CN101891663A - Preparation method of bicalutamide intermediate - Google Patents
Preparation method of bicalutamide intermediate Download PDFInfo
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- CN101891663A CN101891663A CN2010102325758A CN201010232575A CN101891663A CN 101891663 A CN101891663 A CN 101891663A CN 2010102325758 A CN2010102325758 A CN 2010102325758A CN 201010232575 A CN201010232575 A CN 201010232575A CN 101891663 A CN101891663 A CN 101891663A
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Abstract
The invention provides a preparation method of bicalutamide intermediate shown in the formula (II) and the method is more reasonable and more suitable for industrial production. The method comprises the following steps: adding compound (I), potassium carbonate and p-fluorophenol in reaction solvent, stirring while slowly heating the mixture to reaction temperature 30-80 DEG C, reacting for 12-18 hours, extracting, and purifying. The method of the invention is performed under mild conditions, the reagent potassium carbonate is accessible, the price is cheap and the method does not have burning and blast hazards, and the use security is high. Agents are added at room temperature without the protection of nitrogen, the reaction solvent does not need special treatment, the reaction yield is more than 75%, the raw material cost is greatly reduced and the method is more suitable for industrial production.
Description
Technical field
The present invention relates to a kind of anti-androgens medicine bicalutamide intermediates preparation.
Background technology
Bicalutamide (Bicalutamide), chemistry (±)-N-[4-cyano group-3-(trifluoromethyl) phenyl by name]-the 3-[(4-fluorophenyl) alkylsulfonyl]-2-hydroxy-2-methyl propionic acid amide, its structural formula is as follows:
Bicalutamide is an anti-androgens medicine of prompt sharp Kanggong department exploitation, is used for the combination therapy of advanced prostate cancer, and commodity are called Kang Shide.Be 32 editions determined curative effects that record of American Pharmacopeia, the effect high specificity, oral effective, convenient drug administration, better tolerance, and a kind of nonsteroidal androgen antagonist medicine of the transformation period of length is arranged, be the medicine of present unique oral once (50mg/ sheet) treatment prostate cancer.
The practical preparation technology that relatively is suitable for of domestic and foreign literature report has following two kinds at present:
1, with the 2-methacrylic chloride be raw material synthetic route (Howard Tucker J.Med.Chem.1988,31,954-959):
2, with 3-bromo-2-methyl-2 hydroxy propanoic acid be the synthetic route (US Pat 4636505) of raw material:
Also have corresponding deutero-to be used to prepare the synthetic route of racemization, dextrorotation or RBIC in addition, its common characteristic is to add fluoro thiophenol is carried out condensation reaction to obtain in reaction
Bicalutamide intermediate shown in the formula (II).But with to the fluoro thiophenol condensation in to use expensive reagent hydrogen sodium, its chemical reactivity is very high, can spontaneous combustion in damp atmosphere; Be heated or contact and promptly emit heat and hydrogen, cause burning and blast with moisture, acids; With oxygenant kickback can take place, cause burning or blast; Meet moisture and moisture and generate oxyhydroxide, corrodibility is very strong.Therefore reaction conditions is very harsh, requires at 0 ℃ when adding reagent, and need carry out under nitrogen protection, and the reaction solvent tetrahydrofuran (THF) need dewater, and reaction yield is low, is difficult to realize suitability for industrialized production, and final product quality is difficult to guarantee.
Summary of the invention
The preparation formula (II) that the purpose of this invention is to provide a kind of more reasonable, suitability for industrialized production of being more convenient for
The method of shown bicalutamide intermediate.Preparation method provided by the invention is included in and adds compound (I) in the reaction solvent
Wherein R is
Salt of wormwood, to fluoro thiophenol, stir and slowly be heated to 30～80 ℃ of temperature of reaction, in 12～18 hours reaction times, extract purifying.
This method also is included in and adds phase-transfer catalyst in the reaction solvent, and wherein phase-transfer catalyst is a kind of in benzyl trimethyl ammonium chloride, hexadecyl tributyl phosphonium ammonium, the Tetrabutyl amonium bromide, and the weight ratio of itself and compound (I) is 1: 0.01～0.05.
Reaction solvent is a kind of in dimethyl formamide, alcohols, tetrahydrofuran (THF), dioxane or the acetone, is preferably dimethyl formamide, and the weightmeasurement ratio of itself and compound (I) is 1: 3～5.
The weight ratio of salt of wormwood and compound (I) is 1: 0.2～0.6, is 1: 1.05～1.30 to the mol ratio of fluoro thiophenol and compound (I).
Aforementioned extraction comprises and adds entry, extracted with diethyl ether, and anhydrous sodium sulfate drying reclaims solvent.
Aforementioned purifying comprises uses the sherwood oil recrystallization.
Temperature of reaction is preferably 50～60 ℃, and the reaction times is preferably 16 hours.
By aforesaid method, under comparatively gentle condition, carry out condensation reaction, reaction reagent salt of wormwood source is easy to get, and is cheap and do not have the dangerous safe to use of burning or blast.Add reagent and at room temperature carry out, need not nitrogen protection, reaction solvent does not need special processing; temperature is 30～80 ℃ during reaction, and the reaction times is 12～18 hours, and reaction yield is more than 75%; reduce material cost significantly, the technology after the improvement is more suitable for suitability for industrialized production.
A preferred embodiment of the present invention is to add compound (I) in dimethyl formamide
Wherein R is
Or
Salt of wormwood, to fluoro thiophenol, stir and slowly be heated to 50～60 ℃ of temperature of reaction, react 16 hours, add entry, extracted with diethyl ether, anhydrous sodium sulfate drying, the recovery solvent is used the sherwood oil recrystallization.Obtain shown in the formula (II)
The intermediate of bicalutamide, yield is brought up to more than 90%.
The present invention improves the intermediates preparation of synthetic bicalutamide, the method after the improvement, and easy to operate, cost is low, environmental influence is little, and the products obtained therefrom quality is good, has higher industrial value.
Embodiment
Embodiment 1,4 '-cyano group-3-[(4-fluorophenyl) sulphur]-preparation of 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add dimethyl formamide 20ml, 1,2-epoxy-2-methyl-N-[4 '-cyano group-3 '-(trifluoromethyl) phenyl] propionic acid amide 5g, Tetrabutyl amonium bromide 0.10g, salt of wormwood 2g, stirring and dissolving adds fluoro thiophenol 2.8g, slowly be heated to 50～60 ℃ and reacted 16 hours down, cool to room temperature adds entry 100ml, extracted with diethyl ether 2 times, anhydrous Na
2SO
4Dry.Reclaim solvent, get solid 7.7g.Get 6.7g with the sherwood oil recrystallization, 115～117 ℃ of m.p, yield 91%.
Embodiment 2,4 '-cyano group-3-[(4-fluorophenyl) sulphur]-preparation of 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add dimethyl formamide 20ml, 1,2-epoxy-2-methyl-N-[4 '-cyano group-3 '-(trifluoromethyl) phenyl] propionic acid amide 5g, salt of wormwood 2.5g, stirring and dissolving adds fluoro thiophenol 2.8g, slowly is heated to 50～60 ℃ and reacts 16 hours down, all the other treatment processs are with embodiment 1, solid 6.8g, m.p115～116 ℃, yield 92.2%.
Embodiment 3, the fluorine-based phenyl of (R)-(-) 4 '-cyano group-3-[(4-) sulfenyl]-preparation of 2-carbonyl-2-methyl-3 '-(trifluoromethyl) propionanilide
In reactor, add dimethyl formamide 40ml, (R)-(-) 3-bromo-2-hydroxy-2-methyl-N-[4-cyano group-3-(trifluoromethyl)] propionic acid amide 12.7g, salt of wormwood 3g, stirring and dissolving adds fluoro thiophenol 4.9g, stirring slowly is heated to 50～60 ℃ and reacted 16 hours down, and all the other treatment processs get solid 13.2g with embodiment 1,93～96 ℃ of m.p, yield 92%.
Embodiment 4,4 '-cyano group-3-[(4-fluorophenyl) sulphur]-preparation of 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add dehydrated alcohol 20ml, 1,2-epoxy-2-methyl-N-[4 '-cyano group-3 '-(trifluoromethyl) phenyl] propionic acid amide 5g, hexadecyl tributyl phosphonium ammonium 0.20g, salt of wormwood 2.5g to fluoro thiophenol 2.8g, slowly is heated to 70～80 ℃ and reacted 12 hours down under stirring, all the other treatment processs get solid 5.53g with embodiment 1.115～116 ℃ of m.p, yield 75.0%.
Embodiment 5, the fluorine-based phenyl of (R)-(-) 4 '-cyano group-3-[(4-) sulfenyl]-preparation of 2-carbonyl-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add anhydrous methanol 25ml, (R)-(-) 3-bromo-2-hydroxy-2-methyl-N-[4-cyano group-3-(trifluoromethyl)] propionic acid amide 6.4g, salt of wormwood 2.5g, to fluoro thiophenol 2.6g, slowly being heated to 30～40 ℃ under stirring reacted 18 hours down, all the other treatment processs get solid 5.6g with embodiment 1.93～96 ℃ of m.p, yield 77.0%.
Embodiment 6,4 '-cyano group-3-[(4-fluorophenyl) sulphur]-preparation of 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add tetrahydrofuran (THF) 17ml, 1,2-epoxy-2-methyl-N-[4 '-cyano group-3 '-(trifluoromethyl) phenyl] propionic acid amide 5g, salt of wormwood 2.5g, stirring and dissolving adds fluoro thiophenol 2.6g, slowly is heated to 40～50 ℃ and reacts 17 hours down, all the other treatment processs are with embodiment 1, solid 6.5g, m.p115～118 ℃, yield 88.2%.
Embodiment 7,4 '-cyano group-3-[(4-fluorophenyl) sulphur]-preparation of 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide
In reaction vessel, add acetone 22ml, 1,2-epoxy-2-methyl-N-[4 '-cyano group-3 '-(trifluoromethyl) phenyl] propionic acid amide 5g, salt of wormwood 2.5g, benzyl trimethyl ammonium chloride 0.15g, stirring and dissolving adds fluoro thiophenol 3.0g, slowly be heated to 40～50 ℃ and reacted 18 hours down, all the other treatment processs get solid 6.0g with embodiment 1,114～117 ℃ of m.p, yield 81.4%.
Claims (10)
1. the bicalutamide intermediates preparation shown in the formula (II), be included in add compound (I), salt of wormwood in the reaction solvent, to fluoro thiophenol, stir and slowly be heated to 30～80 ℃ of temperature of reaction, 12～18 hours reaction times, extract, purifying,
Formula (II)
Compound (I)
Wherein R is
2. preparation method according to claim 1, this method also are included in and add phase-transfer catalyst in the reaction solvent.
3. preparation method according to claim 2, its described phase-transfer catalyst is a kind of in benzyl trimethyl ammonium chloride, hexadecyl tributyl phosphonium ammonium, the Tetrabutyl amonium bromide.
4. according to the preparation method of claim 3, the weight ratio of its described phase-transfer catalyst and compound (I) is 1: 0.01～0.05.
5. according to each preparation method of claim 1 to 4, its described reaction solvent is a kind of in dimethyl formamide, alcohols, tetrahydrofuran (THF), dioxane or the acetone, is preferably dimethyl formamide.
6. according to each described preparation method of claim 1 to 4, the weightmeasurement ratio of its described reaction solvent and compound (I) is 1: 3～5, the weight ratio of salt of wormwood and compound (I) is 1: 0.2～0.6, is 1: 1.05～1.30 to the mol ratio of fluoro thiophenol and compound (I).
7. according to each described preparation method of claim 1 to 4, its described extraction comprises and adds entry, extracted with diethyl ether, and anhydrous sodium sulfate drying reclaims solvent.
8. according to each described preparation method of claim 1 to 4, its described purifying comprises uses the sherwood oil recrystallization.
9. according to each described preparation method of claim 1 to 4, its described temperature of reaction is 50～60 ℃, and the reaction times is 16 hours.
10. the bicalutamide intermediates preparation shown in the formula (II), be included in add compound (I), salt of wormwood in the dimethyl formamide, to fluoro thiophenol, stir and slowly be heated to 50～60 ℃ of temperature of reaction, reacted 16 hours, and added entry, extracted with diethyl ether, anhydrous sodium sulfate drying, reclaim solvent, use the sherwood oil recrystallization
Formula (II)
Compound (I)
Wherein R is
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336798A (en) * | 2018-11-19 | 2019-02-15 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide sulfide intermediate |
| CN112159372A (en) * | 2020-10-22 | 2021-01-01 | 怀化宝华生物科技有限公司 | Preparation method of bicalutamide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1602299A (en) * | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | Crystals of bicalutamide and process for their production |
-
2010
- 2010-07-21 CN CN2010102325758A patent/CN101891663A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1602299A (en) * | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | Crystals of bicalutamide and process for their production |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336798A (en) * | 2018-11-19 | 2019-02-15 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide sulfide intermediate |
| CN109336798B (en) * | 2018-11-19 | 2021-11-16 | 常州新星联生物科技有限公司 | Preparation method of bicalutamide thioether intermediate |
| CN112159372A (en) * | 2020-10-22 | 2021-01-01 | 怀化宝华生物科技有限公司 | Preparation method of bicalutamide |
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Application publication date: 20101124 |