Cyclohexanone → 4-Androstene-17-carboxylic acid, 3-oxo-, methyl ester

HRID 27330

Reaktionsgleichung

Reaktionsgleichung von HRID 27330
[CH3:1]C([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2CC1)=O.[C:24]([C:27]1[C@:28]2([CH2:46][CH2:45][C@H:44]3[C@@H:33]([CH2:34][CH2:35][C@@H:36]4[C@:42]3([CH3:43])[CH2:41][CH2:40][C@@H:38]([OH:39])[CH2:37]4)[C@@H:30]2[CH2:31][CH:32]=1)[CH3:29])([OH:26])=[O:25].C[O-].[Na+].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1.CO>[CH3:1][O:25][C:24]([CH:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:44]([CH2:45][CH2:46][C@:28]12[CH3:29])[C@:42]1([CH3:43])[C:36](=[CH:37][C:38](=[O:39])[CH2:40][CH2:41]1)[CH2:35][CH2:34]3)=[O:26]

Komponenten

8

Edukt 5

HCID 7967CyclohexanoneHCID 8955PregnenoloneHCID 11143Aluminum isopropoxideHCID 10942334Sodium MethoxideHCID 9957184417-Carboxy androstenol2×

Produkt 1

HCID 228121484-Androstene-17-carboxylic acid, 3-oxo-, methyl ester

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 1140TolueneLösungsmittel

Versuchsvorschrift

A preferred process for preparing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, an especially preferred compound of the present invention, comprises the following steps: (a) pregnenolone (V), an available starting material, is treated by the haloform King reaction with iodine and pyridine to form the 20-pyridinum iodide derivative of the pregnenolone (VI); (b) the pyridinium iodide derivative (VI) is methanolyzed to the methyl ester of 17-carboxy androstenol (VII) with sodium methoxide and methanol, the ester form being preferred for carrying out the following Oppenhauer reaction; (c) the methyl ester of 17-carboxy androstenol (VII) is treated with aluminum isopropoxide and cyclohexanone in an appropriate solvent such as toluene to yield methyl-4-androstene-3-one-17-carboxylate (VIII) (d) the methyl-4-androstene-3-one-17-carboxylate (VIII) thus formed is hydrolyzed to the 17-acid (IX) under acid conditions in a methanol: water solvent of approximately 4:1 proportions; (e) the 17 acid (IX) is then treated with an oxalyl chloride: pyridine complex of approximately 1:1 proportions in toluene or other suitable solvent, e.g. xylene, to form the 17 -acid chloride (X); (f) the 17-acid chloride (X) is then treated in situ with an excess of diethylamine to form the 17β-N,N-diethylcarbamoyl-4-androstene-3-one (XI); (g) the 4-androstene-3-one (XI) thus formed is oxidized by treatment with sodium periodate and potassium permanganate, using tert-butanol and water as a solvent system, to the corresponding 5-oxo-3,5-secoandrostan-3-oic acid (XII); (h) the secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) by treating it with methylamine in ethylene glycol for a period of about 1 hour over which time the reaction mixture temperature is raised to from 140°-180° C. where it is maintained from 0.5 to 5 minutes; (i) the resulting 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is then hydrogenated by treating it with hydrogen at room temperature to 60° C. or higher, using platinum oxide as the catalyst, to form the 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (XIV) final product, which is then separated and purified.

Aufarbeitung

  1. customthe following Oppenhauer reaction

Quellen und Nachweise

ORD-Eintrag
ord-b01cfadabc644815ab56cb9b5069bf1c
Quelldatensatz
uspto-grants-1980_09
Patentnummer
US04220775

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