CN103254271B - The preparation method of a kind of dutasteride - Google Patents
The preparation method of a kind of dutasteride Download PDFInfo
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- CN103254271B CN103254271B CN201310196108.8A CN201310196108A CN103254271B CN 103254271 B CN103254271 B CN 103254271B CN 201310196108 A CN201310196108 A CN 201310196108A CN 103254271 B CN103254271 B CN 103254271B
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- androstane
- ketone
- methane amide
- alkene
- dutasteride
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- 0 CC(CC1)(C(CC2)C3C1C(C)(CCC(N1)=O)C1=CC3)C2C(O*)=O Chemical compound CC(CC1)(C(CC2)C3C1C(C)(CCC(N1)=O)C1=CC3)C2C(O*)=O 0.000 description 3
- YQACAXHKQZCEOI-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2C(O)=O Chemical compound CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3=CC1=O)C2C(O)=O YQACAXHKQZCEOI-UHFFFAOYSA-N 0.000 description 2
- ZRNZBYKIMSNBSY-UHFFFAOYSA-N CC1(CC2)C(C(Nc3c(C(F)(F)F)ccc(C(F)(F)F)c3)=O)=CCC1C(CCC1N3)C2C1(C)C=CC3=O Chemical compound CC1(CC2)C(C(Nc3c(C(F)(F)F)ccc(C(F)(F)F)c3)=O)=CCC1C(CCC1N3)C2C1(C)C=CC3=O ZRNZBYKIMSNBSY-UHFFFAOYSA-N 0.000 description 2
- AIUHDIPAGREENV-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3NC1=O)C2C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)=O Chemical compound CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3NC1=O)C2C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)=O AIUHDIPAGREENV-UHFFFAOYSA-N 0.000 description 1
- MJXIPHMGYJXKLJ-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3NC1=O)C2C(O)=O Chemical compound CC(CC1)(C(CC2)C(CC3)C1C(C)(CC1)C3NC1=O)C2C(O)=O MJXIPHMGYJXKLJ-UHFFFAOYSA-N 0.000 description 1
- BLXUFWFNFRBFNQ-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(N)=O Chemical compound CC(CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(N)=O BLXUFWFNFRBFNQ-UHFFFAOYSA-N 0.000 description 1
- FDESQZBVTKLIQN-UHFFFAOYSA-N CC(CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(O)=O Chemical compound CC(CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(O)=O FDESQZBVTKLIQN-UHFFFAOYSA-N 0.000 description 1
- JWJOTENAMICLJG-AANZWUEFSA-N C[C@](CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)=O Chemical compound C[C@](CC1)(C(CC2)C(CCC3N4)C1C3(C)C=CC4=O)C2C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)=O JWJOTENAMICLJG-AANZWUEFSA-N 0.000 description 1
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Abstract
Present invention is disclosed a kind of dutasteride (N-(2,5-bis-trifluoromethyl)-4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide, I) preparation method, it comprises the steps: with pregnene ketone acid (II) as raw material, be acid amides by amidate action by Carboxylic Acid, obtained androstane-4-alkene-3-one-17 β-methane amide (III); Compound (III) obtains 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide (IV) through peroxidation open loop and the cyclization of ammonia solution; This compound (IV) generates 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide (V) through reduction hydrogenation reaction; This compound (V) generates 4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide (VI) through oxydehydrogenation; Amine exchange reaction is there is and obtains dutasteride (I) in this compound (VI) and 2,5-bis trifluoromethyl aniline (VII) under catalyst action.The concise in technology of this preparation method, raw material is easy to get, quality controllable, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to methodology of organic synthesis design and bulk drug and Intermediate Preparation technical field, the particularly preparation method of a kind of dutasteride.
Background technology
Dutasteride (Dutasteride, chemistry N-(2 by name, 5-bis-trifluoromethyl)-4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide, I) be a kind of I type of being developed by GlaxoSmithKline PLC company and two kinds, the II type selective depressant with work form steroid 5α-reductase.Dutasteride is in June, 2003 through FDA's approval listing, and commodity are called Avodart (Anfu reaches).This medicine, clinically for the treatment of Benign Prostatic Hypertrophy, can improve hyperplasia of prostate symptom for a long time, reduces the sickness rate of prostate cancer.
The preparation method of dutasteride has been reported, patent WO95/07926, WO95/07927 etc. report with pregnene ketone acid (II) for raw material, and the step such as amidation through the transformation of 4-5 position double bond, the oxydehydrogenation of 1-2 position and 20 carboxylic acids prepares the method for dutasteride (I).
Similar with aforesaid method, patent CN1668632, CN102382165 and US20050059692 report a kind of same with pregnene ketone acid (II) for raw material, prepare the method for dutasteride (I) successively through steps such as the amidation of the transformation of 4-5 position double bond, 20 carboxylic acids and the oxydehydrogenations of 1-2 position.
Above-mentioned two synthetic routes prepare the prevailing technology route of dutasteride at present, reacts classical and process stabilizing.But because acylation reaction is in the end carried out, thus need to protect and deprotection carboxyl before and after oxidation open loop and amination closed loop.The chlorizating agent of acylation process use simultaneously, can produce certain influence to environment.
Patent WO95/07926, WO95/07927, CN102746368, US4760071, US4377584, US4179453, US5565476 etc. report with pregnene ketone acid (II) as raw material, first carry out the amidation of 20 carboxylic acids, then prepare the method for dutasteride (I) through steps such as the transformation of 4-5 position double bond and the oxydehydrogenations of 1-2 position.
Acylation reaction is advanceed to the first step by aforesaid method carries out, and eliminates protection and the tedious steps of deprotection, but is difficult to acquisition due to 2,5-bis trifluoromethyl aniline, and add that subsequent reactions is more, yield is not high, and thus the method can not realize the target that reduces costs.And equally inevitably need when acylation reaction to use poisonous chlorizating agent.
For the synthetic route being raw material with pregnene ketone acid (II), patent CN102838653, CN103044517, CN103059097 and CN103059098 and " Chinese Journal of New Drugs " the 20th volume the 20th phase in 2011 the 1972nd page, " printing during chemical industry " the 23rd volume the 3rd phase in 2009 the 41st page, " Jilin University's journal " the 45th volume the 6th phase in 2007 the 1035th page and " Chinese Journal of New Drugs " the 15th volume the 20th phase in 2006 the 1759th page wait document to condensation wherein, reduction, concrete technology and the technique of the reaction such as acidylate and oxydehydrogenation have made careful research further.Its Patent CN102417534 and " Chinese New Products & New Technology " the 23rd phase in 2011 the 13rd page report a kind of amine exchange reaction of acid amides that utilizes to realize linking of side chain 2,5-bis trifluoromethyl aniline (VII) and parent nucleus.
The method is avoided using contaminate environment and the larger chlorizating agent of toxicity, and reaction also easily controls, and is applicable to industrialization reaction.But; due to after the change of all functional groups; just carry out amidation and amine exchange reaction; so for raw material pregnene ketone acid (II); still need protection and the remove-insurance of carrying out carboxyl, thus add reactions steps, total recovery lowers; cost up, makes the method also have the more place needing Improvement and perfection.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of new dutasteride (I), this preparation method improves Atom economy, the selectivity of reaction and the controllability of operation, make the production of dutasteride more controlled, quality product increases, and promotes the development of the economic technology of this bulk drug.
For achieving the above object, present invention employs following core technology scheme: the preparation method of a kind of dutasteride (I), with pregnene ketone acid (II) for raw material, be acid amides by amidate action by Carboxylic Acid, obtained androstane-4-alkene-3-one-17 β-methane amide (III); Androstane-4-alkene-3-one-17 β-methane amide (III) obtains 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide (IV) through peroxidation open loop and the cyclization of ammonia solution; 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide (IV) generates 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide (V) through reduction hydrogenation reaction; 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide (V) generates 4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide (VI) through oxydehydrogenation; Amine exchange reaction is there is and obtains dutasteride (I) in 4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide (VI) and 2,5-bis trifluoromethyl aniline (VII) under catalyst action.
In addition, present invention also offers following attached technical scheme:
Described amidate action can use ammonia or ammoniacal liquor to be amination raw material, wherein pregnene ketone acid (II) and ammonia (NH
3) molar ratio be 1: 10-30, preferably 1: 20.
The solvent of described amidate action is toluene, dimethylbenzene, dioxane, DMF, N,N-dimethylacetamide or methyl-sulphoxide, or the mixed solvent system of water and above-mentioned organic solvent, the mixed system of preferred dimethylbenzene or water and dimethylbenzene.
The temperature of described amidate action is 25-150 DEG C, preferred 70-90 DEG C.
Described reduction hydrogenation reaction can be selected metal zinc, iron powder, aluminium powder, nickel powder or catalytic hydrogenation to realize, preferred catalytic hydrogenation.
The catalyzer of described reduction hydrogenation reaction is platinum charcoal, palladium charcoal or Raney's nickel, preferred palladium charcoal; Adding proportion is 2-10% (w/w), preferably 5% (w/w) relative to intermediate 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide (IV).
The temperature of described reduction hydrogenation reaction is 0-50 DEG C, preferably 25 DEG C (room temperature).
Compared to prior art, the invention has the advantages that: the preparation method of dutasteride provided by the present invention, with pregnene ketone acid (II) for raw material, become amino by carboxylic acid in advance, save its protection and deprotection steps.The generation of acid amides simultaneously also makes sequential reduction reaction realize by clean inexpensive shortening.This preparation method improves Atom economy, the selectivity of reaction and the controllability of operation, and make the production of dutasteride more controlled, quality product increases, and promotes the development of the economic technology of this bulk drug.
Embodiment
Below will to be made technical scheme of the present invention by several specific embodiment and clearly and detailedly explain and illustrate.Wherein open loop and cyclization, dehydrogenation and condensation etc. can with reference to the descriptions of the documents such as " Chinese New Products & New Technology " the 23rd phase in 2011 the 13rd page, " Chinese Journal of New Drugs " the 20th volume the 20th phase in 2011 the 1972nd page, " printing during chemical industry " the 23rd volume the 3rd phase in 2009 the 41st page, " Jilin University's journal " the 45th volume the 6th phase in 2007 the 1035th page and " Chinese Journal of New Drugs " the 15th volume the 20th phase in 2006 the 1759th page.
Embodiment one:
In reaction flask, add pregnene ketone acid (II) (3.16g, 10mmol) and 20% ammoniacal liquor 35mL, be slowly warming up to 75 DEG C, react homogeneous to system dissolving.Continue to be warming up to 85 DEG C, react to system and occur muddiness again.Add dimethylbenzene 50mL, be warming up to backflow, and divide water at reflux, again become clarification to system.Terminate reaction, concentrating under reduced pressure, has solid to separate out.Filter, filter cake toluene wash, vacuum-drying obtains white solid androstane-4-alkene-3-one-17 β-methane amide (III) 3.10g, yield 98.4%.
Embodiment two:
In reaction flask, add pregnene ketone acid (II) (3.16g, 10mmol), dimethylbenzene 50mL and water 5mL, be slowly warming up to 75 DEG C, and pass into ammonia simultaneously, react homogeneous to system dissolving.Continue to be warming up to 85 DEG C, react to system and occur muddiness again.Continue to be warming up to backflow, and divide water at reflux, again become clarification to system.Terminate reaction, concentrating under reduced pressure, has solid to separate out.Filter, filter cake toluene wash, vacuum-drying obtains white solid androstane-4-alkene-3-one-17 β-methane amide (III) 3.08g, yield 97.8%.
Embodiment three:
4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide (IV) (3.16g is added in hydrogenation reaction cauldron, 10mmol), 5% palladium charcoal (0.16g, 5%w/w), acetic acid 1mL and methyl alcohol 50mL, according to hydrogenation working specification, pass into hydrogen.Add that to keep temperature to be 20-35 DEG C and pressure be 2-3 kilogram, continue reaction 10 hours, reaction terminates.Concentrating under reduced pressure, solid acetone recrystallization obtains 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide (V) 3.02g, yield 95.0%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. dutasteride's (I) preparation method,
It is characterized in that described preparation method comprises the steps:
With pregnene ketone acid for raw material, be acid amides by taking dimethylbenzene as solvent generation amidate action by Carboxylic Acid, obtained androstane-4-alkene-3-one-17 β-methane amide; Described androstane-4-alkene-3-one-17 β-methane amide obtains 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide through peroxidation open loop and the cyclization of ammonia solution; Described 4-azepine-androstane-5-alkene-3-ketone-17 β-methane amide adopts 5% palladium charcoal catalytic hydrogenation, and at 0-50 DEG C, reaction generates 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide; Described 4-aza-5 alpha-androstane-3-ketone-17 β-methane amide generates 4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide through oxydehydrogenation; Amine exchange reaction is there is and obtains dutasteride (I) in described 4-aza-5 alpha-androstane-1-alkene-3-ketone-17 β-methane amide and 2,5-bis trifluoromethyl aniline under catalyst action.
2. the preparation method of dutasteride according to claim 1, is characterized in that: described amidate action uses ammonia or ammoniacal liquor to be amination raw material, and wherein the molar ratio of pregnene ketone acid and ammonia is 1:10-30.
3. the preparation method of dutasteride according to claim 1, is characterized in that: the temperature of described amidate action is 25-150 DEG C.
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| CN105017379B (en) * | 2015-06-26 | 2017-10-10 | 大道隆达（北京）医药科技发展有限公司 | A kind of green synthesis method of high-purity dutasteride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004949A1 (en) * | 1978-04-13 | 1979-10-31 | Merck & Co. Inc. | 4-Aza-17-substituted-5-alpha-androstan-3-one, their A and D homo analogs, process for their preparation and pharmaceutical compositions containing them |
| CN101759762A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Application of 4AD in preparing dutasteride |
| CN102417534A (en) * | 2011-08-31 | 2012-04-18 | 重庆万利康制药有限公司 | Synthesis technology of 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059692A1 (en) * | 2003-09-09 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the preparation of 17beta-N-[2,5-bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5-alpha-androst-1-en-3-one |
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- 2013-05-23 CN CN201310196108.8A patent/CN103254271B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004949A1 (en) * | 1978-04-13 | 1979-10-31 | Merck & Co. Inc. | 4-Aza-17-substituted-5-alpha-androstan-3-one, their A and D homo analogs, process for their preparation and pharmaceutical compositions containing them |
| CN101759762A (en) * | 2008-11-06 | 2010-06-30 | 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 |
| CN102417534A (en) * | 2011-08-31 | 2012-04-18 | 重庆万利康制药有限公司 | Synthesis technology of dutasteride |
Non-Patent Citations (1)
| Title |
|---|
| 合成非那雄胺的新方法;姚志艺等;《中国新药杂志》;20111231;第20卷(第22期);第2248-2250页 * |
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