- 【药物名称】4-MA
- 【化学名】N,N-Diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide
- 【CAS登记号】
- 【结构式】
- 【分子式】C24-H40-N2-O2
- 【分子量】388.592
- 【原研厂家】
- 【作用类别】
- 【研发状态】Not Determined
- 【合成情况】
- 〖来源〗Drugs Fut
- 〖合成路线〗
- 〖标题〗4-MA
- 〖合成方法〗The reaction of pregnenolone (I) with I2 and pyridine at 90 C gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NaIO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethylene glycol at 180 C in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid. The cyclization of the acid (VII) with NH3 in ethanol at 180 C in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally, this compound is methylated with CH3I by means of NaH in toluene.
- 〖作者〗Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaer, J.
- 〖参考〗Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaer, J.; 4-MA. Drugs Fut 1983, 8, 4, 323
- 〖出处〗Drugs Fut1983,8,(4):323
- 〖备注〗Synthesis of 4-MA (EN:070128) This compound can be obtained by several different ways (1): 1) The reaction of pregnenolone (I) with I2 and pyridine at 90?gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17betacarboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NalO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethyleneglycol at 180?in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid (Scheme 07012801a). 2) The cyclization of the acid (VII) with NH3 in ethanol at 180?in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally this compound is methylated with CH3I by means of NaH in toluene (Scheme 07012801a). 3) The oxidation of 3-oxo-4-etienic acid (V) with NalO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostan-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180?in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF (Scheme 07012802a). 4) The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene (Scheme 07012802a). 5) The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene (Scheme 07012802a). Description Crystals, m.p. 172-4?(1). Manufacturer Merck Sharp & Dohme (USA). Reference 1. Jobson, R.B., Johnston, D.B.R., Rasmusson, G.H., Reinhold, D.F. and Utne, T. (Merck and Co., Inc.); US 4220775.
- 〖来源〗Drugs Fut
- 〖合成路线〗
- 〖标题〗4-MA
- 〖合成方法〗The oxidation of 3-oxo-4-etienic acid (V) with NaIO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostane-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180 C in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF. The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene. The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene.
- 〖作者〗Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaer, J.
- 〖参考〗Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaer, J.; 4-MA. Drugs Fut 1983, 8, 4, 323
- 〖出处〗Drugs Fut1983,8,(4):323
- 〖备注〗Synthesis of 4-MA (EN:070128) This compound can be obtained by several different ways (1): 1) The reaction of pregnenolone (I) with I2 and pyridine at 90?gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17betacarboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NalO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethyleneglycol at 180?in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid (Scheme 07012801a). 2) The cyclization of the acid (VII) with NH3 in ethanol at 180?in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally this compound is methylated with CH3I by means of NaH in toluene (Scheme 07012801a). 3) The oxidation of 3-oxo-4-etienic acid (V) with NalO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostan-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180?in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF (Scheme 07012802a). 4) The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene (Scheme 07012802a). 5) The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene (Scheme 07012802a). Description Crystals, m.p. 172-4?(1). Manufacturer Merck Sharp & Dohme (USA). Reference 1. Jobson, R.B., Johnston, D.B.R., Rasmusson, G.H., Reinhold, D.F. and Utne, T. (Merck and Co., Inc.); US 4220775.
- 〖来源〗US 4220775
- 〖合成路线〗
- 〖标题〗Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors
- 〖合成方法〗The reaction of pregnenolone (I) with I2 and pyridine at 90 C gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NaIO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethylene glycol at 180 C in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid. The cyclization of the acid (VII) with NH3 in ethanol at 180 C in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally, this compound is methylated with CH3I by means of NaH in toluene.
- 〖作者〗Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.)
- 〖参考〗Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.); Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. US 4220775
- 〖出处〗US 4220775,,():
- 〖备注〗
- 〖来源〗US 4220775
- 〖合成路线〗
- 〖标题〗Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors
- 〖合成方法〗The oxidation of 3-oxo-4-etienic acid (V) with NaIO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostane-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180 C in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF. The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene. The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene.
- 〖作者〗Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.)
- 〖参考〗Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.); Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. US 4220775
- 〖出处〗US 4220775,,():
- 〖备注〗
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