CN105646641A - Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride - Google Patents
Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride Download PDFInfo
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Abstract
The invention provides a method for forming double bonds between the 1-position and the 2-position during synthesis of finasteride and dutasteride. According to the process, a dihydrogen finasteride iodide and a dihydrogen dutasteride iodide are oxidized by oxone for systhesis of finasteride and dutasteride, and the method has the characteristics that reaction operation is simple and convenient, raw materials are low in price and easy to obtain, and the yield and the purity are high. In particular, oxone is non-toxic, stable, easy to operate and more suitable for large-scale industrial production, and reagents which are harmful to the environment and high in price are avoided. The method can be further applied to forming of double bonds between the 1-position and the 2-position of an intermediate in other finasteride and dutasteride processes. The invention further provides a synthesis method of dihydrogen dutasteride; according to the method, a corresponding ester raw material has a one-pot reaction with 2,5-bis(trifluoromethyl)aniline under the activation of boron tribromide, and dihydrogen dutasteride with the yield of 93% is obtained.
Description
Technical field
The present invention relates to a kind of pharmaceutical synthesis method of benign prostatic hyperplasia. Particularly to the synthetic method of finasteride and dutasteride, belong to technical field of medicine synthesis.
Background technology
Finasteride (Finasteride), trade name proscar (Proscar), protect and send out the active drug that only (Propecia) is the old benign prostatic hyperplasia (BPH) for the treatment of and male pattern baldness. The morbidity of such disease and dihydrotestosterone (DHT) have close contact. Finasteride, as II type 5 alpha reductase inhibitor, can effectively suppress the testosterone conversion to dihydrotestosterone. Dutasteride (Dutasteride), trade name Avodart, is developed by GSK, has similar therapeutic effect, but using dosage is less.
Quite ripe through the development of decades by the technique that pregnenolone is raw material production finasteride and dutasteride. Currently also under development with the technique that the less expensive 4-AD (4-AD) being easy to get is raw material. No matter which kind of method and process route, in target molecule, the formation of 1,2 double bond is the most key, because this process typically occurs in the last several steps in whole synthesis technique, directly influences total recovery and the quality of final crude drug. Presently the most effective industrial process is at N, under double; two (TMS) trifluoroacetamide (BSTFA) effect of O-, use 2,3-bis-chloro-5, double; two hydrogen finasteride (F9) oxidative dehydrogenations are formed 1 by 6-dicyan 1,4-benzoquinone (DDQ), 2 double bonds (J.Amer.Chem.Soc., 1988,3318; EP0298652A2):
2,3-bis-chloro-5, the 6-dicyan hydroquinone (DDQ-H being reduced into after the reagent D DQ used in the method and reaction2) there is higher toxicity, and be easy to residual and cause product to show faint yellow in the product. Processed by general activated carbon or recrystallization and also be difficult to remove. BSTFA is expensive on the other hand, and the fluorine-containing waste liquid produced after reaction and waste water also result in solvent recovery and wastewater treatment difficulty. Purified product yield is at 70-75%.
Other method also includes:
(1) benzene seleninic acid acid anhydride oxidizing process (J.Med.Chem., 1984,1690;WO2005075497A): the method uses toxic reagent benzene seleninic acid acid anhydride, and solvent is the chlorobenzene that environment has pollution. Product needed passes through column chromatographic isolation and purification, yield low (62%), is unfavorable for industrialized production.
(2) F9 diphenyl sulfide oxidizing process (WO2008101308A): the method uses the double; two trimethyl silicon based Lithamide. of more expensive reagent, and diphenyl sulfide carries out under low-temperature anhydrous anaerobic harsh conditions. Two-step reaction total recovery only has 60%.
(3) F9 iodo method of elimination (J.Org.Chem., 1993,3384; EP0473225A2; CN101486753A):
The method is first to synthesize double; two hydrogen finasteride iodo thing (F9-I) under trim,ethylchlorosilane catalysis, then eliminates hydrogen iodide 1,2 double bond of formation with large volume highly basic. Obtained finasteride product impurity content is significantly high, and after refining, two-step reaction yield is about 70%.
(4) F9 iodo oxidation method of elimination (WO200500767A; CN104004050A):
The method uses metachloroperbenzoic acid or peracetic acid iodine oxide for thing, can actually obtain quite highly purified product. Can control below 0.1% according to the content of three impurity (A, B and C) of European Pharmacopoeia (EP) finasteride.
Practical situation is to bring new unknown impuritie in the product that the method obtains, and have to be lower than the principle of 0.1% according to unknown impuritie content, and products obtained therefrom needs further refining. Finasteride is due to the reason in structure, it is easy to impurity cocrystallization phenomenon (Org.ProcessRes.Dev., 2013,599) similar to structure occurs, is easily caused the loss of large-tonnage product by the purification process of solvent crystallization. Two step total recovery 76% in international monopoly WO200500767A. Owing in reaction, the use equivalent of oxidising agent is quite big, and metachloroperbenzoic acid is expensive, and production cost is at a relatively high. The price comparison of peracetic acid is low, but peracetic acid is explosive material, and large-scale production has security hidden trouble. Simultaneously in these two sections of patents, solvents tetrahydrofurane is not a good solvent for reaction raw materials iodo thing, saturated NaHCO3The addition of aqueous solution makes the dissolubility of iodo thing reduce further, and reaction is to carry out in heterogeneous system, and the response time is long, and raw material is difficult to abundant conversion, causes the Quality Down of final products and refining difficulty, and this problem is more prominent when iodine scale. It is thus desirable to a kind of cost of exploitation is low, easy to operate, productivity is high, and purity is good, the technique of safer environmental protection.
Summary of the invention
For the deficiency that above several techniques exist, we develop with ammonium persulfate-sodium bisulfate (Oxone) bis oxide hydrogen finasteride iodo thing (F9-I), and high yield, high-purity obtains finasteride. Operation is easy, and raw material is cheap and easy to get. Particularly ammonium persulfate-sodium bisulfate is nontoxic, and stable and ease for operation is more suitable for large-scale industrial production. The selectivity of reaction is also at a relatively high, and unknown impuritie content all meets European Pharmacopoeia (EP) standard (< 0.1%), does not detect known impurities B and C. The content of impurity A can also control below 0.1% (EP, < 0.3%).
The method is not only suitable for producing finasteride, equally possible production dutasteride, intermediate (namely the impurity B in EP) in Mo Shadong technique and other 3 similar oxo 4-azepine-5-��-1-alkene class steroidal compounds. Net reaction is:
Raw material iodo thing is by the method (J.Org.Chem., 1993,3384 of document;EP0473225A2) synthesize. The solvent used in reaction is that also fairly good with the intersolubility of water, this is conducive to potassium hydrogen persulfate dissolubility in reaction medium, and reaction is able to complete in 3 to 4 hours to the iodo better methanol of thing dissolubility, ethanol, acetone. Solvent methanol, oxidant potassium hydrogen persulfate is reactionlessness by ethanol, will not be oxidized or produce dangerous peroxide. Acetone becomes to be widely used as in epoxide solvent and catalyst (J.Org.Chem., 1985,1544) at potassium hydrogen persulfate oxyalkylene. Other water miscible alcohol such as normal propyl alcohols, n-butyl alcohol, DMF, halohydrin is ethylene chlorhydrin such as, trichloro-ethyl alcohol, 2,2,2-trifluoroethanols can also as reaction dissolvent, but the most economic and environment-friendly with methanol, ethanol or acetone.
Potassium hydrogen persulfate is with complex salt (KHSO5.1/2KHSO4.1/2K2SO4) solid or the mode of aqueous solution join in reaction system. It makes consumption be 2 to 10 times of equivalents of iodo thing, with 4 to 6 times of equivalent the bests. Iodine on iodo thing is oxidized eliminate after be finally oxidized to periodate by excessive potassium hydrogen persulfate. In reaction, potassium hydrogen persulfate is reduced deoxidation and forms potassium acid sulfate, and the pH value of system constantly declines with reaction process, and the by-product of reaction can increase. Pre-in reaction system add excessive sodium bicarbonate (10-15 times of equivalent) and reaction system can be controlled maintain about 6 to 7. Other oxidants that can be used on this reaction can be the hydrogen peroxide mentioned in patent WO200500767A, sodium hypochlorite, sodium hypobromite, metachloroperbenzoic acid, peracetic acid, sodium metaperiodate, 2-iodosobenzoic acid, iodoxy benzene. Maximally efficient with potassium hydrogen persulfate and economic and environment-friendly.
Response time can change because of the difference of reaction temperature. Reaction temperature can carry out the scope of 10-50 DEG C. Lower than less than 20 DEG C, reaction needed just can complete at least 15 hours. When higher than 40 DEG C, reaction is basic to be terminated within half an hour, but produces more by-product. Best reaction temperature is 20-30 DEG C, and the response time is 4 to 16 hours.
Reacting obtained crude product without desolventing technology, can obtain clear crystal sterling with ethanol and water recrystallizing and refining, yield is about 93%.
It addition, during synthesis dutasteride, due to the reason of strong electron-withdrawing group group trifluoromethyl in 2,5-double; two (trifluoromethyl) aniline, 17 carboxy amidation are needed higher activating reagent. Concrete dutasteride's synthesis technique summary is referred to patent documentation WO2013/001322A1. The present invention provides a kind of method that ester group is changed into amide by a new step. Relevant list of references has: TetrahedronLett.1977, No.48,4171; TetrahedronLett.1974, No.46,3995. Concrete reaction equation is as follows:
Corresponding ester raw material under the activation of Boron tribromide, and 2,5-double; two (trifluoromethyl) aniline one pot reactions, obtain double; two hydrogen dutasteride with the yield of 93%.
Use above method, it is possible to high yield easily, high-purity obtains finasteride, dutasteride, and synthesizes their precursor in other techniques. Two step total recoverys are about 90%, and product color is good, and purity reaches EP standard. W-response mild condition, process economics environmental protection, it is suitable for large-scale industrial production.
Just with instantiation, the present invention is done further technology below to illustrate. But the present invention is not limited to these examples.
Accompanying drawing explanation
The finasteride that Fig. 1 the inventive method obtains1HNMR spectrogram
Double; two hydrogen dutasterides that Fig. 2 the inventive method obtains1HNMR spectrogram
The dutasteride that Fig. 3 the inventive method obtains1HNMR spectrogram
Embodiment
The synthesis of 1 pair of hydrogen finasteride iodo thing of embodiment
Under nitrogen atmosphere protection, 30 grams of double; two hydrogen finasterides are dissolved in dichloromethane 300 milliliters dry, are subsequently added N, N, N, N-tetramethyl ethylenediamine 36 milliliters dry. Reactant mixture is cooled to 0 DEG C, adds the trim,ethylchlorosilane of 20.3 milliliters. The ammonium salt precipitate of white precipitates out subsequently, and reactant mixture continues stirring 20 minutes. 24.4 gram iodine adds for three times every 10 minutes points. Stirring 1 hour is continued until double; two hydrogen finasteride reacts completely when 0 to 5 DEG C. Reaction is subsequently by 50 milliliters of 10%Na2SO3Solution and 50 milliliters of saturated nacl aqueous solution cancellation. Organic facies after isolation is evaporated to 60 milliliters at less than 40 DEG C after adding 50 milliliters of toluene. 150 milliliters of petroleum ether slowly drip in the concentrate of above-mentioned stirring, the faint yellow solid product of precipitation through filtering, petroleum ether, drying at room temperature is to constant weight: 38.8 grams, 96.7%.
1HNMR (400MHz, CDCl3, 296K): �� 5.79,5.08 (eachs, each1H, NH), 4.77 (dd,3JHH=10.5Hz,3JHH=8.1Hz, 1H, 2-H), 3.18 (dd,3JHH=12.3Hz,3JHH=3.2Hz, 1H, 5 ��-H)), 2.58 (dd,3JHH=13.6Hz,3JHH=8.1Hz, 1H), 1.34 (s, 9H, C (CH3)3), 0.88 (s, 3H, 10-CH3), 0.67 (s, 3H, 13-CH3).
The synthesis of 2 pairs of hydrogen finasteride iodo things of embodiment
Under nitrogen atmosphere protection, 10.00 grams of double; two hydrogen finasterides are scattered in toluene 100 milliliters dry, are subsequently added N, N, N, N-tetramethyl ethylenediamine 12.0 milliliters dry. Reactant mixture is cooled to 0 DEG C, adds the trim,ethylchlorosilane of 6.76 milliliters. Double; two hydrogen finasterides dissolve gradually, have the ammonium salt precipitate of white to precipitate out subsequently simultaneously, and reactant mixture continues stirring 30 minutes. 8.14 grams of iodine add for three times every 20 minutes points. Stirring 2 hours is continued until double; two hydrogen finasteride reacts completely when 0 to 5 DEG C. Reaction is subsequently by 50 milliliters of 10%Na2SO3 solution cancellation. Continuing stir about 1 hour, product slowly precipitates out from reaction mixture. Continue thereafter with and in reaction mixture, drip 50 milliliters of petroleum ether to be fully settled out product. Continue stirred overnight at room temperature, the white solid product of precipitation through filtering, petroleum ether, drying at room temperature is to constant weight: 12.87 grams, 96.2%.
1HNMR (400MHz, CDCl3, 296K): �� 5.79,5.08 (eachbs, each1H, NH), 4.77 (dd,3JHH=10.5Hz,3JHH=8.1Hz, 1H, 2-H), 3.18 (dd,3JHH=12.3Hz,3JHH=3.2Hz, 1H, 5 ��-H)), 2.58 (dd,3JHH=13.6Hz,3JHH=8.1Hz, 1H), 1.34 (s, 9H, C (CH3)3), 0.88 (s, 3H, 10-CH3), 0.67 (s, 3H, 13-CH3).
The synthesis of its male amine of 3 pairs of hydrogen degree of embodiment
16.65 grams of 3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylate methyl esters are dissolved in the dichloromethane of 250 milliliters, the Boron tribromide of the lower dropping 18.95 milliliters of room temperature water (25 DEG C) cooling. Continue to be stirred at room temperature 20 minutes and obtain transparent brown solution. 19.5 double; two (trifluoromethyl) aniline of milliliter 2,5-adds in above-mentioned solution under room temperature water (25 DEG C) cools down. Reacting by heating is to 50 DEG C of stirrings overnight.After reactant liquor is cooled to room temperature, being slowly added into 50 milliliters of water, the hydrogen bromide gas of generation imports Na2CO3In aqueous solution. Continuously add the water of 200 milliliters until all of solid dissolves and obtains biphase clearly. After isolating the dichloromethane organic facies water of 200 milliliters and the saturated common salt washing of 200 milliliters of lower floor, anhydrous Na2SO4Dry. 60 milliliters it are evaporated to after 10 grams of filtered through silica gel. Slowly dripping 100 milliliters of petroleum ether to above-mentioned concentrated solution, product precipitates out with flaxen solid, and through filtering, after petroleum ether, air drying is to constant weight: 24.65g (93%).
1HNMR (400MHz, CDCl3, 296K): �� 8.77 (s, 1H, Ar-6-H), 7.72,7.44 (eachd,3JHH=8.0Hz, each1H, Ar-4-HandAr-3-H), 7.49 (bs, 1H, Ar-NH), 5.83 (bs, 1H, NH), 3.07 (dd,3JHH=4.0Hz,3JHH=12Hz, 1H, 5 ��-H), 0.91 (s, 3H, 10-CH3), 0.78 (s, 3H, 13-CH3).
19F{1H}NMR (376MHz, CDCl3, 298K): ��-61.19 ,-63.56.
The synthesis of its male amine iodo thing of 4 pairs of hydrogen degree of embodiment
Under nitrogen atmosphere protection, 42.40 grams of its male amine of double; two hydrogen degree are dissolved in dichloromethane 420 milliliters dry, are subsequently added N, N, N, N-tetramethyl ethylenediamine 36 milliliters dry. Reactant mixture is cooled to 0 DEG C, adds the trim,ethylchlorosilane of 20.3 milliliters. The ammonium salt precipitate of white precipitates out subsequently, and reactant mixture continues stirring 20 minutes. 24.4 gram iodine adds for three times every 10 minutes points. Stirring 3 hours is continued until its male amine of double; two hydrogen degree reacts completely when 0 to 5 DEG C. Reaction is subsequently by 150 milliliters of 10%Na2SO3Solution and 150 milliliters of saturated nacl aqueous solution cancellation. Organic facies after separation less than 40 DEG C at add 150 ml methanol after concentrating under reduced pressure, continue concentrating under reduced pressure and eliminate dichloromethane, add methanol to cumulative volume about 200 milliliters. Stirring lower 300 milliliters of water and be slowly added drop-wise in above-mentioned solution, the faint yellow solid product of precipitation is through filtering, and in air at room temperature, dark place is dried to constant weight: 48.81 grams, and 93%.
1HNMR (400MHz, CDCl3, 296K): �� 8.77 (s, 1H, Ar-6-H), 7.71,7.45 (eachd,3JHH=8.0Hz, each1H, Ar-4-HandAr-3-H), 7.49 (bs, 1H, Ar-NH), 5.88 (bs, 1H, NH), 4.78 (dd,3JHH=10.5Hz,3JHH=8.1Hz, 1H, 2-H), 3.21 (dd,3JHH=12.3Hz,3JHH=3.2Hz, 1H, 5 ��-H), 2.61 (dd,3JHH=13.6Hz,3JHH=8.1Hz, 1H, 1-H), 0.89 (s, 3H, 10-CH3), 0.77 (s, 3H, 13-CH3).
The synthesis of embodiment 52-iodo-3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylate methyl ester
With reference to embodiment 1, by the obtained crude product of 20.00 grams of 3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylate methyl esters by n-butyl acetate backwash refining after obtain white crystal: 25.20 grams, 92%.
1HNMR (400MHz, CDCl3, 296K): �� 6.01 (s, 1H, NH) 4.76 (dd,3JHH=10.0Hz,3JHH=8.0Hz, 1H, 2-H), 3.67 (s, 1H ,-OCH3), 3.18 (dd,3JHH=12.4Hz,3JHH=3.4Hz, 1H, 5 ��-H)), 2.56 (dd,3JHH=13.6Hz,3JHH=8.1Hz, 1H), 2.32 (t,3JHH=9.1Hz, 1H), 0.88 (s, 3H, 10-CH3), 0.65 (s, 3H, 13-CH3).
The synthesis of embodiment 6 finasteride
10.00 the acetone of gram double; two hydrogen finasteride iodo things and 200 milliliters adds the sodium bicarbonate solid of 25.2 grams after mixing.30.74 a gram ammonium persulfate-sodium bisulfate drips in 2 hours in said mixture after being dissolved in 120 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. Filter reactant mixture, filter the solid stayed after most inorganic salt is removed in 100 milliliters of washings, with the dichloromethane extraction of 70 milliliters, 50 milliliters of 10%Na2SO3After solution washing, anhydrous Na2SO4Dry. Concentrating the crude product after eliminating dichloromethane and obtain white crystal through 15 ml ethanols and 45 milliliters of water recrystallization, after filtration washing, 60 DEG C of vacuum dryings obtain 6.70 grams of sterlings. Yield: 90%. HPLC:99.8%.
1HNMR (400MHz, CDCl3, 296K): �� 6.79 (d,3JHH=8.0Hz, 1H, CH=CH), 5.81 (dd,3JHH=8.0Hz, 1H, CH=CH), 5.56,5.08 (each1H, NH), 3.32 (m, 1H, 5 ��-H), 1.35 (s, 9H, NC (CH3)3) 0.97 (s, 3H, 10-CH3), 0.69 (s, 3H, 13-CH3).
The synthesis of embodiment 7 finasteride
6.00 grams of double; two hydrogen finasteride iodo things are dissolved in the methanol of 65 milliliters. It is subsequently added the sodium bicarbonate solid of 10.08 grams. 22.10 a gram ammonium persulfate-sodium bisulfate drips in 1 hour in said mixture after being dissolved in 90 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. Filtering reactant mixture, filter the solid stayed and merge with gained filtrate after methanol (2 �� 20 milliliters) extracts, after decompression distillation removes methanol, crude product precipitates out with the form of crystallization. 4.15 grams of white crystal sterlings are obtained with the method for post processing in embodiment 6. Yield: 93%. HPLC:99.8%.
The synthesis of embodiment 8 finasteride
2.00 grams of double; two hydrogen finasteride iodo things are dissolved in 2,2, the 2-trifluoroethanols of 20 milliliters. It is subsequently added the sodium bicarbonate solid of 3.36 grams. 6.14 grams of ammonium persulfate-sodium bisulfate drip in 1 hour in said mixture after being dissolved in 24 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. Filtering reactant mixture, filter the solid stayed (2 �� 10 milliliters) in 2,2,2-trifluoroethanols and merge with gained filtrate after extracting, decompression distillation removes after in 2,2,2-trifluoroethanols, precipitates out solid crude product. 1.37 grams of white crystal sterlings are obtained with the method for post processing in embodiment 6. Yield: 92%.
The synthesis of embodiment 9 dutasteride
6.56 grams of double; two hydrogen dutasteride's iodo things add the sodium bicarbonate solid of 12.60 grams after being dissolved in the acetone of 130 milliliters. 18.44 a gram ammonium persulfate-sodium bisulfate drips in 2 hours in said mixture after being dissolved in 73 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. After decompression distillation removes acetone, in remaining aqueous phase, crude product precipitates out with solid. Filter the dichloromethane extraction that the solid that stays is with 50 milliliters, 20 milliliters of 10%Na2SO3After solution washing, anhydrous Na2SO4Dry. Concentrating the crude product after eliminating dichloromethane and obtain white crystal through 10 ml ethanols and 20 milliliters of water recrystallization, after filtration washing, 60 DEG C of vacuum dryings obtain 5.02 grams of sterlings. Yield: 95%. HPLC:99.8%.
1HNMR (400MHz, CDCl3, 296K) :): �� 8.77 (s, 1H, Ar-6-H), 7.73,7.45 (eachd,3JHH=8.0Hz, each1H, Ar-4-HandAr-3-H), 7.50 (bs, 1H, Ar-NH), 6.80 (d,3JHH=8.0Hz, 1H, CH=CH), 5.82 (dd,3JHH=8.0Hz, 1H, CH=CH), 5.59 (shiftdependsonthesolutioncentration, bs, 1H, NH), 3.35 (m, 1H, 5 ��-H), 0.98 (s, 3H, 10-CH3), 0.79 (s, 3H, 13-CH3).
The synthesis of embodiment 10 dutasteride
2.91 grams of double; two hydrogen dutasteride's iodo things are dissolved in the methanol of 30 milliliters.It is subsequently added the sodium bicarbonate solid of 3.72 grams. 8.17 grams of ammonium persulfate-sodium bisulfate drip in 2 hours in said mixture after being dissolved in 30 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. Filtering reactant mixture, filter the solid stayed and merge with gained filtrate after methanol (2 �� 10 milliliters) extracts, after decompression distillation removes methanol, crude product precipitates out with the form of crystallization. 2.20 grams of white crystal sterlings are obtained with method refining in embodiment 9. Yield: 94%.
The synthesis of embodiment 113-ketone-4-aza-5 alpha-androstane-1-alkene-17 ��-carboxylate methyl ester
After the methanol mixed of 5.00 grams of 2-iodo-3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylate methyl esters and 75 milliliters, add the sodium bicarbonate solid of 9.15 grams. 20.08 a gram ammonium persulfate-sodium bisulfate drips in 2 hours in said mixture after being dissolved in 75 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring reaction overnight until reacting completely. Filter reactant mixture, filter the solid stayed after dichloromethane (2 �� 20 milliliters) extracts, 20 milliliters of 10%Na2SO3After solution washing, anhydrous Na2SO4Dry. Concentrating the crude product after eliminating dichloromethane and obtain white crystal through 10 ml ethanols and 20 milliliters of water recrystallization, after filtration washing, 60 DEG C of vacuum dryings obtain 3.28 grams of sterlings. Yield: 91%.
1HNMR (400MHz, CDCl3, 296K): �� 6.79 (d,3JHH=10.0Hz, 1H, CH=CH), 5.80 (dd,4JHH=2.4Hz,3JHH=9.6Hz, 1H, CH=CH), 5.74 (bs, 1H, NH), 3.67 (s, 3H ,-OCH3), 3.32 (m, 1H, 5 ��-H), 0.96 (s, 3H, 10-CH3), 0.70 (s, 3H, 13-CH3).
The synthesis of embodiment 123-ketone-4-aza-5 alpha-androstane-1-alkene-17 ��-carboxylic acid
4.00 grams of 2-iodo-3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylic acids add the sodium bicarbonate solid of 7.55 grams after being dissolved in the methanol of 40 milliliters. 16.56 a gram ammonium persulfate-sodium bisulfate drips in 1 hour in said mixture after being dissolved in 60 milliliters of water, control reaction temperature less than 30 DEG C. Continue stirring 2 hours until reacting completely. Filter reactant mixture, filter solids with methanol (2 �� 10 milliliters) washing stayed and merge with gained filtrate, after decompression distillation removes methanol, gained aqueous phase dropping 2MH2SO4It is 2 to pH value. The white solid precipitated out, through filtering, is washed rear 60 DEG C of vacuum dryings and is obtained 2.59 grams of products. Yield: 91%.
1HNMR (400MHz, DMSO-d6, 296K): �� 11.36 (bs, 1H, OH), 7.32 (bs, 1H, NH), 6.79 (d,3JHH=10.0Hz, 1H, CH=CH), 5.80 (dd,4JHH=2.4Hz,3JHH=9.6Hz, 1H, CH=CH), 3.15 (m, 1H, 5 ��-H), 0.86 (s, 3H, 10-CH3), 0.64 (s, 3H, 13-CH3)��
Claims (9)
1. corresponding iodo thing synthesizing finasteride and dutasteride is aoxidized with oxidant ammonium persulfate-sodium bisulfate (Oxone).
2. potassium hydrogen persulfate is with complex salt (KHSO5.1/2KHSO4.1/2K2SO4) solid or the mode of aqueous solution join in reaction system. It makes consumption be 2 to 10 times of equivalents of iodo thing, with 4 to 6 times of equivalent the bests.
3. the solvent used in reaction is the methanol that iodo thing dissolubility is good, and ethanol, acetone, normal propyl alcohol, n-butyl alcohol, DMF, halohydrin is ethylene chlorhydrin such as, trichloro-ethyl alcohol, 2,2,2-trifluoroethanols. But with methanol, ethanol or acetone for preferred solvent.
4. pre-in reaction system add excessive sodium bicarbonate (10-15 times of equivalent) and reaction system pH can be controlled maintain about 6 to 7, reduce the generation of side reaction.
5. other oxidants that can be used on this reaction are hydrogen peroxide, sodium hypochlorite, sodium hypobromite, metachloroperbenzoic acid, peracetic acid, sodium metaperiodate, 2-iodosobenzoic acid, iodoxy benzene. With potassium hydrogen persulfate (Oxone) for preferred reagent.
6. the response time can change because of the difference of reaction temperature. Reaction temperature can carry out the scope of 10-50 DEG C. Best reaction temperature is 20-30 DEG C, and the response time is 4 to 16 hours.
7. the crude product that reaction is obtained is without desolventing technology, and the solvent used by recrystallizing and refining is ethanol and water.
8. use the method in right 1 to produce other similar 3 oxo-4-azepine-5-��-1-alkene class steroidal compounds: 3-ketone-4-aza-5 alpha-androstane-1-alkene-17 ��-carboxylate methyl ester and 3-ketone-4-aza-5 alpha-androstane-1-alkene-17 ��-carboxylic acid.
9. by 3-ketone-4-aza-5 alpha-androstane-17 ��-carboxylate methyl ester, under the activation of Boron tribromide, and 2,5-double; two (trifluoromethyl) aniline one pot reactions, obtain double; two hydrogen dutasteride with the yield of 93%.
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| CN107698651A (en) * | 2017-09-19 | 2018-02-16 | 江西国药有限责任公司 | A kind of production technology of high-purity dutasteride |
| CN108203455A (en) * | 2016-12-19 | 2018-06-26 | 湖南玉新药业有限公司 | A kind of double hydrogen Finasteride iodide take off iodine and prepare Finasteride new method |
| CN113943340A (en) * | 2021-11-15 | 2022-01-18 | 湖南科瑞生物制药股份有限公司 | 4-aza steroid compound and preparation method and application thereof |
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