WO1997047581A1 - Process for the preparation of halomethylated 2-phenylpropionic acid derivatives - Google Patents

Abstract

A process for the preparation of halomethylated 2-phenylpropionic acid derivatives of general formula (III) (wherein X is halogeno; and R is hydrogen or lower alkyl) characterized by reacting a halomethylated styrene of general formula (I) (wherein X is as defined above) with carbon monoxide and a compound of general formula (II): R-OH (wherein R is as defined above) in the presence of a palladium catalyst.

Description

 Specification

 Method for producing 2-phenylpropionic acid derivative having halomethyl group

Technical field

 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]

(2-oxopentane-111-methyl) phenyl] propionic acid (for example, Japanese Patent Publication No. 58-4699).

Background art

 Conventionally, as a method for producing a 2-phenylpropionic acid derivative having a halomethyl group, (1) a method of halomethylating a 2-phenylpropionic acid derivative using a dialkoxymethane and a condensing agent (Japanese Patent Application Laid-Open No. 138140), (2) A method of halomethylating a 2-phenylpropionic acid derivative using a monohalogenomethyl ether and a metal chloride (JP-A-63-93748), and (3) a method of preparing a halomethylphenylketone and an orthoformate ester. A method of reacting a trivalent odo compound (JP-A-60-116647),

(4) 2- (Method of halogenating a (methylphenyl) propionic acid derivative in the presence of a radical generator (JP-A-62-129250, 62-155237, 62-161740), (5) 2-

(Hydroxymethylphenyl) A method of halogenating a propionic acid derivative [RSP Hsi, LS Stelzer, and WT Stolle, Farmaco, Ed. Sci .. 43. 597 (1988)] and the like are known. However, the methods (1) and (2) require the use of a large amount of corrosive reagents such as aluminum chloride and tin tetrachloride. It has problems such as inevitable production and low yield. The method (3) requires a large amount of eodobenzene diacetate, which is an expensive and powerful oxidizing agent, and thus requires careful handling and is economically disadvantageous. Have a point. 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. In the method (5), 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. As described above, all of the conventional methods for producing a 2-phenylpropionic acid derivative having a halomethyl group have many problems in industrially implementing them.

 On the other hand, as a method for producing a mixture of 2- and 3-phenylpropionic acid derivatives, a method of synthesizing a styrene derivative by reacting it with carbon monoxide and alcohol in the presence of a transition metal catalyst is also known. [For example, "New Syntheses with Carbon Monoxide", Edited by Falbe, Springer-Verlag (1980). Chapter 4, page 309], There is no report on the synthesis of a 2-phenylpropionic acid derivative having a halomethyl group. In benzenes having a halomethyl group, it is known that the halomethyl moiety reacts with a transition metal catalyst [for example, H. Ura is described in N. Hu, H. Maekawa, and T.

Fuchikami, Tetrahedron Lett., 32, 4733 (1991); H. Urata, H. Maekawa, S. Takahashi, and T. Fuchikami, J. Org. Chem., ≤ 6, 4320 (1991).]. For example, it has been reported that the reaction of 4-chloromethylstyrene with methanol in the presence of iron carbonyl catalyst and carbon monoxide produces 4-vinylphenylacetic acid methyl ester. (4-Chloromethylphenyl) Propionate by-product was not observed [SW Wright and LD McClure, Org. Prep. Proced. Int .. 26. # 5, (1994)]. In addition, in the carbonylation reaction, coexistence of hydrogen gas is not preferable because a hydroformylation reaction of the raw material olefin, a hydrogenation reaction, a hydrogenolysis decomposition reaction of a halomethyl group site, etc. are not preferred. It was natural to use carbon monoxide that did not contain it.

Disclosure of the invention

 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.

That is, the present invention relates to a compound represented by the general formula (I):

(Wherein X represents a halogen atom), a styrene having a halomethyl group represented by the following formula: carbon monoxide and a general formula (II)

 R-OH (II)

(Wherein, R represents a hydrogen atom or a lower alkyl group), characterized by reacting with a compound represented by the following general formula (III) (III)

Wherein X and R are the same as defined above, and a method for producing a 2-phenylpropionic acid derivative having a halomethyl group represented by the formula:

 Hereinafter, 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. In the definition of each group of the general formula (I), the general formula (II) and the general formula (III), 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., and the halogen atom and the halogen moiety of the methyl group are fluorine, chlorine. , Bromine, and iodine atoms.

Examples of the palladium catalyst 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. Or 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 dimer, dichlorobis (triphenylphosphine) palladium, dichlorobis (cyclohexyldiphenylphosphine) palladium, dichloro [1, 2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1,4,1-bis (diphenylphosphino) butane] palladium, dichloro [1 , 1'-bis (diphenylphosphino) phenoctene] palladium, dichlorobis (diphenylmethylphosphine) palladium, dichlorobis (trimethylphosphine) palladium, dichlorobis (triethylphosphine) palladium, dichloro [2,2'-1 Bis (diphenylphosphino) 1-1,1'-binaphthyl] palladium, dichlorobis (triphenylarsine) palladium, trans-benzyl (chloro opening) bis (triphenylphosphine) palladium, diacetatebis (triphenylphenylphosphine) Radium, diacetbis (triphenylphosphine) palladium, tetrakis (trifurylphosphine) palladium and the like can be exemplified. 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. In the present invention, 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. Sphine, tricyclohexylphosphine, triallylphosphine, diphenylmethylphosphine, benzyldiphenylphosphine, cyclohexyldiphenylphosphine, bis (2-cyanoethyl) phenylphosphine, diphenylphosphine Inobenzene 1 m-sodium sulfonate, bis (4-sulfonatophenyl) phenylphosphine potassium, tris (3-sulfonatophenyl) sodium, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphine) Ino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) furosene, 2,2'-bis Diphenylphosphino) 1 1, 1 '—binaphthyl,

1,2-bis (dicyclohexylphosphino) ethane, 1,2-bis (getylphosphino) ethane, 1,2-bis (getylphosphorano) benzene, bis

(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. When a coordinating compound is added, 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.

In particular, when cyclohexyldiarylphosphine having at least one substituent at the α-position of the cyclohexane ring represented by menthyldiphenylphosphine and neomenthyldiphenylphosphine is used, this phosphine is incorporated into the catalyst species. Because of its moderate steric hindrance, the reaction proceeds efficiently even under low pressure conditions such as a partial pressure of carbon monoxide of 1 to 5 atm, and the desired product can be obtained in good yield. In addition, the advantage that the by-product of the linear isomer is very small can be obtained at the same time. Examples of the group at the α-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. As the partial pressure of carbon monoxide, a range of 1 to 150 atm, preferably 1 to 80 atm, more preferably 1 to 5 atm can be selected.

 The reaction can be carried out without a solvent, but compound (II) can also be used as a solvent. Further, a solvent that does not participate in the reaction can be suitably used. 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 halogen-based solvents such as methylene chloride, chloroform and dichloroethane.

 The reaction temperature can be selected from the range of room temperature to 150 ° C, preferably 50 to 120 ° C.

In order to suppress the polymerization of styrenes having a halomethyl group, which is a raw material, 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. Ferdazil, hydroquinone, p-benzoquino , 4-methoxyphenol, 2,6-di-tert-butyl-4-methylphenol, 4-tert-butylcatechol, phenothiazine, dithiobenzoyl disulphide, aluminum N-ditrosophenylhydroxylamine, secondary chloride Examples include copper, ferric chloride, and sodium P-toluenesulfonate.

 Next, a method for producing 2- [4- (2-oxopentane-1-ylmethyl) phenyl] propionic acid and the like using a 2-phenylpropionic acid derivative having a halomethyl group as a synthetic intermediate will be described below. .

Formula (I) in the presence of a palladium catalyst

Wherein X is as defined above, a styrene having a halomethyl group, carbon monoxide and a compound represented by the general formula (II)

 R-OH (II)

 (Wherein R has the same meaning as described above)

(III)

(Wherein, X and R have the same meanings as described above), and the resulting compound is used as a 2-phenylpropionic acid derivative having a halomethyl group, and is used to prepare 2- [4- (2-oxobenzoate). In order to produce [111-methyl) phenyl] propionic acid and the like, for example, the steps shown below as Step 1, Step 2, and Step 3 are used.

Process 1

 1 to 2 equivalents of the compound of the formula (IV) based on the compound (III)

 0

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)

(Wherein, R and ^RA are as defined above). The compound (V) is dissolved in sulfuric acid, hydrochloric acid, etc., heated and refluxed for 1 to 3 days to hydrolyze and decarboxylate the compound of formula (VI)

で表わされる化合物を得る。 さらに化合物 （V I) を水、 エタノール等の適当な 溶媒中、 例えばナトリウムメトキシド、 水酸化ナトリウムにより中和すればナト リウム塩を得る。

To obtain a compound represented by the formula: Further, 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.

Step 2.

 General formula (V I I) obtained according to the general method described in New Experimental Chemistry Lecture Vol. 14 (Synthesis and Reaction of Organic Compounds II, pp. 1422-1423, edited by The Chemical Society of Japan, Maruzen)

(Where Υ represents CH ₂ , CH, CH ₂ or OCH ₇ ) The compound (VII) is reacted with 1 to 1.5 equivalents of the compound (III) in a solvent such as toluene or xylene for 1 to 2 days under heating and reflux, and diluted hydrochloric acid is added thereto, followed by treatment at room temperature for 0.5 to 2 hours. And the general formula (VIII)

(Wherein, R has the same meaning as described above). Further, this is hydrolyzed by heating under reflux for 3 to 12 hours in a solvent such as water containing about 10% sodium hydroxide, ethanol-water, etc., and then adjusting the solution to pH 2-3 with hydrochloric acid during purification. And by the general formula (VI)

で表わされる化合物を得る。 さらに工程 1と同様にしてその塩を得る。

To obtain a compound represented by the formula: Further, the salt is obtained in the same manner as in Step 1.

Process 3

で表わされる化合物をまず生成させる。 それには対応するォキシム化合物のテト ラヒドロフラン溶液中、 1〜6当量の n—ブチルリチウムのへキサン溶液を室温 下反応させればよい。 これに化合物 （I X) に対して 0.8〜1当量の化合物When X is not iodine, add 1 to 3 equivalents of sodium iodide in a solvent such as acetone or methyl ethyl ketone, and heat to reflux for 4 to 12 hours to lead to iodine. Is also good. Next, 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)

で表わされる化合物を得る。 さらにこれを例えば 10%硫酸を用いてオーガニッ ク ·シンセシス [Organic Synthesis., Ill, 20 (1995) ] に記載の水蒸気蒸留下の加 水分解反応に付し、 一般式 （V I) (III) is reacted in tetrahydrofuran at room temperature for 10 to 30 minutes, and further hydrolyzed in sodium hydroxide-methanol at room temperature for 6 to 12 hours to obtain the formula (X)

To obtain a compound represented by the formula: This is further subjected to a hydrolysis reaction under steam distillation described in Organic Synthesis, Ill, 20 (1995) using, for example, 10% sulfuric acid to obtain a compound of the general formula (VI)

で表わされる化合物を得る。 さらに工程 1と同様にしてその塩を得る。

To obtain a compound represented by the formula: Further, the salt is obtained in the same manner as in Step 1.

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

 A 100 ml stainless steel autoclave was charged with 4-chloromethylstyrene 763 mg (5.OOmmol), dichlorobis (triphenylphosphine) palladium 70.2 mg (0.1 Ommo1), ethanol 5mI and toluene 35ml. After sufficiently replacing the inside with a mixed gas of carbon monoxide-hydrogen (1: 1), a mixed gas of carbon monoxide-hydrogen (1: 1) was injected so that the pressure became 20 atm. The temperature was raised to 80 with heating and stirring, and the carbonylation reaction was carried out for 16 hours.

After completion of the reaction, the autoclave was cooled to room temperature, subsequently degassed and returned to normal pressure, and the reaction solution was taken out. The reaction solution was mixed with 50 ml of methanol to insolubilize the catalyst, filtered off, and purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1571) to give a colorless liquid 2- (4-chloro-chloroform). Methyl phenyl) propionate 869 mg (yield 77%), colorless liquid 3- (4-chloromethylphenyl) propionate ethyl 66 mg (6% yield) and π

 ^ Yokuiku Mouth: (Nie Otoro __ ^)-£

： (冚 dd) ρ DGD) ΗΙΛΙ Ά (H "8 -9 'Γ' (H ς ς '(ΗΙ'ΖΗΓ ム

: (冚 dd) ρ DGD) ΗΙΛΙ Ά

 翊 く ロ-Ζ

. ^ ¾ (% ^^

Λ (^^ Μ ^ 7 \ η ^ (二 ェ ΐ ^ αα ー)-ε O M m, (% ^ I Smg Rolo — ΐ-Z

牽 ¾ ¾*3ί¾ 二 ^ ς¾ «9 I ^¾i¾ 2)ao 8 ^^ φίΐ{Μ 。 つ Y50¾ (ΐ ： τ)

π： Ό ^u-^m^- ^m-^ ^ ^¾^γί¾¾ ι uig ιく工 ^M ^¾ QT

Towing ¾ * 3ί¾ 2 ^ ς¾ «9 I ^¾ i¾ 2) ao 8 ^^ φίΐ {Μ. One Y50¾ (ΐ: τ)

π: Ό ^ u- ^ m ^-^ m- ^ ^ ^¾ ^ γί¾¾ ι uig ι く 工 ^

9 'Ζ ( ^-1 (I ouiuio ΐ · 0) Smz · 9 S KU OT ^: ^ Nye OT, (1 o UI I g ο · 0) Sui £-ui χ 翊 翊 翊, (i ouiuio 0' S) 3m S 9 ^ ロ 二 — — J "JO S

(H) 0 -0Ζm ^ lZ -WP '(FH'ZH ^ n = r'b) 69' £% UZ 6S '£ Xm ^ UZ' L =?) Vl

： (mdd) Q (^ε οαθ) WJ-Ht ェ ロ （^二ェ乙 ^ ニ く、 ェ— ί - Ζ (U ^ZZ-L-LVL '(H3's),5 '(ΗΖ'^ΖΗΓん =f'b) ' '(Η 'ΖΗ8· =ί "' S6 '(ΗΖ'ΖΗ8·乙 =f'l)I9て '(Η£'ΖΗΓん =η)£Γΐ： (mdd) ρ (^ε \ QJ) Η Μ-Η, ェ翊く^; ¾ロ （ fニェ乙^ 口口/?— ） - 2 '(Ηε¾Π

: (Mdd) Q ( ^ε οαθ) WJ-Ht ロ (^ 2 乙 ^ ^ く 、 ェ-ί (U ^ ZZ-L-LVL '(H3's), 5' (ΗΖ ' ^{Ζ Ζ} = f'b) '' (Η 'ΖΗ8 · = ί "' S6 '(ΗΖ'ΖΗ8 · Otsu = f'l) I9 and' (Η £ 'ΖΗΓ = η) £ Γΐ: (mdd) ρ ( ^ε \ QJ) Η Μ-Η, 翊 ikku ^; ¾ ロ （f ニ 乙 ^ 口 口 /? —）-2

(H -9 Γ Ot '(HZ's) /. G

： (uidd) ρ (^ε οα3) ΗίΜΜ-Η,

- ζ ^'(Ηε' ζ ΗΖ · N -f'P) 6l7'I

: (Uidd) ρ ( ^ε οα3) ΗίΜΜ-Η,

-ζ

. ¾¾ (% ^^ m s iQ ^ ^ ¾ ^^ λ

S € 0r0 / Z.6df / XDd L / L6 OAX 1H-NMR (CDCl ₃ ) δ (ppm): 2.63 (t, J = 7.8Hz, 2H), 2.96 (t, J = 7.8Hz, 2H), 3.67 (s, 3H), 4.57 (s, 2H), 7.17-7.34 (m, 4H)

 2- (4-methoxycarbonylmethylphenyl) methyl propionate

_{1H-NMR (CDC1 3) δ} (ppm): 1.48 (d, J = 7.1Hz, 3H), 3.60 (s, 2H), 3.65 (s, 3H), 3.68 (s, 3H), 3.71 (q, J = 7.1H2, lH), 7.17-7.29 (m, 4H)

Example 3

 In a 50 ml stainless steel autoclave, 4-chloromethylstyrene 763 mg (5.0 Ommo 1), palladium acetate 11.3 mg (0.05 mmo 1), triphenylphenylphosphine 26.2 mg (0.1 Ommo 1), After charging 5 ml of isopropyl alcohol and 10 ml of toluene and thoroughly replacing the system with a mixed gas of carbon monoxide and hydrogen (1: 1), the mixed gas of carbon monoxide and hydrogen was adjusted to 30 atm. : 1) was press-fitted. The temperature was raised to 80 ° C with heating and stirring, and a force-reforming reaction was carried out for 16 hours.

 After completion of the reaction, a post-treatment and purification were carried out in the same manner as in Example 1 to obtain a colorless liquid 2- (4-chloromethylphenyl) isopropyl propionate 84 Omg (yield 70%), a colorless liquid 3- 48 mg (yield 4%) of isopropyl (4-chloromethylphenyl) propionate and 33 mg (yield 2%) of isopropyl 2- (4-isopropyloxycarbonylmethylphenyl) propionate as a colorless liquid were obtained. Was.

 2- (4-chloromethylphenyl) isopropyl propionate

_{1H-NMR (CDC1 3) (} 5 (ppm): 1.14 (d, J = 6.3Hz, 3H), 1.22 (d, J = 6.3Hz, 3H),

1.47 (d, J = 7.2Hz, 3H), 3.67 (q, J = 7.2Hz, lH), 4.58 (s, 2H), 4.99 (sep, J = 6.3Hz, lH), 7.26- 7.37 (m, 4H )

 3- (4-chloromethylphenyl) isopropyl propionate

1H-NMR (CDCl ₃ ) ^ (ppm): 1.20 (d, J = 6.3Hz, 6H), 2.58 (t, J = 7.7Hz, 2H),

2.94 (t, J = 7.7Hz, 2H), 4.57 (s, 2H), 5.00 (sep, J = 6.3Hz, lH), 7.17-7.33 (m, 4H)

 2- (4-isopropyloxycarbonylmethylphenyl) isopionate

_{1H-NMR (CDC1 3) δ} (ppm): 1.13 (d, J = 6.3Hz, 3H), 1.21 (d, J = 6.3Hz, 3H), 1.22 (d, J = 6.3Hz, 6H), 1.46 (d, J = 7.1Hz, 3H), 3.55 (s, 2H), 3.65 (q, J = 7.1Hz, lH),

4.98 (sep, J = 6.3Hz, lH), 5.01 (sep, J = 6.3Hz, lH), 7.15-7.30 (m, 4H)

Example 4

 4-Chloromethylstyrene 153 mg (1.00 mmo 1), dichlorobis (triphenylphosphine) palladium 7. Omg (0.0 lmmo 1), ethanol 0.5 ml and toluene in a 10 ml stainless steel autoclave 2. After charging 5 ml, the inside of the system was sufficiently replaced with carbon monoxide, and then carbon monoxide was injected to 40 atm. The temperature was raised to 80 with heating and stirring, and a carbonylation reaction was carried out for 16 hours.

 After completion of the reaction, the autoclave was cooled to room temperature, subsequently degassed and returned to normal pressure, and the reaction solution was taken out. A 1.1 m glass column packed with the reaction solution and gas chromatography (30% SE-30on Uniport B [manufactured by GE Science Co., Ltd.])

Shimadzu GC-7A (manufactured by Shimadzu) equipped with a thermal conductivity detector (Thermal Conductivity Detector (TCD)), internal standard substance: decane, 100 min. As a result, the yield of 2- (4-chloromethylphenyl) propionate ethyl ester with respect to the raw material 4-chloromethylstyrene was 93%, and the yield was 3— (4— The yield of chloromethylphenyl) ethyl propionate was 2%, and the yield of 2- (4-ethoxycarbonylmethylphenyl) propionate was 5%.

Example 5

 4-Chloromethylstyrene 153 mg (1.0 Ommo 1) as a substrate, dichlorobis (cyclohexyldiphenylphosphine) palladium 7.1 mg (0.1 O lmmo l) as a catalyst, ethanol 1.0 ml as an alcohol, and further dissolved The reaction and analysis were carried out in the same manner as in Example 4 except that 2.0 ml of THF was used as a medium. The yield of 2- (4-chloromethylphenyl) propionate ethyl based on the raw material 4-chloromethylstyrene is 97%, and the yield of 3- (4-chloromethylphenyl) propionate ethyl is 1% or less. — The yield of (4-ethoxycarbonylmethylphenyl) ethyl propionate was less than 1%.

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 ト リ) 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. Raw material for 4-chloromethylstyrene

The yield of 2- (4-chloromethylphenyl) ethyl propionate was 88%,

The yield of 3- (4-chloromethylphenyl) propionate is 1% or less, and the yield of 2- (4-ethoxycarbonylmethylphenyl) propionate is 3%.

Example 7

 153 mg (1.0 Ommo 1) of 4-chloromethylstyrene as a substrate, 2.2 mg (0.0 lmmo 1) of palladium acetate as a catalyst, 2.6 mg (0.O lmmo l) of triphenylphenylphosphine as a ligand, The reaction and analysis were carried out in the same manner as in Example 4, except that 0.5 ml of ethanol was used as the alcohol, and 2.5 ml of toluene was used as the solvent, and the initial carbon monoxide pressure was 30 atm. 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%.

Example 8

4-chloromethylstyrene 153 mg (1.00 mm o 1) as a substrate, palladium acetylacetylacetonate as a catalyst 3.Omg (0.Olmmol), triphenylphenylphosphine 5.2 mg (0 The reaction and analysis were carried out in the same manner as in Example 4, except that 0.5 ml of ethanol was used as the alcohol, 2.5 ml of toluene was used as the solvent, and the initial carbon monoxide pressure was 30 atm. . The yield of 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 89%, and the yield of 3- (4-chloromethylphenyl) propionate ethyl is 4% and 2- (4 The yield of 1-ethoxycarbonylmethylphenyl) ethyl propionate was 3%. Example 9

 153 mg (l. 00 mmol) of 4-chloromethylstyrene as a substrate, palladium acetyl acetonate as a catalyst 3. Omg (O. lmmol), diphenylphosphinobenzene benzene as a ligand 1 m-sulfonic acid Example 4 was repeated except that sodium 7.3 mg (0.02 mmo 1), ethanol 0.5 ml of alcohol and toluene 2.5 ml of solvent were used, and the initial carbon monoxide pressure was 30 atm. Reaction and analysis were performed in the same manner. 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%.

Example 10

 4-chloromethylstyrene 153mg (1.0 Ommo 1) as substrate, tetrakis (triphenylphosphine) palladium 11.6mg as catalyst

 The reaction and analysis were carried out in the same manner as in Example 4 except that (0.5 Olmmol), 0.5 ml of ethanol as an alcohol, and 2.5 ml of toluene as a solvent. The yield of ethyl 2- (4-chloromethylphenyl) propionate based on 4-chloromethylstyrene of the raw material was 85%, and the yield of ethyl 3- (4-chloromethylphenyl) propionate was 1% and 2- (4 —Ethoxycarbonylmethylphenyl) The yield of ethyl propionate was 2%.

Example 1 1

4-chloromethylstyrene 153mg (l.00mmol) as substrate, 5% -palladium on carbon 21.3mg (0.0 lmmo 1) as catalyst, triphenylphenylphosphine 5.2mg (0.02mmo 1) as ligand The reaction and analysis were carried out in the same manner as in Example 4, except that ethanol 1.Oml was used as the alcohol and THF 2.Oml was used as the solvent 2. 2- (4 -Chloromethylphenyl) propionate yield is 89%, 3- (4-chloromethylphenyl) propionate yield is 1%, 2- (4-ethoxycarbonylmethylphenyl) propione The yield of acid ethyl is 4%.

Example 12

 4-chloromethylstyrene 153 mg (1.0 Ommo 1) as a substrate, dichlorobis (cyclohexyldiphenylphosphine) palladium 7.1 mg (0.01 mmo 1) as a catalyst, ethanol 0.5 m as alcohol and further dissolved The reaction and analysis were carried out in the same manner as in Example 4, except that 2.5 ml of THF was used as the medium and the initial carbon monoxide pressure was 70 atm. The yield of 2- (4-chloromethylphenyl) propionate ethyl is 98% based on the raw material 4-chloromethylstyrene, and the yield of 3- (4-chloromethylphenyl) propionate ethyl is 1%. Hereinafter, the yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 1% or less.

Example 13

 4-chloromethylstyrene as substrate 153 mg (l. 00 mmol), dichlorobis (triphenylphosphine) palladium as catalyst 7. Omg (0.0 lmmo 1), ethanol as alcohol 0.5 m1, and solvent as THF 2.5 m The reaction and analysis were carried out in the same manner as in Example 4 except that the initial carbon monoxide pressure was set to 20 atm. The yield of 2- (4-chloromethylphenyl) propionate ethyl is 92% based on the raw material 4-chloromethylstyrene, and the yield of 3- (4-chloromethylphenyl) propionate ethyl is 1%. % Or less, 2—

(4-ethoxycarbonylmethylphenyl) The yield of ethyl propionate was 2%.

Example 14

 4-chloromethylstyrene as substrate 153mg (1.0 Ommo 1), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

(0.01 mm 01), the reaction was carried out in the same manner as in Example 4 except that 0.5 m of ethanol was used as the alcohol, 2.5 ml of THF was used as the solvent, and the initial carbon monoxide pressure was 10 atm. And analysis was performed. The yield of 2- (4-chloromethylphenyl) propionate ethyl ester relative to the raw material 4-chloromethylstyrene is 54%, and the yield of 3- (4-chloromethylphenyl) propionate ethyl ester is 3%. , The yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 2%. Further, 15% of 4-chloromethylstyrene was recovered.

Example 15

 4-chloromethylstyrene as substrate 153mg (l. 00mm o l), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

 The reaction and analysis were carried out in the same manner as in Example 4 except that (0.0 lmmo 1), ethanol (1.0 ml) as an alcohol, and THF (2.0 ml) as a solvent, and the reaction temperature was 70. The yield of ethyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 91%, the yield of ethyl 3- (4-chloromethylphenyl) propionate is 3%, The yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 6%. Example 16

 4-chloromethylstyrene as substrate 153mg (l. 00mm o l), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

 The reaction and analysis were carried out in the same manner as in Example 4 except that (O.llmol), 1.Om of ethanol as an alcohol, and 2.Oml of getyl ether as a solvent. The yield of 2- (4-chloromethylphenyl) propionate to 85% of the raw material 4-chloromethylstyrene is 85%, and the yield of 3- (4-chloromethylphenyl) propionate to 5% is 2%. (4-Ethoxycarbonylmethylphenyl) The yield of ethyl propionate was 5%.

Example 17

4-chloromethylstyrene 153 mg (l.OOmmol) as substrate, dichlorobis (cyclohexyldiphenylphosphine) palladium 7.1 mg (0.0 lmmo 1) as catalyst, ethanol 1.Om as alcohol, and as solvent The reaction and analysis were performed in the same manner as in Example 4 except that acetone 2.Oml was used. The yield of ethyl 2- (4-chloromethylphenyl) propionate based on 4-chloromethylstyrene as a raw material is 78%, and the yield of ethyl 3- (4-chloromethylphenyl) propionate is 1% or less. The yield of 4-ethyloxycarbonylmethylphenyl) ethyl propionate was 1%. 4-chloromethylstyrene 153 mg (l. 00 mmol) as substrate, dichlorobis (cyclohexyldiphenylphosphine) palladium 7.1 mg (0.1 Olmmol) as catalyst, ethanol 1.0 m 〖as alcohol, and further dissolved The reaction and analysis were carried out in the same manner as in Example 4, except that 2.0 ml of hexane was used as a medium. 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%, and the yield of 2- (4 The yield of 1-ethoxycarbonylmethylphenyl) ethyl propionate was 2%.

Example 19

 4-chloromethylstyrene as substrate 153 mg (1.0 Ommo 1), palladium acetate as catalyst 2.2 mg (0.Olmmol), ligand as triphenylphosphine 5.2 or 2 mg (0.02 mmo 1), polymerization inhibition Example 4 was repeated except that 2.5 mg (0.02 mmo 1) of 4-methoxyphenol was used as the agent, 0.25 m of ethanol was used as the alcohol, and 1.25 ml of toluene was used as the solvent, and the initial carbon monoxide pressure was 30 atm. Reaction and analysis were performed in the same manner. The yield of ethyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 81%, and the yield of ethyl 3- (4-chloromethylphenyl) propionate is 81%. The yield of 2%, 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 3%.

Example 20

 Add 153 mg (1.0 Ommo 1) of 4-chloromethylstyrene as a substrate, 2.2 mg (0.Olmmol) of palladium acetate as a catalyst, 5.2 mg (0.02 mmo 1) of triphenylphosphine as a ligand Example 4 except that trioctylphosphine 7.4 mg (0.02 mmo 1) as an agent, ethanol 0.5 ml as an alcohol, and toluene 2.5 ml as a solvent, and the initial carbon monoxide pressure was 30 atm. The reaction and analysis were performed in the same manner as described above. The yield of 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 92%, and the yield of 3- (4-chloromethylphenyl) propionate was 92%.

18 The yield of tyl was 2%, and the yield of ethyl 2- (4-ethoxycarbonylmethylphenyl) propionate was 3%.

Example 21

 4-chloromethylstyrene as substrate 153mg (l. 00mmol), dichlorobis (triphenylphosphine) palladium as catalyst 7. Omg

 The reaction and analysis were carried out in the same manner as in Example 4 except that (0.5 Olmol), 0.5 ml of methanol as an alcohol, and 2.5 ml of THF as a solvent. The yield of methyl 2- (4-chloromethylphenyl) propionate based on 4-chloromethylstyrene as raw material is 88%, and the yield of methyl 3- (4-chloromethylphenyl) propionate is 1% or less. The yield of methyl 2- (4-methoxycarbonylmethylphenyl) propionate was 3%.

Example 22

 4-chloromethylstyrene as substrate 153mg (l. 00mm o l), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

 The reaction and analysis were carried out in the same manner as in Example 4 except that (0. Olmmol), 1.Om of isopropyl alcohol as the alcohol, and 2.Oml of toluene as the solvent. The yield of isopropyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 89%,

The yield of isopropyl (4-monochloromethylphenyl) propionate was 1% or less, and the yield of isopropyl 2- (4-isopropoxycarbonylmethylphenyl) propionate was 2%.

Example 23

153 mg (l. 0 Ommo 1) of chloromethylstyrene (mixture of 3-substituted and 4-substituted-7/3) as a substrate, 2.2 mg (0.0 lmmo 1) of palladium acetate as a catalyst, and trif as a ligand Example 2 Except 5.2 mg (0.02 mm o 1) of enylphosphine, 0.5 ml of ethanol as an alcohol, and 2.5 ml of toluene as a solvent, and an initial carbon monoxide pressure of 30 atm. Reaction and analysis were carried out as in 4. The yield of ethyl 2- (chloromethylphenyl) propionate relative to the raw material chloromethylstyrene was 93%. The yield of 3- (chloromethylphenyl) propionate was 3%, and the yield of 2- (ethoxycarbonylmethylphenyl) propionate was 3%.

Example 24

 4-Monochloromethylstyrene as substrate 53 mg (1.0 Ommo 1), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

 (0.0 lmmo 1), 0.5 ml of ethanol as the alcohol, and 2.5 ml of toluene as the solvent, each gas was adjusted to a carbon monoxide partial pressure of 35 atm and a hydrogen partial pressure of 35 atm. The reaction and analysis were performed in the same manner as in Example 4 except that the injection was performed. The yield of ethyl 2- (4-chloromethylphenyl) propionate based on the raw material 4-chloromethylstyrene is 93%, and the yield of ethyl 3- (4-chloromethylphenyl) propionate is 4%, and the yield of 2- (4 —Ethoxycarbonyl methylphenyl) The yield of ethyl propionate was 3%.

Example 25

 4-chloromethylstyrene as substrate: 153 mg (l.Ommol), dichlorobis (cyclohexyldiphenylphosphine) palladium as catalyst 7.1 mg (0.0 lmmo 1), ethanol as alcohol 1.Om The reaction and analysis were carried out in the same manner as in Example 4 except that toluene was used as the medium and each gas was injected so that the carbon monoxide partial pressure was 35 atm and the hydrogen partial pressure was 35 atm. Was. The yield of 2- (4-chloromethylphenyl) propionate to the raw material 4-chloromethylstyrene is 79%, and the yield of 3- (4-chloromethylphenyl) propionate is 1% or less. — The yield of 4-ethylethoxyproponylmethylphenyl propionate was less than 1%.

Example 26

 4-Monochloromethylstyrene as substrate 53 mg (1.Ommol), dichlorobis (triphenylphosphine) palladium Omg as catalyst

(0.0 lmmo 1), 0.5 ml of ethanol as alcohol, 2.5 ml of toluene as solvent, and pressurized gas mixture of carbon monoxide and hydrogen (1: 1) to 30 atm. Reaction and analysis were carried out in the same manner as in Example 4 except for the above. 2- (4-Chloromethylphenyl) propyl to 4-Chloromethylstyrene as raw material The yield of ethyl ethyl pionate is 84%, the yield of 3- (4-chloromethylphenyl) propyl ethyl pionate is 6%, and the ethyl 2- (4-ethoxycarbonylmethylphenyl) propionate Was 1%.

Example 27

 4-chloromethylstyrene as substrate 153 mg (1.0 Ommo 1), palladium chloride 1.8 mg (0.01 mm 01) as catalyst, triphenylphenylphosphine 5.2 mg (0.02 mmo 1) as ligand, alcohol The reaction and analysis were performed in the same manner as in Example 4 except that 0.5 ml of ethanol was used as the solvent, and 2.5 ml of toluene was used as the solvent, and a mixed gas of carbon monoxide and hydrogen (1: 1) was injected to 30 atm. Was done. 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.

Example 28

 153 mg (l.00 mmol) of 4-chloromethylstyrene as a substrate, 2.2 mg (0.0 lmmo 1) of palladium acetate as a catalyst, 5.2 mg (0.02 mmo 1) of triphenylphosphine as a ligand, alcohol as an alcohol 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 the solvent, and a mixed gas of carbon monoxide and hydrogen (1: 1) was injected to 30 atm. Was done. The yield of 2- (4-chloromethylphenyl) propionate based on the raw material 4-chloromethylstyrene is 80%, the yield of 3- (4-chloromethylphenyl) propionate is 3%, The yield of ethyl 2- (4-ethoxycarbonylmethylphenyl) propionate was 1%. Example 29

153 mg (1.0 Ommo 1) of 4-chloromethylstyrene as substrate, 3.Omg (0.0 lmmo 1) of palladium acetylacetylacetonate as catalyst, 5.2 mg of triphenylphenylphosphine as ligand (0. 02 mm o 1), using 0.5 ml of ethanol as alcohol and 2.5 ml of toluene as solvent, The reaction and analysis were carried out in the same manner as in Example 4, except that a mixed gas of carbon monoxide and hydrogen (1: 1) was injected so that the pressure became 30 atm. 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%.

Example 30

 4-chloromethylstyrene as substrate 153mg (l. 00mmol), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg (0.01mmo1), ethanol as alcohol 0.5ml, and toluene as solvent The same procedure as in Example 4 was carried out except that each gas was injected so that the carbon monoxide partial pressure was 35 atm and the hydrogen partial pressure was 35 atm, and the reaction temperature was 70. Reaction and analysis were performed. The yield of ethyl 2- (4-chloromethylphenyl) propionate based on the raw material 4-chloromethylstyrene is 90%, the yield of ethyl 3- (4-chloromethylphenyl) propionate is 4%, The yield of 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 1%. Example 31

 4-chloromethylstyrene as substrate 153mg (1.0 Ommo 1), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

 (0.0 lmmo 1), 0.5 ml of ethanol as alcohol, and 2.5 ml of THF as solvent, and pressurized gas to achieve a partial pressure of carbon monoxide of 35 atm and a partial pressure of hydrogen of 35 atm. The reaction and analysis were carried out in the same manner as in Example 4, except that the reaction temperature was changed to 70. For raw material 4-chloromethylstyrene

The yield of 2- (4-chloromethylphenyl) ethyl propionate was 84%,

The yield of 3- (4-chloromethylphenyl) ethyl propionate is 2%,

The yield of (4-ethoxycarbonylmethylphenyl) ethyl propionate was 1%.

Example 32

4-Chloromethylstyrene 153mg (1. O Ommol) as substrate, catalyst Using 2.2 mg of palladium acetate (0.2 Olmol), 5.2 mg of triphenylphosphine (0.02 mmol) as ligand, 0.5 mL of ethanol as alcohol and 2.5 mL of THF as solvent, and 30 atm. Reaction and analysis were carried out in the same manner as in Example 4 except that a mixed gas of carbon monoxide and hydrogen (1: 1) was injected so that The yield of 2- (4-chloromethylphenyl) propionate ethyl is 81% based on the raw material 4-monochloromethylstyrene, and the yield of 3- (4-chloromethylphenyl) propionate ethyl is 2%. The yield of, 2- (4-ethoxycarbonylmethylphenyl) ethyl propionate was 3%.

Example 33

 1.53 g (10.00 mmol) of 4-chloromethylstyrene as a substrate, 17.7 mg (0.1 lmmol) of palladium chloride as a catalyst, 76.3 mg of neomethyldiphenylphosphine as a ligand (purity of 85 %, 0.2 mmo 1), 5 ml of ethanol as alcohol, and 25 ml of acetone as solvent, pressurized carbon monoxide-hydrogen mixed gas (1: 1) to 5 atm, and raise the reaction temperature to 60 The reaction and analysis were performed in the same manner as in Example 4 except that the reaction time was changed to 20 hours. The yield of 2- (4-chloromethylphenyl) propionate to 4-chloromethylstyrene as a raw material is 75%, and 3- (4-chloromethylphenyl) ethyl propionate and 2- (4-ethoxycarbonylmethylphenyl) Ethyl propionate was hardly formed.

Example 34

 4-chloromethylstyrene as substrate 153mg (1.0 Ommo 1), dichlorobis (triphenylphosphine) palladium as catalyst 7.Omg

(0.5 lmmol), 0.5 ml of methanol as alcohol, and 2.5 ml of toluene as the solvent, and each gas was injected under a pressure of 30 atm of carbon monoxide and 30 atm of hydrogen. The reaction and analysis were performed in the same manner as in Example 4 except that the reaction was performed. The yield of methyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 77%, and the yield of methyl 3- (4-chloromethylphenyl) propionate is 2%, 2- (4-Methoxycarbonylmethylphenyl) The yield of methyl propionate was 1% or less. Example 35

 4-chloromethylstyrene as substrate 153 mg (1.0 Ommo 1), palladium acetate as catalyst 2.2 mg (0.0 lmmo 1), ligand as triphenylphosphine 5.2 mg (0.02 mmo 1), as alcohol The reaction and analysis were carried out in the same manner as in Example 4, except that 0.5 m of methanol and 2.5 ml of toluene were used as the solvent, and a mixed gas of carbon monoxide and hydrogen (1: 1) was injected to 30 atm. went. The yield of methyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene is 78%, the yield of methyl 3- (4-chloromethylphenyl) propionate is 8%, The yield of methyl 2- (4-methoxycarbonylmethylphenyl) propionate was 3%. Example 36

 4-chloromethylstyrene 153 mg (l. 00 mmol) as substrate, dichlorobis (triphenylphosphine) palladium as catalyst 7. Omg (0.0 lmmo 1), isopropyl alcohol as alcohol 1. Om, and toluene 2 as solvent The reaction and analysis were carried out in the same manner as in Example 4 except that each gas was injected so that the partial pressure of carbon monoxide was 30 atm and the partial pressure of hydrogen was 30 atm using Oml. The yield of isopropyl 2- (4-monomethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 78%, and the yield of isopropyl 3- (4-chloromethylphenyl) propionate was 1%. — (4rsopropoxycarbonylmethylphenyl) The yield of isopropyl propionate was 3%.

Example 37

4-Monochloromethylstyrene as substrate 153 mg (1.0 Ommo 1), palladium acetate as catalyst 2.2 mg (0.0 lmmo 1), ligand as triphenylphosphine 5.2 mg (0.02 mmo 1), as alcohol Except for using isopropyl alcohol 1.Om 1 and toluene 2.Oml as the solvent and injecting a mixed gas of carbon monoxide (1: 1) so that the pressure becomes 30 atm, the same procedure as in Example 4 was carried out. Reaction and analysis were performed. 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%.

Example 38

 4-chloromethylstyrene 15.3 g (10 Ommo 1), palladium acetate 112 mg (0.5 Ommo 1), and triphenylphosphine 262 mg (1.0 Ommo 1) as a ligand in a 1 L stainless steel autoclave , Ethanol

After 50 ml of toluene and 250 ml of toluene were charged and the inside of the system was sufficiently replaced with a mixed gas of carbon monoxide and hydrogen (1: 1), a mixed gas of hydrogen and carbon monoxide was injected to a pressure of 35 atm. The temperature was raised to 80 with heating and stirring, and a force luponylation reaction was carried out for 22 hours.

 After the reaction was completed, the product was analyzed by gas chromatography in the same manner as in Example 4. As a result, the yield of ethyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 96%. The yield of 2- (4-chloromethylphenyl) propionate was 2%, and the yield of 2- (4-ethoxycarbonylmethylphenyl) propionate was 2%.

Example 39

In a 1-L stainless steel autoclave, 15.3 g (10 Ommo 1) of 4-chloromethylstyrene, 67 mg (0.30 mmo 1) of palladium acetate, and 157 mg (0.6 mm) of triphenylphosphine as a ligand Ommo 1), 50 ml of ethanol and 250 ml of toluene were charged, and the system was sufficiently replaced with a mixed gas of carbon monoxide and hydrogen (1: 1), and then a mixed gas of carbon monoxide and hydrogen was brought to 35 atm. Pressed. The temperature was raised to 80 with heating and stirring, and the carbonylation reaction was performed for 30 hours. After the reaction was completed, the product was analyzed by gas chromatography in the same manner as in Example 4. As a result, the yield of 2- (4-chloromethylphenyl) propionate ethyl ester relative to the raw material 4-chloromethylstyrene was 86%. The yield of 3-, 4- (4-chloromethylphenyl) ethyl propionate is less than 1%, and the yield of 2- (4-ethoxycarbonylmethyl) (Ruphenyl) The yield of ethyl propionate was 1%.

Example 40

 In a 1 L stainless steel autoclave, 15.3 g (100 mmo 1) of 4-chloromethylstyrene, 89 mg (0.5 Ommo 1) of palladium chloride, and 382 mg of neomenthyldiphenylphosphine as a ligand ( Purity 85%, 1.00 mmo 1), 50 ml of ethanol and 250 ml of acetone were charged, and the system was sufficiently replaced with a mixed gas of carbon monoxide and hydrogen (1: 1). A mixed gas of carbon monoxide and hydrogen was injected. 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. Was.

 After the reaction, the product was analyzed by gas chromatography in the same manner as in Example 4. As a result, the yield of ethyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 79%. Ethyl, 3- (4-chloromethylphenyl) propionate, and 2- (4-ethoxyethoxycarbonylphenyl) ethyl propionate produced less than 0.2%.

Example 41

 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.

After the reaction was completed, the product was analyzed by gas chromatography in the same manner as in Example 4. As a result, the yield of ethyl 2- (4-chloromethylphenyl) propionate relative to the raw material 4-chloromethylstyrene was 72%. , 3- (4-chloromethylphenyl) propionate, 2- (4-ethoxycarbonylmethylphenyl) pro Ethyl pionate produced less than 0.2%.

Example 42

 91.6 g (60 Ommo 1) of 4-chloromethylstyrene, 1.00 g of aqueous solution of sodium tetrachloride paradate in a 1 L glass autoclave (2 mmol Zg, prepared according to 3 mmo reference example), coordination 1.72 g (purity: 85%, 4.5 Ommo 1) of neomenthyldiphenylphosphine, 10 Om1 of ethanol and 50 Oml of acetone were charged into the system, and a mixed gas of carbon monoxide and hydrogen (1: 1) was introduced into the system. After sufficient replacement with, a mixed gas of carbon monoxide and hydrogen was injected so that the pressure became 5 atm. The temperature was raised to 60 with heating and stirring, and while the carbon monoxide was being replenished, a force luponylation reaction was carried out for 30 hours so that the carbon monoxide partial pressure in the system did not fall below 2 atm.

 After the completion of the reaction, the product was analyzed by gas chromatography in the same manner as in Example 4. As a result, the yield of 2- (4-chloromethylphenyl) propionate ethyl ester relative to the raw material 4-chloromethylstyrene was 74%. Ethyl 3- (4-chloromethylphenyl) propionate and ethyl 2- (4-ethoxycarbonylmethylphenyl) propionate produced less than 0.2%.

Example 43

Synthesis of loxoprofen sodium

 66 mg of potassium hydroxide was added to dimethylformamide (1. Oml), and 164 mg (1. Ommol) of 2-carboethoxycyclopenone was added thereto at room temperature with stirring. After a homogeneous solution was formed, 227 mg (1. Ommo 1) of ethyl 2-((4-chloromethylphenyl) propionate) was added dropwise under ice cooling, and the resulting mixture was stirred at 60 for 2 hours. . After completion of the reaction, the reaction mixture was poured into ice water and extracted with toluene. The organic layer was washed with water, and the solvent was distilled off to obtain 323 mg of an oily crude product (content correction value: 262 mg, yield: 75.6%).

18.5 g of crude product of 2- [4- (1- (1-ethoxycarbonyl) -2-oxocyclopentane-1-dimethyl) phenyl] propionate thus obtained (content correction value: 15.0 g) , 43.3 mmo 1) were added to 25% sulfuric acid (15 OmL) at room temperature, and the mixture was heated under reflux for 37 hours. Extract with toluene and extract After the target substance was transferred to the aqueous layer by treatment with a 1N aqueous solution of sodium hydroxide, the aqueous layer was acidified with hydrochloric acid and extracted again with toluene. The extract was washed with water, and the solvent was distilled off, thereby obtaining 13.8 g of a crude product as a slightly yellow oil (content correction value: 10.7 g, yield: 88.6%). Crystallized with toluene as the solvent and recovered with a 50% recovery rate.

Crystals of [4- (2-oxocyclopentane-111-methyl) phenyl] propionic acid were obtained.

 Subsequently, 10.0 g (40.6 mmo 1) of the crystal was added to ethanol (45 mL) at room temperature, and 0.96 equivalent of sodium methoxide was added and stirred. After ethanol was distilled off under reduced pressure, the residue was crystallized from aqueous acetone to obtain loxoprofen sodium (11.8 g, yield 95.8%).

Reference example

 Preparation of aqueous solution of sodium tetrachloroparadate

 Water was added to and dissolved in 3.55 g (20.0 mmol) of palladium chloride and 2.34 g (40. Ommo 1) of sodium chloride so that the total amount was 10 g.

Industrial applicability

 According to the present invention, there is provided a method for producing a 2-phenylpropionic acid derivative 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.

Claims

The scope of the claims (1) In the presence of a palladium catalyst, the general formula (I)

(Wherein X represents a halogen atom), a styrene having a halomethyl group represented by the following formula: carbon monoxide and a general formula (II)  R-OH (II) (Wherein R represents a hydrogen atom or a lower alkyl group).

(Wherein, X and R are the same as described above). A method for producing a 2-phenylpropionic acid derivative having an octamethyl group represented by the formula:  (2) The method according to claim 1, which is performed in the coexistence of hydrogen.  (3) The production method according to claim 1 or 2, wherein the production is carried out in the presence of cyclohexyldiarylphosphine having at least one substituent at the α-position of the cyclohexane ring.  (4) The production method according to claim 1 or 2, wherein the production is performed in the presence of neomenthyldiphenylphosphine.  (5) The production method according to claim 1 or 2, wherein the production is carried out in the coexistence of menthyldiphenylphosphine.  (6) The method according to claim 2, wherein the partial pressure of carbon monoxide is 1 to 5 atm. (7) General formula (I) in the presence of a palladium catalyst

(Wherein, X is as defined above) and a styrene having a halomethyl group represented by the formula: and carbon monoxide and a general formula (II)  R-OH (II) (Wherein R has the same meaning as described above) (III)

Wherein X and R have the same meanings as defined above, and a 2-phenylpropionic acid derivative having a halomethyl group represented by the general formula (IV)

(Wherein R ^A has the same meaning as R).

Wherein R and R ^A have the same meanings as defined above, and further hydrolyzing and decarboxylating the compound.

A method for producing a compound represented by the formula: or a salt thereof. (8) General formula (I) in the presence of a palladium catalyst

Wherein X is as defined above, a styrene having a halomethyl group, carbon monoxide and a compound represented by the general formula (II)  R-OH (II) (Wherein R has the same meaning as described above)  (I I I)

(Wherein X and R have the same meanings as defined above), and a 2-phenylpropionic acid derivative having a halomethyl group represented by the following general formula (VII) (VII)

(Wherein Y represents CH ₂ , CH ₂ CH ₂ or OCH ₂ ), and the compound represented by the general formula (VIII)

(Wherein R has the same meaning as defined above), which is further hydrolyzed by the general formula (VI)

A method for producing a compound represented by the formula: or a salt thereof.  (9) In the presence of a palladium catalyst, the general formula (I)

(Wherein X represents a halogen atom), a styrene having a halomethyl group represented by the following formula: carbon monoxide and a general formula (II) R-OH (II)  (Wherein, R represents a hydrogen atom or a lower alkyl group) by reacting with a compound represented by the general formula (I I I)

(Wherein X and R are the same as defined above), and a 2-phenylpropionic acid derivative having a halomethyl group represented by the formula (IX) i (IX)

Reacting the compound represented by the formula (X)

A compound represented by the general formula (VI), which is further hydrolyzed:

A method for producing a compound represented by the formula: or a salt thereof.