JPS62129250A - Production of 2-substituted phenylpropionic acid or ester thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an anti-inflammatory agent in high yield without forming isomers, by halogenating 2-(p-methylphenyl) propionic acid or an ester thereof as a raw material in the presence of a radical generating agent. CONSTITUTION:2-(p-Methylphenyl)propionic acid or an ester expressed by formula I (R is H or lower alkyl) as a raw material is reacted with a halogenating agent, e.g. chlorine, bromine, N-bromosuccinimide, etc., in the presence of a radical generating agent (particularly preferably azobisisobutyronitrile or light and preferably in an amount of about 0.5-2.0wt% based on the raw material or while continuously irradiating for the light) to afford the aimed 2-(p- halomethylphenyl)propionic acid or ester thereof expressed by formula II (R is same as defined above; X is halogen atom, e.g. Cl, Br I, etc.).

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides 2-(p-halomethylphenyl) useful as an intermediate for pharmaceuticals, particularly phenylpropionic acid-based anti-inflammatory agents.
This invention relates to a method for producing esters of propionic acid.

[Conventional technology]

Since a, 2-(p-halomethylphenyl)propionic acid "tfc&Z" as a method for producing its ester &'!
Example, t) A method for total synthesis of ethyl 2-(p-halomethylphenyl)propionate by reacting ethyl 2-phenylpropionate and chloromethyl methyl ether in the presence of tin tetrachloride (French Patent No. 2, 134,197), 2-phenylpropionic acid and its ester are reacted with dialkoxymethane in the presence of a halogen-containing condensing agent such as tin tetrachloride or halogen sulfonic acid,
- Method for synthesizing (p-halomethylphenyl)propionic acid or its ester (JP-A-56-138140
No.) etc.

[Problem that the invention seeks to solve]

French Patent No. 2,134,197 is industrially superior because it uses chloromethyl methyl ether, which is considered a carcinogen, and the yield of the target product is extremely low. It is difficult to explain the R construction method. Furthermore, JP-A-56-138140 discloses that when introducing a noromethyl group to the para position of an aryl moiety, it is difficult to suppress the by-products of ortho-substituted products, meta-substituted products, and polysubstituted products; The production method is not necessarily industrially satisfactory, as the separation and purification of positionally substituted products is complicated, and the use of soalkoxymethane and chlorosulfonic acid, which are dangerous to handle, are used as auxiliary raw materials.

[Means for solving problems]

Under these circumstances, the inventors of the present invention have conducted extensive studies, and as a result,
By reacting 2-(p-methylphenyl)7'' rhoonic acid or its ester in the presence of a radical generator without a halogenating agent, 2-(p-heromethylphenyl)propionic acid or its ester, e.g. It has been discovered that a compound represented by the general formula (X & Fully charged.

To explain the method of the present invention in more detail, for example, it is shown by the following reaction formula.

(In the formula, X and R are as defined above) 2-(p-methylphenyl)propionate is 2
-(p-methylphenyl)propion e [- Can be easily obtained by esterification by a conventional method.

The present invention is a method of halogenating the methyl group at the 9-position (in the raw material) as shown in the above reaction formula, and such a method has not been known in the past. Normally, in such genation, there is a possibility that other substituents -IBOOR may be halogenated, and it was surprising that only the methyl group at the p-position was halogenated with good yield.

In the above formula, when R is a lower alkyl group, preferable examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl,
Ethyl, n-propyl, 1-f propyl, n-butyl,
These are groups such as i-7''yl, 5ec-butyl, and tert-butyl.

The halogenating agents used in the method of the present invention include simple halogens such as chlorine, bromine and iodine, as well as N-halogenimides and amides.

Examples include N-halogenosuccinimide, N-halogenocaprolactam, N-halogenophthalimide, 1,3-nohalogeno-5,5-dimethylhydantoin, and sul7lyl halide, and these halogens are chlorine, Indicates bromine and iodine. Among these, chlorine, bromine and N-bromosuccinimide are particularly preferably used. The amount of halogenating agent used should be stoichiometric, but 2
-(p-methylphenyl)propionic acid or its ester, for example, 1.0 to 2.0 times the mole, preferably a slight excess, about 1.2 to 1.5 times the mole, allows the reaction to proceed smoothly. Proceed to.

In the reaction, a solvent may or may not be used, but
Usually an inert solvent is used. Such solvents include, for example, petroleum ether, ligroin, n-hexane%
Aliphatic hydrocarbon solvents such as n-hebutane, n-octane, cyclohexane, carbon tetrachloride, chloroform, dichloromethane, hexachloroethylene, dichloroethane,
Examples include halogenated hydrocarbon solvents such as trichlene, benzene, acetic acid, carbon disulfide, and the like. A radical generator is used in the reaction, but there are no particular restrictions on what is normally used as a radical generator, such as peroxide (e.g. benzoyl peroxide), azobisisobutyronitrile, phosphorus tribromide, Examples include aluminum tribromide and light.Among these, azobisisobutyronitrile and light are particularly preferred.

Use of radical generator jl&X2-(p-methylphenyl)propionic acid or its ester approximately 0.1
~5.0% by weight, preferably about 0.5-2.0% by weight. In the case of light (irradiation is preferably continued during the reaction), the reaction temperature is usually in the range from 0° C. to the boiling point of the reaction solvent system, but is not particularly limited.

〔Example〕

Next, the method of the present invention will be explained in more detail with reference to its implementation, but the method of the present invention is not limited thereto.

Example 1 9.97 g of 2-(p-methylphenyl)propionic acid was dissolved in 1 oomtvcm of benzene, and to this was added 13.9 ml of N-bromococcyl imide (NBS) and 0.9 g of azobisisobutyronitrile (AIBN). 29 Add water, stir, and heat to reflux. After confirming that the reaction mixture became colorless and the NBS was consumed, the reaction was terminated and cooled. The reaction took about 7 hours.The reaction solution was filtered and washed with water.
The solvent was distilled off to obtain 14.6 f of a pale yellow oily substance.

This solidified at room temperature. This crude product was recrystallized in 20 ml of a mixed solvent of kn-hexane:ethyl acetate=4:1 to obtain 10.51 g of white crystals of 2-(p-bromomethylphenyl)propionic acid. GLC purity 97.7%, yield 70.0%. (GLC conditions: Column Chromosor
b GOV-172% 80~l OOmesh 1.
5 m Temperature: 100-270°C heating) NMR (CDC63) δ; 1.5 (3H, d, J = 7Hz), 3.7 (
IH, q, J = 7 Hz), 4.5 (2, H, s
), 7.4 (4H, s), 11.3 (LH, s, b) IR (KBr tablet method) 3400.2950.1700j1420,122 (+
.

600 (1m" m, p, 124-126°C Example 2 2-(p-methylphenyl)propionic acid 99t 1i
Dissolve in 50 g of n-hexane and keep at 10-15°C with stirring. When 12.5 r'i of bromine was added dropwise for about 2 hours while irradiating with a 100 V, 150 W tungsten lamp, white crystals were precipitated. After further aging at the same temperature for 1 hour while fully irradiated with light, the white crystals were separated in a furnace and n-hexane:ethyl acetate = 4:1
(Washing with mixed solvent D for 40 hours and drying yielded 2-(p-bromomethylphenyl)f-ropion [11,65''i).

GLC purity 98.0%, yield 77.6%. IR.

NMR was the same as in Example 1. (GLC conditions are the same as Example 1) Example 3 2-(p-)tylphenyl)propionic acid 9.9? ”k
The mixture was dissolved in 100 ml of carbon tetrachloride and heated to reflux with stirring. Chlorine gas is continuously blown in from the blowing pipe while being irradiated with ultraviolet light using a high-pressure mercury lamp. Chlorine gas was blown in at a rate of 6.42 over a period of approximately 3 hours. After cooling the reaction 'α, it was washed with water and the solvent was distilled off to obtain a pale yellow oil 12.1)ti9. This product 1. Of was separated and purified by silica gel thin layer chromatography (developing solvent: toluene:acetic acid = 9:1), and further 0-
Re-coagulate with a mixed solvent of hexane: ethyl acetate = 3:1,
Obtained 0.42ft of white crystals. It was confirmed from its IR and NMR spectra that it was 2-(p-chloromethylphenyl)propionic acid.

Example 4 Methyl 2-(p-methylphenylonpropionate 10.
8 fk were dissolved in 100 mJ of carbon chloride.

100v, 150 while maintaining 25-30'CtC under stirring
9.6 tons of bromine was irradiated with a W tungsten lamp for 30 minutes.
Added within minutes. After aging at the same temperature for 1 hour, the reaction solution was washed with water.
Washed twice with 0M water and evaporated the solvent to give a yellow oil 15.2
? I got it. This product 1. Separation and purification by Ott silica gel thin layer chromatography (same as above) yielded a pale yellow oil with 0.5
6? I got it. From its NMR1IR spectrum, 2-(
It was confirmed that it was methyl p-bromomethylphenyl)propionate, and tO NMR (CDCt, ) δ: 1.45 (3) J, d, J = 7 Hz), 3.5
8 (3I(,S), 3.65(IH, q, J=7Hz)
, 4.39 (2H, s), 7.23 (4H, 5) IR (KBr tablet method) 2950.1?30.1430,1200.1160°1060.660crrL-' Example 5 2-(p-methyl Methyl phenyl)propionate 10.
Dissolve 100rr of carbon tetrachloride and heat to reflux with stirring. Chlorine gas was continuously blown from the blowing pipe while irradiating ultraviolet light with a high-pressure mercury lamp. 6. In about 3.5 hours.
52 chlorine was injected with suction. The reaction solution was completely cooled, drained and washed with water, and the solvent was distilled off to obtain 14.3f of a pale yellow oil.

This product was distilled under reduced pressure to obtain p, 140-b 9,7 t'i. It was confirmed from its IR and NMR spectra that it was methyl 2-(p-chloromethylphenyl)propionate.

〔Effect of the invention〕

The method of the present invention +12-<p-methylphenyl)propionic acid'1 is a method in which a halogen atom is introduced into the methyl group on the phenyl ring by halogenation of the ester, so there is no generation of isomers and it meets the purpose. The ester of 2-(p-heromethyl7enyl)propionic acid can be obtained in high yield.

Claims (1)

[Claims] 2-(p-halomethylphenyl)propionic acid or its ester, which is characterized by reacting 1,2-(p-methylphenyl)propionic acid or its ester with a halogenating agent in the presence of a radical generator. Production method.