JPS62103088A - Production of 4,5,6,7-tetrahydrothieno(3,2-c)-pyridine or salt thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is a synthetic intermediate for a compound useful as an anti-inflammatory agent, etc., in high yield at a low cost with the simple procedure, by reacting thienyl-ethylamine with formaldehyde and reacting the reaction product with hydrogen chloride. CONSTITUTION:The objective compound of formula II can be produced by (1) reacting 1mol of 2-(2-thienyl)-ethylamine of formula I with preferably 1.1mol of formaldehyde and (2) reacting 1mol of the imine compound produced by the above reaction with 2.2mol (dry basis) of hydrogen chloride. Preferably, the reaction of the compound of formula I with formaldehyde is carried out in an aqueous medium and the reaction of imine with hydrogen chloride is carried out in a neutral polar solvent such as DMF. The imine compound produced by the above reaction is used preferably in a completely dehydrated state without purification.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 5-(2-chlorobenzyl)-4,5,6,7-titrahydrothieno( 3,
2-C) 4, 5, represented by the following formula, which is effectively used as an intermediate raw material when producing pyridine or its salt.
The present invention relates to a novel method for producing 6.7-titrahydrothieno(3,2-C]pyridine or a salt thereof.

BACKGROUND OF THE INVENTION Conventionally, 5- shown by the following formula (3) is known as a drug having anti-inflammatory activity, vasodilatory activity, platelet aggregation activity, etc.
(2-Chlorobenzyl) -4,5,6゜7-titrahydrothieno(3,2-C)pyridine or its salts have been proposed as methods shown in (a) to (c) below. There is.

(a) 5-(2-rioobenzyl)-cheno(3,2-
C: A method for reducing 1-pyridinium chloride (see Publication No. 31357/1983, reaction formula below).

t (b) A method of adding formaldehyde to N-(2-chlorobenzyl)-2-(2-thenyl)ethylamine and heating it in an aqueous hydrochloric acid solution to cyclize it (JP-A-51-1
No. 01996, see reaction formula (B) below).

(a) Method of reacting 4,5,6,7-titrahydrothieno(3,2-C)pyridine with 2-chlorobenzyl chloride (Eur, J, Med,
Chem, -Chemica Terapeutic
aIn addition, other Japanese Patent Application Laid-open No. 53-95994. 55-33
469, 54-19994, 51-48692, 52-36691. 52-91891, 53-97
60, 59-27895, 52-8793, 54
-9298. Special Publication No. 52-31357, C, A,
91.56977v, C, A, 94.47305J
The method described in et al. is known.

In the method for obtaining such a compound of formula (3) or a salt thereof, 4 represented by formula (2) as shown in reaction formula (C)
, 5,6.7-titrahydrothieno(3,2-C]pyridine is useful as a synthetic intermediate for the compound of formula (3) or its salt, but the conventional method for obtaining the compound of formula (21) is (Eur, J, Med, Chem, -Chemiea) of the following reaction formula
Tarapeutica 9 (45) 483-4
86.1974) is known.

Problems to be Solved by the Invention However, the method for producing the compound of formula (2) according to reaction formula (b)K requires a long number of reaction steps during its synthesis, and the operation is cumbersome. There is a disadvantage that the synthesis cost is high and the target compound of formula (3) cannot be produced economically.

Therefore, the above method is industrially disadvantageous, and there has been a demand for the development of a method for producing the compound of formula (2) or a salt thereof that is satisfactory on an industrial scale.

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies on a method for obtaining the compound of the formula (2) in a high yield, easily, and at a lower cost.As a result, the following formula ( 1) 2-(
After reacting 2-chenyl)-ethylamine with formaldehyde, the reaction product imine is reacted with hydrogen chloride to cyclize the imine, thereby producing a compound of formula (2) or a salt thereof. By using the thus obtained compound of formula (2) as an intermediate raw material and synthesizing the compound of formula (3) or its salt, the compound of formula (3) can be obtained with a high yield. The present invention was based on the discovery that a salt thereof can be obtained at low cost.

Therefore, the present invention involves reacting 2-(2-thenyl)-ethylamine represented by the following formula (1) with formaldehyde, and then reacting the reaction product with hydrogen chloride. Cyclize it,
4,5,6,7-titrahydrothieno[3,
2-C) 4 characterized by obtaining pyridine or a salt thereof
, 5°6.7-titrahydrothieno(3,2-C)pyridine or a salt thereof (see reaction formula (g) below).

The present invention will be explained in more detail below.

In the present invention, when obtaining the compound of formula (2) or a salt thereof, first the compound of formula (1) is reacted with formaldehyde, and then the reaction product imine is reacted with hydrogen chloride. In this case, various reaction conditions may be selected, but it is preferable to react 1 to 1.5 mol, particularly about 1.1 mol, of formaldehyde per 1 mol of the compound of formula (1). Further, the reaction is preferably carried out in an aqueous medium, and for example, the reaction can be carried out favorably by adding aqueous formaldehyde i to the compound of formula (1).

Furthermore, it is preferable that the produced imine is made completely anhydrous and then reacted with hydrogen chloride without purification. For example, a completely anhydrous crude imine can be obtained by adding ether to the reaction solution, separating the ether layer, drying it over anhydrous magnesium sulfate, etc., and then concentrating to dryness under reduced pressure.

In addition, when reacting imine with hydrogen chloride, hydrogen chloride, preferably dry hydrogen chloride, is added at 2 to 2 to 1 mole of imine.
It is preferable to react about 46 moles, particularly about 2.2 moles. Furthermore, the reaction is suitably carried out in a neutral polar solvent such as dimethylformamide; for example, by adding a solution of imine in dimethylformamide to a solution of dry hydrogen chloride in dimethylformamide, the ring-closing reaction can be carried out well. Thus, the compound of formula (2) can be obtained in the form of a salt.

Here, the compound of formula (1), which is the starting material for the method of the present invention, can be obtained, for example, by the following method.

That is, 2-chloromethylthiophene was reacted with sodium cyanide in a mixed solvent of dimethyl sulfoxide and tetrahydro2rane to obtain 2-cyanomethylthiophene, which was then hydrogenated in anhydrous ether using aluminum chloride as a catalyst. Reduce with aluminum lithium (J, C, S.

Parkfn l + 138 + 19766 (refer to reaction formula q) below), 2-thiophene aldehyde is condensed with nitromethane to obtain 2-(β-nitrovinyl)thiophene, which is further reduced with lithium aluminum hydride in anhydrous ether. (J, O, C, 15, 807 (1
950): Certain Journal 74.1301 (1954); see reaction formula (G) below) is a method for obtaining a compound of formula (1), whereby a compound of formula (1) can be obtained in good yield. It is something that can be done.

Furthermore, the compound of formula (2) obtained by the method of the present invention can be suitably used as a raw material when synthesizing the compound of formula (3) or a salt thereof.

The compound or its salt can be obtained satisfactorily (see reaction formula (b) below).

Here, the reaction conditions in the above reaction (b) are not necessarily limited, but 1 to 1.5 mol, particularly about 1.1 mol of 2-chlorobenzaldehyde and formic acid are added to 1 mol of the compound of formula (2). It is preferable to react about 2 to 2.5 moles, particularly about 2.2 moles. Also, the reaction is 90-1
It is preferable to carry out the reaction at 00° C. for 2 to 8 hours, particularly about 4 hours, until no carbon dioxide is generated.

The compound of formula (3) thus obtained can be converted into a pharmaceutically acceptable inorganic or organic acid salt by a conventional method.

Second, the compound of formula (3) or its salt can be produced in high yield and at low cost.

That is, as mentioned above, conventional methods for obtaining the compound of formula (3) include reaction formula, (B), (C), etc., but methods (4) and (C) have been adopted. The method (B) has a low yield of the target product, and the method (B) uses an alkali metal or a Grignard reagent in the synthesis of the intermediate, making the operation complicated and requiring expensive raw materials such as 2-chlorobenzylamine. There was a problem that a large amount had to be used. Therefore, there was a need to solve this problem, but according to the method of reaction formula (6), (3
) or a salt thereof can be produced simply and economically with good yield.

As described in detail of the invention, according to the manufacturing method of the present invention, the above (3)
) of the formula 5-(2-chlorobenzyl) -4,5,6,7
-Titrahydrothieno[:3 .2-C] Pyridine or its salt can be obtained in good yield and at low cost.

Hereinafter, the present invention will be specifically illustrated by Examples and Reference Examples.

〔Example〕

2-(2-chenyl)ethylamine of formula (1) 4.70
3.5 g of a 35% formaldehyde aqueous solution was added to the mixture at room temperature and allowed to react. In this case, the reaction solution generates heat and imine is produced within several minutes. After the reaction is complete, add ether 5 to the reaction solution.
QmA! is added, the ether layer is separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain crude imine 4.689, which is a reaction intermediate.

Next, a solution of the queen imine in dimethylformamide (5rlLl) was added dropwise at room temperature with stirring into a solution prepared by dissolving dry hydrogen chloride in 17 m/m of dimethylformamide in a molar ratio of 2.2 times the mole of the imine. The reaction solution generates heat and crystals precipitate after a while. Stirring was continued for 3 hours, and the obtained crystals were washed several times with acetone and dried to obtain hydrochloric acid of 4.5.6.7-titrahydrothieno(3,2-C)pyridine of formula (2). Salt 4.609 was obtained (mp222-225
°C, yield 70 cm).

When the IR spectrum and NMR spectrum of the obtained compound were compared with the same spectrum data of separately synthesized standard product 4.5,6.7-titrahydrothieno(3,2-C)pyridine hydrochloride, it was found that both It was a perfect match.

[Reference Example 1] 3.21 g of 2-chlorobenzaldehyde was added to 2.90 g of the compound of formula (2) (free base) obtained according to the example.
9 (1.1 times the mole relative to the compound of formula (2)) and 2.11 g of formic acid (2.2 times the mole relative to the compound of formula 21) were added, and heated to 90 to 100°C while stirring. and 4
Allow time to react.

Next, the reaction solution is cooled, 30 ml of water and an aqueous solution of caustic soda are added thereto to make it basic, and then extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5,509 as an oil. This oil was dissolved in anhydrous ether, and dry hydrogen chloride gas was introduced into the solution to separate the precipitated crystals, which were then recrystallized from ethanol to form 5-(2-chlorobenzyl)-4 of formula (3). ,5,6,7-titrahydrothieno(3,2
-C) 4.55 g of pyridine hydrochloride was obtained (mp203
~205°C, yield 73%).

[Reference Example 2] Compound of formula (2) (free 〇 base) obtained according to the example 2. 2-chlorobenzaldehyde 3,79 to sog
9 (1.5 times the mole relative to the compound of formula (2)) and formic acid 2.0717 (2.5 times the mole relative to the compound of formula (2)) were added, and the mixture was heated to 90 to 1001:1 with stirring. Heat and react for 4 hours.

Thereafter, treatment was carried out in the same manner as in Reference Example 1 to obtain 350 g of the hydrochloride of the compound of formula (3) (mp 203-205°C, yield 6
5%).

[Reference Example 3] Compound of formula (2) obtained according to Example (free base>2.sog to 2-chlorobenzaldehyde 2.78
9 (1.1 times mole relative to the compound of formula (2)) and formic acid 1.82.9 times ('2.2 times mole relative to the compound of formula (2)) were added, and while stirring, the Heat to 100°C and react for 8 hours.

Thereafter, it was treated in the same manner as in Reference Example 1 to obtain 3.2411 hydrochloride of the compound of formula (3) (mp 203-205°C, yield 60%).

In addition, the IR spectrum and NMR spectra of the compounds obtained in Reference Examples 1 to 3 were obtained using the separately synthesized standard product 5-(2
-Chlorobenzyl) -4,5,6,7-titrahydrothieno[:3.2-C]pyridine When compared with the same spectrum data, the two completely matched. Moreover, the mass spectra of the compounds obtained in Reference Examples 1 to 3 were 263 (MW-HCl).

Claims (1)

[Claims] 1. After reacting 2-(2-thienyl)-ethylamine represented by the following formula (1) ▲Mathematical formulas, chemical formulas, tables, etc.▼...(1) with formaldehyde, The reaction product is cyclized by reacting the reaction product with hydrogen chloride,
4,5,6,7-tetrahydrothieno[3,
2-C] 4 characterized by obtaining pyridine or a salt thereof
, 5,6,7-tetrahydrothieno[3,2-C]pyridine or a salt thereof.