CN1718586A - Synthesis method of N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androl-1-end-17 beta-formamide - Google Patents
Synthesis method of N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androl-1-end-17 beta-formamide Download PDFInfo
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- CN1718586A CN1718586A CN 200510018885 CN200510018885A CN1718586A CN 1718586 A CN1718586 A CN 1718586A CN 200510018885 CN200510018885 CN 200510018885 CN 200510018885 A CN200510018885 A CN 200510018885A CN 1718586 A CN1718586 A CN 1718586A
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Abstract
A process for synthesizing N-tert-butyl-3-carbonyl-4-a2Q-5 alpha-androst-1-ene-17 beta-formamide, that is phenandrostamine, includes such steps as providing 4-androstene-3, 17-dione as raw material, oxidizing for opening loop to obtain 5, 17-dicarbonyl-3, 5-openloop-androst-3-acid, reacting on ammonium acetate for closing loop to obtain 4-azasterol compound, cyanoalcoholizing, dewatering, Ritter reaction on tert-butanol, hydrogenating and dehydrogenating.
Description
Technical field
The present invention relates to the method for a kind of synthesizing steroid medicine finasteride (being the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide).
Background technology
Finasteride is a kind of 5 inhibitor, is the novel specifics of a class of treatment benign prostate hyperplasia (BPH).Its chemical name is: the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide, and molecular formula is: C22H36N2O2, structural formula is:
Existing synthetic method mainly contain people such as the Rasmusson of Merck company synthetic method (United States Patent (USP): 4760071), its route is:
2 can be that raw material is synthetic (referring to J Med Chem 1984,27,1690-1701) by Vitarrine.The subject matter that aforesaid method exists: it is too much to count this method reactions steps of preparation of 2 in; Need use expensive deleterious sulfide by 4 preparations 5.
European patent on above-mentioned route basis: 0599376 and United States Patent (USP): 2886184 utilize the magnesium halide salts of tertiary butyl ammonia and 17 tertiary butyl lists of ester prepared in reaction substituted amide of 17, and its route is:
But reaction is easy to generate by product, separation difficulty.
United States Patent (USP): 567043 utilize tertiary butyl ammonia and 17 s' acyl chloride reaction to introduce the tertiary butyl, and its route is:
The preparation of the acyl chlorides that reactant is 17 will use the thionyl chloride of contaminate environment and the post of wanting separates.
It is raw material synthesizing finasteride (referring to " medicine industry " magazine 1996 and the paper delivered in 2003) with the Vitarrine that Zheng Jin letters in 1996 etc. have taken the lead in delivering at home, this route is with reference to United States Patent (USP): 4760071 and United States Patent (USP): 567043 synthetic method designs, productive rate is a little more than bibliographical information, but same people such as route Rasmusson have delivered the article of 17 the two substituted amides of analogue that are used to prepare finasteride (referring to J Med Chem 1984 on J Med Chem, 27,1690-1701), so this design lacks novelty.Its reactions steps is:
Summary of the invention
The object of the present invention is to provide the synthetic method route that a technology is simple, novel, with low cost, be suitable for industrial steroid drugs finasteride.
Synthetic method route of the present invention is:
Promptly earlier by starting raw material 4-androstene-3,17-two oxidation of ketones open loops make open-loop products (3), heating close encircle compound (4), carry out 17 cyanohydrination reaction again with sodium cyanide, get compound (5) and carry out the Ritter reaction then, get α, β unsaturated amides (7) gets purpose compound (1) through reduction and dehydrogenation at last.
Concrete synthetic method of the present invention is as follows:
A. by starting raw material 4-androstene-3, the 17-diketone carries out the oxidation open loop with KMnO4-NaIO4 under the trimethyl carbinol-Na2CO3 water solution system, make 5,17-dicarbapentaborane-3,5-open loop-androstene-3-acid; (DDQ:2,3-two chloro-5,6-dicyanobenzoquinone; BSTFA:N, N-TMS trifluoroacetamide).
B. above-mentioned product 5,17-dicarbapentaborane-3,5-open loop-androstene-3-acid under acetate system, directly add ammonium acetate heating close encircle compound 4-azepine-5-androstene-3, the 17-diketone;
C. with product 4-azepine-5-androstene-3 of step B, the 17-diketone carries out 17 cyanohydrination reaction with sodium cyanide in the presence of methylene dichloride, methyl alcohol, acetic acid, 17 Alpha-hydroxy prussiate;
D. under the Alpha-hydroxy prussiate anhydrous pyridine system with 17 of step C products therefroms, with phosphorus oxychloride dewater α, the unsaturated cyanogen of β, its temperature of reaction is 115-135 ℃;
E. with the α of step D gained, special (Ritter) reaction in carrying out with the vitriol oil and the trimethyl carbinol under the Glacial acetic acid system of the unsaturated cyanogen compound of β, α, the β unsaturated amides, its temperature of reaction is lower than 40 ℃;
F. with the α of step e gained, the β unsaturated amides under formic acid system with palladium carbon reduce 17 β-amide compound;
G.. use 2,3-two chloro-5,6-dicyanobenzoquinone (DDQ) carry out oxydehydrogenation to the 17 β-amide compound of step F gained and get the purpose compound: the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide.
The synthetic method route of steroid drugs finasteride of the present invention has following superiority:
Adopted the NEW BEGINNING raw material; Owing to adopt ammonium acetate to close ring, has simple to operate, crystallization purifying advantage easily; Carry out the Ritter reaction with the trimethyl carbinol and introduce 17 β-N-tert-butylamides, have the advantages that raw material is cheap, simple to operate, reactions steps is few; Reduced the consumption of facility investment, reagent and other dressing, making synthetic method of the present invention drop into industrial production becomes possibility.The productive rate of the final product N-tertiary butyl of synthetic method route gained of the present invention-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide is 18.6%, a little more than bibliographical information.
Embodiment
Below in conjunction with concrete embodiment technical scheme of the present invention is further described:
Embodiment 1
One, 5,17-dicarbapentaborane-3,5-open loop-androstane-3-acid (3)
4-androstene-3,17-diketone (2) 4.0g, trimethyl carbinol 100ml at the 50-60 ℃ of aqueous solution that drips potassium permanganate 0.54g, Anhydrous potassium carbonate 4.0g, sodium periodate 16.9g down, finish, and remain on 50-60 ℃ of reaction 3h down.Be chilled to room temperature, the filtering solid.Filtrate decompression is steamed and is removed most of trimethyl carbinol, and the debris ice bath transfers to about pH2 with the hydrochloric acid of 6mol/L down.Use dichloromethane extraction, anhydrous sodium sulfate drying, evaporate to dryness get white solid 3 (3.8g, 91.2%), IR (KBr): 3050-3500,1735,1702.
Two, 4-azepine-5-androstene-3,17-diketone (4)
Above-mentioned product (3) 3.8g, ammonium acetate 2.9g, Glacial acetic acid 40ml, stirring heating backflow 4h boils off acetic acid, and residuum sprinkles in the entry, the washing of precipitation suction filtration, dry white crystal 4 (2.8g, 78.6%), IR:3185,3071,1739,1676,1662 of getting.1HMNR(CDCl3),δ(ppm):7.11(brs,1H,NH),4.82(m,1,H-6),1.13(s,3H,19-CH3),0.92(s,3H,18-CH3)。
Three, 4-azepine-5-androstene-17 Alpha-hydroxy-17 beta-cyanos-3-ketone (5)
Above-mentioned product (4) (2.0g), methyl alcohol (3ml), methylene dichloride (3ml), potassium cyanide (1g), injection glacial acetic acid 500 (μ l) under the room temperature with the bubbler sealing, stirs 24h under the room temperature.Remove methylene dichloride, add entry 100ml, stir 30min, filter, dry white solid 5 (1.0g, 91.4%) IR:3271,2222,1680,1650,1612 of getting.
Four, 4-azepine-androstane-5,16-diene-17-cyanogen-3-ketone (6)
Above-mentioned product (5) (1.0g), the mixed solution of pyridine (10ml), phosphorus oxychloride (2ml) slowly is warmed up to 120 ℃ of backflow 20min, and cooling a little is under vigorous stirring, splash in frozen water (200g) solution that contains 36% hydrochloric acid 10ml, stir 40min, filter, washing, dry greyish white solid 6 (0.75g, 79.5%) IR:3412,3204,2212,1693,1659.
Five, the N-tertiary butyl-3-carbonyl-4-azepine-5,16-androstane diene-17 β-methane amide (7)
Above-mentioned product (6) (1.0g), the trimethyl carbinol (5ml), acetate (15ml) splashes into the vitriol oil (3ml) under the ice bath, stirred 3 hours.Splash in the frozen water, suction filtration gets greyish white solid 7 (1.0g, 79.9%) IR:3425,3211,1695,1675,1655,1593,1506,1391,1364,1217.1HMNR (CDCl3) δ 1.04 (s, 3H, 18-CH3), 1.14 (s, 3H, 19-CH3), 1.38 (s, 9H, C (CH3) 3), 2.52 (m, 2H, H-2), 4.92 (s, 1H, H-6), 5.47 (br, 1H, NH), 6.19 (s, 1H, H-16), 7,79 (brs, 1H, NH).
Six, the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide (8)
Above-mentioned product (7) (1g) under logical condition of nitrogen gas, is dissolved in the solution of 40ml formic acid, adds the muddy liquid that contains 1g palladium carbon and 6ml water.Stir 10h under the room temperature, filter catalyzer, wash with the solution of ethanol/methylene (1: 1).The mother liquor evaporate to dryness gets solid 8 (0.71g, 70%), mp276-277 ℃.IR:3425,1698,1670,1502,1367。1HMNR(CDCl3)δ(ppm):5.39(s,1H,NH),5.07(s,1H,NH),3.04(m,1,5α-H),1.35(s,9H,C(CH3)3),0.91(s,3H,18-CH3),0.69(s,3H,19-CH3)。
Seven, finasteride (1)
Above-mentioned product (8) (1g), DDQ (1g), dioxane 7mL, logical N2 adds under stirring, and drips BSTFA3mL, reflux 18 hours, cool to room temperature adds the sodium disulfide aqueous solution 6ml of CH2Cl230ml and 1%, isolate the CH2Cl2 layer, the NaHSO3 solution extraction twice with 25ml 5% is concentrated into dried, grind with ether, filtration drying gets solid 1 (0.70g, 75.3%), mp253 ~ 255 ℃.IR(KBr)(cm-1):3429,3240,3114,2967,2936,1687,1668,1599,1450,1383,1364,1255,1219,1127,814。1HMNR(CDCl3)δ(ppm):6.78(d,2H,2-H),5.80(dd,2H,1-H),5.37(brs,1H,4-NH),5.07(brs,1H,17-CONH),3.32(m,1H,5α-H),2.14(dd,1H,H-17),1.35(s,9H,C(CH3)3),0.97(s,3H,19-CH3),0.69(s,3H,18-CH3)。
Claims (2)
1. the method for the synthetic N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide, it is characterized in that: earlier by starting raw material 4-androstene-3,17-two oxidation of ketones open loops make open-loop products, heating close encircle compound, carry out 17 cyanohydrination reaction again with sodium cyanide, get compound and carry out Ritter reaction then, get α, the β unsaturated amides gets the purpose compound through reduction and dehydrogenation at last.
2. method according to claim 1 is characterized in that concrete synthesis step is:
A. by starting raw material 4-androstene-3, the 17-diketone is at the trimethyl carbinol-Na
2CO
3Use KMnO under the water solution system
4/ NaIO
4Carry out the oxidation open loop, make 5,17-dicarbapentaborane-3,5-open loop-androstene-3-acid;
B. above-mentioned product 5,17-dicarbapentaborane-3,5-open loop-androstene-3-acid under acetate system, directly add ammonium acetate heating close encircle compound 4-azepine-5-androstene-3, the 17-diketone;
C. with product 4-azepine-5-androstene-3 of step B, the 17-diketone carries out 17 cyanohydrination reaction with sodium cyanide in the presence of methylene dichloride, methyl alcohol, acetic acid, 17 Alpha-hydroxy prussiate;
D. under the Alpha-hydroxy prussiate anhydrous pyridine system with 17 of step C products therefroms, with phosphorus oxychloride dewater α, the unsaturated cyanogen of β, its temperature of reaction is 15-135 ℃;
E. with the α of step D gained, the unsaturated cyanogen compound of β carries out Ritter reaction with the vitriol oil and the trimethyl carbinol under the Glacial acetic acid system, gets α, the β unsaturated amides, and its temperature of reaction is lower than 40 ℃;
F. with the α of step e gained, the β unsaturated amides under formic acid system with palladium carbon reduce 17 β-amide compound;
G. with 2-chloro-2-cyano group benzoquinones the 17 β-amide compound of step F gained is carried out oxydehydrogenation and get the purpose compound: the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-methane amide.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603862A (en) * | 2012-02-29 | 2012-07-25 | 蒋勇 | Finasteride purification method |
CN102838653A (en) * | 2011-06-21 | 2012-12-26 | 重庆医药工业研究院有限责任公司 | Preparation method of 3-carbonyl-4-aza-5 alpha-androstane compound |
CN101759762B (en) * | 2008-11-06 | 2013-03-20 | 天津金耀集团有限公司 | Application of 4AD in preparing dutasteride |
CN102838653B (en) * | 2011-06-21 | 2016-12-14 | 重庆医药工业研究院有限责任公司 | A kind of preparation method of 3-carbonyl-4-aza-5 alpha-androstane |
CN109438549A (en) * | 2018-12-13 | 2019-03-08 | 湖北葛店人福药业有限责任公司 | A method of preparing -17 β of N- tert-butyl -3- oxo -4- aza-5 alpha-androstane-formamide |
CN110229211A (en) * | 2018-12-13 | 2019-09-13 | 湖北葛店人福药业有限责任公司 | A kind of refinery decolorization method of Finasteride |
-
2005
- 2005-06-09 CN CN 200510018885 patent/CN1718586A/en active Pending
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101759762B (en) * | 2008-11-06 | 2013-03-20 | 天津金耀集团有限公司 | Application of 4AD in preparing dutasteride |
CN102838653A (en) * | 2011-06-21 | 2012-12-26 | 重庆医药工业研究院有限责任公司 | Preparation method of 3-carbonyl-4-aza-5 alpha-androstane compound |
CN102838653B (en) * | 2011-06-21 | 2016-12-14 | 重庆医药工业研究院有限责任公司 | A kind of preparation method of 3-carbonyl-4-aza-5 alpha-androstane |
CN102603862A (en) * | 2012-02-29 | 2012-07-25 | 蒋勇 | Finasteride purification method |
CN102603862B (en) * | 2012-02-29 | 2013-09-18 | 蒋勇 | Finasteride purification method |
CN109438549A (en) * | 2018-12-13 | 2019-03-08 | 湖北葛店人福药业有限责任公司 | A method of preparing -17 β of N- tert-butyl -3- oxo -4- aza-5 alpha-androstane-formamide |
CN110229211A (en) * | 2018-12-13 | 2019-09-13 | 湖北葛店人福药业有限责任公司 | A kind of refinery decolorization method of Finasteride |
CN109438549B (en) * | 2018-12-13 | 2022-01-04 | 湖北葛店人福药业有限责任公司 | Method for preparing N-tert-butyl-3-oxo-4-aza-5 alpha-androstane-17 beta-formamide |
CN110229211B (en) * | 2018-12-13 | 2022-04-01 | 湖北葛店人福药业有限责任公司 | Refining and decoloring method of finasteride |
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