water (1.5 L) was added below 30°C. The mass was extracted with di-isopropyl ether. [(3R)-tetrahydrofuran-3-yl] benzoate (65 g) was isolated by distillation. The product isolated was having ee. : 97%

Example 2 - Preparation of (3R)-hydroxy tetrahydrofuran (I)
[(3R)-tetrahydrofuran-3-yl] benzoate (100 g) obtained in example 1, was charged to potassium hydroxide (43.8 g) in methanol (500 ml). The mixture was maintained at room temperature for sufficient time. The reaction mass was filtered after completion of the reaction to remove excess potassium hydroxide. The methanol layer was concentrated. The product was dissolved in water and extracted with heptane (100 ml x 3) to remove organic impurities. The product was isolated by distillation under vacuum. The pure compound (3R)-hydroxy tetrahydrofuran isolated has ee 97% (yield: 25 g).

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:
1. A process of preparing (3R)-hydroxy tetrahydrofuran comprising
i) reacting (S)-sulfonyloxy derivative of tetrahydrofuran of Formula (II)

where, R1 is lower alkyl, phenyl and phenyl substituted by CH3, -NO2
with a primary alcohol, secondary alcohol or a benzoic acid derivative in presence of a base and a solvent forming a compound of Formula (III);

where R2 is:
,
where R3 and R4 is selected from H, lower alkyl (1-4C), lower alkoxy (1-4C) and halo, R5 is H, -CH3
and
ii) deprotecting R2 group of compound of Formula (III).

2. The process as claimed in claim 1, wherein deprotecting R2 group of the compound of Formula (III), where R2 is a benzyl derivative comprises hydrogenating in presence of metal catalyst selected from Palladium (Pd), Platinum (Pt), Rhodium (Rh) and Nickel (Ni) and a solvent.

3. The process as claimed in claim 1, wherein deprotecting R2 group of the compound of Formula (III), where R2 is a benzoyl derivative comprises acid or alkali hydrolysis of compound of Formula (III) in the presence of a solvent.

4. The process as claimed in claim 1, wherein primary alcohol is selected from of benzyl alcohol, p-methyl benzyl alcohol, p-methoxy benzyl alcohol and p-chlorobenzyl alcohol, and the like and the secondary alcohol is selected from alpha-methylbenzylalcohol, p-methyl alpha-methylbenzylalcohol, p-methoxy alpha-methylbenzylalcohol, p-chloro alpha-methylbenzylalcohol, and the like.

5. The process as claimed in claim 1, wherein the benzoic acid derivative is selected from benzoic acid, sodium benzoate, potassium benzoate, 4-methyl benzoic acid, 4-methoxy benzoic acid and 4-chloro benzoic acid or salt thereof.

6. The process as claimed in claim 1, wherein the base is selected from the group comprising of alkali metal hydroxides, alkali metal alkoxides, metal hydrides, alkali metal carbonates, alkali metal bicarbonates or like.
7. The process as claimed in claim 6, wherein the alkali metal hydroxide is selected from hydroxide, potassium hydroxide; the alkali metal alkoxide used is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide; the metal hydride is selected sodium hydride, potassium hydride; the alkali metal carbonate is selected from sodium carbonate, potassium carbonate, caesium carbonate; and the alkali metal bicarbonates is selected from sodium bicarbonate, potassium bicarbonate.

8. The process as claimed in claim 1, wherein the solvent is selected from dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.

9. The process as claimed in claim 2 or 3, wherein the solvent is selected from water, alcohol and etheral solvent or mixtures thereof.

10. The process as claimed in claim 3, wherein acid hydrolysis is carried out in presence of mineral acid selected from hydrochloric acid, sulfuric acid, or trifluoracetic acid.

11. The process as claimed in claim 3, wherein the alkali hydrolysis is carried out in the presence of alkali metal hydroxide, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates or like selected from a group of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or like.
12. The process as claimed in claims 1 to 11, wherein (3R)-hydroxy tetrahydrofuran prepared by the process has a purity of 97% to 99.5% HPLC purity.