WO2004039791A1 - A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide - Google Patents

A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide Download PDF

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WO2004039791A1
WO2004039791A1 PCT/PL2003/000111 PL0300111W WO2004039791A1 WO 2004039791 A1 WO2004039791 A1 WO 2004039791A1 PL 0300111 W PL0300111 W PL 0300111W WO 2004039791 A1 WO2004039791 A1 WO 2004039791A1
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cyano
trifluoromethylphenyl
dicarboxylic acid
acid anhydride
group
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PCT/PL2003/000111
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French (fr)
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Michal Odrowaz-Sypniewski
Lukasz Kaczmarek
Roman Balicki
Wieslaw Szelejewski
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Instytut Farmaceutyczny
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Priority to AU2003301681A priority Critical patent/AU2003301681A1/en
Publication of WO2004039791A1 publication Critical patent/WO2004039791A1/en

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    • 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

Definitions

  • the present invention relates to a process for the production of N- (4-cyano-3-trifluoromethylphenyl) -2, 3-epoxy- 2-methylpropanamide on the way of epoxidizing N- (4-cyano-3- trifluoromethylphenyl) -2-methylpropenamide .
  • N- (4-cyano-3-trifluoromethylphenyl) -2 , 3-epoxy-2-methyl- propanamide (formula 1) is an intermediate . in the production of bicalutamide, which is an antiandrogen used in the treatment of prostate cancers.
  • European patent EP 0 100 172 disclosed a number of processes for the synthesis of bicalutamide in the racemic form.
  • One of the methods comprises the application of N-(4- cyano-3-trifluoromethylphenyl) -2, 3-epoxy-2-methylpropanamide (formula 1) as an intermediate.
  • N- (4-cyano-3- trifluoromethylphenyl) -2, 3-epoxy-2-methylpropanamide was prepared by epoxidation of N- (4-cyano-3-trifluoromethyl- phenyl) -2-methylpropenamide with m-chloroperbenzoic acid
  • MCPBA MCPBA
  • epoxidation reaction was carried out in 1,1,1- trichloroethane in the presence of 4-methyl-2, 6-di- tert- butyl-phenol at reflux temperature.
  • This method although it proved to be reliable on a laboratory scale, it is associated with essential drawbacks upon scaling-up.
  • the reagent used for the oxidation reaction is highly explosive. The transportation of larger amounts of this reagent is seriously hazardous, as is its handling. Moreover, it is a very expensive reagent .
  • Patent EP 0 100 172 discloses an Example, according to which the synthesized crude N- (4-cyano-3-trifluoromethylphenyl) -2 , 3-epoxy-2-methylpropanamide has to be purified, before its use in further steps of the synthesis.
  • the purification is carried out initially on a chromatographic column, filled with silica gel and eluted with a mixture of ethyl acetate and petroleum ether, and then by crystallization from petroleum ether.
  • the double bond present in N- (4-cyano-3- trifluoromethylphenyl) -2-methylpropenamide is epoxidized using the complex of hydrogen peroxide and urea (urea- hydrogen peroxide complex, UHP) , in a mixture with a dicarboxylic acid anhydride of formula 3 or 4.
  • the groups Ri and R 2 in formula 3 are the same or different and are a hydrogen atom, a C ⁇ - -alkyl group, an aryl group or a halogen atom.
  • the substituent X in formula 4 is a hydrogen atom, a C ⁇ _ -alkyl group, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group.
  • cyclic dicarboxylic acid anhydrides suitable for use according to the process of the present invention are, for example, maleic anhydride or phthalic anhydride.
  • a molar excess of the complex of hydrogen peroxide and urea is used, compared to the amount of the cyclic dicarboxylic acid anhydride of formula 3 or .
  • the molar ratio of the complex of hydrogen peroxide and urea to the dicarboxylic acid anhydride is from about 1.1:1 to about 6.0:1, preferably 4:1.
  • the molar ratio of the dicarboxylic acid anhydride to the olefin initially present in the reaction mixture is preferably from about 1:1 to about 3:1, and especially 2:1.
  • the complex of hydrogen peroxide with urea [urea- hydrogen peroxide complex, H 2 0 2 *CO (NH 2 ) 2 ] is an inexpensive and safe reagent, produced on an industrial scale.
  • the known applications of this complex inter alia include its use as a detergent-improving additive.
  • the application of the complex of hydrogen peroxide with urea (UHP) for the epoxidation of the double bond present in N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide allows for elimination of the risks associated with handling the explosive m-chloroperbenzoic acid, it is cost-saving and it does not generate the environmentally noxious byproduct, m-chlorobenzoic acid, which is troublesome to dispose of.
  • the substrate N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide
  • Suitable solvents are, for example, aromatic hydrocarbons, cyclic ethers or organic esters, such as ethyl acetate.
  • the acid anhydride and the complex of hydrogen peroxide with urea (UHP) are successively added to this solution, and the mixture is stirred at 25-30 °C, until all the propenamide reacted.
  • the progress of the reaction can be monitored by TLC.
  • reaction mixture is neutralized with an aqueous hydroxide solution, for example with a solution of sodium hydroxide, and the product is extracted with a water-immiscible solvent, for example with ethyl acetate.
  • aqueous hydroxide solution for example with a solution of sodium hydroxide
  • a water-immiscible solvent for example with ethyl acetate.
  • the phases are separated and the solvent from the organic phase is evaporated, leaving the crude product, which is purified by a single crystallization from isopropanol.
  • the process of the present invention ensures ready access to N- (4-cyano-3-trifluoromethylphenyl) -2, 3-epoxy-2- methylpropanamide of high purity, sufficient for its immediate application in the next step of bicalutamide synthesis, and without a need for complicated purification methods .
  • N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide (10.2 g, 40.1 mmol) and phthalic anhydride (10.2 g, 80.3 mmol) were dissolved in ethyl acetate (100 mL) .
  • the UHP complex (15.0 g, 159 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours.
  • N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide (10.2 g, 40 mmol) and maleic anhydride (7.8 g, 80 mmol) were dissolved in ethyl acetate (100 mL) .
  • the UHP complex (15.1 g, 160 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours. Subsequently, the reaction mixture was neutralized with a solution of NaOH (6.4 g, 160 mmol) in water (25 L) . After the phases separated, the organic phase was washed first with a solution of Na 2 S0 3 (lg) in water, followed by washing with water.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for the production of N-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide is characterized in that N-(4-cyano-3-trifluoromethylphenyl)-2-ethylpropenamide is epoxidized using a mixture of the urea-hydrogen peroxide complex (UHP) with either a cyclic dicarboxylic acid anhydride of formula 3, where groups R1 and R2 are the same or different and are a hydrogen atom, a C1-4-alkyl group, an aryl group or a halogen atom, or with a cyclic dicarboxylic acid anhydride of formula 4, where X is a hydrogen atom, a C1-4-alkyl group, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group. N- (4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-ethylpropanamide is an intermediate in the production of an antiandrogenic substance.

Description

A PROCESS FOR THE PRODUCTION OF N- (4-CYANO-3-TRIFLUORO- METHYLPHENYL) -2,3 -EPOXY-2-METHYLPROPANAMIDE
The present invention relates to a process for the production of N- (4-cyano-3-trifluoromethylphenyl) -2, 3-epoxy- 2-methylpropanamide on the way of epoxidizing N- (4-cyano-3- trifluoromethylphenyl) -2-methylpropenamide .
N- (4-cyano-3-trifluoromethylphenyl) -2 , 3-epoxy-2-methyl- propanamide (formula 1) is an intermediate . in the production of bicalutamide, which is an antiandrogen used in the treatment of prostate cancers.
European patent EP 0 100 172 disclosed a number of processes for the synthesis of bicalutamide in the racemic form. One of the methods comprises the application of N-(4- cyano-3-trifluoromethylphenyl) -2, 3-epoxy-2-methylpropanamide (formula 1) as an intermediate. N- (4-cyano-3- trifluoromethylphenyl) -2, 3-epoxy-2-methylpropanamide was prepared by epoxidation of N- (4-cyano-3-trifluoromethyl- phenyl) -2-methylpropenamide with m-chloroperbenzoic acid
(MCPBA) . The epoxidation reaction was carried out in 1,1,1- trichloroethane in the presence of 4-methyl-2, 6-di- tert- butyl-phenol at reflux temperature. This method, although it proved to be reliable on a laboratory scale, it is associated with essential drawbacks upon scaling-up. The reagent used for the oxidation reaction is highly explosive. The transportation of larger amounts of this reagent is seriously hazardous, as is its handling. Moreover, it is a very expensive reagent . Patent EP 0 100 172 discloses an Example, according to which the synthesized crude N- (4-cyano-3-trifluoromethylphenyl) -2 , 3-epoxy-2-methylpropanamide has to be purified, before its use in further steps of the synthesis. The purification is carried out initially on a chromatographic column, filled with silica gel and eluted with a mixture of ethyl acetate and petroleum ether, and then by crystallization from petroleum ether.
Presently, it has unexpectedly been discovered that the inconveniences associated with the application of MCPBA and with the troublesome purification of the product may be avoided. Thus, according to the process of the present invention, the double bond present in N- (4-cyano-3- trifluoromethylphenyl) -2-methylpropenamide is epoxidized using the complex of hydrogen peroxide and urea (urea- hydrogen peroxide complex, UHP) , in a mixture with a dicarboxylic acid anhydride of formula 3 or 4.
The groups Ri and R2 in formula 3 are the same or different and are a hydrogen atom, a Cχ- -alkyl group, an aryl group or a halogen atom. The substituent X in formula 4 is a hydrogen atom, a Cι_ -alkyl group, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group.
The cyclic dicarboxylic acid anhydrides suitable for use according to the process of the present invention are, for example, maleic anhydride or phthalic anhydride.
According to the process of the present invention, a molar excess of the complex of hydrogen peroxide and urea is used, compared to the amount of the cyclic dicarboxylic acid anhydride of formula 3 or . The molar ratio of the complex of hydrogen peroxide and urea to the dicarboxylic acid anhydride is from about 1.1:1 to about 6.0:1, preferably 4:1.
According to the process of the present invention, the molar ratio of the dicarboxylic acid anhydride to the olefin initially present in the reaction mixture is preferably from about 1:1 to about 3:1, and especially 2:1.
The complex of hydrogen peroxide with urea [urea- hydrogen peroxide complex, H202*CO (NH2) 2] is an inexpensive and safe reagent, produced on an industrial scale. The known applications of this complex inter alia include its use as a detergent-improving additive. The application of the complex of hydrogen peroxide with urea (UHP) for the epoxidation of the double bond present in N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide allows for elimination of the risks associated with handling the explosive m-chloroperbenzoic acid, it is cost-saving and it does not generate the environmentally noxious byproduct, m-chlorobenzoic acid, which is troublesome to dispose of.
According to the process of the present invention, the substrate, N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide, is dissolved at room temperature in an organic solvent resistant to oxidation under the reaction conditions. Suitable solvents are, for example, aromatic hydrocarbons, cyclic ethers or organic esters, such as ethyl acetate. Subsequently, to this solution are successively added the acid anhydride and the complex of hydrogen peroxide with urea (UHP) , and the mixture is stirred at 25-30 °C, until all the propenamide reacted. The progress of the reaction can be monitored by TLC. After completion of the reaction, the reaction mixture is neutralized with an aqueous hydroxide solution, for example with a solution of sodium hydroxide, and the product is extracted with a water-immiscible solvent, for example with ethyl acetate. Next, the phases are separated and the solvent from the organic phase is evaporated, leaving the crude product, which is purified by a single crystallization from isopropanol.
The process of the present invention ensures ready access to N- (4-cyano-3-trifluoromethylphenyl) -2, 3-epoxy-2- methylpropanamide of high purity, sufficient for its immediate application in the next step of bicalutamide synthesis, and without a need for complicated purification methods .
The present invention is illustrated by the following, non-limiting examples. EXAMPLE 1
N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide (10.2 g, 40.1 mmol) and phthalic anhydride (10.2 g, 80.3 mmol) were dissolved in ethyl acetate (100 mL) . The UHP complex (15.0 g, 159 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours.
Subsequently, a solution of NaOH (6.4 g, 160 mmol) in water (25 mL) was added to the reaction mixture. After the phases separated, the organic phase was washed first with a solution of Na2S03 (lg) in water (25 mL) , and then with water. The solvent was evaporated, resulting in the crude product (10.2 g) , which was crystallized from isopropanol to give pure N- ( -cyano-3-trifluoromethylphenyl) -2, 3-epoxy-2- methylpropanamide (7.9 g; 73%); m.p. 90-92°C; IR (KBr): 3348, 3081, 2933, 2228, 1707, 1618, 1592, 1531, 1327, 1148, 906, 849, 748, 560 cm"1. EXAMPLE 2
N- (4-cyano-3-trifluoromethylphenyl) -2-methylpropenamide (10.2 g, 40 mmol) and maleic anhydride (7.8 g, 80 mmol) were dissolved in ethyl acetate (100 mL) . The UHP complex (15.1 g, 160 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours. Subsequently, the reaction mixture was neutralized with a solution of NaOH (6.4 g, 160 mmol) in water (25 L) . After the phases separated, the organic phase was washed first with a solution of Na2S03 (lg) in water, followed by washing with water. The solvent was evaporated, affording the crude product (10.3 g) , which was crystallized from isopropanol to give pure N- (4-cyano-3- trifluoromethylphenyl) -2, 3-epoxy-2-methylpropanamide; yield: 8.1 g (75%) .

Claims

1. A process for the production of N- (4-cyano-3- trifluoromethylphenyl) -2, 3 -epoxy-2-methylpropanamide by epoxidizing N- (4-cyano-3-trifluoromethylphenyl) -2- methylpropenamide, characterized in that the oxidizing agent used is a mixture of the urea-hydrogen peroxide complex with either a cyclic dicarboxylic acid anhydride of formula 3, where groups Ri and R2 are the same or different and are a hydrogen atom, a Cι_4-alkyl group, an aryl group or a halogen atom, or it is a mixture with a cyclic dicarboxylic acid anhydride of formula 4, where X is a hydrogen atom, a C1-4- alkyl group, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group.
2. A process according to claim 1, characterized in that the urea-hydrogen peroxide complex is used in a molar excess, compared to the cyclic dicarboxylic acid anhydride.
3. A process according to claim 2, characterized in that the molar ratio of the urea-hydrogen peroxide complex to the dicarboxylic acid anhydride is from about 1.1:1 to about 6.0:1.
4. A process according to claim 3, characterized in that the molar ratio of the urea-hydrogen peroxide complex to the dicarboxylic acid anhydride is 4:1.
5. A process according to claim 1, characterized in that the molar ratio of the dicarboxylic acid anhydride to N- (4- cyano-3-trifluoromethylphenyl) -2-methylpropenamide is from about 1:1 to about 3:1.
6. A process according to claim 5, characterized in that the molar ratio of the dicarboxylic acid anhydride to N- (4- cyano-3-trifluoromethylphenyl) -2-methylpropenamide is 2:1.
PCT/PL2003/000111 2002-10-30 2003-10-28 A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide WO2004039791A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008102659A1 (en) * 2007-02-22 2008-08-28 Adeka Corporation Oxidizing agent composition for the epoxidation of olefins and process for the epoxidation of olefins
CN106748884A (en) * 2016-12-13 2017-05-31 山西振东制药股份有限公司 A kind of preparation method of Bicalutamide 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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EP0100172A1 (en) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Amide derivatives
US4590286A (en) * 1985-10-28 1986-05-20 Fmc Corporation Process for epoxidizing an olefin
US5723636A (en) * 1996-04-12 1998-03-03 National Starch And Chemical Investment Holding Corporation Methyltrioxorhenium-urea hydrogen peroxide epoxidation of olefins

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EP0100172A1 (en) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Amide derivatives
US4590286A (en) * 1985-10-28 1986-05-20 Fmc Corporation Process for epoxidizing an olefin
US5723636A (en) * 1996-04-12 1998-03-03 National Starch And Chemical Investment Holding Corporation Methyltrioxorhenium-urea hydrogen peroxide epoxidation of olefins

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ROCHA GONSALVES A. M. D'A. ET AL.: "Dissociation of hydrogen peroxide adducts in solution: the use of such adducts for epoxidation of alkenes", JOURNAL OF CHEMICAL RESEARCH. SYNOPSES, no. 8, 1991, GBLONDON, pages 208 - 209, XP008027619 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008102659A1 (en) * 2007-02-22 2008-08-28 Adeka Corporation Oxidizing agent composition for the epoxidation of olefins and process for the epoxidation of olefins
JP5364572B2 (en) * 2007-02-22 2013-12-11 株式会社Ａｄｅｋａ Olefin epoxidation process
CN106748884A (en) * 2016-12-13 2017-05-31 山西振东制药股份有限公司 A kind of preparation method of Bicalutamide intermediate
CN106748884B (en) * 2016-12-13 2021-08-20 山西振东制药股份有限公司 Preparation method of bicalutamide 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
WO2022083082A1 (en) * 2020-10-22 2022-04-28 怀化宝华生物科技有限公司 Method for preparing bicalutamide

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PL356895A1 (en) 2004-05-04
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