NZ204613A - Electrochemical process for the preparation of sulphoxides of thioformamide derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £04613 Priority Date(s): Complete Specification Filed: J6.

Class: CSvi A~ Publication Date: .1 .EEfi $.??.

P.O. Journal, No: J3/3P.

NO DRAW1N6: NEW ZEALAND THE PATENTS ACT 1953 PATENTS FORM NO. 5 COMPLETE SPECIFICATION "ELECTROCHEMICAL PROCESS FOR THE PREPARATION OF SULPHOXIDES OF THIOFORMAMIDE DERIVATIVES. WHICH ARE USEFUL AS MEDICAMENTS" WE, RHONE—POULENC. SANTE, a French body corporate, "Les Miroirs", 18, Avenue d'Alsace, 92400 Courbevoie, France, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: -1- {followed by page la) 204613 - 2A.- The present invention relates to a process for the preparation of sulphoxides of thioforinamide derivatives of the general formula: PSNHR wherein R represents a hydrogen atom or a straight- or branched-chain alkyl radical containing 1 to A carbon atoms, Het represents a heterocyclic radical selected from pyridin-3-yl (optionally substituted by a straight-or branched-chain alkyl -radical containing 1 to 4 carbon atoms or by a halogen atom), quinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, thiazol-5-yl, thieno[2,3-b]pyri-din-5-yl and thieno[3,2-b]pyridin-6-yl, and Y represents a valency bond or a methylene radical. sulphur atom creates an asymmetry in the molecule which, in association with the adjacent asymmetric carbon atom, theoretically leads to 4 possible stereoisomers which, optionally, can be separated into two racemic pairs. The present invention relates to a selective (I) 0 The presence of an oxygen atom on the ring 204613 2 the preparation of the sulphoxide products of general formula (I), i.e. the products in which the sulphoxide is in the trans position relative to the thioamide group.

According to the invention, the sulphoxides of general formula (I) are obtained by electrochemical oxidation of the ring sulphur atom of a thioformamide derivative of the general formula: CSNHR (II) Het (wherein Het, R and Y are as hereinbefore defined), the reaction being carried out in an electrolyte with a considerable water content, the percentage of water in the electrolyte being between 10 and 99% by volume, at a pH of between 7 and 7.5 and in the presence of a specific oxidising agent X+ obtained in situ from a halide x" by an electrochemical method, and at an imposed electrode potential similar to the oxidation potential of X~.

In practice, to produce the oxidising agent + X , it is particularly advantageous to use an alkali metal iodide such as potassium iodide, or an ammonium halide such as ammonium iodide, trie thy 1-n-propylammonium iodide or tetraethylammonium bromide, or otherwise an aryl iodide such as phenyl iodide, the reaction being carried out at an imposed electrode potential similar to relative to a saturated calomel reference elec the oxidation potential of the iodide (0.6 to 204613 The electrolyte in which the reaction is carried out generally consists of: - an organic solvent miscible with water capable of dissolving the substance of general formula (II) to be oxidised, such as acetonitrile or an alcohol, e.g. methanol or ethanol, - distilled or deionised water, and - an aqueous buffer solution at pH 7, generally consisting of a mixture of 0.1M aqueous solutions of ammonium hydrogenphosphate and ammonium dihydrogenphosphate.

The relative proportions of water and organic solvent depend on the solubility in water of the sulphide of general formula (II) to be oxidised. The total percentage of water in the electrolyte can vary between and 99% by volume; it is generally between 40% and 80% by volume.

The quantity of electricity required in practice to oxidise a sulphide of general formula (II) to a sulphoxide of general formula (I) is A to 8 Faradays per mol.

Preferably, the oxidation is carried out in a diaphragm electrolyser at a temperature between 0°C and the reflux temperature of the reaction mixture, preferably at between 20° and 60°C.

In a preferred embodiment of the proce^p^f^p^^v?^ 25 electrolytic oxidation is carried out in an eldG^rolyser comprising an anode and a reference electrode, lanf 4f)tfiel985 til V. ^ / compartment, a separating diaphragm, a cathode cx^im^rtin^.NyK and a cathode, the characteristics of which are as 2 04 6 1 3 _ 4 - follows: a) The anode is a solid which cannot be attacked at the potential at which the reaction is carried out, and consists of an electrically conducting material, preferably platinum, on which the oxidation of the sulphide of general formula (II) takes place at a potential below the oxidation potential of the constituents of the solvent; this potential is measured relative to a saturated calomel reference electrode separated 10 from the electrolyte by an agar-agar gel with KC1. b) The anode compartment contains the electrolyte indicated above and the sulphide of general formula (II) to be oxidised. c) The separating diaphragm consists of a porous 15 material such as a plate, a sleeve or a filter candle made of sintered glass or porcelain, or alternatively consists of an ion exchange membrane, preferably a cation exchange membrane. It is particularly advantageous to use a NAFION 125 membrane (Dupont registered 20 trademark). d) The cathode compartment contains the same electrolyte as the anode compartment. e) The cathode consists of an electrically conducting material, the nature of which is not essential to the operation of the process, and which can therefore be identical to or different from the anode material.

In a preferred embodiment of the invention, the anode, the cathode and the separating diaphragm are 2 04 6 1 arranged in vertical parallel planes. Moreover, several individual electrolysers can be combined like filter presses.

A pump can be used to circulate the anolyte 5 in closed circuit. The circuit can also comprise additional devices such as heat exchangers or expansion vessels; an expansion vessel of this type makes it possible, in particular, to feed the anolyte with sulphide of general formula (II) and also makes it possible to 10 effect a withdrawal in order to extract the sulphoxide of general formula (I).

The catholyte can also be circulated. In a preferred embodiment of the invention, the catholyte circuit is similar to the anolyte circuit, which makes 15 it possible to equilibrate the pressures on either side of the separating diaphragm.

In another particular embodiment of the invention, spacers are arranged in the anode and cathode compartments. The purpose of these spacers is, on the 20 one hand, to prevent the ion exchange membrane from deforming and, on the other hand, to prevent this membrane from coming into contact with the electrodes. They are also used to improve the homogeneity of the anolyte concentration. They also create turbulences which assist 25 the electrolysis. These spacers are generally manufactured from chemically inert and electrically non-conducting synthetic polymers. They can be made in the form of interlaced, intersecting, knotted or welded filaments 2046 1 3 (woven fabrics, grids, nets) or alternatively in the form of plates possessing holes or grooves. In practice, these spacers are orientated in planes parallel to those of the electrodes and of the diaphragm.

In another embodiment of the invention, the cell can consist simply of a parallelepipedal or cylindrical vessel made of a material which is inert towards the constituents of the electrolytes. This vessel contains the working electrode, the nature of 10 which is the same as that defined above. The shape of this working electrode is made to suit the shape of the vessel.

In general, any electrolytic cell comprising an anode and a cathode separated by one or more diaphragms 15 ensuring the ionic conductivity can be employed, the arrangement of the elements not being essential to the operation of the process.

The products obtained by the process according to the invention can be purified by the usual physico-20 chemical methods, in particular crystallisation and chromatography.

The sulphides of general formula (II) can be prepared by using or adapting the methods described in ** {OfcMj ZtccCccu_oL Sp (Oo . 1J~]07( the European Patent Application published under No. iifer 1 25 0040,417~.

Indirect electrochemical oxidation using an iodonium ion I+ is known from the publication by 2 04 6 1 TATSUYA SHONO et al. [Tetrahedron Letters, (1979), 165-168]. However, there is nothing in this publication to suggest that the process could be used to oxidise sulphides of general formula (II), and even less to 5 oxidise them selectively.

The sulphoxides of general formula (I) obtained by the process according to the invention possess antihypertensive properties making them useful as medicaments for treating hypertension. 10 At doses of between 0.02 and 50 mg/kg animal body weight,administered orally, they lower the arterial pressure in spontaneously hypertensive rats (SHR) of the OKAMOTO—AOKI strain. The use of spontaneously hypertensive rats for studying antihypertensive products 15 is described by J.L. ROBA, Lab. Anim. Sci., 26, 305 (1976).

Their lethal dose (LD^q) in mice is generally more than 300 mg/kg animal body weight administered orally.

The following non-limitative Examples illustrate the invention.

EXAMPLE 1 N-Methyl-2-(pyridin-3-yl)tetrahydrothiophen-2-carbothioamide (2 g), acetonitrile (67.5 cc), deionised 25 water (7.5 cc), aqueous ammonium phosphate buffer [0.1M in respect of NH^^PO^; 0.1M in respect of (NH^^HPO^] at pH 7 (75 cc) and triethyl-n-propylammonium iodide (0.4 g) are introduced successively into an electrolysis 2 046 13 cell of 150 cc capacity, comprising a working electrode consisting of a platinum grid with a surface area of 2 16 cm , a counter-electrode consisting of a platinum 2 grid with a surface area of 4.5 cm , and a saturated 5 calomel reference electrode separated from the electrolyte by an agar-agar gel with KC1. The reaction mixture, stirred by means of a polytetrafluoroethylene-coated magnetic bar, is deoxygenated by bubbling therethrough a stream of nitrogen. The potential of the working 10 electrode is set at +0.8V relative to the saturated calomel electrode (this is denoted as +0.8V/SCE). After the passage of 1150 Coulombs, the solution warms up by the Joule effect and reaches a temperature of 42°C. The potential of the working electrode is then reduced 15 to +0.65V/SCE so as to maintain a temperature of about 45°C. The current passing through the cell is between 400 and 500 mA. During the electrolysis, an approximately 5N aqueous ammonia solution is added in order to keep the pH value close to or greater than 7. The electrolysis 20 is stopped when the quantity of electricity which has passed through the cell is equal to 3188 Coulombs, i.e. 3.93 Faradays per mol of sulphide to be oxidised.

The reaction mixture is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). 25 The residue is extracted twice with diethyl ether (140 cc in total); the ether phases are washed with distilled water (50 cc) and discarded. The aqueous phases are combined and extracted with ethyl acetate (20 x 50 cc). 2046 1 3 The organic extracts are combined and dried over sodium sulphate. The solution is filtered and the filtrate is evaporated to dryness under reduced pressure (20 mm 11gm, 2.7 kPa) at 40°C. This gives a first batch of the trans 5 form of N-methyl-2-(pyridin-3-yl)tetrahydrothiophen-2-carbothioamide 1-oxide (1394 mg) in the form of a white product melting at 207°C after recrystallisation from ethyl acetate.

[Rf = 0.24; chromatography on a thin layer 10 of silica gel: solvent: ethyl acetate/methanol (75/25 by volume)].

The aqueous layer originating from the above extraction with ethyl acetate is taken up and extracted 3 times with butanol (180 cc in total). The organic 15 phases are combined, dried over sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 ram Hg; 2.7 kPa ) at 40°C.

This gives a crude product (450 mg) which is purified by preparative chromatography on a thin layer of silica 20 gel (eluent: ethyl acetate/methanol, 70/30 by volume). After scratching the zone containing the product (identified by UV), the product is desorbed with a mixture of ethyl acetate and methanol (50/50 by volume). This gives a second batch of the trans form of N-methyl-25 2-(pyridin-3-yl)tetrahydrothiophen—2-carbothioamide 1-oxide (155 mg) melting at 207°C.

The N-methyl-2-(pyridin-3-yl)tetrahydrothio-phen—2-carbothioamide can be prepared as described in 2046 1 3 - io - |Oeo_?~2« MAOU_C-^- <ipe.C( firoM-x^svv. ° • 7^*71 the European Patent Application published under No. [c 9040,417: w* 1 EXAMPLE 2 N-Methyl-2-(pyridin-3-yl)tetrahydrothiopyran-5 2-carbothioamide (2 g), acetonitrile (67.5 cc), deionised water (7.5 cc), aqueous ammonium phosphate buffer [0.1M in respect of (NH^^HPO^: 0.1M in respect of NH^I^PO^] at pH 7 (75 cc) and ammonium iodide (0.25 g) are introduced successively into an electrolysis cell of 150 10 cc capacity, comprising a working electrode consisting 2 of a platinum grid with a surface area of 16 cm , a counter-electrode consisting of a platinum grid with a 2 surface area of 8 cm , and a saturated calomel reference electrode separated from the electrolyte by an agar-agar 15 gel with KC1.

The reaction mixture, stirred by means of a polytetrafluoroethylene-coated magnetic bar, is deoxygenated by bubbling therethrough a stream of nitrogen. The potential of the working electrode is 20 set at +0.8V relative to the saturated calomel electrode (this will be denoted as +0.8V/SCE). The current passing through the cell decreases from 700 mA to 150 mA.

During the electrolysis, an approximately 5N aqueous ammonia solution is added so as to keep the 25 pH at a value close to or greater than 7. The electrolysis is stopped when the quantity of electricity which has passed through the cell is equal to 5484 Coulombs, i.e. 7.15 Faradays per mol of sulphide to be oxidised- 2 046 1 3 - n - The reaction mixture is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue is extracted 3 times with diethyl ether (50 cc in total); the ether phases are washed with 5 distilled water (2 x 30 cc) and discarded. The aqueous phases are combined and extracted 10 times with ethyl acetate (300 cc in total) in order to remove the non-polar by-products. The organic phases are washed with distilled water (5 x 50 cc).

The aqueous phases are combined and extracted 3 times with butan-l-ol (150 cc in total). The organic phases are combined, dried over sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2,7 kPa.) at 30°C. This 15 gives a crude product (850 mg) which is purified by preparative chromatography on a thin layer of silica gel (eluent: ethyl acetate/methanol, 70/30 by volume). After scratching of the zone containing the product (identified by UV), the product is desorbed with a 20 mixture of ethyl acetate and methanol (50/50 by volume). This gives the trans form of N-methyl-2-(pyridin-3-yl) tetrahydrothiopyran-2-carbothioamide 1-oxide (392 mg) melting at 228°C.

[Rf = 0.24; chromatography on a thin layer of 25 silica gel; solvent: ethyl acetate/methanol (75/25 by volume)].

N-Methyl-2-(pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide can be prepared as described in the ~Le ciM-oi. ec i P-*P° • (^70~7( European Patent Application publiahod under No. 204613

Claims (10)

WHAT WE CLAIM IS:

1. A process for the preparation of sulphoxides of thioformamide derivatives of the general formula: / / CSNHR (I) S ^ Het i o wherein R represents a hydrogen atom or a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms, Het represents a heterocyclic radical selected from pyridin-3-yl (optionally substituted by a straight-or branched-chain alkyl radical containing 1 to 4 carbon atoms or by a halogen atom), quinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, thiazol-5-yl, thieno[2,3-b]-pyridin-5-yl and thieno[3,2-b]pyridin-6-yl, and Y represents a valency bond or a methylene radical, which comprises oxidising the ring sulphur atom of a thioformamide derivative of the general formula: rv \ sy I x. „CSNHR (II) Het. (wherein the symbols R, Het and Y are as hereinbefore defined) by an electrochemical method, the reaction being carried out in an electrolyte with a considerable water content, the percentage of water in the electrolyte being between 10 and 99% by volume, at a pH of between 7 S«?1 and 7.5 and in the presence of a specific oxidis^rcn^feent Xr obtained in situ from a halide X by an el^'c^rochemJ 0'\: method, and v't WECmsZjj . ti 204613 - 14 - at an imposed electrode potential similar to the oxidation potential of X~, and then isolating the product obtained.

2. A process according to claim 1, in which the oxidising agent X+is obtained from an ammonium halide.

3. A process according to claim 2, in which the ammonium halide is ammonium iodide.

4. A process according to claim 2, in which the ammonium halide is triethyl-n-propylammonium iodide.

5. A process according to claim 1, in which the imposed electrode potential is between 0.6 and 0.8V relative to a saturated calomel electrode.

6. A process according to claim 1, in which the electrolyte with a considerable water content contains a water-miscible organic solvent.

7. A process according to claim 6, in which the water-miscible organic solvent is acetonitrile.

8. A process according to any one of the preceding claims in which the percentage of water in the electrolyte is between 40 and 80% by volume.

9. A process according to claim 1 substantially as hereinbefore described with especial reference to ■v) Example 1 or 2.

10. Sulphoxides of thioformamide derivativ^fTEN^v of general formula (I) depicted in claim 1, whereiav R, Het and Y are as defined in claim 1, when preparek1 1985 f the process claimed in any one of claims 1 to 9._ DATED THIS (l> DAY OF A, J. RARK & SON - PER AGENTS FOR THE APPLICANTS