CN101418033A - Method for synthesizing finasteride - Google Patents
Method for synthesizing finasteride Download PDFInfo
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- CN101418033A CN101418033A CNA2008102024768A CN200810202476A CN101418033A CN 101418033 A CN101418033 A CN 101418033A CN A2008102024768 A CNA2008102024768 A CN A2008102024768A CN 200810202476 A CN200810202476 A CN 200810202476A CN 101418033 A CN101418033 A CN 101418033A
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Abstract
The invention provides a method for synthesizing finasteride. The method comprises the following steps: (1) dissolving trifluoroacetamide in solvent, reacting the solvent with trimethylchlorosilane in the presence of organic alkali or inorganic alkali, filtering out solid from reaction products, and collecting filtrate; and (2) dissolving the filtrate obtained in step (1) in the solvent, adding 3-carbonyl-4-aza-5 alpha-androstane-17 belta-tert-butylformamide and dehydrogenation agent into the solvent for reaction, and collecting target products from reaction products. The method has the advantages that the method has higher yield, high selectivity, and is simple and safe; after simple purification, the purity of the finasteride can reach more than 99 percent; moreover, the method has easily obtained reagents used in the whole reaction, simultaneously having high reaction yield and mild reaction conditions, reclaiming the solvent and facilitating the industrialized production.
Description
Technical field
The present invention relates to a kind of method for preparing finasteride.
Background technology
Finasteride (finasteride, trade(brand)name Proscar, code name MK-906) is the medicine of the benign prostate hyperplasia of Merck company development, in listing in 1992.Benign prostate hyperplasia (BPH) is the common disease of elderly men, also is to cause the modal cause of disease of male sex's misnicturition.The rising of discovering dihydrotestosterone content is the reason that causes BPH.The 5 inhibitor can suppress testosterone and be converted into dihydrotestosterone and reach the purpose for the treatment of BPH.Make outgrowth prostate gland can not get Standone and atrophy, thereby show curative effect.This medication is imitated definite, and side effect is little.Its structural formula is as follows:
At present, committed step is the process that 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides dehydrogenation obtains 3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-tert-butylamides (finasteride) in the existing technology.
As U.S. Pat 5116983, a kind of method for preparing finasteride is provided, in the time of in the process of its committed step 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides dehydrogenation acquisition 3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-tert-butylamides (finasteride), used expensive N, two (TMS) trifluoroacetamides (BSTFA) of O-, and this reagent all has problem because of it easily decomposes in the transportation storage process water sensitive.Limited its use in suitability for industrialized production.
J.Med.Chem., 1984,27 (12), 1690 provide a kind of method, this method is that oxygenant obtains 3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-tert-butylamides (finasteride) by 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides dehydrogenation with the benzene seleninic acid acid anhydride, and this method is solvent with the chlorobenzene, the reflux temperature height, by product is more, not only separation and purification difficulty need to separate with chromatographic column, and yield is lower, use reagent costliness, toxicity is big.Be not suitable for large-scale industrial production.
Summary of the invention
The synthetic method that the purpose of this invention is to provide finasteride is to overcome the above-mentioned defective that prior art exists.
The method of present method comprises the steps:
(1) with trifluoroacetamide in the presence of organic bases or mineral alkali, in solvent, react 2～24h with trimethylchlorosilane (TMSC1), temperature of reaction is 20～100 ℃, from reaction product, white solid is filtered out then, filtrate is N, the solution of two (TMS) trifluoroacetamides (BSTFA) of O-, the not purified the next step that is directly used in, yield is 80～99.5%, and reaction equation is as follows:
Organic bases is pyridine, Trimethylamine, triethylamine, N, and N-dimethyl-4-aminopyridine, Tributylamine, trioctylamine or DBU etc. are preferably pyridine or triethylamine;
Mineral alkali is the carbonate of metal, comprises Quilonum Retard, salt of wormwood, yellow soda ash, barium carbonate, cesium carbonate, Strontium carbonate powder or lime carbonate, and preferred carbonate is salt of wormwood or yellow soda ash;
Described solvent is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene;
The mol ratio of trimethylchlorosilane and trifluoroacetamide is 1～5:1 in reaction;
The mol ratio of organic bases or mineral alkali and trifluoroacetamide is 1～5:1;
In the solvent, the content of trifluoroacetamide is 0.1～1.5mol/mL;
(2) with the filtrate of step (1), 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides and dehydrogenation reagent in solvent shown in the adding formula (2), 20～120 ℃ were reacted 0.1～24 hour, from reaction product, collect target product (1) then, yield is 80～99%, and reaction equation is as follows:
Said dehydrogenation reagent is 2,3-two chloro-5,6-dicyan para benzoquinone (DDQ) or 2,3,5,6-chloranil (chloranil);
It is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1 that described solvent is selected from described solvent, 4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene;
The BSTFA in the preparation-obtained solution of step (1) and the mol ratio of compound (2) are 2～5:1
The mol ratio of dehydrogenation reagent and compound (2) is 1～5:1.
In the solvent, the content of compound (2) is 0.1～1.0mol/mL;
Compound (2) can be according to document J.Med.Chem., 1984,27,1690; J.Med.Chem., play-by-play is arranged in 1986,29,2298, repeat no more herein.
The present invention can obtain the higher product of purity with higher yields and highly selective, and employed method is simple, safety, and one kettle way prepares not purified formula (2) the preparation finasteride that is directly used in of BSTFA.We's bright institute reported method has been avoided problems such as the product purification difficulty, the yield that are run in this compounds traditional synthesis are low, has been greatly reduced production cost.Avoided simultaneously big, unstable, the problem such as the by product environmental pollution is serious of the reagent toxicity that uses." three wastes " discharging reduces significantly in its production technique.This is that additive method is beyond one's reach.With of the present invention and the finasteride for preparing of method because its reaction conditions gentleness reacts more complete, can reach more than 99% through its purity after the simple purification.Employed reagent all comparatively is easy to get in entire reaction, while reaction yield height, and the reaction conditions gentleness, solvent can be recycled, thereby is convenient to industrializing implementation.
Embodiment
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds trifluoroacetamide (11.30g successively; Fw:113.04; 100mmol), anhydrous triethylamine (24.29g; Fw:101.19; 240mmol); System at room temperature stirs 10min subsequently, with trimethylchlorosilane (20.64g; Fw:108.64; 190mmol) be transferred to constant pressure funnel.System temperature is risen to 50 ℃, trimethylchlorosilane is slowly dropped in the system, hierarchy of control temperature is no more than 50 ℃, drips about 2h and finishes.After dropwising, system continues to stir 10h at 50 ℃, and reaction finishes, and has a large amount of triethylamine hydrochlorides in the reaction process and separates out from system.
After reaction treated that system is cooled to room temperature after finishing, available dry toluene 50mL diluted system removed by filter behind the triethylamine hydrochloride with dry toluene 50mL washing leaching cake, merged organic phase and got colorless clear liquid and be used for the next step.
Embodiment 2
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds trifluoroacetamide (11.30g successively; Fw:113.04; 100mmol), anhydrous triethylamine (50.60g; Fw:101.19; 500mmol); Toluene 1000mL, system at room temperature stirs 10min subsequently, with trimethylchlorosilane (54.32g; Fw:108.64; 500mmol) be transferred to constant pressure funnel.System temperature is risen to 50 ℃, trimethylchlorosilane is slowly dropped in the system, hierarchy of control temperature is no more than 50 ℃, drips about 2h and finishes.After dropwising, system continues to stir 2h at 110 ℃, and reaction finishes, and has a large amount of triethylamine hydrochlorides in the reaction process and separates out from system.
After reaction treated that system is cooled to room temperature after finishing, available dry toluene 50mL diluted system removed by filter behind the triethylamine hydrochloride with dry toluene 50mL washing leaching cake, merged organic phase and got colorless clear liquid and be used for the next step.
Embodiment 3
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds trifluoroacetamide (11.30g successively; Fw:113.04; 100mmol), 1,4-dioxane 67mL, anhydrous pyridine (7.91g; Fw:79.10; 100mmol); System at room temperature stirs 10min subsequently, with trimethylchlorosilane (10.86g; Fw:108.64; 100mmol) be transferred to constant pressure funnel.System temperature is remained on 20 ℃, trimethylchlorosilane is slowly dropped in the system, hierarchy of control temperature is no more than 20 ℃, drips about 2h and finishes.After dropwising, system continues to stir 24h at 20 ℃, and reaction finishes, and has a large amount of pyridine hydrochlorides in the reaction process and separates out from system.
After reaction treated that system is cooled to room temperature after finishing, available 1,4-dioxane 50mL diluted system removed by filter behind the pyridine hydrochloride with anhydrous 1,4-dioxane 50mL washing leaching cake, and the merging organic phase gets colorless clear liquid and is used for the next step.
Embodiment 4
In being full of the 250mL there-necked flask that is equipped with constant pressure funnel, thermometer, reflux condensing tube, magnetic agitation of nitrogen, a drying adds trifluoroacetamide (11.30g successively; Fw:113.04; 100mmol), 1,4-dioxane 50mL, Anhydrous potassium carbonate (33.17g; Fw:138.20; 240mmol); System at room temperature stirs 10min subsequently, with trimethylchlorosilane (20.64g; Fw:108.64; 190mmol) be transferred to constant pressure funnel.System temperature is remained on 50 ℃, trimethylchlorosilane is slowly dropped in the system, hierarchy of control temperature is no more than 50 ℃, drips about 2h and finishes.After dropwising, system continues to stir 12h at 50 ℃.
After reaction treated that system is cooled to room temperature after finishing, available 1,4-dioxane 50mL diluted system removed by filter behind the inorganic salt with anhydrous 1,4-dioxane 50mL washing leaching cake, and the merging organic phase gets colorless clear liquid and is used for the next step.
Embodiment 5
The preparation of finasteride
Be full of at an exsiccant and add 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides (1.00g in the 50mL four-hole boiling flask that is equipped with thermometer, magnetic agitation, constant pressure funnel and reflux condensing tube of nitrogen; Fw:374.56; 2.7mmol), add DDQ (0.78g subsequently; Fw:227.01; 3.4mmol).In dry toluene 20mL adding system, 25 ℃ are stirred 20min.Slowly will go up the BSTFA solution (5.4mmol) for preparing of step subsequently and be added dropwise to system, about 5min dropwises, and system temperature is controlled at 25 ℃ in the dropping process.After dropwising, system continues stirring reaction 18h at 25 ℃.System is warming up to 110 ℃ of stirring 4h that continue to reflux afterwards, is cooled to room temperature after question response finishes.
After reaction finished, system temperature was added chloroform 15mL after being cooled to room temperature in system, 10% aqueous solution of sodium bisulfite 15mL was added in the constant pressure funnel be added dropwise in the system, after to be added the finishing, continued to stir 1.5h; Subsequently the quinhydrones of separating out is filtered, filter cake washs molten thing with the no product of conclusive evidence with minimum of chloroform again), merge organic phase, organic phase is washed 3 times with 10% aqueous sodium carbonate again, saturated sodium-chloride washs once.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 0.94g, HPLC content〉99%.
Embodiment 6
The preparation of finasteride
Be full of at an exsiccant and add 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides (1.00g in the 50mL four-hole boiling flask that is equipped with thermometer, magnetic agitation, constant pressure funnel and reflux condensing tube of nitrogen; Fw:374.56; 2.7mmol), add DDQ (3.06g subsequently; Fw:227.01; 13.5mmol).With anhydrous 1, in the 4-dioxane 20mL adding system, be warmed up to 35 ℃ and stir 20min.Slowly will go up the BSTFA solution (13.50mmol) for preparing of step subsequently and be added dropwise to system, about 5min dropwises, and system temperature is controlled at 35～40 ℃ in the dropping process.After dropwising, system continues stirring reaction 24h at 110 ℃.After finishing, question response is cooled to room temperature.
After reaction finished, system temperature was added chloroform 15mL after being cooled to room temperature in system, 10% aqueous solution of sodium bisulfite 15mL was added in the constant pressure funnel be added dropwise in the system, after to be added the finishing, continued to stir 1.5h; Subsequently the quinhydrones of separating out is filtered, filter cake washs molten thing with the no product of conclusive evidence with minimum of chloroform again), merge organic phase, organic phase is washed 3 times with 10% aqueous sodium carbonate again, saturated sodium-chloride washs once.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 0.99g, HPLC content〉99%.
Embodiment 7
The preparation of finasteride
Be full of at an exsiccant and add 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides (1.00g in the 50mL four-hole boiling flask that is equipped with thermometer, magnetic agitation, constant pressure funnel and reflux condensing tube of nitrogen; Fw:374.56; 2.7mmol), add DDQ (0.91g subsequently; Fw:227.01; 4mmol).With anhydrous 1, in the 4-dioxane 20mL adding system, be warmed up to 35 ℃ and stir 20min.Slowly will go up the BSTFA solution (10.8mmol) for preparing of step subsequently and be added dropwise to system, about 5min dropwises, and system temperature is controlled at 35～40 ℃ in the dropping process.After dropwising, system continues stirring reaction 18h at 100 ℃.After finishing, question response is cooled to room temperature.
After reaction finished, system temperature was added chloroform 15mL after being cooled to room temperature in system, 10% aqueous solution of sodium bisulfite 15mL was added in the constant pressure funnel be added dropwise in the system, after to be added the finishing, continued to stir 1.5h; Subsequently the quinhydrones of separating out is filtered, filter cake washs molten thing with the no product of conclusive evidence with minimum of chloroform again), merge organic phase, organic phase is washed 3 times with 10% aqueous sodium carbonate again, saturated sodium-chloride washs once.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 1.05g, HPLC content〉99%.
Embodiment 8
The preparation of finasteride
Be full of at an exsiccant and add 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides (1.00g in the 50mL four-hole boiling flask that is equipped with thermometer, magnetic agitation, constant pressure funnel and reflux condensing tube of nitrogen; Fw:374.56; 2.7mmol), add tetrachlorobenzoquinone (0.98g subsequently; Fw:245.88; 4mmol).With anhydrous 1, in the 4-dioxane 20mL adding system, be warmed up to 35 ℃ and stir 20min.Slowly will go up the BSTFA solution (10.8mmol) for preparing of step subsequently and be added dropwise to system, about 5min dropwises, and system temperature is controlled at 100 ℃ in the dropping process.After dropwising, system continues stirring reaction 18h at 100 ℃.After finishing, question response is cooled to room temperature.
After reaction finished, system temperature was added chloroform 15mL after being cooled to room temperature in system, 10% aqueous solution of sodium bisulfite 15mL was added in the constant pressure funnel be added dropwise in the system, after to be added the finishing, continued to stir 1.5h; Subsequently the quinhydrones of separating out is filtered, filter cake washs molten thing with the no product of conclusive evidence with minimum of chloroform again), merge organic phase, organic phase is washed 3 times with 10% aqueous sodium carbonate again, saturated sodium-chloride washs once.Organic phase with anhydrous sodium sulfate drying, remove inorganic salt and get weak yellow liquid, be concentrated into dried, ethyl acetate refining product 1.05g, HPLC content〉99%.
Claims (8)
1. the synthetic method of finasteride is characterized in that, comprises the steps:
(1) with trifluoroacetamide in the presence of organic bases or mineral alkali, in solvent,, from reaction product, solid is leached then with trimethylchlorosilane reaction, collect filtrate;
(2) with the filtrate of step (1), in solvent, add 3-carbonyl-4-aza-5 alpha-androstane-17 β-tert-butylamides and dehydrogenation reagent react, from reaction product, collect target product then.
2. method according to claim 1 is characterized in that, the reaction times of step (1) is 2～24h, and temperature of reaction is 20～100 ℃.
3. method according to claim 1 is characterized in that, organic bases is pyridine, Trimethylamine, triethylamine, N, N-dimethyl-4-aminopyridine, Tributylamine, trioctylamine or DBU;
Mineral alkali is the carbonate of metal, comprises Quilonum Retard, salt of wormwood, yellow soda ash, barium carbonate, cesium carbonate, Strontium carbonate powder or lime carbonate;
Described solvent is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene.
4. method according to claim 1 is characterized in that, in the reaction of step (1), the mol ratio of trimethylchlorosilane and trifluoroacetamide is 1～5:1; The mol ratio of organic bases or mineral alkali and trifluoroacetamide is 1～5:1; In the solvent, the content of trifluoroacetamide is 0.1～1.5mol/mL.
5. method according to claim 1 is characterized in that, the temperature of reaction of step (2) is 20～120 ℃, and the time is 0.1～24 hour.
6. method according to claim 1 is characterized in that, said dehydrogenation reagent is 2,3-two chloro-5,6-dicyan para benzoquinone (DDQ) or 2,3,5,6-chloranil (chloranil).
7. method according to claim 1, it is characterized in that, the described solvent of step (2) is selected from tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1,4-dioxane, glycol dimethyl ether, glycol ether dme, methylene dichloride, 1, more than one of 2-ethylene dichloride, Skellysolve A, normal hexane, sherwood oil, normal heptane, toluene or dimethylbenzene.
8. method according to claim 1, it is characterized in that the BSTFA in the preparation-obtained solution of step (1) and the mol ratio of compound (2) are 2～5:1, the mol ratio of dehydrogenation reagent and compound (2) is 1～5:1, in the solvent, the content of compound (2) is 0.1～1.0mol/mL.
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| CNA2008102024768A CN101418033A (en) | 2008-11-10 | 2008-11-10 | Method for synthesizing finasteride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558290A (en) * | 2012-01-11 | 2012-07-11 | 长沙理工大学 | Novel technology for synthesis of finasteride via chlorination and dehydrogenation |
| CN102911247A (en) * | 2012-01-06 | 2013-02-06 | 长沙理工大学 | Novel method for synthesizing finasteride by bromization elimination two-step process |
| 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 |
-
2008
- 2008-11-10 CN CNA2008102024768A patent/CN101418033A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911247A (en) * | 2012-01-06 | 2013-02-06 | 长沙理工大学 | Novel method for synthesizing finasteride by bromization elimination two-step process |
| CN102558290A (en) * | 2012-01-11 | 2012-07-11 | 长沙理工大学 | Novel technology for synthesis of finasteride via chlorination and dehydrogenation |
| 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 |
| 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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Open date: 20090429 |