JPS5946498B2 - Method for producing α-aromatic group substituted ester - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula Arcoo1CHC(R2-(I), where Ar is a phenyl group or thienyl group, and Y is CH=
CH or S, and R and R2 are lower alkyl groups.

) The present invention relates to a method for producing an α-monoaromatic group-substituted ester represented by: Many of the corresponding carboxylic acids obtained by hydrolysis of the compound represented by the general formula (I) according to the present invention, in which R is a methyl group, have anti-inflammatory, analgesic or antipyretic effects. It is a so-called profen anti-inflammatory analgesic. For example α−
(benzoylphenyl)propionic acid, α-(5-
benzoyl-2-thienyl)propionic acid and α-[p
-(2-thienylcarbonyl)phenyl]propionic acid is currently used medicinally as ketoprofen, thioprofenic acid and suprofen. Hitherto, many methods for producing α-aromatic group-substituted propionic acid or its derivatives have been proposed, and a typical process is as follows, taking ketoprofen as an example.

1) Synthesize (benzoylphenyl)acetonitrile by the reaction of (bromomethyl)benzophenone and sodium cyanide, and react with diethyl carbonate in the presence of sodium ethoxide to produce α-cyano (benzoylphenyl). Use it as the sodium salt of ethyl acetate.

The reaction of this sodium salt with methyl iodide yields ethyl α-cyano α-(benzoylphenyl)propionate, which is hydrolyzed and subjected to a decarboxylation reaction to produce α-cyano α-(benzoylphenyl)propionate.
Synthesize (benzoylphenyl)probionitrile. A method for producing α-(m-benzoylphenyl)propionic acid by alkaline hydrolysis of this α-(benzoylphenyl)probionitrile [British Patent No. 11
64585 (1969)]. 2) Produce α-(m-carboxyphenyl)propionitrile by reacting pensain generated from 2-chlorobenzoic acid in the presence of a stronger base with propionitrile [R. Biehl, J. Org. C
hem. , J”, 602 (1966).

]. This α-(m-carboxyphenyl)propionitrile is converted to α-(m-chlorocarbonylphenyl)propionitrile using thionyl chloride. Friedel-Crafts reaction of α(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride yields α-(m-benzoylphenyl)propionitrile. A method for producing α-(m-benzoylphenyl)propionic acid by hydrolyzing this α-(m-benzoylphenyl)propionitrile with methanol and sodium monohydroxide (Japanese Patent Publication No. 52-8301). However, this method 1) uses highly toxic sodium cyanide during the production of (m-benzoylphenyl)acetonitrile, and is therefore not suitable as an industrial production method. Furthermore, method 2) requires harsh reaction conditions during the production of α-(m-carboxyphenyl)propionitrile and has a low yield. The inventors of the present invention have made extensive studies to overcome such drawbacks.
A readily available general formula (wherein Ar.Y, .R and R2 are the same as above, and R1 is a lower alkyl group or a phenyl group).

) We have established a method to selectively reduce and desulfurize only the α-thio (RlS) group without reducing the acyl (ArCO) group, leading to the desired compound using the α-thioester represented by , and completed the present invention. This is what I have come to do. The starting compound () of the present invention can be produced according to the following formula.

First step (→) This step involves reacting an aromatic aldehyde with formaldehyde mercaptal S-oxide in the presence of a base.

If desired, common organic solvents such as dimethylformamide, dioxane, methanol, ethanol, benzene, etc. can be used as reaction solvents. The base is preferably a base such as sodium hydride, potassium t-butoxide, Triton B, sodium hydroxide, potassium hydroxide, etc. In this case, the reaction proceeds smoothly at room temperature to 150°C. Second Step (→) In this step, the ketene mercaptal S-oxide (5) obtained in the above step is reacted with thionyl chloride.

In carrying out this step, the raw materials are used in approximately equimolar amounts, and preferably methylene chloride, chloroform,
The reaction is carried out in an aprotic solvent such as tetrahydrofuran, ether, or benzene. The reaction is smoothly carried out at a temperature of -100° C. to room temperature, but from the viewpoint of ease of operation, the temperature is preferably -30° C. to room temperature. Further, it is preferable that a base be present in order to capture by-produced hydrogen chloride. As the base, organic bases such as diethylamine, cyclohexylamine, pyridine, and triethylamine can be suitably used. Third step (→) This step combines α-chloroketene mercaptal formed in the previous step with the general formula R2OH (wherein R2 is a lower alkyl group).

) in the presence of an acid is an essential requirement. As the acid, inorganic acids such as sulfuric acid, perchloric acid, hydrogen chloride, and hydrogen bromide, and organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, and trichloroacetic acid can be suitably used. The amount of acid used is sufficient to be the so-called contact amount. In carrying out the third step, there is no problem in using a solvent that does not participate in the reaction, but an excess amount of alcohol used as a reaction reagent can be used as a solvent.

Although the reaction proceeds smoothly at a temperature of room temperature to 150° C., it is preferable to carry out the reaction at the reflux temperature of the reaction system from the viewpoint of ease of operation. Fourth step (→) This step consists of the α-aromatic group-substituted α obtained in the previous step.
-thioacetic acid ester (VO (wherein R2 is a lower alkyl group).

) is reacted with an alkylating agent in the presence of a base. Examples of the base used include metal hydrides such as sodium hydride and potassium hydride, organic thio compounds such as methyllithium, butyllithium and lithium diethylamide, alkali metal amides such as sodium amide, and naphthalene-sodium. Further, as the alkylating agent, alkyl halides such as alkyl iodides, active alkyl esters such as dialkyl sulfates, trialkyl phosphoric acids, alkyl fluorosulfonates, etc. can be used. The base and alkylating agent are used in approximately equimolar amounts relative to the starting compound, and it is preferable to use an aprotic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, or 1,2-dimethoxyethane in carrying out the reaction. The reaction proceeds smoothly at 0 to 100°C. The method of the present invention converts α-thioester represented by the general formula () into thiolade (
R3S-M+, where R3 is a lower alkyl group or a phenyl group.

) is an essential requirement. Thiolades include alkali metal salts of mercaptans and thiophenols such as sodium methyl mercaptide, sodium ethyl mercaptide, sodium thiophenolate, etc., and the amount used is determined according to the above general formula () which is the raw material compound. It is sufficient to use approximately equimolar amounts. Furthermore, as the alcohol, readily available alcohols commonly used in industry, such as methanol and ethanol, can be used.

An equimolar amount of alcohol is sufficient, but an excess amount may be used in combination as a solvent. In carrying out the reaction, if desired, a solvent that does not directly participate in the reaction, such as diethyl ether, tetrahydrofuran, dioxane, etc., may be used without using an excess amount of alcohol.

Although the reaction proceeds without using any special heating or cooling means, the reaction can be accelerated by heating. In addition, since the conditions of the present invention are alkaline, the produced α
Monoaromatic group-substituted esters may be hydrolyzed to partially give the corresponding carboxylic acid.

This carboxylic acid can be converted back into an ester using a conventional method (acid-alcohol combination), but when it is desired to finally obtain a carboxylic acid, it is sufficient to perform alkaline hydrolysis without subjecting the reaction mixture to a single operation; This is one embodiment of the present invention. Under the above conditions, the reaction proceeds smoothly and the target compound can be produced in high yield; however, when the method of the present invention is applied to other compounds that are not substituted with an acyl group, harsh reaction conditions are required. As a result, side reactions occur and completely satisfactory results cannot be obtained.

That is, the feature of the present invention lies in the use of the raw material compound () specified in the present invention, that is, an α-thio-α monoaromatic group-substituted ester derivative substituted with an acyl group. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference Example 1 902η of m-benzoylbenzaldehyde was dissolved in formaldehyde dimethylmercaptal S-oxide 1d, 60 mg of sodium hydroxide was added, and the mixture was heated and stirred at 95° C. for 70 minutes under an argon atmosphere.

Add 20ml of water and extract with methylene chloride (50d, 30ml
1) and the organic layer was dried over anhydrous sodium sulfate. Concentrate under reduced pressure and separate the residue using column chromatography (silica gel, methylene chloride) to obtain 1-methylsulfinyl-1-methylthio-2-(m-benzoylphenyl).
1.035 g of ethylene was obtained as an oil. Yield 76
(F6OIR(Neat): 1657(s), 1320
, 1290, 1065, 723, 711cTn-1NM
R(CDCl3): δ2.30(S,3H), 2.76
(S, 3H), 7.69 (S, lH), 7.3-7.9
(M, 7H), 8.07 (DOft, J=7.0, 1.
5Hz, 1H), 8.28 (DJffuseds, 1H)
). MS (70eV): m/E3l6(2,M+),3
00(9), 253(90), 238(45), 161
(21), 133 (16), 105 (100). Reference example 2 1-methylsulfenyl-1-methylthio-2-(m-
4.48 g of (benzoylphenyl)ethylene was dissolved in 20 ml of methylene chloride, 37.11 pyridine was added thereto, and a solution of 1.86 g of thionyl chloride in methylene chloride (3d) was added dropwise over 5 minutes with stirring under ice cooling.

After stirring for another 30 minutes under ice cooling, methylene chloride 20
ml was added and washed with water (101n1 x 3 times). After drying over anhydrous sodium sulfate, concentrate under reduced pressure and subject the residue to column chromatography (Florisil, hexane and benzene).
1,1-bis(methylthio)-2-chloro-2-(m-benzoylphenyl)ethylene 3.5
74 g was obtained as colorless crystals. Yield 75%0m. p. :
94-96°C (from methanol). R (KBr): 16
55, 1295, 1215, 760, 720, 650C
f1L-1. NMR (CDCl3): δ2.14 (S,
3H), 2.41 (S, 3H), 7.3-7.9 (M.
9H). Calculated value as Cl7Hl5CIOS2: C, 6O. 97; H, 4.52; S, l9. l
5%, measured value: C, 6O. 88:H, 4.56:S, l
9.27%. Reference example 31,1-bis(methylthio)-
2-chloro-2(m-benzoylphenyl)ethylene 3
．． 20 ml of anhydrous methanol was added to 429 g, and 0.3 ml of hydrogen chloride saturated methanol solution was added thereto, followed by heating under reflux for 7 hours.

After concentrating under reduced pressure, the residue was separated by column chromatography (silica gel, benzene and methylene chloride), and 1.080 g of oil (A) was obtained from the benzene fraction and α-methylthio (m-benzoyl fluoride) from the methylene chloride fraction. 2.175 g of methyl (enyl)acetate was obtained. The oily substance (A) was separated again by column chromatography (silica gel, benzene) to obtain 299 methyl α-methylthio(m-benzoylphenyl)acetate. Total capacity 81%. IR(Nea
t): 1740, 1660, 1280, 1150, 71
0c! n-1 NMR (CDC3): δ2,06(S,3
H), 3.70 (S, 3H), 4.52 (S, lH),
7.3-7.9 (M, 9H). Calculated value as Cl7Hl6O3S: C, 67.97:H, 5.37:S, lO.
68%. Measured value: C, 67.84: H, 5. l9:S,
lO. 5Of). Reference example 4α-Methylthio(m-benzoylphenyl)methyl acetate 450W19 was dissolved in anhydrous dimethyl sulfoxide 3a, and sodium hydride 65 (containing 65(!)) was added on a 15°C water bath and stirred for 15 minutes. 0.15 ml of methyl chloride was added dropwise.

After stirring for another 5 minutes, ammonium chloride aqueous solution (0.5
g/20T1I0 was added and extracted with ether (20TILI
x3 times) and washed with water (10ml). After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure and purified by column chromatography (silica gel, benzene methylene chloride) to obtain colorless methyl α-methylthio-α-(m-benzoylphenyl)propionate 402η. Obtained as an oily substance. Samples for elemental analysis and physical property measurement with a yield of 85% are:
This was subjected to simple distillation [170~18'C (bath temperature)/0.01T]
0rr]. N25l. 593
4. D I R (Neat): 1730, 1660, 1600, 14
50, 1320, 1285, 1245, 1210, 71
5,700,645 (7n-1 NMR (CDCl3):
δ1.84 (S, 3H), 2.02 (S, 3H), 3.
79(S,3H), 7.4-8.0(M.9H)・Cl
Calculated value as 8Hl8O3S: C, 68, 76: H, 5
．． 77; S, lO. 20%. Measured value: C, 68, 57:
H, 5.96; S, lO. Ol(f). Example 1α-
Methylthio-α-(m-benzoylphenyl)propionate 314~ is dissolved in 1 ml of anhydrous methanol,
To this was added 1.0 ml of a methanol solution (2.34 M) of the sodium salt of methyl mercaptan, and the mixture was heated under reflux for 2.5 hours.

Next, for the purpose of hydrolyzing the ester, 100 η of sodium hydroxide and 0.5 ml of water were added to the mixture, and the mixture was further heated under reflux for 30 minutes. After diluting with 20ml of water, add concentrated hydrochloric acid and P
Hl and then ether extraction (30Tn1, then 10m
After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the oily residue was purified by column chromatography (silica gel, methylene chloride) to obtain α-(m-benzoylphenyl). ) Propionic acid 2247
! ! F7 was obtained as colorless crystals. Yield 88% 0m-p・
:95~96! C (from hexane-ether). 1R (
KBr): 3300-2500, 1700, 1655,
1290, 1230, 970, 715, 705, 690
cr11-1NMR (CDCl3): δ1.52 (D,
J=7Hz, 3H), 3.77(Q, J=7Hz, 1H
), 7.3-7.8 (M, 9H), 11.6 (BrOa
ds, lH). Calculated value as Cl6Hl4O3: C, 7
5.57; H, 5.55%. Measured value: C, 75.53;
H, 5.6l%. Example 2 α-methylthio-α-(m
-Methyl mercaptan (benzoyl phenyl) propionate 628 ~ was dissolved in 271 L of anhydrous methanol, and a methanol solution of the sodium salt of methyl mercaptan (2.34 M
) was added thereto, and the mixture was heated under reflux for 1.5 hours.

After cooling, ammonium chloride aqueous solution (2.0g/10ml
) was added to stop the reaction, diluted with 10 ml of water, and extracted with ether (30 ml, then 10 ml x 2).
The extract was washed with 20 ml of saturated aqueous sodium bicarbonate solution, then with 5 ml of water, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel, methylene chloride) to obtain α-(m-
Methyl benzoyl phenyl propionate 363W! 9
was obtained as a colorless oil. Yield: 68% o A sample for elemental analysis was prepared by simple distillation [150-1600C (bath temperature)/0.
01T0rr]. NoR (Neat): 1740
,1660,1600,1450,1320,1290
,1210,1165,720,705,645cm-
1NMR (CDCI3): δ1.51 (D, J = 7Hz
, 3H), 3.66 (S, 3H), 3.78 (Q, J27Hz, lH), 7.3-7.9 (M, 9H). Cl7
Calculated value as Hl6O3: C, 76. lO; H, 6. Ol%. Measured value: C
, 75.93; H, 6. O9%. Also, combine the washing liquid,
After making PHL with concentrated hydrochloric acid, ether extraction (20ml,
Next, the mixture was washed with water (10 ml x 2 times), washed with water (10 ml of anhydrous sodium sulfate, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 34η (7%) of α-(m-benzoylphenyl)pcapionic acid.

Example 3 Methyl α-methylthio-α-(m-benzoylphenyl)propionate 221Tf19 was added to 2ml of anhydrous methanol.
Dissolved in 0.20 ml of thiophenol and 0.20 methanol solution of sodium methoxide (2.53M)
m1 was added thereto, and the mixture was heated under reflux for 48 hours under an argon atmosphere.

After adding ammonium chloride aqueous solution (0.5g/30m0), extraction with ether (20ml x 2) was performed. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, the residue was applied to a silica gel column, and excess thiophenol was eluted with benzene. Then, when eluted with methylene chloride, a colorless oily substance 11
I got 2~. NMR revealed that this product was a mixture of methyl α-(m-benzoylphenyl)propionate and the raw material methyl α-methylthio-α-(m-benzoylphenyl)propionate, and the mixing ratio [ 122:25 (molar ratio)], the yield of methyl α-(m-benzoylphenyl)propionate was calculated to be 48%. Example 4 288 ~ of methyl α-methylthio-α-[p-(2-thienylcarbonyl)phenyl]propionate was dissolved in 1 ml of anhydrous methanol, and 1.0 ml of a methanol solution (2.34 M) of the sodium salt of methyl mercaptan was added. The mixture was stirred at room temperature for 1 hour, then heated to reflux for 30 minutes.

After cooling, ammonium chloride aqueous solution (1.5g/20ml
) and methylene chloride extraction (20ml, then 10WL)
IX twice). The organic layer was washed with 20 ml of a saturated aqueous solution of sodium bicarbonate, then with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain α
-Methyl [p(2-thienylcarbonyl)phenyl]propionate 117W9 (yield 47%) was obtained. The aqueous layer and washings were combined, acidified (PHI) by adding concentrated hydrochloric acid, and then extracted with ether (15ml x 3 times). The extract was washed with water (10d), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain α-[p-(2-thienylcarbonyl)phenyl]propionic acid 120η (yield 51(
Ff)) was obtained. Example 5 α-methylthio-α-[p
-(2-Thienylcarbonyl)phenyl]Methyl propionate (499η) was dissolved in 2d of anhydrous methanol, and a methanol solution of sodium salt of methyl mercaptan (2.3
1.5 ml of 4M) was added and heated under reflux for 2.5 hours.

Next, for the purpose of hydrolyzing the ester, sodium hydroxide 4
00Tn9 and 2 ml of water were added and the mixture was heated under reflux for 3 hours. After diluting with 20a of water, extraction with methylene chloride (10a
m1). The aqueous layer was made into PHL by adding concentrated hydrochloric acid, extracted with methylene chloride (20d x 3 times), and washed with water (10m0
did. After drying with anhydrous magnesium sulfate, concentrate under reduced pressure to α
405 mg of -[p-(2-thienylcarbonyl)phenyl]propionic acid was obtained. Yield 99.901). M. p
．． :125-126℃ (from acetonitrile; literature value 1
24.31CIR(KBr):3200-2800,1
735, 1605, 1420, 1410, 1365, 1
355, 1320, 1235, 1055, 865, 74
0,7150f1L-1. NMR (CDCl3): δ1
．． 53 (D, J = 7Hz, 3H), 3.89 (Q, J =
7Hz, 1H), 7.08 (DOfd, J=4Hz, 5
Hz, 1H), 7.40, 7.79 (A2B2q, J=
8Hz), 7.5~Z8(M, 2H), 8.7(BrO
ads, lH) Calculated value as Cl4Hl2O3S: C, 64.59: H, 4.65; S, l2.3
2%. Measured value: C, 64.64: H, 4.66: S, l
2.40%. (Reference) P. G. H. VanDaele,
J. M. Boey, V. K. SipidO, M. F. L
．． DeBruyn, P. A. J. JansSen, Ar
zneim-FOrsch. (DrugRes.)25
, 1495 (1975). Example 6 α-methylthio-
Dissolve 320 g of methyl α-(5-benzoyl-2-thienyl)propionate in 1 ml of anhydrous methanol, and add a methanol solution of sodium salt of methyl mercaptan (
1.0 ml of 2.34M) was added and heated under reflux for 1 hour.

Claims (1)

[Claims] 1. Treating an α-thioester represented by the general formula ▲numerical formula, chemical formula, table, etc.▼ with a thiolate represented by the general formula R^3S^-M^+ in the presence of an alcohol. Method for producing an α-aromatic group-substituted ester represented by the characteristic general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Ar is a phenyl group or thienyl group, Y is CH=
CH or S, R^1 and R^3 are lower alkyl groups or phenyl groups, R and R^2 are lower alkyl groups, and M is an alkali metal. ]