- Hydrogenation reaction mother liquor recycling material preparation 3-carbonyl-4-aza-5-androstene -17 β carboxylic acid derivatives
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The invention provides a method for preparing 3-carbonyl-4-aza-5-androstene-17 beta carboxylic acid derivative 01 from mother solution reclaimed materials of a hydrogenation reaction. The method comprises the following steps: (1) dissolving the mother solution reclaimed materials, which are obtained by preparing 3-carbonyl-4-aza-5 alpha-androstane-17 beta carboxylic acid derivative 03 by performing hydrogenation reaction on 3-carbonyl-4-aza-5-androstene-17 beta carboxylic acid derivative 01, into glacial acetic acid, and adding a palladium-carbon catalyst, introducing oxygen, pressurizing and heating to perform dehydrogenation reaction; (2) cooling the reaction system, filtering to obtain a filter cake, washing the filter cake by using glacial acetic acid, and performing suction filtration until the filter cake is dried, thereby obtaining a waste palladium-carbon filter cake; and (3) performing vacuum concentration on a filtrate until the filtrate is almost dried, adding methanol into the system, performing freezing crystallization, performing swinging filtration to obtain a filter cake, washing the filter cake by using methanol, performing swinging filtration until the filter cake is dried, and drying to obtain the 3-carbonyl-4-aza-5-androstene-17 beta carboxylic acid derivative 01. By adopting the method provided by the invention, wastes are recycled to synthesize an important medical intermediate, the cost is reduced, and pollution is reduced. Original auxiliary materials are simple, easily available and recyclable, and the process is simple and is suitable for industrial implementation.
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Paragraph 0040-0041
(2017/03/23)
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- A synthetic 3-carbonyl-4-nitrogen mixed male steroid -17 β derivative method
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The invention discloses a method for synthesizing 3-carbonyl-4-azaandrost-17beta derivative I, which comprises the following steps: (1) in the presence of an acidic catalyst, dissolving A-norandrostane-3,5-cracked-androst-5-one-3-carboxylic acid-17beta derivative II in dioxane aqua ammonia, heating, and slowly and dropwisely adding reducer-dissolved aqua ammonia to simultaneously perform reduction amination reaction and ring-closing reaction; (2) adding acid to destroy the reducer, concentrating under normal pressure, and recovering dioxane; (3) cooling, and carrying out centrifugal filtration to obtain a filter cake; washing the filter cake with water to a neutral state, and carrying out centrifugal drying to obtain a 3-carbonyl-4-azaandrost-17beta derivative I crude product; and (4) pulping the 3-carbonyl-4-azaandrost-17beta derivative I crude product with methanol, carrying out centrifugal filtration to obtain a filter cake, washing the filter cake with methanol, carrying out centrifugal drying, and baking to obtain the 3-carbonyl-4-azaandrost-17beta derivative refined product. By completing the reduction amination reaction and ring-closing reaction in one step, the method has the advantages of low reaction temperature, high product yield and good product quality, is economical and environment-friendly, and is suitable for industrialization.
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Paragraph 0056-0065; 0066-0067
(2017/01/26)
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- PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE
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The synthesis consists of reaction steps as follows: oxidizing the α,β-unsaturated ketone system of ring "A" of pregn-4-ene-3,20-dion- of formula (II) with sodium metaperiodate in tert-butanol in the presence of potassium permanganate and alkali metal carbonate, reacting the obtained 3,5-seco acid with an ester of chloroformic acid in the presence of tertier organic base below 0°C, reacting the obtained new compound after isolation or without isolation with ammonia or ammonium acetate, cyclization of the resulting carboxamides with an acid, cathalytic hydrogenating the obtained ene lactame, and oxidizing the side chain at position 17 of the obtained pregnane compound with an alkali metal hypobromide in aqueous dioxane below 10°C. Thereafter on one hand the obtained (5α,17β)-3-oxo-4-aza-5-androstane-17-carboxylic acid is reacted with chloroformic acid ester, the obtained new compound is reacted with 2,5-bis(trifluoromethyl)-aniline in the presence of a Lewis acid, the obtained amide is reacted with trimethyl chlorosilane in inert atmosphere in the presence of Ν,Ν,Ν',Ν'-tetramethyl-ethylendiamine, then en excess iodine is added to the reaction mixture and the product of the iodination reaction is crystallized from acetonitrile, then the obtained 2-iodo-3-oxo-4-aza-17β-carboxamide is reacted with potassium tert-butylate to furnish final product. On the other hand, (5α,17β)-3-oxo-4-aza-5-androstane-17-carboxylic acid is transformed into methylester by known method, this latter is transformed into methyl (2α,5α,17β)-2-iodo-3-oxo-4-aza-5-androstane-17-carboxylate according to known method, the obtained compound is reacted with potassium-tert-butylate, the obtained (5α,17β)-3-oxo-4-aza-5-androst-1-ene-17-carboxylic acid is reacted with an ester of chloroformic acid, then the obtained new compound is coupled with 2,5-bis(trifluoromethyl)-aniline in the presence of a Lewis acid catalyst to gain final product.
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- Process for making fluorinated 4-azasteroid derivatives
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The present invention relates to synthetic processes useful in the preparation of fluorinated 4-azasteroid derivatives that modulate androgen receptors and have application in the treatment of conditions caused by androgen deficiency or androgen receptor hyperactivity, such as osteoporosis, periodontal disease, bone fracture, frailty, erectile dysfunction, loss of libido, androgen-dependent cancers and sarcopenia. The present invention also encompasses intermediates useful in the disclosed synthetic processes and the methods of their preparation.
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Page/Page column 10
(2010/11/24)
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- NOVEL PROCESS FOR PREPARING 17 BETA-SUBSTITUTED 4-AZAANDROSTANE DERIVATIVES
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The invention relates to a novel process for preparing 17 beta -substituted 4-azaandrostane derivatives of general formula (I) wherein R represents hydrogen or a C1-3alkyl group; R represents a carboxamido group mono- or disubstituted by C1-8alkyl group(s); or a free carboxyl group; or a carboxyl group esterified with a C1-5 alcohol; and the - &cir& _- &cir& _- &cir& _- &cir& _ bond line represents a single or double bond; as well as their salts. The process comprises reacting a 17-halogeno-4-azaandrostene derivative of general formula (II) wherein R and the - &cir& _- &cir& _- &cir& _- &cir& _ bond line are as defined above, and X is chlorine, bromine or iodine, with a primary or secondary alkylamine or a C1-5 alcohol, in dimethylformamide or dimethylsulfoxide medium in the presence of a palladium(II) salt and phosphines or a palladium(II) complex and a tertiary amine base in carbon monoxide atmosphere at a temperature between 35 DEG C and 80 DEG C, then, if desired, transforming an obtained compound of general formula (I) to another compound of general formula (I) by hydrogenation, hydrolysis or salt forming reaction.
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- Azasteroids: Structure-activity relationships for inhibition of 5α-reductase and of androgen receptor binding
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A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5α-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included 4-cyano-3-oxoΔ4 system in the carbocyclic series and 1α-CN, 1α-CH3, 1α,2α-CH2, 2β-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (α and β) or C-16 (α and β) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17β-COOH. Enhanced 5α-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-Δ4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5α-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17β-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.
- Rasmusson,Reynolds,Steinberg,Walton,Patel,Liang,Cascieri,Cheung,Brooks,Berman
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p. 2298 - 2315
(2007/10/02)
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