WO1997047581A1 - Procede de preparation de derives de l'acide 2-phenylpropionique halomethyle - Google Patents

Procede de preparation de derives de l'acide 2-phenylpropionique halomethyle Download PDF

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Publication number
WO1997047581A1
WO1997047581A1 PCT/JP1997/002035 JP9702035W WO9747581A1 WO 1997047581 A1 WO1997047581 A1 WO 1997047581A1 JP 9702035 W JP9702035 W JP 9702035W WO 9747581 A1 WO9747581 A1 WO 9747581A1
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WO
WIPO (PCT)
Prior art keywords
yield
propionate
general formula
chloromethylphenyl
palladium
Prior art date
Application number
PCT/JP1997/002035
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English (en)
Japanese (ja)
Inventor
Yukitoshi Fukuda
Iwao Chujo
Takamasa Fuchikami
Chitaru Hirosawa
Noriko Wakasa
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Sagami Chemical Research Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd., Sagami Chemical Research Center filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU31068/97A priority Critical patent/AU3106897A/en
Publication of WO1997047581A1 publication Critical patent/WO1997047581A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/36—Preparation of carboxylic acid esters by reaction with carbon monoxide or formates
    • C07C67/38—Preparation of carboxylic acid esters by reaction with carbon monoxide or formates by addition to an unsaturated carbon-to-carbon bond

Definitions

  • the present invention relates to a method for producing a 2-phenylpropionic acid derivative having a halomethyl group.
  • 2-Phenylpropionic acid derivatives having a halomethyl group are useful compounds as synthetic intermediates for pharmaceuticals, agricultural chemicals, etc., and include, for example, anti-inflammatory analgesics 2- [4-1]
  • the method (4) requires a large amount of an expensive halogenating agent such as N-bromosuccinimide or the reaction under light irradiation, which is disadvantageous for industrial implementation. It also has problems such as low yield.
  • a method for synthesizing a 2- (hydroxymethylphenyl) propionic acid derivative, which is a raw material is carried out by using 2- [4-1- (2-methyl-1 O) Ozone oxidation of propionic acid must be used, which is dangerous and disadvantageous for industrial implementation, and wastes carbon resources and is economically disadvantageous. are doing.
  • all of the conventional methods for producing a 2-phenylpropionic acid derivative having a halomethyl group have many problems in industrially implementing them.
  • An object of the present invention is to provide a simple and inexpensive method for producing a 2-phenylpropionic acid derivative having a halomethyl group.
  • the present inventors have found that a target compound can be produced with high yield and high selectivity by subjecting styrenes having a halomethyl group to sulfonylation using a palladium catalyst, and reached the present invention.
  • the present invention relates to a compound represented by the general formula (I):
  • R represents a hydrogen atom or a lower alkyl group
  • the compounds represented by the general formula (I), the general formula (II) and the general formula (III) are referred to as a compound (I), a compound (II) and a compound (III), respectively.
  • the lower alkyl group is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, for example, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, hexyl, heptyl, -octyl, etc.
  • the halogen atom and the halogen moiety of the methyl group are fluorine, chlorine. , Bromine, and iodine atoms.
  • the palladium catalyst examples include palladium metals, metal salts, gold complex compounds, organometallic complexes having carbon monoxide as a ligand, organometallic complexes having a halogen atom as a ligand, tertiary phosphine or tertiary arsine.
  • organometallic complexes having ligands such as olefins or acetylenes, and palladium compounds supported on carriers such as calcium carbonate, barium sulfate, activated carbon, silica, and alumina Things and the like can be used.
  • Suitable palladium catalysts include palladium / carbon, palladium / silica, palladium alumina, palladium Z barium sulfate, palladium calcium carbonate, palladium black, palladium powder, Palladium oxide, palladium nitrate, palladium sulfate, palladium chloride, palladium bromide, palladium iodide, sodium tetrachloride palladate, potassium tetrachloride palladate, ammonium tetrachloride palladate, dichlorodiamine palladium, palladium acetate, palladium trifluoro Loacetate, palladium acetylacetonate, tris (dibenzylideneacetone) dipalladium, dichlorobis (acetitolitol) palladium, dichlorobis (benzonitrile) palladium, dichloro (cyclooctane) palladium, aryl palladium Chloride dim
  • the palladium catalyst can be suitably used in the range of 0.0005 to 0.5 molar equivalent relative to compound (I), and more preferably in the range of 0.001 to 0.02 molar equivalent.
  • the reaction may be carried out by adding a suitable coordinating compound as an additive.
  • Coordinating compounds that can be used include triphenylphosphine, tri (0-tolyl) phosphine, tris (p-methoxyphenyl) phosphine, trimethylphosphine, triethylphosphine, trioctylphosphine, and triisopropylphosphine.
  • (2-diphenylphosphinoethyl) tertiary phosphines such as phenylphosphine, 1-diphenylphosphino 2-diphenylarsinoethane, menthyldiphenylphosphine, neo-menthyldiphenylphosphine, triphenylphosphite, triethylphos
  • Examples include lower-grade phosphites such as phyto, tributyl phosphite, and trioctyl phosphite, and tertiary arsines such as triphenyl arsine, trimethyl arsine, and triethyl arsine.
  • the amount of the coordinating compound used is preferably in the range of up to 20.0 molar equivalents with respect to the above-mentioned palladium catalyst.
  • Examples of the group at the ⁇ -position of the cyclohexane ring include a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl —Butyl, pentyl, isoamyl, neopentyl, hexyl and the like.
  • the fact that the desired product can be obtained with high yield even when the reaction is performed at such a low pressure is an important merit from an industrial viewpoint. If the desired product can be obtained with high yield only at high pressure, expensive equipment such as a reactor with high pressure resistance is required, and Disadvantageous in terms of aspect.
  • Compound (I) is industrially available and can also be easily synthesized by halogenating the corresponding methylstyrenes.
  • Compound (II) is industrially available, and its amount is at least 0.5 molar equivalent, preferably at least 1 molar equivalent, relative to compound (I). .
  • the carbon monoxide used in the present invention is industrially available. Further, in the present invention, the reaction suitably proceeds even in the presence of hydrogen gas. Therefore, a mixed gas of carbon monoxide and hydrogen, a synthetic gas, a water gas, or the like, which is industrially available at low cost, can be used as the oxo gas.
  • a range of 1 to 150 atm, preferably 1 to 80 atm, more preferably 1 to 5 atm can be selected.
  • solvents that can be used include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; aliphatic hydrocarbon solvents such as hexane, cyclohexane, heptane, and octane; Jethyl ether, tetrahydrofuran (THF), Ether solvents such as dioxane, dimethyl kishetan, dibutyl ether, etc .; ketone solvents such as acetone, methyl ethyl ketone and cyclohexanone; nitrile solvents such as acetate nitrile, propionitrile, benzonitrile, dimethylformamide And aprotic polar solvents such as N-methylpyrrolidone and dimethylsulfoxide; and
  • the reaction temperature can be selected from the range of room temperature to 150 ° C, preferably 50 to 120 ° C.
  • a polymerization inhibitor may be added.
  • the polymerization inhibitor that can be used is not particularly limited as long as it does not hinder the desired reaction. Examples thereof include nitromethane, nitrobenzene, nitrosobenzene, picric acid, tri-p-nitrophenylphenylmethyl, and triphenyl.
  • Examples include copper, ferric chloride, and sodium P-toluenesulfonate.
  • X is as defined above, a styrene having a halomethyl group, carbon monoxide and a compound represented by the general formula (II)
  • COOFT (IV) (Wherein R A has the same meaning as R) is dissolved in an aprotic polar solvent, for example, dimethylformamide, dimethylsulfoxide, etc., for example, a base such as potassium hydroxide, sodium hydroxide, etc .; By stirring for 1 to 3 hours at room temperature to 60 in the presence of 2 equivalents, general formula (V)
  • the compound (VI) is neutralized with a suitable solvent such as water or ethanol, for example, with sodium methoxide or sodium hydroxide to obtain a sodium salt.
  • a suitable solvent such as water or ethanol, for example, with sodium methoxide or sodium hydroxide to obtain a sodium salt.
  • Equation (IX) The compound represented by is first produced. This can be achieved by reacting 1 to 6 equivalents of a hexane solution of n-butyllithium in a solution of the corresponding oxime compound in tetrahydrofuran at room temperature. 0.8 to 1 equivalent of compound (IX)
  • Example 6 153 mg (l. 00 mmol) of 4-chloromethylstyrene as a substrate, 1.8 mg (0.0 lmmol) of palladium chloride as a catalyst, 5.2 mg (0.02 mmo ⁇ ⁇ ) of triphenylphosphine as a ligand, alcohol as an alcohol
  • the reaction and analysis were carried out in the same manner as in Example 4, except that 0.5 ml of ethanol and 2.5 ml of toluene were used as a solvent.
  • the yield of 2- (4-chloromethylphenyl) propionate with respect to the raw material 4-chloromethylstyrene is 90%, and the yield of 3- (4-chloromethylphenyl) propionate with ethyl is 1%. % Or less, the yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 2%.
  • the yield of 2- (4-chloromethylphenyl) propionate ethyl was 88% based on the raw material 4-chloromethylstyrene, and the yield of 3- (4-chloromethylphenyl) propionate ethyl was 7%.
  • the yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 4%.
  • the yield of 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 83%
  • the yield of 3- (4-chloromethylphenyl) propionate ethyl is 1%
  • the yield of 2- (4 The yield of 1-ethoxycarbonylmethylphenyl) ethyl propionate was 2%.
  • the yield of isopropyl (4-monochloromethylphenyl) propionate was 1% or less, and the yield of isopropyl 2- (4-isopropoxycarbonylmethylphenyl) propionate was 2%.
  • the yield of 2- (4-chloromethylphenyl) propionate to the raw material 4-chloromethylstyrene is 85%
  • the yield of 3- (4-chloromethylphenyl) propionate to ethyl is 5%
  • the yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 1% or less.
  • the yield of 2- (4-chloromethylphenyl) propionate ethyl is 83% based on the raw material 4-chloromethylstyrene, and the yield of 3- (4-monochloromethylphenyl) propionate is 5%.
  • the yield of ethyl 2-, 4- (4-ethoxycarbonylmethylphenyl) propionate was 1%.
  • the yield of isopropyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is The yield of isopropyl 3- (4-chloromethylphenyl) propionate was 4%, and the yield of isopropyl 2- (4-isopropoxycarbonylmethylphenyl) propionate was 4%.
  • the temperature was raised to 60 with heating and stirring, and the inside of the system was replaced with a mixed gas of carbon monoxide and hydrogen at appropriate times so that the carbon monoxide partial pressure in the system did not fall below 2 atm, and the carbonylation reaction was carried out for 30 hours.
  • a mixed gas of carbon monoxide and hydrogen at appropriate times so that the carbon monoxide partial pressure in the system did not fall below 2 atm, and the carbonylation reaction was carried out for 30 hours.
  • 1 L stainless steel autoclave 15.3 g (10 Ommo 1) of 4-chloromethylstyrene, 0.5 g (2 mmo 1 Zg, 1.0 Ommo 1) of sodium tetrachloride parade, reference example ), 38 lmg of neomenthyl diphenylphosphine (purity 85%, 1.00 mmol), 50 ml of ethanol and 250 ml of acetone as ligands, and carbon monoxide mixed in the system After sufficient replacement with gas (1: 1), a mixed gas of carbon monoxide and hydrogen was injected so that the pressure became 5 atm. The temperature was raised to 6 Ot: while heating and stirring, and the inside of the system was replaced with a mixture of carbon monoxide and hydrogen at appropriate times so that the carbon monoxide partial pressure in the system did not fall below 2 atm. Was done.
  • 2-phenylpropionic acid derivatives having a halomethyl group simply and inexpensively.
  • 2-Phenylpropionic acid derivatives having an octamethyl group are useful compounds as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.

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

Abstract

L'invention concerne un procédé de préparation de dérivés d'acide 2-phénylpropionique halométhylé représenté par la formule générale (III), dans ladite formule X est halogéno et R est hydrogène ou alkyl inférieur. Ce procédé consiste à faire réagir un styrène halométhylé de formule générale (I), où X est défini comme indiqué ci-dessus, avec un monoxyde de carbone et un composé de formule générale (II): R-OH, où R est défini comme indiqué ci-dessus, en présence d'un catalyseur au palladium.
PCT/JP1997/002035 1996-06-13 1997-06-12 Procede de preparation de derives de l'acide 2-phenylpropionique halomethyle WO1997047581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31068/97A AU3106897A (en) 1996-06-13 1997-06-12 Process for the preparation of halomethylated 2-phenylpropionic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/152620 1996-06-13
JP15262096 1996-06-13

Publications (1)

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WO1997047581A1 true WO1997047581A1 (fr) 1997-12-18

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002069030A (ja) * 2000-08-30 2002-03-08 Kyowa Hakko Kogyo Co Ltd ナトリウム２−｛４−［（２−オキソシクロペンチル）メチル］フェニル｝プロピオネート２水和物の製造法
US6441218B2 (en) 2000-02-10 2002-08-27 Nippon Petrochemicals Company, Limited Process for producing 2-substituted propionic acid
KR100501993B1 (ko) * 1998-11-20 2005-10-26 주식회사 코오롱 페닐프로피온산 유도체 또는 그의 염의 제조방법
CN100378145C (zh) * 2001-06-21 2008-04-02 花王株式会社 研磨液组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5318533A (en) * 1976-07-31 1978-02-20 Mitsubishi Petrochem Co Ltd Preparation of alpha-(substituted aryl) propionic acids
JPS53135958A (en) * 1977-04-05 1978-11-28 Sankyo Co Ltd Substituted phenylacetic acid derivatives and their preparation
JPS62161740A (ja) * 1986-01-09 1987-07-17 Sankyo Yuki Gosei Kk フエニルプロピオン酸誘導体の製法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5318533A (en) * 1976-07-31 1978-02-20 Mitsubishi Petrochem Co Ltd Preparation of alpha-(substituted aryl) propionic acids
JPS53135958A (en) * 1977-04-05 1978-11-28 Sankyo Co Ltd Substituted phenylacetic acid derivatives and their preparation
JPS62161740A (ja) * 1986-01-09 1987-07-17 Sankyo Yuki Gosei Kk フエニルプロピオン酸誘導体の製法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100501993B1 (ko) * 1998-11-20 2005-10-26 주식회사 코오롱 페닐프로피온산 유도체 또는 그의 염의 제조방법
US6441218B2 (en) 2000-02-10 2002-08-27 Nippon Petrochemicals Company, Limited Process for producing 2-substituted propionic acid
JP2002069030A (ja) * 2000-08-30 2002-03-08 Kyowa Hakko Kogyo Co Ltd ナトリウム２−｛４−［（２−オキソシクロペンチル）メチル］フェニル｝プロピオネート２水和物の製造法
CN100378145C (zh) * 2001-06-21 2008-04-02 花王株式会社 研磨液组合物

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