DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Elacestrant or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION:

Elacestrant is approved as dihydrochloride salt (coded as RAD1901.2HCl), (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol compound of Formula I and represented by following structural formula:

Formula I

Elacestrant was discovered and developed by Eisai R&D Management Co Ltd and marketed by Stemline Therapeutics and it is approved for the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. It is approved in USFDA and EMEA and it is marketed under the trade name Orserdu®.

US 7,612,114 B2 (herein after referred as ‘114) discloses Elacestrant. US ‘114 discloses the process the preparation of Elacestran, which is schematically shown below in scheme I:

Scheme I

Further the prior art route involves column purification in many steps, which is not economically suitable for commercial scale. As well involves the use of 2,2-dimethyl-1-(2-thioxothiazolidin-3-yl)propan-1-one compound for pivolylation, which is expensive and lithium aluminium hydride which is difficult to handle industrially.

Further the prior art process leads to the formation of nitro-anisole dimer impurity represented by the following structural formula:

US 20220162233 (herein after referred as ‘233) discloses an alternate process for preparation for Elacetsrant dihydrochloride, which is schematically as shown below in scheme II:

Scheme II
There are limited routes for the preparation of Elacestrant or its pharmaceutically acceptable salts and there is a need another alternate process for the synthesis of Elacestrant or its pharmaceutically acceptable salts.

In view of this, the present inventors have now found an alternate process for preparation of Elacestrant or its pharmaceutically acceptable salts, which is simple, cost-effective, industrially feasible, easier to handle, and provides Elacestrant or its pharmaceutically acceptable salts with higher yield and purities.

OBJECTIVES OF THE INVENTION

The objective of the present invention is to provide commercially and industrially feasible process for preparation of Elacestrant or its pharmaceutically acceptable salts.

Another objective of the present invention is to provide a process for preparation of Elacestrant or its pharmaceutically acceptable salts having high yield and high purity.

Yet, another objective of the present invention is to provide a cost-effective process for preparation of Elacestrant or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an improved process for preparation of Elacestrant or its pharmaceutically acceptable salts of Formula I,

Formula I
which comprises:
a) reacting the compound of Formula II

Formula II
with the compound of Formula III

Formula III
to obtain compound of Formula IV,

Formula IV
b) reducing the compound of Formula IV in presence of a base to obtain compound of Formula V,

Formula V
c) reacting the compound of Formula V with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI,

Formula VI
d) reacting the compound of Formula VI with pivaloyl chloride to obtain compound of Formula VII,

Formula VII
e) converting the compound of Formula VII into compound of Formula I,
f) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.

In another embodiment, the present invention provides an improved process for preparation of compound of Formula IV,

Formula IV
which comprises reacting the compound of Formula II

Formula II
with the compound of Formula III

Formula III
to obtain compound of Formula IV.

In another embodiment, the present invention provides an improved process for preparation of compound of Formula V,

Formula V
which comprises reducing the compound of Formula IV

Formula IV
in presence of a base to obtain compound of Formula V.

In another embodiment, the present invention provides an improved process for preparation of compound of Formula VI,

Formula VI
which comprises reacting the compound of Formula V

Formula V
with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI,

In another embodiment, the present invention provides an improved process for preparation of compound of Formula VII,

Formula VII
which comprises reacting the compound of Formula VI

Formula VI
with pivaloyl chloride to obtain compound of Formula VII.
DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention provides an improved process for preparation of Elacestrant or its pharmaceutically acceptable salts compound of Formula I, which comprises: a) reacting the boronate ester compound of Formula II with the compound of Formula III to obtain compound of Formula IV, b) reducing the compound of Formula IV in presence of base to obtain compound of Formula V, c) reacting the compound of Formula V with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI, d) reaction of the compound of Formula VI with pivaloyl chloride to obtain compound of Formula VII, e) converting the compound of Formula VII into compound of Formula I, f) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.
The process is represented schematically as shown below in scheme III:

Scheme III
In another aspect of the present invention, preparation of compound of Formula IV (i.e., reaction of boronate ester of Formula II and compound of Formula III) is carried out in presence of transition metal catalyst and a base in solvent, wherein the said transition metal catalyst containing Pd (II), Cu (0) or Pd (0), or any combinations thereof, wherein the said base is inorganic or organic base, preferably inorganic base.

In another aspect of the present invention the transition metal catalyst is selected from the group consisting of Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd2(Dba)3, Pd(PCy3)2, and any combinations thereof.

In another aspect of the present invention the inorganic base is selected from the groups consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, or cesium bicarbonate, preferably potassium carbonate.

In another aspect of the present invention preparation of compound of Formula II and compound of Formula III is carried out in a solvent, preferably 1,2-dimethoxyethane.

Further the comparision of yield of compound of Formula IV obtained by present invention w.r.to prior art are as follows:
Reference Yield (%)
US ‘114 (prior art) 40.68 %
Present invention 64.5 %

The present invention provides compound of Formula IV with high purity and yield when compared to prior art. Further the present invention provides compound of Formula IV with low level of Nitro-Anisole dimer Impurity.

In another aspect of the present invention, a process preparation of compound of Formula V (i.e., reduction of compound of Formula IV) is carried out by hydrogenation in presence of metal catalyst, a base and solvent, wherein metal catalyst is pd catalyst, base is aq. ammonia, solvent is alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol, preferably methanol.

Further the comparison of yields of the compound of Formula V of present invention w.r.to prior art are as follows:
Reference Yield (%)
US ‘114 (prior art) 60.56 %
Present invention 93.49%

In another aspect of the present invention provides a process for preparation of compound of formula VI, which comprises: reacting the compound of Formula V with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI.

In another aspect of the present invention preparation of compound of Formula VI, the reaction of compound of Formula V and acetaldehyde is carried out in alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol and the like, preferably ethanol.

In another aspect of the present invention preparation of compound of Formula VI, the reduction is carried out in presence of reducing agent, wherein reducing agent is sodium borohydride.

Further the comparison of yields of the compound of Formula VI of present invention w.r.to prior art are as follows:

Reference Yield (%)
US ‘114 (prior art) 60.38 %
Present invention 76 %

In another aspect of the present invention preparation of compound of Formula VII, the reaction of compound of Formula VI and pivaloyl chloride is carried out in presence of base in a solvent, wherein base selected from inorganic or organic base, preferably organic base, wherein the organic base is triethylamine; solvent is selected from the group consisting of dichloromethane, dichloroethane or chloroform, preferably dichloromethane. Further the preparation of compound of Formula VII also carried out in presence of catalytic amount of dimethylaminopyrimidine.

In another aspect of the present invention, the conversion of compound of Formula VII into Elacestrant or its pharmaceutically acceptable salts is carried out by the process known in prior art such as US ‘114.

The Abbreviations used throughout the invention are as follows:
Pd(OAc)2 : Palladium (II) acetate
Pd(PPh3)4 : Tetrakis(triphenylphosphine)palladium(0)
PdCl2(PPh3)2: Bis(triphenylphosphine)palladium chloride
Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd2(Dba)3: Tris(dibenzylideneacetone)dipalladium(0)
Pd(PCy3)2 : Bis(tricyclohexylphosphine)palladium(0)

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples:
Example 1: preparation of compound of Formula IV
Bis(pinaclaoto)diborane (147.8 grams), potassium acetate (130.9 grams), dichlorobis(triphenylphosphine)palladium (II) (4 grams) were added to a mixture of 4-bromo-3-nitro anisole (100 grams) and 1,2-dimethoxyethane (1000 mL) at 25-30°C. The reaction mixture was heated and stirred for 4 hours provides its corresponding boronate derivative of Formula II. After completion of the reaction, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene compound of Formula III (100 grams), potassium carbonate (131.5 grams), 1,2-dimethoxyethane (100 mL), PdCl2(PPh3)2 (4 grams) were added to the reaction mixture at 25-30°C. The reaction mixture was heated and stirred for 5 hours. After completion of the reaction, quenched the reaction mixture with water and extracted with dichloromethane. The organic layer was treated with carbon and then distilled to get crude compound. The crude compound is purified by using Ethyl acetate (50 mL) and hexane (100 mL) to get pure title compound.
Yield: 82 grams; Purity by HPLC (%): 98.72 %.
Example 2: Preparation of compound of Formula IV
Bis(pinaclaoto)diborane (386.7 grams), potassium acetate (354.9 grams), dichlorobis (triphenylphosphine)palladium (II) (2 grams) were added to a mixture of 4-bromo-3-nitro anisole (276 grams) and 1,2-dimethoxyethane (3000 mL) at 25-30°C. The reaction mixture was heated and stirred for 4 hours provides its corresponding boronate derivative of Formula II. After completion of the reaction, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene compound of Formula III (300 grams), 1,2-dimethoxyehane (1200 mL), potassium carbonate (263 g), PdCl2(PPh3)2 (4.67 grams) were added to the reaction mixture at 25-30°C. The reaction mixture was heated and stirred for 19 hours. After completion of the reaction, quenched the reaction mixture with water and extracted with toluene. The organic layer was treated with carbon and then distilled to get crude compound. The crude compound is purified by using Ethyl acetate (300 ml) and diisopropylether (600 mL) to get pure title compound.
Yield: 265 grams; Purity by HPLC (%): 98.82 % .
Example 3: preparation of compound of Formula V
10 % pd/C (15 grams) was added to a mixture of compound of Formula IV (80 grams), aq. Ammonia (90 mL), methanol (2000 mL). Hydrogen gas was passed into the reaction mixture and stirred for overnight. After completion of the reaction, filtered the reaction mixture and distilled off the solvent from filtrate to get crude compound. The crude compound is purified by using hexane (160 mL) to get pure title compound.

Yield: 52 grams; Purity by HPLC (%): 96.15 %.
Example 4: Preparation of compound of Formula VI
Acetaldehyde (58.9 grams) was added to a mixture of compound of Formula V (50 grams) in ethanol (500 mL) at 0-5°C. Raised the temperature of the reaction to 25-30 °C and stirred for overnight. After completion of the reaction, sodium borohydride (21 grams) was added to the reaction mixture at 0-5 °C. Raised the temperature of the reaction mixture to 25-30 °C and stirred for 3 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. Distilled off the solvent from organic layer to get crude compound. The crude compound is purified by using ethyl acetate (50 ml) and hexane (100 mL) to get pure title compound.
Yield: 42 grams; Purity by HPLC (%): 93.08 %

Example 5: preparation of compound of Formula VII
Dimethylaminopyridine (500 milligrams), triethylamine(10.6 grams), pivolyl chloride (12.6 grams) were added to a mixture of compound of Formula VI (26 grams) and dichloromethane (260 mL) at 0-5°C and stirred for 2 hours. After completion of the reaction, quenched with aq. sodium bicarbonate solution and extracted with dichloromethane. Concentrated the dichloromethane layer to get title compound.
Yield: 32.0 grams.
,CLAIMS:We Claim:

1. An improved process for preparation of Elacestrant or its pharmaceutically acceptable salts of Formula I,

Formula I
which comprises:
a) reacting the compound of Formula II

Formula II
with the compound of Formula III

Formula III
to obtain compound of Formula IV,’

Formula IV
b) reducing the compound of Formula IV in presence of a base to obtain compound of Formula V,

Formula V
c) reacting the compound of Formula V with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI,

Formula VI
d) reacting the compound of Formula VI with pivaloyl chloride to obtain compound of Formula VII,

Formula VII
e) converting the compound of Formula VII into the compound of Formula I,
f) optionally converting the compound of Formula I into its pharmaceutically acceptable salts.
2. An improved process for preparation of compound of Formula IV

Formula IV
which comprises reacting the compound of Formula II

Formula II
with the compound of Formula III

Formula III
to obtain compound of Formula IV.

3. The process as claimed in claims 1 and 2, wherein step a) is carried out in presence of transition metal catalyst and a base in solvent, wherein the said transition metal catalyst containing Pd (II), Cu (0) or Pd (0), the base is inorganic or organic base.

4. The process as claimed in claim 1 to 3, wherein transition metal catalyst is selected from the group consisting of Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd2(Dba)3 or Pd(PCy3)2.

5. The process as claimed in claims 1 to 3, wherein inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or cesium bicarbonate; the solvent is 1,2-dimethoxyethane

6. An improved process for preparation of compound of Formula V,

Formula V
which comprises reducing the compound of Formula IV

Formula IV
in presence of a base to obtain compound of Formula V.

7. The process as claimed in claim 6, wherein reduction of compound of Formula IV is carried out by hydrogenation in presence of metal catalyst, a base and solvent, wherein metal catalyst is pd catalyst, base is aq. ammonia, solvent is alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol.

8. An improved process for preparation of compound of Formula VI

Formula VI
which comprises reacting the compound of Formula V

Formula V
with acetaldehyde to form shiff base, followed by reduction to obtain compound of Formula VI,

9. The process as claimed in claim 8, wherein reaction of compound of Formula V with acetaldehyde is carried out in alcoholic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or butanol; reduction is carried out by using sodium borohydride.

10. An improved process for preparation of compound of Formula VII

Formula VII
which comprises reacting the compound of Formula VI

Formula VI
with pivaloyl chloride to obtain compound of Formula VII.

Dated 29th day of March, 2024

Dr. RATHNAKAR REDDY KURA
DIRECTOR
HETERO LABS LIMITED