JPS61167640A - Production of alpha-aromatic group-substituted alkanoic acid - Google Patents

Abstract

PURPOSE:To produce the titled substance by the rearrangement reaction of 1,1-dimethoxy-1-(4-isobutylphenyl)-2-hydroxypropane, etc. in the presence of triphenyl phosphine, etc., hexachloroacetone, etc. or chlorine, etc. CONSTITUTION:The compound of formula II (R<6> is H or alkyl) is produced by carrying out the rearrangement reaction of the compound of formula I (Ar is aryl or hetero-cyclic group; R<1> and R<2> are alkyl or together form a cyclic acetal; R<3> and R<4> are H or alkyl) in the presence of the compound of formula R<5>3P (R<5> is phenyl or alkyl) and the compound of formula CX3Y (X is halogen; Y is halogen or acyl) or formula XZ (Z is halogen or imido) at -60-+100 deg.C for 1min-20hr. USE:Anti-inflammatory analgesic agent, its intermediate or intermediate for agricultural chemicals.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to α-α, which is useful as a pharmaceutical having an anti-inflammatory and analgesic effect and its intermediates, or as an intermediate for agricultural chemicals such as insecticides and herbicides.
-Regarding a method for producing aromatic group-substituted alkanoic acids.

BACKGROUND ART In the compound represented by general formula (1), R3 or R
When one of 4 is hydrogen, a method is known in which the hydroxyl group is tosylated and then heated, for example, in an aqueous calcium carbonate solution to obtain a compound represented by the general formula (5) [Kamiyoko et al. Tetrahedron Letters.

22, Nα43.4305 (1981)).

Object of the Invention Means for solving the problem of α-aromatic group-substituted alkali which is always industrially excellent. According to the method of the present invention, the general formula (1) (wherein Ar is a substituted or unsubstituted aryl group or a hetero represents a cyclic group, R' J and R2 may be the same or different, represent an alkyl group, or R1 and R2 may be combined to form a cyclic acetal, R3 and R2 may be the same or different;
4 are the same or different and represent a hydrogen atom or an alkyl group. ) A compound represented by general formula (2) and general formula (3) or (4) R', P
(2) CX 3 Y (3) XZ (4) (wherein, RS represents a phenyl group or an alkyl group, and
represents a halogen atom, Y represents a halogen atom or an acyl group, and Z represents a halogen atom or an imide group.
General formula (5)% formula (5) (wherein Δr, R' and R4 have the same meanings as above, R
6 represents a hydrogen atom, an alkyl group or a substituted alkyl group. ) It is possible to produce α-aromatic group-substituted alkanoic acids represented by:

The aryl group in Ar includes aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl groups.

Substituents for the substituted aryl group include alkyl groups having 1 to 5 carbon atoms [for example, methyl, ethyl, propyl, butyl,
Isobutyl, pentyl groups, etc. (including dialkyl groups)],
Substituted alkyl group [the alkyl moiety has the same meaning as above, and substituents include phenyl group, halogen atom (e.g., chlorine, fluorine, bromine atom, etc.), hydroxy group, amino group, nitro group, etc.], Alkoxy groups having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, phenoxy, methylenedioxy groups, etc.).

Halogen atoms (e.g. chlorine, fluorine, bromine atoms, etc.),
Lower alkylthio groups (e.g. methylthio.

ethylthio, isopropylthio, butylthio groups, etc.).

Acyl groups having 1 to 7 carbon atoms (eg, acetyl, propionyl, phenylcarbonyl, etc.), benzoyloxy, acetyloxy, hydroxy, amino.

Nitro, cyano, cyclohexyl groups, etc. are included.

Examples of the heterocyclic group include ] etc. are included.

As the alkyl group for R1-R6, a C1-C5 noalkyl group, such as methyl, ethyl, flohyl, butyl, pentyl group, etc. As the substituent for the substituted alkyl group for R1,
A hydroxy group, a halogen atom (eg, chlorine, fluorine, etc.), and the like are included.

In the following, compounds represented by general formulas (1), (2), etc. are referred to as compounds (1), (2), etc.

In carrying out the present invention, a compound (
1) with compound (2) and compound (3) or compound (
2) and compound (4) are added and reacted to form compound (
1) The rearrangement reaction is carried out.

When R'i6 and R4 are both hydrogen or an alkyl group, compound (1) can be prepared by, for example, reducing arylglyoxylic acid ester dialkyl acecure with lithium aluminum hydride or the like, or by reducing R' When one of the hydrogen atoms is hydrogen, it can be obtained, for example, by reacting an α-haloalkylaryl ketone such as α-halopropiophenone with a base such as a metal alkoxide in an alcohol solvent [see above, Tetrahedron Letters, 22
．． N (R43, 4305 (1981)).

Compound (2) is triphenylphosphine.

Examples include triethylphosphine.

Compound (3) includes carbon tetrachloride and carbon tetrabromide.

Examples include hexachloroacetone.

Compound (4) includes chlorine, bromine, N-chlorocoba 9
1!11 imide, N-bromosuccinimide, and the like.

As the organic solvent used in the reaction, any solvent inert to the reaction can be used, and examples thereof include aromatic hydrocarbons such as benzene and toluene, and halogenated compounds such as methylene chloride and chloroform.

The reaction is carried out at -100 to 150°C, preferably -60 to 100°C.
It is carried out in the range of °C. At this temperature the reaction time is generally 1 minute to 20 hours.

The reaction product thus obtained is isolated and purified by conventional methods. For example, high-quality compound (5) can be obtained by concentrating the reaction solution, adding water to the residue, extracting the product with chloroform, etc., and fractionating the target substance by gel chromatography.

Furthermore, in order to obtain optically active compound (5), optically active compound (1) may be used.

Examples are shown below.

Example 1 1.1-dimethoxy-1-(4-inbutylphenyl 1
2.52 gk of 2-hydroxypropane and 5.0 Og of hexachloroacetone were dissolved in 40 ml of methylene chloride, 3.00 g of triphenylphosphine was added, and the mixture was stirred at room temperature for 18 hours. After the reaction, it was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate system) to obtain 1.70 g of methyl 2-(4-isobutylphenyl)propionate (yield: 78%).
・.

Example 2 140 μl of N-chlorosuccinimide was dissolved in 5 ml of tetrahydrofuran, and under water cooling, triphenylphosphine 2
A solution prepared by dissolving 70 ml of tetrahydrofuran in 2 ml of tetrahydrofuran was added dropwise with stirring.

Then, a solution of 250 mg of 1,1-dimethoxy-1-(4-inbutylphenyl 12-hydroxypropane dissolved in 2 ml of tetrahydrofuran) was added.
After stirring for a minute, quantitative analysis using gas chromatography revealed that 2-(4-isobutylphenyl)
The yield of methyl propionate was 41%.

Gas chromatography conditions column 2% DIEGS on Gas Chrom
Q3mmφ 1.5m Glass Column temperature 100 → 200℃ Inlet temperature 200℃ In addition, the sample was analyzed by gas chromatography using N,O-bis(trimethylsilyl)acetamide, hexamethyldisilazane, and trimethylsilyl chloride under the following conditions. As a result, 2-(4-inbutylphenyl)propionic acid was produced.

Gas chromatography conditions column 2%Sε-52on Chromosorb
W3mmφ 3m Glass Column temperature 165 → 260°C Inlet temperature 270°C Example 3゜R-1,1-dimethoxy-1-(4-inbutylphenyl)-2-hydroxypropane 5.04g J3 and triphenylphosphine 10. 5 g methylene chloride 1
00ml, add 3.84g of bromine under water cooling,
The mixture was stirred at room temperature for 18 hours. After the reaction, the same post-treatment as in Example 1 was performed to obtain (-)-2-(4-isobutylphenyl)
Obtained 3.06 g of methyl propionate (yield 68%)
. The NMR of this product completely matched that of the standard specimen.

[α]. -56,2'(C=1.CHCA's)
Example 4゜1.1-dimethoxy-1-(3-chlorophenyl)-2
2.45 g of -hydroxy-2-methylpropane and 3.00 g of triphenylphosphine were dissolved in 20+111 of tetrahydrofuran, 3.31 g of carbon tetrabromide was added, and the mixture was stirred at room temperature for 18 hours. After the reaction, the same post-treatment as in Example 1 was performed to obtain 1.62 g of methyl 1.1-dimethyl-(3-chlorophenyl)acetate. (Yield 76%) Furthermore, it was hydrolyzed by a conventional method, and 1,1-dimethyl-(
3-chlorophenyl)acetic acid.

Melting point 66.5-67.5°C Elemental analysis C3°H,, O, H as C1 Theoretical value (%) 60.46 5.58 Actual value (%
) 60.40 5.60 Effects of the Invention By the method of the present invention, α-aromatic group-substituted alkanoic acids can be obtained in good yield.

Claims (1)

[Claims] General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, and R^1 and R^2 may be the same or different, and may represent an alkyl group, or R^1 and R^2 may be combined to form a cyclic acetal, and R^3
and R^4 may be the same or different and represent a hydrogen atom or an alkyl group. ), the compound represented by general formula (2) and general formula (3) or (4) R^5_
3P(2) CX_3Y(3) XZ(4) (wherein, R^5 represents a phenyl group or an alkyl group,
X represents a halogen atom, Y represents a halogen atom or an acyl group, Z represents a halogen atom or an imide group)
General formula (5) characterized by a rearrangement reaction in the presence of a compound represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼
(5) (In the formula, Ar, R^3 and R^4 have the same meanings as above, and R^6 represents a hydrogen atom, an alkyl group or a substituted alkyl group.) Method for producing substituted alkanoic acids.