JPH0560836B2 - - Google Patents

Description

[Detailed description of the invention] [Industrial field of application] The present invention is based on the formula () 5-(2-chlorobenzyl)-4,5, represented by
Regarding 6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid and its production method,
More specifically, a useful intermediate for producing 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride (generic name: ticlopidine hydrochloride), which is useful as a medicine. 5-
The present invention relates to (2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid and a method for producing the same.

[Conventional technology]

Ticlopidine hydrochloride has a platelet function suppressing effect and is currently widely used as a pharmaceutical. As a method for producing this compound, methods described, for example, in French Patent No. 7303503, Japanese Patent Publication No. 59-31513, etc. are known.

[Problem that the invention seeks to solve]

However, the above-mentioned methods have not always been satisfactory due to poor yields, unstable raw materials, and a large number of difficult operational steps.

The object of the present invention is to overcome these problems of the prior art methods and to provide a highly useful formula ().
An object of the present invention is to provide a thienopyridine derivative represented by the following formula and a method for producing the same.

[Means for solving problems]

The compound represented by formula () in the present invention is
General formula () (In the formula, R ₁ and R ₂ represent the same or different lower alkyl groups, respectively) by hydrolyzing the compound represented by the formula () in the presence of a base. Form a compound represented by the formula (), and then convert the compound represented by the formula () to the compound represented by the formula (). (In the formula, X represents a halogen atom) by reacting it with a compound represented by the formula (X represents a halogen atom) in the presence of a base.

Here, as the halogen atom, chlorine atom, bromine atom and iodine atom are particularly suitable.

The hydrolysis reaction of the compound of formula () can be carried out in various solvents (eg, water, aqueous methanol, aqueous ethanol), but water is most preferred. At this time, examples of the base used include sodium hydroxide, potassium hydroxide, and lithium hydroxide. The appropriate reaction temperature is room temperature to reflux temperature.
The time varies from 2 to 6 hours depending on conditions. The thus obtained compound of formula () is a new compound that has not been described in any literature. In the method of the present invention, the reaction product can be used as it is in the next step reaction without being particularly isolated.

The condensation reaction between the compound of formula () and the compound of formula () can be carried out by adding an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., or an organic base such as triethylamine, pyridine, etc. together with an appropriate amount of water. . The reaction temperature is selected within the range of 0° C. to reflux temperature, but it is preferably carried out around room temperature. The reaction time in that case is 4 to 6 hours. The compound of formula () thus obtained is a novel compound whose pattern has not yet been published.

The compound of formula () can be quantitatively converted into pharmaceutically useful ticlopidine hydrochloride by decomposition with an acid such as hydrobromic acid, sulfuric acid, or hydrochloric acid.

Formula () which is the starting material in the method of the invention
The compound has the formula () (In the formula, R ₂ has the same meaning as above) is reacted with a Willsmeier reagent prepared from dimethylformamide and phosphorus oxychloride to give the formula () (in the formula, R ₂ has the same meaning as above) is formed, and then the compound of formula () is formed by forming the compound of formula () HSCH ₂ COOR ₁ () (in the formula, R ₁ has the same meaning as above). ) by reacting with a compound represented by the formula () (In the formula, R ₁ and R ₂ have the same meanings as above) is formed, and the compound of formula () is further reacted with a base such as potassium hydroxide to obtain it in high yield. I can do it.

Also, the compound () is 1-(2-chlorobenzyl)-4-piperidone () 1-
(2-chlorobenzyl)-3-formyl-4-chloro-1,2,5,6-tetrahydropyridine () 1-(2-chlorobenzyl)-3-formyl-4-alkoxycarbomethylthio-1,2,5,6-tetrahydropyridine () by forming and then reacting with a thioglycolic acid alkyl ester. (R ₁ :lower alkyl group) and further reacted with a base such as potassium hydroxide to form 5-(2-chlorobenzyl)
-Tetrahydrothieno[3,2-C]pyridine-
2-Carboxylic acid alkyl ester () It can also be produced by forming and hydrolyzing this. Furthermore, tetrahydro-4H-pyran-
6,7-dihydro-4H-thieno[3,2-C]pyran-2 obtained by reacting 4-one in the same manner
-Carboxylic acid () to 2-chlorobenzylamino () The compound () can also be produced by reacting with.

A more detailed explanation will be given below using Examples and Reference Examples.

Example 1 2,5-diethoxycarbonyl-4,5,6,
7-tetrahydrothieno[3,2-C]pyridine
5g (17.6 mmol) in 3.5N potassium hydroxide aqueous solution
The mixture was added to 30 ml and heated under reflux for 4 hours. After the reaction was completed, it was acidified with hydrochloric acid, the precipitated crystals were collected by filtration, and 4,5,
3.2 g of 6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid hydrochloride was obtained. (yield
82.5%) Melting point 277℃ (decomposition) IR (KBr, υcm ^-1 ): 1700cm ^-1 NMR (DMSO _- d ₆ , δppm): 2.8-3.6 (4H, m) 4.17 (2H, S) 7.59 (1H, S ) 9.5-10.8 (3H,b) Example 2 4,5,6,7-tetrahydrothieno[3,2
-C]Pyridine-2-carboxylic hydrochloride 3.0g
(13.7 mmol) in 3.5N potassium hydroxide aqueous solution 15
2-chlorobenzyl chloride after dissolving in ml
2.8 g (17.4 mmol) was added and stirred at room temperature for 6 hours. After the reaction was completed, the mixture was acidified with hydrochloric acid and refluxed. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration.
The obtained crystals were recrystallized from methanol and 5-(2
3.9 g of pyridine-2-carboxylic acid hydrochloride was obtained. (Yield 83.0%) Melting point 230℃ (decomposition) IR (KBr, υcm ^-1 ): 1680cm ^-1 NMR (pyridine _- d ₅ , δppm): 2.94 (4H, S) 3.77 (2H, S) 4.00 (2H, S) 7.20-7.90 (6H, m) Example 3 2,5-diethoxycarbonyl-4,5,6,
7-tetrahydrothieno[3,2-C]pyridine
30g (0.106mol) in 3.5N potassium hydroxide aqueous solution 180
ml and heated under reflux for 4 hours. Then, cool to room temperature and add 22 g of 2-chlorobenzyl chloride.
(0.137 mol) was added and stirred at room temperature for 6 hours. After the reaction was completed, the mixture was made acidic by adding hydrochloric acid and heated to reflux.
The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to give 5-(2-chlorobenzyl)-tetrahydrothieno[3,2-
C] 31.0 g of pyridine-2-carboxylic acid hydrochloride was obtained. (Yield: 85.0%) The melting point and various spectra were consistent with the results of Example 2.

Reference example 1 5-(2-chlorobenzyl)-4,5,6,7-
Tetrahydrothieno[3,2-C]pyridine-2
-3 g (8.7 mmol) of the carboxylic hydrochloride was suspended in 24 ml of 48% hydrobromic acid, heated and refluxed for 9 hours. After the reaction was completed, the mixture was neutralized with sodium hydrogen carbonate and the liberated oil was extracted with dichloromethane. After washing the dichloromethane layer with water and drying, dichloromethane was distilled off. The obtained residue was purified by silica gel chromatography to obtain 5-(2-chlorobenzyl)-4,
5,6,7-tetrahydrothieno[3,2-C]
2.4 g of pyridine was obtained. (Yield 91.7%) NMR (CDC ₃ , δppm): 2.8 (4H, S) 3.6 (2H, S) 3.77 (2H, S) 6.6-7.6 (6H, m) Reference example 2 1-ethoxycarbonylpiperidine-4 −on
Dissolve 26.6 g (0.155 mol) in 20 ml dichloromethane and add 34 g (0.456 mol) dimethylformamide in advance.
mol) and 47.6 g (0.310 mol) of phosphorous oxychloride to a Willsmeier reagent prepared with water cooling. After the dropwise addition, the mixture was stirred at room temperature for 3 hours and then left overnight. After the reaction was completed, 100 g of ice and 80 g of sodium acetate were added, stirred, and extracted with benzene. The benzene layer was washed with water, washed with a saturated aqueous sodium bicarbonate solution, dried, and then the benzene was distilled off to give 1-ethoxycarbonyl-3-formyl-4-chloro-1,2,
28.6 g of 5,6-tetrahydropyridine was obtained. (Yield 85.0%) IR (neat, υcm ^-1 ): 1700cm ^-1 1680cm ^-1 NMR (CDC ₃ , δppm): 1.27 (3H, t) 2.50-2.85 (2H, m) 3.65 (2H, t) 3.95 ~4.30 (4H, m) 10.10 (1H, s) Reference example 3 1-ethoxycarbonyl-3-formyl-4-
Chloro-1,2,5,6-tetrahydropyridine
After dissolving 27.4 g (0.126 mol) and 19.7 g (0.164 mol) of thioglycolic acid ethyl ester in 50 ml of pyridine, 16.6 g (0.164 mol) of triethylamine was added dropwise under water cooling. After the addition, the mixture was stirred at room temperature for 3 hours, and then 70 g of a 50% aqueous potassium hydroxide solution was added dropwise under water cooling. After the addition, the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added and the mixture was extracted with benzene. The benzene layer was washed with water, dried, and then benzene was distilled off. The obtained residue was purified by silica gel chromatography to obtain 2,5-
26.0 g of diethoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine was obtained. (Yield 72.8%) IR (neat, υcm ^-1 ): 1700cm ^-1 NMR (CDC ₃ , δppm): 1.30 (3H, t) 1.36 (3H, t) 2.83 (2H, t) 3.75 (2H, t) 4.17 (2H, q) 4.28 (2H, q) 4.50 (2H, s) 7.44 (1H, s) Pharmacological test [Analgesic effect of acetic acid stretching method in mice] 1 group of ICR male mice weighing 23-26 g It was used as a fish. The test compound () was dissolved in distilled water and administered orally at 0.1 ml/10 g, and 30 minutes later, 0.1 ml/10 g of a 1% aqueous acetic acid solution was intraperitoneally injected. After that, the number of writhing symptoms (stretching symptoms) exhibited by the mice was counted for 20 minutes, and the suppression rate (%) was calculated using the following formula.

A-B/A×100 = Inhibition rate (%) A = Number of stretches in the control group B = Number of stretches in the test compound () administration group As a result, the inhibition rate at 100 mg/Kg oral administration of the test compound () was 53.1 %, and there was a significant difference from the control group at a risk rate of 5%, indicating that the test compound () had an analgesic effect.
The control group here refers to a group to which distilled water was orally administered at 0.1 m/10 g.

Pharmacological test [Suppressing effect on vascular hyperpermeability in mice by Whittle method] ICR male mice weighing 23 to 26 g were used in groups of 10 mice.

Dissolve the test compound () in distilled water and add 0.1ml/
10 g was administered orally, and 20 minutes later, 0.1 ml/10 g of a 7% polytamine sky blue aqueous solution was injected into the tail vein.
After another 10 minutes, 0.1 ml/10 g of a 1% acetic acid solution was intraperitoneally injected, and 30 minutes later, the animal was sacrificed and its abdomen opened, and the dye leaked into the peritoneal cavity was washed out with 10 ml of distilled water and collected.
The absorbance at 600 nm was measured, and the inhibition rate (%) was determined using the following formula.

C-D/C×100 = Inhibition rate (%) C = Absorbance of control group D = Absorbance of test compound () administration group As a result, the inhibition rate of 100 mg/Kg oral administration of test compound () was 41.7%. There was a significant difference with respect to the control group at a risk rate of 1%, indicating that the test compound () had an inhibitory effect on vascular hyperpermeability. The control group here was distilled water.
Refers to the group administered orally at 0.1ml/10g.

Claims (1)

[Claims] 1 Formula () 5-(2-chlorobenzyl)-4,5, represented by
6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid. 2 General formula () A thieno[3,2-C]pyridine derivative represented by the formula (in which R ₁ and R ₂ are the same or different lower alkyl groups) is hydrolyzed in the presence of a base, and the formula () Obtain 4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid represented by
Then the general formula () Formula () in which a benzyl derivative represented by (in the formula, X represents a halogen atom) is reacted in the presence of a base. 5-(2-chlorobenzyl)-4,5, represented by
A method for producing 6,7-tetrahydrothieno[3,2-C]pyridine-2-carboxylic acid.