JPS5951953B2 - α-thio-α-(2-thienyl)carboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula Y□+-CooR2-(I) [wherein R and R2 are hydrogen or an alkyl group, R1 is a lower alkyl group, and Y is an acyl group or an acetal group] It is a protected acyl group.

] This relates to an α-thio α-(2-thienyl)carboxylic acid derivative represented by the following. Although the compound represented by the general formula (I) is a novel compound unknown in the literature, it is useful as a pharmaceutical intermediate.

That is, the compound represented by the general formula (I) is subjected to reductive desulfurization treatment and optionally hydrolyzed to obtain α-(2-thienyl)carboxylic acid represented by the general formula Y□H-CooH-(■). derivatives can be derived.

(See reference example below). A compound represented by the general formula (■) in which Y is an acyl group is, for example, α-(5-benzoyl-2
-Thienyl) propionic acid is known to have remarkable anti-inflammatory and analgesic effects. These general formulas (■)
A comparison with known synthetic methods of the compound is as follows, taking α-(5-benzoyl-2-thienyl)propionic acid as an example. So far α-(5-benzoyl-2
-Thienyl)propionic acid is produced by α-(2
A method of benzoylating (thienyl) propionic acid with benzoyl chloride in the presence of aluminum chloride has been proposed (Japanese Patent Publication No. 49-24915). α of raw material in this method
Mono(2-thienyl)propionic acid is produced in the following order. That is, (2-thienyl)acetonitrile obtained by the reaction of 2-(chloromethyl)thiophene and sodium cyanide is reacted with diethyl carbonate in the presence of metallic sodium to synthesize α-cyano(2-thienyl)ethyl acetate. [in, Pettersson. Acta, Chem
, Scand, 7, 1311 (1953) lo This was then methylated with methyl iodide in the presence of sodium ethoxide, and then hydrolyzed with ethanol-potassium hydroxide to produce α-(2-thienyl). Decarboxylation of -α-cyanopropionic acid to obtain α-(2-thienyl)propionitrile. By hydrolyzing this α-(2-thienyl)propionitrile with ethanol-potassium hydroxide, α-(2-thienyl)propionic acid can be produced [M. Berc, Ot-Vatter
Oni, R. C. MoreanetP. Reynavd
．． Bvll. SOc. Chim. France. l82
0 (1961). ]. The first raw material for this method, 2-
(Chloromethyl)1thiophene is synthesized by chloromethylation of thiophene [F. F. Blickea
ndF. LeHonord. J. Amer. Chem. S
Oc. , 68, l934 (1946). ], in this case carcinogenic bis(chloromethyl)ether is produced as a by-product. is known to occur.

Also, the yield of this chloromethylation is low (47%). Additionally, 2-(chloromethyl)thiophene has been reported to be explosive. Then, when converting this into (2-thienyl)acetonitrile, the use of highly toxic sodium cyanide is unavoidable. Therefore, it can be said that this conventional method is difficult to implement industrially. As a result of intensive studies aimed at solving these drawbacks, the inventors of the present invention have discovered the compound of the present invention, which can be safely and in high yield produced into a useful compound using a thiophene aldehyde derivative as a raw material.
The compounds of the present invention can be prepared according to the following formula. (In the formula, R1 is a lower alkyl group, R2 is hydrogen or an alkyl group, R3 is an alkyl group, and Y is an acyl group or an acyl group protected with an acetal.

) Step A This step consists of combining a thiophene aldehyde derivative with the general formula RISCH2SORl (wherein R1 is a lower alkyl group).

) with formaldehyde mercaptal S-oxide in the presence of a base.

In this reaction, common organic solvents such as dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, and benzene can be used as reaction solvents. Formaldehyde mercaptal S used as raw material
- When the oxide is a liquid substance, the reaction proceeds smoothly even without the use of a solvent. Further, as the base, relatively strong bases such as sodium hydride, potassium hydride, Triton B, sodium hydroxide, potassium hydroxide, etc. are preferable. The reaction temperature is room temperature to 150°C, but the reaction temperature is 50 to 150°C.
10°C is particularly suitable. Under the above reaction conditions, the general formula (
ketene mercaptal S-oxide can be formed.

Step B This step involves reacting the compound of general formula (B) with an acid chloride.

Examples of acid chlorides include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, acetyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, etc.; Thionyl chloride and phosphorus oxychloride are preferred from the viewpoint of high yield.

In carrying out this step B, the raw materials are used in approximately equimolar amounts, and the reaction is preferably carried out in an aprotic solvent such as methylene chloride, chloroform, tetrahydrofuran, ether, or benzene. The reaction is carried out smoothly at -100°C to room temperature, but preferably at -80°C to room temperature from the viewpoint of easy operation. Further, it is preferable that a base be present in order to capture hydrogen chloride produced as a by-product in step B. As the base, organic bases such as diethylamine, cyclohexylamine, pyridine, and triethylamine can be suitably used. The compound formed in Step B has the general formula (where R1 is a lower alkyl group and Y is an acyl group or an acyl group protected with an acetal).

α-chloroketene mercaptal represented by ) can be isolated or subjected to step C as a crude product without being completely isolated. Step C In step C, a compound represented by the general formula ([V)] and the general formula R2OH (wherein R2 is an alkyl group) are used.

) 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 so-called contact amount of acid is sufficient. In carrying out this 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.

By the above operation, α-thio-
α-(2-thienyl)carboxylic acid ester derivatives can be formed. In addition, in this step, general formula (5)
When Y in is an acyl group, this carbonyl moiety partially reacts with alcohol to form an acetal derivative, but it can be easily converted to a carbonyl group by acid hydrolysis.

Furthermore, if desired, the carbonyl form and the acetal form may be subjected to Step D without being separated, and then subjected to acid hydrolysis treatment. Furthermore, the carbonyl form formed in this step may be converted into an acetal form by a conventional method and subjected to Step D. The esters can, if desired, be converted to the corresponding carboxylic acids by alkaline hydrolysis. Step D This step involves reacting a compound of the general formula (IY) 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, naphthalene-sodium, and the like. Further, as the v-rulating agent, an alkyl halide such as methyl iodide, or an active alkyl ester such as dimethyl sulfate, trimethyl phosphoric acid, methyl fluorosulfonate, etc. can be used. When R2 is an alkyl group in the general formula (IY), the base and alkylating agent are used in approximately equimolar amounts based on the starting compound, and when R2 is hydrogen, it is sufficient to use 2 equivalents of the base.Reaction In carrying out, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,2
- It is preferred to use an aprotic solvent such as dimethoxyethane, and the reaction proceeds smoothly at temperatures between 0 and 100°C.
The above reaction forms an α-thio-α-(2-thienyl)carboxylic acid derivative (IY, but if desired, the ester can be converted to the corresponding carboxylic acid by alkaline hydrolysis. .

Alkaline hydrolysis in steps C and D can be easily carried out by using potassium carbonate or sodium hydroxide in an equivalent molar amount or more based on the raw material compound, and using water, alcohol, water-1,2-dimethoxyethane or water-tetrahydrofuran as the solvent. can be achieved. Under the above conditions, a desired α-thio-α-(2-thienyl)carboxylic acid derivative represented by the general formula (1) can be formed. The present invention will be explained in more detail below with reference to Reference Examples and Examples.

Reference example 1 1-(methylthio)-1-(methylsulfinyl)-
2.27 g (7.05 mm) of 2-(5-benzoyl-2-thienyl)ethylene was added to 20 g of anhydrous toluene.
After adding dissolved cal and 1.0 g (12 mm) of pyridine to the solution, add 1.101 g (12 mm) of thionyl chloride while stirring under ice-cooling.
．． A toluene solution (5 mm) of 25 mm 01) was added dropwise over 5 minutes.

After further stirring for 15 minutes under ice-cooling, the mixture was diluted with 50 g of benzene and washed with water (15 g. x 3 times). After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure and purified by column chromatography (Florisil, benzene-methylene chloride) to give 1,1-bis(methylthio)-2-chloro-
2.21 g of 2-(5-benzoyl-2-thienyl)ethylene was obtained as pale yellow crystals. Yield 92%. M.
p. :69-70℃ (from isopropyl alcohol) I
R (KBr): 1625, 1490, 1425, 130
0,865,810,720cm-1NMR (CDCl
3): δ2.31 (S, 3H), 2.46 (S,
3H), 7.3-7.6 (M, 5H), 7.7-7
．． 9(M,2H)C,, Calculated value as Hl3ClOS2: C, 52.84; H, 3.84; S, 28.2
2; Cl, lO. 4O% measured value: C, 52.82; H,
3.72; S, 28. l5; Cl, lO. 36% Example 1 1,1-bis(methylthio)-2-chloro-2-( 5
-benzoyl-2-thienyl)ethylene 341m9 (
Add 5 g of anhydrous methanol to 1.00 mm (0.1 mm), and then add 0.1 g of a saturated methanol solution of hydrogen chloride to 6 g.
The mixture was stirred at 0°C for 10 hours.

The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, benzene) to obtain methyl 290~ of α-methylthio(5-benzoyl-2-thienyl)acetate as an oily substance. Samples for elemental analysis were subjected to simple distillation [200°C (bath temperature) / 0.03 mmHg]
I got it. Yield 95%. IR(Neat):1740,
1635, 1455, 1295, 1155, 870, 7
20,700CffLNMR (CDCl3): δ2.
12 (S, 3H), 3.62 (S, 3H), 4.7
6 (S, IH), 7.12 (D, J= 4Hz, I
H), 7.3 ~ -7.6 (M, 4H), 7.7 ~
Calculated value as 7.9(M,2H)C,,Hl4O3S2: C: 58.80; H: 4.61; S: 20.93
% measured value: C; 58.94: H: 4.56; S: 2
0.99% Example 21,1-bis(methylthio)-2
-Chloro-(5-benzoyl-2-thienyl)ethylene 1.8319 (5.37 mm01) was added with 20 g of anhydrous methanol, and then hydrogen chloride saturated methanol solution 0.0 g was added.
After adding 2 oz., the mixture was heated under reflux for 5 hours.

To this was added 4.0 g of methyl orthoformate, and the mixture was further heated under reflux for 3 hours. The reaction solution was ice-cooled, and 20 g of a saturated aqueous solution of sodium bicarbonate was added, followed by 20 g of water, extracted with ether (20 g x 3 times), and washed with water (10 g). After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure and purified using column chromatography (Florisil, benzene) to obtain α-methylthio[5-(α,α-dimethoxybenzyl)-2-thienyl]acetic acid. Methyl 1.3
159 was obtained as a clear oil. Yield 70%. IR
(Neat): 2825, 1740, 1250, 119
0,1170,1155,1085,1060,765
,705CgLNMR (CDCl3): δ2.10(S,3H),3.1
8 (S, 6H), 3.76 (S, 3H), 4.70 (
S, IH), 6.75 (D, J= 4Hz, IH),
6.95 (D, J= 4Hz, IH), 7.2~7
．． 4 (M, 3H), 7.5-7.7 (M, 2H) MS (
70eV): m/E352(3,M+),3
21 (57), 305 (100), 274 (35),,
231 (87), 151 (25), 105 (65), 7
7(48) Example 3 α-Methylthio[5-(α,α-dimethoxybenozyl)
-2-thienyl] methyl acetate 1.162 g (3.30
mm01) was dissolved in anhydrous DMSO6, sodium hydride 150W9 (65%, 4.06 mm01) was added thereto, and the mixture was stirred at room temperature for 30 minutes.

After adding 0.30 g (4.8 mm) of methyl iodide to this and stirring at room temperature for 15 minutes, an aqueous ammonium chloride solution (0.59/30 g) was added, followed by ether extraction (
20TfLI! x3 times). The extract was washed with water (10 times twice), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Florisil, benzene) to obtain α-methylthio-α-
5-(α,α-dimethoxybenzyl)-2-thienyl]
Methyl propionate 932W9 was obtained as white crystals.

Yield 77%. M. p. : 61.5-62.5°C (from n-hexane) IR (KBr): 2830, 1730, 1
240, 1090, 1050, 990, 760, 705C! ! L-1 NMR (CDCl3): δ1.86 (S.3H), 2
．． 00 (S.3H), 3.12 (S.6H), 3.72
(S.3H), 6.65 (D.J=4Hz, 1H), 6
．． 84 (D, J = 4Hz, 1H), 7.2-7.4 (M
,3H),7.4-7.6(M,2H)Cl8H,2O
Calculated value as 4S2: C, 58.99; H, 6. O5; S, l7.5
O% measured value: C, 59. O8; H, 6. OO;S,l7
．． 6l% Example 4 Methyl α-methylthio-α-[5-(α,α-dimethoxybenzyl)-2-thienyl]propionate 887η(
2.42 mmOl) were added with 5 d of methanol and 1 d of water, and further added with 0.2 d of concentrated hydrochloric acid, and heated under reflux for 1 hour.

After cooling, the mixture was concentrated under reduced pressure, 100 d of benzene was added to the residue, and the mixture was concentrated under reduced pressure again.

The residue was purified by column chromatography (silica gel, benzene) to obtain 754 methyl α-methylthio-α-(5-benzoyl-2-thienyl)propionate as an oily substance. Yield 97q60IR (Neat):
1735, 1635, 1450, 1290, 1250,
1105,865,715,700c! n-1 NMR (CDCl,): δ1.92 (S, 3H), 2
．． 07 (S, 3H), 3.76 (S, 3H), 7.11
(D, J=4Hz, 1H) 7.4-7.6 (M, 4H)
,7.7~7.9(M,2H) MS(70e):m/E32O(2,M+),273(
100), 261 (21), 213 (25), 105 (
86), 77(62) Reference Example 2 432 mg (2.00 mm01) of methyl α-methylthio-α-(2-thienino(ha)propionate) was dissolved in 4d of acetic acid, and 1 g (0.20 mm01) of anhydrous copper sulfate and zinc powder were dissolved. 400η was added and heated under reflux for 3.5 hours while stirring.

After cooling, ether 30d was added and insoluble matter was filtered off, followed by washing with ether 10a. After washing the filtrate with water (10d),
After adding 20 d of water and gradually adding sodium carbonate to neutralize the acetic acid contained therein, the organic layer was separated.

After washing with water (10wL1) and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to simple distillation [100-110℃
(bath temperature)/8 mmHg] to obtain methyl α-(2-thienyl)propionate 297W9 as a colorless oily substance.

Yield 87%0 IR (Neat): 1740, 1455, 1435, 1
380,1330,1200,1165,1 1055,855,700 (71L NMR (CDCl3): δ1.59 (D, J = 7Hz
, 3H), 3.70 (S, 3H), 4.01 (Q, J=
7Hz, 1H), 6.9-7.0 (M, 2H), 7.1
~7.3 (M, lH) Calculated value as C8H, OO2S: C; 56.44; H; 5.92; S; 18.8
4(f) Measured value: C; 56.26; H; 5.88; S;
18.74% Reference Example 3 Methyl α-methylthio-α-(5-benzoyl-2-thienyl)propionate 3201!9 (1.00mm01
) in 1 WLt of anhydrous methanol, and add 1.0 ml of methanol solution of sodium salt of methyl mercaptan to this.
(2.34M:2.34mm01) was added and heated under reflux for 1 hour.

Claims (1)

[Claims] 1 α-thio-α-(2-thienyl)carboxylic acid derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R and R_2 are hydrogen or an alkyl group, R_1 is a lower alkyl group, and Y is an acyl group or an acetal-protected acyl group. ].