FORM 2
The Patent Act 1970 (39 of 1970)
& The Patent Rules, 2005 COMPLETE SPECIFICATION [See Section 10 and Rule 13]
Process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran”
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 Empagliflozin intermediates and more particularly, to a process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran.
Background of the invention
(3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran of Formula I is an important intermediate in the manufacturing of Empagliflozin, chemically known as (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.
Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2) and causes sugar in the blood to be excreted by the kidneys and eliminated in urine and hence used in the treatment of Type 2 diabetes in adults.
Prior art article literature Org. Lett., vol. 16, nb. 16, 2014, p. 4090-4093 and patent documents US 9,127,034 and US 7,772,191 covers processes of preparation of compound of Formula I. The reactions proceeds through preparation of (5-halo-2-chloro-phenyl)-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methanone, wherein halo is bromine or iodine. Further, (5-halo-2-chloro-phenyl)-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl] methanone is reduced to provide compound of Formula I. However, this reaction is exothermic and

requires special precaution and attention during reaction. In addition, the reaction time for this reported reaction is about 16 hours and requires the temperature to be maintained at 0-20 °C during the reaction.
Accordingly, there is a need for a process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran that overcomes the above mentioned drawbacks of the prior art.
Objects of the invention
An object of the present invention is to provide a novel process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran that is suitable for industrial production.
Another object of the present invention is to provide the process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran which avoids use of hazardous chemicals.
Another object of the present invention is to provide a process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran which avoids formation of impurities.
Still another object of the present invention is to provide a process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran which provides higher yield and better chiral purity.

Summary of the invention
Accordingly, the present invention teaches a process for preparing (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran of Formula 1. The process comprises condensing 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2 with [(3R)-tetrahydrofuran-3-yl]benzenesulfonate derivative of Formula 3 in the presence of a base and solvent.
wherein,
Hal is halogen selected from bromine and iodine,
Group P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo.
The invention also provides a process for preparation of [(3R)-tetrahydrofuran-3-yl]benzenesulfonate derivative of Formula 3. The process comprises reacting benzenesulfonyl chloride derivative of Formula 4 with (3R)-hydroxy tetrahydrofuran of Formula 5 in the presence of a base and solvent. The reaction is carried out at a temperature in a range of about 0 °C to 20 °C, preferably the temperature is about 10 °-15 °C.

wherein, Group P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo.
The present invention also provides a process for preparation of 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2. The process comprises reducing (5-halo-2-chloro-phenyl)-(4-alkoxy-phenyl)-methanone of Formula 6 using reducing agent in the presence of a first solvent to form 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7. Further, 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7 is de-alkylated in the presence of an acid and a second solvent to form compound of Formula 2.
wherein,
Hal is halogen selected from bromine and iodine,
Group R1 is selected from -C1-4 alkyl, -CH2-O-(C1-4) alkyl, -CH2-O-Tert butyl dimethyl
silane and -CH2-O-Tert butyl diphenyl silane.

Detailed description of the invention
An embodiment of the present invention teaches a process for preparing (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran of Formula 1. The process comprises condensing 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2 with [(3R)-tetrahydrofuran-3-yl]benzenesulfonate derivative of Formula 3 in the presence of a base and solvent. In an embodiment, the reaction is carried out under basic conditions as a classical nucleophilic substitution reaction.
The base is selected from alkali and alkaline metal salts and tertiary amine base. The alkali and alkaline metal salts is selected from carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, hydroxides such as sodium hydroxide, potassium hydroxide, alcoholates such as methoxides, ethoxides, tert-butoxides and metal hydrides such as sodium hydride. The tertiary amine base is selected from triethylamine, pyridine and di-isopropylethylamine.
The solvent is polar or non-polar solvent. Preferably, the solvent is selected from the group consisting of toluene, dimethyl formamide, tetrahydrofuran, acetone, water, dimethyl acetamide, N-methyl pyrollidone, dimethylsulfoxide, dichloromethane, acetonitrile, dioxane, xylene, pyridine, alcohols such as methanol, ethanol, isopropanol, butanol and mixtures thereof.
In one embodiment, the reaction is carried out at 20-40 °C, preferably at 25-30 °C in the presence of the solvent selected from dimethyl formamide, alcohol solvents such as methanol, ethanol, isopropanol and butanol, N-methyl pyrollidone, dimethylsulfoxide and tetrahydrofuran.
In another embodiment, the reaction is carried out at reflux condition in the presence of the solvent selected from acetone and aromatic hydrocarbon such as toluene and xylene.

The reaction scheme of preparing compound of Formula 1 is represented below:
Hal is halogen selected from bromine and iodine.
Group P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo.
The present invention also provides a process for preparation of [(3R)-tetrahydrofuran-3-yl]benzenesulfonate derivative of Formula 3. The process comprises reacting benzenesulfonyl chloride derivative of Formula 4 with (3R)-hydroxy tetrahydrofuran of Formula 5 in the presence of a base and solvent. The reaction is carried out at a temperature in a range of about 0 °C to 20 °C, preferably the temperature is about 10 °C to 15 °C.
The base is selected from triethylamine, pyridine, 3-methyl pyridine and 4-dimethylaminopyridine.
The solvent is selected from toluene, cyclohexzane, benzene, methylene dichloride, ethylene dichloride, chloroform, xylene, pyridine, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, methanol and ethanol.
The reaction scheme of preparing compound of Formula 3 is represented below:

Group P1 is selected from H, -C1-4 alkyl, nitro, halogen selected from chloro, bromo and iodo.
The present invention also provides a process for preparation of 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2. The process comprises reducing (5-halo-2-chloro-phenyl)-(4-alkoxy-phenyl)-methanone of Formula 6 using reducing agent in the presence of a first solvent to form 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7.
The reducing agent is selected from aluminium hydrides such as lithium aluminium hydride and sodium bis(2-methoxyethoxy)aluminum dihydride and borohydrides such as sodium borohydride and potassium borohydride.
The first solvent is selected from tetrahydrofuran, dioxane, and dimethoxy ethane, preferably tetrahydrofuran.
The reduction is carried out optionally in presence of Lewis acids selected from boron trifluoroetherate and aluminum trichloride.
Further, 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7 is de-alkylated in the presence of an acid and a second solvent. However, it is understood here that the de-alkylation of 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7 may be carried out under neutral and basic conditions.

The acid is selected from boron trichloride, boron tribromide, boron triiodide, trimethylsilyl iodide, aluminium chloride, aluminium bromide, hydrobromic acid, hydrochloric acid, trifluoroacetic acid and trifluoromethylsulfonic acid.
The second solvent is selected from halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, acetonitrile, toluene, acetic acid and combinations thereof.
The reaction scheme of preparing compound of Formula 2 is represented below:
Hal is halogen selected from bromine and iodine.
Group R1 is selected from -C1-4 alkyl, -CH2-O-(C1-4) alkyl, -CH2-O-Tert butyl dimethyl
silane and -CH2-O-Tert butyl diphenyl silane, preferably -CH3.
EXAMPLES
The following examples illustrate the invention, but are not limiting thereof.
Example 1
Preparation of (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone
5-bromo-2-chlorobenzoic acid (100 g) was charged to methylene dichloride (400 ml) and dimethyl formamide (5 ml) was added to a reaction mixture. Thionyl chloride was added

gradually at 25-30 °C over the period of 30 minutes and the mixture was refluxed at 40-42 °C for 6 hours. Methylene dichloride was distilled off at 40-42 °C under atmospheric conditions and stripping of cyclohexane (100 ml) was given. Cyclohexane was distilled off and the residue was maintained at 50-55 °C for 30 minutes. Methylene dichloride (400 ml) was added to the residue.
Solution of aluminium trichloride was prepared by dissolving aluminium trichloride (68.5 g) in methylene dichloride (400 ml) and stirring for 1 hour at 25-30 °C. The solution was cooled to 15-20 °C and added slowly to the above reaction mixture at 15-20 °C over the period of 30 minutes. The temperature was raised to 25-30 °C and stirred for 1 hour. The reaction mass was cooled to 15-20 °C.
The solution of anisole (44.2 g) in methylene dichloride (200 ml) was prepared separately and was added to above reaction mass at 15-20 °C over the period of 30 minutes. The temperature was raised to 25-30 °C and maintained for 4 hours. The reaction mass was quenched into chilled hydrochloric acid solution in water (prepared by adding concentrated hydrochloric acid (100 ml) in chilled water (300 ml)) below 15 °C. The mass was stirred for 30 minutes at 15-20 °C.
The layers were separated and aqueous layer was extracted with methylene dichloride (100 ml). Methylene dichloride layers were combined and washed with water (100 ml x 2 times) followed by washing with 5% aqueous sodium bicarbonate solution (100 ml x 2 times) at 25-30 °C. Methylene dichloride layer was dried over sodium sulfate (10 g). Methylene dichloride was distilled under vacuum at reflux and stripped with cyclohexane (100 ml). Cyclohexane (200 ml) was added and the mass was stirred for 30 minutes. The mass was cooled to 10-15 °C and maintained for 1 hour. The solid was washed with cyclohexane (100 ml) and dried under vacuum at 55-60 °C to yield (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone (123 g) as white solid. Yield: 86.76%

HPLC purity: 99.2%
Example 2
Preparation of 4-bromo-1-chloro-2-[(4-methoxyphenyl)methyl]benzene
Sodium borohydride (46 g) was charged to tetrahydrofuran (1 L) at room temperature under inert atmosphere. Boron trifluoro etherate (470 g) was added drop wise to the reaction mixture at 20-25 °C and stirred for 30 min. (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone (200 g) as prepared in example 1 was added at 25-30 °C and stirred for 30 minutes. The reaction mass was refluxed at 60-65 °C for 6 hours. The mass was chilled at 10-15 °C. 20% NaOH solution was added slowly and two layers were separated. Tetrahydrofuran layer was distilled under vacuum and the residue obtained was charged in chloroform. The mixture was stirred and chloroform layer was distilled under vacuum. Methanol (600 ml) was added to the residue and stirred for 1 hour. The suspension was cooled to 10-15 °C and filtered. The precipitate was washed with methanol (200 ml) and dried under vacuum at 50-55 °C to obtain 4-bromo-1-chloro-2-[(4-methoxyphenyl)methyl]benzene (159 g) as white solid. Yield: 83% HPLC Purity: 99.5%.
Example 3
Preparation of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol
4-bromo-1-chloro-2-[(4-methoxyphenyl)methyl]benzene (100 g) as prepared in example 2 was charged in acetic acid (350 ml) and the mixture was heated to 105-110 °C. 48% HBr solution (350 ml) was added gradually at 105-110 °C over the period of 1-2 hours. The mass was maintained till completion of the reaction. Chloroform (400 ml) and water (400 ml) was added to the mass. Both the layers were separated and aqueous layer was extracted with chloroform (200 ml). All chloroform layers were combined and washed with water

and distilled under vacuum and degassed well. Cyclohexane (350 ml) was added to the
residue obtained and heated to 70 °C. The solution was cooled gradually to room
temperature, filtered and washed with cyclohexane (50 ml). The precipitate was dried
under vacuum at 50-55 °C to yield 4-[(5-bromo-2-chloro-phenyl)methyl]phenol (81 gm) as
white solid.
Yield: 83%
HPLC purity: 99.3%
Example 4
Preparation of [(3R)-tetrahydrofuran-3-yl]-4-nitrobenzenesulfonate
(3R)-Tetrahydrofuranol (50 g) was charged to methylene dichloride (100 ml) and the mixture was stirred for 10-15 minutes. To the reaction mixture, separately prepared solution of p-nitrobenzene sulfonyl chloride (138 g) in methylene dichloride (400 ml) was added. Triethylamine (86 g) was added gradually to the reaction mass over the period of 30-45 minutes. The reaction mass was maintained for 4-5 hours at room temperature and water (250 ml) was added at room temperature. pH of the solution was adjusted to neutral using 20% acetic acid and stirred for 20-30 minutes at room temperature. The aqueous and organic layers were separated and the organic layer was washed with water (25 ml x 2 times). The organic layer was dried with sodium sulfate and distilled under vacuum at 40 °C. To the reaction mass, di-isopropyl ether (300 ml) was added and the mixture was stirred for 1 hour at 15-20 °C. The suspension was filtered and washed with di-isopropyl ether (25 ml x 2 times). The wet cake was dried under vacuum at 35-40 °C to yield [(3R)-tetrahydrofuran-3-yl]- 4-nitrobenzenesulfonate (120 g) as off-white powder. Yield: 77% HPLC Purity: 98.22% Chiral purity: 99.89% SOR: +5.11° (1% solution in methanol at 589 nm at 20 °C)

Example 5
Preparation of [(3R)-tetrahydrofuran-3-yl]-4-nitrobenzenesulfonate
Toluene (1 L) was charged to (3R)-tetrahydrofuranol (100 g) and stirred for 10-15 minutes at room temperature. P-nitrobenzene sulfonyl chloride (277 g) was dissolved in toluene (800 ml) and the solution was added to the above reaction mixture within 30-40 minutes at 10 °C. Triethylamine (172 g) was added slowly to the reaction mass in 60-70 minutes at 10-15 °C. The reaction mixture was maintained for 3-4 hrs at room temperature. Ethyl acetate (1 L) was added and stirred for 10-15 min. Water (1 L) was added at room temperature for 30 min and aqueous and organic layers were separated. The organic layer was washed with 10% acetic acid (1 L). The aqueous and organic layers were separated and organic layer was washed with water (500 ml). The aqueous and organic layers were separated and organic layer was dried with sodium sulphate (100 g). All the organic layers were combined and distilled under vacuum at 40-45 °C. Isopropyl alcohol (500 ml) was added to the residue and stirred for 1 hour at 5-10 °C. The suspension was filtered and solid product obtained was washed with di-isopropyl ether (400 ml). The solid was dried under vacuum at 35-40 °C to yield [(3S)-tetrahydrofuran-3-yl]-4-nitrobenzenesulfonate (243 gm). Yield: 78% HPLC purity: 98.21 % Chiral Purity: 99.92 % SOR: +4.93° (in 1% methanol at 20 °C)
Example 6
Preparation of (3S)-3-[4-[(5-bromo-2-chloro-phenyl)methyl]phenoxy]
tetrahydrofuran
[(3R)-tetrahydrofuran-3-yl]-4-nitrobenzenesulfonate (25 g) obtained in example 4 was added to the mixture of dimethyl formamide (125 ml) and sodium hydroxide (3.7 g). The

reaction mixture was stirred and maintained at 25-30 °C. The reaction mass was filtered and the precipitate was washed with cyclohexane (25 ml). The solvent was distilled at 60-65 °C under vacuum. Cyclohexane (125 ml) and water (125 ml) was added to the residue obtained. The mixture was stirred for 30 minutes. The organic and aqueous layers were separated and aqueous layer was extracted with cyclohexane (50 ml). The cyclohexane layers were combined and washed with water (100 ml) followed by addition of 10% sodium hydroxide solution (100 ml). The cyclohexane layer was washed with 10% HCl solution (100 ml) followed by addition of water (100 ml). Cyclohexane was distilled off to yield colorless to yellowish oil. Strippings of isopropyl alcohol (50 ml) were given and isopropyl alcohol (125 ml) was added to residue. The mass was heated to 50-55 °C and cooled gradually to 25-30 °C. The mass obtained was chilled to 0-5 °C and stirred at 0-5 °C for 30 minutes. The suspension was filtered and residue obtained was dried under vacuum at 25 °C to 30 °C to yield (3S)-3-[4-[(5-bromo-2-chloro-phenyl)methyl]phenoxy] tetrahydrofuran (20 g) as white solid. Yield: 64% HPLC purity: 99.5% Chiral purity: 99.5% SOR: +5° (in 1% methanol at 20 °C)

We Claim:
1. A process for preparation of (3S)-3-[4-[(5-halo-2-chlorophenyl)methyl]phenoxy] tetrahydrofuran of Formula 1
comprising condensing 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2 with [(3R)-tetrahydrofuran-3-yl]benzenesulfonate derivative of Formula 3 in the presence of a base and solvent.
wherein,
Hal is halogen selected from chlorine, bromine and iodine,
P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo.
2. The process as claimed in claim 1, wherein the base is selected from alkali and alkaline metal salts and tertiary amine base.
3. The process as claimed in claim 2, wherein the alkali and alkaline metal salts are selected from carbonates such as potassium carbonate, sodium carbonate, cesium

carbonate, hydroxides such as sodium hydroxide, potassium hydroxide, alcoholates such as methoxides, ethoxides, tert-butoxides and metal hydrides such as sodium hydride.
4. The process as claimed in claim 2, wherein the tertiary amine base is selected from triethylamine, pyridine and di-isopropylethylamine.
5. The process as claimed in claim 1, wherein the solvent is selected from toluene, dimethyl formamide, tetrahydrofuran, acetone, water, dimethyl acetamide, N-methyl pyrollidone, dimethylsulfoxide, dichloromethane, acetonitrile, dioxane, xylene, pyridine, and alcohols such as methanol, ethanol, isopropanol, butanol and mixtures thereof.
6. The process as claimed in claim 1, wherein the reaction is carried out at 20-40 °C.
7. The process as claimed in claim 6, wherein the solvent is selected from dimethyl formamide, alcohol solvents such as methanol, ethanol, isopropanol and butanol, N-methyl pyrollidone, dimethylsulfoxide and tetrahydrofuran.
8. The process as claimed in claim 1, wherein the reaction is carried out at reflux condition.
9. The process as claimed in claim 8, wherein the solvent is selected from acetone and aromatic hydrocarbon solvent such as toluene and xylene.
10. The process as claimed in claim 1, wherein [(3R)-tetrahydrofuran-3-
yl]benzenesulfonate derivative of Formula 3 is prepared by reacting benzenesulfonyl
chloride derivative of Formula 4 with (3R)-hydroxy tetrahydrofuran of Formula 5 in the
presence of a base and solvent.

wherein, Group P1 is selected from H, -C1-4 alkyl, nitro and halogen such as chloro, bromo and iodo.
11. The process as claimed in claim 10, wherein the temperature of the reaction is maintained in a range of about 0 °C to 20 °C.
12. The process as claimed in claim 10, wherein the temperature of the reaction is maintained in a range of about 10 °C to 15 °C.
13. The process as claimed in claim 10, wherein the base is tertiary amine base selected from triethylamine, pyridine, 3-methyl pyridine and 4-dimethylaminopyridine.
14. The process as claimed in claim 10, wherein the solvent is selected from toluene, cyclohexane, benzene, methylene dichloride, ethylene dichloride, chloroform, xylene, pyridine, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, methanol and ethanol.
15. A process for preparation of 4-[(5-halo-2-chloro-phenyl)methyl]phenol of Formula 2
wherein, Hal is halogen selected from bromine and iodine

comprising the steps of:
i) reducing (5-Halo-2-chloro-phenyl)-(4-alkoxy-phenyl)-methanone of Formula 6 using reducing agent in the presence of a first solvent to form 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7; and
wherein,
Hal is halogen selected from bromine and iodine,
Group R1 is selected from -C1-4 alkyl, -CH2-O-(C1-4) alkyl, -CH2-O-Tert butyl dimethyl
silane and -CH2-O-Tert butyl diphenyl silane.
ii) de-alkylating 4-halo-1-chloro-2-(4-methoxy-benzyl)-benzene of Formula 7 in the presence of an acid and a second solvent.
16. The process as claimed in claim 15, wherein the reducing agent used in step i) is selected from aluminium hydrides such as lithium aluminium hydride and sodium bis(2-methoxyethoxy)aluminum dihydride and borohydrides such as sodium borohydride and potassium borohydride.
17. The process as claimed in claim 15, wherein step i) is carried out in presence of Lewis acids selected from boron trifluoroetherate and aluminum trichloride.
18. The process as claimed in claim 15, wherein the first solvent is selected from tetrahydrofuran, dioxane, and dimethoxy ethane.

19. The process as claimed in claim 15, wherein the first solvent is tetrahydrofuran.
20. The process as claimed in claim 15, wherein the acid used in step ii) is selected from boron trichloride, boron tribromide, boron triiodide, trimethylsilyl iodide, aluminium chloride, aluminium bromide, hydrobromic acid, hydrochloric acid, cerium chloride, trifluoroacetic acid and trifluoromethylsulfonic acid.
21. The process as claimed in claim 15, wherein the second solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, acetic acid and mixtures thereof.