Claims:
1) A process for the preparation of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate compound having the structure of formula (A)
;
wherein represents or or unresolved isomer;
the process comprising reacting 3-tetrahydrofuran-ol with p-tosylchloride in the presence of one or more than one inorganic base to obtain the compound of formula (A);
wherein the obtained compound of formula (A) is substantially free of a tritosyl impurity having the structure of formula (B)

2) The process as claimed in claim 1, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, and combinations thereof.

3) The process as claimed in claim 1 or claim 2, wherein compound of formula (A) is an R isomer (AR) and the process comprises reacting (3R)-tetrahydrofuran-ol with p-tosylchloride in the presence of one or more than one inorganic base.
4) The process as claimed in claim 1 or claim 2, wherein compound of formula (A) is an S isomer (AS) and the process comprises reacting (3S)-tetrahydrofuran-ol with p-tosylchloride in the presence of one or more than one inorganic base.
5) The process as claimed in claim any one of the preceding claims wherein the alkali hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide; the alkali metal carbonate is selected from the group consisting of sodium carbonate and potassium carbonate; and the alkali metal alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
6) The process as claimed in any one of the preceding claims, wherein the inorganic base is a mixture of alkali hydroxides and alkali metal alkoxides.
7) The process as claimed in any of the preceding claim, wherein the reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, diethyl ether, toluene, xylene and any combination thereof.
8) The process as claimed in claim 7, wherein the reaction is carried out in tetrahydrofuran.
9) The process as claimed in claim 1, further comprising converting compound (A) to 3-[4-[(2-chloro-5-halo-phenyl)methyl]phenoxy]tetrahydrofuran of formula (D) by reacting compound (A) with 4-[(2-chloro-5-halo-phenyl)methyl]phenol of formula (C)
wherein X is iodo or bromo.

10) The process as claimed in claim 9, wherein the reaction is carried out in the presence of a base selected from the group consisting of alkali and alkaline metal salts and tertiaryamines.
11) The process as claimed in claim 10, wherein the alkali and alkaline metal salts are carbonates selected from the group consisting of potassium carbonate, sodium carbonate, and cesium carbonate; hydroxides selected from the group consisting of sodium hydroxide and potassium hydroxide; alcoholates selected from the group consisting of methoxides, ethoxides and tert-butoxides; and metal hydrides.
12) The process as claimed in claim 10, wherein the tertiary amine is selected from the group consisting of triethylamine, pyridine and di-isopropylethylamine.
13) The process as claimed in any one of claims 10-12, wherein the reaction is carried out in a solvent selected from the group consisting of toluene, dimethyl formamide, tetrahydrofuran, acetone, water, dimethyl acetamide, N-methyl pyrollidone, dimethylsulfoxide, acetonitrile, dioxane, xylene, pyridine, methanol, ethanol, isopropanol, butanol and any combination thereof.
, Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)

&

THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10, Rule 13]

IMPROVED PROCESS FOR PREPARATION OF [TETRAHYDROFURAN-3-YL]-4-METHYLBENZENESULFONATE;

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 71, UDYOG KSHETRA, 2NDFLOOR, 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.
Improved process for preparation of [tetrahyd
Field of the Invention
[001] The present disclosure pertains to an improved process for preparation of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate.
Background and prior art
[002] [Tetrahydrofuran-3-yl]-4-methylbenzenesulfonate of formula (A), especially when resolved to [(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (AR) and [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (AS), constitutes an important raw material useful in the preparation of key intermediates for (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).

[003] The chemical and chiral purity and yield of compounds (AR) and (AS) ultimately impacts the purity and cost of manufacturing of Empagliflozin intermediates such as the intermediates shown below.

[004] Processes for preparation of compound (A), particularly compounds (AR) and (AS) are known in the art and disclosed in various journal articles and patents.
[005] US 2013010257 reports a reaction of solution of tetrahydrofuran-3-ol in pyridine with 4-methylbenzene-1-sulfonyl chloride. The reaction mixture was stirred at room temperature for 1 hour, poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to give 3-(p-toluenesulfonato)-tetrahydrofuran. The yield obtained was very poor (26%).
[006] WO 201655982 describes a process for preparing (3S)-tetrahydrofuran-4-methyl benzenesulfonate, wherein the process comprises reacting a solution of (3S-tetrahydrofuran-3-ol in pyridine at 0°C with 4-methyl benzenesulfonyl chloride. The reaction mixture was stirred for 1 hr at 0°C and overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography with a gradient of 0-30% ethyl acetate in heptane. The pure fractions were collected to give [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate as a colorless oil (Yield is 40%).
[007] A reaction of 3-hydroxytetrahydrofuran in anhydrous pyridine with 4-toluene sulfonyl chloride is also reported in US 8,080,580 and its equivalent EP 2334687. The reaction mixture was stirred for 18 hours at room temperature and concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 3-(p-toluenesulfonato)-tetrahydrofuran as a colorless oil (51% yield) .
[008] WO 2015 25197 discloses addition of triethylamine to a cooled (0°C) solution of DL-tetrahydrofuran-3-ol followed by addition of toluene-4-sulfonyl chloride. The mixture was stirred at room temperature for 30 min. Saturated sodium bicarbonate solution was added, the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to obtain a white solid, which was purified by column chromatography on silica gel to obtain tetrahydrofuran-3-yl-4-methylbenzenesulfonate as an off white solid (2.5 g, 45% yield).
[009] All the above mentioned processes need silica column chromatography for purification and the reported yields are very low.
[0010] US 8,334,292 reports addition of 4-methylbenzene-1-sulfonyl chloride to the mixture of (R)-tetrahydrofuran-3-ol and triethylamine. The mixture was stirred at room temperature for 8 h and washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to yield [(3R)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate (83% yield).
[0011] The reaction of (S)-tetrahydrofuran-3-ol in THF with 4-methyl-benzenesulfonyl chloride in tetrahydrofuran in presence of sodium hydride base is described in WO201449133. The reaction mixture was maintained at 25°C for 15 h. The mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness. Flash chromatography gave [(3S)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate as a colorless solid. (80% yield)
[0012] The yield reported in the above processes is good, but requires flash chromatography which makes the processes troublesome and inefficient for scale up and production.
[0013] WO 2016021192 describes use of N-methylmorpholine and 1-methyl imidazole as base in the reaction of (R)-tetrahydrofuran-3-ol and p-toluenesulfonyl chloride. The reaction mass was stirred at 15 to 25°C till completion of reaction. After completion of the reaction, the reaction mass was quenched by water and the layers were separated followed by back extraction of aqueous layer using toluene. The combined toluene layer was subsequently washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and finally by aqueous sodium chloride solution. The toluene layer was concentrated under reduced pressure maintaining temperature below 40°C to give of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate as an oil (100.24% yield).
[0014] The yield reported is good in the reaction and chromatography technique is not required in the purification of the product. However it is observed that a tritosyl impurity of formula (B) is formed in the process which is very difficult to remove during isolation of pure (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate. The structure of the impurity is shown below:

[0015] It is observed that even after repeated purifications, the impurity (B) is not removed completely.
[0016] There is need for a process for preparation of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate, which is simple, efficient, industrially scalable, and avoids formation of the impurity (B) shown above while also providing higher yields and better purity without the use of unwieldy purification techniques like silica gel chromatography and/or flash chromatography.

Summary of the invention
[0017] Provided herein is an improved process for synthesis of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (A), [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate (AR) and [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (AS). The process described herein provides a simple and high yield method for preparation of (A), (AR) and (AS) of desired purity without involving any tedious purification techniques such as chromatography and while also avoiding/reducing formation/occurrence of the impurity of structure (B) during the reaction and/or after purification.
[0018] The process comprises, consists of, or consists essentially of, reaction of 3-tetrahydrofuran-ol with p-tosylchloride in the presence of an inorganic base or a mixture of inorganic bases (e.g., a base selected from the group consisting of alkali hydroxides, alkali metal carbonates, alkali metal alkoxides and/or mixtures thereof). The compound [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate prepared by the process described herein is converted further to Empagliflozin.
Detailed description of the invention
[0019] Described herein is an improved process for synthesis of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (A), [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate (AR) and [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (AS). Advantageously, the process described herein for preparation of (A), (AR) and (AS), avoids formation of tritosyl impurity and other by-products which typically affect overall purity and yield of Empagliflozin intermediate(s).
[0020] The process described herein provides (A), (AR) and/or (AS) in purities of > 99% as measured by HPLC. By contrast the use of amine bases (See comparative example below) provide HPLC purities of about 98%. Accordingly the process described herein provides improved purities for (A), (AR) and/or (AS) when compared to other processes.
[0021] Except in the examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties of materials and/or use are to be understood as modified by the word "about."
[0022] It should be noted that in specifying any range of concentration or amount, any particular upper concentration or amount can be associated with any particular lower concentration or amount.
[0023] “A” or “an” are not meant to be associated with the singular alone and may also indicate a plurality depending on the context.
[0024] Described herein is a process for the preparation of [tetrahydrofuran-3-yl]-4-methylbenzenesulfonate compound having the structure of formula (A)
;
wherein represents or or unresolved isomer;
the process consisting essentially of reacting 3-tetrahydrofuran-ol with p-tosylchloride in the presence of one or more than one inorganic base to obtain the compound of formula (A);
wherein the obtained compound of formula (A) is substantially free of a tritosyl impurity having the structure of formula (B)

[0025] As used herein “substantially free of a tritosyl impurity of formula (B)” means that in one embodiment, the impurity is an amount of less than 1% in the referenced product (e.g., compound (A)). In another embodiment, the impurity is an amount of less than 2% in the referenced product (e.g., compound (A)). In a further embodiment, the impurity is an amount of less than 3% in the referenced product (e.g., compound (A)). In an additional embodiment, the impurity is an amount of less than 4% in the referenced product (e.g., compound (A)). In a yet another embodiment, the impurity is an amount of less than 5% in the referenced product (e.g., compound (A)).
[0026] Depending on the starting material, [Tetrahydrofuran-3-yl]-4-methylbenzenesulfonate prepared by present invention is either unresolved [(3RS)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate isomer or resolved isomers [(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate and [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate.
[0027] The schematic representation of the process is represented as follows-

represent or or without any specific configuration i.e. unresolevd isomer.
[0028] The reaction involves the use of a suitable isomer of tetrahydrofuran-3-ol. For preparation of [(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate isomer (3R)-tetrahydrofuranol is used as starting material and for preparation of [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate isomer (3S)-tetrahydrofuranol is used as starting material.
[0029] In an embodiment, the one or more than one inorganic base used in the reaction is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal alkoxide and/or mixtures thereof.
[0030] The alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide. Lithium hydroxide, or any other alkali metal hydroxide is also contemplated within the scope of embodiments presented herein. Alkali metal carbonate is selected from sodium carbonate and potassium carbonate. Lithum carbonate, cesium carbonate, or any other alkali metal carbonate is also contemplated within the scope of embodiments presented herein. The alkali metal alkoxide is preferably selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. Other alkali metal alkoxides are also contemplated within the scope of embodiments presented herein.
[0031] In a preferred embodiment the reaction is carried out in presence of a mixture of alkali metal alkoxides and alkali metal hydroxides or a mixture of alkali metal alkoxides and alkali metal carbonates. In a most preferred embodiment the reaction is carried out in the presence of potassium tert-butoxide and potassium hydroxide.
[0032] The reaction is carried out in a solvent selected from tetrahydrofuran, diethyl ether, toluene and xylene, and/or any combination thereof.
[0033] The base is suspended in the solvent at room temperature and tetrahydrofuran-3-ol is added drop wise at lower temperature, preferably at 20-30°C. p-toluenesulfonyl chloride is added in portions to the reaction mixture at 20-30°C, preferably at 20-25°C. The reaction mass is chilled to 0 to -5°C. Water is added drop wise and the product is isolated from the organic layer.
[0034] In an embodiment of the present invention the compound of formula (A), (AR) and/or (AS) as prepared by the process described above is further converted to 3-[4-[(2-chloro-5-halo-phenyl)methyl]phenoxy]tetrahydrofuran (D) as shown below:
wherein X is iodo or bromo.
[0035] The aforementioned reaction is carried out under basic conditions as a classical nucleophilic substitution reaction. Suitable bases are alkali and alkaline metal salts, preferably carbonates selected from potassium carbonate, sodium carbonate, cesium carbonate; hydroxides selected from sodium hydroxide and potassium hydroxide; alcoholates selected from methoxides, ethoxides and tert-butoxides; and metal hydrides such as sodium hydride. The base used in the reaction can also be tertiaryamine base selected from triethylamine, pyridine and di-isopropylethylamine. Other tertiary amines including and not limited to N-methyl morpholine, N-methyl piperidine, N-methyl pyrolidine, or N,N-dimethyl piperazine are also contemplated within the scope of embodiments presented herein.
[0036] The reaction is conducted in polar or non-polar solvents. Thus the reaction is preferably carried out in the presence of a solvent selected from the group consisting of toluene, dimethyl formamide, tetrahydrofuran, acetone, dimethyl acetamide, N-methyl pyrollidone, dimethylsulfoxide, dioxane, xylene, pyridine. alcohols such as methanol, ethanol, isopropanol or butanol and mixtures thereof.
[0037] The reaction is carried out at 20-40°C, preferably at 25-30°C, when the solvent used is dimethyl formamide, alcohol solvents, N-methyl pyrollidone, dimethylsulfoxide, or tetrahydrofuran. The reaction is typically carried out at reflux temperatures when the reaction is carried out in aromatic solvents such as xylene or toluene.
[0038] In an alternative aspect, provided herein is a process comprising, consisting of, or consisting essentially of the following steps:
i) reacting 3-tetrahydrofuran-ol with p-tosylchloride in the presence of an inorganic base or a mixture of inorganic bases to obtain the compound of formula (A)
;
wherein represents or or unresolved isomer;
wherein the obtained compound of formula (A) is substantially free of a tritosyl impurity having the structure of formula (B)
; and
ii) converting compound (A) to 3-[4-[(2-chloro-5-halo-phenyl)methyl]phenoxy]tetrahydrofuran of formula (D) by reacting compound (A) with 4-[(2-chloro-5-halo-phenyl)methyl]phenol of formula (C)
wherein X is iodo or bromo;
wherein the inorganic bases and/or process conditions are as described above and herein.
EXAMPLES
[0039] The following examples are provided so that the invention might be fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
Comparative example
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0040] Toluene (125 ml) was charged to p-toluene sulfonyl chloride (144 gms)) at 25 - 30°C and stirred for 10 - 15 min. Reaction mixture was cooled to 0 - 5°C and slowly added to (3R)-tetrahydrofuranol (50 gm) and the container was flushed with toluene (25ml) at 0 - 5°C. The reaction mixture was stirred for 10- 15min at 0-5°C. Separately prepared solution of N-methyl morpholine (86 gms) and 1-methyl imidazole (23.5 gms)) in toluene (50 ml) was added to the reaction mixture at 0-5°C. The mixture was stirred for 15 - 20 min at 0 - 5°C. Cooling was removed and the mixture was heated to 20 - 25°C. The reaction mixture was stirred at 20 - 25°C for 2hr. Water (250 ml) was slowly charged at 0 - 10°C and the mixture was stirred for 10 - 15min. Temperature was raised to 20 - 25°C and the reaction mixture was stirred for 10 - 15min. Stopped stirring and separated the aqueous and toluene layer. Aqueous layer was back extracted with toluene (150 ml) and continued stirring for 30min at 20 - 25°C.
[0041] Dil HCl was added to combined organic (toluene) layer and stirred for 10 - 15min at 20 - 25°C. Organic layer (Toluene) was extracted with 5% NaHCO3 solution at 20 - 25°C. The organic layer was separated and extracted with 10% NaCl solution at 20 - 25°C. Finally toluene layer was dried on sodium sulfate (5 gm). Toluene was removed under vacuum below 60°C to yield [(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate as an oil = 129 - 130 gm.
HPLC purity: 98.21%
Chiral purity: 99.40%

Example 1
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0042] Potassium Tert-butoxide (82.7 gm) was charged to dry toluene (500 ml) at 25-30°C under an inert atmosphere. The reaction mixture was stirred for 15 minutes. (3R)-tetrahydrofuran-ol (50 g) was added drop wise to the reaction mixture over 30 minutes - 60 minutes at 25-30°C and stirred for 10 minutes. The reaction mass was chilled to 0-5°C. P-toluene sulfonyl chloride (113.5 gm) was added to the reaction mass in portions at the interval of 10-15 minutes. After completion of addition, the temperature was raised to 20-25°C and stirring was maintained for 2 hours. After completion of reaction, the reaction mass was chilled to 0-5°C. Water (250 ml) was added drop wise at 0-5°C. Temperature was raised to 25°C and the aqueous layer was extracted with toluene (150 ml) at 25-30°C. Both Toluene layers were combined and washed with dilute HCl and stirred for 10-15 minutes at 25-30°C. The toluene layer was washed with 5% NaHCO3 solution (250 ml). The separated toluene layer was washed with 10% NaCl Solution (250 ml) at 25-30°C.
[0043] Finally the separated toluene layer was concentrated at 40°C under vacuum. n-heptane (260 ml) was charged and heated to 40 - 45°C with stirring for 30 min. n-heptane was decanted at 40 - 45°C. Again n-heptane 260 ml was charged and heated to 40 - 45°C with constant stirring for 30 min. Gradually cooled to 25-30°C, then chilled to 0 - 5°C. Precipitation of solid was observed. The suspension was stirred for 1 hr at 0-5°C and filtered. The solid was washed with chilled n-heptane (0-5°C) and dried under suction.
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate obtained was dried under vacuum at 25 - 30°C. Dry wt:121 gm
HPLC purity: 99.63%
Chiral Purity: 99.80%

Example 2
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0044] Potassium Tert-butoxide (57.3 gm) was charged to dry toluene (500 ml) at 25-30°C under an inert atmosphere. Potassium hydroxide powder (12.7 g) was charged to 25-30°C and stirred for 30 minutes. (3R)-tetrahydrofuran-ol (50 g) was added drop wise to the reaction mixture within 30 minutes - 60 minutes at 25-30°C and stirred for 10 minutes. The reaction mass was chilled to 0-5°C. P-Toluene sulfonyl Chloride (113.5 gm) was added to the reaction mass in portions at the interval of 10-15 minutes. After completion of addition, the temperature was raised to 20-25°C maintained for 2 hours. After completion of reaction, the reaction mass was chilled to 0-5°C. Water (250 ml) was added drop wise at 0-5°C. Temperature was raised to 25°C and the aqueous layer was extracted with toluene (150 ml) at 25-30°C. Both Toluene layers were combined and washed with dilute HCl and stirred for 10-15 minutes at 25-30°C. The toluene layer was washed with 5% NaHCO3 solution (250 ml). The separated toluene layer was washed with 10% NaCl Solution (250 ml) at 25-30°C.
[0045] Finally the separated toluene layer was distilled at 40°C under vacuum. Stripping of the toluene layer with n-heptane (100ml) was conducted as follows. n-heptane (260 ml) was charged to organic layer and heated to 40 - 45°C with stirring for 30 min. n-heptane was decanted at 40 - 45°C. Again n-heptane 260 ml was charged and heated to 40 - 45°C with constant stirring for 30 min. Gradually cooled to 25-30°C, then chilled to 0 - 5°C. Precipitation of solid was observed. The suspension was stirred for 1 hr at 0-5°C and filtered. The solid was washed with chilled n-heptane (0-5°C) and dried under suction.
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate obtained was dried under vacuum at 25 - 30°C. Dry wt: 123gm.
HPLC purity: 99.51%
Chiral Purity: 99.82%

Example 3
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0046] Sodium methoxide (40 g) was charged to Toluene (500 ml) and stirred for 5-10 minutes. 3-hydroxy THF (50 g) was added drop wise to white slurry below 30°C. After complete addition, the mixture was cooled to 0-5°C. PTSCl (113.5 g) was added to the reaction mixture in portions below 5°C.
[0047] After completion of addition cooling was removed and maintained for 1-2 hours. Sodium methoxide (9 gm) was charged to the reaction mass and p toluene sulfonyl chloride (21 g) was added. The mixture was stirred for 2 hours at 25-30°C. The mass was cooled to 0-5°C and water (250 ml) was charged and stirred for 15 minutes at 0-5°C. Temperature raised to 20-25°C and stirred for 15 minutes. The layers were separated and aqueous layer was extracted with Toluene (150 ml) and combined Toluene layers were washed with dil. HCl (250 ml). Toluene layer was washed with 5% NaHCO3 (250 ml) followed by washing with 10% NaCl solution (250 ml). The organic layer was distilled under vacuum and degassed. N-heptane (240 ml) was charged to the organic layer and heated to 40-45°C. The mixture was stirred for 30 minutes and decanted twice. N-heptane was added to the residue, heated to 40-45°C for 30 minutes. The mass was cooled to room temperature, chilled and filtered. The title compound obtained was dried under vacuum (107 g) (Yield: 77.93%).
HPLC purity: 99.23%
Chiral Purity: 99.60%

Example 4
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0048] Potassium tert butoxide (11.46 g) was charged to Toluene (200 ml) at 30°C and stirred for 5 minutes at 25-30°C. Potassium carbonate (6.23 gm) was charged to above mixture at 25-30°C and stirred at 25-30°C for 30 minutes. 3-tetrahydro furanol (10 gm) was added slowly to the thick reaction mass at 25-30°C. After completion of addition, reaction mass was chilled to 0-5°C. Para tolune sulfonyl chloride (23 gms) was added slowly in lots to the reaction mass at 0-5°C. Thick mass obtained was stirred for 10 minutes at 0-5°C. The temperature was raised to 20-25°C and maintained for 2 hours.
[0049] The mass was cooled to 0-5°C and water (50 ml) was charged and stirred for 15 minutes at 0-5°C. Temperature raised to 20-25°C and stirred for 15 minutes. The layers were separated and aqueous layer was extracted with Toluene (30 ml) and combined Toluene layers were washed with dil. HCl (50 ml). Toluene layer was washed with 5% NaHCO3 (50 ml) followed by washing with 10% NaCl solution (50 ml). The organic layer was distilled under vacuum and degassed. N-heptane (50 ml) was charged to the organic layer and heated to 40-45°C. The mixture was stirred for 30 minutes and decanted twice. N-heptane was added to the residue, heated to 40-45°C for 30 minutes. The mass was cooled to room temperature, chilled and filtered. The title compound obtained was dried under vacuum (25 g)
HPLC purity: 99.41%
Chiral Purity: 99.53%

Example 5
(3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0050] Sodium hydroxide (4.5 gm) was charged to toluene (200 ml) and stirred for 10-15 mins. 3R-tetra hydrofuranol (10 g) was added drop wise to the reaction mass below 30°C and cooled to 0 - 5°C. para toluene sulfonyl chloride (22.8 gm) was added in portions to the reaction mass. Temperature was raise to 25-30°C and maintained for 1 to 2 hours.
[0051] The mass was cooled to 0-5°C and water (50 ml) was charged and stirred for 15 minutes at 0-5°C. Temperature raised to 20-25°C and stirred for 15 minutes. The layers were separated and aqueous layer was extracted with Toluene (30 ml) and combined Toluene layer was washed with dil. HCl (50 ml). Toluene layer was washed with 5% NaHCO3 (50 ml) followed by washing with 10% NaCl solution (50 ml). The organic layer was distilled under vacuum and degassed. N-heptane (50 ml) was charged to the organic layer and heated to 40-45°C. The mixture was stirred for 30 minutes and decanted twice. N-heptane was added to the residue, heated to 40-45°C for 30 minutes. The mass was cooled to room temperature, chilled and filtered. The title compound obtained was dried under vacuum.
HPLC purity: 99.62%
Chiral Purity: 99.2%

Example 6
(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate
[0052] (3S)-tetra hydrofuranol (15 g) was charged to Toluene (300 ml) at 0-5°C. Potassium tert-butoxide (25 gm) was charged and stirred for 1 hour. P-toluene sulfonyl chloride (34 g) was added slowly at 0-5°C. After completion of addition, temperature was raised to 15-20°C and stirred for 2-3 hours. Water (75 ml) was charged to the reaction mass slowly and stirred for 30 minutes. Aqueous layer was extracted with Toluene (45 ml x 2 times). Toluene layer was washed with dil Hydrochloric acid (79 ml), followed by washing with 5% sodium bicarbonate. Further the Toluene layer was extracted with 10% sodium chloride solution (75 ml). Toluene layer was dried over sodium sulfate (10 g) and concentrated and degassed.
[0053] N-heptane stripping (50 ml x 3 times) was conducted as described in previous examples. N-heptane (90 ml) was charged to the solid obtained and heated to 55-60°C for 1 hour. The solution was cooled to room temperature and further to 10-15°C and filtered. The solid was washed with n-heptane and dried under vacuum to yield (3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (18 gm).
HPLC purity: 99.32%
Chiral Purity: 99.63%

Example 7
(3S)-3-[4-[(2-chloro-5-iodo-phenyl)methyl]phenoxy]tetrahydrofuran (D)
[0054] Charge 4-(2-chloro-5-iodobenzyl) phenol (150 g) in N,N-dimethylacetamide (400 ml) followed by addition of potassium hydroxide (4.5 g). The reaction mass was stirred under nitrogen atmosphere. (3R)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (110.25 g) was charged to the reaction mixture followed by addition of N,N- Dimethylacetamide (50 ml). The reaction mass was stirred and temperature was raised to yield clear dark brown solution. potassium hydroxide (30 g) was added in portions to the solution with constant stirring. The reaction mass was cooled and water (1.8 l) was added over 30-45 minutes. Chloroform (450 ml) was charged to the reaction mixture, stirred and allowed to settle. The aqueous layer was extracted with chloroform (150 ml x 3 times). All the organic layers were washed with 5% bicarbonate solution (150 ml). Further organic layer was washed with water (150 ml) and the layer was dried with sodium sulfate (50 g). Activated charcoal (10 g) was added to the organic layer, filtered and solvent was distilled under vacuum. Isopropyl alcohol (IPA) (150 ml) was charged and distilled off under vacuum below 50°C and degassed for 30 minutes. IPA (450 ml) was charged again and heated to 40-45°C to get clear solution. The solution was slowly cooled to 25-30°C to obtain white turbid mass. The mass was cooled slowly to 0-5°C and maintained for 1 hour. The mass was filtered and dried under suction. The precipitate was washed with IPA (150 ml) and dried to yield (3S)-3-[4-[(2-chloro-5-iodo-phenyl) methyl]phenoxy]tetrahydrofuran (120 g).
HPLC Purity: 99.55%
Chiral Purity: 99.71%
[0055] The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.