Claims:
1) A process for purification of Norethisterone acetate comprising;
a) dissolving Norethisterone acetate in acetone to obtain solution;
b) adding water to the obtained solution; and
c) isolating the pure Norethisterone acetate.

2) The process as claimed in claim 1, wherein the dissolution of Norethisterone acetate is carried out at ambient temperature or by heating.

3) The process as claimed in claim 1, wherein, the isolation of pure Norethisterone acetate is carried out at 10-15°C.

4) A process for preparation of pure Norethisterone acetate comprising;
a) reacting Norethisterone with acetic anhydride in presence of a base and catalyst to obtain crude Norethisterone acetate;
b) dissolving the crude Norethisterone acetate in acetone to obtain solution;
c) adding water to the obtained solution; and
d) isolating the pure Norethisterone acetate.

5) The process as claimed in claim 4, wherein, the base is selected from a group consisting of monomethyl amine, dimethylamine, diethylamine, trimethylmine, triethyl amine and diisopropyl ethylamine.

6) The process as claimed in claim 4, wherein, the base is triethyl amine.

7) The process as claimed in claim 4, wherein, the catalyst is 4-dimethylamino pyridine.

8) The process as claimed in claim 4, wherein, the base is used in the range of 1.0 to 5.0 moles based on Norethisterone.

9) The process as claimed in claim 4, wherein, the catalyst is used in the range of 0.1 to 0.5 moles based on Norethisterone.

10) The process as claimed in claim 4, wherein, the reaction of Norethisterone with acetic anhydride is carried out at ambient temperature; the dissolution of Norethisterone acetate is carried out at ambient temperature or by heating and the isolation of pure Norethisterone acetate is carried out at 10-15°C.
, Description:Field of invention:
The present invention relates to an improved process for preparation of substantially pure Norethisterone acetate.

Background of the invention:
Norethisterone acetate is also known as Norethindrone acetate and also referred with various chemical names such as 17a-Ethinyl-19-nortestosterone 17ß-acetate, 17ß-Acetoxy-19-nor-17a-pregn-4-en-20-yn-3-one and 19-Nor-17a-pregn-4-en-20-yn-3-one, 17-hydroxy-, acetate.

Norethisterone acetate is a progestin which is used in hormonal contraception, hormone replacement therapy, and to treat gynecological disorders.
Norethisterone acetate is having following structural formula I.

Norethisterone acetate was first disclosed in US2964537 patent. This patent discloses reaction of 17-ethinyl-19-nor-testosterone with acetic anhydride in presence of p-toluenesulfonic acid. Pure product is isolated after repeated purifications from methylene chloride/hexane.

Another US patent, US3761496, discloses preparation of Norethisterone acetate by reacting 17-ethinyl-19-nor-testosterone with acetic anhydride in presence of zinc chloride.

JP53065866 & JP53079849 patents reported process for preparation of Norethisterone acetate by reacting 17-ethinyl-19-nor-testosterone with acetic anhydride in presence of pyridine base.

The problem features, albeit of significance of the disclosed processes in the above mentioned patents are described below.

Firstly, use of acetic anhydride as a reagent as well as solvent envisages low yields due to the losses while attempting to make the product free from the excess of acetic anhydride and further increases effluent load thus making the process environmentally non-benign.

Secondly, acetic anhydride being a controlled and expensive substance, use of excess acetic anhydride makes the discussed processes not economically viable.
Another PCT publication, WO2014162230, reports preparation of Norethisterone acetate by reacting 17-ethinyl-19-nor-testosterone with acetic anhydride using toluene as solvent and 4-dimethylamino pyridine as catalyst. The crude product is obtained via extractive work up of the reaction mixture followed by alumina column wherein the product is eluted with toluene - cyclohexane mixture, appropriate fractions collected, concentrated to a residue and finally filtered from n-heptane. The obtained crude is then purified twice, first from DCM-Heptane mixture and finally from Ethanol- water mixture.

The disclosed process has the following evident drawbacks viz.,
• the process employs column chromatography in the isolation step thereby making the process unscalable and commercially unviable; and
• the isolation of pure product requires two crystallizations resulting in low yield hence making the process economically unviable.

Another publication J. Am. Chem. Soc., 1959, 81 (2), pp 436-438 reported crystallization of Norethisterone acetate from acetone-hexane mixture. However when we repeated crystallization from acetone-hexane mixture, impurities in Norethisterone acetate remained at levels higher than the required pharmacopoeial level.

Therefore, the object of the present invention is to overcome the above stated drawbacks of the prior art processes by providing an economical and industrially scalable process for preparing substantially pure Norethisterone acetate.

Summary of the invention:
The present inventors have, surprisingly, found a novel, high yielding and easy to operate process for preparation of Norethisterone acetate having high purity.
Accordingly, one aspect of the present invention provides a purification process for Norethisterone acetate which comprises;
a) dissolving Norethisterone acetate in acetone to obtain solution;
b) adding water to the obtained solution; and
c) isolating the pure Norethisterone acetate.

In a preferred embodiment, the Norethisterone acetate is dissolved in acetone by heating to obtain a solution, then water is added to the solution to obtain purified Norethisterone acetate.

Another aspect of the present invention provides a process for preparation of Norethisterone acetate which process comprises;
a) reacting Norethisterone with acetic anhydride in presence of a base and catalyst to obtain crude Norethisterone acetate;
b) dissolving the crude Norethisterone acetate in acetone to obtain a solution;
c) adding water to the obtained solution; and
d) isolating the pure Norethisterone acetate.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

The process of the present invention is illustrated in the following Scheme 01 as described below

Scheme 01

Accordingly, one aspect of the present invention provides a process for preparation of Norethisterone acetate which process comprises;
a) reacting Norethisterone with acetic anhydride in presence of a base and catalyst to obtain crude Norethisterone acetate;
b) dissolving the crude Norethisterone acetate in acetone to obtain a solution;
c) adding water to the obtained solution; and
d) isolating the pure Norethisterone acetate.

According to the present invention, Norethisterone is taken in a solvent such as dichloromethane followed by addition of a base and a catalyst to the solution.
The base may be selected appropriately from an organic or inorganic class of compounds. However, organic bases are preferred. Organic bases include but not limited to alkyl amines for example monomethyl amine, dimethylamine, diethylamine, trimethylmine, triethyl amine, diisopropyl ethylamine or the like. However, most preferred base is triethyl amine.

The base is conveniently used in an amount, although not limited to, equal or greater than molar equivalents relative to the starting compound, Norethisterone, preferably in a range between 1.0 to 5.0 moles, more preferably between 2.5 to 3.5 moles.

Catalyst may be selected from pyridine, 4-dimethylaminopyridine and tetrabutylammonium hydroxide. However, most preferred catalyst is 4-dimethylaminopyridine. The quantity of the catalyst may be used in a range between 0.1 to 0.5 moles based on Norethisterone. However, preferred range is 0.2 to 0.3 moles.

The reaction may be conducted at a temperature range of 20 to 45°C and pH of the reaction mass is to be maintained at 8-10. However, surprisingly it is found that, at ambient temperature and under slightly basic conditions (about 9 pH) the diacetate impurity formation is observed to be minimal.

Usually the acetylation reaction is completed in a period of 14-21 hours period. After completion of reaction, the reaction mass is washed sequentially with water, 10% HCl and further concentrated the reaction mass. To the concentrated mass, hexane or heptanes is added and heated further to about 70°C, then the mass is cooled to room temperature and filtered to obtain crude Norethisterone acetate.

According to another aspect, the present invention provides purification process of Norethisterone acetate. As per the purification process of present invention, the crude Norethisterone acetate is dissolved in acetone solvent. Dissolution may be carried out at room temperature or by heating the contents to reflux. The acetone solution may be optionally treated with activated carbon to obtain clarified solution. To the acetone solution water is added slowly at ambient temperature to precipitate Norethisterone acetate. The reaction mass is further cooled to about 10-15°C and filtered to obtain purified Norethisterone acetate.

Quantity of the acetone may be used between 3 volumes to 6 volumes based on Norethisterone acetate. However, quantity of water addition is critical in the present invention. As the rejection of impurities, particularly, diacetate impurity depends on quantity of water in the crystallization mass. The water addition to the acetone solution is restricted to only about 50% of the acetone volume. After completion of water addition, the obtained slurry may be filtered at room temperature or optionally it may be further cooled to 10-15°C and filtered. The cake obtained upon filtration is washed with water and dried at 50-60°C under vacuum to obtain purified Norethisterone acetate. The purity of the obtained Norethisterone acetate is found to be >99.8% by HPLC and total impurities are below 0.1%.

The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES:
Reference Example 1: Procedure for the preparation of 17-ethinyl-19-nor-testosterone Acetate (Norethisterone acetate) as per example 2 (a) of US Patent no 2964537.
2.98g of 17-ethinyl-19-nor-testosterone was suspended in 30 cc. of acetic anhydride and a solution of 1.9 g. of paratoluenesulphonic acid in 19 cc. acetic anhydride was gradually added while cooling and stirring. Complete dissolution takes place after about one hour. After additional 30 to 60 minutes, a thick, pasty mass was separated. The reaction was permitted to continue for a period of five hours, whereupon water was added to the reaction mixture and the 3-enol-17-diacetate which separated out after stirring for one to two hours was filtered off, washed until neutral and dried in vacuo over calcium chloride at room temperature. In order to prepare the mono-acetate, the crude diacetate was suspended in 150 cc. of methanol and after adding 1.5 cc. concentrated hydrochloric acid, heated to boiling for 15 minutes in a nitrogen atmosphere. The crude mono-acetate which separated out upon the addition of water after cooling is filtered off, washed and dried in vacuo over calcium chloride at room temperature. The pure 17-acetate, obtained after repeated recrystallizations from methylene chloride/ hexane has a melting point of 161- 162° C.

Example 1: Preparation of Norethisterone Acetate
Norethisterone (50g, 0.16moles) was taken in Dichloromethane (250 ml) at 28-30° C. To the obtained reaction mass triethyl amine (50.82g, 0.502moles) followed by N,N’-Dimethyl pyridine-4-amine (5g, 0.040moles) and Acetic Anhydride (34.26g, 0.335moles) were added sequentially at the same temperature. The obtained reaction mass was then stirred for 21 hours at 28-30° C where upon it was washed sequentially with DM Water (200ml), 10 % HCl solution (50ml) and DM Water (200ml). The layers were separated and the separated organic layer was then concentrated under vacuum at 40-45°C to provide a solid residue. To the obtained solid residue, Heptane (500ml) was added and the contents were heated at 50-55°C for 60minutes. The reaction mass was then cooled to 25-30°C wherein the precipitated solid was filtered, washed with heptane (50ml) and suck dried to provide Norethisterone Acetate as a cream colored solid in almost quantitative yield.

Analytical Details (by HPLC)
Analysis type Norethisterone acetate
% Unreacted Norethisterone % Diacetate impurity
%
At the end of reaction 98.61 0.29 0.39
Purity of isolated product 99.72 0.14 0.06

Example 2: Preparation of Norethisterone Acetate
Norethisterone (10g, 0.032moles) was taken in Dichloromethane (50 ml) at 28-30° C. To the obtained reaction mass triethyl amine (10.16g, 0.10moles) followed by N,N’-Dimethyl pyridine-4-amine (1g, 0.008moles) and Acetic Anhydride (7.02g, 0.069moles) were added sequentially at the same temperature. pH of the reaction mass was maintained at about 9.0. The obtained reaction mass was then stirred for 21 hours at 28-30° C where upon it was washed sequentially with DM Water (40ml), 10 % HCl solution (10ml) and DM Water (40ml). The layers were separated and the separated organic layer was then concentrated under vacuum at 40-45°C to provide a solid residue. To the obtained solid residue, Hexane (25ml) was added and the contents were heated at 40-45°C for 60minutes. The reaction mass was then cooled to 25-30°C and stirred for 30minutes. The precipitated solid was then filtered, washed with hexane (10ml) and suck dried to provide Norethisterone Acetate as a cream solid in almost quantitative yield.
Analytical Details (by HPLC)
Analysis type Norethisterone acetate
% Unreacted Norethisterone % Diacetate impurity
%
At the end of reaction 98.56 0.48 0.28
Purity of isolated product 99.24 0.30 0.19

Example 3: Preparation of high purity Norethisterone Acetate
Norethisterone (75g, 0.251moles) was taken in Dichloromethane (375ml) at 28-30° C. To the obtained reaction mass triethyl amine (76.2g, 0.753moles) followed by N,N’-Dimethyl pyridine-4-amine (7.5g, 0.061moles) and Acetic Anhydride (51.75g, 0.506moles) were added sequentially at the same temperature. The obtained reaction mass was then stirred for 14 hours at 28-30° C where upon it was washed sequentially with DM Water (300ml), 10 % HCl solution (75ml), 5% Sodium bicarbonate solution and DM Water (300ml). The layers were separated and the separated organic layer was then concentrated atmospherically below 60°C to provide a solid residue. To the obtained residue heptane (75ml) was added and residual dichloromethane was co-distilled under vacuum below 65° C to obtain solid. To this obtained solid. Heptane (375ml) was added and the contents were heated at 70°C for 60minutes. The reaction mass was then cooled to 25-35°C wherein the precipitated solid was filtered, washed with heptane (75ml) and suck dried for 30minutes to provide Norethisterone Acetate crude as a solid. The Norethindrone acetate thus obtained was dissolved in acetone (300ml) at 40-45 °C. To the obtained clear solution a slurry of activated carbon (7.5g) in acetone (30ml) was added and the contents maintained at 40-45° C for 30minutes. Activated charcoal was then filtered off through a celite bed, which was washed twice with acetone (75ml X 2). The obtained clear filtrate was then cooled to 25-30° C. To the cooled filtrate process water (300ml) was charged and the contents were cooled further to 10-15° C and maintained for 60minutes. The precipitated solid was then filtered, washed twice with water (75ml X 2), suck dried and finally dried at 45-55° C under vacuum for 10 hours to provide Pure Norethisterone acetate as a crystalline solid.
Yield: 70g (82% Theoretical yield)

Analytical Details (by HPLC)
Analysis type Norethisterone acetate
% Unreacted Norethisterone % Diacetate impurity
%
At the end of reaction 98.61 0.39 0.29
Purity of isolated product 99.88 0.05 ND
Characterization of the crystalline Pure Norethisterone acetate:
1H-NMR in CDCl3 at 400MHz (ppm): 0.93 (s, 3H), 2.60 (s, 1H), 5.83(s, 1H)
13C-NMR in CDCl3 at 100MHz (ppm): 13.39, 21.41, 23.36, 26.15, 26.56, 30.69, 32.84, 35.42, 36.50, 37.24, 40.75, 42.50, 47.57, 47.61, 48.98, 75.01, 83.16, 84.29, 124.65, 166.23, 169.48, 199.75
Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 341.19 a.m.u which corresponds to [M+H]+ peak of title compound.
DSC Analysis: Onset temperature of melting starts at around 162°C.
XRPD Data: Characteristic 2? values at 14.71°,16.51°, 19.69°, 20.8°, 22.43° corresponding to the polymorphic form-1.
Example 4: Purification of Norethisterone acetate crude
Norethindrone acetate (12g, 0.034moles) having more than 0.5% of un-reacted Norethisterone and more than 0.2% Diacetate impurity, was dissolved in acetone (36ml) at 25-30 °C. The temperature of the clear solution was raised upto 40°C whereupon water (36ml) was added. The obtained slurry was then stirred for 30 minutes at 40°C, further cooled to 10-15° C whereupon the precipitated solid was filtered, washed with water (24ml) and dried under vacuum at 40-45°C to provide Norethisterone acetate as a pure solid.
Analytical Details
HPLC Analysis Details:
Details Norethisterone acetate (II)
% Unreacted Norethisterone (IV) % Diacetate impurity (III)
%
Before purification 98.49 0.58 0.27
After purification 99.87 0.07 0.08

The solid state characteristics of the pure Norethisterone Acetate thus obtained meets the requirement of Form-1 as stated in the example 3.
Purification of Norethisterone Acetate as per Reference: JACS Vol. 81, Pages 436-8.
Norethisterone acetate crude obtained above was crystallized from Acetone(50ml) and Hexane(200ml) mixture at room temperature as reported in the prior art and further it was cooled up to 0-5°C. Filtered the solid and the wet cake was washed with 25 ml hexane. Wet cake was dried at 50-55°C and the purity of Norethisterone acetate was obtained by HPLC.
HPLC results comparing IPCA’s purification method with the JACS reference are tabulated in following table.
Details RT 5.81 11.01 11.90
(API) 22.57 22.88 24.11
(Diacetate) Total impurities
Crude NEA (%) 0.12 0.06 98.49 0.29 0.17 0.40 1.51
After purification in Acetone: Hexane(%) as per JACS reference 0.10 0.04 99.31 0.10 0.07 0.15 0.69
Purification with Acetone:Water(%) as per Ipca’s process ND 0.03 99.82 0.03 0.02 0.07 0.18