Field of the Invention:

The present invention relates to an improved process for the preparation of N-tert-buyl-3-oxo-4-aza-5a-androst-l-ene-17p-carboxamide and it's intermediate. N-tert-buyl-3-oxo-4-aza-5a-androst-l-ene-17p-carboxamide is commonly known as Ministered and is represented by the following structural formula-1.

Ministered is a 5a-reductase inhibitor, which function in many androgen-sensitive tissues by converting the major circulating androgenic hormone, testosterone, into the intracellular androgenic metabolite dihydrotestosterone. Ministered is marketed under the brand name of PROSCAR for the treatment of hyper androgenic conditions, such as acne vulgarism, seborrhea and benign prostate hypertrophy.

Background of the Invention:

Ministered and process for its preparation is disclosed in US 4760071. In general, process for the preparation of ministered involves the introduction of 1,2-double bond by dehydrogenation either in the final stage or intermediate stage. Dehydrogenation reaction in US 4760071 was carried out using benzeneselenic anhydride in refluxing chlorobenzene. The said process is not suitable for commercial production as it involves the usage of highly toxic material like benzeneselenic anhydride.

US patent 5116983 discloses a process wherein the 1,2-double bond was introduced by refluxing with 2,3-dichloro-5,6-dicyano-4-benzoquinone(DDQ) and bis(trimethylsilyl)trifluoroacetamide(BSTFA) in dioxin for longer hours. Even though the said process provides good yields, the usage of BSTFA in high mole ratio and tedious workup procedure and long duration of maintenance increases the cost of production as well as time cycle for the its preparation and makes it difficult to produce in commercial scale.

Moreover the prior art processes involves tedious workup procedure at dehydrogenation reaction. For example involves repeated washings of the reaction mixture (approximately 12 to 15 times) with sodium sapphire solution and aqueous basic solution at higher. temperature in order to remove the byproducts and process impurities formed after reaction completion. It makes the process difficult to carry out at industrial level as it increases the time cycles and effluent wastes also not recommendable in safety point of view as the washing carried out at higher temperature. Hence there is a need in the art for an improved process with good yields, purity and simple workup procedure.

Brief Description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of fmasteride compound of formula-l, which comprises of reacting N-tert-buyl-3-oxo-4-aza-5a-androst-l-ane-17P-carboxamide compound of formula-2 with 2,3-dichloro-5,6-dicyano-4-benzoquinone (herein after referred as "DDQ") and bis(trimethylsilyl)trifluoroacetamide (herein after referred as "BSTFA") in the presence of trimethylsilylchloride in a suitable solvent to provide mastered compound of formula-l.

The second aspect of the present invention is to provide an improved process for the preparation of 3-oxo-4-aza-5a-adrost-l-ene-17β-carboxylic acid compound of formula-3, which comprises of reacting the 3-oxo-4-aza-5a-adrost-l-ane-17P-carboxylic acid compound of formula-4 with DDQ and BSTFA in the presence of trimethylsilylchloride in a suitable solvent to provide the compound of formula-3.

The third aspect of the present invention is to provide an improved process for the purification of finasteride compound of formula-l.

The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-I of fmasteride.

Advantageous of the Present Invention:
• Decrease the usage of costly reagent such as BSTFA there by reduces the oost of production compared to the prior art reported process.
• Usage of TMS-Cl increases the rate of reaction thereby decrease the time cycle of the reaction. Decrease of time cycle reduces the economics of the production.
• Avoids number of aqueous sodium sulphite washings of the reaction mixture at higher temperature there by reduces the time cycle and avoids the generation of effluent.
• Commercially viable process with good yield and purity
Detailed Description of the Invention:
Accordingly the first aspect of the present invention provides an improved process for the preparation of finasteride compound of formula-1,

which comprises of reacting the N-tert-buyl-3-oxo-4-aza-5a-androst-l-ane-17P-carboxamide compound of formula-2 with2,3-dichloro-5,6-dicyano-4-benzoquinone(DDQ) and bis(trimethylsilyl)trifluoro acetamide(BSTFA) in the presence of trimethylsilylchloride(TMSCl) in a suitable solvent, characterized in that the BSTFA is used in the mole ratio of 3 moles or less with respect to the compound of formula-2.
Further the process for the preparation of finasteride compound of formula-1 of the present invention may comprises of the followings steps,

a) Treating the N-tert-buyl-3-oxo-4-aza-5a-androst-l-ane-17P-carboxamide compound of formula-2 in a suitable solvent with DDQ, BSTFA and TMSCl imder nitrogen atmosphere and stirred,
b) heating the reaction mixture and stirring,
c) cooling the reaction mixture,
d) adding aqueous sodium sulphite having pH in the range of 7-8 at 60-65°C and stirred,
e) separating the layers at 60-65 °C,
f) distilling off the solvent completely from organic layer under reduced pressure,
g) adding suitable solvent and distilled off the solvent completely,
h) adding a suitable solvent,
i) heating the reaction mixture and stirred, j) adding aqueous basic solution at 25-35°C and stirred,
k) filtering the solid, washed with a suitable solvent and then dried to get the compound offormula-4.
In a preferred embodiment, the preparation of finasteirde compound of formula-1 comprises of the followings steps,
a) Treating the N-tert-buyl-3-oxo-4-aza-5a-androst-l-ane-17p-carboxamide compoimd of formula-2 in toluene with DDQ, BSTFA and TMSCl at 25-30°C under nitrogen atmosphere and stirred,
b) heating the reaction mixture to 90-95°C and stirring it for 18-20 hours,
c) cooling the reaction mixture to below 65-70°C,
d) adding aqueous sodium sulphite having pH in the range of 7-8 at 60-65°C and stirred,
e) separating the layers at 60-65°C,
f) distilling off the solvent completely from toluene layer under reduced pressure,
g) adding toluene and distilled off then adding cyclohexane and distilled off the solvent completely,

h) adding tetrahydrofuran at 25-30°C, i) heating the reaction mixture to 40-45 °C and stirred, j) adding aqueous sodium hydroxide solution at 25-35°C and stirred, k) filtering the solid, washed with water followed by aqueous acetic acid solution and then dried to get finasteride compound of formula-1.
The second aspect of the present invention provides an improved process for the preparation of 3-oxo-4-aza-5α-adrost-l-ene-17β-carboxylic acid compound of formula-3,

which comprises of reacting the 3-oxo-4-aza-5α-adrost-l-ane-17P-carboxylic acid compound of formula-4
with DDQ and BSTFA in the presence of trimethylsilylchloride in a suitable solvent, characterized in that the BSTFA is used in the mole ratio of 3 moles orless with respect to the compound of formula-3.
As per the prior art process disclosed in US 5116983 for the preparation of compound of formula-1 and formula-3 involves the reaction of N-tert-buyl-3-oxo-4-aza-5α-androst-l-ane-17β-carboxamide or 3-oxo-4-aza-5α-adrost-l-ane-17β-carboxylic acid with DDQ and BSTFA (used in 4 moles per 1 mole of N-tert-buyl-3-oxo-4-aza-5α-androst-l-ane-17β-carboxamide or 3-oxo-4-aza-5α-adrost-l-ane-17β-carboxylic acid) in dixoane medium. The reaction initially maintained for 22 hours at room temperature and

then quenched with cyclohexane-l,3-dione and stirred for 3 hours. The resultant solution was heated to reflux and maintained for 20 hours. The reaction mixture was cooled and treated with aqueous sodium bisulfite solution and methylene chloride and treated with hydrochloric acid. The heterogeneous mixture obtained was filtered and layers were separated from the filtrate. Methylene chloride layer was washed with sodium hydroxide solution and then distilled off. Isopropyl acetate was added and distilled and the obtained suspension was cooled to get compound of formula-1 or formula-3 respectively. The said process involves the usage of BSTFA in high molar ratio (4 moles) with respect to starting compound of formula-2. BSTFA is very costly raw material and usage of the same in high mole ratio increases the cost of production. Moreover the said process involves tedious work up procedure and maintenance for longer hours increases the cost of production, time cycle and makes the process commercially not suitable.
We the present inventors working on the same reaction to reduce the amount of BSTFA as well as reduce the tedious workup procedure and time cycles; after conducting various experiments we surprisingly found that the above reaction was carried out in presence of catalytic amount of TMSCl reduces the amount of BSTFA used in the reaction and there by reduces the cost of production. TMSCl is a very cheap and commercially readily available. The present invention also avoid the initial maintenance of 22 hours at room temperature and 3 hours after quenching as carried out in the prior art thereby reduces the time cycle and tedious workup procedure associated with it. Hence the present invention is more advantageous than the prior art process by reducing the cost as well as the time cycle of product and make it commercially viable.
The suitable solvent used for the reaction in the present invention is selected from hydrocarbon solvents like toluene, xylene, heptane and cyclohexane. The solvent used for workup procedure, isolation and purification is selected from alcohol solvents like methanol, ethanol, isopropanol; ester solvents like ethyl acetate, methyl acetate and isopropyl acetate; keto solvents like acetone, methyl isobutyl ketone and ether solvent like tetrahydrofuran and their mixtures.

The process for the preparation of 3-oxo-4-aza-5a-adrost-l-ene-17P-carboxylic acid compound of formula-3 of the present invention may comprises of the foUowings steps,
a) Treating the 3-oxo-4-aza-5a-adrost-l-ane-17P-carboxylic acid compound of fonnula-4 in a suitable solvent with DDQ, BSTFA and TMSCl under nitrogen atmosphere and stirred,
b) heating the reaction mixture and stirring,
c) coollng the reaction mixture,
d) distilling off the solvent completely under reduced pressure,
e) adding suitable solvent and distilled off the solvent completely,
f) adding a suitable solvent and stirred,
g) cooling the reaction mixture and stirred,
h) filtering the solid, washed with a suitable solvent and then dried to the compound of formula-4.
In a preferred embodiment, the process for the preparation of 3-oxo-4-aza-5a-adrost-l-ene-17p-carboxylic acid compound of formula-3 comprises of the foUowings steps,
a) Treating the 3-oxo-4-aza-5a-adrost-l-ane-17P-carboxylic acid compound of formula-4 in toluene with DDQ, BSTFA and TMSCl at 25-30°C under nitrogen atmosphere and stirred,
b) heating the reaction mixture to 90-95 °C and stirring it for 20 hours,
c) cooling the reaction mixture to below 65-70°C,
d) distiUing off the solvent completely under reduced pressure,
e) adding cyclohexane and distilled off foliowed by adding acetone and distilled off completely,
f) adding methanol and stirred at 25-30°C,
g) cooling the reaction mixture to 0-5 °C and stirred for an hour,
h) filtering the solid, washed with a methanol and then dried to get the compound of formula-3.

According to the present invention trimethylsilylchloride (TMSCl) is used in the mole ratio of 0.01 to 2 moles with respect to the starting compound of formula-2 or fonnula-4.
The third aspect of the present invention provides a process for the purification of finasteride compound of formula-1, which comprises of the following steps,
a) dissolving the finasteride in a suitable alcoholic solvent like methanol at 55-65°C,
b) subjecting the reaction mixture to carbon treatment and stirred,
c) filtering the reaction mixture and washing with methanol,
d) distilling off the solvent from the filtrate under reduced pressure,
e) adding ethyl acetate to the crude and distilled off completely under reduced pressure,
f) cooling the reaction mixture to 25-35°C,
g) adding a mixture of ethyl acetate and tetrahydrofuran, h) heating the reaction mixture to 45-55°C and stirred,
i) adding water to the reaction mixture at 30-35°C, j) cooling the reaction mixture to -5 to 0°C and stirred,
k) filtering the solid, washed with a mixture of ethyl acetate and tetrahydrofiiran then dried to get the pure finasteride compound of formula-l.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-I of finasteride, which comprises of the foUowing steps,
a) Suspending finasteride in a suitable solvent,
b) heating the reaction mixture to and stirred,
c) cooling the reaction mixture,
d) adding aqueous basic solution and stirred,
e) filtering the reaction mixture and washed with aqueous basic solution,
f) washing the solid with water foliowed by aqueous acid and then dried to get the crystalline form-I.
According the present aspect of the invention, the suitable base used is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide and a suitable

solvent selected from teterhydrofuran and diisopropylether and aqueous acid used is acetic acid.
In a preferred embodiment of the invention, the process for the preparation of crystalline form-1 of finasteride comprises of the foUowing steps,
a) Suspending finasteride in a tetrahydrofuran
b) heating the reaction mixture to 40-45°C and stirred,
c) cooling the reaction mixture to 25-30°C,
d) adding aqueous sodium hydroxide solution and stirred at 25-3 0°C,
e) filtering the reaction mixture and washed with aqueous sodium hydroxide solution,
f) washing the solid with water foliowed by aqueous acetic acid and then dried to get the crystalline form-I of finasteride.
Finasteride compound of formula-1 prepared according to the present invention is more than 99.00% by HPLC, preferably more than 99.30% by HPLC.
The present invention is represented by the following schemes: Scheme-1:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of finasteride:
2,3-dichloro-5,6-dicyano-4-benzoquinone (DDQ) (44 grams) in toluene was added to a mixture of N-tert-buyl-3-oxo-4-aza-5a-androst-l-ane-17P-carboxamide (60 grams), bis(trimethylsilyl)trifluoroacetamide(BSTFA)(123.5 grams), trimethylsilyl chloride (0.174 gram) in toluene (1800 ml) under nitrogen atmosphere and stirred for 15 minutes. The reaction mixture was heated to 90-95°C and stirred for 20 hours. The reaction mixture was cooled to 60-65°C and aqueous sodium sulphite solution was added at 60-65°C. The layers were separated and water was added to organic layer. The aqueous and organic layer was separated at 60-65°C. The solvent from the organic layer was distilled off completely under reduced pressure. Toluene was added to the residue and distilled off under reduced pressure. Cyclohexane was added to the residue and distilled off under the reduced pressure. Tetrahydrofuran(60 ml) was added to the residue and heated the reaction mixture to 40-45°C and stirred for 25 minutes then cooled to 25-30°C. 2% sodium hydroxide solution (360 ml) was added and stirred for 45 minutes. The solid was filtered and washed with aqueous sodium hydroxide solution, water and aqueous acetic acid to get the crude compound. Purification of finasteride:
The crude material was dissolved in methanol (400 ml) at 55-65°C. Carbon was added to it and stirred for 15 minutes at 55-65°C. The reaction mixture was cooled to 45-55°C and filtered. The filtrate was distilled off completely at below 60°C under reduced pressure. Ethyl acetate was added to the obtained residue and distilled off. The reaction mixture was cooled to 25-30°C. Ethyl acetate(50 ml) and tetrahydrofuran(50 ml) was added to the obtained residue and heated to 45-55°C then stirred for 45 min. The reaction mixture was cooled to 30-35°C and water(4 ml) was added to it. The reaction mixture was cooled to -5 to 0°C and stirred for 2 hours. The solid was filtered, washed with a mixture of ethyl acetate and tetrahydrofuran and then dried to get the pure title compound.

Yield: 50 grams;
Purity by HPLC: 99.46%; Impurity-C: 0.37% and Formula-2: 0.08%
Example-2: Preparation of 3-oxo-4-aza-5α-adrost-l-ene-17p-carboxylic acid compound of formula-3:
Bis(trimethylsilyl)trifluoroacetamide(BSTFA) (241.5 grams) was added to a mixture of 3-oxo-4-aza-5a-adrost-l-ane-17P-carboxylic acid (100 grams), trimethyl silylchloride (0.35 grams), DDQ(82.5 grams) in toluene (3000 ml) under nitrogen atmosphere at 25-30°C. The reaction mixture was heated to 95-100°C and stirred for 24 hours. The reaction mixture was cooled to 65-70°C and distilled off the solvent completed under reduced pressure. Cyclohexane was added to the obtained residue and distilled off under reduced pressure. The obtained residue was cooled and acetone(200 ml) was added to it and distilled off under reduced pressure. The obtained residue was cooled and methanol (250 ml) was added then stirred for 45 minutes at 25-30°C. The reaction mixture was further cooled to 0-5 °C and stirred for an hour. The solid formed was filtered, washed with methanol and then dried to get the title compound. Yield: 80 grams
Example-3: Preparation of crystalline form I of finasteride:
A mixture of tetrahydrofuran (200 ml) and finasteride (55 grams) was heated to 40-45°C and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C and 2% sodium hydroxide solution (360 ml) was added to it and stirred for 45 minutes. The solid formed was filtered and washed with aqueous sodium hydroxide solution, water and aqueous acetic acid then dried to get the title compound. Yield: 49.5 grams

We Claim:
1. A process for the preparation of finasteride compound of formula-1,

which comprises of reacting the N-tert-buyl-3-oxo-4-aza-5α-androst-l-ane-17β-carboxamide compound of formula-2 With 2,3-dichloro-5,6-dicyano-4-benzoquinone(DDQ)and bis(trimethylsilyl)trifluoro acetamide(BSTFA) in the presence of trimethylsilyIchloride(TMSCl) in a suitable solvent, characterized in that the BSTFA is used in the mole ratio of 3 moles or less with respect to N-tert-buyl-3-oxo-4-aza-5α-androst-l-ane-17β-carboxamide compound of formula-2.

2. A process for the preparation of 3-oxo-4-aza-5α-adrost-l-ene-17β-carboxylic acid compound of formula-3, which comprises of reacting the 3-oxo-4-aza-5α-adrost-l-ane-17β-carboxylic acid compound of formula-4 with DDQ and BSTFA in the presence of trimethylsilylchloride in a suitable solvent, characterized in that the BSTFA is used in the mole ratio of 3 moles or less with respect to the compound of formula-3.

3. A process according to claim 1 & 2, wherein the suitable solvent used is hydrocarbon solvents and is selected from toluene, xylene, hexane, cyclohexane and heptane.

4. The process for the preparation of finasteride compound of formula-l of the present invention may comprises of the followings steps,

a) Treating the N-tert-buyl-3-oxo-4-aza-5α-androst-l-ane-17β-carboxamide compound of formula-2 in toluene with DDQ, BSTFA and TMSCI at 25-30°C under nitrogen atmosphere and stirred,

b) heating the reaction mixture to 90-95°C and stirring it for 18-20 hours,

c) cooling the reaction mixture to below 65-70°C,

d) adding aqueous sodium sulphite having pH in the range of 7-8 at 60-65°C and stirred,

e) separating the layers at 60-65°C,

f) distilling off the solvent completely from toluene layer under reduced pressure,

g) adding toluene and distilled off then adding cyclohexane and distilled off the solvent completely,

h) adding tetrahydrofuran at 25-30°C,

i) heating the reaction mixture to 40-45 °C and stirred,

j) adding aqueous sodium hydroxide solution at 25-35°C and stirred.

k) filtering the solid, washed with water followed by aqueous acetic acid solution and then dried to get finasteride compound of formula-l.

5. A process for the preparation of 3-oxo-4-aza-5a-adrost-l-ene-17P-carboxylic acid compound of formula-3, which comprises of the folio wings steps,

a) Treating the 3-oxo-4-aza-5a-adrost-l-ane-17P-carboxylic acid compound of formula-4 in toluene with DDQ, BSTFA and TMSCI at 25-30°C under nitrogen atmosphere and stirred,

b) heating the reaction mixture to 90-95°C and stirring it for 20 hours,

c) cooling the reaction mixture to below 65-70°C,

d) distilling off the solvent completely under reduced pressure,

e) adding cyclohexane and distilled off followed by adding acetone and distilled off completely,

f) adding methanol and stirred at 25-30°C,

g) cooling the reaction mixture to 0-5 °C and stirred for an hour,

h) filtering the solid, washed with a methanol and then dried to get the compound of formula-3.

6. A process according to any of the preceding claims, wherein the BSTFA used in the mole ratio of 3 or less and TMSCI used in the mole ratio of 0.01 to 1 moles with respect to the starting compound of formula-2/formula-4.

7. A process for the preparation of finasteride compound of formula-l, which comprises of preparing 3-oxo-4-aza-5a-adrost-l-ene-17P-carboxylic acid compound of formula-3 according to any of the process claimed in claim 2 or 5; and converting the compound of formula-3 into finasteride.

8. Use of trimethylsilylchloride in the preparation of finasteride compound of formula-l and in the preparation of 3-oxo-4-aza-5α-adrost-l-ene-17β-carboxylic acid compound of formula-3.

9. A process for the preparation of crystalline form-1 of finasteride comprises of the following steps,

a) Suspending finasteride in a tetrahydrofuran,
b) heating the reaction mixture to 40-45 °C and stirred,
c) cooling the reaction mixture to 25-3 0°C,
d) adding aqueous sodium hydroxide solution and stirred at 25-
30°C,
e) filtering the reaction mixture and washed with aqueous solution hydroxide solution,
f) washing the solid with water followed by aqueous acetic acid and then dried to get the crystalline form-1 of finasteride.

10. A process for the purification of finasteride compound of formula-1, which comprises of the following steps,

a) dissolving the finasteride in a suitable alcoholic solvent like methanol at 55-65°C,

b) subjecting the reaction mixture to carbon treatment and stirred,

c) filtering the reaction mixture and washing with methanol,

d) distilling off the solvent from the filtrate under reduced pressure,

e) adding ethyl acetate to the crude and distilled off completely under reduced pressure,

f) cooling the reaction mixture to 25-35°C,

g) adding a mixture of ethyl acetate and tetrahydrofuran,

h) heating the reaction mixture to 45-55°C and stirred,

i) adding water to the reaction mixture at 30-35°C,

j) cooling the reaction mixture to -5 to 0°C and stirred,

k) filtering the solid, washed with a mixture of ethyl acetate and tetrahydrofuran then dried to get the pure finasteride compound of formula-1.