INTRODUCTION:

Finasteride (1), an inhibitor of 5a-reductase, was first synthesized in the 1980s.¹ Currently, finasteride is among the most effective drugs for the treatment of benign prostatic hyperplasia (BPH). A regime of 5 mg of finasteride for 3 months reduces the prostate gland’s size by 19% and increases the urine flow by 22-23%.^2,3 Thus, finasteride reverses the enlargement of the prostate, thereby improves the symptoms of BPH very effectively. In the United States, finasteride alone (brand name Proscar^(R)) generated the sale of about 360 millions USD in 2005 and is one of the most prescribed drugs for the treatment of BPH.³

To meet the high demand of finasteride of the market at a reasonable price, there is a need to implement an efficient synthesis of finasteride. Based on the literature search, there are two main routes for the synthesis of finasteride; one from 3-oxo-4-androsten-17b-carboxylic acid¹ and the other from 4-androsten-3,17-dione (AD).⁴ Since 3-oxo-4-androsten-17b-carboxylic acid is practically obtained from AD currently, we decided to choose the later route for initiation of finasteride synthesis. During the implementation process we have devised and improved the conditions of several steps to make them more cost effective and commercially more viable. Hereby the details of this study are reported.

EXPERIMENTAL:

General Procedures

All products were homogenous, as examined by thin-layer chromatography (TLC), performed on Whatman^® 250 mm Silica Gel GF Uniplates and visualized under UV light at 254 nm. Melting points were determined with an Electrothermal Melting Point apparatus and are uncorrected. Chromatographic purification was done by the open flash silica gel column chromatography using Merck silica gel 60 (240 to 400 mesh). Nuclear magnetic resonance spectra (¹H NMR) were recorded using tetramethylsilane as an internal standard on a Bruker 400 MHz spectrometer with CDCl₃ as solvent unless otherwise indicated. Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane as internal standard. Electrospray ionization (ESI) and high-resolution mass spectra were obtained using PE Biosystems API 2000 and Mariner® mass spectrometers, respectively. Electron-impact mass spectra were recorded using HP-5989B-MS. Infrared spectra were obtained by Perkin-Elmer spectrometer. Reagents and solvents were purchased from Aldrich or Fluka Chemical Corp. (Milwaukee, WI, USA) unless noted otherwise. Solvents were distilled and dried before use.

Preparation of 5,17-dioxo-A-nor-3,5-secoandrostan-3-oic acid (3)

A solution of 2 (40.0 g, 140 mmol) in a mixture of 800 mL of tert-BuOH and 120 mL of 40% aqueous Na₂CO₃ at 60^oC was treated with a solution of 169 g of sodium metaperiodate and 5.4 g of potassium permanganate in 600 mL of water at the same temperature. After addition of the reagents, the mixture was incubated at 60^oC for another 4 hours with occasional stirring. Then, the reaction mixture was cooled to 30^oC, and after 15 min, the solids were removed by filtration and washed with water. The combined filtrates were concentrated under reduced pressure to remove most of tert-BuOH. The aqueous residue was cooled and acidified (pH 2) with 15% HCl solution (~400 mL). After extraction with CH₂Cl₂ (250 ml x 2) the organic layers were combined and washed with water and dried over Na₂SO₄. Removal of solvent gave 3 (40.6 g, 94.9%) as a colorless oil. R_f = 0.38 (MeOH/DCM = 1/9). EI-MS (70 eV) m/z: 307 [(M+H)^+.], 289 [(M-OH)^+.], 260 [(M-OH-CO)^+.], 247 [(M-OH-CO-CH₃)^+.], 234 [(M-OH-CO-2CH₃)^+.], 219 [(M-OH-CO-2CH₃-O)^+.]. IR (KBr) (cm^-1): 3500-3050, 2918, 1738, 1713, 1681. ¹H NMR (CDCl₃) δ (ppm): 0.94 (s, 3H, 19-CH₃), 1.15 (s, 3H, 19-CH₃), 1.26-1.37 (4H, m), 1.55-1.66 (4H, m), 1.85-1.92 (2H, m), 1.93-2.03 (1H, m), 2.06-2.15 (3H, m), 2.17-2.36 (3H, m), 2.47-2.52 (1H, m), 2.56-2.63 (1H, m). ¹³C NMR (CDCl₃) δ (ppm): 13.73 (C18), 20.36 (C19), 20.73 (C11), 21.79 (C15), 28.99 (C8), 29.28 (C7), 29.93 (C1), 30.87 (C2), 30.96 (C16), 34.45 (C12), 35.65 (C6), 37.68 (C8), 47.61 (C9), 48.01 (C10), 50.47 (C13), 50.73 (C14), 178.23 (C3; -COOH), 214.10 (C5, -C=O), 220.08 (C17, -C=O).

Preparation of 4-aza-5-androsten-3,17-dione (4)

A mixture of 3 (37.0 g, 121 mmol) and ammonium acetate (28.0 g, 367 mmol) in 190 ml of dioxane and 10 ml of glacial acetic acid was stirred and heated at reflux for 4 h. After cooling the reaction mixture to room temperature, it was poured 400 mL of cold water with gentle stirring. The brown precipitates formed were filtered and washed with cold water. Recrystallization twice from dimethylformamide/ethanol afforded 4 (25.5 g, 73.4%) as ivory-white crystal needles. R_f = 0.63 (MeOH/DCM = 1/9). Mp > 300 ^oC. EI-MS (70 eV) m/z: 287 [(M+H)^+.], 272 [(M-CH₃)^+.], 244 [(M-2CH₃-O)^+.], 230 [(M-2CH₃-2O)^+.]. IR (KBr) (cm^-1): 3186, 2942, 2901, 2827, 1740, 1662, 1457, 1388. ¹H NMR (DMSO-d₆), δ (ppm): 0.83 (s, 3H, 18-CH₃), 1.03 (s, 3H, 19-CH₃), 1.06-1.12 (1H, m), 1.17-1.23 (1H, m), 1.29-1.36 (2H, m), 1.37-1.44 (1H, m), 1.48-1.56 (1H, m), 1.62-1.74 (4H, m), 1.81-1.88 (2H, m), 1.98-2.05 (1H, m), 2.12-2.17 (1H, m), 2.20-2.25 (1H, m), 2.29-2.36 (1H, m), 2.38-2.44 (1H, m), 4.87-4.88 (1H, m, H-6), 9.30 (broad, 1H, NH). ¹³C NMR (DMSO-d₆) δ (ppm): 13.25 (C18), 18.41 (C19), 19.79 (C11), 21.30 (C15), 28.14 (C7), 30.62 (C2), 30.92 (C12), 31.06 (C9), 33.54 (C10), 35.25 (C16), 46.91 (C1), 47.60 (C9), 50.67 (C13), 55.98 (C14), 100.69 (C6), 140.78 (C5), 167.72 (C3; -CONH), 219.45 (C17, -C=O).

Preparation of 4-aza-5-androsten-17-hydroxy-17-cyano-3-one (5)

Acetic acid (10 mL) was added to a stirred suspension of 4 (20.0 g, 69.7 mmol) and KCN (15 g) in MeOH (120 mL) at room temperature. Stirring was continued for 24 h, after which acetic acid (20 mL) and water (800 mL) were added. The precipitate was filtered, washed with water, and dried to give 5 (21.8 g, 99.4%) as white powder. R_f = 0.51 (MeOH/DCM = 1/9). EI-MS (70 eV) m/z: 315 [(M+H)^+.], 288 [(M-OH-N)^+.]. IR (KBr) (cm^-1): 3276, 2952, 2252, 1680, 1650, 1458, 1386. ¹H NMR (DMSO-d₆), δ (ppm): 0.86 (s, 3H, 18-CH₃); 1.03 (s, 3H, 19-CH₃), 1,07-1,45 (5H, m), 1,51-1,75 (6H, m), 1,82-1,95 (2H, m), 1,96-2,44 (5H, m), 4.88-4,89 (m, 1H, H-6), 9.28 (1H, NH). ¹³C NMR (DMSO-d₆) δ (ppm): 15.94 (C18), 18.44 (C19), 19.87 (C11), 23.42 (C15), 28.15 (C7), 29.20 (C2), 29.36 (C12), 31.12 (C9), 31.49 (C10), 33.44 (C16), 37.27 (C1), 47.18 (C9), 47.87 (C13), 48.44 (C14), 76.54 (C17), 100.92 (C6), 121.77 (-CºN), 140.77 (C5), 173.33 (C3; -CONH).

Preparation of 4-azaandrost-5,16-dien-17-cyano-3-one (6)

A suspension of 5 (20 g, 63.6 mmol) in a mixture of POCl₃ (20 mL) and pyridine (120 mL) was refluxed for 15 minutes. After cooling to about 60-70 ^oC, the reaction mixture was dropped with vigorous stirring into a mixture of ice-water (2000 mL) and 37% aqueous HCl (100 mL), stirring was continued for another 60 minutes. The precipitate was filtered, washed with water and dried, yielding crude 6 (13.8 g, 70.7%) as a brown powder. R_f = 0.61 (MeOH/DCM = 9/1). Mp: 248-250^oC. EI-MS (70 eV) m/z: 297 (M+H)^+., 296 (M^+.), 281 [(M-CH₃)^+.], 256 [(M-CH₃-CN)^+.]. IR (KBr) (cm^-1): 3193, 3006, 2929, 2860, 2214, 1678, 1640, 1518, 1458, 1394. ¹H NMR (CDCl₃), δ (ppm): 0.98 (s, 3H, 18-CH₃); 1.15 (s, 3H, 19-CH₃), 1.21-1.31 (3H, m), 1.45-1.64 (4H, m), 1.64-1.86 (4H, m), 1.86-2.02 (2H, m), 2.36-2.49 (2H, m), 4.88-4.89 (1H, m, H-6), 6.64 (1H, H-16), 7.67 (1H, 4-NH).

Preparation of 3-oxo-4-azaandrosta-5,16-dien-17-(N-tert-butylcarboxamide) (7)

A solution of 6 (14.0 g, 47.3 mmol), acetic acid (150 mL), and tert-BuOH (50 mL) cooled in an ice-bath was treated with concentrated sulfuric acid (30 mL) while stirring in order to keep the temperature below 40^oC during the addition and subsequent reaction for 3 h. The reaction mixture was poured onto 200 g of crushed ice and the precipitate was filtered and dried. Recrystallization from acetone/n-hexane afforded 7 (13.7 g, 78.2%) as white crystals. R_f = 0.53 (MeOH/DCM = 9/1). Mp: 267-270^oC. EI-MS (70 eV) m/z: 370 (M^+.), 355 [(M-CH₃)^+.], 314 [(M-C₄H₉)^+.], 298 [(M-C₄H₉-NH₂)^+.]. IR (KBr) (cm^-1): 3447, 2964, 1656 (overlap), 1515, 1457, 1394, 1222. ¹H NMR (CDCl₃), δ (ppm): 1.03 (s, 3H, 18-CH₃), 1.14 (s, 3H, 19-CH₃), 1.38 (s, 9H, C(CH₃)₃), 2.47-2.50 (m, 2H, H-2), 4.83 (s, 1H, H-6), 5.46 (1H, 4-NH), 6.19 (s, 1H, H-16), 7.42 (broad, 1H, 17-CONH).

Preparation of 3-oxo-4-aza-5α-androstan-17β-(N-tert-butylcarboxamide (8)

7 (10 g, 27 mmol) in C₂H₅OH (100 mL) was hydrogenated in the presence of 2.0 g of Pd/C 5% under atmospheric pressure at room temperature for 4 hours. The catalyst was removed by filtration over Celite, and the filtrate was concentrated to give a residue. Recrystallization from ethyl acetate afforded 8 (7.4 g, 73.5%) as white crystal needles. R_f = 0.55 (MeOH/DCM = 1/9). Mp: 278^oC. EI-MS (70 eV) m/z: 374 (M^+.), 359 [(M-CH₃)^+.], 319 [(M-C₄H₉)^+.], 302 [(M-C₄H₉-NH₂)^+.]. IR (KBr) (cm^-1): 3425, 3197, 2919, 1699, 1670, 1504, 1454, 1397, 1363. ¹H NMR (CDCl₃), δ (ppm): 0.69 (s, 3H, 19-CH₃), 0.90 (s, 3H, 18-CH₃), 1.35 (s, 9H, C(CH₃)₃), 2.39-2.42 (m, 2H, H-2), 3.04-3,07 (m, 1H, 5a-H), 5.07 (s, 1H, 17-CONH), 5.67 (s, 1H, 4-NH)).

Preparation of finasteride (1)

A 50mL round bottom flask equipped with reflux condenser and a magnetic stirrer was charged with 8 (10 g, 26.7 mmol), DDQ (10 g) and dioxane (60 mL). Heating the mixture at reflux for 10 minutes yielded a clear solution. The solution was refluxed for 18 hours at the end of which complete disappearance of starting material was observed by TLC. The suspension was cooled to room temperature and added to a mixture of 200 mL of CH₂Cl₂ and 50 mL of 1% aqueous sodium bisulfite solution to precipitate the hydroquinone byproduct, which was separated by filtration. The CH₂Cl₂ layer was washed again twice with 150 mL of 5% NaHSO₃ each, then concentrated to give a thick oil, which after trituration with diethyl ether (300 mL) afforded the solids. Rescrystallization from ethanol twice gave 1 as while amorphous powder (7.1 g, 71.1%). R_f = 0.50 (MeOH/DCM = 1/9). Mp: 252-254^oC. [a]_D = +12,8^o. EI-MS (70 eV) m/z: 372 (M^+.), 357 [(M-CH₃)^+.], 317 [(M-C₄H₉)^+.], 301 [(M-C₄H₉-NH₂)^+.], 272 [(M-C₄H₉-NH₂-CO)^+.], 258 [(M-C₄H₉-NH₂-CO-CH₃)^+.], 245 [(M-C₄H₉-NH₂-CO-2CH₃)^+.], 230 [(M-C₄H₉-NH₂-2CO-2CH₃)^+.], 216 [(M-C₄H₉-NH₂-2CO-2CH₃-N4)^+.]. IR (KBr) (cm^-1): 3428, 3240, 2937, 1681, 1600, 1507, 1451, 1364, 1255, 1222, 1126, 816, 600, 504. ¹H NMR (CDCl₃), δ (ppm): 0.69 (s, 3H, 18-CH₃), 0.97

(s, 3H, 19-CH₃), 1.35 (s, 9H, C(CH₃)₃), 2.13-2.20 (m, 1H, H-17), 3.30-3.34 (m, 1H, 5a-H), 5.14 (broad, 1H, 17-CONH), 5.80 (dd, 2H, H-1), 6.44 (broad, 1H, 4-NH), 6.78 (d, 2H, H-2). ¹³C NMR (CDCl₃), δ (ppm): 11.91 (C19), 13.19 (C18), 21.16 (C11), 23.18 (C7), 24.19 (C16), 25.73 (C6), 28.96 (C(CH₃)₃), 29.36 (C15), 35.24 (C8), 38.34 (C10), 39.26 (C12), 43.84 (C13), 47.55 (C(CH₃)₃), 50.97 (C9), 55.57 (C5), 57.35 (C14), 59.57 (C17), 122.95 (C2), 150.79 (C1), 166.69 (C3; -CONH), 271.53 (C17, -C=O).

RESULTS AND DISCUSSION:

For implementation of the finasteride synthesis we mainly adopted the synthetic pathway reported by Jiang and coworkers⁴starting from AD (2, Scheme 1).

The first step of the process was the oxidative A-ring opening reaction of AD (2) to give the acid 3. The reaction was effected by a combination of sodium metaperiiodate and potassium permanganate (NaIO₄-KMnO₄). It was significant that we were able to obtain the acid 3 in the average yield of 94.9%, higher than that reported in literature (88.8%)⁴ while NaIO₄ was used about 10% less since NaIO₄ was the cost-determining factor of the first step.

Employing refluxing conditions in glacial acetic acid for cyclization as reported⁴ did not give the desired 4-aza product 4, probably due to the decomposition of the reactants as well as the newly formed compound. After trying several other solvents and conditions we were able to obtain 4 in 73.4% with 5% glacial acetic acid in anhydrous dioxane under refluxing for 4 hours.

Next, the nucleophilic reaction carried out on compound 4 to give a cyanide 5 was completed using potassium cyanide in anhydrous methanol as a solvent. The product was a mixture of two compounds, probably 17b-cyano- and 17α-cyano-isomers, as evidenced by two closely overlapped spots observed on TLC but a single molecular pic of 315 [(M+H)^+.], corresponding to the mass of the expected product, appeared on the mass spectrum. The ratio of the two isomers was 1:1 as analyzed by ¹H NMR. However, after dehydration using POCl₃ in pyridine under refluxing for 15 minutes, both two isomers gave the same product 6. We have also investigated other dehydrating reagents such as methanesulfonyl chloride/pyridine or acetyl chloride/anhydride acetic/pyridine. However, these reagents were not as effective as POCl₃/pyridine.

The formation of the amide 7 was achieved using the Ritter reaction with standard reagents and conditions ((CH₃)₃COH, CH₃COOH, H₂SO₄)).^5,6 For hydrogenation of 7 to give compound 8, Jiang and coworkers reported the use of Pd/C 10% in 0.5 weight equivalent to the starting material under 10 kPa pressure and 50^oC for 8 hours. We had optimized the hydrogenation conditions and found that 0.2 weight equivalent of Pd/C 5% at atmospheric pressure and 25^oC (room temperature) for 4 hours gave a comparable high average yield (78.2%). This result was very significant both in term of cost and easiness for reaction scale-up.

In the final step, to achieve dehydrogenation at position 1 we simply used dichlorodicyanobenzoquinone (DDQ) in dioxane. According to our experiences,^7-10 some other agents for this reaction may be used such as chloranil or anhydride benzenselenic. However, chloranil often gives the lower yield meanwhile anhydride benzenselenic is not eco-friendly and is also more expensive than DDQ. Regarding the solvent, chlorobenzene, xylene or benzene may also be used. However, in general, these solvents have disadvantages such as toxicity (benzene), higher boiling point or immiscibility in water (chlorobenzene, xylene), which makes the work-up process less convenient, especially when applied for a larger scale reaction. As the results, we decided to use DDQ/dioxane and synthesized a large amount of compound 1 (finasteride). Rescrystallization of the obtained crude product from ethanol twice gave 1 as while amorphous powder (71.1% in average), which fully met British Pharmacopeia 2007’s standard.

CONCLUSION:

In conclusion, we have implemented an improved synthesis of finasteride starting from 4-androsten-3,17-dione with several steps using less expensive conditions and commercially more viable. The overall yield achieved 20.01%, higher than the yields reported in literature (16-18%).^1,4 The process is easily scalable since the purification of each step involves only crystallization and recrystallization techniques. The products and all intermediates were fully characterized using physical and spectroscopic methods.

ACKNOWLEDGEMENT:

Financial support from the Ministry of Health of Vietnam (Project No. ACD00606) is greatly acknowleged.

REFERENCES:

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3. Rittmaster, R. S. Finasteride. NEJM 1994, 330, 120-125.

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6. Plaut H, Ritter JJ. A new reaction of nitriles. VI. Unsaturated amides. J. Am. Chem. Soc. 1951, 73, 4076–4077.

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8. You YJ, Kim Y, Nam NH, Ahn BZ. derivatives: Synthesis and Cytotoxicities: Aminoacid Derivatives. Yakhak Hoeji 2002, 46, 301-306.

9. You YJ, Kim Y, Nam NH, Ahn BZ. Synthesis and cytotoxicity of A-ring modified betulinic acid derivatives. Bioorg. Med. Chem. Lett. 2003, 13, 3137-3140.

10. Bang SC, Kim Y, Yun MY, Ahn BZ. 5-Arylidene-2(5H)-furanone derivatives: Synthesis and structure-activity relationship for cytotoxicity. Arch. Pharm. Res. 2004, 27, 485-494.

Received on 11.09.2009 Modified on 02.02.2010

Asian J. Research Chem. 3(4): Oct. - Dec. 2010; Page 1099-1102