CS238391B2 - Thioformamide derivatives sulphoxides production method - Google Patents

Abstract

Process for the production of thioformamide sulfoxides derivatives of formula (I) CSNHR 2 I fteř 0 (AND) electrochemical oxidation, characterized by by electrochemically oxidizing the compound of formula II cx Het CSNHR in an electrolyte containing at least 55% water at pH 7 to 7.5 in the presence of oxidative of reagent I + obtained directly in the reaction mixture electrochemically from ammonium iodide; an electrode with inserted potential is used in the range of 0.6 to 0.8 V followed by isolating the resulting product.

Description

The present invention provides a process for the preparation of sulfoxides of thioformamide derivatives of the general formula IcX

I Hat

CSNHR dl where

R represents a hydrogen atom or a straight or branched chain alkyl radical of 1 to 4 carbon atoms,

Het means an aromatic heterocyclic radical comprising 3-pyridyl, optionally substituted by a straight or branched chain alkyl group having 1 to 4 carbon atoms or a halogen atom, 3-quinolyl, 4-pyrldazinyl, 5-pyrlmidinyl, 5-thiazolyl, thieno [2,3] -b] -5-pyridyl and thieno [3,2-b-6-pyrldyl a

Y represents a chemical bond or a methylene residue, by electrochemical oxidation, characterized in that a compound of formula II cX is electrochemically oxidized

CSNHR

Het lil) where

R, Het and Y are as hereinbefore defined, in an electrolyte containing at least 55% water at pH 7 to 7.5 in the presence of a ⁴ L oxidizing agent obtained directly in the reaction mixture by electrochemically ammonium iodide using an inserted potential electrode, in the range of 0.6 to 0.8 V, followed by isolation of the resulting product.

The presence of an oxygen atom on the sulfur atom is the cause of the asymmetry of the molecule, which, together with the asymmetric carbon atom adjacent to the sulfur atom, theoretically causes four stereoisomers, which may optionally be separated as two pairs of racemates.

The advantage of the process according to the invention over the prior art is that it is possible to obtain compounds in which the sulfoxide group is in the trans position relative to the thioformamide group.

From a practical point of view, it is particularly advantageous to use as the oxidizing agent I ^{+ an} agent which produces an alkali metal iodide such as potassium iodide, ammonium iodide or triethyl-n-propylammonium iodide or aryl iodide such as phenyl iodide. (0.6 to 0.8 V relative to the calomel saturated electrode reference).

The electrolyte in which the reaction is carried out usually consists of: - a water-miscible organic solvent which allows the compound of formula II to be dissolved, for example acetonitrile or an alcohol such as methanol or ethanol, - distilled or demineralized water, - a pH 7 buffer water, the buffer is usually a mixture of a 0.1 M aqueous solution of dibasic phosphate and ammonium dihydrogenphosphate.

The relative proportion of water and organic solvent depends on the water solubility of the sulfide of formula II. The percentage of water in the electrolyte is usually in the range 10 to 99%, preferably 40 to 80%, especially at least 55%.

The amount of electricity required to oxidize the compound of Formula II to the compound of Formula I is about 4 to 8 F / mol.

Preferably, the oxidation is carried out in an electrolysis apparatus equipped with a septum at a temperature of from 0 ° C to the reflux temperature of the reaction mixture, preferably at a temperature of 20 to 60 ° C.

According to a preferred embodiment of the method according to the invention, the electrolytic oxidation is carried out in an apparatus comprising an anode and a reference electrode, an anode compartment, a partition, a cathode compartment and a cathode, the apparatus having these properties.

a) The anode is of a solid, non-corrosive material that conducts electric current, preferably of platinum, so that the oxidation of the compound of formula II occurs at a voltage slightly lower than the oxidation potential of the components in the solvent, said voltage being measured compared to a reference saturated calomel electrode separated from the electrolyte by potassium chloride agar.

b) The anode compartment contains the above-mentioned electrolyte for oxidizing the compound of formula II.

c) The partition consists of a porous material, for example a glass or porcelain frit or an ion-permeable membrane, preferably a cation-exchange membrane. [It is particularly advantageous to use NAFLON 125 (Dupont).]

d) The cathode compartment contains the same electrolyte as the anode compartment.

e) The cathode is made of a conductive material, the nature of which is not essential in carrying out the process according to the invention, it can be the same material as the anode or another material.

According to a preferred embodiment of the method according to the invention, the anode, cathode and the splitter gate 38381 are mounted in a vertical plane. In addition, pressure filters can be used.

the electrolyte flow in the anode compartment in the closed circuit compartment can be ensured by the pump. The circuit may further comprise other additional devices such as heat exchangers and expansion flasks. In particular, the expansion flask allows the electrolyte to be fed to the anode compartment while supplying the sulfide of formula II and the sulfoxide of formula I for subsequent extraction.

The electrolyte on the cathode can also circulate. In a preferred embodiment of the method according to the invention, this circulation is similar to that in the anode compartment, which makes it possible to equalize the pressure on both sides of the separating membrane.

According to a further preferred embodiment of the method according to the invention, the intervening elements are incorporated into the anode and cathode compartments. These elements, on the one hand, prevent deformation of the membrane which provides ion exchange and, on the other hand, prevent the membrane from contacting the electrodes. These elements also ensure better homogeneity of the electrolyte concentration in the anode compartment. At the same time, turbulence arises, which improves electrolysis. These elements are also made of synthetic, chemically inert polymers that do not conduct electricity. These may be cross-linked fibers, processed in the form of a fabric or grid, or in the form of a non-woven fabric. In most cases, these elements are oriented parallel to the electrodes and the partition.

According to another embodiment of the invention, the chamber may consist of only a single vessel, cylindrical or approximately cylindrical in shape, of an inert material with respect to the electrolyte components. The chamber comprises a working electrode of the above type. The shape of the electrode is adapted to the shape of the chamber.

In general, any electrolysis chamber comprising an anode and a cathode separated from one another by a plurality of ion conducting baffles may be used, the exact location of the elements being not essential to the practice of the present invention.

The products obtained by the process according to the invention can be purified by conventional physicochemical methods, in particular crystallization and chromatography.

The compounds of formula (II) may be obtained in a manner known per se, for example according to the European patent application published under 0046 417.

Indirect electrochemical oxidation using an I ⁺ ion is known from Tatsuya Shono et al. (Tetrahedron Letters (1979), 165-168). However, this publication does not disclose that a similar method could be used to oxidize the sulfides of Formula II and selectively oxidize them.

The compounds of formula I obtainable by the method of the invention have antihypertensive properties and can be used to treat elevated blood pressure.

At doses of 0.02 to 50 mg / kg orally, these agents reduce arterial blood pressure in spontaneously hypertensive rats (SHR rats) of the Okamoto-Aoki strain. The use of these rats to monitor antihypertensive agents has been described in J. L. Roba, Lab. Anim. Sci., 28, 305 (1976).

The DL 50 for these agents in mice is usually greater than 300 mg / kg orally.

The invention will be illustrated by the following examples.

Example 1

In a 150 ml electrolysis chamber containing a working electrode consisting of a 16 cm ² platinum grid, another electrode, also a 4.5 cm ² platinum grid and a saturated calomel reference electrode, separated from the electrolyte by a potassium chloride agar gel 2 g of N-methyl 1-2- (3-pyridyl) -2-tetrahydrothiophenecarbothioamide, 67.5 ml of acetonitrile, 7.5 ml of demineralized water, 75 ml of a buffer of an aqueous solution of ammonium phosphate [NH3 H5 POx 0.1 ml] are successively introduced. PH 7 and 0.4 g of triethyl-n-propylammonium iodide were stirred with a magnetic stirrer made of polytetrafluoroethylene and de-oxygenated by bubbling nitrogen. The working electrode voltage was adjusted to a constant value of +0.8. In relation to the calomel electrode. After passing in 1150 koulombů solution is heated at 42 ³ C. Then the voltage at the working electrode is adjusted to a value in order to maintain the temperature of 1 1a of 45 ^C C. The current flowing through chamber 11 is adjusted to a value from 400 to 500 mA. A 5 N aqueous ammonia solution is added during electrolysis to maintain a pH of 11a equal to or greater than 7. The electrolysis is stopped when the amount of electricity passing through the chamber reaches 3188 spheres, i.e. 3.93 farads per mole of oxidized product.

The reaction mixture is then evaporated to dryness under reduced pressure (2.7 kPa). The residue is extracted twice with a total of 140 ml of ethyl ether. The ether phases are washed with 50 ml of distilled water and discarded. The aqueous phases are combined and extracted 20 times with 50 ml of ethyl acetate each time. The organic extracts were combined and dried over sodium sulfate. The solution is filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C. In this way, a first portion of 1395 mg of N-methyl-2- (3-pyridyl) -2-tetrahydrothiophenecarbothioamide-1-oxide is obtained in the form of a trans as a white solid, m.p. 207 DEG C., recrystallized from ethyl acetate.

Rf = 0.24 on silica gel 11a thin layer chromatography, eluting with ethyl acetate / methanol: 75/25;

The aqueous layer after extraction with ethyl acetate was further extracted three times with a total amount of 180 ml butanol. The organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness at 40 ^DEG C. under reduced pressure (2.7 kPa) to give 450 mg of crude product, which is purified by preparative thin layer chromatography on silica gel using ethyl acetate and ethyl acetate. of methanol in a volume ratio of 70:30. The product-containing zone is excised after detection of the product in ultraviolet light and the product is eluted with a 50:50 v / v mixture of ethyl acetate and methanol. A second crop of 155 mg of N-methyl-2- (3'-pyridyl) -2-tetrahydrothiophenecarboamide-1-oxide is obtained in the form of a trans, m.p. 207 ° C.

N-Methyl-2- (3-pyridyl) -2-tetrahydrothiophenecarbothioamide can be obtained by the method of European Application Publication No. 0046 417.

Example 2

A 150 ml electrolytic cell containing a working electrode consisting of a platinum grid of 16 tin ² surface, another electrode also consisting of a platinum grid of 8 cm ² surface and a reference electrode of saturated calorael separated from the electrolyte by an agar gel with potassium chloride is gradually fed 2 g of N-methyl-2- (3-pyridyl) -2-tetrahydrothiopyrancarbothiamide, 67.5 ml of acetonitrile, 7.5 ml of demineralized water, 75 ml of a buffer with an aqueous ammonium phosphate solution of pH 7 ((NH4zHPOi (0.1 Μ)) NH 3 H 2 PO 4 (0.1 H) and 0.25 g ammonium iodide.

The reaction mixture is stirred with a magnetic stirrer overlaid with polytetrafluoroethylene and degassed with a nitrogen stream. The working electrode voltage 11a is adjusted to a constant value of +0.8 V with respect to the saturated calomel electrode. The passing current is 700 to 150 mA.

During the electrolysis, an additional 5 N solution was added to the aqueous ammonia solution to maintain a pH of 7 or higher. Electrolysis is stopped when 5484 coulombs, i.e. 7.15 farad per 1 mol of oxidized product, pass through the chamber.

The reaction mixture is then evaporated to dryness under reduced pressure (2.7 kPa). The residue is extracted three times with a total of 50 ml of ethyl ether, the ether phases are washed twice with 30 ml of distilled water and discarded. The aqueous phases are combined and extracted ten times with a total of 300 ml of ethyl acetate to remove the non-polar by-products. The organic phases are washed five times with 50 ml of distilled water.

The aqueous phases are combined and extracted 3 times with a total of 150 ml of 1-butanol. The organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 30 ° C. 850 g of crude product are obtained, which is purified by thin layer chromatography on silica gel using a 70/30 mixture of ethyl acetate and methanol. The product-containing area is excised as determined by ultraviolet light and eluted with a mixture of ethyl acetate and ethanol by volume. 50:50 ratio. In this way, 392 mg of N-methyl-2- (3-pyridyl) -2-tetrahydropyrancarbothioamide-1-oxide are obtained in the form of trans, m.p. 228 DEG C.

_Rf = 0.24 in thin layer chromatography, silica gel 11 using ethyl acetate: methanol = 75:: 25th

N-methyl-2- (3-pyridyl) -2-tetrahydropyrancarbothioamide can be obtained by the method described in the European application published under 0046 417.

Claims (4)

A process for preparing sulfoxides of thioformamide derivatives of the general formula I cX I Het CSN.HR AT). where IR represents a hydrogen atom or a straight or branched chain alkyl radical of 1 to 4 carbon atoms, Het is an aromatic heterocyclic radical selected from the group consisting of 3-pyridyl, optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms or halogen, 3-quinolyl, 4-pyridazinyl, 5-pyrimidinyl, 5-thiazolyl, thleno [2 3-b] -5-pyridyl and thieno [3,2-b] -6-pyridyl a Y represents a chemical bond or a methylene residue, by electrochemical oxidation, characterized in that the compound of the formula II γ CSNHR cx is electrochemically oxidized Het (II) wherein R, Het and Y are as hereinbefore defined in an electrolyte containing at least 55% water at pH 7 to 7.5 in the presence of an oxidizing agent I ⁺ , obtained directly in the reaction mixture electrochemically from ammonium iodide using electrodes with an inserted potential in the range of 0.5 to 0.6 V, followed by isolation of the resulting product. 2. A process according to claim 1 wherein the ammonium iodide is triethyl-n-propylammonium iodide. 3. A process according to claim 1, wherein the water-containing electrolyte comprises a water-miscible organic solvent. 4. The process of claim 3, wherein the water-miscible organic solvent is acetonitrile.