CS228505B2 - Method for the production of new 2-/2-pyridyl/tetrahydrothiophene derivates - Google Patents

Description

(54) A process for the preparation of novel 2- (2-pyridyl) tetrahydrothiophene derivatives

The present invention provides a process for the preparation of the novel 2- (2-pyridyl) tetrahydrothiophene derivatives of formula (I)

(I) in which

R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms;

R 1 and R 2, identical or different, represent a hydrogen atom or an alkyl radical of from 1 to 15 carbon atoms optionally substituted by hydroxy, alkylamino or dialkylamino having 1 to 4 carbon atoms, phenyl, carboxyl or an alkoxycarbonyl group having an alkyl moiety of 1 to 4 carbon atoms, or

R 1 and R 2 together form a heterocyclic radical having 5 or 6 members which optionally contains another heteroatom selected from the group consisting of an oxygen atom, a sulfur atom or a nitrogen atom and is optionally substituted with an alkyl radical o. 1 to 4 carbon atoms, as well as their addition salts with nitrogenous bases, their metal salts and their acid addition salts, characterized by treatment with an amine of the formula II

R1

Z HN

R2 (II) wherein

R 1 and R 2 are as defined above for the dithioester of formula III

in which

R is as defined above and

.............. 3 & з represents an alkyl radical containing from 1 to 4 carbon atoms, a benzyl radical or a carboxy-methyl radical, the obtained substance is isolated and optionally converted to a nitrogen base addition salt, a metal salt or an acid addition salt.

They both work in an excess of the amine of the formula II, without a solvent or in an organic solvent, such as an aromatic hydrocarbon, an ether or a low molecular weight alcohol or a mixture of these solvents, at a temperature between 20 and 130 ° C. increased pressure.

When R 1 and / or R 2 represent an alkyl radical containing from 1 to 15 carbon atoms which is substituted with an alkylamino group, it is preferable to protect the amino function of the radical (s) with an alkylaminolabile protecting group which is reacted with a dithioester of formula III release. Attachment and deprotection may be accomplished by any of the known methods that do not affect the rest of the molecule.

Examples are benzyl or benzoyloxycarbonyl, followed by hydrogenolysis in the presence of palladium on carbon, or tert-butoxycarbonyl or trityl, followed by acidolysis in an anhydrous medium.

The dithioesters of formula (III) may be obtained by treating an 2- (2-pyridyl) tetrahydrothiophene of formula (IV) with an - organolithium derivative ......

in which

R is as defined above, followed by the action of carbon disulfide and then the compound of formula V

R3-Y (V) wherein

R 3 is as defined above and

Y represents a hydrogen atom or an active ester residue, preferably a chlorine, bromine or iodine atom, or a mesyloxy or tosyloxy group.

The reaction is generally carried out in an organic anhydrous solvent such as hexamethylphosphoric triamide to which - an ether such as tetrahydrofuran is usually added at a temperature in the range of -80 to -40 ° C.

An organolithium derivative which is particularly suitable is preferably an alkyl lithium such as butyl lithium, isopropyllithium or phenyl lithium in a solution in an inert solvent such as hexane.

The 2- (2-ppyidyl) -carbonyl IV can be obtained by any of the following methods: .....

1. cyclization with an organic base, such as an alkali alcoholate, which cyclizes a pyridine derivative of the general formula VI ^S (VII in which:

R is as defined above and

X represents a halogen atom or an active ester residue, preferably a chlorine or bromine atom, or a mesyloxy or tosyloxy group, the reaction being carried out in an organic anhydrous solvent such as tetrahydrofuran or hexamethylphosphoric triamide or a mixture of these solvents at 25 ° C. Potassium tert-butylate is preferably used as the organic base.

The pyridine derivatives of formula (IV) may be obtained by alkaline hydrolysis, preferably with an aqueous solution of an alkali hydroxide such as sodium hydroxide, an isothiourea salt of formula (VII).

R

(VII I in which

R is as defined above, at a temperature between 50 ° C and the boiling point of the reaction mixture, followed by treatment with a compound of formula VIII

X- (CH 2) 3 -X (VII) wherein the symbols

X the same or different, each represents a hydrogen atom or an active ester residue, preferably a chlorine or bromine atom, or a mesyloxy or tosylbxy group, at 20 ° C in the presence of an alkali hydroxide such as sodium hydroxide.

A pyridine derivative of the general Formula IX can be obtained as an intermediate

i / x;

in which

R is as defined above, which is derived from the alkaline hydrolysis of an isothiourea of formula VII, then reacting a compound of formula VIII in the presence of an alkali hydroxide such as sodium hydroxide.

The isothiourea of formula VII in the form of a salt, such as a dihydrochloride, can be obtained by treating the pyridine derivative of formula X (X) with thiourea with

R is as defined above and

X 1 represents a hydrogen atom, preferably a chlorine or bromine atom, optionally in the form of a salt, such as a halohydrate, in an organic solvent such as an alcohol (ethanol) at the reflux temperature of the reaction mixture.

The pyridine derivatives of formula X can be obtained according to the method _; by W. Mathes and H. Schůly, Angew. Chem. Intern. Ed. 2, 144 (1963).

2. The action of a compound of formula VIII on a pyridine derivative of formula IX

The reaction is usually carried out in an organic anhydrous solvent such as tetrahydrofuran in the presence of a sufficient amount of an organolithium compound such as alkyl lithium and / or dialkylamide lithium at a temperature in the range of -80 to -40 ° C.

The novel compounds of formula (I) may, if desired, be purified by known methods such as crystallization, chromatography or sequential extraction in acidic and then basic conditions.

The novel compounds of the formula I in which at least R @ 1 represents an alkyl radical substituted by a carboxy or amino-containing radical can be converted, if necessary, into a metal salt or a nitrogen base or acid addition salt using known methods. They can be converted into an acid addition salt by reaction with an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. The salts with metals or nitrogen bases may be obtained by treating the compounds of formula I in a suitable solvent such as an alcohol, a ketone, an ether or water by treating an alkali metal or alkaline earth metal hydroxide, ammonia or nitrogen base. The salt formed crystallizes, optionally after concentration of its solution, by filtration or decantation.

The novel compounds of the invention, as well as their salts, have particularly good pharmaceutical properties associated with small toxicity. They show remarkable effects. antisecretory and antiulcer. These have been demonstrated in rat experiments at doses between 1a1 and 100 mg / kg by the oral route, primarily by the technique described by Rossi et al., C. R. Soc. Biol., 150, 2124 (1956) and Shay et al., Gastroenterology, 5, 43 (1945).

Toxic Dose (D 50) u. mice are generally greater than 300 mg / kg when administered orally.

In the therapeutic use of the compounds of the invention, the novel compounds of formula (I) may be used either directly or, if desired, in the form of their pharmaceutically acceptable salts, i.e. salts which are nontoxic at the dosages administered.

Examples of pharmaceutically acceptable salts include alkali metal salts (such as potassium, sodium or lithium salts), or alkaline earth metal salts, ammonium salts, salts with nitrogen bases (ethanolamine, lysine), and inorganic acid addition salts (e.g. such as chlorides, sulfates, nitrates, phosphates) or organic (for example, acetates, propionates, succinates, benzoates, fumarates, maleicans, methanesulfonates, isothionates, theophylline acetates, salicylanes, phenolphthaleinates, 'methylene-bis- / Sooyyaaphonates) of these compounds.

The compounds of formula I in which R @ 1 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, R @ 2 represents a hydrogen atom and R @ 1 represents a hydrogen atom or an alkyl radical having from 1 to 4 atoms, have particularly good properties. carbon and is not substituted.

In particular, those compounds of the formula I in which R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, 'R 2 represents a hydrogen atom and R 1' represents a methyl or hydrogen atom, and in particular N- methyl [2- (2-pyridyl) tetrahydro-thiophene] thiocarboxamide.

The following examples, which illustrate the invention without limiting it, show how the process according to the invention can be carried out.

In the following examples, the chromatography was carried out on SiO 2 having a grain size of 0.063-0.20 mm and on alumina 's granulomas of 0.125-0.15 mm.

He translated

An anhydrous ammonia gas stream is discharged into a solution of 25.5 g of [2- (2-pyridyl) -2-tetrahydro-thiophene] carbodithioic acid methyl ester in 360 ml of a mixture of ethyl ether and anhydrous ethanol (83: 17, v / v) for 5 hours. minutes at 25 ° C. The reaction mixture is then stirred for 15 hours at the same temperature and then ammonia gas is added again for 7 hours. The resulting crystals are collected by filtration, washed with 25 ml of ethyl ether and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ^DEG C. This gives a first fraction of the compound, total 12 g. The stirred filtrate is re-saturated with ammonia. for 1 hour and 30 minutes at about 24 ° C. The mixture is allowed to stand for 15 hours at a temperature of about 20 ° C and then stirred again with the addition of ammonia gas for 6 hours at a temperature of about 24 ° C. The crystals formed are separated by filtration, washed with 25. ml of ether and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. The obtained substance (5 g) is added to the first fraction of 12 g, dissolved in 400 ml of boiling acetonitrile and the solution to which activated carbon is added is filtered hot and then, after cooling, left for 1 hour at room temperature. temperature around 0 ° C. The crystals formed are separated by filtration and dried under reduced pressure (2.7 kPa) at a temperature of about 20 DEG C. The product obtained (14.5 g) is dissolved in 350 ml of boiling acetonitrile and the solution is filtered hot and then cooled. It is kept for 1 hour at a temperature of about 0 [deg.] C. The formed crystals are filtered off, washed with 25 ml of acetonitrile and dried under reduced pressure at a temperature of 60 [deg.] C. 12.8 g of [2-] are thus obtained. (2-pyridyl) -2-tetrahydrothienyl] thiocarboxamide, m.p. 192 ° C.

The required [2- (2-pyridyl) -2 H -etrahydrothienol] carbodithioic acid methyl ester is obtained as follows:

To 432 ml of a solution of 1.6 M n-butyllithium in hexane, maintained under argon and cooled to -65 ° C, 320 ml of a mixture of hexamethynossortriamide and anhydrous tetrahydrofuran (47: 53 by volume) was added dropwise over 10 minutes.

Then a solution of 66 g of 2- (2-pyridyltetrahydrothiophene) in 320 ml of hexamethylphosphoric triamide / anhydrous tetrahydrofuran (v / v 47:53) is added over 18 minutes, and after stirring at -65 ° C for 15 minutes. 53 g of carbon disulphide in 300 ml of a mixture of hexamethylphosphoric triamide and anhydrous tetrahydrofuran (47: 53, v / v) are added over 15 minutes. At 60 ° C, 98.6 g of methyl iodide in solution in 300 ml of hexamethylphosphoric triamide and anhydrous tetrahydrofuran (volume ratio 47:53) are added over 30 minutes at a temperature which is still -60 ° C. After stirring for 1 hour at this temperature and then for 55 minutes, the temperature is allowed to rise gradually to +15 [deg.] C. After addition of 2000 ml of distilled water, the reaction mixture is extracted twice with 1800 ml of total ethyl acetate. ml dessi After drying over anhydrous sodium sulfate, filtration and evaporation, 145 g of a brown oil are obtained. 135 g of this substance are chromatographed on 1100 g of neutral silica gel contained in a 6.5 cm diameter column. Wash with 3500 ml of methylene chloride to give 500 ml fractions. Fractions 6 and 7 were combined and evaporated to dryness; the residual (38 g) obtained is dissolved in 150 ml of boiling isopropyl oxide and the solution to which 0.5 g of activated carbon is added is filtered hot and then left to cool at about 0 ^DEG C. for one hour after cooling The crystals formed are separated by filtration, washed with 12 ml of diisopropyl oxide, then twice with 24 ml of total petroleum ether and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 30 g of compound are thus obtained. 15 g of this. The mixture was dissolved in boiling diisopropyloxide (80 ml) and the solution, to which 0.3 g of activated carbon was added, was filtered hot and filtered. cooling is maintained at about 0 ° C for 1 hour. The crystals formed are separated by filtration, washed with 10 ml of dipropyl oxide and then twice with a total of 20 ml of petroleum ether and dried under reduced pressure (0.13 kPa) at a temperature of about 20 ° C. There was thus obtained [2- (2-piperidin-2-yl) -2-tetrahydrothienyl] carbodithioic acid methyl ester (12.4 g), m.p. 64 ° C.

2- (2-trans-tetrahydrofi) tetrahydrothiophene can be obtained by any of the following methods:

(a) 330 g of 2-pyridylmethyl-3-chloropropylmethylsulfide in solution in 400 ml of anhydrous tetrahydrofuran is added dropwise over 20 minutes at a temperature. 25 ° C to a solution of 283 g of potassium tert-butylate in a mixture of 428 ml of hexamethylossortriamide and 2300 ml of anhydrous tetrahydrofuran. After stirring for one hour, the reaction mixture was added to a mixture of 4200 mL of distilled water and 2500 mL of ether. After decantation, the aqueous phase is extracted again with 1700 ml of ether. The ether extracts are combined and washed three times with a total of 12,600 ml of distilled water, dried over anhydrous sodium sulfate and evaporated. ......

189 g of tetramhydrothiophene are thus obtained in the form of a brown oil (Rf = 0.56); a thin layer of silica gel; a solvent: ethyl acetate; .beta.-cyclohexane (volume ratio.: 50:50).

(b) A solution of 152 g of dilsopropylamine in 500 ml of tetrahydrofuran anhydrous. add dropwise over 15 minutes to 940 ml of a solution of 1.6 M n-buuylithium in hexane, which is cooled to -50 ° C. After stirring for 10 minutes and then cooling to -70 ^DEG C., a mixture of 62.5 g of 2-pyridylmethanethiol and 84 g of 1-bromo-3-chloropropane in solution in 1000 ml is added dropwise over 25 minutes. ml of anhydrous tetrahydrofuran. The reaction mixture is then stirred for one and a half hours at -70 ° C and then allowed to rise from -70 ° C to + 5 ° C for 30 minutes. After addition of 2500 ml of distilled water, the mixture is extracted twice with a total of 2500 ml of ether. The ether extracts were combined, washed three times in a total of 7500 mL of distilled water, dried over sodium sulfate (anhydrous) and evaporated.

75.5 g of a brown oil are obtained. 68 g of this oil are chromatographed on 350 g of silica gel contained in a column of diameter

4.6 cm. Wash successively with 10 000 ml methylene chloride, 2000 ml methylene chloride / ethyl acetate (95: 5 by volume) and 1000 ml methylene chloride / ethyl acetate (90: 10 by volume) to give the following fractions in succession: 1000 ml (1) , 330 ml (2), 670 ml (3) and 11 1000 ml fractions (4 to 14), fractions 3 to 14 were combined and evaporated to give 38 g of 2- (2-pyridyl) tetrahydrothiophene as oils.

2-Pyridylmethahthiol can be obtained by the method described in US Patent No. 2,951,848.

2-Pyridylmethyl-3-chloropyridopyridine can be obtained by any of the following methods:

a] 3.1 g of 2-pyridylmethanethiol are added over 10 minutes to a solution of 2 g of potassium lozenge (85%) in 10 ml of distilled water maintained at about 20 ° C. After stirring for 10 minutes, 3.95 g of 1-bromo-3-chloropropane was added over 10 minutes.

The reaction mixture is stirred for 16 hours at the same temperature and then 50 ml of methylene chloride are added. The organic phase is separated by decantation and then washed twice in 100 ml of totally distilled water, dried over anhydrous sodium sulphate and evaporated. 4.3 g of a reddish-brown liquid are obtained, which is collected. chromatograph on 11 g of neutral silica contained in a column 1.4 cm in diameter. Wash sequentially with 300 ml of cyclohexane, 100 ml of cyclohexane / ethyl acetate (99: 1 by volume) and 100 ml of cyclohexane / ethyl acetate (98: 2 by volume) to give fractions. 100 ml. Fractions 35 are combined and concentrated under reduced pressure (2.7 kPa) at 40 ° C. This is obtained

2.7 g of yellow liquid containing undissolved matter. After addition of 25 ml of ether, the insoluble component is separated by filtration. The filtrate is evaporated under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 2.3 g of 2-pyridylmethyl-3-fluorophenyl sulfate are thus obtained in the form of a yellow clear liquid. (Rt = 0.51; thin layer chromatography on silica gel; solvent: ethyl acetate and cyclohexane 50/50 by volume).

(b) A solution of 151 g of sodium hydroxide in 342 ml of distilled water is added to a solution of 453 g of 2- (2-pyrimidylmethylisothiourea dihydrochloride in 840 ml of distilled water which is cooled to 5 ^DEG C. over 5 minutes at a temperature not exceeding 10 DEG C. heating the reaction mixture to about 70 ° C over 20 minutes and, after cooling to 3 ° C, a solution of 92.5 g of sodium hydroxide in - 210 ml of distilled water is added dropwise over 3 minutes. 303 g of 1-bromo-3-chloropropane are added at 10 DEG C. Stirring is continued for 20 hours at a temperature of about 20 DEG.

The reaction mixture is then extracted four times with 1100 ml of methylene chloride. The organic extracts were combined, washed three times with a total of 600 ml of distilled water, and then dried over anhydrous sodium sulfate. After filtration, the solution obtained is poured onto 360 g of neutral silica gel contained in a 6 cm diameter column and then washed with 2700 ml of methylene chloride. The first 600 ml fraction was eliminated and then a second 3200 ml fraction was obtained, which was evaporated under reduced pressure (2.7 kPa) at 20 ° C. 330 g of 2-pyrirylmethyl-3-chloropropylmethylsulfide are thus obtained in the form of a yellow liquid.

2- (2-Pyridylmethyl) thiourea dihydride can be obtained as follows:

To 17.6 g of thiourea in suspension in 100 ml of boiling ethanol is added dropwise over 15 minutes 30 g of hydrochloride-2-celhrmethyl-2-pyridine in a solution of 100 ml of ethanol at 60 ^DEG C. The boiling is maintained for 90 minutes and then cooled the resulting crystals filtered, washed twice with total 100 ml of ethanol and dried under reduced pressure (2.7 kPa) at a temperature of about ⁷ 20 ° C in the presence of KOH pastilles. There was thus obtained 2- (2-pyrimidylmethyl) isothiourea dihyrrhchloride (41.7 g), m.p. 220 ° C.

2-Chloromethylpyridine hydrochloride can be obtained by the method described in German Patent No. 1,204,231.

Example 2

The procedure of Example 1 is followed but starting from 13.5 g of [2- (6-methyl-2-pyridyl) -4-tetrahydro-thienyl] carbodithioic acid methyl ester, after filtration of the first and second fractions, 5.8 g and 1.8 g are obtained. crystallized compound followed by 5.1 g of the residue resulting from the concentration of the filtrate. The two fractions (7.6 g total) were combined and dissolved in boiling ethanol (140 mL). The solution to which the activated carbon is added is filtered while hot and then, after cooling, kept at 0 ° C for one hour. The resulting crystals are separated by filtration, washed twice with a total of 10 ml of ethanol and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 5.9 g of crystallized substance are thus obtained. The residue (5.1 g) was dissolved in boiling ethanol (100 ml) and the solution to which activated charcoal was added was filtered hot and then, after cooling, kept at 0 ° C for one hour. The crystals formed are separated by filtration, washed twice with a total of 10 ml of ethanol and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 2.8 g of crystallized material are thus obtained, which is added to the 5.9 g obtained previously.

The mixture was dissolved in boiling ethanol (150 ml) and the solution to which activated charcoal was added was filtered hot and then stored for one hour at about 20 ^DEG C. After cooling, the resulting crystals were collected by filtration, washing twice with a total of 20 ml of ethanol. and dried under reduced pressure (0.13 kPa) at 50 ° C. There was thus obtained [2- (6-methyl-2-pyridyl) -2-tetrahydrothienyl] thiacarboxamide (7.4 g), m.p. 171 ° C.

[2- (6-Methyl-2-pyridyl) -2-tetrahydro-thienyl] -carbithioic acid methyl ester is obtained as follows:

Proceed as in Example 1 to prepare [2- (2-pyridyl) -2-tetrahydrothienyl] carbodithioic acid methyl ester, but starting from 32.8 g of 2- (6-methyl-2-pyridyl) tetrahydrothiophene and 171 ml of 1.6 M-n-butyllithium in hexane gave 73.4 g of crude product which was chromatographed on 700 grams of neutral silica gel contained in a 5.6 cm diameter column.

Wash with 3300 mL of cyclohexane / ethyl acetate (95: 5, v / v) to give 1 fraction of 1300 mL and 6 fractions of 30 mL each. Fractions 3-7 are combined and evaporated under reduced pressure (2.7 kPa) at 40 ° C and the residue is dissolved in 200 ml of diisopropyl oxide (residue weight 39.3 g). After cooling, the solution is left at about 0 ° C for one hour. The resulting crystals are separated by filtration, washed twice in total in 50 ml of diisopropyl oxide and dried under reduced pressure (0.13 kPa) at 50 ° C.

There was thus obtained [2- (6-methyl-2-pyridyl) -2-tetrahydrothienyl] carbodithioic acid methyl ester (30.3 g) melting at 80 ° C.

2- (6-methyl-2-pyridyl) tetrahydrothiophene can be obtained as follows:

A solution of 113 g of diisopropylamine in 380 ml of anhydrous tetrahydrofuran was added dropwise to 663 ml of a solution of 1.6 M n-butyllithium in hexane cooled to -60 ^° C. After stirring for 5 minutes, a mixture of 55.4 g of (6-methyl-2-pyridyl) methanethiol and 58 g of 1-bromo-3-chloropropane in solution in 760 ml of anhydrous tetrahydrofuran was added dropwise over 16 minutes at the same temperature. then stirred for one and a half hours at -70 ° C and then for one and a half hours while allowing the temperature to rise from -70 ° C to about 20 ° C.

After addition of 1300 ml of distilled water, the mixture is extracted three times with 2600 ml of ethyl acetate. The organic extracts were combined, washed three times with a total of 1500 ml of distilled water, dried over sodium sulfate and evaporated. The residue (63.3 g) is chromatographed on 330 g of silica gel contained in a 4.5 cm diameter column. 4500 ml of cyclohexane, 2000 ml of a mixture of cyclohexane and ethyl acetate (98: 2 by volume) and 200 ml of a mixture of cyclohexane and ethyl acetate (90: 10 by volume) are dissolved, yielding 500 ml fractions. Fractions 5 to 17 are combined, evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This afforded 33.3 g of 2- (6-methyl-2-pyridyl) tetrahydrothiophene as a yellow oil _(Rf = 0.65, thin layer chromatography on silica gel, solvent: ethyl acetate and cyclohexane in the volume ratio 50: 50) .

(6-Methyl-2-pyridyl) methanthiol can be obtained as follows:

To a solution of 37 g of sodium hydroxide in tablets in 140 ml of distilled water is added dropwise over 15 minutes a solution of 114.7 g of 2- (6-methyl-2-pyridylmethyl) -isothiourea dihydrochloride in 280 ml of distilled water, cooled to 15 ° C. After cooling to 20 DEG C., the reaction mixture is extracted three times with a total of 480 ml of ether, the ether extracts are combined, washed three times with 300 ml of totally distilled water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. pressure 2.7 kPa) at 30 ° C.

55.4 g of (6-methyl-2 ' -Pyridyl) methanthiumium are thus obtained in the form of a yellow oil.

2- (6-methyl-2-pyridylmethyl) -isothiourea dihydrochloride can be obtained as follows:

2 g of 2-chloromethyl-6-methylpyridine hydrochloride is dissolved in 300 ml of ethanol at 60 ^{DEG C.} and the solution obtained is added dropwise to 47.5 g of thiourea in suspension in 300 ml of boiling ethanol over a period of 5 minutes. The boiling is maintained for 90 minutes and then, after cooling to 5 ° C, the crystals formed are separated by filtration, washed twice with a total of 100 ml of ethanol and then with 20 ml of diisopropyl oxide. After drying under reduced pressure (2.7 kPa) at about 20 ° C in the presence of sodium hydroxide in tablets, 111.7 g of dihydrochloride are obtained.

2- (6-methyl-2-pyridylmethyl) isothiourea melting at 222 ° C.

2-Chloromethyl-6-methylpyridine hydrochloride can be obtained according to the method described in German Patent No. 1,204,231.

Example 3

To a solution of 10 g of [2- (2-pyridyl) -2-tetrahydrothienyl] carbodithioic acid methyl ester in 25 ml of ethanol, maintained at about 20 ° C, was added dropwise

7.5 ml of a solution of methylamine in ethanol (33 why, weight / volume). The solution is maintained at about 20 ° C for 30 minutes and crystals appear after cooling to about 0 ° C for 30 minutes. These are separated by filtration, washed twice with a total of 20 ml of ethanol and dried under reduced pressure (2.7 kPa) at 20 ° C.

The material thus obtained (8.7 g) is dissolved in 55 ml of boiling ethanol and the solution, to which 0.2 g of activated carbon is added, is filtered and then cooled to 0 ^DEG C. for 30 minutes.

The crystals formed are separated by filtration, washed twice with a total of 20 ml of ethanol and dried under reduced pressure (2.7 kPa).

7.4 g of N-methyl- [2- (2-pyridyl-28505-dyl-g-tetr-ahydrothienyl) -thiocarboxamide, melting at 131 ° C, are thus obtained.

Example 4

A solution of [2- (2-pyridinyl) -2-tetrahydrothienyl] carbodithioic acid-6,4-g-methyl ester and 2.9 g of n-heptylamine in 75 ml of ethanol is heated to boiling temperature. under reflux - condenser - for 2 hours 30 minutes.

The reaction mixture is concentrated under reduced pressure (2.7 kPa) at 40 ° C. Evaporation reaction mixture (8.2 g) to which is added

6.8 g of the substance obtained under the same conditions are chromatographed on 150 g of neutral silica gel contained in a column of diameter

3,5- cm. 7300 ml of a mixture of cyclohexane and ethyl acetate are eluted (volume ratio: -98: -2) to give the following fractions: fractions -1-600 ml, fractions 2 to -8 each 250 ml. Fractions 14 to 40 were pooled and evaporated under reduced pressure (0.27 kPa) at -40 ° C.

Takto- - with '- yield - 8.3 g -NN-heptyl (2- (2-pyri.dyi) -2- tetrahydropyran othienyl jthiokarboxamidu in the - form of a clear yellow liquid - (R _f - 0.40, chromatography thin film - silica gel, solvent: - cyclohexane and ethyl acetate - 80:20 by volume].

Example 5

A solution of 10 g of [2- (2-pyridyl) -2-tetrahydrothienyl] carbodithioic acid methyl ester in 15-g of n-dodscylamine is heated for 50 minutes at - 110 ° C. The reaction mixture is chromatographed on 200 g of silica gel contained in a 3.7 cm diameter column. Elute with 1800 mL of cyclohexane-ethyl acetate - (90:10 by volume) to give fractions of 300 mL and -3 each - 500 mL. Fractions 2-4 are combined and concentrated under reduced pressure ( 2.7 kPa) at a temperature of 40 DEG C. The residue is dissolved in 75 ml of ethanol, the solution to which 0.3 g of activated carbon is added is filtered while hot, and, after cooling, stored at 30 DEG C. for 30 minutes. The crystals formed are separated by filtration, washed twice with a total of 40 ml of ethanol and dried under reduced pressure of -2.7 kPa at a temperature of about 20 ° C.

The obtained substance (11.5 g) is dissolved in 75 ml of boiling ethanol and the solution to which 0.3 g of active charcoal is added is filtered and, after cooling, stored for 30 minutes at room temperature. temperature of the eye * · lo '-Q cc. The crystals formed are separated by filtration, washed twice - total 50 ml of ethanol and dried - under reduced pressure (0.13 kPa) at -35 ° C.

Thus. 10.2 g of N-n-dodecyl (2- (2-pyridyl) -2-tetrahydrothienyl) thiocarboxamide melting at -60 DEG C. are obtained.

Example. 6

A solution of - 10 g of (2- (2-pyridyl) -2-tetrahydrothienyl) carbodithioic acid methyl ester in 100 ml of benzylamine is heated for

- minute - - at a temperature of 110 ° C. After evaporation of the reaction mixture is obtained. 17.2 g of residue, - which is - chromatographed on 150. g silica gel. containing a 3.7 cm diameter column. Elute 1500 ml of the mixture - cyclohexane and ethyl acetate - (volume ratio - 90: 1.0) - and obtain fractions of 250 ml. Fractions 3 to 6 are combined and evaporated under reduced pressure. 2.7-kPa and -40 ° C.

The residue (10.5 g) is dissolved in -50 ml of boiling ethanol, and the solution, to which 0.2 g of activated carbon is added, is filtered while hot and then cooled. It is kept at about 5 ° C for about 15 hours The crystals formed are separated by filtration, washed twice with a total of 20 ml of ethanol and dried under reduced pressure of -0.13 kP.a at a temperature of about 40 ° C. .

There was thus obtained N-benzyl- (2 (2-pyridyl) -2-tetrahydrothienyl) thiocar boxamide melting at 71 ° C.

Example 7

A solution of 12.8 g of (2- (2-pyridyl) -2-etrahydrothienyl) carbodithioic acid methyl ester and -3 g of ethanolamine in 150 ml of ethanol is heated at reflux for one hour. After 30 minutes of evaporation of the reaction mixture under reduced pressure of 2.7 kPa and at 50 DEG C., the residue obtained (14.8 g) is dissolved in 80 ml of ethanol having a boiling point and a solution until the reaction mixture is stirred at room temperature. to which 0.3 g of activated charcoal is added, is filtered while hot, and then, after cooling, stored for one hour at a temperature of about -0 DEG C. The formed crystals are separated by filtration, washed twice for a total of 30. ml of ethanol and dried under reduced pressure (0.13 kPa) at a temperature of 50 ° C.

There was thus obtained 11.4 g of N-2-hydroxyethyl [2- (2-pyridyl) -2-tetrahydro-thienyl] thio carboxamide, m.p. = 132 ° C.

Example 8

A solution of 15 g of methyl [2t (2-pyridyl) -2-trahydrothienyl] carbodithioic acid methyl ester in 20.7 g of N, N-dimethylethylenediamine is heated for - 55 minutes at room temperature. After concentrating the reaction mixture under reduced pressure (0.27 kPa) at 60 [deg.] C., the residue obtained (18.4 g) is dissolved in 70 ml of ethanol and the solution into which 4 ml of methanesulfonic acid are added, the evaporation is - under reduced pressure - (2.7 kPa) - at -50 ...

The residue obtained is dissolved in 25 ml of distilled water and the solution, the alkalinity of which is raised to pH 8 by addition of 35 ml of a 2 M aqueous sodium hydroxide solution, is extracted three times with a total of 450 ml of ethyl ether. The organic extracts are combined and washed twice with a total of 100 ml of distilled water, dried over anhydrous sodium sulphate. addition of 0.5 g of activated carbon is filtered and evaporated under reduced pressure (2.7 kPa) at 40 DEG C. The residue (16 g) is chromatographed on 160 g of alumina contained in a 2.7 cm column. Elute with 1500 ml of cyclohexane / ethyl acetate (90: 10 by volume) to give 1 fraction of 500 ml and 10 fractions of 100 ml each. Fractions 2 to 11 are combined and evaporated under reduced pressure (2.7 g). kPa) at 40 DEG C. The residue (11.6 g) is dissolved in 200 ml of ethanol and the solution to which 3.8 g of methanesulfonic acid is added is kept at a temperature of about 20 DEG C. for two hours. filtration, washed twice with a total of 40 ml of ethanol and dried under reduced pressure (0.13 kPa) at 55 DEG C. 7.2 g of N-2-dimethylaminoethyl [2- (2-pyridyl) -2- (2-pyridyl) -2- methanesulfonate are thus obtained. tetrahydrothienyl] thiocarboxamide having a melting point of 138 ° C.

Example 9

A solution of 20 g of methyl [2- (2-pyridyl) -4-tetrahydro-thienyl] carbodithioic acid in 100 ml of dimethylamine is heated in an autoclave for 3 hours 40 minutes to a temperature of about 125 ° C. After cooling to about 20 ° C, the autoclave is evacuated and rinsed with 200 ml of methylene chloride which is added to the reaction mixture. The solution is evaporated under reduced pressure (2.7 kPa) at 40 ° C. The residue obtained (20.7 g) is dissolved in 50 ml of boiling ethanol and the solution to which 0.5 g of activated carbon is added is filtered hot and then, after cooling, stored at about 0 ° C for one hour. . The crystals formed are separated by filtration, washed twice with a total of 20 ml of ethanol and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C.

The obtained material was dissolved in boiling ethanol (45 ml), activated carbon (0.5 g) was added, the solution was filtered hot and then stored at 0 ° C for one hour after cooling. The crystals formed are separated by filtration, washed twice with a total of 20 ml of ethanol and dried under reduced pressure (0.13 kPa) at 45 ° C.

There was thus obtained 11.8 g of N, N-dimethyl- [2- (2-pyridyl) -2-tetrahydrothienyl] thiocarboxamide, melting at 100 ° C.

Example 10

A solution of 19 g of [2- (2-pyridyl) -2-tetrahydrothienyl] carbodithioic acid methyl ester in 280 ml of morpholine was heated at reflux for 2 hours. Evaporation of the reaction mixture under reduced pressure (0.27 kPa) at 90 ° C gives 23 g of a residue which is dissolved in 200 ml of boiling ethanol and a solution to which 0.2 g of activated carbon is added. , heat filtered and then, after cooling, stored at about 0 ° C for one hour. The crystals formed are separated by filtration, washed with 20 ml of ethanol and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C.

The thus obtained substance (16.5 g) is dissolved in 145 ml of boiling ethanol and a solution to which 0.2 g of activated carbon is added. It is filtered hot and then, after cooling, kept at about 0 ° C for one hour and thirty minutes. The crystals formed are separated by filtration and washed with 15 ml of ethanol and then with 15 ml of diisoproprole oxide. After drying under reduced pressure (0.13 kPa) at 55 ° C, 12.5 g of 2-morpholinothiocarbonyl-2- (2-pyridyl) -etrahydrothiophene with a melting point of 139 ° C is obtained.

Example 11

A solution of 20 g of [2- (2-pyridyl) -2-tetrahydro-thienyl] carbodithioic acid methyl ester in 100 ml of piperidine was heated at about 100 ° C for 1 hour. Evaporation of the reaction mixture at 60 DEG C. under reduced pressure (0.27 kPa) yields 26.1 g. brown. oil which is chromatographed on 260 g of silica gel contained in a 4 cm diameter column. Elute successively with 1250 ml of cyclohexane, 1250 ml of a mixture of cyclohexane and ethyl acetate (volume ratio 99: 1), 1250 ml. mixtures of cyclohexane and ethyl acetate (98: 2 by volume), 3250 ml of cyclohexane and ethyl acetate (97: 3 by volume) and 4250 ml of cyclohexane and ethyl acetate (95: 5 by volume) to give 250-ml fractions. . Fractions 29 to 46 are combined and concentrated under reduced pressure (2.7 kPa) at 40 ° C. The product obtained (10.5 g) is dissolved in 55 ml of boiling isopropanol and the solution to which 0.2 g of activated carbon is added is filtered hot and then, after cooling, kept at a temperature of about 0 ° C.

The crystals formed are separated by filtration, washed twice with a total of 20 ml of isopropanol and dried under reduced pressure (0.13 kPa) at 50 ° C.

5.4 g of 2-piperidine-thiocarbonyl-2- (2-pyridyl) -tetrahydrothiophene with a melting point of 90 DEG C. are thus obtained.

Example 12

A solution of 20 g of methyl 4- (4-pyridyl) -4-tetrahydrothienyl] carbodithioic acid methyl ester in 35 ml of N-methylpiperazine was heated at 110 ° C for 1 hour 15 minutes. After concentration of the reaction mixture under reduced pressure (0.27 kPa) at 70 ° C,

26.7 g of residue which is chromatographed on 270 g of alumina contained in a 3.4 cm diameter column. 1900 ml of a mixture of cyclohexane and ethyl acetate (80:20 by volume) are eluted and 100 ml fractions are obtained. Fractions 5 to 14 are combined and evaporated under reduced pressure (2.7 kPa) at 40 ° C. Ressduum (20.4 g) was dissolved in boiling ethanol (45 ml) and the solution, to which 0.4 g of activated carbon was added, was then stored at about 0 ° C for one hour after cooling. The crystals formed are separated by filtration, washed twice with 20 ml of diisopropyl oxide and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 5.4 g of crystalline material are obtained and, after evaporation of the filtrate under reduced pressure (2.7 kPa) at 40 DEG C., a residue of 13.5 g is obtained. The latter residue is chromatographed on 135 g of alumina contained in a column of diameter. 2.7 cm. Elute successively with 1000 ml of cyclohexane, 200 ml of cyclohexane and ethyl acetate (99: 1 volume ratio), 1800 ml of cyclohexane and ethyl acetate (98: 2 volume ratio) and 2000 ml of cyclohexane and ethyl acetate (96: 4 volume ratio). ) and fractions of 100 ml each were obtained. Fractions 13 to 50 are combined and evaporated under reduced pressure (2.7 kPa) at 40 ° C. The residue obtained (6.2 g) was dissolved in 40 ml of boiling diisopropyl oxide and the solution was kept for one hour at about 0 ° C after cooling. The resulting crystals are separated by filtration, washed twice in total in 4 ml of diisopropyl oxide and dried under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. The material obtained (1.9 g), to which the 5.4 g fraction isolated previously was added, was dissolved in 35 ml of boiling ethanol and the solution to which 0.2 g of activated carbon was added was filtered hot and then cooled. is stored for one hour at about 0 ° C. The crystals formed are separated by filtration, washed twice with a total of 10 ml of ethanol and dried under reduced pressure (0.13 kPa) at 40 ° C.

There was thus obtained 2 - [(4-methyl-1-piperazinyl) thiocarbonyl] -2- (2-pyridyl) tetrahydrothiophene (5.3 g) melting at 124 ° C.

In a similar manner, the compounds of the following examples can be obtained:

Example 13

N-methyl-2- (6-methyl-2-pyridyl) -2-tetrahydrothiophenecarbothloamide, m.p. 121 ° C.

Example 14

N-ethyl-2- (2-pyridyl) -2-tetrahydrothiophenecarbothioamide, m.p. 96 ° C.

Example 15

N-n-butyl-2- (2-pyridyl) -2-tetrahydrothiophenecarbothioamide, b.p. 178-183 ° C.

Example 16

N-methyl-2- (4-methyl-2-pyridyl) -2-tetrahydrothiophenecarbothioamide, m.p.

Example 17

N-methyl-2- (5-methyl-2-pyridyl) -2-tetrahydrothiophenecarbothioamide, m.p. 134 ° C.

Example 18

2- (4-n-Butyl-2-pyridyl) -2-methylaminocarbothioyltetrahydrothiophene, m.p. 120 ° C.

Claims (5)

SUBJECT A process for the preparation of the novel 2- (2-pyridyl) tetrahydro-thiophene derivatives of the general formula I in which R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and R 1 and R 2, identical or different, represent a hydrogen atom or a C 1 -C 15 alkyl radical optionally substituted by a hydroxy, alkylamino or dialkylamino radical having 1 to 4 carbon atoms, a phenyl radical, a carboxyl group or a alkoxycarbonyl group C 1 -C 4 alkyl; or R 1 and R 2 together form a 5 or 6 membered heterocyclic moiety which optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen and is optionally substituted with C 1 -C 4 alkyl, as well as 1 nitrogen addition salts thereof bases, their metal salts and their acid addition salts, characterized in that they are treated with an amine of the formula II Ri Z HN X Rz (П) in which R 1 and R 2 are as defined above, to the dithioester of formula III wherein: R is as defined above and R 3 represents a C 1 -C 4 alkyl radical, a benzyl radical or a carboxymethyl radical, the substance obtained is isolated and optionally converted into a nitrogen base addition salt, a metal salt or an acid addition salt. 2. A process according to claim 1 wherein the amine of formula (I) wherein at least one of R1, R2 is an alkyl radical substituted with an alkylamino or hydroxy group is used to produce a compound of formula I. Ri / HN \ Rz where R1 and R2 are as defined above, with the substituents R1 and R2 in protected form and upon completion of the reaction with the dithioester, the protecting group is eliminated, the compound isolated and optionally converted into an acid addition salt. 3. The process of item 1 for the preparation of 2- (2-pyridyl) tetrahydrothiophene derivatives of the general formula I wherein R represents a hydrogen atom or R represents an alkyl radical containing from 1 to - R @ 4 represents a hydrogen atom and R @ 1 represents an alkyl radical containing from 1 to 4 carbon atoms, characterized in that - an amine of the general formula II is reacted - in which R @ 1 and R @ 2 are as defined above - the dithioester of the formula III, - in which -R is as defined above and R3 'represents an alkyl radical having from 1 to 4 carbon atoms, benzyl' or 'carboxymethyl and then recovering the obtained compound. 5. The process of item 1 for the preparation of a 2- (2-pyridyl) tetrahydrothiophene derivative of the Formula I wherein R is hydrogen or an alkyl radical containing from 1 to 4 carbon atoms and either R2 is hydrogen and R1 is unsubstituted alkyl, containing from 5 to 15 carbon atoms or an alkyl radical containing from 1 to 15 carbon atoms, substituted by hydroxy, alkylamino or dialkylamino, the alkyl moieties of which contain from 1 to 4 carbon atoms, phenyl, carboxyl or alkyloxycarbonyl, the alkyl moiety thereof contains from 1 to 4 carbon atoms, or R1 and R2 are each hydrogen or identical or different, and represent each alkyl radical containing from 1 to 15 carbon atoms, optionally substituted by hydroxy, - alkylamino or dialkylamino, - whose alkyl the moieties contain from 1 to 4 carbon atoms, phenyl, hydroxyl or alkyloxycarbon yl of which the alkyl moiety contains from 1 to 4 carbon atoms, or R 1 and R 2 together form a heterocyclic ring of 5 or 6 atoms, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen, is optionally - substituted with an alkyl radical containing from 1 to 4 carbon atoms and addition salts of compounds of formula I in which R, R 1 and R 2 are as defined above, nitrogenous bases, metal salts and - acid addition salts thereof characterized in that an amine of formula (II) in which R1 and R2 are as defined above is reacted with a dithioester of formula (III) in which R is as defined above and R3 is - either an alkyl radical containing from 1 to 4 carbon atoms or a benzyl residue, or a carboxymethyl group, and recovering the obtained compound, which is optionally converted into a nitrogen base addition salt, a metal salt or an addition salt with acid.