CN106905265A - N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method - Google Patents

N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method Download PDF

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Publication number
CN106905265A
CN106905265A CN201710135596.XA CN201710135596A CN106905265A CN 106905265 A CN106905265 A CN 106905265A CN 201710135596 A CN201710135596 A CN 201710135596A CN 106905265 A CN106905265 A CN 106905265A
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phenyl
trifluoromethyl
cyano group
methyl
phthalic anhydride
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李红功
韦幸红
李大娟
孙克周
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Changzhou Wintop Chemical Technology Co Ltd
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Changzhou Wintop Chemical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Epoxy Compounds (AREA)

Abstract

The present invention relates to a kind of N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method, it is characterized by by N [4 cyano group 3（Trifluoromethyl）Phenyl] acrylamide of 2 methyl 2 and phthalic anhydride be added in solvent, and hydrogen peroxide is added dropwise, and after dripping off, in 20~90 DEG C of insulation reactions, raw material N [4 cyano group 3 is controlled in HPLC（Trifluoromethyl）Phenyl] acrylamide content of 2 methyl 2 less than 0.5% reaction terminate, decompression steams solvent afforded crude material after reaction terminates, crude product is added in the water of 5~10 times of phthalic anhydride weight, it is sufficiently stirred for 0.3~1.5 hour after adding alkali and sodium sulfite, filtering, water washing, finished product N [4 cyano group 3 are obtained after drying（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2.The present invention has the advantages that production safety reliability, production cost are relatively low.

Description

N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides Preparation method
Technical field
The present invention relates to a kind of preparation method of Bicalutamide intermediate, more particularly to a kind of N- [4- cyano group -3-（Trifluoro Methyl）Phenyl] -2,3- epoxy -2- methyl propanamides preparation method.
Background technology
Bicalutamide is a non steroidal antiandrogen, and its specific action is strong, oral effective, convenient drug administration, Better tolerance, is the choice drug for treating prostate cancer.
And N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides are prepare Bicalutamide one Individual important intermediate, N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides structural formula it is as follows：
。
N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides preparation method mostly by N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamides by epoxidation be obtained, N- [4- cyano group -3-（Trifluoro Methyl）Phenyl] -2- methyl -2- acrylamides structural formula it is as follows：
。
Document J Med Chem, 1988,31,954-959 and J Med Chem, on N- [4- in 1988,31,885-887 Cyano group -3-（Trifluoromethyl）Phenyl] a kind of preparation method of -2,3- epoxy -2- methyl propanamides is by N- [4- cyano group -3-（Three Methyl fluoride）Phenyl] -2- methyl -2- acrylamides and metachloroperbenzoic acid flow back in trichloroethanes together（120℃）Instead Should, the defect of the technique is that at this temperature, metachloroperbenzoic acid has the risk of blast, and metachloroperbenzoic acid It is expensive, cause final products high cost.
American documentation literature US20020086902 discloses N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxies - A kind of preparation method of 2- methyl propanamides is to use trifluoro Peracetic acid as oxidant, with N- [4- cyano group -3-（Fluoroform Base）Phenyl] -2- methyl -2- acrylamides are reacted, and the defect of its technique is also expensive raw material trifluoro Peracetic acid, And there is risk of explosion.
American documentation literature US20030073742 discloses N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxies - Another preparation method of 2- methyl propanamides is to use hydrogen peroxide and acetic anhydride as oxidant, wolframic acid as catalyst, with Compound ii is reacted, and the defect of its technique is too low yield, only 50% or so.
The content of the invention
For disadvantages mentioned above, it is an object of the invention to provide the N- [4- that a kind of production safety is reliable, production cost is relatively low Cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides preparation method.
Technology contents of the invention are, a kind of N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl-props The preparation method of acid amides, it is characterized by by N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamides and adjacent benzene Dicarboxylic acid anhydride is added in solvent, and hydrogen peroxide is added dropwise, and after dripping off, in 20~90 DEG C of insulation reactions, raw material N- [4- cyanogen is controlled in HPLC Base -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamide contents less than 0.5% reaction terminate, reaction terminate after depressurize steam Go out solvent afforded crude material, crude product is added in the water of 5~10 times of phthalic anhydride weight, filled after adding alkali and sodium sulfite Divide stirring 0.3~1.5 hour, filtering, water washing obtains finished product N- [4- cyano group -3- after drying（Trifluoromethyl）Phenyl] -2,3- Epoxy -2- methyl propanamides；Wherein
The solvent is toluene, dimethylbenzene, mesitylene, dichloromethane, 1,2- dichloroethanes or chloroform；
Described alkali is NaOH, potassium hydroxide, sodium carbonate, sodium acid carbonate, potassium carbonate or saleratus；
N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamides and solvent w/v（g:ml）For 1：3~1:20；
N- [4- cyano group -3-（Trifluoromethyl）Phenyl] mol ratio of -2- methyl -2- acrylamides and phthalic anhydride is 1:1 ~1:3；
Phthalic anhydride is 1 with the mol ratio of hydrogen peroxide:1~1:2；Described hydrogen peroxide concentration is 30~55 weight %；
The addition of alkali is 0.3~0.8 times of phthalic anhydride weight, and sodium sulfite addition is phthalic anhydride weight 0.1~0.5 times.
In above-mentioned N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides preparation method in protect Warm reaction temperature is 30~60 DEG C；The preferred dichloromethane of solvent, chloroform or 1,2- dichloroethanes；N- [4- cyano group -3-（Fluoroform Base）Phenyl] -2- methyl -2- acrylamides and phthalic anhydride mol ratio preferably 1:1.2~1:1.8.
Reaction equation of the invention is as follows：
。
The present invention have the advantage that compared with prior art for：
（1）, avoid using expensive raw material, low production cost；
（2）, the raw material that use of the present invention it is safe and reliable, production security is protected.
Specific embodiment
Example 1, by N- [4- cyano group -3-（Trifluoromethyl）Phenyl] 25.4 grams of -2- methyl -2- acrylamides（0.1mol）, it is adjacent 19.2 grams of phthalate anhydride（0.13mol）It is added in 153ml dichloromethane, is added dropwise 9.7 grams（0.14mol）50% hydrogen peroxide, drop After complete, in 35~40 DEG C of insulation reactions, raw material N- [4- cyano group -3- are controlled in HPLC（Trifluoromethyl）Phenyl] -2- methyl -2- third Acrylamide content terminates less than 0.5% reaction, and decompression steams dichloromethane and obtains crude product after reaction terminates, and crude product is added into 153 grams In water, it is sufficiently stirred for 0.5 hour after adding 11 grams and 5 grams sodium sulfites of sodium carbonate, is filtered, is fully washed with 50 grams of water, in Finished product N- [4- cyano group -3- are obtained after 55 DEG C of dryings（Trifluoromethyl）Phenyl] -23 grams of 2,3- epoxy -2- methyl propanamides, yield 85%。
Example 2, by N- [4- cyano group -3-（Trifluoromethyl）Phenyl] 25.4 grams of -2- methyl -2- acrylamides（0.1mol）, it is adjacent 20.7 grams of phthalate anhydride（0.14mol）It is added in 177ml chloroforms, is added dropwise 10.2 grams（0.15mol）50% hydrogen peroxide, drips off Afterwards, in 35~40 DEG C of insulation reactions, raw material N- [4- cyano group -3- are controlled in HPLC（Trifluoromethyl）Phenyl] -2- methyl -2- propylene Amide content terminates less than 0.5% reaction, and reaction is depressurized after terminating and steams the crude product of chloroform, and crude product is added in 153 grams of water, It is sufficiently stirred for 0.5 hour after adding 14 grams and 6 grams sodium sulfites of potassium carbonate, is filtered, is fully washed with 50 grams of water, it is dry in 55 DEG C Finished product N- [4- cyano group -3- are obtained after dry（Trifluoromethyl）Phenyl] -24 grams of 2,3- epoxy -2- methyl propanamides, yield 88.9%.
Example 3, by N- [4- cyano group -3-（Trifluoromethyl）Phenyl] 50.8 grams of -2- methyl -2- acrylamides（0.2mol）, it is adjacent 47.3 grams of phthalate anhydride（0.32mol）350ml 1 is added to, in 2- dichloroethanes, 23.1 grams is added dropwise（0.34mol）50% pair Oxygen water, after dripping off, in 35~40 DEG C of insulation reactions, controls raw material N- [4- cyano group -3- in HPLC（Trifluoromethyl）Phenyl] -2- first Base -2- acrylamide contents terminate less than 0.5% reaction, and decompression steams 1,2- dichloroethanes and obtains crude product after reaction terminates, by crude product It is added in 300 grams of water, is sufficiently stirred for 0.5 hour after adding 26 grams and 13 grams sodium sulfites of sodium carbonate, filters, with 50 grams of water Fully washing, in obtaining finished product N- [4- cyano group -3- after 55 DEG C of dryings（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propionyl 49 grams of amine, yield 90.7%.

Claims (2)

1.N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides preparation method, it is characterized by will N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamides and phthalic anhydride be added in solvent, be added dropwise Hydrogen peroxide, after dripping off, in 20~90 DEG C of insulation reactions, controls raw material N- [4- cyano group -3- in HPLC（Trifluoromethyl）Phenyl] -2- Methyl -2- acrylamide contents terminate less than 0.5% reaction, and decompression steams solvent afforded crude material after reaction terminates, and crude product is added to In the water that 5~10 times of phthalic anhydride weight, it is sufficiently stirred for 0.3~1.5 hour after adding alkali and sodium sulfite, is filtered, Water washing, finished product N- [4- cyano group -3- are obtained after drying（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides；Wherein
The solvent is toluene, dimethylbenzene, mesitylene, dichloromethane, 1,2- dichloroethanes or chloroform；
Described alkali is NaOH, potassium hydroxide, sodium carbonate, sodium acid carbonate, potassium carbonate or saleratus；
N- [4- cyano group -3-（Trifluoromethyl）Phenyl] w/v of -2- methyl -2- acrylamides and solvent is 1：3~1: 20；
N- [4- cyano group -3-（Trifluoromethyl）Phenyl] mol ratio of -2- methyl -2- acrylamides and phthalic anhydride is 1:1 ~1:3；
Phthalic anhydride is 1 with the mol ratio of hydrogen peroxide:1~1:2；Described hydrogen peroxide concentration is 30~55 weight %；
The addition of alkali is 0.3~0.8 times of phthalic anhydride weight, and sodium sulfite addition is phthalic anhydride weight 0.1~0.5 times.
2. N- [4- cyano group -3- according to claim 1（Trifluoromethyl）Phenyl] -2,3- epoxy -2- methyl propanamides Preparation method, it is characterized by insulation reaction temperature is 30~60 DEG C；Solvent is dichloromethane, chloroform or 1,2- dichloroethanes；N- [4- cyano group -3-（Trifluoromethyl）Phenyl] -2- methyl -2- acrylamides and phthalic anhydride mol ratio be 1:1.2~1: 1.8。
CN201710135596.XA 2017-03-09 2017-03-09 N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method Pending CN106905265A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111087367A (en) * 2019-11-19 2020-05-01 苏州永健生物医药有限公司 Synthesis method of N- (4 cyano-3- (trifluoromethyl) phenyl) -2-methyl epoxy propylene-2-amide
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 (2)

* Cited by examiner, † Cited by third party
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
EP1679306A1 (en) * 2003-10-16 2006-07-12 Sumitomo Chemical Company, Limited Process for producing bicalutamide and method of purifying intermediate therefor

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
EP1679306A1 (en) * 2003-10-16 2006-07-12 Sumitomo Chemical Company, Limited Process for producing bicalutamide and method of purifying intermediate therefor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
柴洪伟 等，: "N-[4-氰基-3-(三氟甲基)苯基-2-甲基-2-环氧丙酰胺合成工艺改进研究", 《精细化工中间体》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111087367A (en) * 2019-11-19 2020-05-01 苏州永健生物医药有限公司 Synthesis method of N- (4 cyano-3- (trifluoromethyl) phenyl) -2-methyl epoxy propylene-2-amide
CN111087367B (en) * 2019-11-19 2022-05-10 苏州永健生物医药有限公司 Synthesis method of N- (4 cyano-3- (trifluoromethyl) phenyl) -2-methyl epoxy propylene-2-amide
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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Inventor after: Sun Fuqiang

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