WO2012035553A1

WO2012035553A1 - Process for preparing androstenone derivatives

Info

Publication number: WO2012035553A1
Application number: PCT/IN2011/000625
Authority: WO
Inventors: Singh Sarin Gurdeep; Sivaji Aavula; Bhaskar Bhirud Shekhar
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2010-09-15
Filing date: 2011-09-13
Publication date: 2012-03-22

Abstract

Provided is a process for preparing androstenone derivatives, specifically 3-oxo-4-aza-5α-androstene-17β-carboxylic acid of Formula I, a key intermediate for dutasteride.

Description

TITLE OF THE INVENTION

PROCESS FOR THE PREPARATION OF ANDROSTENONE DERIVATIVES FIELD OF THE INVENTION

The present invention provides a process for the preparation of androstenone derivatives; specifically 3- oxo-4-aza-5a-androstene- l 7P-carboxylic acid of formula I, a key intermediate for dutasteride.

Formula I

The present invention also provides an improved and efficient process for preparation of pure dutasteride.

BACKGROUND OF THE INVENTION

Dutasteride, chemical ly known as 17P-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-4-aza-5a-androst- l -en-3-one, has structure of formula,

is useful in the treatment of androgen responsive and mediated diseases. It is a selective inhibitor of type I and type 2 isoforms of steroid 5a-reductase (5 AR), an intracellular enzyme that converts testosterone to 5a-dihydrotestosterone (DHT). It is used for the treatment of prostate disease such as prostate cancer, acne, male pattern baldness, hirsutism, and prostate gland enlargement.

Dutasteride and related compound were first disclosed in U.S. patent no. 5,565,467. The patent discloses two methods for synthesis of dutasteride. According to first method, dutasteride is prepared by reaction of 3-oxo-4-androstene-17 -carboxylic acid with a halogenating agent such as thionyl chloride or oxalyl chloride in the presence of pyridine as base followed by condensation of coiresponding acid chloride compound with 2,5-bis(trifluoromethyl)aniline to form an amide intermediate which is isolated by column chromatography. The amide intermediate is then oxidized using sodium permanganate and sodium periodate to give 5-oxo-A-nor-3,5-secoandrostan-3-oic acid, which is then reacted with aqueous ammonia in ethylene glycol to from 17 -M-[2,5-bis(trifluoromethyl) phenyl]carbamoyl-4-aza-androst- 5-en-3-one which is isolated by column chromatography. The above intermediate is then hydrogenated to yield l 7P-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-4-aza-5a-androstane-3-one, which upon dehydrogenation in the presence of dehydrogenating reagent such as 2,3-dichloro-5,6-dicyano-l ,4- benzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide in dry dioxane as solvent gives dutasteride which is also isolated by column chromatography and crystallized from a mixture of ethyl acetate: heptane.

According to second method, dutasteride is prepared by three step sequence of reaction, starting from 3- oxo-4-aza-5a-androstene-17P-carboxylic acid of formula I which on treatment with halogenating agent such as thionyl chloride in pyridine provides the corresponding acid chloride derivative followed by condensation with 2,5-bis (trifluoromethyl)aniline to yield dutasteride.

The processes described in above patent involve the use of pyridine as a base as well solvent during acid chloride formation, which exhibits unpleasant odour. Further, process involves isolation of most of intermediates as well as dutasteride by column chromatography which is considered to be time consuming and tedious process, thereby makes the process not amenable from industrial point of view. US patent 5,998,427 discloses preparation of dutasteride and its analogues from 3-oxo-4-aza-5a- androstene-17p-carboxylic acid of formula 1 by the following scheme:

wherein R is 2,5-bis(trifluoromethyl)phenyl group

3-Oxo-4-aza-5a-androstene-17P-carboxylic acid used for the reaction is in turn prepared by hydrolysis of the corresponding alkyl ester by treatment with a moderate to strong base such as metal hydroxide in a protic or aprotic solvent such as dioxane/waler. It has been observed that intermediate of formula 1 prepared by the above described process contains a number of impurities which are difficult to remove from the product and may get carried over to final API i.e. dutasteride.

An article, namely, Journal of Medicinal Chemistry, 1986, Vol. 29, No. 11 pp. 2298-2315, discloses a process for the preparation of compound of formula I, a key intermediate of dutasteride by hydrolysis of methyl 3-oxo-4-aza-5a-androstene-17 -carboxylate in presence of potassium hydroxide in a mixture of methanol: water. It is also mentioned that product obtained after hydrolysis, is a mixture of desired compound of formula I and its corresponding methanol adduct in 1 : 1 ratio, which could not be resolved at this stage. Resolution of mixture requires derivatisation followed by chromatographic separation, thus yield of the desired compound obtained is very low. The process is very lengthy, since it involves the steps of hydrolysis, derivatisation, and separation by chromatography followed by conversion of the obtained derivative in to intermediate of formula I, thus adding three extra steps to the process. Process involves chromatographic separation which is time consuming thus cannot be applied for large-scale synthesis.

Another article, namely, Organic Process Research & Development, 2007, 11, 842-845 discloses a process for the synthesis of compound of formula 1 by hydrolysis of methyl 3-oxo-4-aza-5a-androstene- 17p-carboxyIate in presence of caustic lye in water and methanol, mixture. Product obtained after the hydrolysis is found to be impure and yield is very low, thereby making the process unsuitable for industrial scale.

Purity of intermediate is very important in the field of pharmaceutical chemistry. Therefore intermediates used for the synthesis of pharmaceutically active ingredient need to be pure and free from impurities or impurities must be present in acceptable amounts. Impurities present in the intermediates may get carry forward to final API i.e. dutasteride, thus control of impurities at intermediate stage is necessary and also a critical issue to pharmaceutical industry. The presence of unwanted chemicals, even in small amounts may influence the efficacy and safety of the pharmaceutical products. So, International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities. Also, regulatory authorities worldwide insist that drug manufacturers should isolate, identify and characterize the impurities present in the products. Moreover, it is required to control the levels of these impurities in the drug compound obtained by the manufacturing process and to ensure that the impurity must be present at the lowest possible levels, even if the identification of the impurity is not possible.

All the prior art references involve basic hydrolysis of ester intermediate of formula II for preparation of compound of formula I. As described above, most of the processes result in impure compound of formula I which contain a number of impurities and is difficult to purify. We have not found any reference wherein preparation of compound of formula I from corresponding ester other than using basic hydrolysis is described. In view of the above, there is a need to provide an improved process for the preparation of compound of formula I, which gives product with high purity and preferably free from impurities or impurities are present in acceptable amount. Thus, the present invention fulfills the need in the art and provides a process for the preparation of androstenone derivatives such as intermediate of formula I, which avoids the formation of impurities and makes it suitable to use as intermediate for the synthesis of pharmaceutical drug molecules such as dutasteride. The present invention also provides an industrially advantageous process for the preparation of highly pure dutasteride.

3

SUBSTITUTE SHEET RULE 26 OBJECTIVE OF THE INVENTION

It is the foremost objective of the present invention to provide an industrially advantageous and efficient process for the preparation androstenone derivatives, specifically 3-oxo-4-aza-5a-androstene-17P- carboxylic acid of formula 1.

Another object of the present invention is to provide a process for the preparation of 3-oxo-4-aza-5a- androstene-17p-carboxylic acid of formula I that circumvents the generation of impurities in final API i.e. dutasteride.

Another object of the present invention is to provide a process for the preparation of highly pure dutasteride having less than 0.15 % of identified impurities and/or less than 0.10% of unidentified impurities.

Another object of the present invention is to provide a chloro impurity of dutasteride.

Still another object of the present invention is to isolate and identify chloro impurity.

Yet another object of the present invention is to provide a process for removal of chloro impurity from dutasteride.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an industrially advantageous and efficient process for preparation of 3-oxo-4-aza-5a-androstene- 17 -carboxylic acid of formula I,

Formula I

a key intermediate for the synthesis of dutasteride, comprising steps of:

a), providing ester in

Formula II

wherein Ri is selected from alkyl, aryl or aralkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl, substituted benzyl, phenyl, substituted phenyl and the like

b). hydrolyzing the same in the presence of a suitable acid;

c). isolating 3-oxo-4-aza-5a-androstene- 17P-carboxylic acid of formula I; and

d). optionally, purifying 3-oxo-4-aza-5a-androstene- 17P-carboxylic acid of formula I.

SUBSTITUTE SHEET (RULE 26 According to another embodiment, the present invention provides a process for the preparation of dutasteride, comprising steps of:

a), hydrolyzing ester intermediate of formula II using a suitable acid to form 3-oxo-4-aza-5a- androstene-17P-carbox lic acid of formula I;

b). optionally, isolating 3-oxo-4-aza-5a-androstene-l 7p-carboxylic acid of formula I;

c) . activating 3-oxo-4-aza-5a-androstene- l 7p-carboxylic acid of formula I with a suitable activating reagent to form intermediate of formula 111,

Formula III

d) . condensing intermediate of formula I I I with 2,5-bis(trifluoromethyl)aniline in the presence of a suitable Lewis acid;

e) . isolating dutasteride from the reaction mixture; and

f) . optionally, purifying dutasteride.

According to another embodiment, the present invention provides a process for the preparation of dutasteride, comprising steps of:

a), dehydrogenating intermediate of formula IV,

Formula IV wherein Ri is as defined above

to form ester intermediate of formula II;

b) . hydrolyzing ester intermediate of formula II using a suitable acid to form 3-oxo-4-aza-5a- androstene-1 7P-carboxylic acid of formula I;

c) . optionally, isolating 3-oxo-4-aza-5a-androstene- 17P-carboxylic acid of formula I;

d) . activating 3-oxo-4-aza-5a-androstene- 17P-carboxylic acid of formula I with a suitable activating agent to form intermediate of formula I II;

e) . condensing intermediate of formula I I I with 2,5-bis(trifluoromethyl)aniline in the presence of a suitable Lewis acid;

f) . isolating dutasteride from the reaction mixture; and

g) . optionally, purifying dutasteride. According to another embodiment, the present invention provides a novel chloro impurity of formula V:

Formula V

According to another embodiment, present invention provides a process for the removal of impurity of formula V from dutasteride, comprising the steps of:

a), providing a solution of dutasteride containing impurity of formula V;

b) . treating with dehydrohalogenating agent, and

c) . isolating pure dutasteride from the reaction mixture.

According to another embodiment, the present invention provides highly pure dutasteride having less than 0.15 % of identified and/or less than 0.10% of unidentified impurities.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of androstenone derivatives, specifically 3- oxo-4-aza-5a-androstene-17P-carboxylic acid of formula I, a key intermediate for dutasteride, by the acidic hydrolysis of corresponding ester intermediate.

Generally, the process involves hydrolysis of ester intermediate of formula II in the presence of a suitable acid at a temperature of 0 to 100 °C for few minutes to several hours. Suitable acid employed for the reaction can be organic acid which includes carboxylic acid such as trifluoroacetic acid, formic acid and the like; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like; or inorganic acid selected from sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like or combination thereof. Usually, the reaction can be carried out at a temperature of 10 to 50 °C for 10 minutes to 12 hours, preferably till the completion of the reaction. The reaction completion can be monitored by suitable chromatographic techniques such as thin layer chromatography (TLC), high- pressure liquid chromatography (HPLC), Gas chromatography (GC) or ultra-pressure liquid chromatography (UPLC) and the like. After completion of reaction, the resulting intermediate of formula 1 can be isolated from the reaction or can be preceded as such for the next step. Specifically, the intermediate of formula 1 can be isolated by the adding reaction mixture to cold water or crushed ice followed by optional stirring. Intermediate of formula I thus precipitated can be isolated from the resulting mixture by filtration, centrifugation, decantation and the like.

It is highly advantageous to perform hydrolysis reaction in the presence of a suitable acid as product obtained by acidic hydrolysis is pure. It is observed that the product formed using basic hydrolysis has very low purity (approx 70-80 %) as it contains number of impurities. The main reason for the formation of impurities may be due to presences of hydroxide or alkoxide anion generated from the alkali or alkaline metal hydroxide or alkoxide base used for the reaction and/or alkoxide anion generated from the use of alcoholic solvent. The hydroxide and/or alkoxide anion generated during basic hydrolysis reaction may undergo Michael addition reaction on α,β-unsaturated double bond present in acid compound of formula I as well ester intermediate of formula II which will results in several by product in the reaction mixture and thus makes the product impure. Impurities thus generated during basic hydrolysis were found to be very difficult to remove from the intermediate of formula I via crystallization using several solvent or by acid base treatment. Some of the impurities are found to be carboxylic acid derivatives, which will react with reagents, used for the conversion of intermediate of formula II into dutasteride, resulting in impurities in final compound i.e. dutasteride. Such impurities are very difficult to remove at final stage since they possess structural features similar to that of dutasteride. Therefore, the present invention provides a process for the preparation of intermediate of formula I which circumvents the formation of impurities and provides pure intermediate of formula I having impurities in acceptable amounts or free from identified as well as identified impurities. The present invention circumvents the generation of hydroxide or alkoxide and provides an efficient method for the synthesis of acid compound of formula I by carrying out reaction in a suitable acid. Further, the present invention avoids the use of alcoholic solvent.

Intermediate of formula I, thus prepared may be optionally purified to further enhance the purity of product and to remove unreacted ester intermediate of formula II, if present. Preferably, intermediate of formula I can be purified by salt formation that forms a novel part of the invention.

Generally, the process involves reaction of intermediate of formula I with a suitable base at a temperature -25 to 100 °C for 5 minutes to 24 hours, preferably till completion of salt formation. Suitable base includes amines, such as primary, secondary or tertiary amine which may be selected from the group consisting of Ci_-8 alkyl amine such as methylamine, ethylamine, n-propylamine, n-butyl amine, dicyclohexyl amine , ammonia and the like. Preferably ammonia can be used for the salt formation. Salt formation can be carried out in the presence of a suitable solvent such as water, halogenated solvents such as dichloromethane, chloroform, 1 ,2-dichlorethane; C_3-6 ester such as methyl acetate, ethyl acetate, n-propyl acetate, C₄-8 aliphatic ether such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, dibutyl ether; aromatic solvent such as toluene, xylene and the like or mixture thereof. Inorganic base may be optionally added to solution of intermediate of formula I prior to addition of suitable amine used for the salt formation. Inorganic base employed includes alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. A suitable solvent can be added to the reaction mixture to make a biphasic system. Suitable water immiscible solvent can be added to extract impurities from the reaction mixture, such as unreacted intermediate of formula II. Solvent used for the extraction can be same as used for the reaction or different and can be selected from the list of solvents as given above. Purpose of adding water immiscible solvent is to remove impurities, so manner and order of addition of solvent does not have impact on the purity and yield of the desired product. Solvent can be added during the salt formation or after salt formation to remove impurities. The amine salt of intermediate of formula I can be isolated from the resulting aqueous layer or can be in situ treated with a suitable acid to give purified intermediate of formula I. Specifically, resulting aqueous layer can be treated with a suitable acid at a temperature of -10 to 100 °C for few minutes to 6 hours, preferably till reaction mixture attains pH 1 to 2; more preferably till the complete precipitation of the product. Suitable acids include organic acid such as acetic acid, formic acid and the like; inorganic such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and the like. Purified intermediate of formula I can be isolated from resulting reaction mixture by suitable techniques such as filtration, centrifugation, decantation and the like.

3-Oxo-4-aza-5a-androstene-17P-carboxylic acid of formula I, thus prepared, displays purity of more than 97.5 %, preferably more than 99.0 %, more preferably more than 99.9 % by HPLC. 3-Oxo-4-aza- 5ot-androstene-^-carboxylic acid of formula I may contain unidentified as well as identified impurities including unreacted intermediate of formula II less than 0.15 % by HPLC; more preferably free from these impurities.

Intermediate of formula I_fprepared by the process of present invention can be converted to dutasteride of formula I by formation of reactive derivative of acid intermediate followed by its reaction with 2,5- bis(trifluoromethyl)aniline in presence of Lewis acid that further forms the novel feature of the invention.

Generally, process involves reaction of intermediate of formula I with a suitable activating reagent at a temperature of -5 to 80 °C for few minutes to few hours to form a reactive derivative of formula III.

Organic solvent includes halogenated solvent such as dichloromethane, chloroform, 1 ,2-dichloroethane; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane, diethyl ether; aliphatic or aromatic solvent such as toluene, xylene and the like or mixture thereof.

Suitable activating reagents include thionyl chloride, phosphorus pentachloride, or oxalyl chloride and the like. It is preferable to employ the reaction using thionyl chloride. Usually the reaction can be carried out at a temperature of -5 to 80 °C for 2 to 12 hours, preferably till the completion of the reaction.

Reaction completion can be monitored by several chromatographic techniques as described above. After completion of reaction, intermediate of formula 111 may be isolated from the reaction mixture after

8

SUBSTITUTE SHEET RULE 26 recovery of solvent under anhydrous condition or can be in situ proceeded for the next stage, preferably used as such in situ for further reaction.

Intermediate of formula III can be condensed with bis(trifluoromethyl)aniline in the presence of a Lewis acid to form dutasteride of formula I.

Generally, process involves condensation of intermediate of formula III with bis(trifluoromethyl)aniIine in the presence of a suitable Lewis acid at a temperature of -5 to 80 °C for few minutes to several hours. Preferably, reaction can be carried out at a temperature of 20 to 50 °C for 12 to 24 hours, more preferably till the completion of the reaction. Lewis acids which may be employed in the present invention includes a catalyst from the group consisting of boron trifluorideetherate, boron trichloride, aluminium trichloride, titanium tetrachloride, tin (IV) chloride, ferric chloride, zinc chloride, cerium chloride, ruthenium chloride and the like. Most preferably borontrifluoride etherate is used for the condensation reaction. The reaction can be carried out in a solvent selected from halogenated solvent such as dichloromethane, chloroform, 1 ,2-dichloroethane; ethers such as 1 ,2-diethoxyethane, 1 ,2- dimethoxyethane, tetrahydrofuran, 2-methyl tetrahydrofuran and the like or mixture thereof. The reaction may be carried out at a temperature in the range of 20 to 90 °C, preferably 60-80 °C. Completion of the reaction is monitored by various chromatographic techniques such as HPLC, GC, TLC or UPLC and the like. After completion of reaction, the reaction mixture can be quenched with a suitable quenching agent, wherever required. Quenching agent employed for the reaction is selected from water, a suitable base which includes alkali or alkaline metal hydroxide, carbonate or bicarbonates thereof such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium chloride and the like. Organic layer containing desired compound may be optionally washed with a suitable base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Dutasteride can be isolated from the resulting reaction mixture using suitable techniques that can be used for solvent removal such as evaporation, distillation etc.

Product of a chemical reaction is rarely a single product; similarly dutasteride may contain certain impurities. As is known in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and by identifying the parameters that influence the amount of impurities in the final product. One of the major impurities, that may be generated during the synthesis of dutasteride from intermediate of formula I, has been identified as chloro impurity of formula V.

The main reason for the formation of this impurity is the presence of impurity of formula VI,

Formula VI

in the reaction mixture containing intermediate of formula III. Impurity of formula VI may be generated during the reaction of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid of formula I with activating reagent which results in the generation of impurity of formula VI and/or impurity of formula VII,

Formula VII along with desired intermediate of formula III. The impurity of formula VI may be generated by the reaction of insitu generated intermediate of formula III and/or impurity of formula VII with activating agent. Impurity of formula VI, thus generated, further reacts with 2,5- bis(triflouromethyl)aniline to form chloro impurity of formula V.

Chloro impurity of formula V can be isolated from the reaction mixture by suitable chromatography method such as preparative high pressure liquid chromatography, column chromatography, preparative thin layer chromatography and the like or it can be prepared in higher proportions by the synthetic procedure such as reaction of intermediate of formula I with a suitable halogenating agent such as phosphorus pentachloride followed by reaction with 2,5- bis(triflouromethyl)aniline. Thus isolated or synthesized impurity of formula V can be characterized by various spectroscopic techniques like Ή Nuclear magnetic resonance (Ή - NMR)and ^l C Nuclear magnetic resonance (¹³C- NMR), Ultraviolet spectroscopy (UV), Mass spectrometry (MS), Infrared spectroscopy (IR) and the like. The isolated impurity of formula V of the present invention is characterized by following spectral data:

Ή-NMR δ (CDCb): 0.78 (3H, s, CH₃); 1 .01 (3H, s, CH₃); 1 .05-2.44 ( 16H, m, 6CH₂ &.3CH); 2.78 (1 H, d, CH); 2.94-3.05 1 H, dd, CH__axial); 3.60-3.64 ( 1 H, dd, CH _«,^ι); 4.26 (1 H, d, CH); 5.99 ( 1 H, bs, CONH); 7.43-7.49 (2H, m, Ar-H); 7.78 (1 H, d, Ar-H) and 8.76 ( I H, s, CONH)

Mass analysis: displays M+l peak at 565.02

As it is known, that impurities in pharmaceuticals are unwanted chemicals that may be present in the active pharmaceutical ingredients (APIs), may generate during its synthesis as by products or may form during formulation, or upon aging of both API and formulated APIs to medicines. Presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products. Various pharmacopoeias, such as the British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP), require that API either have impurities in allowable limits or preferably be free from impurities. Therefore, in order to comply with regulatory requirements, the present invention provides a method to minimize the impurity of formula V from the final product by its conversion to dutasteride. Dutasteride of formula I may be optionally purified by treatment with a dehydrohalogenating reagent to remove impurity of formula V.

Specifically, process involves the treatment of mixture of dutasteride and chloro impurity of formula V with a suitable dehydrohalogenating reagent, in a suitable solvent at a temperature of 0 to 150 °C for few minutes to several hours. The amount of impurity of formula V that may be present in crude dutasteride can vary from 0.2 % to 35 %. Suitable dehydrohalogenation reagent includes 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and the like; or amine bases such as pyridine, triethyl amine, diisopropyl ethyl amine, tri-isopropyl amine, tri n-butyl amine and the like; or inorganic base which includes alkali or alkaline metal hydroxides, carbonats, bicarbonates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium, carbonate, sodium carbonate, sodium bicarbonate, - potassium bicarbonate, lithium carbonate, cerium carbonate; and the like or combination thereof. Solvents used can be selected from aprotic solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,2- diethoxyethane, 1 ,2-dimethoxyethane, and the like or mixture thereof. The reaction can be carried out in the presence of a metal halide to enhance the kinetics of the reaction. Metal halides used for reaction include monovalent or divalent metal halides such as an alkali metal, and alkaline earth metal or a suitable transition element metal. Particularly suitable metals include lithium, sodium, calcium and the like. The preferred metal is lithium. The halide may be anions such as chloro, fluoro, bromo or iodo. The preferred halides are chlorides and bromides. The most preferred metal halides are lithium chloride, sodium chloride, calcium chloride and the like. Usually, the reaction mass can be stirred at a temperature of 10 to 120 °C for 30 minutes to 12 hours, preferably till complete conversion of chloro impurity of formula V to dutasteride take place. Reaction completion can be monitored by suitable chromatographic techniques such as HPLC, TLC, UPLC and the like. After completion of the reaction, purified dutasteride of formula I can be isolated from the reaction mixture employing conventional methods known in the art. Preferably, reaction mixture can be diluted with water to precipitate purified dutasteride which can be isolated by a suitable technique such as filtration, centrifugation or decantation and the like. Alternatively, dehydrohalogenating agent with or without metal halide can be added to the reaction mixture during condensation reaction of intermediate of formula III with 2,5-bis(trifluoroniethyl)aniline to prepare dutasteride which is free from chloro impurity or present in acceptable amounts.

Dutasteride of formula I thus obtained is found to contain less than 0.15 % of impurity of formula V, preferably free from the impurity of formula V. The process of present invention is highly advantageous as simple crystallization, using different solvents, found to be effective for the removal of impurity of formula V. The present invention provides a method which avoids multiple crystallization (huge yield loss) and hence minimum yield loss takes place for removal of impurity of formula V from the resulting product. Further, the present invention provides a method of removal of impurity by its conversion to dutasteride and thus enhancement in yield..

Dutasteride, if desired, can be optionally purified to remove identified as well as unidentified impurities present in the final product. Any suitable purification method can be employed for the purification depending upon the nature of impurities present. According to one method, dutasteride can be optionally purified by treating dutasteride in a solvent with thionyl chloride.

Specifically, purification involves treatment of dutasteride with thionyl chloride in a suitable organic solvent at a temperature of -20 to 50 °C for few minutes to 1 to 3 hours, preferably at a temperature of 25 to 40 °C for 60 minutes. Suitable solvents include C_2-6 nitriles such as acetonitrile, propionitrile, butyl nitrile; C^sesters such as methyl acetate, ethyl acetate, propyl acetate, n-propyl acetate and the like or mixture thereof. For the purpose of purification, either dutasteride in a solvent can be treated with thionyl chloride or dutasteride can be treated with thionyl chloride in a solvent. The order as well as manner of combining the reactant or solvent has no impact on the process and purity of dutasteride. Thereafter, reaction mixture can be optionally cooled to 20 to 25 ⁰ C and stirred for 1 to 3 hours. Purified dutasteride can be isolated from the resulting mixture by suitable techniques such as filtration, centrifugation or decantation and the like. This purification is highly efficient in removing des methyl impurity of following formula, if present.

It is found that des methyl impurity may be present in some samples of dutasteride up to 0.2 to 0.5 % by HPLC which can be efficiently removed by the above purification method and makes the product either free from des methyl impurity along with other impurities or contain less than 0.15 % by HPLC. According to another method, dutasteride can be purified by treating the solution containing dutasteride with a suitable base.

Specifically, purification involves dissolution of dutasteride in a suitable solvent at a temperature of 10 to 70 °C followed by treatment of the resulting solution with a suitable base. Suitable base employed includes alkali or alkaline metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Preferably the base employed as aqueous solution of alkali or alkaline metal hydroxides. Suitable solvent used for the dissolution of dutasteride includes halogenated solvent such as dichloromethane, chloroform, 1 ,2-dichloroethane and the like. Purpose of treating solution of dutasteride with a base is to remove impurities, which have acid functionality such as intermediate of formula 11 along with other impurities. Such impurities will eliminate in form of their alkali or alkaline metal salts from the solution. Organic layer can be optionally washed with water and/or dried over suitable drying agent. Purified product can be isolated from the resulting solution by the removal of solvent by suitable techniques such as evaporation, distillation and the like.

According to still another method, dutasteride can be purified using a suitable solvent or solvent mixture thereof.

Specifically, the process involves dissolution of dutasteride in a suitable solvent or solvent mixture thereof. Suitable solvent employed can be selected from halogenated solvents such as dichloromethane, chloroform, 1 ,2-dichloroethane; ester such as ethyl acetate, n-propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate; and the like or mixture thereof. Preferably, the solution of dutasteride in halogenated solvent can be distilled off to remove the solvent completely or partially. If complete removal of solvent is desired, then another solvent may be added to the reaction mixture followed by distillation (partial or complete) to ensure the complete removal of halogenated solvent. Thereafter, resulting product can be precipitated from the remaining reaction mixture either by lowering the temperature or by the addition of anti solvent such as aliphatic hydrocarbons such as n-heptane, n- pentane or n-hexane. In another method, the resulting mass obtained after removal of the halogenated solvent (partial or complete) may be purified by addition of ethyl acetate followed by addition of aliphatic hydrocarbon to give pure dutasteride. Similarly, dutasteride may be purified using the solvent in any sequence and in any manner.

Dutasteride can be purified optionally with one or more purification methods as described by the present invention. In order to purify dutasteride same purification method can be repeated or can be combined with other purification methods.

Dutasteride obtained by the process of present invention is highly pure and contains identified impurities such as des methyl dutasteride, intermediate of formula I, chloro impurity of formula V and/or • unidentified impurities less than 0.15%, preferably less than 0.05%; more preferably free from impurities. Dutasteride may have purity more than 99.0 %, preferably more than 99.5 %, more preferably 99.99% by H PLC.

The starting compound of formula 11 can be procured from the commercial sources or can be prepared by any method known in the art or by the method described herein for the reference.

Specifically, ester intermediate of formula II can be prepared from compound of formula IV by dehydrogenation. The process involves reaction of compound of formula IV with a suitable dehydrogenating reagent, for the incorporation of double bond, in a suitable solvent at a temperature of 80 to 150 °C for few minutes to 12 hours. Preferably, reaction mixture can be earned out at a temperature of 100 to 120 °C till the completion of the reaction. Suitable reagents can be selected from the reagent known in the art that serve the purpose of incorporation of double bond in compound of formula IV. Preferably dehydrogenating reagent can be selected from mixture of 2,3-dichIoro-5,6- dicyano-l ,4-benzoquinone and bis(trimethylsilyl) trifluoroacetamide and the like or combination thereof. Suitable solvents includes aliphatic or aromatic hydrocarbons such as toluene, 1 ,2-xylene, 1 ,4-xylene; aprotic solvent such as dimethylformamide, dimethylsulfoxide, dimethylacetamide; ether such as dioxane, 1 ,2-diethoxyethane, 1 ,2-dimethoxyethane, and the like or mixture thereof. After completion of reaction, intermediate of formula II can be isolated from the reaction mixture or can be used as such for the further reaction. Preferably, after completion of the reaction, reaction mass can be optionally cooled to 15 to 30 °C for 20 minutes to 3 hours. Reaction mixture can optionally be quenched with a suitable quenching agent, wherever required. Suitable quenching agent includes sodium sulfite, sodium meta- bisulfite and the like. Thereafter, reaction mixture can be filtered to remove any insoluble particulate followed by layer separation. The resulting aqueous layer can be optionally extracted with a suitable solvent same as used for carrying out the reaction. It is preferable to wash the organic layer with sodium bisulfite and/or water or can be charcoalized. Intermediate of formula II can be isolated from the resulting solution using techniques such as evaporation, distillation and the like.

Intermediate of formula II can be optionally purified employing a suitable purification method such as using a solvent or treatment with a suitable acid.

According to one method, intermediate of formula II can be purified using a suitable solvent.

Specifically, a solution of intermediate of formula II in a suitable solvent can be stirred at a temperature of 10 to 70 °C for few minutes to 12 hours. Preferably, mixture can be stirred at a temperature of 30 to 60 °C for 3 hours. Suitable solvent includes aliphatic esters such as ethyl acetate, n-propyl acetate, n-butyl acetate; alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof. Intermediate of formula 11 can be isolated from the mixture using suitable techniques such as filtration, centrifugation, decantation and the like.

According to another method, intermediate of formula 11 can be purified by treating solution of intermediate of formula II in a solvent with a suitable acid.

Specifically, intermediate of formula 11 in a solvent is treated with a suitable acid at temperature of 10 to 80 °C for few minutes to 12 hours. Preferably, mixture can be stirred at a temperature of 25 to 60 °C for 3 hours. Suitable acid includes hydrochloric acid, sulfuric acid, nitric acid and the like or combination thereof. Preferably acid employed for the reaction is used as aqueous solution. Suitable solvent includes aliphatic esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate; alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof. Intermediate of formula II can be isolated from the mixture using suitable techniques such as filtration, centrifugation, decantation and the like. Purification processes described by present invention are efficient in removing dichloro dicyano dihydroquinol (DDHQ) which is formed as by product in the reaction as well as unreacted dichlorodicyano quininone (DDQ) and other impurities that may be present. Intermediate of formula 11 can be purified by employing one or more purification by repeating the same purification method or in combination with other. Intermediate of formula II thus obtained is highly pure in nature and have purity more than 98 % by HPLC, preferably more than 99.0%, more preferably 99.5 % by HPLC.

Major advantage of the present invention is to provide a process for the synthesis of highly pure 3-oxo-4- aza-5a-androstene- I 7p-carboxylic acid of formula I having impurities in acceptable amount or free from the impurities. Another advantage of the present invention is to provide a new method for hydrolysis of ester intermediate of formula II using a suitable acid. The present invention also provide highly pure dutasteride having chloro impurity, des methyl impurity, intermediate of formula 1 or any other identified impurity less than 0.15 % or free from these impurities.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Reference example: Preparation of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid

To a suspension of methyl-3-oxo-4-aza-5-a-androstene-17p-carboxylate (7.65 g) in in methanol (96 ml) at 20-30 °C , potassium hydroxide (3 g in 15 ml water) was added and the reaction mixture was refluxed at 70-75 °C for 5 hours. After completion of the reaction (monitored by TLC), reaction mass was cooled to 5-10°C and IN hydrochloric acid solution was added till reaction mixture attains pH 2. Solid thus precipitated was filtered and dried under vacuum for 10 hours at 50-55 °C to give 5.1 g of title compound having purity 59.99 % by HPLC and containing number of by products out of which three major impurities are 21.95%, 10.71 % and 5.15% by HPLC.

EXAMPLES

Example 1: Preparation of methyl-3-oxo-4-aza-5a-androstene-17p-carboxylate

To a mixture of methy 1-3 -oxo-4-aza-androstane-17p-carboxy late (300 g) and 2,3-dichloro-5,6-dicyano benzoquinone (249g) in toluene (3L) under nitrogen gas atmosphere, N,0-bis-(trimetylsilyl)trifluoro acetamide (870 g) was added drop wise at 25-30 °C and stirred for 6 hours. The reaction mixture was heated to 105-1 10°C for 12 hours. After the completion of reaction, reaction mixture was cooled to 20- 30°C and 10% sodium sulfite solution (750 ml) was added to the reaction mixture. The reaction mixture was stirred for 25-30 minutes at 20-30 °C. The aqueous layer was extracted with toluene (300 ml). Combined organic layer is successively washed with 10% sodium bisulfite solution (750 ml), water (750ml) and charcoalised. Solvent was distilled off under vacuum at 60-65°C to give 255 g of title compound having purity 85.5 % by HPLC.

Example 2: Preparation of methyl-3-oxo-4-aza-5a-androstene-17p-carboxylate

To a mixture of methyl-3-oxo-4-aza-androstane-17P-carboxylate (300 g) and 2,3-dichloro-5,6- dicyanobenzoquinone (249 g) in toluene (3 L) under nitrogen gas atmosphere, N,0-bis- (trimetylsilyl)trifluoroacetamide (870 g) was added drop wise at 25-30 °C and stirred for 6 hours. The reaction mixture was heated to 105-1 10°C for 6 hours. After completion of reaction, reaction mixture was cooled to 20-30°C and 10% sodium sulfite solution (750 ml) was added and stirred for 25-30 minutes. Layers were separated and aqueous layer was extracted with toluene (100 ml). Combined organic layer is successively washed with 10% sodium bisulfite solution and water (750 ml) and charcoalised. The reaction mixture was filtered through hyflow bed and bed was washed with toluene (2x150 ml). Solvent was distilled off under vacuum at 60-65°C. The resulting residue was stirred in ethyl acetate (750 ml) at 25-30 °C for 30 minutes, filtered and dried for 30 minutes. The resulting product was stirred in a mixture of ethyl acetate (2.5 L) and cone, hydrochloric acid (2.5 L) at 40-45 °C for 60 minutes, filtered and successively washed with, water (2 x 250 ml), 8 % sodium bicarbonate solution (250 ml), water (2 x 250 ml). The resulting product was dried at 60-65 °C to give 216 g of title compound having purity 99.65 % by HPLC.

Example 3: Preparation of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid

Concentrated sulfuric acid (1000 ml) was added to methyl-3-oxo-4-aza-5a-androstene-17P-carboxylate (200 g) at 20-30°C and stirred for 3 hours. After completion of reaction (monitored by HPLC), reaction mass was poured into crushed ice and stirred for 1.5 hours. The precipitated solid was filtered, washed with cold water (2 x 100 ml) and dried to give 176.2 g of title compound having purity 97.66 % by HPLC.

Example 4: Preparation of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid

Concentrated sulfuric acid (1000 ml) was added slowly to methyI-3-oxo-4-aza-5a-androstene- 17P- carboxylate (200 g) at 20-30°C and stirred for 3 hours. After the completion of the reaction (monitored by HPLC), reaction mass was poured into crushed ice and stirred for 1.5 hours at 0-5°C. The precipitated solid was filtered, washed with cold water (5 x 400 ml) and dried for 60 minutes. The resulting solid was dissolved in a 20-25 % ammonia solution (250 ml) and extracted with dichloromethane (2 x 100 ml) followed by layer separation. Aqueous layer was cooled to 0-5°C and acidified to pH 1 -2 by the addition of cone, hydrochloric acid (approx. 600 ml). Reaction mixture was stirred for 60 minutes at 0-5°C, filtered, washed with water (4 x 250 ml) and dried at 40-45 °C to give 159.32 g of title compound having purity 99.75 % by HPLC.

Example 5: Preparation of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid

Concentrated sulfuric acid (1000 ml) was added slowly to methyl-3-oxo-4-aza-5a-androstene- 1 7P- carboxylate (200 g) at 20-30°C and stirred for 3 hours. After completion of the reaction (monitored by HPLC), reaction mass was poured into crushed ice stirred for 1.5 hours at 0-5°C. The precipitated solid was filtered, washed with cold water (5 x 400 ml) and dried for 60 minutes. The resulting product was suspended in cold water (1000 ml) at 5-10 °C and pH was adjusted to approx. 6.0-6.5 by the addition of 10 % sodium hydroxide. Thereafter, 20-25 % ammonia solution (250 ml) was added to the resulting mixture till pH 13-14. Reaction mixture was extracted with dichloromethane (2 x 250 ml) followed by layer separation. Aqueous layer was cooled to 0-5°C and acidified till pH 1 -2 by addition of cone, hydrochloric acid (approx. 600 ml). The reaction mixture was stirred for 60 minutes at 0-5°C, filtered, washed with water (4x 250 ml) and dried at 40-45 °C to 155 g of title compound having purity 99.85 % by HPLC.

Example 6: Preparation of 3-oxo-4-aza-5a-androstene-17p-carboxylic acid

Concentrated sulfuric acid (1 125 ml) was added to methyI-3-oxo-4-aza-5-alpha-androstene- 17-beta- carboxylate (225 g) at 20-30°C stirred for 3 hours. After completion of reaction, reaction mass was poured into crushed ice and stirred for 1.5 hours at 0-5°C. The precipitated solid was filtered, washed with water (2x 100 ml) and dried for 60 minutes. The resulting solid was suspended in dichloromethane (100 ml) at 0-5 °C followed by addition of 10-12% sodium hydroxide till pH 6.0-6.5. Thereafter, 20- 25% ammonia solution was added to the. reaction mixture till pH 13-14. Organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The aqueous layer was cooled to 0-5°C and acidified to pH 1 -2 by addition of cone, hydrochloric acid and stirred for 60 minutes at 0-5°C. The

17

SUBSTITUTE SHEET RULE 26 resulting solid was filtered, washed with water (4x 250 ml) and dried to give 189.20 g of the title compound having purity 99.81 % by HPLC as white crystalline solid.

Example 7: Preparation of dutasteride

To a solution of 3-oxo-4-aza-5a-androstene-17P-carboxylic acid (135g, 0.426 mol) in dichloromethane (1620 ml) at 25-30 °C under nitrogen gas atmosphere, thionyl chloride (60.85 g) in dichloromethane (67.5 ml) was added for 30 minutes. After completion of reaction (monitored by HPLC), borontriflouoride etherate (90.7 g) was added to reaction mixture for 10-15 minutes at 25-30 °C and stirred for 1 hour. Thereafter, bis(trifluoromethyl)aniline ( 102.39 g, 0.447 mol) was added to the reaction mixture and heated to 40-42 °C. Reaction mixture was refluxed for 12 hours and quenched by addition of 10% ammonium chloride solution followed by stirring. Layers were separated and the organic layer was successively washed with 2% sodium hydroxide solution (945 ml) and brine. Resulting organic layer was dried over sodium sulfate and solvent was removed under vacuum to give thick oily mass having purity 94.62 %; chloro impurity: 3.38%; des methyl impurity: 0.22%; intermediate of formula I: 0.28 %; and bis(trifluoromethyI)aniline: 1.5 % by HPLC.

Dry dimethylformamide (675 ml), lithium chloride (1.7 g) and l ,8-diazabicyclo[5.4.0]undec-7-ene (5.44 g) were added to the resulting residue and stirred for 2-3 hours at 40 °C. Thereafter, water (2.43 L) was added to reaction mixture and stirred for 30 minutes. Resulting product was filtered, washed with water (300 ml) and dried for 30 minutes to give dutasteride having purity 98.50 %; chloro impurity: 0.02%; des methyl impurity: 0.08 %; intermediate of formula I: 0.14 and bis(trifluoromethyl)aniIine: 0.5 % by HPLC.

Acetonitrile ( 1350 ml ) and thionyl chloride (67.5 ml) were added to resulting product and stirred at 40- 45 °C for 60 minutes. Reaction mixture was cooled to 25-30 °C and stirred for 60 minutes. The resulting solid was filtered and dried for 30 minutes to give dutasteride having purity 99.64%; chloro impurity: not detected; des methyl impurity: 0.08 ; intermediate of formula I: 0.03 % and bis(trifluoromethy!)aniline: not detected by HPLC.

The resulting solid was dissolved in dichloromethane ( 1350 ml) and was successively washed with 1 % sodium hydroxide solution (540 ml), and brine solution (945 ml), dried over sodium sulfate and filtered through hyflow bed. Dichloromethane was distilled off at atmospheric pressure to give residue having purity 99.88 %; chloro impurity: not detected; des methyl impurity: not detected; intermediate of formula I: 0.01 % by HPLC.

Ethyl acetate (2970 ml) was added to the resulting residue and was partially distilled off under vacuum at 50-60 °C. n- Heptane (405 ml) was added to the reaction mixture at 50-55 °C. The reaction mixture was stirred for 60 minutes, cooled to 10-15 °C stirred for 2 hours, filtered and dried under vacuum at 70-75 °C for 12 hours to give 148.5 g of dutasteride having purity: 99.90 %; chloro impurity: not detected; des methyl impurity: not detected; intermediate of formula 1: 0.01 % and bis(trifluoromethyl)aniline: not detected by HPLC.

Example 8: Preparation of dutasteride

Thionyl chloride (60.85 g) in dichloromethane (62.5 ml) was added to 3-oxo-4-aza-5a-androstene- l 7P- carboxylic acid (135 g) in dichloromethane (1620 ml) at 25-30°C for 30 minutes. After completion of the reaction (monitored by HPLC), borontriflouoride etherate (90.7 g) was added for 10-15 minutes at 25-30 °C, and reaction mixture was stirred for 1 hour. Thereafter, bis(trifluoromethyl)aniline (1 16.51 g ) was added to the reaction mixture and refluxed for 12 hours. The reaction was cooled at 0-5 °C and quenched by adding 10% ammonium chloride solution to the reaction mass, stirred for 10 minutes and layers were separated. The organic layer was successively washed with 3% sodium hydroxide solution (945 ml) and brine solution (675 ml) and dried over sodium sulfate. Dichloromethane was distilled off at 40-45 °C under atmospheric pressure to give thick oily mass to which dimethylformamide (675 ml), lithium chloride (1.79g ) and 1 ,8-diazabicyclo [5.4.0]undec-7-ene (4.7 lg) were added. The reaction mixture was stirred for 2-3 hours at 40 °C. After the completion of reaction (monitored by HPLC, absence of chloro impurity), water (2.43 L) was added to the mixture and stirred for 30 minutes. The precipitated solid was filtered, washed with water (3 x 135 ml) and dried for 30 minutes. To the wet solid, acetonitrile (1350 ml) and thionyl chloride (45 ml) were added and stirred at 40-45 °C for 60 minutes. Reaction mass was cooled to 25-30 °C and stirred for 60 minutes. The resulting solid was filtered and dried for 30 minutes. The wet solid was dissolved in dichloromethane (1350 ml) and successively washed with 1.0% sodium hydroxide solution ( 540 ml) and brine solution (945 ml), dried over sodium sulfate, filtered through hyflow bed. A portion of dichloromethane layer (135 ml) was used as such for the isolation of pure dutasteride.

Example 9: Purification of dutasteride

Method A: Dichloromethane was completely distilled off under atmospheric pressure from the resulting organic layer at 38-45 °C. Ethyl acetate (250 ml) was added to the residue thus obtained and heated to 70-80 °C to dissolve the material. Ethyl acetate (~ 90 %) was distilled off under vacuum at 50-60 °C and n-heptane (40 ml) was added to the reaction mass. The reaction mass was slowly cooled to 15-20 °C and stirred for 2 hours. The resulting solid was filtered, washed with cold ethyl acetate (10 ml) and n- heptane (10 ml) and dried under vacuum at 75-80 °C to give 14.85 g of title compound having purity 99.90 % by HPLC.

Method B] Dichloromethane was distilled off (-80 %) under atmospheric pressure from the resulting organic layer. A mixture of ethyl acetate (135 ml) and n-heptane (135 ml) was added at 30-35 °C to the resulting mixture and the, mixture was stirred for 60 minutes. The reaction mass was slowly cooled to 1 -20 °C and stirred for 2 hours. The resulting solid was filtered, washed with n-heptane and dried under vacuum at 60-65 °C for 12 hours to give 13.62 g of the title compound having purity 99.86 % by HPLC. By following similar procedure, 14.1 g of dutasteride having purity 99.80 % by HPLC was obtained by replacing mixture of ethyl acetate and n-heptane with pure ethyl acetate.

Method C: Dichloromethane was distilled off (~80 %) under atmospheric pressure from the resulting organic layer. A mixture of ethyl acetate (135 ml) and n-heptane (135 ml) was added at 30-35 °C to the resulting mixture followed by complete removal of dichloromethane and the mixture was stirred for 60 minutes at 30-35 °C. The reaction mass was cooled to 15-20 °C and stirred for 2 hours. The resulting solid was filtered, washed with n-heptane and dried under vacuum at 60-65 °C for 12 hours to give 12.65 g of the title compound having purity 99.90 % by HPLC.

By following similar procedure, 13.1 1 g of dutasteride having purity 99.73 % by HPLC was obtained by replacing mixture of ethyl acetate and n-heptane with ethyl acetate.

Method D: Ethyl acetate (50 ml) was added to the dichloromethane layer followed by complete distillation of dichloromethane and the mixture was stirred for 60 minutes at 30-35 °C. The reaction mixture was cooled to 15-20 °C and stirred for 2 hours. The resulting solid was filtered, and dried under vacuum at 60-65 °C to give 13.55 g of the title compound having purity 99.93 % by HPLC.

By following similar procedure, 12.9 g of dutasteride having purity 99.67 % by HPLC was obtained by replacing ethyl acetate with mixture of ethyl acetate and n-heptane.

Claims

WE CLAIM:

1) . A process for the preparation of 3-oxo-4-aza-5a-androstene-l 7p-carboxylic acid of formula 1,

Formula I

comprising the steps of:

a) , providing ester intermediate of formula II,

Formula II

wherein Ri is selected fro alkyl, aryl or aralkyl

b) . hydrolyzing the same in the presence of a suitable acid;

c) . isolating 3-oxo-4-aza-5a-androstene-17p-carboxylic acid of formula I; and

d) . optionally, purifying 3-oxo-4-aza-5a-androstene-17p-carboxylic acid of formula I.

2) . The process according to claim I , wherein in step b) suitable acid is organic acid and inorganic acid.

3) . The process according to claim 2, wherein organic acid is selected from carboxylic acid such as trifluoroacetic acid, formic acid and the like; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like;

4) . The process according to claim 2, wherein inorganic acid is selected from sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like or combination thereof

5) . The process according to claim 1 , wherein suitable acid is preferably sulfuric acid.

6) . The process according to claim 1 , wherein in step d) compound of formula I is purified by amine salt formation.

7) . A process for the preparation of dutasteride, comprising the steps of:

a), dehydrogenating intermediate of formula IV,

Formula IV wherein R_/ is as defined above

to form ester intermediate of formula II,

b) . hydrolyzing ester intermediate of formula II using a suitable acid to form 3-oxo-4-aza-5a- androstene-17P-carboxylic acid of formula I,

c) . optionally, isolating 3-oxo-4-aza-5a-androstene-17 -carboxylic acid of formula I;

d) . activating 3-oxo-4-aza-5a-androstene-17P-carboxylic acid of formula I with a suitable activating agent to form intermediate of formula HI,

Formula III

e) . condensing intermediate of formula III with 2,5-bis(trifluoromethyl)aniline in the presence of a suitable Lewis acid;

f) . isolating dutasteride from the reaction mixture; and

g) . optionally, purifying dutasteride of formula I.

8) . The process according to claim 7, wherein in step a) dehydrogenating agent includes 2,3-dichloro-

5,6-dicyano-l ,4-benzoquinone and bis(trimethylsilyl) trifluoro acetamide and the like or combination thereof;

9) . The process according to claim 7, wherein in step b) suitable acid is organic acid selected from carboxylic acid such as trifluoroacetic acid, formic acid and the like; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like; or inorganic acid such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like or combination thereof. .

10) . The process according to claim 7, wherein in step d) activating agent is selected from thionyl chloride, phosphorus pentachloride, or oxalyl chloride and the like;

11) . The process according to claim 7, wherein in step e) Lewis acid catalyst selected from boron trifluorideetherate, boron trichloride, aluminium trichloride, titanium tetrachloride, tin (IV) chloride, ferric chloride, zinc chloride, cerium chloride, ruthenium chloride and the like.

12) . A chloro impurity of formula V,

Formula V 13). A process for the removal of impurity of formula V from dutasteride, comprising the steps of: a) , providing dutasteride containing impurity of formula V in a suitable solvent;

b) . treating the mixture with dehydrohalogenating agent, and

c) . isolating pure dutasteride from the reaction mixture.

14). The process according to claim 13, wherein in step a) a suitable solvent is aprotic solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,2-diethoxyethane, 1 ,2-dimethoxyethane;

15). The process according to claim 13, wherein in step b) dehydrohalogenating agent is selected from l ,8-diazabicyclo[5.4.0]undec-7-ene and the like; or amine bases such as pyridine, t iethyl amine, diisopropyl ethyl amine, tri-isopropyl amine, tri n-butyl amine and the like; or inorganic base which includes alkali or alkaline metal hydroxides, carbonats, bi carbonates thereof such as lithium, sodium or potassium hydroxide; potassium, sodium, cerium or lithium carbonate; sodium or potassium bicarbonate; and the like or combination thereof.