DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See Section 10, Rule 13]

“PROCESS FOR PREPARATION OF 3-[4-[(2-CHLOROPHENYL)METHYL]PHENOXY] TETRAHYDROFURAN DERIVATIVES”

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the Invention
The present invention relates to a process for preparation of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives.

Background of invention
3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives of Formula (I) are key starting compound of an inhibitor of sodium glucose co-transporter-2 (SGLT-2) Empagliflozin. Empagliflozin is approved for the treatment of type 2 diabetes to lower the blood glucose levels. It reduces the risk of heart attack and heart failure in Type 2 diabetes.

One of the US patent literature i.e. US 9,127,034 discloses a preparation of (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene by etherification of (2-chloro-5-iodo-phenyl)-(4-fluoro-phenyl)-methanone with (S)-3-hydroxytetrahydrofuran.

(2-Chloro-5-iodo-phenyl(4-[(S)tetrahydrofuran-3-yl)oxyl-phenyl}-methanone obtained was reduced using triethyl silane and boron trifluoride diethyl etherate at 20°C. The reaction can be represented schematically as shown below in scheme 1. The reaction is carried out in tetrahydrofuran and potassium tert-butoxide as base.
A non-patent literature i.e. Organic Letters, 16(16), 4090-4093; 2014 discloses synthesis of (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl) methanone and (S)-(2-chloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl) methanone. The process involves reacting (4-fluorophenyl)methanone derivative with (S)-tetrahydrofuran-3-ol in tetrahydrofuran and potassium-tert-butoxide as base.
The processes requires critical monitoring on the molar amount of potassium tert-butoxide as both starting material and product disintegrates at a higher concentration and there is incomplete reaction if the base is at a lower molar quantity.
Another patent application CN106905305A discloses a process for preparation of (5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone and (2-chloro-5-iodo-phenyl)-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methanone with another base potassium carbonate. The process involves reacting corresponding (4-fluorophenyl)methanone derivative with (3R)-chloro-tetrahydrofuran or (Tetrahydrofuran-3-yl)-4-methylbenzenesulfonate.

The reaction proceeds in presence of potassium carbonate and potassium iodide in acetonitrile. However yield of the phenoxy tetrahydrofuran derivative obtained is 85 to 91%.
Thus there is a need for an improved process for the preparation of compound of Formula (I).
Summary of the invention

In a general aspect, the present invention provides a process for preparing 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives of Formula (I) having 99% - 99.9% HPLC purity.

The process comprises coupling a compound of Formula (II) with (S)-3-hydroxy tetrahydrofuran of Formula (III)

wherein R1 is (=O) or H; X is bromo or iodo
in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

In an embodiment, the present invention relates to process for preparation of the derivative of Formula (I). The derivative can be (5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IA) and (2-chloro-5-iodo-phenyl)-(4-(3S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IB).

The process for preparing compound (IA) comprises coupling (5-bromo-2-chloro-phenyl)-(4-fluorophenyl)methanone of Formula (IIA) with (S)-3-hydroxy tetrahydrofuran of Formula (III) in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

The process for preparation compound (IB) comprises coupling (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone of Formula (IIB) with (S)-3-hydroxy tetrahydrofuran of Formula (III) in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

The alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide and lithium hydroxide. The phase transfer catalyst can be selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA). The coupling reaction can be carried out at 50°C to 70°C in the presence of a solvent wherein the solvent can be selected from hydrocarbon solvent or etheral solvent. The hydrocarbon solvent can be selected from toluene, xylene, benzene, heptane, cyclohexane. The etheral solvent can be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether.

Description of the invention
The present invention provides an improved process for the preparation of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives of Formula (I) having 99% - 99.9% HPLC purity.

In one embodiment, the process for preparation of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives of Formula (I) comprises coupling compound of Formula (II) with (S)-3-hydroxy tetrahydrofuran of Formula (III)

wherein R1 is (=O) or H; X is bromo or iodo.
The reaction can be carried out in the presence of a catalyst and a base which is preferably an alkali hydroxide. The alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide and lithium hydroxide. Preferably, the base is potassium hydroxide.
The reaction can be carried out at 50°C to 70°C in the presence of a solvent. The solvent can be selected from hydrocarbon solvent, etheral solvent or mixtures thereof. The hydrocarbon solvents can be selected from toluene, xylene, benzene, heptane, cyclohexane and mixtures thereof. The etheral solvent can be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether and mixtures thereof, wherein preferably, the solvent is toluene. The catalyst can be a phase transfer catalyst selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA).
The purity of the compound obtained by the process of the present invention is 99% - 99.9%.

In an embodiment, the desired derivative of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran prepared by the process of the present invention includes (5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IA). The process for preparation of compound (IA) is provided.

The process for preparation of compound (IA) comprises coupling of (5-bromo-2-chloro-phenyl)-(4-fluorophenyl)methanone of Formula (IIA) with (S)-3-hydroxy tetrahydrofuran of Formula (III).

In another embodiment, the desired derivative of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran prepared by the process of the present invention includes (2-chloro-5-iodo-phenyl)-(4-(3S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IB). The process for preparation of compound (IB) is provided.

The process for preparation of compound (IB) comprises coupling (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone of Formula (IIB) with (S)-3-hydroxy tetrahydrofuran of Formula (III).

The process for preparation of compound (IA) and (IB) is carried out in the presence of a catalyst and a base preferably an alkali hydroxide. The reaction of the process can proceed at a temperature of 50°C to 70°C. The alkali hydroxide can be selected from sodium hydroxide, potassium hydroxide and lithium hydroxide. The reaction can be carried out in presence of a solvent selected from toluene, xylene, benzene, heptane, cyclohexane, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether. The process can be carried out in presence of phase transfer catalyst selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA). Preferably, the solvent is toluene.

In the context of the present invention, alkali hydroxides being mild base, provides better alternative to strong bases such as alkali alkoxides and alkali carbonates. Use of alkali hydroxides avoid disintegration of compound (I) and compound (II), which avoids yield loss and avoids impurity formation. Further, as the reaction conditions are mild, the chiral purity of compound (I) is also maintained thus provides ease of isolation. Use of phase transfer catalyst increases the reaction rate and reaction goes to completion in lesser time thus making the process economical and industrially feasible.

EXAMPLES
Example and implementation is provided herein below for illustration of the invention. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Example 1
Preparation of (5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone (Formula IA)

Potassium hydroxide (27 g) was charged to toluene (400 ml) and the mixture was stirred thoroughly. 3-hydroxy tetrahydrofuran of Formula (III) (31 g) and tetrabutylammonium bromide (10 g) was added to the above reaction mixture and the reaction mixture was stirred. A solution of (5-bromo-2-chloro-phenyl)-(4-fluorophenyl)methanone of Formula (IIA) (100 g) in toluene (300 ml) was prepared separately. The temperature of the above reaction mixture was increased to 55-60°C. The solution of (5-bromo-2-chloro-phenyl)-(4-fluorophenyl) methanone (300 ml) was charged dropwise to the reaction mixture at 60-65°C in 1.5 - 2 hours. The mixture was maintained for at least 1 hour at 60-65°C. The reaction mass was cooled to 25-30°C and water (200 ml) was charged and stirred. The layers were separated and toluene layer was washed with water (200 ml). The toluene layer was distilled under reduced pressure and de-gassed well. Toluene (50 ml) was charged to the viscous liquid obtained at 55-60°C. To the clear solution obtained, cyclohexane (400 ml) was added slowly at 55-60°C over 30 minutes. The mixture was maintained for half an hour at 25-30°C and the solid obtained was filtered. The precipitate obtained was washed with cyclohexane and suck dried. The pure solid compound (IA) obtained was suck dried and dried further at 45-50°C for at least 12 hours. Dry weight of the product (IA) obtained is 100 g (82.5%) with HPLC purity of 99.2%.

Example 2
Preparation of (2-chloro-5-iodo-phenyl)-(4-(3S)-tetrahydrofuran-3-yloxy-phenyl)-methanone (Formula IB)

Potassium hydroxide (27 g) was charged to toluene (400 ml) and the mixture was stirred at 30-35°C. 3S-hydroxy tetrahydrofuran of Formula (III) (31 g) and tetrabutylammonium bromide (10 g) was charged to the above reaction mixture and the reaction mixture was stirred at 30-35°C for 10-20 minutes. A solution of (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone of Formula (IIB) (100 g) in toluene (300 ml) was prepared separately. The temperature of the above reaction mixture was increased to 60-65°C. The solution of (2-chloro-5-iodophenyl)-(4-fluorophenyl) methanone (300 ml) was charged dropwise to the reaction mixture at 60-65°C in 1.5 - 2 hours. The mixture was maintained for at least 3-4 hour at 60-65°C. The reaction mass was cooled to 30-35°C and water (200 ml) was charged and stirred for 15-20 minutes. The layers were separated and toluene layer was washed with water (200 ml). The toluene layer was distilled under reduced pressure and de-gassed well. Toluene (50 ml) was charged to the viscous liquid obtained at 55-60°C. To the clear solution obtained, cyclohexane (400 ml) was charged at 55-60°C. The mixture was maintained for one hour and gradually cooled to 20-25°C and the mixture was stirred for 1.5-2 hours at 20-25°C. The solid obtained was filtered, washed with cyclohexane and suck dried. The pure solid compound (IB) obtained was suck dried and dried further at 45-50°C for at least 12 hours. Dry wt. obtained was 95 g (80%). HPLC purity of the product was 99.10%
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:We claim:

1. A process for preparation of 3-[4-[(2-chlorophenyl)methyl]phenoxy]tetrahydrofuran derivatives of Formula (I) having 99% - 99.9% HPLC purity comprising:

coupling a compound of Formula (II) with (S)-3-hydroxy tetrahydrofuran of Formula (III)

wherein R1 is (=O) or H; X is bromo or iodo
in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

2. A process for preparation of the derivative of Formula (I) as claimed in claim 1, wherein said derivative is (5-bromo-2-chloro-phenyl)-(4-(S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IA) comprising:

coupling (5-bromo-2-chloro-phenyl)-(4-fluorophenyl)methanone of Formula (IIA) with (S)-3-hydroxy tetrahydrofuran of Formula (III) in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

3. A process for preparation of the derivative of Formula (I) as claimed in claim 1, wherein said derivative is (2-chloro-5-iodo-phenyl)-(4-(3S)-tetrahydrofuran-3-yloxy-phenyl)-methanone of Formula (IB) comprising:

coupling (2-chloro-5-iodophenyl)-(4-fluorophenyl)methanone of Formula (IIB) with (S)-3-hydroxy tetrahydrofuran of Formula (III) in presence of a phase transfer catalyst and a base selected from alkali hydroxide.

4. The process as claimed in claims 1, 2 and 3, wherein the alkali hydroxide is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.

5. The process as claimed in claim 1, 2 and 3, wherein the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA).

6. The process as claimed in claim 1, 2 and 3, wherein the coupling is carried out at 50°C to 70°C in the presence of a solvent.

7. The process as claimed in claim 6, wherein the solvent can be selected from hydrocarbon solvent or etheral solvent.

8. The process as claimed in claim 7, wherein the hydrocarbon solvent is selected from toluene, xylene, benzene, heptane, cyclohexane and the etheral solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether.

Dated this: 09th day of March 2021.

For AARTI INDUSTRIES LIMITED By their Agent
GIRISH VIJAYANAND SHETH (IN/ PA- 1022)
KRISHNA AND SAURASTRI ASSOCIATES LLP