DESC:Field of the Invention:
The present application relates to an improved process for the preparation of Ospemifene and its intermediate’s thereof, represented by the following structural formula-I

Formula-I

Background of the Invention:
Ospemifene, having chemical name as Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl) phenoxy] ethanol was approved is USA on 2013 for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause with the brand name of OSPHENA® as tablets, for oral use.
The US patent number US5750576A, first disclosed ospemifene as a mixture of isomers and synthetic process involves isolation of ospemifene as a mixture of isomers i.e., cis and trans isomers. The US patent US6395785B1 reported a process for preparation of specific isomer of ospemifene (Z- isomer) and intermediates thereof. The other International patent applications WO 99/42427 and WO 96/07402 reported different processes for preparation of different derivatised tetra-substituted alkenes, the former describing the preparation of E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol. The said processes are reported for mixture of isomers, separation of stereoisomers is difficulty by conventional methods.
The patent US9321712B2 reported another process for preparation of ospemifene by using different intermediates and key starting materials.
There are various processes reported for ospemifene and intermediates thereof by using different solvents and reagents.
Based on drawbacks in the prior art processes, there is a need for providing an improved process for the preparation of ospemifene, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure ospemifene.
The present invention provides an improved process for preparation of ospemifene and intermediates thereof and free from other isomers. The present invention also involves by using cheap and easily available key starting material, reagents and solvents, which are efficient, industrially viable and cost effective.

Brief Description:
The first aspect of the present invention is to provide a process for the preparation of ospemifene.

Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of ospemifene compound of formula-1.

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxy ethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;

The first aspect of the present invention provides an improved process for the preparation of ospemifene compound of formula-I

Formula-I
Comprising of:
a) Reacting compound of formula-1

with compound of formula-A (wherein X is halo such as chloro, bromo, iodo ) in presence of suitable reagent to produce compound of formula-2,

b) reacting the compound of formula-2 with 3-chloro-1-phenylpropan-1-one in presence of suitable solvent and reagents to provide compound of formula-3,

c) reducing the compound of formula-3 with suitable reagent to provide the compound of formula-I.

d) optionally purifying the compound obtained in step-c) with suitable solvent to provide ospemifene.
Wherein in step-a) the suitable solvent is selected from chloro solvents, ether solvents, acetone, polar aportic solvent, polor protic solvent, alcohols or any mixture thereof; suitable bases inorganic base, suitable reagents ethyl-2-bromo acetate, ethyl-2-chloroacetate, ethyl-2-iodoacetate;
Wherein in step-b) the suitable solvent is selected from hydrocarbon solvents, toluene, xylene, 2-methyltetrahydrofuran, chloro solvents, ether solvents, ketone solvents, ester solvents or any mixture thereof; the suitable reagents are zinc dust, titanium chloride.
Wherein in step-c) the suitable reducing agent is sodium borohydride, lithium borohydride, sodium bis(2-methoxyethoxy)aluminium hydride (vitride) the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, alcohol solvents, toluene or any mixture thereof;
Wherein in step-d) the suitable solvent is selected from chloro solvents, ether solvents, ester solvents, polar aprotic solvents, polar protic solvents, alcoholic solvents, water or any mixture thereof;

Preferred embodiment of the present invention provides a process for the preparation of the compound of formula-I,

Formula-I

Comprising of:
a) Reacting compound of formula-1

with ethyl-2-chloroacetate in presence of potassium carbonate in dimethylformamide to get compound of formula-2,

b) reacting the compound of formula-2 with 3-chloro-1-phenylpropan-1-one in presence of zinc dust, titanium tetrachloride in 2-methyltetrahydrofuran to provide compound of formula-3,

c) reducing the compound of formula-3 with sodium borohydride in methanol to provide the compound of formula-I.

The other preferred embodiment of the present invention provides a process for the preparation of the compound of formula-I,

Formula-I

Comprising of:
a) Reacting compound of formula-1

with ethyl-2-chloroacetate in presence of potassium carbonate in dimethylformamide to get compound of formula-2,

b) reacting the compound of formula-2 with 3-chloro-1-phenylpropan-1-one in presence of zinc dust, titanium tetrachloride in 2-methyltetrahydrofuran to provide compound of formula-3,

c) reducing the compound of formula-3 with sodium bis(2-methoxyethoxy)aluminium hydride (vitride) in toluene to provide the compound of formula-I.

d) stirring the compound obtained in step-c) in methanol and water to provide the pure crystalline form of compound of formula-I.
The process for the preparation of ospemifene developed by the present inventors produces highly pure product with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
Ospemifene and its polymorphs produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of ospemifene was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.

The process of the present invention can be represented schematically as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1 (250 g), dimethyl formamide (500 mL), potassium carbonate (261.45 g) and ethyl-2-chloroacetate (185.24 g) were heated to 90-100°C and stirred for 5 hr at same temperature. The reaction mass filtered and washed with DMF and charged with water (1L) and methanol (250 mL). The reaction mixture was heated to 55-65°C and stirred for 2 hr. Filtered the precipitated solid and washed with water. The wet compound was stirred in a mixture for water and methanol for 2 hr and the obtained solid was filtered and washed with water and dried to get the title compound.
Yield: 340 g.
Example-2: Preparation of the compound of formula-3.
A round bottom flask was charged with compound of formula-2 (100 g), 2-methyl tetra hydrofuran (1L), 3-chloropropiophenone (59.3 g) and zinc dust (87.3 g) were stirred for 10 min at 25-35°C. The reaction mixture was cooled to 5-15°C, charged with titanium tetrachloride (128 g) and heated to 40-50°C and stirred for 2 hr. The reaction mixture was distilled off completely and co-distilled with dichloromethane. The reaction mixture was quenched with water (400 mL), HCl (170 mL) and charged dichloromethane (400 mL) were stirred for 2 hr at 25-35°C. The two layers were separated and the aqueous layer was extracted with dichloromethane (2x 50 mL). The combined organic layer was washed with brine solution, dil HCl and evaporated to get the crude compound. The obtained crude compound was co distilled with ethanol, the obtained compound was stirred in ethanol and stirred for 3 hr. Filtered the obtained solid and dried to get the title compound.
Yield: 42.0 g.
Example-3: Preparation of the compound of formula-I.
A round bottom flask was charged with compound of formula-3 (50 g), tetra hydrofuran (250 mL) and stirred for 10 min. To the reaction mixture charged sodium borohydride (15.7 g), ethanol (250 mL) and the reaction mixture was stirred for 5 hr. The reaction mixture was charged slowly to a pre cooled solution of dil HCl (300 mL) and stirred for 1 hr at 25-35°C.
The both layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with sodium bicarbonate solution and brine solution and dried under sodium sulphate and evaporated to get crude compound. The crude compound was stirred in water for 1 hr at 40-50°C, the obtained solid was filtered and dried to get the title compound. The PXRD of the compound obtained is depicted in figure -1.
Yield: 38.5 g
Example-4: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1 (50 g), dimethyl formamide (100 mL), potassium carbonate (52.2 g) and ethyl-2-chloroacetate (37.09 g) were heated to 90-100°C and stirred for 3 hr at same temperature. The reaction mass filtered and washed with DMF and charged with water and n-butanol and further, the reaction mixture was heated to 55-65°C and stirred for 2 hr at same temperature. Filtered the precipitated solid and washed with water and n-butanol, the obtained solid was filtered and washed with water and dried to get the title compound.
Yield: 63.0 g.
Example-5: Preparation of the compound of formula-3.
A round bottom flask was charged with compound of formula-2 (100 g), 2-methyl tetra hydrofuran (1L), 3-chloropropiophenone (59.3 g) and zinc dust (87.3 g) were stirred for 10 min at 25-35°C. The reaction mixture was cooled to 5-15°C, charged with titanium tetrachloride (128 g) and heated to 40-50°C and stirred for 2 hr. The reaction mixture was distilled off completely and quenched with water; HCl and dichloromethane were stirred for 2 hr at 25-35°C. The two layers were separated and the aqueous layer was extracted with dichloromethane (2x 50 mL). The combined organic layer was washed with brine solution, dil HCl and evaporated to get the crude compound. The obtained crude compound was stirred in a mixture of water and acetone for 1 hr. Filtered the obtained solid and dried to get the title compound.
Yield: 38.8 g.
Example-6: Preparation of the compound of formula-I.
A round bottom flask was charged with compound of formula-3 (50 g), toluene (250 mL) and stirred for 10 min. The reaction was cooled to -35 to -25 ° C, charged vitirde solution
(66.03 g) slowly and the reaction mixture was stirred for 3 hr at same temperature. The reaction mixture was quenched slowly with dil HCl and water, and gradually heated to 0-10°C stirred for 1 hr . The both layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with sodium bicarbonate solution and brine solution and dried under sodium sulphate and evaporated to get crude compound. The crude compound was charged with methanol and stirred at 55-65°C for 15 min and charged with carbon and stirred for 30 min. Filtered the reaction mixture, and the filtrate was charged with water and stirred at 55-65°C for 1 hr. Filtered the obtain solid and dried to get the title compound. The PXRD of the obtained compound is similar to the figure -1.
Yield: 43.6 g
Example 7: Purification process for ospemefine
A Round bottom flask was charged with methanol (1400 mL), compound-I (100 g) and heated the reaction mass to 55-65°C and maintained for 15 min. The reaction mass was charged with activated carbon at 55-65°C and stirred for 20 min. Filtered the reaction mass through hyflo and washed with methanol . The filtrate solution was charged with water, was heated to 55-65°C and maintained for 15 min. Cooled the reaction mixture and filtered the solid and washed with methanol, water and dried the compound to get the title compound.
Yield: 77.36 g

,CLAIMS:We claim:
1. An improved process for preparation of ospemifene compound of formula-I

Formula-I
Comprising of:
a) Reacting compound of formula-1

with compound of formula-A (wherein X is halo such as chloro, bromo, iodo ) in presence of suitable reagent to produce compound of formula-2,

b) reacting the compound of formula-2 with 3-chloro-1-phenylpropan-1-one in presence of suitable solvent and reagents to provide compound of formula-3,

c) reducing the compound of formula-3 with suitable reagent to provide the compound of formula-I.

d) optionally purifying the compound obtained in step-c) with suitable solvent to provide ospemifene.
2. A process for preparation of compound of formula I as claimed in claim 1 wherein in step-a) the suitable solvent is selected from chloro solvents, ether solvents, acetone, polar aportic solvents, polor protic solvents, alcohols or any mixture thereof; suitable bases inorganic base, inorganic base, suitable reagents ethyl-2-bromo acetate, ethyl-2-chloroacetate, ethyl-2-iodoacetate; Wherein in step-b) the suitable solvent is selected from hydrocarbon solvents, toluene, xylene, 2-methyltetrahydrofuran, chloro solvents, ether solvents, ketone solvents, ester solvents or any mixture thereof; the suitable reagents are zinc dust, titanium chloride.
Wherein in step-c) the suitable reducing agent is sodium borohydride, sodium bis(2-methoxy ethoxy)aluminium hydride (vitride), lithium borohydride, the suitable solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, alcohol solvents, or any mixture thereof;
Wherein in step-d) the suitable solvent is selected from chloro solvents, ether solvents, ester solvent, polar aprotic solvents, polar protic solvents, alcoholic solvents, water or any mixture thereof;
3 An improved process for the preparation of the compound of formula-I,
comprising of

Formula-I

Comprising of:
a) Reacting compound of formula-1

with ethyl-2-chloroacetate in presence of potassium carbonate in dimethylformamide to get compound of formula-2,

b) reacting the compound of formula-2 with 3-chloro-1-phenylpropan-1-one in presence of zinc dust, titanium tetrachloride in 2-methyltetrahydrofuran to provide compound of formula-3,

c) reducing the compound of formula-3 with vitride in toluene to provide the compound of formula-I.

d) stirring the compound obtained in step-c) in methanol and water to provide the pure crystalline form of compound of formula-I.

4. A process for preparation of crystalline form of ospemifene compound of formula-I
Comprising of
a) Stirring the compound of formula-I in methanol and water at 55-65°C.
b) isolating the compound obtained in step-a) to get the pure crystalline form of compound of formula-I.
5. Ospemifene compound of formula-I obtained according to any of preceding claims having purity > 95%, preferably > 99% by HPLC.

Dated this day 15-Apr-2023.