JPS5913489B2 - Method for producing α-alkyl-α-phenylacetic acid - Google Patents

Description

[Detailed description of the invention] This invention (referred to as the present invention).

The same applies hereinafter) relates to a new method for producing α-alkyl-α-phenylacetic acid. α-Alkyl-α-phenylacetic acid is widely used as an excellent anti-inflammatory drug, and several methods for its production have been provided, including Japanese Patent Publication No. 7491/1983 and Japanese Patent Publication No. 471-18105. .

However, all of these methods require many steps. For example, Special Publication No. 40-749115 is P
- Isobutylphenyl acetic acid is converted into a malonic acid derivative, then methylated and decarboxylated.
In No. 1, P-isobutylacetophenone is converted to hydantoin, then converted to amino acid, and the desired product is obtained by deamination. However, these methods require a long process from isobutylbenzene and have problems in terms of yield. As a result of various studies to solve these problems, they discovered a method for obtaining α-alkyl-α-phenylacetic acid in good yield under relatively mild conditions, and thus completed the present invention. That is, the present invention provides general formula [I] R-CH=CH-NR1[I] (wherein R is (1)□ group, and RO is alkyl (C2-C6), cycloalkyl (C3-C7), R
In the □35(2)□ group, R° and R° may be the same or different and are hydrogen, halogen, or an alkyl group.

w indicates a n-butyl group or an isobutyl group. ) and the enamines represented by the general formula [] R'X [] (wherein R7 represents lower alkyl, and X represents iodo or bromine.

) is reacted with an alkyl halide, the resulting product represented by the general formula [] (in the formula R.R/, KU is the same as above) is hydrolyzed, and then this is oxidized. The present invention relates to a method for producing α-alkyl-α-phenylacetic acid.

The enamines represented by the general formula [1] used in the present invention are prepared in a nitrogen stream without a solvent or in an inert solvent such as benzene, toluene, xylene, acetonitrile, ether, etc. with a base such as an alkali metal or alkaline earth. In the presence of metal carbonates or hydroxides or amines, WNH (R.R'' in the formula and in the formulas described below,
All KUs are the same as above.

) and R-CH2CHO in a good yield. That is, the R'''l!NH amine solution containing the base is cooled and R-CH2CHO is added dropwise while stirring, and the mixture is stirred while cooling for 10 hours. After the reaction, the reaction liquid is filtered and the liquid is fractionated. The enamines of the general formula [1] can be obtained in high yield.Subsequently, the obtained enamines of the general formula [1] and twice the mole of the alkyl halide are mixed in anhydrous acetonitrile and benzene in a stream of inert gas. Heat under reflux for 10 to 20 hours in an inert solvent such as acetic acid.After the reaction, add sodium acetic acid monoacetate buffer solution and reflux for 4 hours in a nitrogen stream.Then, the reaction solution is cooled, added with H2O, and extracted with benzene. The benzene extract layer is collected, washed with an aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dehydrated with magnesium sulfate, and then distilled off the benzene to obtain a crude product of the general formula [ ].If necessary, perform fractional distillation. The enamine of the general formula [] obtained was refluxed in an acidic aqueous solution for 5 hours, and after cooling, the reaction solution was extracted with benzene, and the benzene layer was extracted with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. After washing with water, obtain sulfuric acid magne CHO.If necessary, a refined product can be obtained by fractional distillation, but there is no particular need for purification in order to obtain the object of the present invention.This aldehyde is For example, oxidation with permanganate, peroxide, nitric acid, chromic acid, metal oxide, etc. is carried out by a conventional method used for oxidation. Oxidation with silver oxide or potassium permanganate is preferable Add silver oxide or potassium permanganate to water or alcoholic water, add the aldehyde dropwise over several hours, and then heat the reaction solution under reflux.After the reaction, add H2O and filter.
After making the solution acidic, it is extracted with a solvent such as benzene, ethyl acetate, or ether, and purified by a conventional method to obtain α-alkyl-
α-phenylacetic acid is obtained. Note that R-C used in the present invention
By oxidation of the corresponding alcohol, H2CHO is
Alternatively, R-CHO can be condensed with a haloacetate ester to form a glycite cap ester, which is then decarboxylated, or by reduction of R-CH2COOH, each of which can be obtained in good yield. Reference example HN (CH2CH2CH2CH3) 225.8f7 (0
．． 2 m01) of amine, 50 m1 of ether (benzene, toluene, xylene, no solvent can be used instead of ether) and anhydrous K2CO328y are stirred in a nitrogen stream, and iced? ?
- 35.27 (0.2 m01) of aldehyde was added dropwise overnight to obtain 48.8 y (yield 85%) Example 1 5.74 y (0.02 m0) of N(C4H9)2 enamine
1) and CH3l5.687 (0.04m01) to CH3
Heating under reflux in a nitrogen stream in Oml of CN2, and after completion of the reaction, CH3COONal7, acetic acid 2ml and 10
m1f) Add a buffer solution containing H2O and reflux under a nitrogen stream for 4 hours.

After the reaction, extract with H2O and 25 ml of diluted benzene. The benzene layer is washed with HCl, H2Ol saturated NaHCO3aq, saturated Naclaq, dried over NgSO4 and the benzene is distilled off to give 4.827 (80% yield), which is then heated under reflux with 45 ml of INHclaq for 5 hours.

The cooled reaction solution was extracted with benzene, and the benzene layer was extracted with Dll.
-Hcl. H2Ol saturated NaHCO3 aqueous solution, saturated Na
After washing with Cl water and dehydrating with NgSO4, benzene was distilled off, and 8y was dissolved in 100 ml of ethanol.
Dissolve 3.57 ml of NO3 in 50 ml of H2Ol and add NaOH
The silver oxide obtained by adding 6.57 was stirred and heated under reflux for 4 hours, the ethanol was distilled off, the hot water of step 11 was added, the reaction solution was filtered, the f solution was cooled, and COnc-Hcl (' PH3
The extract was extracted with benzene, the extract was extracted with a dilute aqueous alkaline solution, acidified with Dil-Hcl, extracted with ether, and the ether was removed to obtain residue 77 (yield 80%). P75-77℃, elemental analysis, theoretical value C75.7%
H8.7%, measured value C75.5% H8.9%, shows no drop in melting point even when mixed with standard product.

Example 2 (1) Preparation of raw materials 225.8 t (0.2 mol) of HN (C4H9), 50 ml of ether and 328 t of anhydrous K2CO were mixed with N2CH2
CHO4Of7 (0.2 mol) aldehyde was dissolved in benzene and added dropwise. After stirring overnight, Sawafila, SawaN(C4H,)2
A crude enamine product is obtained.

53.17 (2) Methylated enamine 5.74t (0.02 mol) and CH3l5.
68t (0.04 mol) in CH3CN2Oml, N2
Heat to reflux in a stream of air.

Add this to 2 ml of CH3COONalyl acetic acid and H2O
Add 10 ml of buffer solution and reflux under N2 for 4 hours.

After the reaction, the same procedure as in Example 1 was carried out and the reaction was carried out in the same manner as in Example 1. =CH-
5.27 tons of crude product of N(C4H,)2 is obtained.

(3) Hydrolyze 6.427 (0.02 mol) with 45 ml of INHClaq
Heat under reflux for 5 hours.

After cooling, the same treatment as in Example 1 was carried out to obtain CHO crude product 4.
Get 077.

(4) Oxidation 8.47 H-CHO dissolved in 100 ml of ethanol was mixed with 3 liters of AgNO.
57 was dissolved in 50ml of H2Ol and 6.5t of NaOH was added to the obtained silver oxide, which was then stirred and heated to 80°C for 4 hours under reflux, the ethanol was distilled off, hot water from 11 was added, and the reaction solution was filtered through f-filtration. (pass through the silver crystals), cool the slurry and remove CO.
The pH was adjusted to 3 with ncHCl, extracted with benzene, and the extract was extracted with a dilute alkaline aqueous solution (10% NaOH). H.C.
After acidifying with l and extracting with ether, remove the ether and add n
- The desired product was obtained by recrystallization from hexane (yield: 83%).

Its physical and chemical properties are as follows.

Elemental analysis: Calculated value C79.64% H6. l9% actual value C8O. l7% H6.73% infrared absorption spectrum: 3100-2850, 3000-2500, 170
011380, (Crn-1)M. P:121-123
°C Properties: White microcrystalline powder, with a slight pungent odor and pungent odor.

Claims (1)

[Claims] 1 General formula [I] R-CH=CH-NR″_2 [I] (In the formula, R is (1)▲A mathematical formula, a chemical formula, a table, etc.▼,
R^[3] is alkyl (C_2 to C_6), ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ group, and R^[4] and R^[
5] may be the same or different, and are hydrogen, halogen, or an alkyl group. R'' represents n-butyl group or isobutyl group) and general formula [II] R'X [II] (where R' represents a lower alkyl group. The general formula [III] ▲ formula obtained by reacting the alkyl halide represented by
There are chemical formulas, tables, etc. ▼ [III] (In the formula, R, R', R
A method for producing α-alkyl-α-phenylacetic acid, the method comprising: hydrolyzing a product represented by the formula (“ is the same as above) and then oxidizing it.