Claims:1) A process for preparation of methyl testosterone of formula-III comprising;
a) Reacting a compound of formula-I, wherein R denotes independently linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl and benzyl, with a reducing agent to obtain compound of formula-II and
b) Deprotecting the compound of formula-II to obtain methyl testosterone of formula-III.

2) The process according to claim 1, wherein the reducing agent is selected from a group consisting of lithium aluminum hydride, sodium borohydride, alkyl aluminum hydrides and alkoxy aluminium hydrides.
3) The process according to claim 1, wherein the reducing agent is sodium borohydride.
4) The process according to claim 1, wherein the reaction of step 1-a) is conducted in a solvent selected from a group consisting of water, alcohols, aromatic hydrocarbons and polar aprotic solvents or mixtures thereof.
5) The process according to claim 4, wherein the alcohol solvent is methanol or isopropanol.
6) The process according to claim 1, wherein the reaction of step 1-a) is conducted at ambient temperature to the reflux temperature in the range of 10°C -110°C of the solvent used.
7) The process according to claim 6, wherein the reaction is conducted at 50-60°.
8) The process according to claim 1, wherein the deprotection of compound of formula-II is conducted in presence of an acid.
9) The process according to claim 8, wherein the acid is selected from a group consisting of hydrochloric acid, hydro bromic acid, Hydro iodic acid, phosphoric acid and sulphuric acid.
10) The process according to claim 1, wherein the hydrolysis reaction is carried out at a temperature ranging from 0°C to reflux temperature of the solvent used.
, Description:Field of invention:
The present invention relates to a novel industrially safe process for the preparation of Methyltestosterone. Particularly, the invention relates to an improved process for the preparation of Methyl testosterone by ring opening of epoxide of formula-I using a reducing agent.

Background of the invention:
Methyltestosterone, is also known as 17a-Methyltestosterone and 17?-hydroxy-17-methyl androst-4-en-3-one. Methyltestosterone is a derivative of testosterone with the C17 of the chemical structure substituted by a methyl group. It is a classical drug that has functions of androgen and protein synthesis and has been in use for several decades to treat males with a testosterone deficiency. The chemical structure of Methyl testosterone is as follows:

Methyl testosterone (Formula-III)

Journal Helv Chimica Acta (1935), 18, 1487-98 reported preparation of Methyl testosterone from ?5,6-17- methyl trans androsten-3,17-diol by dissolving the ?5,6-17- methyl trans androsten-3,17-diol in mixture of acetic acid and bromine followed reacting with chromium trioxide in glacial acetic acid to obtain corresponding dibromide derivative which was further treated with zinc dust in acetic acid to obtain Methyl testosterone. The same reaction was also reported in the later published US2143453 patent. This process suffers as the process involves use of chromium trioxide reagent which generates effluent problem because of heavy metal presence.

Another US patent 2386331 disclosed preparation of Methyltestosterone by reacting androstendione-3-mono-enol ethyl ether in toluene with a Grignard reagent, methyl magnesium bromide, followed by decomposing the Grignard adduct with excess ammonium chloride to obtain 3-enol ether of 17-methyl testosterone which was further converted to 17-Methyltestosterone using an acid agent, which involves industrial hazards and safety concern. Other US patents, 3019241 & 3121042 also reported the same process for preparation of Methyl testosterone using Methyl magnesium bromide.

A Chinese patent CN 101089011 disclosed preparation of Methyltestosterone from Androstadiene via oxime reaction, rearrangement, Grignard reaction and oxidation, wherein Grignard reagent is composed of magnesium dust, THF, bromomethane and iodine.

A latest published patent application, CN 105294797, disclosed preparation of Methyl testosterone from 4-androstene-3,17-dione comprising selective ketalization of 3-oxo group of 4-androstene-3,17-dione, then Grignard addition and hydrolysis to generate the Methyl testosterone.

All these processes are involving use of Grignard reagent which required anhydrous reaction conditions and yields are also very less due to moisture sensitivity of the reaction. Because of the moisture sensitivity, the reaction conditions demand stringent controls which are difficult to implement on commercial scale.

Therefore, the object of the invention is to provide an economical and industrially applicable and safe novel process to prepare Methyltestosterone that overcome the problems of the prior art. The present invention addresses the need by providing increased yield and ease of process to produce Methyltestosterone.

Summary of the invention:
The present inventors have, surprisingly, found a novel, high yielding and easy to operate process for preparation of Methyl testosterone.
Accordingly, present invention provides a process for preparation of Methyl testosterone of formula-III comprising;
a) Reacting a compound of formula-I, wherein R denotes independently linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl and benzyl, with a reducing agent to obtain compound of formula-II, wherein R denotes independently linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl and benzyl; and
b) Deprotecting the compound of formula-II to obtain Methyltestosterone of formula-III.

The reducing agents include, but not limited, to metal hydrides such as Lithium aluminium hydride and Sodium borohydride; alkyl aluminum hydrides such as Diisobutyl aluminum hydride (DIBAL), or alkoxy aluminium hydrides such as Sodium bis (2-methoxyethoxy) aluminum hydride (Vitride), Lithium diethoxyaluminiumdihydride and Lithium tri-tert-butoxyaluminum hydride.

In a preferred embodiment of the invention, compound of formula-I, wherein R is ethyl, is reacted with sodium borohydride to obtain compound of formula-II, wherein R is ethyl; and deprotection of compound of formula-II, wherein R is ethyl, to obtain Methyl testosterone of formula-III.

Detailed description of the invention:
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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. 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" means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

The present inventors have, surprisingly, found a novel & safe, high yielding and easy to operate process for preparation of Methyl testosterone in high yields.
Accordingly, present invention provides a process for preparation of Methyl testosterone of formula-III comprising;
a) Reacting a compound of formula-I, wherein R denotes independently linear or branched (C1-C8)-alkyl, cycloalkyl, phenyl and benzyl, with a reducing agent to obtain compound of formula-II and
b) Deprotecting the compound of formula-II to obtain methyl testosterone of formula-III.

The reducing agents include, but not limited to, metal hydrides such as Lithium aluminium hydride and Sodium borohydride; alkyl aluminum hydrides such as Diisobutylaluminium hydride (DIBAL), or alkoxy aluminium hydrides such as Sodium bis(2-methoxyethoxy)aluminum hydride (Vitride), Lithium diethoxyaluminiumdihydride and Lithium tri-tert-butoxyaluminum hydride. However preferred reducing agent is sodium borohydride.

The reduction reaction for ring opening of the epoxide compound of Formula-I may be conducted in a suitable solvent medium. The solvent medium includes, but not limited to, water, alcohols, esters, aromatic hydrocarbons and polar aprotic solvents or mixtures thereof. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, iso butanol and tertiary butanol etc. Polar aprotic solvents include dimethyl sulphoxide or dimethyl formamide. Aromatic hydrocarbons include toluene or xylene. Ethers include tetrahydrofuran, diisopropyl ether or diethyl ether. However preferred solvent is methanol, ethanol or isopropanol.

The ring opening reaction may be conducted at ambient temperature to the reflux temperature in the range of 10°C -110°C of the solvent used. Typically, the reaction is conducted at 50-60°C for a couple of hours till completion of ring opening reaction. After completion of reaction, water is added into the reaction mass, cooled and filtered to isolate the product of Formula-II.

The compounds of Formula-II are further subjected for deprotection of the 3-enol ether group of compounds of Formula-II by hydrolysis with suitable acid.

The acids include organic or inorganic/mineral acids. Mineral acids include hydrochloric acid, hydro bromic acid, Hydro iodic acid, phosphoric acid, sulphuric acid etc. and organic acids include acetic acid, sulphonic acids, alkyl substituted sulphonic acids, trifluoro acetic acid etc. The acids may be used in concentrated or diluted form. However, dilute mineral acid such as hydrochloric acid is preferred.
Hydrolysis may be conducted in solvent which includes water or water miscible organic solvents such as alcohols, aprotic polar solvents etc. The aprotic polar solvents are selected from dimethyl formamide, dimethyl acetamide, dimethyl sulphoxide etc., However, preferred solvent is dimethyl formamide.

The hydrolysis reaction is carried out at a temperature ranging from 0°C to reflux temperature of the solvent used. Preferably, the reaction is carried at ambient temperature. Usually reaction completes in an hour. After completion of hydrolysis, the product, Methyl testosterone, is isolated by conventional methods such as filtration. The obtained Methyl testosterone may, further, be purified using suitable solvent such as aqueous methanol.

Starting material of compound of formula-I may be prepared starting from Androst-4-en-3,17-dione of formula-IV as per the procedures known in the art. Typically the Androst-4-en-3,17-dione is reacted with suitable alkyl /aryl orthoformate in dimethyl formamide solvent to obtain corresponding 3-alkyl/aryl substituted compounds of formula-V. The 3-alkyl/aryl substituted compounds of formula-V are further reacted with trimethylsulphoxonium bromide or trimethylsulphoxonium iodide in presence of sodium ethoxide in a solvent such as tetrahydrofuran, DMSO or mixture thereof to obtain epoxides of formula-I.
The scheme for preparation of epoxides of formula-I, wherein R denotes ethyl, is mentioned below.

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

EXAMPLES:

Stage I: Androst-4-en-3,17-dione to 3-methoxy-androst-3,5-diene-17-one:
Androst-4-en-3, 17-dione(100 gms) was dissolved under stirring in Dimethyl formamide (250 ml) and then charged Trimethyl orthoformate (140 ml) followed by 8% Methanolic sulfuric acid (20 ml) (pH=2-3) at temp. 300C ±20C. Stirred the reaction mass for 120 minutes at 300C ± 20C. Checked TLC for completion of 3, 17-dimethoxy (intermediate) reaction. Then cooled the reaction mass to 10-200C. Added purified water, immediately added Triethylamine (8-12 ml)(pH=7.5-8) and stirred for 15 minutes followed by addition of 8% Methanolic sulfuric acid solution (20-30 ml) (pH=2-3) at 10-20°C and further stirred for half an hour till conversion of 3, 17-dimethoxy to 3-methoxy-androst-3, 5-diene-17-one is completed. Then added Triethylamine (20-30 ml) (pH=7.5-8) and stirred for 15 minutes. Cooled the reaction mass to 00C ±20C, filtered the reaction mass and washed the product first with chilled dimethyl formamide and then washed with mixture of methanol (100 ml) and pyridine (0.5 ml). Finally washed the cake with purified water and dried the cake at RT.
Yield: 98 Gms, Moisture: NMT: 0.5%

Stage II: 3-methoxy-androst-3,5-diene-17-one to 3-methoxy-androst-3,5-diene-17-Epoxide:
Charged Dimethyl Sulphoxide (300 ml), tetrahydrofuran (140 ml), sodium ethoxide (70gms) and heated the reaction mass to 600C ± 50C for 2 hours. Cooled the reaction mass to 300C ± 20C and finally to 50C ± 20C. Then charged Trimethyl Sulphoxonium bromide (100 gms) into the reaction mass and stirred for 30 minutes at 50C ± 20C. Further, charged 3-methoxy-androst-3, 5-diene-17-one (98 gms) and tetrahydrofuran (150 ml) and stirred the reaction mass for 2 hrs till conversion of 3-methoxy-androst-3, 5-diene-17-one to 3-methoxy-androst-3, 5-diene-17-epoxide is completed. Then quenched the reaction mass in to ice and water mixture and stirred for 3 hrs at temperature of 00C ± 20C. Then filtered the reaction mass and washed the product with Purified Water till pH 6.5 to 7.0. Dried in Air Tray Dryer at 250C ± 50C.
Yield: 100 gms Moisture NMT:0.5%

Stage III: 3-Ethoxy-androst-3,5-diene-17-Epoxide to 17?-Hydroxy-17-methyl-3-Ethoxy-androst-3,5-diene:
3-Ethoxy-androst-3,5-diene-17-epoxide (100 gms) was dissolved under stirring at 250C ± 20C in methanol 10 times of epoxide intermediate. Charged sodium hydroxide solution (30 gms in 35 ml water) at 250C ± 20C. To the reaction mass added slowly sodium borohydride (75 gms) at 250C ± 20C. The mass is maintained at 500C ± 20C for 150 min till conversion of 3-ethoxy-androst-3, 5-diene-17-Epoxide to 17?-Hydroxy-17-methyl-3-ethoxy-androst-3,5-diene is completed. Cooled the reaction mass at to room temperature and purified water (100 ml) was added. Further, the reaction mass was chilled to 50C ± 20C and maintained for1 hour. Then filtered the obtained precipitate and washed the product with purified water till pH 6.5 to 7.0. Charged wet cake and dissolved in methanol at 300C ± 20C for 30 minutes. Then chilled to 00C and stirred for 1 hour. Then Filtered the reaction mass to get Wet 17?-Hydroxy-17-methyl-3-ethoxy-androst-3, 5-diene.
Wet cake approximate 90 gms, used for next stage.

Stage IV: 17?-Hydroxy-17-methyl-3-ethoxy-androst-3,5-diene to 17?-Hydroxy-17- methylandrost-4-en-3-one Crude:
The wet 17?-Hydroxy-17?-methyl-3-ethoxy-androst-3,5-diene was dissolved in dimethyl formamide (500 ml). Filtered the solution on Hyflo bed made using dimethyl formamide. Then added 10% HCl (approx. 20 ml) to adjust the pH of the filtrate 2-3 at 250C ± 50C. Stirred the reaction mass for 15 minutes at 250C ± 50 till conversion of 17?-Hydroxy-17?-methyl-3-Ethoxy-androst-3,5-diene to 17?-Hydroxy-17?-methylandrost-4-en-3-one is completed. Then added purified water in to reaction mass within 60 minutes at 250C ± 20C and further cooled to 00C and maintained for 60 min. Then filtered the precipitate and washed with purified water.
The obtained wet cake is taken for next stage.

Stage V: 17?-Hydroxy-17-methylandrost-4-en-3-one Crude to 17?-Hydroxy-17- methylandrost-4-en-3-one Pure:
The wet 17?-Hydroxy-17?-methylandrost-4-en-3-one crude (152 gms) is dissolved in methanol (1.5 lit). Heated the solution to 400C ± 20C, added activated carbon (5.0 gms) and stirred for 15 mins. Filtered the reaction mass through Hyflo bed prepared using methanol. Washed the Hyflo bed with methanol (100 ml). To the filtrate, added purified water (350-400 ml) slowly within 60 minutes at 250C ± 20C. Then cooled to 00C and stirred for 60 min to obtain precipitate. Then filtered the precipitate under vacuum and washed the cake with chilled mixture of methanol and water (80ml +20 ml). Dried in VTD (Vacuum Tray Dryer) at 550C ± 50C.
Wt of 17?-Hydroxy-17- methylandrost-4-en-3-one: 70.0 gms Purity:99.5%