DESC:FIELD OF THE INVENTION
The present invention provides an improved process for preparation of pure Desogestrel and its intermediate thereof.
BACKGROUND OF THE INVENTION
Desogestrel is chemically known as 13-ethyl-11-methylene-18,19-dinor-17a-pregn-4-en-20-yn-17-ol and is represented by formula (I).

Desogestrel is the most popular third-generation progestin of the 1990s, which is used in combination with ethinyl estradiol as a birth control pill to prevent pregnancy. It is a powerful progestogen and widely used in oral contraceptives. Desogestrel is thought to act as a contraceptive primarily by preventing the ovulation. Desogestrel is the fifth progestogen to be marketed as progestogen-only pill for contraception. Desogestrel has been found to inhibit ovulation to a greater extent than levonorgestrel.
US 3,927,046 patent discloses the process for the preparation of Desogestrel is shown in scheme-1.
E.J.Corey et.al. a short enantioselective total synthesis of the third –generation oral contraceptive Desogestrel” discloses process for the preparation of 13-ethyl-11-methylenegona-4-en-17-one (intermediate of Desogestrel) and Desogestrel as shown in below scheme-2;
Most of the earlier methods for preparation of Desogestel are having many disadvantages like lengthy or complex procedures for preparation of Desogestel, difficulty in handling of reactants, safety issues, high pressure drop, mass transfer limitations, filtration of catalyst and excess elemental sulfur formation in intermediate stage preparation of 13-ethyl-11-methylenegona-4-en-17-one (key intermediate of Desogestel), which is effects a purity of final Desogestel API.
The present invention provides an improved process for preparation of pure Desogestrel and also avoids drawbacks of the excess elemental sulfur formation in the prior art methods.
The present invention also provides a process for the preparation of highly pure 13-ethyl-11-methylenegona-4-en-17-one free from elemental sulfur impurity, wherein purity is more than 99% by HPLC.
OBJECT AND SUMMARY OF THE INVENTION
The main object of the present invention relates to an improved process for preparation of Desogestrel free from elemental sulfur impurity.
Another object of the present invention relates to process for the preparation of pure 13-ethyl-11-methylenegona-4-en-17-one free from elemental sulfur impurity.
The present invention provides an improved process for the preparation of Desogestrel free from elemental sulfur impurity comprising the steps of;
a) treating 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of organic solvent,
b) adding a base or mixtures thereof,
c) removing the solvent,
d) dissolving the material obtained in step c) in organic solvent,
e) isolating pure 13-Ethyl-11-methylenegona-4-en-17-one,
f) treating step e) with acetylene gas, and
g) isolating pure desogestrel free from elemental sulfur impurity.

The present invention provides an improved process for the preparation of 13-Ethyl-11-methylenegona-4-en-17-one free from elemental sulfur impurity and having purity more than 99% by HPLC comprising the steps of;
a) treating 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of organic solvent,
b) optionally adding a base or mixtures thereof,
c) removing the solvent,
d) dissolving the material obtained in step c in an organic solvent, and
e) isolating 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity.
Detail Description of the Invention:
One aspect of the present invention provides a process for the preparation of pure desogestrel.
In one of the embodiment, the present invention relates to an improved process for the preparation of pure desogestrel is free from elemental sulfur impurity as shown in scheme -3 below:
Scheme-3

Another aspect of the present invention provides an improved process for the preparation of pure Desogestrel is free from elemental sulfur impurity comprising the steps of;
a) treating 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of organic solvent,
b) adding a base or mixtures thereof,
c) removing the solvent,
d) dissolving the material obtained in step c) in an organic solvent,
e) cooling the reaction mass, isolating pure 13-Ethyl-11-methylenegona-4-en-17-one
f) treating step e) with acetylene gas, and
g) isolating pure desogestrel is free from elemental sulfur impurity.

According to the present invention, 13-Ethyl-11-methylenegona-4-en-17a-ol is dissolved in suitable solvent selected from chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1 ,4-dioxane and ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitri te solvents such as acetonitri le, propionitrile, isobutyronitrile and the like; alcohol solvents such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1 ,2-dio I, propane- 1 ,2-diol and the like; polar solvents such as water; formic acid, acetic acid, propanoic acid or mixture of any of the aforementioned solvents thereof. Treating above solution with Dess-Martin periodinane in presence of a base; base is selected from ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydride, lithium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium thiosulphate, potassium thiosulfate or mixture thereof.
According to the present invention, crude 13-Ethyl-11-methylenegona-4-en-17-one is dissolved in suitable solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, hydrocarbon solvents such as toluene,xylene,n-hexane,n-heptane,cyclohexane; esters such as ethylacetate,n-propyl acetate,n-butyl acetate,t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl formamide, dimethyl sulfoxide, dioxane or a mixture thereof.
According to the present invention, isolating pure 13-Ethyl-11-methylenegona-4-en-17-one by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art.
According to the present invention, 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity.
According to the present invention, isolating compound 13-Ethyl-11-methylenegona-4-en-17-one is treating with acetylene to give pure Desogestrel is free from elemental sulfur impurity.
Yet another aspect of the present invention provides an improved process for the preparation of 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity having a purity more than 99% by HPLC comprising the steps of;
a) treating 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of organic solvent,
b) optionally adding a base or mixtures thereof,
c) removing the solvent,
d) dissolving the material obtained in step c) in an organic solvent, and
e) isolating 13-Ethyl-11-methylenegona-4-en-17-one.

According to the present invention, 13-Ethyl-11-methylenegona-4-en-17a-ol is dissolved in a solvent selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, preferably dichloromethane. Adding Dess-Martin periodinane and a base; base is selected from ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydride, lithium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium thiosulphate, Potassium thiosulfate or mixture thereof, preferably sodium bicarbonate and 10% sodium thiosulphate or it mixture thereof. Removing the solvent by using distillation under vacuum and the obtained residue is crystallizing by dissolving in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol, preferably methanol; cool the reaction mass to 0-5°C and filtered the reaction mass, thus obtained pure 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity.
Yet another aspect, the present invention provides a process for the preparation of 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity having a purity more than 99% by HPLC comprising the steps of;
a) dissolving 13-Ethyl-11-methylenegona-4-en-17-one in a organic solvent,
b) cooling the reaction mass and
c) isolating 13-Ethyl-11-methylenegona-4-en-17-one having a purity more than 99% by HPLC.
According to the present invention, 13-Ethyl-11-methylenegona-4-en-17-one is dissolving in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol, preferably methanol; cooling the reaction mass to 0-5°C and filtered the reaction mass, thus obtained pure 13-Ethyl-11-methylenegona-4-en-17-one with absence elemental sulfur impurity.
According to the present invention, pure 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity can be prepared by employing technique known in the art.
According to the present invention, pure 13-Ethyl-11-methylenegona-4-en-17-one is treating with acetylene gas by employing technique known in the art.
Pure 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity and pure Desogestrel is free from elemental sulfur impurity obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, when measured by using high performance liquid chromatography (HPLC) and the details are given below;
Instrument : HPLC equipped with Pump, UV detector and Recorder.
Column : Zorbax SB-C18 (4.6 x 250mm), 5µm.
Wavelength : UV Detector 240nm
Flow rate : 1.5mL/min
Injection volume : 20?L.
Auto sampler temperature: 10°C
Column oven temperature: 50°C
According to the present invention, starting materials 13-ethyl-17beta-hydroxy-11-methylenegona-4-en-3-one and 13-ethyl-11-methylenegona-4-en-17 beta-ol are obtained by methods known in the literature.
Pharmaceutical compositions containing the Desogestrel of the present invention may be prepared by using one or more pharmaceutically acceptable carriers, diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Examples
Example-1: Process for the preparation of pure 13-Ethyl-11-methylenegona-4-en-17-one.
Charged 13-Ethyl-11-methylenegona-4-en-17a-ol 10 g (34.9 mmol), dichloromethane (200 ml), stirred the reaction mass and treated with Dessmartin Periodinane 11.74g (27.7mmol) at room temperature, the reaction mass was stirred for 2-3hrs at room temperature. After completion of the reaction, reaction mass was added with saturated sodium bicarbonate solution (174 ml) at room temperature for 30 minutes, followed by addition of 10% Sodium thiosulfate solution (174ml) and stirred the reaction mass for 2 hrs. Organic layer was separated and solvent was removed under reduced pressure. The obtained reaction mass was dissolved in methanol (100 ml) and the reaction mass was cooled to 0-5°C. The obtained solid was filtered and washed with methanol (0±5°C) and dried under vacuum.
Yield: 77.6%
HPLC purity: 99.09 %
Elemental sulfur impurity: Not detected
Example-2: Process for the preparation of pure Desogestrel.
Charged potassium tertiary butoxide 110g in dimethyl acetamide (280ml) and 1,4-dioxane 40ml at room temperature, stirred for 20 min. The reaction mass was cooled to 2 to 5°C, ethylene diamine (12ml) was added and purged acetylene gas at a temperature at 2°C to the reaction mass.In another flask 13-Ethyl-11-methylenegona-4-en-17-one 20g was dissolved in 100ml dimethylacetamide, this solution was added to the first reaction mass. The reaction mass was stirred for 2hrs, quench the mass with ethylacetate and water mixture. Adjusted PH of the reaction mass between 2.5 to 3 by adding hydrochloric acid solution. Organic phase and aqueous phase were separated and organic layer was concentrated under vacuum and crystallized in n-heptane.
Yield: 57.6%
HPLC purity: 99.9 %
Elemental sulfur impurity: Not detected
,CLAIMS:1. An improved process for the preparation of 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity comprising the steps of;
a) treating 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of organic solvent,
b) adding a base or mixtures thereof,
c) removing the solvent,
d) dissolving the material obtained in step c) in an organic solvent, and
e) isolating 13-Ethyl-11-methylenegona-4-en-17-one.
2. The process as claimed in claim 1, wherein the organic solvent in step a is selected from dichloromethane, chloroform or carbon tetrachloride.
3. The process as claimed in claim 1, wherein the organic solvent in step a is dichloromethane.
4. The process as claimed in claim 1, wherein the base in step b is sodium bicarbonate and 10% sodium thiosulfate solution.
5. The process as claimed in claim 1, wherein the organic solvent in step d is methanol, ethanol, isopropanol, n-propanol or tertiary-butyl alcohol.
6. The process as claimed in claim 1, wherein the organic solvent in step d is methanol.
7. 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity obtained by the process according to claim 1 to 6 is used for the preparation of pure Desogestrel.
8. Isolated 13-Ethyl-11-methylenegona-4-en-17-one is free from elemental sulfur impurity obtained by the process according to claim 1 to 7 is having a purity more than 99% by HPLC.
9. An improved process for the preparation of pure desogestrel is free from elemental sulfur impurity comprising the steps of;
a) condensing 13-Ethyl-11-methylenegona-4-en-17a-ol with Dess-Martin periodinane in presence of dichloromethane solvent ,
b) adding a base selected from sodium bicarbonate and 10% sodium thiosulfate solution or mixtures thereof,
c) removing the solvent dichloromethane,
d) dissolving the material obtained in step c) in methanol,
e) isolating pure 13-Ethyl-11-methylenegona-4-en-17-one
f) treating step e) with acetylene gas, and
g) isolating pure desogestrel.
10. The process as claimed in claim 1 and 9, wherein the organic solvent is removed by using suitable techniques such as distillation, distillation by using a rotational distillation, distillation under vacuum, filtration, filtration under vacuum and centrifugation.