(5α, 17β)-N-(1 ,1-dimethylethyl)-3-oxo-4-aza-androst-1-ene-17-carboxamide, finasteride, a 4-aza-steroid compound 5 which exhibits pharmaceutical activity as an inhibitor of the enzyme testosterone 5-α-reductase, and is useful in the treatment of prostate cancer

Finasteride;YM-152;MK-906;Prodel;Propecia;

Chibro-Proscar;Finastid;Prostide;Andozac;Proscar

Finasteride (brand names Proscar and Propecia by Merck, among other generic names) is a synthetic drug for the treatment of benign prostatic hyperplasia (BPH) and male pattern baldness (MPB). It is a type II 5α-reductase inhibitor. 5α-reductase is an enzymethat converts testosterone to dihydrotestosterone (DHT).

Figure . Conversion of testosterone to dihydrotestosterone.

Chemical synthesis

Propecia (finasteride) 1 mg tablets

Propecia 1 mg & Finpecia 1 mg tablets

Finasteride is synthesized fromprogesterone:

History

In 1974, Julianne Imperato-McGinley of Cornell Medical College in New York attended a conference on birth defects. She reported on a group of intersex children in the Caribbean who appeared sexually ambiguous at birth, and were initially raised as girls, but then grew external male genitalia and other masculine characteristic post-onset of puberty. Her research group found that these children shared agenetic mutation, causing deficiency of the 5α-reductase enzyme and male hormone dihydrotestosterone (DHT), which was found to have been the etiology behind abnormalities in male sexual development. Upon maturation, these individuals were observed to have smaller prostates which were underdeveloped, and were also observed to lack incidence of male pattern baldness.

In 1975, copies of Imperato-McGinley’s presentation were seen by P. Roy Vagelos, who was then serving as Merck’s basic-research chief. He was intrigued by the notion that decreased levels of DHT led to the development of smaller prostates. Dr. Vagelos then sought to create a drug which could mimic the condition found in these children in order to treat older men who were suffering from benign prostatic hyperplasia.

In 1992, finasteride (5 mg) was approved by the U.S. Food and Drug Administration (FDA) for treatment of benign prostatic hyperplasia(BPH), which Merck marketed under the brand name Proscar.

In 1997, Merck was successful in obtaining FDA approval for a second indication of finasteride (1 mg) for treatment of male pattern baldness (MPB), which was marketed under the brand name Propecia.

CHEMISTRY
Formerly known as MK-906, finasteride (Figure 1) ([5-, 17--N-(1,1-dimethylethyl) -3-oxo-4-azaandrost- 1-ene-17-carboxamide) belongs to the 4-azasteroid structural class of compounds. (Click on the structure to the right to view a Chime rotatable structure.) Its synthesis, shown in Scheme 1, was published by Rasmusson et al. in 1986.[2] Briefly, beginning with a previously synthesized intermediate, the A-ring of the steroid skeleton was converted from its 3- keto precursor (1) to the required 4-aza system (3) through an open analog (2). Saturation of the B-ring using catalytic hydrogenation gave intermediate 4. Use of the 2-pyridyl thio ester (5) gave a reactive substrate to form the tertiary butyl carboxamide (6). The final step in the synthesis, dehydration of the A-ring with benzeneselenic anhydride, gave the final product, finasteride (7).

Scheme 1. Key intermediates in the synthesis of finasteride by Rasmusson et al. Reagents: a, KMnO4-NaIO4, t-BuOH, reflux; b, NH3, heat; c, H2, Pt, ArOH; d, 2,2′-dipyridyl disulfide, triphenylphosphine, toluene; e, t-butyl amine, THF; f, benzeneselenic anhydride, chlorobenzene.

The preparation of finasteride is described and claimed in U.S. Patent 4.377.584 and further described in U.S. Patent 4.760.071. Other patents which pertain to the preparation of finasteride include Canadian patent application 2.029.859: U.S. patents 5.084.574 and 5.116.983: and Canadian patent applications 2.049.882 and 2.049.881. All these teach the conversion of a final intermediate tofinasteride, which is purified and isolated as a crystalline solid. Althoughfinasteride polymorphs are not mentioned specifically in these items of prior art, the finasteride obtained using them, as a crystalline solid, must be in one or other of the known polymorphic forms, or a mixture of both of them.

Aforementioned Canadian Patent Application 2.103.107 Dolling et a published May 20, 1994, describes preparations of finasteride and the specific polymorphic Form I and Form II thereof. In particular, it teaches that polymorphic Form I can be prepared by crystallization from a mixture of finasteride in an organic solvent and optionally water, such that the amount of organic solvent and water in the mixture is sufficient to cause the solubility of the non-solvated form of finasteride(Form I) to be exceeded and the non- solvated form of finasteride to be less soluble than any other form of finasteride in the mixture. It also teaches that the polymorphic Form I of finasteride can be prepared by heating the polymorphic Form II of finasteride to at least 25°C in water or an organic solvent for a sufficient period of time to effect the conversion. The same reference teaches that polymorphic Form II finasteride can be prepared by crystallization from a mixture of finasteride in an organic solvent and water, such that the amount of organic solvent and water in the mixture is sufficient to cause the solubility of the solvated form of finasteride to be exceeded and the solvated form of finasteride to be less soluble than any other form of finasteride in the mixture, followed by recovery of the solid and removal of the solvent therefrom; or by heating polymorphic Form I finasteride to at least to about 150°C for sufficient time to complete the conversion.

MORE INFO

• Finasteride, marketed under the tradename of PROSCAR®, by Merck & Co., Inc is 17β-(N-tert-butyl carbamoyl)-4-aza-5α-androst-1-en-3-one and is a 5α-reductase inhibitor for use in treating acne, female hirsutism, and particularly benign prostatic hyperplasia. See US Patent 4,760,071 (1988), the entire disclosure of which is incorporated herein by reference..
• [0002]
  The synthesis of finasteride in US Patent 4,760,071 involves reacting the 17β-(2-pyridylthio) carboxylate of 4-aza-5α-androst-1-ene-3-one with t-butylamine. A further synthesis of finasteride is described in Synthetic Communications, 30 (17), p. 2683-2690 (1990). including the reacting of the 17-acylimidazole of 4-aza-5α-androst-1-en-3-one with t-butylamine.
• [0003]
  However, both of these reactions require the use of heterocyclic aromatic amines which are expensive and give rise to environmental safety and toxicity considerations. Both of these intermediates are prepared from the 17β-carboxylic acid.
• [0004]
  The Bodroux reaction, described by F. Bodroux in the references, Bull. Soc. Chim. France 33, 831 ( 1905); 35, 519 (1906); 1, 912 (1907); Compt. Rend. 138, 1427 (1904); 140, 1108 (1905); 142, 401 (1906) discloses the reaction of the magnesium halide salts of amines with esters. However, there is no description or teaching that the reaction can be applied to the reaction of a sterically hindered amine, e.g. t-butyl amine, with a sterically hindered ester such as 1.
• 

The first method (International Patent: W0200507M97A) is finasteridedihydro as raw materials, benzeneseleninic anhydride synthesis of finasteride, the reaction is as follows:

Used in this reaction toxic and expensive reagents benzeneseleninic anhydride, yield only about 50%, and the product to column chromatography to separate, while the use of certain toxic chlorobenzene as solvent, the cost is very high , environmental hazards large.

[0005] The second method (U.S. Patent No.: US20070167477A1) is finasteridedihydro as raw materials, the use of DDQ / BSTFA (i.e. 3,3 – dichloro-5 ,6 – dicyano-p-benzoquinone / second (third trimethylsilyl) trifluoroacetamide) Oxidation get finasteride, the reaction is as follows:

The reaction yield about 65%, the resulting fluorine-containing wastewater intractable, quinones great harm to the environment.

[0006] The third method (international patent: W02008101308A) is dihydrofinasteride as raw material, the use of phenyl sulfide oxidation get finasteride, the reaction is as follows:

The method steps and more complicated to operate, the total yield of only 60%, the use of expensive lithium diisopropylamide, lithium bis trimethylsilyl test Qi IJ, the cost is higher.

REF

Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Substd.-4-aza-5alpha-androstenones and their use as 5alpha-reductase inhibitors. AU 8539167; EP 0155096; EP 0314199; ES 8702430; JP 1985222497; JP 1989093600; US 4760071 .

    Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); Treatment of prostatic carcinoma with 17beta-N-monosubstd.-carbamoyl-4-aza-5-alpha-androst-1-en-3-ones. EP 0285383 .

    Rasmusson, G.H.; Reynolds, G.F.; Steinberg, N.G.; Walton, E.; Patel, G.F.; Liang, T.; Cascieri, M.A.; Cheung, A.H.; Brooks, J.R.; Berman, C.; Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. J Med Chem 1986, 29, 11, 2298.

    Castaner, J.; Prous, J.; Finasteride. Drugs Fut 1991, 16, 11, 996.

The oxidative cleavage of N-tert-butyl-3-oxo-5alpha-androst-4-ene-17beta-carboxamide (I) with NaIO4 and KMnO4 in tert butanol – aqueous Na2CO3 gives the seco-ketoacid (II), which is cyclized with liquid ammonia in ethylene glycol at 180 C to afford the DELTA5-azasteroid (III). Hydrogenation of (III) with H2 over PtO2 in acetic acid yields the corresponding saturated aza-steroid (IV), which is finally dehydrogenated with benzeneseleninic anhydride in refluxing chlorobenzene or with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide (BSTFA) in refluxing dioxane.