JPS61275281A - Production of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine - Google Patents

Abstract

PURPOSE:To obtain in high yield and in high purity the titled compound showing an inhibitory action on blood platelet aggregation, etc., by reacting 4,5,6,7- tetrahydro-thieno[3,2-c]pyridine with a specific compound and hydrogenating the reaction product with a metallic hydride. CONSTITUTION:4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine shown by the formula I is condensed with a compound shown by the formula II (X is O or S) preferably in a solvent such as benzene, etc., inn the presence of an organic amine such as triethylamine, etc., at 15-100 deg.C to form a thienopyridine derivative. Then, the reaction product is hydrogenated with a metallic hydride such as lithium aluminum hydride, etc., in a solvent such as diethyl ether, etc., at 15-100 deg.C or reduced electrolytically, to give the aimed compound having an inhibitory action on blood platelet adhesion ability. EFFECT:The raw materials and the reaction product have correlation from basic substance to neutral substance and neutral substance to basic substance, separation and purification are easily carried out, so this process is an industrial, economic process.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 5-(2-chloro-benzyl)-4,5゜6
．． The present invention relates to a novel method for producing 7-titrahydrothieno(3,2-C)pyridine.

The object of the present invention is to provide 5-(2-chloro-benzyl)-4,5, which has an inhibitory effect on platelet aggregation and platelet adhesion.
6,7-titrahydrothieno(3,2-C:1 pyridine and its salts) can be produced industrially in high yields.

(Prior art) 4.5,6.7-titrahydrothieno(3,2-C1
) There are the following two methods for producing pyridine derivatives.

(1) The method described in Japanese Patent Publication No. 52-31357 is to convert cheno[3,2-C)pyridine represented by the following formula (IV) into the following formula (V).
(In the formula, Hat represents a halogen atom.) It is condensed with a halide represented by the following formula (to) (in the formula, H
al has the same meaning as above. ) to obtain a pyridinium salt, and then hydrogenate the pyridinium salt,
The method consists of obtaining a compound represented by the above formula 〇.

(2) JP-A No. 51-151-1C and % development 1971-151-1C
The method described in the 1994 publication.

A compound represented by the following formula (VID (in the formula, R1 represents a substituted alkyl, aryl or aralkyl group) is condensed with an amine represented by the following formula (Vl) to form a compound represented by the following formula (■) and then cyclized with formaldehyde to obtain the compound represented by the formula (n).

(Problem to be solved by the invention) However, in method (1), the raw material Cheno [3°2
-C]pyridine] is synthesized by converting 3-thiophenaldehyde into diethylaminoacetal and then cyclizing it, but the yield from diethyl-3-thenylidene aminoacetal represented by the following formula (X) is・Op the American・
Chemical Society (J, Am.

Chem, Soc, )-Otsu 5.5122 (1953)
According to &C, it is only 10%, and it cannot be called an economical and industrial implementation process.

In addition, in method (2), a large amount of by-products such as tertiary amines are produced in the reaction of 2-(2-chenyl)-dityl tosylate and 2-chloro-benzylamine, so it is very difficult to purify and separate. Requires complicated operations. In order to avoid the by-product of tertiary or higher class amines, the amine must be used in a molar ratio of at least twice that of the tosylate, and even with this, the formation of by-products cannot be avoided.

The biggest weakness in the industrial implementation of these two methods is that both the raw materials and products are basic substances, making separation and purification extremely difficult.

(Means and effects for solving the problems) As a result of intensive studies to solve the above problems, we found that 4,5,6,7-titrahydrothieno[3
,2-C]pyridine and a compound represented by the following formula (II) (wherein, X is oxygen or a sulfur atom) are condensed in the presence of an organic amine, and Either obtain a chenopyridine derivative, or when X is an oxygen atom, treat with phosphorus pentasulfide to obtain a compound represented by the following formula (■'), and then hydrogenate these compounds with a metal hydride or electrolytic reduction. However, high purity 5-(2-chloro-benzyl)-4,5,6,7-titrahydrothieno[3,2-C)pyridine, which is completely free of by-products such as quaternary amines, is prepared. We have found a method to produce it with high yield.

The method of implementing the present invention will be explained in detail below.

First, in the condensation step, the reaction temperature is 15 to 100C; the higher the reaction temperature, the more by-products are produced. Desirably it is 15-50C.

The reaction is carried out using a solvent that does not decompose the acid chloride, e.g. ttf
, 7-t) Nitrile, benzene, toluene, xylene,
It is advantageously carried out with dioxane, THF, etc. Acetonitrile and benzene are preferable.

Examples of organic amines used include triethylamine, pyridine, and triethylenediamine. Preferred are triethylamine and pyridine. The amount of organic amine added is 4,5,6,7-titrahydrothieno(
3,2-C) It is 1 to 10 times the mole amount, preferably 1 to 1.5 times the mole amount, relative to pyridine.

As for the method of adding the reagents, they may be added at the same time and reacted. This is preferably carried out by gradually adding a solution of tetrahydro-cheno(3,2-C)pyridine to a solution of 2-chloro-benzoyl chloride.

The compound of formula (ffl) is a neutral substance and can be easily separated from the raw material by only an extraction operation. In addition, the raw material Fi can be recovered and recycled for the next reaction.

In the next &C% hydrogenation step, the metal hydride is
Examples include lithium aluminum hydride, lithium octahydride, foxosodium hydride, and diborane.

Preferred is lithium aluminum hydride.

The amount of metal hydride to be used is 0.5 to 5 times the mole, preferably 0.5 to 1 times the mole of the compound of formula (III).

The reaction temperature is 15-100C. Preferably 15~
It is soC.

The reaction is advantageously carried out with diethyl ether, THF, dioxane, benzene, toluene, and the like.

10,000, in the electrolytic reduction method, the current density is 1.25
It is practical in the range of ~50 A/d. Preferably 1.
25-5. This is the range of OA/dgo.

Furthermore, although the reaction proceeds even when no supporting electrolyte coexists in the system, it is preferable that the reaction coexist with a supporting electrolyte. As the supporting electrolyte, both organic and inorganic compounds are practical, but organic compounds are preferable because they increase solubility in aqueous solutions. For example, methyltetramethylammonium sulfate, ethyltetraethylammonium sulfate, tetra-n-butylammonium fluoride, ethyl ethyl tri-n-butylammonium sulfate, bistetraethylammonium sulfate A, tetra-n-butylammonium hydrate, hydroxide. Practical examples include N-benzyltrimethylammonium, odorant n-butylammonium, and tetramethylammonium bromide. Preferably a quaternary ammonium salt compound having a lower alkyl group, methyltetramethylammonium sulfate,
Ethyltetraethylamsonium sulfate.

The reaction temperature is 5 to 95 C'), preferably 10 to 40 C'
It is C.

The electrode may be hydrogenated using lead, cadmium or mercury, preferably lead.

A diaphragm such as tLTII4mki, a cation exchange membrane obtained by sulfonating a divinylbenzene-styrene-butadiene copolymer, is placed between the anode and the cathode.

The reaction solvent is an inorganic acid aqueous solution such as sulfuric acid or hydrochloric acid. The concentration is 5~aov7''vs), preferably F
There are i5-20 v/v tste. The reaction proceeds even if polar organic solvents such as dimethyl sulfoxide, dimethylformamide, acetic acid, methanol, ethanol, dimethylacetamide, pronol, and butanol are present in the inorganic acid aqueous solution. The reaction also proceeds in a mixed solvent of dimethylsulfoxide, dimethylformamide, dimethylacetamide, methanol, ethanol and water, that is, a neutral solvent.

5-(2-chloro-benzyl) thus obtained
-4,5,6,7-titrahydrothieno[3,2-C
lPyridine is a basic substance, and the compound (IID) before hydrogenation can be easily isolated by an extraction operation.

(Effects of the invention) As mentioned above, separation and purification is easy due to the relationship between raw materials and products: from basic substances to neutral substances, and from neutral substances to basic substances. It is a practical and economical implementation process.

(Example) Next, an example of the present invention will be given, but the present invention is not limited to this example.

Example 1 5-(2-chloro-benzyl)-4,5,6,7-titrahydrothieno(5,2-Cl pyridine (1) 5
- (2-chloro-benzoyl)-4,5,4゜7-titrahydrothieno(3,2-C]pyridine 2-chloro-benzoyl chloride 12.5?(72
mmot) and triethylamine 11m (79mmot)
Kb 4e5s'e7-titrahydrothieno[3,2-Cl pyridine 10, Of
9. Add the benzene solution contained in '(72mmot)' dropwise. After stirring at room temperature for 2 hours, the mixture was washed three times with 50 Wlt of water. After that, benzene layer t-2N-hydrochloric acid 50W1t
Washed twice, and further washed with 50ml of 2N sodium hydroxide for 50 minutes.
Washed twice. After drying the benzene layer, it was distilled off to give 5-(2-
Chloro-benzoyl)-4,5゜6.7-titrahydrothieno(3,2-C]Billy/y18.5F (92%
) was obtained.

N M R (CDC4) δ (Solution) 2.90 (t, 2H)5.
55 (t, 2H) 4.50 (s, 2H) 4.80 (dd j 2H) 7.55 (m, 4H) Elemental analysis theoretical value Analysis value 0 60.54chi 60.42% H4,52% 4 .551 N 5,05% 4,98%0
5.77chi 5.88% cl 12,791 12.714S 11
,55% 11,48% (2) 5-(2-chloro-benzyl)-4,5,6,7-titrahydrothieno(5,2-(:)pyridine lithium aluminum hydride 0.95 f (25 mmoL 5-(2-chloro-benzoyl)-4,5,6,7-titrahydrothieno[3,2-Cl pyridine obtained in 1(1)] in diethyl ether 50- containing 6.9 f (25m
30-diethyl ether containing moA ) was added dropwise, and the mixture was allowed to react at room temperature for 5 hours. After the reaction was completed, excess lithium aluminum hydride was inactivated by dropwise addition of water 1-2-. Remove insoluble materials such as aluminum hydroxide from door to door, and add 2 liters of F solution.
Extracted three times with 50 d of N-hydrochloric acid. The aqueous layer was adjusted to pH 10 with 2N sodium hydroxide, and 50% diethyl ether was added.
Extracted 3 times with m. After drying the ether layer, the ether was distilled off to give 5-(2-chloro-benzyl)-4,5,6,7
-titrahydrothieno(3,2-C)pyridine 5,1
I got f (77chi) as a friend.

N M R (CDCt,) δ (ppm) 2.90 (s, 4H) 5.60
(s, 2H) 5.85 (s, 2H) 6.90 (dd, 2H) 7.30 (m, 4H) Elemental analysis theoretical value Analysis value C65,76 Arrogance 6358 Chi H5,31* 5.59% N 5.51% 5.27%C/,
13.47% 13.25%5 1
2.14% 12.511 Example 2 5-(2-chloro-benzyl)-4,5,6,7-tetraζDrocheno(3,2-C) pyridine electrolytic cell has a capacity of 200 sdOH cell, and the electrode is lead. (4 m), the anode solvent was 20 v/m% sulfuric acid, and the diaphragm was a cation exchange membrane obtained by sulfonating a divinylbenzene-styrene-phtadiene copolymer.

5-(2-chloro-benzoyl)-4,5,6,7-tetraζdrocheno(3,2
-C] Pyridine o,7f (2.5 mmol) was placed in a reaction vessel on the cathode side along with 5+d of sulfuric acid, 80-1 of water, and 40-1 of an aqueous solution of ethyltetraethylammonium sulfate (24.5 w/w). 14 hours at room temperature, current density 2,5A
p electrolytic reduction was performed using /dTrt.

The reaction solution was adjusted to pH 10 with 2N sodium hydroxide, and extracted three times with 50W of diethyl ether.

After drying the ether layer, the ether was distilled off under reduced pressure to obtain 5-(
2-chloro-benzyl)-4,5,6,7-tetraζdrocheno(3,2-C)pyridine a,6t (a S
%) I'm sorry.

Example 3 5-(2-chloro-benzyl)-4,5,6,7-tetraζdrocheno(5j2-C]pyridine(1) 5-(
2-chloro-thiobenzoyl)-4゜5.6.7-tetraζdrocheno(3,2-C]pyridine 5-(2-chloro-benzoyl)-4,5 obtained in Example 1 (1) ,6,7-tetraζdrocheno(3,2
-C) Pyridy7f (25mmol) and phosphorus pentasulfide 1.1? (2,5 mmot) and dioxa 7
The mixture was heated under reflux in 50ag for 10 hours. Dioxane was distilled off under reduced pressure to obtain reaction mixture 7.62. This reaction product was purified by silica gel column chromatography with 'IIIM (Solution 31).
m solution: benzene/ethyl acetate 7:5)(,te,5(2-
chloro-thiobenzoyl)-4,5,6,7-tetraζ
Drocheno[3,2-C]pyridine 5, Of (68
%) was obtained.

(2) 5-(2-chloro-benzyl)-4,5,6°7
5-(2-chloro-thiobenzoyl) obtained with -tetraζdrocheno[:3.2-C]pyridine (1)
-4,5,6,7-tetraζdrocheno [3゜2-C
] 0.8 t of pyridine was electrolytically reduced under the same conditions as in Example 2, and the same post-treatment was performed to obtain 5-(2-chloro-
benzyl)-4,5,4,7-tetraζdrocheno(
0.689 (95%) of 3,2-C]pyridine was obtained.

Example 4 5-(2-chloro-benzyl)-4,5,6,7-tetraζdrocheno(5,2-C)pyridine (1) 5-(
2-Chloro-thiobenzoyl)-4,5,6,7-tetraζdorocheno[3,2-C]pyridine 2-cxo-thiobenzoyl-chloride 13.7y
(72 mmot) and triethylamine 11sd (79
Benzene solution containing 70dIC, 4,5,6
゜30- of benzene containing 10 f (72 mmol) of 7-tetraζ-drocheno(3.2-C)pyridine was added dropwise and stirred at room temperature for 4 hours.The reaction solution was washed three times with 50 mg of water, and the benzene layer was was washed three times with 50-2N hydrochloric acid, and then three times with 50-2N sodium hydroxide.After drying the benzene layer, the benzene was distilled off to give 5-
(2-aa-thiobenzoyl)-4,5,6,7-tetra-drocheno(5,2-C)pyridine 18,8
f (88chi) was obtained.

(2) 5-(2-chloro-benzyl)-4,5°6.7
5-(2-chloro-thiobenzoyl) obtained with -tetraζdrocheno(5,2-C]pyridine (1)
-4,5,6,7-tetraζdrocheno [5゜2-C
] 0.8 t of pyridine was electrolytically reduced under the same conditions as in Example 2, and the same post-treatment was performed to obtain 5-(2-chloro-
benzyl)-4,5,6,7-titrahydrothieno[
0.68f (95%) of 3,2-C]pyridine was obtained.

Claims (1)

[Claims] 4,5,6,7-tetrahydro-thieno [3
, 2-C] pyridine and a compound represented by the following formula (II) ▲Mathematical formula, chemical formula, table, etc.▼(II) (wherein, X is an oxygen or sulfur atom) is condensed to obtain a The following formula (III) ▲ formula,
There are chemical formulas, tables, etc. ▼ (III) 5-(2- A method for producing chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine.