FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF OSPEMIFENE”
Glenmark Pharmaceuticals Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

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 the preparation of ospemifene.

BACKGROUND OF THE INVENTION
Ospemifene, also known as Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, is represented by the structure of formula I.
I
Ospemifene is an estrogen agonist/antagonist indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. Ospemifene is marketed under the brand name OSPHENA® in the United States.
There is a need in the art for a cost-effective synthesis of ospemifine, which would be advantageous over the reported processes known in the art.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of ospemifene, a compound of formula I,

I
the process comprising:
(a) preparing a compound of formula II, wherein R1 and R2 are independently
selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo, nitro and cyano; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S;

II
(b) hydrolyzing the compound of formula II to obtain a compound of formula III;

III
and
(c) reacting the compound of formula III with a reducing agent.
The present invention provides a process for the preparation of ospemifene, a compound of formula I,

I
the process comprising reacting the compound of formula III

III
with a reducing agent.
The present invention provides a compound of formula II, wherein R1 and R2 is phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine ring represented by compounds of formula IIA and IIB respectively.

IIA IIB

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of ospemifene, a compound of formula I,

I
the process comprising:
(a) preparing a compound of formula II, wherein R1 and R2 are independently
selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo, nitro and cyano; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S;

II
(b) hydrolyzing the compound of formula II to obtain a compound of formula III;

III
and
(c) reacting the compound of formula III with a reducing agent.
The term "C1-6 alkyl" as used herein includes a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "C1-6alkyl, C6-12 aryl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylaryl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term "C6-12 aryl" as used herein, refers to aromatic ring systems, which may include fused rings. Representative examples of aryl include, but are not limited to, phenyl, and naphthyl, anthracenyl, phenanthrenyl.
The term “monocyclic ring” as used herein, refers to the groups consisting of pyridyl, thiazolyl, oxazolyl, pyrimidinyl, morpholinyl and imidazolyl and the like.
The term “bicyclic ring” as used herein, refers to the groups consisting of phthalimide, benzisoxazolyl, indolyl and the like.
The term “halogen” as used herein, refers to chloro, bromo, iodo, fluoro.

In one embodiment, the present invention provides a process for the preparation of the compound of formula II, by reacting a compound of formula IV with a compound of formula V,

IV V
wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo, nitro and cyano; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S.
In one embodiment, the present invention provides a process for the preparation of compound of formula II, by reacting a compound of formula IV with a compound of formula V, wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl and phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a six membered monocyclic ring, optionally containing O.
In one embodiment, the reaction of a compound of formula IV with a compound of formula V is carried out in presence of a base.
The base may be selected from an organic base or inorganic base. The inorganic base may be selected from the hydroxides, carbonates or bicarbonates of alkali metals, alkaline earth metal and the like; for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and the like. The organic base may be selected from the group consisting of triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine and the like.

The reaction of the compound of formula IV with the compound of formula V may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl formamide, dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is acetone.
In one embodiment, the present invention provides a process for the preparation of the compound of formula II, by reacting a compound of formula VI,

VI
wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro and cyano; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S, with 3-chloropropiophenone.
In one embodiment, the present invention provides a process for the preparation of compound of formula II, by reacting a compound of formula VI, wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl and phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a six membered monocyclic ring, optionally containing O,with 3-chloropropiophenone.
In one embodiment, the reaction of the compound of formula VI with 3-chloropropiophenone may be carried out in presence of a polyvalent metal chloride in combination with a reducing agent. The polyvalent metal chloride may be titanium halide. The reducing agent may be selected from the group consisting of zinc metal, Zn/Cu, LiAlH4, alkali and alkali earth metals, lithium arenes, and butyllithium.
In one embodiment, the reaction of the compound of formula VI with 3-chloropropiophenone may be carried out in presence of titanium tetrachloride and zinc metal.
In one embodiment, the reaction of the compound of formula VI with 3-chloropropiophenone may be carried out in presence of a solvent. The solvent may be selected as discussed supra.
In one embodiment, the reaction of compound of formula VI with 3-chloropropiophenone may be carried out in presence of an ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like.
In one embodiment, in step (b), the compound of formula II is hydrolyzed to obtain a compound of formula III. The hydrolysis may be carried out by using a base.
The base may be selected from the hydroxides of alkali metals, alkaline earth metals and the like; for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
In one embodiment, in step (b), the hydrolysis of the compound of formula II may be carried out by using a base in combination with hydrogen peroxide.
In one embodiment, in step (b), the compound of formula II is hydrolyzed with an alkali metal hydroxide in presence of hydrogen peroxide to obtain a compound of formula III.

In one embodiment, in step (c), the compound of formula III is reacting with a reducing agent to form ospemifene, compound of formula I.
In one embodiment, in step (c), the compound of formula III is converted to ospemifene by reacting with a reducing agent in presence of a solvent.
The reducing agent may be selected from alkali metal borohydride, alkali metal borohydride in combination with titanium halide and titanium borohydride.
The alkali metal borohydride may be selected from lithium borohydride, potassium borohydride, sodium borohydride and the like.
In one embodiment, the alkali metal borohydride is used in combination with titanium tetrachloride.
In one embodiment, in step (c), the compound of formula III is converted to ospemifene by reacting with titanium borohydride. The titanium borohydride may be generated in the reaction vessel in situ or may be pre-formed.
In one embodiment, in step (c), the compound of formula III is reacted with sodium borohydride and titanium tetrachloride to obtain ospemifene.
In one embodiment, in step (c), sodium borohydride and titanium tetrachloride are reacted to form titanium borohydride and the compound of formula III is added to this preformed titanium borohydride.
In one embodiment the solvent may be selected as discussed supra.
In one embodiment the solvent in step (c) may be selected from ether solvents like tetrahydrofuran, diglyme, 1,2-dimethoxyethane and the like.
In one embodiment, the present invention provides a process for the preparation of ospemifene, a compound of formula I, the process comprising:
(a) preparing a compound of formula II, wherein R1 and R2 is phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine ring;

II
(b) hydrolyzing the compound of formula II to obtain a compound of formula III; and
(c) reacting the compound of formula III with a reducing agent.
In one embodiment, the present invention provides a process for the preparation of ospemifene, a compound of formula I, the process comprising:
(a) preparing a compound of formula II, wherein R1 and R2 is phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine ring;
(b) hydrolyzing the compound of formula II to obtain a compound of formula III; and
(c) reacting the compound of formula III with titanium borohydride or sodium borohydride and titanium tetrachloride in an ether solvent.
In one embodiment, the process of the present invention provides ospemifene, wherein the level of E-isomer of ospemifene is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC).
In one embodiment, the process of the present invention provides ospemifene wherein the level of compound of formula A is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC).

A
In one embodiment, the process of the present invention provides ospemifene wherein the level of E-isomer of ospemifene or compound of formula A is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC).
In one embodiment, the present invention provides a compound of formula II, wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S.

II
In one embodiment, the present invention provides a compound of formula II, wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl and phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a six membered monocyclic ring, optionally containing O.
In one embodiment, the present invention provides a compound of formula II, wherein R1 and R2 is phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine ring represented by compounds of formula IIA and IIB respectively.

IIA IIB
In one embodiment, the present invention provides a compound of formula IIA, characterized by 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 4.46 (s, 2 H), 6.49 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.2 Hz, 2H), 7.16?7.41 (m, 20H).
In one embodiment, the present invention provides a compound of formula IIB, characterized by 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.37?3.42 (m, 4H), 3.44 (t, J = 6.0 Hz, 2H), 3.47?3.52 (m, 4H), 4.68 (s, 2H), 6.59 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.17?7.40 (m, 10H).
In one embodiment, the present invention provides a compound of formula III, characterized by1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 4.52 (s, 2H), 6.57 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.16?7.42 (m, 10H), 12.91 (s, 1H).

III
In one embodiment, the present invention provides a process for the preparation of ospemifene, a compound of formula I,

I
the process comprising reacting the compound of formula III,

III
with a reducing agent.
The reducing agent may be selected as discussed supra.
In one embodiment, the compound of formula III is prepared by hydrolyzing a compound of formula VII, wherein R3 is selected from the group consisting of C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo, nitro and cyano.

VII
The hydrolysis may be carried out using a base.
In one embodiment, the compound of formula VII is prepared by a process comprising reacting compound of formula X, wherein R3 is as supra, with 3-chloropropiophenone.

X
In one embodiment, the compound of formula VII is prepared by treating a compound of formula IV, with a compound of formula VIII, wherein R3 is selected from the group consisting of C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro and X is a halogen

IV VIII
In one embodiment, the compound of formula III is prepared by reacting a compound of formula IV, with a compound of formula VIII wherein R3 is H and X is a halogen.
The reaction of the compound of formula IV with the compound of formula VIII wherein R3 is H and X is a halogen may be carried out using base for example cesium carbonate.

In one embodiment, the present invention provides a compound of formula III, wherein the level of E-isomer of the compound is less than 1.0% w/w, by a process comprising crystallizing the compound of formula III from a mixture of methanol and water or isopropanol and heptane
In one embodiment, the present invention provides a process for preparing the compound of formula IV by reacting 4-hydroxybenzophenone with 3-chloropropiophenone.
In one embodiment, the present invention provides a process of directly converting a compound of formula II to ospemifene, a compound of formula I by reacting with lithium aluminium hydride.
In one embodiment, the present invention provides a process of directly converting a compound of formula VII to ospemifene by reduction of the ester group using lithium aluminum hydride in an ether solvent preferably tetrahydrofuran.

VII
In one embodiment, the present invention provides a process for preparing ospemifene by reacting a compound of formula III with ethyl chloroformate in the presence of a base like triethylamine to obtain a compound of formula IX,

IX
followed by treating compound of formula IX with alkali metal borohydride, preferably sodium borohydride.
In one embodiment, the process of the present invention provides compound A

A
characterized by (1H NMR (300 MHz, DMSO-d6): ? ppm 0.82, 2.35, 3.60, 3.81, 4.75, 6.57, 6.70 7.09-7.36.
In one embodiment the present invention provides a method for preparing ospemifene, comprising the steps of:(a) providing a batch of ospemifene;(b)assessing the purity of said batch of ospemifene, by using compound A as a reference marker to determine the level of compound A; and(c) selecting the batch of ospemifene only if the percentage of compound A, is less than 0.15% w/w as determined by HPLC.
In one embodiment the present invention provides a method for assessing the purity of ospemifene and pharmaceutical compositions containing them comprising the steps of:
(a) providing a standard solution of compound A
(b) using the solution as a reference marker to determine the level of compound A impurity.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantage.

EXAMPLES
EXAMPLE 1 : (Z)-4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenol
To a stirred and cooled (-10 °C) suspension of zinc dust (131.17 g,) in dry tetrahydrofuran was added titanium tetrachloride (190.7 g,) drop-wise over 1?? h. The mixture was then refluxed for 2 h. The mixture was then cooled to 30 °C and a solution of 4-hydroxybenzophenone (100.0 g,) and 3-chloropropiophenone (84.86 g) in THF was added to the mixture over 30 min. The mixture was then refluxed for 2 h under stirring. The mixture was quenched with aqueous potassium carbonate and allowed to stand overnight at room temperature. The heterogeneous mixture was filtered through a hi-flow bed and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to result in a residue. The residue was crystalized from a mixture of methanol and water to give 54 g of a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.83 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 6.43 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 7.10?7.40 (m, 10H, ArH).

EXAMPLE 2 : 2-(4-Benzoylphenoxy)-1-morpholinoethanone
To a stirred solution of 4-hydroxybenzophenone (5.0 g) in acetone (50 ml) was added anhydrous potassium carbonate (6.96 g) and sodium iodide (0.75 g). A solution of 2-chloro-1-(morpholin-4-yl)ethanone (4.95 g) in acetone was added and the mixture heated to reflux for 6 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with water and brine. The oily mass obtained after evaporation of the solvent was triturated with a mixture of toluene and hexane mixture to give 7.0 g of the product as a solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 3.59?3.69 (m, 8H), 4.79 (s, 2H), 7.01?7.03 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 6.0 Hz, 2H), 7.55????? (m, 1H), 7.73 (dd, J = 6.0, 3.1 Hz, 2H), 7.82 (d, J = 7.2 Hz, 2H). APCI-MS (m/z) 326 (M + H)+.

EXAMPLE 3: 2-(4-Benzoylphenoxy)-N,N-diphenylacetamide
To a stirred solution of 4-hydroxybenzophenone (5.0 g) in acetone (50 mL) was added potassium carbonate (6.91 g), diphenylchloroacetyl chloride (7.37 g), and sodium iodide (0.75 g). The reaction mixture was then heated to reflux for 12?14 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with water and brine. The oily mass obtained after evaporation of the solvent was triturated with a mixture of toluene and hexane mixture to give 5.6 g of the product. 1H NMR (400 MHz, DMSO-d6): ? ppm 4.72 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 6.4 Hz, 2H), 7.64?7.73 (m, 15H). APCI-MS (m/z) 408 (M + H)+.

Example 4: (Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-1-morpholinoethanone
Method A:
To a stirred solution of (Z)-4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenol (20.0 g, 0.059 mol) in DMF was added potassium carbonate (16.50 g) and sodium iodide (1.78 g) at room temperature. 2-Chloro-1-(morpholin-4-yl)ethanone (13.6 g) in DMF was added and the mixture was stirred at room temperature for 8?10 h. The mixture was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was crystallized from a mixture methanol and water to give 26.3 g of the product as a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.37?3.42 (m, 4H), 3.44 (t, J = 6.0 Hz, 2H), 3.47?3.52 (m, 4H), 4.68 (s, 2H), 6.59 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.17?7.40 (m, 10H). APCI-MS (m/z) 462 (M + H)+.

Method B:
To a stirred and cooled (-10 °C) suspension of zinc dust (3.97 g) in dry tetrahydrofuran was added titanium tetrachloride (5.78 g) drop-wise over 1?? h. The mixture was then refluxed for 2 h. The mixture was then cooled to 30 °C and a solution of 2-(4-benzoylphenoxy)-1-morpholinoethanone (5.0 g) and 3-chloropropiophenone (2.59 g) in THF was added to the mixture over 30 min. The mixture was then refluxed for 2 h under stirring. The mixture was quenched with aqueous potassium carbonate and allowed to stand overnight at room temperature. The heterogeneous mixture was filtered through a hi-flow bed and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 50 % ethyl acetate in hexane yielded pure olefin as a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.37?3.42 (m, 4H), 3.44 (t, J = 6.0 Hz, 2H), 3.47?3.52 (m, 4H), 4.68 (s, 2H), 6.59 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.17?7.40 (m, 10H). APCI-MS (m/z) 462 (M + H)+.

Example 5: (Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-N,N-diphenylacetamide
Method A:
To a solution of (Z)-4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenol (5.0 g,) and potassium carbonate (4.11 g) in dry acetone was added 2-chloro-N,N-diphenylacetamide (3.66 g) and sodium iodide (0.45 g). The reaction mixture was refluxed for 12 h. The mixture was cooled and diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was triturated with hexane to give 6.8 g of the product as white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 4.46 (s, 2 H), 6.49 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.2 Hz, 2H), 7.16?7.41 (m, 20H). APCI-MS (m/z) 544, 546 (M + H)+.
Method B:
To a stirred and cooled (-10 °C) suspension of zinc dust (6.34 g) in dry tetrahydrofuran was added titanium tetrachloride (9.20 g) drop-wise over 1?? h. The mixture was then refluxed for 2 h. The mixture was then cooled to 30 °C and a solution 2-(4-benzoylphenoxy)-N,N-diphenylacetamide (5.0 g) and 3-chloropropiophenone (2.0 g, 0.012 mol) in THF was added to the mixture over 30 min. The mixture was then refluxed for 2 h under stirring. The mixture was quenched with aqueous potassium carbonate and allowed to stand overnight at room temperature. The heterogeneous mixture was filtered through a hi-flow bed and the filter cake was washed with ethyl acetate. The filtrate was diluted with water and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to result in a residue. The residue was purified by silica gel column chromatography using 50 % ethyl acetate in hexane yielded pure olefin as a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 4.46 (s, 2 H), 6.49 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.2 Hz, 2H), 7.16?7.41 (m, 20H). APCI-MS (m/z) 544, 546 (M + H)+.

Example 6: (Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)acetic acid
To a stirred solution of (Z)-2-(4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-1-morpholinoethanone (20.0 g) in methanol (100 mL) was added a solution of lithium hydroxide (3.64 g) in water. The mixture was stirred at 25?30 °C for 12 h. The organic solvent was evaporated under reduced pressure and the mixture was diluted with water and the pH of the solution was adjusted to 2 by addition of conc. hydrochloric acid. The mixture was extracted with dichloromethane. The combined organic extracts were washed with water and dried. The residue obtained after evaporation of the solvent was crystallized from a mixture of methanol and water to give 15.7 g of the acid as a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 4.52 (s, 2H), 6.57 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.16?7.42 (m, 10H), 12.91 (s, 1H). APCI-MS (m/z) 393 (M + H)+.
Hydrolysis of (Z)-2-(4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-N,N-diphenylacetamide (5.0 g,) using lithium hydroxide monohydrate (1. 1 g) in water as described for (Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-1-morpholinoethanone afforded 2.45 g of the title compound as a white solid.

Example 7: (Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)acetic acid
To a stirred solution of (Z)-2-(4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)-N,N-diphenylacetamide (5.0 g) in tetrahydrofuran was added lithium hydroxide monohydrate (1.1 g) and 35 % aqueous solution of hydrogen peroxide. The mixture was stirred at 60 °C for 12 h. Reaction mass diluted with water and pH of the solution was adjusted to 2 by the addition of con. hydrochloric acid. The mixture was extracted with dichloromethane. The organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixture of methanol and water to give 1.35 g of the product as a white solid. 1H NMR (400 MHz, DMSO-d6): ? ppm 2.84 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 4.52 (s, 2H), 6.57 (d, J = 7.2 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 7.16?7.42 (m, 10H), 12.91 (s, 1H). APCI-MS (m/z) 393 (M + H)+.

Example 8: Preparation of ospemifene
To a stirred suspension of sodium borohydride (3.18 g) in anhydrous 1,2-dimethoxyethane (50 mL) at 0?5 °C was added titanium tetrachloride (5.29 g) drop-wise over 10 min. A solution of (Z)-2-(4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)acetic acid (10.0 g) in anhydrous 1,2-dimethoxyethane (100.0 mL) was added drop-wise to the mixture at room temperature and further stirred for 16 h. The mixture was cooled (0?5 °C) and quenched by the addition of water to result a clear solution. The aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solution was evaporated under vacuum to result an oily mass. The oily mass was treated with aqueous methanol to result a white solid. The solid was recrystallized from a mixture of isopropyl alcohol and heptane to afford the pure product as a white crystalline solid. The deschloro impurity (compound A) is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC). The E-isomer of ospemifene is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC).

Example 9: Preparation of ospemifene
To a stirred suspension of lithium borohydride (0.222 g) in anhydrous 1,2-dimethoxyethane (10 mL) at 0?5 °C was added titanium tetrachloride (0.532 g) drop-wise over 10 min. A solution of (Z)-2-(4-(4-chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)acetic acid (1.0 g) in anhydrous 1,2-dimethoxyethane (100.0 mL) was added drop-wise to the mixture at room temperature and further stirred for 16 h. The mixture was cooled (0?5 °C) and quenched by the addition of water to result a clear solution. The aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solution was evaporated under vacuum to result an oily mass. The oily mass was treated with aqueous methanol to result a white solid. The solid was recrystallized from a mixture of isopropyl alcohol and heptane to afford the pure product as a white crystalline solid. The deschloro impurity (compound A) is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC). The E-isomer of ospemifene is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC).
,CLAIMS:WE CLAIM
1. A process for the preparation of ospemifene, a compound of formula I,

I
the process comprising:
(a) preparing a compound of formula II, wherein R1 and R2 are independently
selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S;

II
(b) hydrolyzing the compound of formula II to obtain a compound of formula III;

III
and
(c) reacting the compound of formula III with a reducing agent.

2. The process as claimed in claim 1, wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl and phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a six membered monocyclic ring, optionally containing O.

3. The process as claimed in claim 1, wherein the compound of formula II is prepared by reacting a compound of formula IV with a compound of formula V,

IV V
wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S.
4. The process as claimed in claim 1, wherein the compound of formula II is prepared by reacting a compound of formula VI,

VI
wherein R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro; or R1 and R2 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic ring, optionally containing N, O or S, with 3- chloropropiophenone.

5. The process as claimed in claim 1, wherein the reducing agent is titanium borohydride.

6. The process as claimed in claim 1, wherein the level of E-isomer of ospemifene is less than 0.10% w/w and the level of compound of formula A is less than 0.15% w/w with respect to ospemifene, as determined by high performance liquid chromatography (HPLC)

Compound A.
7. A process for the preparation of ospemifene, a compound of formula I,

I
the process comprising reacting the compound of formula III

III
with a reducing agent.
8. The process as claimed in claim 7, wherein the compound of formula III is prepared by hydrolyzing a compound of formula VII, wherein R3 is selected from the group consisting of C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo, nitro and cyano

VII.
9. The process as claimed in claim 7, wherein the compound of formula VII is prepared by treating a compound of formula IV, with a compound of formula VIII, wherein R3 is selected from the group consisting of C1-6 alkyl, C1-6 alkyl C6-12 aryl and C6-12 aryl optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, halo and nitro and X is a halogen

IV VIII.

10. A compound of formula II, wherein R1 and R2 is phenyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine ring represented by compound of formula IIA and IIB respectively

IIA IIB.

Dated this 30th day of January, 2018

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED