JPS5823873B2 - Method for producing substituted phenylacetic acid derivatives - Google Patents

Description

[Detailed description of the invention] i The present invention is based on the general formula [In the formula, R1 is a lower alkyl group.

] The present invention relates to a method for producing substituted phenylacetic acid represented by:

More specifically, in an aprotic polar solvent, the general formula (wherein,
R is an alkyl group or the three R's together form an alkylene group, and R1 is a lower alkyl group.

) is reacted with a metal cyanide to form a compound of the general formula (wherein R and R1 are the same as above).

The present invention relates to a method for producing a substituted phenylacetic acid derivative represented by the general formula (1) by obtaining a cyanide compound represented by the formula (1) and then hydrolyzing this cyanide compound in the presence of a mineral acid.

Examples of the substituted phenylacetic acid derivatives represented by the general formula (I) obtained by the present invention include sprophene CP, G, and H, which have excellent analgesic and anti-inflammatory effects.

Van Daele et al.
Forscb+25°1495 (1975)] and the like are known.

As a method for producing these compounds, the following are representative examples of conventional methods using sporufene as an example.

(1) Method of sequentially reacting thiophene and methylmalonic acid ester using P-fluorobenzoic acid chloride as a raw material CGer, Of fen 2, 353,
357].

(2) A method of reacting fluorobenzene with 2-thenoyl chloride and further reacting with methylmalonic acid ester (see C, A, , 84, 43737X).

(3) A method in which thallium nitrate is allowed to act on a phenylacetylene derivative [see JP-A-52-36642].

(4) A method in which a diester is alkylated and then hydrolyzed and decarboxylated [see JP-A-49-93346].

(5) A method for obtaining an acetophenone derivative by subjecting it to Will-Geroth reaction in the presence of rhodanine [Unexamined Japanese Patent Application Publication No. 1983-1991]
-93346].

(6) Method of cyanating and hydrolyzing an α-haloethylbenzene derivative [JP-A-49-93346, P, G
-H, Van Daele et al, tArzn
eim-Forsch, 25, 1495 (1975)].

However, these methods have drawbacks such as long reaction steps, difficulty in obtaining raw material compounds, and steps with low reaction yields*.
It was difficult to easily adopt it industrially.

Among these methods, method (6) is considered to be the most advantageous as an industrial manufacturing method.

The reaction formula for method (6) is as follows.

(In the formula, Y is a halogen atom.

) However, when we conducted a detailed follow-up study of this method, we found that in the step of synthesizing compound (b) by reacting sodium cyanide with compound @), a by-product G- ) was produced in a considerable amount as a by-product, and it was found that the yield of compound (b) was extremely low.

This fact is consistent with the fact that the yield of sprophene from compound C4) is only 10 times higher, as described in Van Dacle et al.

Specifically, the present inventors prepared compound (b) from compound 0) based on the method disclosed in JP-A No. 49-93346.
We have investigated the process in detail, but the yield of compound (B) is only 25% at most, and the by-product (A) is always 45%.
It was found that it existed in the reaction system with a yield higher than fb (see Comparative Example below).

This by-product II? X) is the raw material compound (/1')
and the target compound (b), and (
The by-product of /8) is a very big hindrance to obtaining compound (b) in high yield, and cannot be adopted as an industrial production method.

The present inventors have conducted various theoretical and experimental studies on a method for eliminating the formation of these by-products and obtaining only the target compound (2) or its derivatives in high yield.As a result, the para-position We found that a ketalized cyanide compound can be derived in high yield by ketalizing the carbonyl group of The present invention for producing a substituted aromatic acetic acid derivative represented by the general formula (I) has been completed.

The present invention is expressed as a reaction formula as follows.

(In the formula, R and R1 are the same as above, and Y is a halogen atom.

) The compound represented by the general formula (V) is a compound represented by the general formula (V).
It can be obtained by reacting the ketone derivative represented by IV) with an alcohol or an orthoester.

The compound of the general formula (■) can be easily obtained by reacting an alkylbenzene and 2-thenoyl chloride under Friedel-Krach reaction conditions [see References below and N.

P., Buu-Hoi et al., Buu-Hoi et al.
1. Soc, Chem.

Fr., 447 (1959)].

The compound represented by the general formula (II) can be obtained by reacting the compound represented by the general formula (V) with a halogenating agent.

Examples of the halogenating reagent include halogenated imides such as N-y' romosuccinimide and N-chlorosuccinimide, chlorine, bromine, t-butyl hypopromide, trichloromethanesulfonyl chloride, and trichlorobromomethane. I can do it.

This step is preferably carried out under radical-generating conditions in order to accelerate the reaction and obtain the product in good yield.

The radical generation conditions can be easily achieved, for example, in the presence of a radical generator or under light irradiation.

Examples of radical generators include organic peroxides such as benzoyl peroxide, diacetyl peroxide or di-1-butyl peroxide, azo compounds such as azobisisobutyronitrile, iron chloride, copper chloride, copper oxide, palladium complexes, Examples include transition metal compounds such as rhodium complexes.

In carrying out the reaction, it is desirable to use a solvent.

Examples of solvents include carbon tetrachloride, halogenated hydrocarbons such as chloroform, aromatic hydrocarbons such as benzene, hexane,
A solvent that does not participate in the reaction, such as a hydrocarbon such as cyclohexane, can be suitably used.

The reaction can be carried out at room temperature to 150°C, although it varies depending on the conditions.

For ease of operation, it is desirable to carry out the reaction at room temperature or around the reflux temperature of the solvent.

The cyano compound represented by the general formula (III) is obtained by reacting the halide represented by the general formula (II) with a metal cyanide such as sodium cyanide, potassium cyanide, copper cyanide, etc. Examples of the compound of general formula (III) include (4-cyanmethylphenyl)(2-chenyl)dimethoxymethane, (4-
(1-cyanoethyl)phenyl)(2-chenyl)dimethoxymethane, [4-(1-cyanoethyl)phenyl)
(2-chenyl)jethoxymethane, 2-(C4-(1
-Cyanethyl)phenyl)(2--)enyl))1.
Examples include 3-dioxolane.

The use of aprotic polar solvents is essential.

Dimethyl sulfoxide as an aprotic polar solvent;
Dimethylformamide, hexamethylphosphoramide, etc. are mentioned.

The present invention requires that the cyanide compound represented by the general formula (III) described above be hydrolyzed in the presence of a mineral acid.

The amount of mineral acid to be used is not limited depending on the conditions, but it is used in a catalytic amount to a large excess amount relative to the cyanide compound of general formula (III) as a raw material.

In carrying out the reaction, use 3 equivalents or more of water relative to the raw material compound, and if necessary, use a solvent miscible with water, such as formic acid, acetic acid, or an ether solvent such as dioxane or dimethoxyethane, as a co-solvent. can do.

The reaction can be carried out at room temperature to 150°C, but at approximately 10°C.
The process is preferably carried out at 0°C or the reflux temperature of the solvent.

Hereinafter, the present invention will be explained in more detail with reference to comparative examples, reference examples, and examples.

Comparative Example Sodium cyanide 0.2899 to dry dimethyl sulfoxide 3.2! 1 and heat to 60°C to dissolve.

To this solution was added 0.59 g of (1-bromoethyl) phenylchenyl ketone synthesized according to the method described in JP-A No. 49-93346, and further 4.
Stirred for 5 hours.

Thereafter, the reaction mixture was worked up in the same manner as in Example 17 of JP-A-49-93346, and the crude product was purified by silica gel column chromatography.

As a result, the yield of the target (1-cyanoethyl) phenylchenyl ketone was 0.12 g (yield 25%).
There was a time.

At the same time, 0.22g of 2,3-di(4-(2-thenoyl)phenyl)-2-methylbutyronitrile, a by-product.
(Raw material consumption rate: 48%).

Nuclear magnetic resonance absorption spectrum of by-product (deuterochloroform) One diastereoisomer: δ795-7.0 (m.

14H), 3.25 (q, IH), 156 (s, 3H)
, 1.29 (d, 3H).

Other diastereoisomer: δγ9-6.95 (m.

14H), 3.22 (q, IH), 1.90 (s, 3
H), 1.60 (d, 3H).

Reference example 1 Ethylbenzene 20TLl and 2-thenoyl chloride 73
Mix 3g of powdered anhydrous aluminum chloride at room temperature.
g was added little by little.

After the addition was completed, stirring was continued for another 2 hours at room temperature, and then the reaction mixture was poured into ice water and extracted with ether.

The ether layer was washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate, and brine, and then dried.

After filtering, concentrating and distilling the crude product under reduced pressure,
8.97 g of 4-(2-thenoyl)ethylbenzene having a boiling point of 144-145°C/0.3 tnrnHg was obtained.

Yield: 83. Nuclear magnetic resonance absorption spectrum of product (carbon tetrachloride): δ7.8-7.4 (m, 4H),
7.35-6.9 (m, 3H), 2.65 (q, 2
H), 1.17 (t, 3H).

Reference Example 2 2.4 g of 4-(2-thenoyl)ethylbenzene and 51 rLl of ethyl orthoformate were dissolved in absolute ethanol,
Three drops of concentrated sulfuric acid were added.

This solution was heated to reflux with stirring for 10 hours.

After cooling, the mixture was neutralized by adding powdered sodium carbonate, concentrated under reduced pressure, and the residue was poured into aqueous sodium bicarbonate and extracted with ether.

The ether layer was washed with brine and then dried over anhydrous sodium carbonate.

After filtration and concentration, the crude product was distilled under reduced pressure to a boiling point of 117°C.
/ 0.2 mmHg (4-ethylphenyl)
2.935g of (2-chenyl)jethoxymethane was obtained.

Yield: 91. Nuclear magnetic resonance absorption spectrum of product (carbon tetrachloride): δ7.5-6.9 (m, 5H),
6.9-6.7 (m.

2H), 3.35 (q, 4H), 2.62 (q.

2H), 1.22 (t, 3H), 1.20 (t.

6H).

Reference example 3 (4-ethylphenyl)(2-f-enyl)jethoxymethane 1.45g and N-bromosuccinimide 0.98g
g was mixed with 10 ml of carbon tetrachloride, and benzoyl peroxide (30 ml immediately) was added thereto.

The mixture was heated under an argon atmosphere and continued stirring at 80° C. for 1 hour.

After cooling, sulfur carbonate powder was added and stirred for a while, then insoluble matter was filtered, and the filtrate was concentrated under reduced pressure.
845 g of (4-(1-bromoethyl)phenyl, 1(
A crude product of 2-chenyl)jetoxymethane was obtained.

Nuclear magnetic resonance absorption spectrum of bromide (carbon tetrachloride): δ
7.44 (d, IH), 7.27 (d, I
H).

7.07 (t, LH), 6.78 (d, 2H).

5.05 (q, LH), 3.32 (q, 4H).

' 1.97 (d, 3H), 1.18 (t, 6H
).

Example 1 Dry dimethyl sulfoxide 7,5 rul! 7257 to
'nI? of sodium cyanide and heat to 60°C to dissolve.

To this solution, add 1.785 g of crude raw material obtained in Reference Example 3.
A solution dissolved in 1 ml of dry dimethyl sulfoxide was added to 6
It was quickly added dropwise at 0°C, and heating and stirring were continued for about 1 hour.

After cooling, the mixture was poured into water, extracted with ether (3 times), and the ether layer was washed with water and brine, and then dried over anhydrous magnesium sulfate.

After filtration, the filtrate was concentrated and the crude product was purified by silica gel column chromatography to obtain 960
4-(1-cyanoethyl)phenyl](2-chenyl)
Jetoxymethane was obtained.

Yield 63% through bromination and cyanation.

Nuclear magnetic resonance absorption spectrum of by-product (carbon tetrachloride):
δ7.50 (d, 2H), 7.19 (d, 2H).

7.06 (t, IH), 6.79 (d, 2H).

3.71 (q, IH), 3.30 (q, 4H) 1.53
(d, 3H), 1.37 (t, 6H) obtained (4-
317 ml of (1-cyanoethyl)phenyl(2-fenyl)jethoxymethane was dissolved in 1 ml of dioxane.

4 ml of 50% sulfuric acid was added to this solution, and heating under reflux was continued for 2 hours while stirring.

4 ml of the drained water was newly added, and the mixture was further heated under reflux with stirring for 2 hours.

After cooling, a large amount of water was added and extracted with ethyl acetate, and the organic layer was washed with brine and dried.

After filtration and concentration, 245 m9 of crude product was obtained.

This product was recrystallized from acetonitrile to obtain 220 μm of α-methyl-4-(2-thenoyl)phenylacetic acid.

Yield: 85. Melting point: 120-121°C Nuclear magnetic resonance absorption spectrum of product (deuterochloroform): δ11.5 (s, IH), 7.77 (d.

2H), 7.62 (d, IH), 7.57 (d, IH)
), 7.43(d, 2H).

7.07 (t, IH), 3.79 (q.

IH), 1.53 (d, 3H).

Reference example 4 4-(2-thenoyl)ethylbenzene 1. ．． Dissolve 1g in 10ml of dry benzene and add ethylene/7"
2 ml of IJ cole was added, and further 10 mg of p-toluenesulfonic acid was added, followed by heating and stirring.

Water produced as the reaction progressed was removed to the outside of the thread using a Dean-Stark type reactor.

After reacting overnight, the reaction mixture was poured into aqueous sodium bicarbonate and extracted with ether.

The ether layer was washed with water and brine, dried, filtered, and concentrated to give 1.29 g of 2-((4-ethylphenyl)(2
-chenyl))-1,3-dioxolane was obtained.

Boiling point: 173-174°C/1.2 mmHg Reference Example 5 1.23 g of the product obtained in Reference Example 4 and 925~ of N-bromosuccinimide were mixed in 10 ml of carbon tetrachloride, and 20 mg of benzoyl peroxide was added. added.

The mixture was heated to reflux under an argon atmosphere for about 3 hours.

After cooling, about 5 ml of dry hexane was added, and insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 1.55 g.
2-((4-(1-bromoethyl)phenyl))(2-
Chenyl)))-L3-dioxolane was obtained.

Nuclear magnetic resonance absorption spectrum of product (carbon tetrachloride): δ
7.43 (d, 2H), 7.32 (d,
2H).

7.10 (m, IH), 6.9-6.7 (
m, 2H) 5.03 (q, IH), 4.
15-3.7 (m.

4H), 1. ．． 94(a, 3H).

Example 2 150 g of the product obtained in Reference Example 5 was dissolved in dry dimethyl sulfoxide 2rd.

This solution was quickly added dropwise to 2 ml of dry dimethyl sulfoxide in which 0.5 g of thorium cyanide had been dissolved, which had been preheated to 90°C.

After continuing to heat and stir for about 40 minutes, the same post-treatment as in Example 1 was performed.

The crude product was purified by silica gel column chromatography to obtain 0.74 g of 2-((4-(1--fj
','ethyl))phenyl)(2-chenyl))-1,
3-dioxolane was obtained.

Yield of 57 through bromination and cyanation.

Nuclear magnetic resonance absorption spectrum of product (carbon tetrachloride): δ
7.52 (d, 2H), 7.20 (d, 2H)
.

7.15 (m, IH), 6.9-6.65
(m.

2H), 4°15-3.8 (m, 4H),
3.73 (q, IH), 1.47 (d, 3H).

Example 1 using the obtained cyano compound 2857719
The same operation as above was carried out to obtain α-methyl-4-(2-thenoyl)phenylacetic acid 2057/19.

Yield 79%.

Claims (1)

[Claims] 1. A halide represented by the general formula is reacted with a metal cyanide in an aprotic polar solvent to obtain a cyanide compound represented by the general formula, and then in the presence of a mineral acid,
A method for producing substituted phenylacetic acid represented by the general formula, which is characterized by hydrolyzing this cyano compound [wherein R is an alkyl group, or the three R's together form an alkylene group, and R1 is a lower It is an alkyl group, and Y is a halogen atom. ].