CN1793164A - Steroid compound with 5-alpha reductase active and preparation process thereof - Google Patents

Steroid compound with 5-alpha reductase active and preparation process thereof Download PDF

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CN1793164A
CN1793164A CN 200510136009 CN200510136009A CN1793164A CN 1793164 A CN1793164 A CN 1793164A CN 200510136009 CN200510136009 CN 200510136009 CN 200510136009 A CN200510136009 A CN 200510136009A CN 1793164 A CN1793164 A CN 1793164A
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carbonyl
androstene
azepine
oxime
mole
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CN100355772C (en
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刘东志
杨雄文
周雪琴
李爱军
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Tianjin University
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Tianjin University
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Abstract

The invention discloses a structure of steroid class compound that has 5alpha-reductase to restrain activity that belongs to medicine chemical field. R<SUB>1</SUB> is hydrogen, alkyl and benzyl of C<SUB>1</SUB>-C<SUB>5</SUB>; R<SUB>2</SUB> is alkyl of C<SUB>1</SUB>-C<SUB>8</SUB>, alkanoyl of C<SUB>1</SUB>-C<SUB>8</SUB>, one from benzyl, substituted benzyl, benzoyl, and phenylacetyl and substituted benzoyl. It uses androstenedione as raw material, oxidizing open loop to form 5, 17-carbonyl-A-decarbonization-3, 5-cracking-androstane-3-carboxylic acid and taking reaction with oximation to form intermediate that would react with halogenated hydrocarbon or acyl chloride to gain the product. The advantages of the invention are that it uses common raw material, simple technology, has the activity restraining function to 5alpha-reductase.

Description

Have 5 and suppress active steroidal compounds and preparation method thereof
Technical field
The present invention relates to a kind ofly have 5 and suppress structure of active steroidal compounds and preparation method thereof, this technology belongs to the pharmaceutical chemistry field.
Background technology
Steroid 5 alpha-reductases are the membranins that are positioned on the target cell microsome, rely on dihydrocoenzyme II (NADPH) as hydrogen donor, a series of steroid substrates of catalytic reduction such as testosterone, 17 Alpha-hydroxy Progesterone, rotex etc.Change in the process of the stronger male sex hormone dihydrotestosterone [dihydrotestos-terone (DHT)] of activity at catalytic reduction androgenic testosterone [Testosterone (T)], 5 plays keying action.It can reduce 4,5 unsaturated double-bonds of testosterone, and makes the hydrogen on the C-5 position keep the α configuration.
T and reductive metabolites DHT thereof keep male sex's dominant character and sexually matured essential androgen, account for about 80% of males internal hormone, and wherein DHT is considered to the strongest male sex hormone of effect in the body.After T enters target cell, be reduced to DHT through 5 alpha-reductases, after DHT enters nucleus, combine, excite transcribing of dna sequence dna with the nuclear androgen receptor protein, produce mRNA, along with the rising of mRNA level, cause proteinic synthesizing, these protein comprise enzyme acceptor and excreted factor, they follow the induced hormone effect, regulate function, growth and the differentiation of cell then.If the DHT too high levels will cause the body disorder in the body, endocrine disturbance, be the cause of disease of many endocrinopathys, can produce such as common disease such as prostate cancer PC (prostatic cancer), benign prostatic hyperplasia BPH (benign prostatic hyperplasia), acne, female hirsutism, the male sex be bald.
Along with the arriving of astogeny society, androgen-dependent disorders such as benign prostatic hyperplasia BPH more and more are subjected to people's generally attention.Because these diseases are caused that by excessive DHT in the body therefore, the method for the treatment of this class disease in recent years adopts 5 alpha reductase inhibitors usually, suppresses the generation of T → DHT process.T combines with the mixture (E-NADPH) that 5 and its coenzyme NADP 11 form, and under the effect of 5 catalytic reduction, relies on dihydrocoenzyme II (NADPH) as hydrogen donor, and T is reduced to DHT.If there is certain inhibitor (Inhibitor) to exist, because the structure and the T of inhibitor are similar, inhibitor equally also can combine with the mixture machine, inhibitor is just vied each other with T and is combined with mixture like this, thereby reduced the conversion of T to DHT, thereby having reduced the content of DHT in the body, this has just alleviated in the body because all disease that the DHT too high levels causes.
Finding to have 5 the earliest, to suppress active compound be that Brooks equals synthetic 4-MA in 1981, yet it also can suppress 3-β hydroxy steroid dehydrogenase type and liver is had toxicity and not by clinical employing.Subsequently, people are by structure design and high flux screening, obtained multiplely to have 5 and suppress active steroidal or nonsteroidal compound, wherein finasteride obtained the FDA approval in 1988, was synthetic 5 inhibitor and be applied to the clinical treatment benign prostatic hyperplasia the earliest.So far, had several steroid drugss to enter the I phase and the II phase clinical, comprise finasteride, dutasteride and epristeride.Wherein, finasteride (Finasteride) can suppress the generation of blood plasma 70% Standone, the Standone that can suppress 85-95% in the prostata tissue, more obvious for prostate volume greater than the patient treatment effect of 30mL, and can be used for treating diseases such as male pattern alopecia.Yet its IC 50Only be 52nM, clinical application also shows untoward reactions such as hyposexuality, sexual dysfunction, semen volume minimizing.
Dutasteride (Dutasteride) is considered to a more efficiently 5 double inhibitor, more can reduce DHT concentration in patient's blood plasma effectively than Finasteride, it is clinical that treatment BPH research has at present entered the III phase, and it is clinical that the research of treatment male baldness has entered the II phase.Epristeride (Epristeride) is a kind of novel noncompetitive 5 inhibitor, can make in the prostate gland body of gland and DHT level reduction in the serum, and do not influence testosterone levels in the serum, and prostate volume is obviously dwindled, suppressing testosterone transforms to Standone, reduce Standone content in the prostata tissue, thereby dwindle prostate volume, reduce voiding resistance, reach the purpose of improving benign prostatic hyperplasia (BPH) controlled micturition difficulty symptom, entered IV phase clinical experiment at present.But these drug effects all valency are slower, and all produce the toxic side effect to reproductive system, and therefore a kind of new 5 inhibitor is still the direction that people seek.
Summary of the invention
The object of the present invention is to provide a kind ofly to have 5 and suppress structure of active steroidal compounds and preparation method thereof, this compounds has 5 alpha-reductases and suppresses active, can be used for preparing 5 alpha reductase inhibitors.
The present invention realized by following technical proposals, and a kind of have 5 and suppress active steroidal compounds, it is characterized in that structural formula is as follows:
Wherein: R 1For: hydrogen, C 1-C 5Alkyl and benzyl in a kind of; R 2For: C 1-C 8Alkyl, C 1-C 8Alkyloyl, benzyl, substituted benzyl, benzoyl, a kind of in the benzoyl of phenylacetyl and replacement.
Above-mentioned have 5 and suppress active steroidal compounds and comprise following compound:
3-carbonyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-propyl group-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-butyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-isopentyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-chlorobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-homoanisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-ethyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isobutyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-.
Above-mentioned have a preparation method that 5 suppresses active steroidal compounds, and its preparation general formula is:
Figure A20051013600900081
a)NalO 4/KMnO 4，Na 2CO 3，t-BuOH，reflux；b)NH 3，HOCH 2CH 2OH，180℃；c)NaH，Mel，DMF，r.t.；d)MeNH 2，EtOH，HOCH 2CH 2OH，180℃；e)NH 2OH·HCl，AcOK，EtOH，H 2O，r.t.；f)R 1I，KOH，DMF，r.t.；g)R 2COCl，DMAP，CH 2Cl 2，r.t.
One of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 60-80 ℃, react 3-carbonyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) and 3-carbonyl-4-alkane (virtue) base-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction under the potassium hydroxide effect of 2-4 mole.
Two of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 60-80 ℃, react 3-carbonyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
Three of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3, the methylamine of 5-cracking-etioallocholane-3-carboxylic acid and 10-20 mole in 15-180 ℃ down reaction generate 3,17-carbonyl-4-methyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-methyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction in the presence of the potassium hydroxide of 3-4 mole.
Four of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3, the methylamine of 5-cracking-etioallocholane-3-carboxylic acid and 10-20 mole in 15-180 ℃ down reaction generate 3,17-carbonyl-4-methyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester or 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
Five of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene can obtain 3 in 20-50 ℃ of reaction, 17-carbonyl-4-methyl-4-azepine-5-androstene with the methyl iodide of 4-6 mole in the presence of the sodium hydride of 1.0-1.1 mole; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-methyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction in the presence of the potassium hydroxide of 3-4 mole.
Six of method, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene can obtain 3 in 20-50 ℃ of reaction, 17-carbonyl-4-methyl-4-azepine-5-androstene with the methyl iodide of 4-6 mole in the presence of the sodium hydride of 1.0-1.1 mole; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester or 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
The invention has the advantages that the steroid drugs synthesizing new raw material Androstenedione (AD) cheaply to be easy to get is a raw material, technology is simple, prepared product has 5 and suppresses active, can be used for preparing the 5 inhibitor, be used to alleviate or treat the relative disease that causes owing to DHT is excessive.
Embodiment
One. the preparation of steroidal compounds
Embodiment 1:3-carbonyl-4-ethyl-4-azepine-5-androstene-17-oxime N-O-ethyl ether
Step 1:5,17-carbonyl-A-loses carbon-3, the preparation of 5-cracking-etioallocholane-3-carboxylic acid:
With androstane-4-alkene-3,17-diketone (10.0g, 35.0mmol) be dissolved in the trimethyl carbinol (350mL), stirring is following to the aqueous solution that wherein adds anhydrous sodium carbonate (23g, 20%), and is warming up to 90 ℃, slowly drip sodium periodate (41.2g, 0.2mol) and potassium permanganate (0.33g, 2.1mmol) water-soluble (250mL) solution of forming drips off in 1.5h.After dropwising, backflow 5h.Be cooled to room temperature, filtration, water (50mL * 4) washing leaching cake, most of trimethyl carbinol is removed in the filtrate decompression distillation, transfers pH ≈ 1.5 with dilute hydrochloric acid, methylene dichloride (100mL * 3) extraction, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets light yellow paste.Column chromatography is separated (ethyl acetate/petroleum ether=3/7), gets white solid product (8.75g, 81.8%). 1HNMR(400MHz，CDCl 3)δ：0.81(s，3H，18-CH 3)，1.02(s，3H，19-CH 3)，10.05(broad，1H，-COOH)。IR(KBr，v/cm-1)：3351(broad)，2974，2932，1710，1472，1373，1198，1023，912，749。
Step 2:3, the preparation of 17-carbonyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, and ice bath feeds ammonia down, and (6.0g 0.35mol), slowly is warming up to 180 ℃ then, and reacts about 0.5h under this temperature, is cooled to room temperature.Dilute with water stirs 1h.Transfer pH ≈ 1.5 with dilute hydrochloric acid, leave standstill, filter, the thorough washing filter cake, drying obtains off-white color pressed powder (6.7g, 81.5%). 1H NMR(400MHz，CDCl 3)δ：0.89(s，3H，18-CH 3)，1.10(s，3H，19-CH 3)，4.91(t，1H，6-H)，8.10(s，1H，4-H)。 13C NMR(400MHz，CDCl 3)δ：13.62，18.72，20.26，21.78，28.14，28.64，31.17，31.30，31.34，34.32，35.72，47.57，48.13，51.53，103.31(6-C)，140.09(5-C)，169.95(3-C)，220.21(17-C)。EI-MS(m/z)：287.1(M +)，137.1，44.0。
The preparation of step 3:3-carbonyl-4-azepine-5-androstene-17-oxime:
With 3,17-carbonyl-4-azepine-5-androstene (6.7g, 23.3mmol) be suspended in aqueous ethanolic solution (50%, 80mL), then with oxammonium hydrochloride (12.2g, 0.18mol) and Potassium ethanoate (13.8g 0.14mol) is dissolved in aqueous ethanolic solution (50%, 180mL) and join in the above-mentioned suspension, 60 ℃ of reaction 10h.Be cooled to the room temperature after-filtration, it is neutral washing filter cake to filtrate with massive laundering, obtains off-white color solid (6.75g, yield 95.7%). 1H NMR(400MHz，DMSO-d 6)δ：0.85(s，3H，18-CH 3)，1.01(s，3H，19-CH 3)，4.85(s，1H，6-H)，9.28(s，1H，4-NH)，10.05(s，1H，-OH)。 13C NMR(400MHz，DMSO-d 6)δ：17.03，18.41，20.03，22.72，24.77，28.15，28.67，30.48，31.06，33.52，33.83，42.94，47.74，53.49，100.80(6-C)，140.75(5-C)，167.75(17-C)，167.80(3-C)。EI-MS(m/z)：302.1(M +)，286.1，230.1，189.1，176.0，137.0，96.0，44.0，28.0。
The preparation of step 4:3-carbonyl-4-ethyl-azepine-5-androstene-17-oxime N-O-ethyl ether:
With 3-carbonyl-4-azepine-5-androstene-17-oxime (1.0g, 3.3mmol) with potassium hydroxide (0.56g 9.9mmol) joins N, in the dinethylformamide (70mL), stirring and dissolving, drip iodoethane (1.7mL, 21.1mmol), 50 ℃ of reaction 8h.Reaction solution is chilled to room temperature, adds water (140mL), dichloromethane extraction (70ml * 3).Organic phase distilled water wash (50ml * 10), anhydrous sodium sulfate drying filters, concentrating under reduced pressure, column chromatography is separated (ethanol/methylene=1/99), obtains white solid 0.7g. 1H NMR(400MHz，CDCl 3)δ：0.83(s，3H，18-CH 3)，0.85(s，3H，19-CH 3)，2.48(m，2H，N-CH 2CH 3)，4.03(m，2H，-OCH 2CH 3)，4.95(t，1H，6-H)。EI-MS(m/z)：358.0(M +)，315.1，259.0，165.0，122.0，57.0，41.0。Obtain 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-ethyl ether 0.3g simultaneously. 1H NMR(400MHz，CDCl 3)δ：0.95(s，3H，18-CH 3)，1.02(s，3H，19-CH 3)，3.53(m，2H，-OCH 2CH 3)，5.04(t，1H，6-H)，7.14(s，1H，4-NH)。EI-MS(m/z)：330.3(M +)，287.3，272.2，176.1，137.1，55.1，43.0。
The preparation of embodiment 2:3-carbonyl-4-benzyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether:
The step 1 of present embodiment, step 2, step 3 are with embodiment 1.
The preparation of step 4:3-carbonyl-4-benzyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether:
With 3-carbonyl-4-azepine-5-androstene-17-oxime (0.5g, 1.66mmol) with potassium hydroxide (0.38g 6.64mmol) joins N, in the dinethylformamide (60mL), stirring and dissolving, drip benzyl chloride (1.2mL, 9.93mmol), 70 ℃ of reaction 12h.Reaction solution is chilled to room temperature, adds water (100mL), dichloromethane extraction (50mL * 3).Organic phase distilled water wash (50mL * 10), anhydrous sodium sulfate drying filters, concentrating under reduced pressure, column chromatography is separated (ethanol/methylene=1/99), obtains white solid 0.46g. 1H NMR(400MHz，CDCl 3)δ：0.93(s，3H，18-CH 3)，1.08(s，3H，19-CH 3)，4.698(m，2H，N-CH 2C 6H 5)，5.07(m，2H，-OCH 2C 6H 5)，5.22(t，1H，6-H)，7.15～7.35(m，10H，-CH 2C 6HH 5)。EI-MS(m/z)：482.1(M +)，377.1，279.0，166.9，149.0，91.0，43.0。Obtain 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether 0.05g simultaneously. 1H NMR(400MHz，CDCl 3)δ：0.99(s，3H，18-CH 3)，1.15(s，3H，19-CH 3)，4.43(m，2H，-OCH 2C 6H 5)，5.09(t，1H，6-H)，7.06(s，1H，4-NH)，7.29～7.38(m，5H，-OCH 2C 6H 5)。EI-MS(m/z)：392.2(M +)，285.2，91.0，44.0。
The preparation of embodiment 3:3-carbonyl-4-isobutyl--4-azepine-5-androstene-17-oxime N-O-isobutyl ether:
The step 1 of present embodiment, step 2, step 3 are with embodiment 1.
The preparation of step 4:3-carbonyl-4-isobutyl--4-azepine-5-androstene-17-oxime N-O-isobutyl ether:
With 3-carbonyl-4-azepine-5-androstene-17-oxime (0.5g, 1.66mmol) with potassium hydroxide (0.23g 4.1mmol) joins N, in the dinethylformamide (50mL), stirring and dissolving, drip different butyl iodide (1.52mL, 9.93mmol), 30 ℃ the reaction 20h.Reaction solution is chilled to room temperature, adds water (100mL), dichloromethane extraction (50mL * 3).Organic phase distilled water wash (50mL * 10), anhydrous sodium sulfate drying filters, concentrating under reduced pressure, column chromatography is separated (ethanol/methylene=1/99), obtains white solid 0.04g. 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，0.90(s，3H，19-CH 3)，3.08(t，2H，N-CH 2CH(CH 3) 2)，3.83(t，2H，-OCH 2CH(CH 3) 2)，5.08(t，1H，6-H)。EI-MS (m/z): 414.1 (M +), 359.0,285.0,270.0,205.0,113.9,57.0,41.0 obtain 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isobutyl ether 0.18g simultaneously. 1H NMR(400MHz，CDCl 3)δ：0.91(s，3H，18-CH 3)，1.12(s，3H，19-CH 3)，3.79(d，2H，-OCH 2CH(CH 3) 2)，4.86(t，1H，6-H)，7.46(s，1H，4-NH)。EI-MS(m/z)：358.1(M +)，287.1，176.1，137.1，43.0，28.0
The preparation of embodiment 4:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether:
The step 1 of present embodiment, step 2, step 3 are with embodiment 1.
The preparation of step 4:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether:
With 3-carbonyl-4-azepine-5-androstene-17-oxime (0.5g, 1.66mmol) with potassium hydroxide (0.37g 6.6mmol) joins N, in the dinethylformamide (60mL), stirring and dissolving, drip different iodopropane (4.0mL, 0.04mmol), 50 ℃ the reaction 30h.Reaction solution is chilled to room temperature, adds water (100mL), dichloromethane extraction (50ml * 3).Organic phase distilled water wash (50ml * 10), anhydrous sodium sulfate drying filters, concentrating under reduced pressure, column chromatography is separated (ethanol/methylene=1/99), obtains white solid 0.24g. 1H NMR(400MHz，CDCl 3)δ：1.06(s，3H，18-CH 3)，1.30(s，3H，19-CH 3)，2.52(m，1H，-OCH(CH 3) 2)，4.88(t，1H，6-H)，7.45(s，1H，4-NH)。EI-MS(m/z)：344.2(M +)，287.1，285.1，228.1，176.1，137.1，91.0，43.0，28.0。Obtain 3-carbonyl-4-4-sec.-propyl-azepine-5-androstene-17-oxime N-O-isopropyl ether 0.08g simultaneously. 1H NMR(400MHz，CDCl 3)δ：0.91(s，3H，18-CH 3)，0.92(s，3H，19-CH 3)，3.41(m，1H，-OCH(CH 3) 2)，3.87(m，1H，N-CH(CH 3) 2)，4.98(t，1H，6-H)。EI-MS(m/z)：386.1(M +)，358.1，285.0，179.9，148.9，57.0，43.0。
Adopt the preparation method of embodiment 1, embodiment 2, embodiment 3 and embodiment 4, use the iodoethane in the step 4 among the embodiment, benzyl chloride, different butyl iodide or different iodopropane instead other alkane iodide, bromo alkane, bromobenzyl, iodine benzyl or replace bromobenzyl, replacement benzyl chloride, replacement iodine benzyl, halogeno-benzene ethane and halogeno-benzene propane, can synthesize following compounds: 3-carbonyl-4-azepine-3-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-propyl group-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-butyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-isopentyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-chlorobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether.
The preparation of embodiment 5:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether:
Step 1:5,17-carbonyl-A-loses carbon-3, the preparation of 5-cracking-etioallocholane-3-carboxylic acid:
With androstane-4-alkene-3,17-diketone (10.0g, 35.0mmol) be dissolved in the trimethyl carbinol (350mL), stirring is following to the aqueous solution that wherein adds anhydrous sodium carbonate (18.6g, 20%), and is warming up to 100 ℃, slowly drip sodium periodate (37.4g, 0.18mol) and potassium permanganate (0.55g, 3.5mmol) water-soluble (250mL) solution of forming drips off in 1.5h.After dropwising, backflow 5h.Be cooled to room temperature, filtration, water (50mL * 4) washing leaching cake, most of trimethyl carbinol is removed in the filtrate decompression distillation, transfers pH ≈ 1.5 with dilute hydrochloric acid, methylene dichloride (100mL * 3) extraction, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets light yellow paste.Column chromatography is separated (ethyl acetate/petroleum ether=3/7), gets white solid product (5.71g, 53.4%). 1HNMR(400MHz，CDCl 3)δ：0.81(s，3H，18-CH 3)，1.02(s，3H，19-CH 3)，10.05(broad，1H，-COOH)。IR(KBr，v/cm-1)：3351(broad)，2974，2932，1710，1472，1373，1198，1023，912，749。
Step 2:3, the preparation of 17-carbonyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, and ice bath feeds ammonia down, and (8.3g 0.49mol), slowly is warming up to 150 ℃ then, and reacts about 0.5h under this temperature, is cooled to room temperature.Dilute with water stirs 1h.Transfer pH ≈ 1.5 with dilute hydrochloric acid, leave standstill, filter, the thorough washing filter cake, drying obtains off-white color pressed powder (4.7g, 57.2%). 1H NMR(400MHz，CDCl 3)δ：0.89(s，3H，18-CH 3)，1.10(s，3H，19-CH 3)，4.91(t，1H，6-H)，8.10(s，1H，4-H)。 13C NMR(400MHz，CDCl 3)δ：13.62，18.72，20.26，21.78，28.14，28.64，31.17，31.30，31.34，34.32，35.72，47.57，48.13，51.53，103.31(6-C)，140.09(5-C)，169.95(3-C)，220.21(17-C)。EI-MS(m/z)：287.1(m +)，137.1，44.0。
The preparation of step 3:3-carbonyl-4-azepine-5-androstene-17-oxime:
With 3,17-carbonyl-4-azepine-5-androstene (6.7g, 23.3mmol) be suspended in aqueous ethanolic solution (50%, 80mL), then with oxammonium hydrochloride (10.5g, 0.15mol) and Potassium ethanoate (17.1g 0.17mol) is dissolved in aqueous ethanolic solution (50%, 180mL) and join in the above-mentioned suspension, 80 ℃ of reaction 8h.Be cooled to the room temperature after-filtration, it is neutral washing filter cake to filtrate with massive laundering, obtains off-white color solid (6.38g, yield 90.5%). 1H NMR(400MHz，DMSO-d 6)δ：0.85(s，3H，18-CH 3)，1.01(s，3H，19-CH 3)，4.85(s，1H，6-H)，9.28(s，1H，4-NH)，10.05(s，1H，-OH)。 13C NMR(400MHz，DMSO-h 6)δ：17.03，18.41，20.03，22.72，24.77，28.15，28.67，30.48，31.06，33.52，33.83，42.94，47.74，53.49，100.80(6-C)，140.75(5-C)，167.75(17-C)，167.80(3-C)。EI-MS(m/z)：302.1(M +)，286.1，230.1，189.1，176.0，137.0，96.0，44.0，28.0。
The preparation of step 4:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester:
(100mg, 0.33mmol) (40.5mg 0.33mmol) is dissolved in the methylene dichloride (15mL), and (93.1mg, 0.66mmol), stirring at room is reacted 3h to Benzoyl chloride with the 4-Dimethylamino pyridine with 3-carbonyl-4-azepine-5-androstene-17-oxime.Concentrating under reduced pressure then, column chromatography (MeOH/CH 2Cl 2=2/98) separates, obtain white crystal (67.2mg, yield 50.0%). 1H NMR(400MHz，CDCl 3)δ：0.92(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，4.93(t，1H，6-H)，7.42～8.04(m，5H，-C 6H 5)，8.75(s，1H，4-NH)。 13C NMR(400MHz，CDCl 3)δ：17.01，18.84，20.50，23.20，27.34，28.40，29.25，31.24，31.53，33.40，34.30，34.34，45.29，48.04，103.10(6-C)，140.19(5-C)，164.06(17-C)，170.05(3-C)，179.10(-OCO-)，128.50～133.15(6C，-C 6H 5)。EI-MS(m/z)：406.1(M +)，368.2，286.1，228.0，174.0，137.1，96.0，41.0
The preparation of embodiment 6:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester:
The step 1 of present embodiment, step 2, step 3 are with embodiment 5.
The preparation of step 4:3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester:
With 3-carbonyl-4-azepine-5-androstene-17-oxime (100mg, 0.33mmol) (40.5mg 0.33mmol) is dissolved in the methylene dichloride (15mL) with the 4-Dimethylamino pyridine, to methyl benzoyl chloride (54.4mg, 0.35mmol), 50 ℃ of stirring reaction 2h are concentrating under reduced pressure then, column chromatography (MeOH/CH 2Cl 2=2/98) separates, obtain white crystal (86.3mg, yield 62.3%). 1H NMR(400MHz，CDCl 3)δ：0.92(s，3H，18-CH 3)，1.08(s，3H，19-CH 3)，2.48(s，3H，-C 6H 4CH 3)，4.99(t，1H，6-H)，7.29(s，1H，4-NH)，7.93～8.01(m，4H，-C 6H 4CH 3)。EI-MS(m/z)：420.2(M +)，285.2，135.0，91.1，39.0
Adopt the preparation method of embodiment 5 and embodiment 6, to methyl benzoyl chloride be used instead fat acyl chlorides such as anisoyl chloride, paranitrobenzoyl chloride, other substituted benzoyl chloride, phenyllacetyl chloride, formyl chloride, Acetyl Chloride 98Min. and substituted benzoic acid, substituted phenylacetic acid, formic acid, acetate lipid acid in the step 4 among Benzoyl chloride in the step 4 among the embodiment 5 or the embodiment 6, can synthesize following compounds: 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate.
The preparation of embodiment 7:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester:
Step 1:5,17-carbonyl-A-loses carbon-3, the preparation of 5-cracking-etioallocholane-3-carboxylic acid:
With androstane-4-alkene-3,17-diketone (10.0g, 35.0mmol) be dissolved in the trimethyl carbinol (350mL), stirring is following to the aqueous solution that wherein adds Anhydrous potassium carbonate (72.4g, 20%), and is warming up to 80 ℃, slowly drip sodium periodate (56.2g, 0.26mol) and potassium permanganate (1.0g, 6.3mmol) water-soluble (250mL) solution of forming drips off in 2.0h.After dropwising, backflow 6h.Be cooled to room temperature, filtration, water (50mL * 4) washing leaching cake, most of trimethyl carbinol is removed in the filtrate decompression distillation, transfers pH ≈ 1.5 with dilute hydrochloric acid, methylene dichloride (100mL * 3) extraction, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets light yellow paste.Column chromatography is separated (ethyl acetate/petroleum ether=3/7), gets white solid product (7.15g, 66.8%). 1HNMR(400MHz，CDCl 3)δ：0.81(s，3H，18-CH 3)，1.02(s，3H，19-CH 3)，10.05(broad，1H，-COOH)。IR(KBr，v/cm-1)：3351(broad)，2974，2932，1710，1472，1373，1198，1023，912，749。
Step 2:3, the preparation of 17-carbonyl-4-methyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, adds methylamine alcohol solution (33g, 33%), one night of stirring at room.Slowly be warming up to 180 ℃ then, react 0.5h under this temperature, be cooled to room temperature, thin up stirs 1h.Be acidified to pH ≈ 1.5 with dilute hydrochloric acid, filter, the thorough washing filter cake, drying gets yellow solid (6.0g, yield 69.3%). 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，3.10(s，3H，N-CH 3)，5.03(t，1H，6-H)。 13C NMR(400MHz，CDCl 3)δ：13.57，18.85，20.24，21.77，28.83，29.56，30.63，31.17，31.20，31.68，35.49，35.76，47.49，48.96，51.49(N-CH 3)，103.71(6-C)，144.42(5-C)，168.28(3-C)，220.36(17-C)。EI-MS(m/z)：301.4(M +)，151.3，96.0，44.0
The preparation of step 3:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime:
With 3,17-carbonyl-4-methyl-4-azepine-5-androstene (7.3g, 24.3mmol) be dissolved in aqueous ethanolic solution (100mL, 50%) in, then with oxammonium hydrochloride (12.7g, 0.18mol), (14.3g 0.15mol) is dissolved in aqueous ethanolic solution (100mL to Potassium ethanoate, 50%) 60 ℃ of reaction 5h and join in the above-mentioned solution.Reaction finishes ethanol is steamed, and filters, and gets off-white color solid (7.0g, yield 91.4%). 1H NMR(400MHz，DMSO-d 6)δ：0.85(s，3H，18-CH 3)，0.99(s，3H，19-CH 3)，2.99(s，1H，N-CH 3)，5.04(s，1H，6-H)，10.06(s，1H，-OH)。 13C NMR(400MHz，DMSO-d 6)δ：16.97，18.55，20.00，22.70，24.78，28.41，29.54，29.86，30.43，30.99，33.82，34.89，42.86，48.46，53.37(N-CH 3)，103.09(6-C)，143.96(5-C)，166.96(17-C)，167.56(3-C)。EI-MS(m/z)：316.3(M +)，244.2，151.2，108.1，55.0，41.0。
The preparation of step 4:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether:
With 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime (100mg, 0.32mmol) (40.5mg 0.32mmol) is dissolved in the methylene dichloride (15mL), drips methyl benzoyl chloride (148.4mg with the 4-Dimethylamino pyridine, 0.96mmol), 40 ℃ of stirring reaction 3h.Concentrating under reduced pressure then, column chromatography (MeOH/CH 2Cl 2=2/98) separates, obtain white crystal (115.8mg, yield 83.4%). 1H NMR(400MHz，CDCl 3)δ：1.09(s，3H，18-CH 3)，1.12(s，3H，19-CH 3)，2.42(s，3H，-C 6H 4CH 3)，3.13(s，3H，N-CH 3)，5.05(t，1H，6-H)，7.24～7.26(m，2H，-C 6H 4CH 3)，7.92～7.94(m，2H，-C 6H 4CH 3)
The preparation of embodiment 8:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester:
Step 1:5,17-carbonyl-A-loses carbon-3, the preparation of 5-cracking-etioallocholane-3-carboxylic acid:
With androstane-4-alkene-3,17-diketone (10.0g, 35.0mmol) be dissolved in the trimethyl carbinol (350mL), stirring is following to the aqueous solution that wherein adds Anhydrous potassium carbonate (50.7g, 20%), and is warming up to 90 ℃, slowly drip sodium periodate (47.1g, 0.22mol) and potassium permanganate (0.91g, 5.8mmol) water-soluble (250mL) solution of forming drips off in 1.5h.After dropwising, backflow 5h.Be cooled to room temperature, filtration, water (50mL * 4) washing leaching cake, most of trimethyl carbinol is removed in the filtrate decompression distillation, transfers pH ≈ 1.5 with dilute hydrochloric acid, methylene dichloride (100mL * 3) extraction, anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets light yellow paste.Column chromatography is separated (ethyl acetate/petroleum ether=3/7), gets white solid product (8.78g, 82.1%). 1H NMR(400MHz，CDCl 3)δ：0.81(s，3H，18-CH 3)，1.02(s，3H，19-CH 3)，10.05(broad，1H，-COOH)。IR(KBr，v/cm-1)：3351(broad)，2974，2932，1710，1472，1373，1198，1023，912，749。
Step 2:3, the preparation of 17-carbonyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, and ice bath feeds ammonia down, and (9.0g 0.53mol), slowly is warming up to 170 ℃ then, and reacts about 0.5h under this temperature, is cooled to room temperature.Dilute with water stirs 1h.Transfer pH ≈ 1.5 with dilute hydrochloric acid, leave standstill, filter, the thorough washing filter cake, drying obtains off-white color pressed powder (6.4g, 77.9%). 1H NMR(400MHz，CDCl 3)δ：0.89(s，3H，18-CH 3)，1.10(s，3H，19-CH 3)，4.91(t，1H，6-H)，8.10(s，1H，4-H)。 13C NMR(400MHz，CDCl 3)δ：13.62，18.72，20.26，21.78，28.14，28.64，31.17，31.30，31.34，34.32，35.72，47.57，48.13，51.53，103.31(6-C)，140.09(5-C)，169.95(3-C)，220.21(17-C)。EI-MS(m/z)：287.1(M +)，137.1，44.0。
Step 3:3, the preparation of 17-carbonyl-4-methyl-4-azepine-5-androstene:
With 3,17-carbonyl-4-azepine-5-androstene (0.8g, 2.79mmol) and sodium hydride (0.14g, 52%, 3.0mmol) be dissolved among the DMF (15mL), stir down 15min at 24 ℃; (0.56mL, 9.0mmol), after stirring 30min under 24 ℃, (0.19mL 3.0mmol), rises to 50 ℃ with temperature of reaction, reaction 2h to add methyl iodide again to drip methyl iodide.Cooling adds distilled water (75mL) dilution, puts into the refrigerator internal cooling, leaves standstill, filter yellow solid (0.3g, yield 37.5%). 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，3.10(s，3H，N-CH 3)，5.03(t，1H，6-H)。 13C NMR(400MHz，CDCl 3)δ：13.57，18.85，20.24，21.77，28.83，29.56，30.63，31.17，31.20，31.68，35.49，35.76，47.49，48.96，51.49(N-CH 3)，103.71(6-C)，144.42(5-C)，168.28(3-C)，220.36(17-C)。EI-MS(m/z)：301.4(M +)，151.3，96.0，44.0。
The preparation of step 4:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime:
With 3,17-carbonyl-4-methyl-4-azepine-5-androstene (7.3g, 24.3mmol) be dissolved in aqueous ethanolic solution (100mL, 50%) in, then with oxammonium hydrochloride (17.1g, 0.22mol), (23.2g 0.24mol) is dissolved in aqueous ethanolic solution (100mL to Potassium ethanoate, 50%) 40 ℃ of reaction 8h and join in the above-mentioned solution.Reaction finishes ethanol is steamed, and filters, and gets off-white color solid (6.8g, yield 88.8%). 1H NMR(400MHz，DMSO-d 6)δ：0.85(s，3H，18-CH 3)，0.99(s，3H，19-CH 3)，2.99(s，1H，N-CH 3)，5.04(s，1H，6-H)，10.06(s，1H，-OH)。 13C NMR(400MHz，DMSO-d 6)δ：16.97，18.55，20.00，22.70，24.78，28.41，29.54，29.86，30.43，30.99，33.82，34.89，42.86，48.46，53.37(N-CH 3)，103.09(6-C)，143.96(5-C)，166.96(17-C)，167.56(3-C)。EI-MS(m/z)：316.3(M +)，244.2，151.2，108.1，55.0，41.0。
The preparation of step 5:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester:
With 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime (100mg, 0.32mmol) (40.5mg 0.32mmol) is dissolved in the methylene dichloride (15mL), drips paranitrobenzoyl chloride (118.8mg with the 4-Dimethylamino pyridine, 0.64mmol), stirring at room reaction 3h.Concentrating under reduced pressure then, column chromatography (MeOH/CH 2Cl 2=2/98) separates, obtain yellow crystals (110.6mg, yield 74.3%). 1H NMR(400MHz，CDCl 3)δ：1.10(s，3H，18-CH 3)，1.11(s，3H，19-CH 3)，3.13(s，3H，N-CH 3)，5.04(t，1H，6-H)，8.20～8.32(m，4H，-C 6H 4NO 2)
The preparation of embodiment 9:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether:
The step 1 of present embodiment is with embodiment 7.
Step 2:3, the preparation of 17-carbonyl-4-methyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, adds methylamine alcohol solution (53.7g, 33%), one night of stirring at room.Slowly be warming up to 150 ℃ then, react 0.5h under this temperature, be cooled to room temperature, thin up stirs 1h.Be acidified to pH ≈ 1.5 with dilute hydrochloric acid, filter, the thorough washing filter cake, drying gets yellow solid (5.54g, yield 63.9%). 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，3.10(s，3H，N-CH 3)，5.03(t，1H，6-H)。 13C NMR(400MHz，CDCl 3)δ：13.57，18.85，20.24，21.77，28.83，29.56，30.63，31.17，31.20，31.68，35.49，35.76，47.49，48.96，51.49(N-CH 3)，103.71(6-C)，144.42(5-C)，168.28(3-C)，220.36(17-C)。EI-MS(m/z)：301.4(M +)，151.3，96.0，44.0
The preparation of step 3:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime:
The step 3 of present embodiment is with embodiment 7.
The preparation of step 4:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether:
(100mg, 0.32mmol) (40.5mg 0.33mmol) is dissolved in the methylene dichloride (15mL), and (88.8mg, 0.64mmol), stirring at room is reacted 3h to drip Benzoyl chloride with the 4-Dimethylamino pyridine with 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime.Concentrating under reduced pressure then, column chromatography (MeOH/CH 2Cl 2=2/98) separates, obtain clear crystal (106.2mg, yield 80.0%). 1H NMR(400MHz，CDCl 3)δ：0.89(s，3H，18-CH 3)，1.06(s，3H，19-CH 3)，3.09(s，3H，N-CH 3)，5.01(t，1H，6-H)，7.38～8.01(m，5H，-C 6H 5)。 13C NMR(400MHz，CDCl 3)δ：16.69，18.68，20.22，22.92，27.11，28.63，29.90，30.29，31.01，31.46，33.18，35.27，44.96，48.59，53.58(N-CH 3)，103.68(6-C)，144.19(5-C)，163.75(17-C)，168.25(3-C)，178.82(-OCO-)，128.20～132.89(6C，-C 6H 5)。EI-MS(m/z)：420.2(M +)，300.2，244.1，190.1，122.0，77.0，51.0
Adopt the preparation method of embodiment 7, embodiment 8 and embodiment 9, with Benzoyl chloride, the paranitrobenzoyl chloride of step 4 among step 5 and the embodiment 9 among step 4, the embodiment 8 among the embodiment 7, methyl benzoyl chloride is used instead fat acyl chlorides such as anisoyl chloride, other substituted benzoyl chloride, phenyllacetyl chloride, formyl chloride, Acetyl Chloride 98Min. and substituted benzoic acid, substituted phenylacetic acid, formic acid, acetate lipid acid, can synthesize following compounds: 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-methyl-4-azepine-5--androstene-17-oxime N-O-benzoic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-homoanisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate.
The preparation of embodiment 10:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether:
The step 1 of present embodiment is with embodiment 7.
Step 2:3, the preparation of 17-carbonyl-4-methyl-4-azepine-5-androstene:
With 5,17-carbonyl-A-loses carbon-3, and (8.75g 28.6mmol) is dissolved in 60mL ethylene glycol to 5-cracking-etioallocholane-3-carboxylic acid, adds methylamine alcohol solution (40.3g, 33%), one night of stirring at room.Slowly be warming up to 170 ℃ then, react 0.5h under this temperature, be cooled to room temperature, thin up stirs 1h.Be acidified to pH ≈ 1.5 with dilute hydrochloric acid, filter, the thorough washing filter cake, drying gets yellow solid (6.4g, yield 73.9%). 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，3.10(s，3H，N-CH 3)，5.03(t，1H，6-H)。 13C NMR(400MHz，CDCl 3)δ：13.57，18.85，20.24，21.77，28.83，29.56，30.63，31.17，31.20，31.68，35.49，35.76，47.49，48.96，51.49(N-CH 3)，103.71(6-C)，144.42(5-C)，168.28(3-C)，220.36(17-C)。EI-MS(m/z)：301.4(M +)，151.3，96.0，44.0
The preparation of step 3:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime:
With 3,17-carbonyl-4-methyl-4-azepine-5-androstene (7.3g, 24.3mmol) be dissolved in aqueous ethanolic solution (100mL, 50%) in, then with oxammonium hydrochloride (9.9g, 0.14mol), (18.1g 0.19mol) is dissolved in aqueous ethanolic solution (100mL to Potassium ethanoate, 50%) 80 ℃ of reaction 3h and join in the above-mentioned solution.Reaction finishes ethanol is steamed, and filters, and gets off-white color solid (5.9g, yield 77.1%). 1H NMR(400MHz，DMSO-d 6)δ：0.85(s，3H，18-CH 3)，0.99(s，3H，19-CH 3)，2.99(s，1H，N-CH 3)，5.04(s，1H，6-H)，10.06(s，1H，-OH)。 13C NMR(400MHz，DMSO-d 6)δ：16.97，18.55，20.00，22.70，24.78，28.41，29.54，29.86，30.43，30.99，33.82，34.89，42.86，48.46，53.37(N-CH 3)，103.09(6-C)，143.96(5-C)，166.96(17-C)，167.56(3-C)。EI-MS(m/z)：316.3(M +)，244.2，151.2，108.1，55.0，41.0。
The preparation of step 4:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether:
With 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime (1.0g, 3.16mmol) and potassium hydroxide (0.54g 9.6mmol) is dissolved among the DMF (60mL), drip different iodopropane (1.6mL, 15.8mmol), 40 ℃ the reaction 8h.Add water (100mL) dilution, methylene dichloride (50mL * 3) extraction.Organic phase is washed with distilled water (50mL * 10), and anhydrous sodium sulfate drying filters, concentrating under reduced pressure, and column chromatography is separated (ethanol/methylene=2/98), gets off-white color solid (0.33g, yield 29.2%). 1H NMR(400MHz，CDCl 3)δ：0.96(s，3H，18-CH 3)，1.10(s，3H，19-CH 3)，3.15(s，3H，N-CH 3)，4.32(m，1H，-OCH(CH 3) 2)，5.08(t，1H，6-H)。EI-MS(m/z)：358.1(M +)，299.1，242.0，179.9，151.0，91.0，43.0，29.0。
The preparation of embodiment 11:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether:
The step 1 of present embodiment, step 2 are with embodiment 8.
Step 3:3, the preparation of 17-carbonyl-4-methyl-4-azepine-5-androstene:
With 3,17-carbonyl-4-azepine-5-androstene (0.8g, 2.79mmol) and sodium hydride (0.14g, 52%) be dissolved among the DMF (15mL), stir down 15min at 20 ℃; (0.7mL, 11.2mmol), after stirring 30min under 24 ℃, (0.3mL 4.8mmol), rises to 50 ℃ with temperature of reaction, reaction 2h to add methyl iodide again to drip methyl iodide.Cooling adds distilled water (75mL) dilution, puts into the refrigerator internal cooling, leaves standstill, filter yellow solid (0.27g, yield 33.8%). 1H NMR(400MHz，CDCl 3)δ：0.88(s，3H，18-CH 3)，1.05(s，3H，19-CH 3)，3.10(s，3H，N-CH 3)，5.03(t，1H，6-H)。 13C NMR(400MHz，CDCl 3)δ：13.57，18.85，20.24，21.77，28.83，29.56，30.63，31.17，31.20，31.68，35.49，35.76，47.49，48.96，51.49(N-CH 3)，103.71(6-C)，144.42(5-C)，168.28(3-C)，220.36(17-C)。EI-MS(m/z)：301.4(M +)，151.3，96.0，44.0。
The preparation of step 4:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime:
The step 4 of present embodiment is with embodiment 8.
The preparation of step 5:3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether:
With 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime (1.0g, 3.16mmol) and potassium hydroxide (0.54g 9.6mmol) is dissolved among the DMF (60mL), drip benzyl chloride (2.12mL, 18.96mmol), 50 ℃ of reaction 8h.Add water (100mL) dilution, methylene dichloride (50mL * 3) extraction.Organic phase is washed with distilled water (100mL * 5), and anhydrous sodium sulfate drying filters, concentrating under reduced pressure, and column chromatography is separated (ethanol/methylene=2/98), gets off-white color solid (0.46g, yield 35.9%). 1H NMR(400MHz，CDCl 3)δ：0.92(s，3H，18-CH 3)，1.07(s，3H，19-CH 3)，3.12(s，3H，N-CH 3)，4.25(s，2H，-CH 2C 6H 5)，5.07(t，1H，6-H)，7.26～7.36(m，5H，-C 6H 5)。EI-MS(m/z)：406.1(M +)，299.1，256.1，169.1，111.0，57.0，43.0。
Adopt the preparation method of embodiment 10 and embodiment 11, benzyl chloride in the step 5 among different iodopropane in the step 4 among the embodiment 10 or the embodiment 11 is used instead halogenated alkane such as methyl iodide, iodoethane, different butyl iodide, monobromethane, monobromethane, alkane iodide, bromo alkane or replaced benzyl chloride, bromobenzyl, replacement bromobenzyl, bromobenzene ethane, bromobenzene propane, can synthesize following compounds: 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-ethyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isobutyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-.
Two. the 5 of steroidal compounds suppresses active
Step 1: the preparation of steroidal 5:
Get 3 female sd inbred rats (about body weight 300g), fasting is got liver after one night, the vein perfusion also immerses in PBS 7.2 liquid, clean about the every part of 1g in back, on the ice platform, shred (2mm size), add PBS 7.2 liquid of 10 times of volumes, use the ULTRA-TURRAX refiner in the ice bath with 12000g/min homogenate three times, each 5 seconds, 30 seconds at interval.Should keep low temperature in the operating process, agents useful for same and articles for use also must low temperature.Homogenate is centrifugal with supercentrifuge 12000g * 25min, carefully extract supernatant liquor, get PMS.PMS is centrifugal with ultracentrifuge 100000g * 1h, outwell supernatant, precipitation is resuspended in PBS (containing 30% glycerine, 1: 5 (v/v)), get the microsome suspension liquid.It is standby to place-70 ℃ of refrigerators to preserve.
Step 2: the mensuration of enzymic activity:
5 catalysis testosterone changes the participation that needs coenzyme NADP 11 in the dihydrotestosterone process into.Reduced-NADP H has characteristic absorbance at the 340nm place, carrying out NADPH and will change oxidized form NADP into along with reaction +, the characteristic absorbance at its 340nm wavelength place disappears.Change in the characteristic absorbance at 340nm wavelength place according to NADPH in the reaction process, can screen the inhibitor of 5.
(I) mensuration of blank: add Buffer 2ml in the reaction tubes, testosterone 100 μ l, PBS 200 μ l, coenzyme NADP 11 15 μ l add 15 μ l 5s at last, mix the back and measure A 340nmValue is hatched for 37 ℃, measures A behind the reaction 10min 340nmValue.Deduction NADPH blank decline background values is measured blank drop-out value (the Δ A of DMSO 0).Each triplicate when experiment beginning and end.
(II) mensuration of compound sample: add Buffer 2ml in the reaction tubes, testosterone 100 μ l, (starting point concentration is 10 to inhibitor -5If mol/L is inhibiting rate＞50%, then dilution downwards) 200 μ l, NADPH 15 μ l add 15 μ l enzymes at last, mix the back and measure A 340nmValue is hatched for 37 ℃, measures A behind the reaction 10min 340nmValue.Deduction NADPH blank decline background values is measured inhibitor drop-out value (Δ An).With the positive medicine of epristeride, calculate the inhibiting rate of enzyme.The experiment triplicate.
Calculation formula: I (%)=(Δ A 0-Δ An)/Δ A 0* 100%
(III) result judges: if 10 -5The inhibiting rate of given the test agent under the mol/L concentration.＞50%, can think that given the test agent has stronger 5 and suppresses active, can carry out next step screening, then the given the test agent concentration dilution is 10 times, suppresses active mensuration once more, and the rest may be inferred.
Step 3: compound sample is to the inhibition activity of mouse 5
Each test-compound the results are shown in following table to the inhibition activity test of mouse 5.The result shows that each test-compound all has 5 in various degree to suppress active, and wherein sample 1,2,3 and 4 is 10 in concentration -5During mol/L to the inhibiting rate of 5 all greater than 50%, illustrated that 5 suppresses active preferably.
It is object of reference that epristeride is selected in this experiment.Under this experiment condition, with the epristeride comparison of same concentrations, wherein the inhibition of 1,2,3 pairs of 5s of sample is active suitable with epristeride.
Table 1 compound sample is to the inhibiting rate of mouse 5
Test-compound Concentration (mol/L) Test routine number n I％
Blank - 6 -
Epristeride 10 -5 3 62.93±6.36
10 -6 3 37.52±4.76
Sample 1 (example 1) 10 -5 3 68.06±1.07
Sample 2 (example 2) 10 -5 3 64.57±4.22
Sample 3 (example 3) 10 -5 3 63.86±4.27
Sample 5 (example 5) 10 -5 3 33.80±5.61
Sample 7 (example 7) 10 -5 3 40.79±5.70
Sample 8 (example 8) 10 -5 3 34.45±14.36
Sample 9 (example 9) 10 -5 3 26.89±3.03
Sample 11 (example 11) 10 -5 3 32.21±1.75
Sample 12 (embodiment is outer) 10 -5 3 50.35±1.85
Sample 13 (embodiment is outer) 10 -5 3 43.59±7.34
Sample 14 (embodiment is outer) 10 -5 3 32.63±4.10

Claims (8)

1. one kind has 5 and suppresses active steroidal compounds, it is characterized in that structural formula is as follows:
Figure A2005101360090002C1
Wherein: R 1For: hydrogen, C 1-C 5Alkyl and benzyl in a kind of; R 2For: C 1-C 8Alkyl, C 1-C 8Alkyloyl, benzyl, substituted benzyl, benzoyl, a kind of in the benzoyl of phenylacetyl and replacement.
2. have 5 and suppress active steroidal compounds by claim 1 is described, comprise following compounds: 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-propyl group-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-butyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-isopentyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-chlorobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether, 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-manthanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-acetic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propionic ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopentanoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-capronate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzoic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-phenylacetate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-methylbenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-anisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-p-nitrobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-homoanisic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-parabromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-o-bromobenzoic acid ester; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to trifluoro methyl benzoate; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-methyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-ethyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-propyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isopropyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-butyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isobutyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-isoamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-benzylic ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to methoxy-benzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to nitrobenzyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-styroyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-hydrocinnamyl ether; 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-is to bromobenzyl ether; The adjacent bromobenzyl ether of 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime N-O-.
3. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 60-80 ℃, react 3-carbonyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) and 3-carbonyl-4-alkane (virtue) base-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction under the potassium hydroxide effect of 2-4 mole.
4. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 60-80 ℃, react 3-carbonyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
5. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3, the methylamine of 5-cracking-etioallocholane-3-carboxylic acid and 10-20 mole in 15-180 ℃ down reaction generate 3,17-carbonyl-4-methyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-methyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction in the presence of the potassium hydroxide of 3-4 mole.
6. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3, the methylamine of 5-cracking-etioallocholane-3-carboxylic acid and 10-20 mole in 15-180 ℃ down reaction generate 3,17-carbonyl-4-methyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester or 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
7. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene can obtain 3 in 20-50 ℃ of reaction, 17-carbonyl-4-methyl-4-azepine-5-androstene with the methyl iodide of 4-6 mole in the presence of the sodium hydride of 1.0-1.1 mole; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is generated 3-carbonyl-4-methyl-4-azepine-5-androstene-basic ether of 17-oxime N-O-alkane (virtue) with halohydrocarbon in 30-80 ℃ of reaction in the presence of the potassium hydroxide of 3-4 mole.
8. one kind has a preparation method that 5 suppresses active steroidal compounds by claim 1 is described, it is characterized in that comprising following process: be solvent with the trimethyl carbinol, androstane-4-alkene-3 with 1 mole, the 17-diketone acts on 80-100 ℃ of following oxidation with the salt of wormwood of the potassium permanganate of the sodium periodate of 5-8 mole and 0.05-0.2 mole and 1～3 mole or yellow soda ash and generates 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid; With 1 mole 5,17-carbonyl-A-loses carbon-3,5-cracking-etioallocholane-3-carboxylic acid is 3 with the ammonia of 10-20 mole in 150-180 ℃ of cyclization, 17-carbonyl-4-azepine-5-androstene; With 1 mole 3,17-carbonyl-4-azepine-5-androstene can obtain 3 in 20-50 ℃ of reaction, 17-carbonyl-4-methyl-4-azepine-5-androstene with the methyl iodide of 4-6 mole in the presence of the sodium hydride of 1.0-1.1 mole; With 1 mole 3,17-carbonyl-4-methyl-4-azepine-5-androstene with the Potassium ethanoate of the oxammonium hydrochloride of 5-10 mole and 5-10 mole under 30-80 ℃, react 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime; 1 mole 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime is obtained 3-carbonyl-4-azepine-5-androstene-17-oxime ester or 3-carbonyl-4-methyl-4-azepine-5-androstene-17-oxime ester with the acyl chlorides of 1-3 mole in 15-60 ℃ of following condensation under 1 mole 4-Dimethylamino pyridine effect.
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CN110628735A (en) * 2019-04-23 2019-12-31 天津科技大学 5 alpha-reductase mutant, genetically engineered bacterium and application of genetically engineered bacterium in efficient catalysis of 5 alpha-AD production

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CN101759762B (en) * 2008-11-06 2013-03-20 天津金耀集团有限公司 Application of 4AD in preparing dutasteride
CN110628735A (en) * 2019-04-23 2019-12-31 天津科技大学 5 alpha-reductase mutant, genetically engineered bacterium and application of genetically engineered bacterium in efficient catalysis of 5 alpha-AD production
CN110628735B (en) * 2019-04-23 2022-04-08 天津科技大学 5 alpha-reductase mutant, genetically engineered bacterium and application of genetically engineered bacterium in efficient catalysis of 5 alpha-AD production

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