Process for the preparation of 17C1-6-substituted-3-oxo-4-aza-5a-androstane derivatives, which are useful intermediates for the synthesis of 3-oxo-4-aza-5a-androst-1-ene derivatives including finasteride is provided.
Chemically, finasteride is N-tert-butyl-3-oxo-4-aza-5a-androst-1-ene-17|3-carboxamide and is known from US patent number 4,760,071. It is a 5a-reductase inhibitor, which plays an important function in many androgen-sensitive tissues by converting the major circulating androgenic hormone, testosterone, into the more potent intracellular androgenic metabolite dihydrotestosterone (DHT). Finasteride is used in the treatment of hyperandrogenic conditions, such as acne vulgaris, seborrhea, female hirsutism and benign prostate hypertrophy. Several processes have been reported for the preparation of finasteride such as US 4,377,584; US 4,760,071; US 5,084,574; US 5,237,061; US 5,120,847; US 5,670,643; US 5,021,575; US 6,509,466; WO 02/46207; J. Med. Chem., 1986, 29, 2298-2315; J. Med. Chem., 1984, 27, 1690-1701; and Heterocycles, 1998,47, 703.
All the reported references disclose the conversion of 17|3-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acid to 17ß-substituted-3-oxo-4-aza-5a-androstane derivative in two steps. J. Med. Chem., 1984, 27, 1690; J. Med. Chem., 1986, 29, 2298 and US 4,377,584 disclose the use of methylamine or liquid ammonia in the presence of ethylene glycol or ethanol for the ring closure of 17ß-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acid to get corresponding 17P-substituted-3-oxo-4-aza-5a-androst-5-ene derivative. In all the above references, the product was isolated and then hydrogenated in the presence of platinum oxide in acetic acid to obtain the corresponding 17p-substituted-3-oxo-4-aza-5a-androstane derivative. Heterocycles, 1998,47, 703 reports the use of ammonium acetate in the presence of acetic acid for the ring closure reaction and the product was isolated, which was then hydrogenated in the presence of palladium-carbon in acetic acid to obtain 17ß-substituted-3-oxo-4-aza-5a-androstane derivative. An alternate method for reducing 17ß-substituted-3-oxo-4-aza-5a-androst-5-ene derivative is given in Heterocycles, 1998,47, 703 in which formic acid and potassium carbonate are used in DMF for reduction to obtain the 17ß-substituted-3-oxo-4-aza-5a-androstane derivative. WO 02/46207 teaches the use of ammonium salt of lower alkyl carboxylic acids in the catalytic hydrogenation process.
. Med. Chem., 1984, 27, 1690 and US 4,377,584 disclose the preparation of N-alkyl-3-oxo-5a-androst-4-ene-17ß-carboxamide comprising reacting 3-oxo-5a-androst-4-ene-17ß-carboxylic acid with oxalyl chloride, pyridine and corresponding alkyl amine. Heterocycles, 1998,47, 703 discloses the use of thionyl chloride, pyridine and corresponding alkyl amine for the preparation of N-alkyl-3-oxo-4-aza-5a-androst-4-ene-17ß-carboxamide. WO 03/27132 reports the use of pivaloyi chloride with tertiary butyl amine in the presence of a base for the conversion of androst-4-en-3-one-17ß-carboxylic acid to 17ß(N-tert-butylcarbamoyl)-androst-4-ene-3-one.
In one aspect, a one pot process for the preparation of 17ß-substituted-3-oxo-4-aza-5-α-androstane derivative of formula I, as shown in the accompanied drawings, wherein R represents hydrogen; hydroxyl; C1-6 straight or branched chain alkyl;C1-6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, C1-6 straight or branched chain alkyl, aryl or arylalkyi; comprising reacting compound of formula II as shown in the accompanied drawings, wherein R is as defined above, with an ammonium salt in a suitable solvent followed by further reaction after addition of formic acid, is provided.
In another aspect, a process for the preparation of N-alkyl-3-oxo-4-aza-5a-androst-4-ene-17P-carboxamide of formula III, as shown in the accompanied drawings, wherein R1 represents C1-6 straight or branched chain alkyl, comprising reacting 3-oxo-4-aza-5-a-androstene-17ß-carboxylic acid of formula IV with phosphorous oxychloride and alkyl amine of formula R1NH2, wherein R1 is as defined above in the presence of pyridine, is provided.
The one pot synthesis of compound of formula I from the compound of formula II gives good yields and avoids time consuming workup procedures used for isolating 17|3-substituted-3-oxo-4-aza-5a-androst-5-ene derivative of formula VI as shown in the accompanied drawings, wherein R is as defined above.
In some particular examples R represents N-tertiary-butyl carboxamide.
Examples of ammonium salts include ammonium formate, ammonium acetate, ammonium propionate, ammonium sulfate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium chloride, ammonium bromide, ammonium iodide and ammonium fluoride.
Suitable solvents for the reaction of compounds of formula II with ammonium salt are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include glycols such as ethylene glycol or propylene glycol; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof.
Temperature for the reaction of compound of formula II with ammonium salt is not critical and the reaction may be performed at temperatures of from room temperature to about 220°C. The reaction may be performed at temperatures of from about 150°C to about 180°C in some particular embodiments.
In the preparation of N-alkyl-3-oxo-4-aza-5a-androst-4-ene-17p-carboxamide, examples of alkyl group of alkyl amine include C1-6 straight or branched chain alkyl group. In some particular embodiments, tertiary butyl amine is used.
The reaction of compounds of formula IV with phosphorous oxychloride, pyridine and alkyl amine may performed in an inert solvent. Examples of such solvents include hydrocarbon such as benzene, xylene, toluene, heptane, hexane, cyclohexane or octane; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof.
Temperature for the reaction of compound of formula IV with phosphorous oxychloride, pyridine and alkyl amine may be in the range of from about -10°C to about room temperature. The reaction may be performed at temperatures of from about -10°C to about 10°C in some particular embodiments.
17p-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acid of formula II may be prepared by the conventional methods described in prior art including Heterocycles, 1998,47, 703; WO 02/46207 and US 4,377,584 which are incorporated herein by reference. In general, It may be prepared by oxidizing 17ß-substituted-3-oxo-4-aza-5a-androst-4-ene-derivatives, for example with sodium periodate and potassium permanganate, or using ozone. In some particular embodiments 17ß-substituted-3-oxo-4-aza-5a-androst-4-ene-derivative may be the compound of formula VII, as shown in the accompanied drawings, wherein R1 is as defined above, which may be prepared from oxidation of compound of formula III. The compound of formula III, in turn, may prepared by the process comprising reacting compound of formula IV with phosphorous oxychloride and alkyl amine of formula R1NH2, wherein R1 is as defined above in the presence of pyridine, as described herein.
17p-substituted-3-oxo-4-aza-5a-androstane derivative of formula I may be further converted to 3-oxo-4-aza-5-a-androst-1-ene derivative of formula V, as shown in the accompanied drawings, wherein R is as defined above by methods described in the literature including US 5120847; US 5084574; US 5021575; WO96/12034; J. Med. Chem., 1986, 29, 2298; and J. Med. Chem., 1984, 27, 1690 which are incorporated herein by reference.
In general, it may be converted by refluxing the compound of formula I with benzeneseleninic anhydride in chlorobenzene.
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the artExample-1
Preparation of N-tert-butyl-3-oxo-5a-androst-4-ene-17p-carboxamlde:
A solution of 3-oxo-4-androst-4-ene-17p-carboxylic acid (50 g, 2.37 mmol) in toluene (700 ml) was refluxed azeotropically to remove moisture. Reaction mixture was then cooled to room temperature and pyridine (13 g, 2.411 mmol) was added to it. It was now cooled to 0 to 5°C and treated with phosphorous oxychloride (32 g, 3.13 mmol), maintaining anhydrous condition under nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. Tertiary butylamine (159.9 g, 19.989 mmol) was then added at 0 to 5°C and was stirred for 15 minutes. It was then warmed to room temperature and was stirred for 3 hours at the same temperature. Reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through hyflo and filtrate was washed twice with distilled water (500 ml each) and 10% aqueous sodium chloride solution (500 ml each). Toluene was recovered completely under reduced pressure at 40-45°C and residue was treated with hexane (197 ml) to crystallize the title product. The product was filtered, washed with hexane (50 ml) and dried under reduced pressure. Yield: 54.8 g
Exampie-2
Preparation of 17p-(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5-secoandrostane-3-oic acid:
A solution of N-tert-butyl-3-oxo-5a-androst-4-ene-17p-carboxamide (50 g, 2.153 m mol) in a mixture of tertiary butanol (1.5 I) and aqueous solution of sodium carbonate (22 g in 80 ml distilled water) was treated with a solution of sodium periodate (200 g, 14.961 mmol) and potassium permanganate (2 g, 0.202 mmol) in distilled water (1.5 I) at 35 - 45°C. Reaction mixture was stirred for 12 hours at 35 - 45°C. Reaction was monitored by TLC. After completion of reaction, reaction mixture was filtered and filtrate was again treated with sodium carbonate (2 g) and filtered. Tertiary butanol was recovered under reduced
pressure at 50 - 60°C. Concentrated mixture was diluted with distilled water (750 ml). It was then treated with activated carbon (5 g), filtered through hyflo and filtrate was treated with 6N-hydrogen chloride (pH ~2) to precipitate the title product. The product was filtered, washed with distilled water and dried under reduced pressure Yield: 40.1 g
Example-3
Preparation of N-tert-butyl-3-oxo-4-aza-5a-androstane-17p-carboxamide via N-tert-butyl-3-oxo-4-aza-5a-androst-4-ene-17p-carboxamide:
A solution of 17p-(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5-secoardrostane-3-oic acid (50 g, 1.532 mmol) and ammonium formate (100 g, 19.029 mmol) in ethylene glycol (375 ml) was stirred at room temperature for 2 hours. Reaction mixture was gradually heated to 160 - 170°C and was stirred for 4 hours at the same temperature. Reaction was monitored by TLC. After completion of reaction, formic acid (150 ml) was added at 70 -SOX. After addition of formic acid reaction mixture was gradually heated to 140 - 150°C and was stirred for 12 hours at the same temperature. Reaction was monitored by TLC. After completion of reaction, reaction mixture was quenched by distilled water (1.75 I) and stirred for 30 minutes. Product crystallized out at this stage. The product was filtered and washed with distilled water. This wet solid was dissolved in dichloromethane (350 ml) and water layer was separated. Dichloromethane solution was then treated with activated carbon (5 g). It was filtered through hyflo and dichloromethane was recovered completely under reduced pressure at 35 - 40°C. Residue was stirred with ethyl acetate to crystallize the product. The product was filtered, washed with ethyl acetate and dried under reduced pressure. Yield: 19.4 g
Example-4
Preparation of N-tert-butyl-3-oxo-4-aza-5a-androst-1 -ene-17p-carboxamide (Finasteride):
A suspension of N-tert-butyl-3-oxo-4-aza-5a-androstane-17p-carboxamide (50 g, 0.534 mmol) and benzeneseleninic anhydride (100 g, 1.11 mmol) in toluene (1.5 I) was refluxed for 18 hours at 110 - 112°C. Reaction was monitored by HPLC. After completion of reaction, toluene was completely recovered under reduced pressure at 45 - 55°C. Resulting residue was dissolved in dichloromethane (600 ml) and washed twice with 10% aqueous sodium hydroxide solution and then with 10% aqueous sodium chloride solution. Dichloromethane layer was separated, concentrated and residue was crystallized by refluxing it with hexane for 30 minutes. The above hot mixture was filtered at 60 - 65°C and obtained solid was washed with hot hexane. This wet solid was dissolved in dichloromethane (400 ml) and again washed with 10% aqueous sodium hydroxide and 10% aqueous sodium chloride solution. Dichloromethane layer was separated and treated with activated carbon (5 g) and neutral alumina (10 g). It was then filtered through hyflo and dichloromethane was recovered completely from the filtrate under reduced pressure at 35 - 40°C. The residue was crystallized by refluxing it in hexane for 30 minutes. The hot mixture was filtered at 60 - 65°C, washed with hot hexane and dried under reduced pressure. Yield: 25.6 g

WE CLAIM:
1. A one pot process for the preparation of 17p-substituted-3-oxo-4-aza-5a-androstane derivative of formula I, as shown in the accompanied drawings, wherein R represents hydrogen; hydroxyl; C1-6 straight or branched chain alkyl; C1-6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, C1-6 straight or branched chain alkyl, aryl or arylalkyi; comprising reacting compound of formula II as shown in the accompanied drawings, wherein R is as defined above, with an ammonium salt in a suitable solvent followed by further reaction after addition of formic acid.
2. A process for the preparation of N-alkyl-3-oxo-4-aza-5a-androst-4-ene-17p-carboxamide of formula III, as shown in the accompanied drawings, wherein R1 represents C1-6 straight or branched chain alkyl, comprising reacting 3-oxo-4-aza-5a-androstene-17ß-carboxylic acid of formula IV with phosphorous oxychloride and alkyl amine of formula R1NH2, wherein R1 is as defined above in the presence of pyridine
3. The process according to claim 1, wherein R is N-tertiary-butyl carboxamide.
4. The process according to claim 1, wherein ammonium salt is selected from the group consisting of ammonium formate, ammonium acetate, ammonium propionate, ammonium sulfate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium chloride, ammonium bromide, ammonium iodide and ammonium fluoride.
5. The process according to claim 1, wherein suitable solvent is selected from the group consisting of glycols, alkyl ethers, alcohols, ketones, chlorinated hydrocarbons, esters, nitriles, dipolar aprotic solvents, cyclic ethers and mixtures thereof.
6. The process according to claim 5, wherein glycol is selected from the group consisting of ethylene glycol, propylene glycol and mixtures thereof.
7. The process of preparing compound of formula I according to claim 1, wherein the compound of formula II is compound of formula VII, as shown in the accompanied drawings, wherein R1 is as defined above.
8. The process of preparing compound of formula I according to claim 7, wherein the compound of formula VII is prepared by oxidizing the compound of formula III.
9. The process of preparing compound of formula I according to claim 8, wherein the compound of formula III is prepared by the process of claim 2.

10.The process according to claim 2, wherein the reaction is performed in an inert solvent, selected
from the group consisting of alkyl ethers, alcohols, ketones, nitriles, chlorinated hydrocarbons,
esters, hydrocarbons, dipolar aprotic solvents, cyclic ethers and mixtures thereof. 11.The process according to claim 10, wherein hydrocarbon is selected from the group consisting of
benzene, xylene, toluene, heptane, hexane, cyclohexane, octane and mixtures thereof. 12.The process as claimed in claim 1 or 9, further comprising conversion of compound of formula I,
wherein R is as defined above to compound of formula V, as shown in the accompanied
drawings, wherein R is as defined above. 13.The process as claimed in claim 12, wherein the conversion to compound V is achieved by the
reaction of compound of formula I with benzeneseleninic anhydride. 14.The process as claimed in claim 12, wherein compound of formula V is N-tertiary-butyl-3-oxo-4-
aza-5a-androst-1 -ene-17ß-carboxamide. 15.The process for preparing compound of formula I as herein described and illustrated by the
examples herein.