CA1189017A - Electrochemical process for preparing thioformamide derivatives sulfoxides useful as therapeutic agents - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives of formula (I) <IMG> (I) in which R = H or alkyl (1 to 4C), Het = pyridyl-3 (optionally substituted by alkyl (1 to 4 C) or halogen), quinolyl-3, pyridazinyl-4, pyrimidinyl-5, thiazolyl-5, thieno ¢ 2,3-b! pyridyle-5 or thieno ¢ 3,2-b! pyridyle-6 and Y represents a valence bond or a methylene radical, by electrochemical oxidation of the products of formula (II) <IMG> (II) by operating in an electrolyte with high water content, at a pH between 7 and 7 , 5 in the presence of a specific oxidizing agent X? obtained from a halide X ?, by working at an imposed electrode potential close to the oxidation potential of X ?. The process allows the selective preparation of derivatives of formula (I) in which the sulfoxide is in the trans position relative to the thioamide group.

Description

The present invention relates to a preparation process sulfoxides of thioformamide derivatives of general formula:
y CSNHR
CSX (I) Het O
In the general formula (I), R represents an atom hydrogen or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, Het represents a heterocyclic radical of aromatic character containing one or two nitrogen atoms chosen from pyridyl-3 (optionally substituted by an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain or by a halogen atom), quinolyl-3, pyridazinyl-4, pyrimidinyl-5, thiazolyle-5, thieno ~ 2,3-b ~ pyridyle-5 and thieno [3,2-b ~ pyridyle-6 and Y represents a valence bond or a methylene radical.
The presence of an o ~ ygene atom on the sulfur created in the molecule an asymmetry which, associated with asymmetric carbon neighbor, conduit theoriquemenc ~ 4 s ~ possible ereoisomers, event ~ el-Lely separable into two racemic couples ~ The present invention relates to a selective process for the preparation of the products of formula general (I) that is to say in which the sulfoxide is found in trans position with respect to the thioamide group.
According to the invention, the products of general formula (I) can be obtained by electrochemical oxidation of products of general formula:
y CSNHR
CSX (He) Het in which Het, R and Y are defined as above, in operating in an electrolyte with a high water content, at a pH understood between 7 and 7.5 and in the presence of a specific oxidizing agent X obtained in situ electrochemically ~ from a halide X and by working ~ an imposed electrode potential close to the oxidation potential of X.
In practice, it is particularly advantageous for give birth to oxidizing agent X to use iodide alkali metal such as potassium iodide or halide am ~ onium such as ammonium iodide or triethyl iodide n-propylammonium or tetraethylammonium bromide, or a aryl iodide such as phenyl iodide, operating at a potential 1 ~ of an imposed electrode close to the iodide oxidation yotential (0.6 to 0.8 V compared to a calomel reference electrode saturated).
The electrolyte in which the reaction takes place consists usually :
- an organic solvent miscible with water to dissolve the substance ~ oxidize of general formula (II), such as acetoni-trile or an alcohol such as methanol or ethanol, - distilled or fined water, - a buffer solution at pH 7 in water generally made up with a mixture of 0.1 M aqueous hydrogen phosphate solution ammonium and ammonium dihydsogenophosphate.
The relative proportions of water and organic solvent depend on the water solubility of the sulphide of formula general (II) to be oxidized. The total percentage of water in the electro-lyte can vary between 10 and 99; it is generally between 40 and 80%.
The amount of electricity required in practice for perform the oxidation of a product of general formula (II) to a product of general formula (I) is 4 to 8 Faradays per mole.
Preferably, the oxidation takes place in an electrolyser has diaphragm by operating ~ a temperature between 0C and the reflux temperature of the reaction mixture, preferably between 20 and 60C.

According to a preferred implementation of the process, the electrolytic oxidation is carried out in an electrolyser comprising a anode and a reference electrode, an anode compartment, a diaphragm separator, a cathode compartment and a cathode with the following characteristics:
a) The anode is an unassailable solid at the potential at which it takes place the reaction and consisting of an electrically conductive material, preferably platinum on which the oxidation of the product general formula (II) takes place at a potential lower than the potential oxidizing the constituents of the solvent; this potential is measured compared to a separate saturated calomel reference electrode of the electrolyte with an agar gel with KCl.
b) The anode compartment contains the electrolyte indicated above.
ment and the product of general formula (II) to be oxidized.
c) The diaphragm separa ~ eur is constituted by a porous material such as a plate, a sleeve or a sintered glass candle or porcelain or even by an ion exchange membrane, preferably a cation exchange membrane. It is particularly advantageous to use a membrane N ~ FION 125 (Trademark, Dupont).
d) The cathode compartment contains the same electrolyte as cell of the anode compartment.
e) The cathode consists of an electrically conductive material a city whose nature is not essential to the implementation of the process and which can therefore be identical to the material of the anode or be different from it.
According to a preferred implementation of the invention, the anode, the seal and the diaphragm separator are arranged according to vertical parallel planes. In addition, several electrolysers elementary can be associated with the way of filter presses.
The closed loop anolyte route can be provided by a pump. The circuit may further include additional sitives such as heat exchangers or expansion vessels;

such an expansion tank makes it possible in particular to supply the anolyte in sulfide of general formula (II) and also makes it possible to carry out a racking for the extraction of the sulfoxide of general formula (I).
The catholyte can also be subjected to circulation.
According to a preferred embodiment of the invention, the circuit of the catholyte is similar to that of the anolyte, which allows to balance the pressures on both sides of the separating diaphragm.
According to another particular embodiment of the invention, there are dividers in the compartments anodic and cathodic. These dividers are used to avoid, of a firstly, the deformations of the ion exchange membrane and secondly apart, the contacts of this membrane with the electrodes. They serve also to improve the homogeneity of concentration of the anolyte.
They also create turbulence which promote electrolysis ~ These tS dividers are usually made from polymers chemically inert syntheses that do not conduct electricity.
They can be put in the form of intertwined, intertwined, knotted threads or welded (fabrics, grids, nets) or even 90U13 form of plates with holes or grooves. In practice cel ~ dividers are oriented along planes parallel to those of the electrodes and diaphragm.
According to another implementation of the invention, the cell can simply consist of a container, parallelepiped or cyclindric, in an inert material vis-à-vis the constituents electrolytes. This container contains the working electrode, the nature is the same as that defined above. The form of this working electrode is adapted to the shape of the container.
Generally speaking, any electrolytic cell comprises both an anode and a cathode separated by one or more diaphragms ensuring ionic conductivity is likely to be used, the arrangement of the elements not being essential to the implementation of the process.

The products obtained by the process according to the invention can be purified by the usual physico-chemical methods, including crystallization and chromatography.
The products of general formula (II) can be prepared by using or adapting the methods described in European patent application published under number 0046 417.
Indirect electrochemical oxidation using an ion iodonium I is known from the publication of T ~ TSUY ~ SHONO et al.
~ Tetrahedron Letters, (1979), 165-168 ~. However, nothing in this publication did not suggest that the process would be usable to oxidize sulfides of general formula (II) and even less to selectively oxidize them.
The products of general formula (I) obtained by the process according to the invention have anti-hyper-tensives making them useful as drugs intended to treat hypertenaions At doses between 0.02 and 50 mg / kg po, they lower blood pressure in spontaneously hyper-strained (SHR rat) of OKAMOTO-AOKI strain. The use of the rat spontaneously hypertensive for the testing of antihypertensive products ~ described by JL ROBA, I.ab. Anim. ~ ci., 26, 305 (1976).
Their dose (LD50) in the mouse is generally higher ~ 300 mg / kg po The following examples, given ~ non-limiting, show how the invention can be put into practice.
E ~ EMPLE 1 -In an electrolysis cell with a capacity of 150 cm3 comprising a working electrode consisting of a grid platinum with a surface area of 16 cm2, a counter electrode consisting of platinum grid with a surface area of 4.5 cm2 and a reference electrode saturated calomel separated from the electrolyte by an agar-agar gel with KCl, 2 g of N-methyl (pyridyl-3) -2 are successively introduced tetrahydrothiophenecarbothioamide-2, 67.5 cm3 of acetonitrile, 7.5 cm3 of deionized water, 75 cm3 of ammonium phosphate buffer 4 2 4 0.1 M; (NH4) 2HP04 0.1 ~ J ~ pH 7 and 0 4 g of i d of triethyl n-propylammonium. The reaction mixture, stirred by means of a magnetic bar covered ~ rt of polytetrafluoroethyl ~ ne, is deoxygenated by bubbling a stream of nitrogen. We fix the potential of the working electrode at ~ 0.8 v compared to the electrode at saturated calomel (which we note: +0.8 v / DHW). After passing 1150 Coulombs, the solution heats up by Joule effect and reaches the temperature of 42C. We then bring the potential of the electrode working at ~ o, 65 v / DHW so as to maintain a temperature about 45C. The current across the cell is between 400 and 500 mA. During the electrolysis, a solution is added aqueous ammonia about 5N in order to maintain the pH at a value close to or greater than 7. Electrolysis is stopped when the amount of electricity that passed through the cell is equal to 3188 Coulombs, or 3.93 Faradays per mole of product to be oxidized.
The reaction mixture is then concentrated ~ dry under reduced pressure (20 mmg; 2.7 kPa). The residue is extracted 2 times with 140 cm3 in total of ethyl ether; the ethereal phases are washed with 50 cc of distilled water and removed. The aqueous phases ~ have r ~ united and extracted 20 times with 50 cm3 each time of acetate ethyl. The organic extracts are combined and dried on sodium sulfate The solution is filtered and evaporated ~ dry under 25 reduced pressure (20 mmg; 2.7 kPa) at 40C. We thus obtain a first batch of 1394 mg of N-methyl (pyridyl-3) -2 tetrahydrothio ~
phenecarbothioamide-2 oxide-l. trans form, as a product white ~ rippling at 207C after recrystallization from acetate ethyl.
~ Rf = 0.24; thin layer gel chromatography silica; solvent: Ethyl acetate-methanol (75-25 by volume) ~
The aqueous layer from the previous extraction with ethyl acetate is taken up and extracted with 3 times 180 cm3 at total butanol. The organic phases are combined, dried over sodium sulfate, filtered and concentrated to dryness under pressure reduced (20 mm of mercury; 2.7 kPa) to 40C. We thus obtain 450 mg of a crude product which is purified by chromatography preparative on thin layer of silica gel (eluent: acetate ethyl / methanol 70/30 by volume). After scraping the area containing the product (identified by UV), it is desorbed by a mixture of ethyl acetate and methanol (50/50 by volume).
A second batch of 155 mg of N-methyl (3-pyridyl) -2 is thus obtained.
o tetrahydrothiophenecarbothioamide-2 oxide-l trans form fondant 207C.
N-methyl (pyridyl-3) -2 tetrahydrothioph ~ necarbothio-amide-2 can be prepared as described in the patent application European publication number 0046 417.
lS YEMPLE 2 -In an electrolysis cell with a capacity of 150 cm3 comprising a working electrode consisting of a grid 16 cm2 platinum surface, built-up counter electrode of a platinum rille with a surface area of 8 cm2 and an electrode of r ~ f ~ rence with saturated calomel separated from the electrolyte by a gel of ngar-agar with KCl, 2 g of N-methyl are successively introduced (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2, 67.5 cm3 acetonitrile, 7.5 cm3 of deionized water, 75 cm3 of phosphate buffer aqueous am ~ onium [(NH4) 2HP04 0.1 M; NH4H2P04 0.1 ~ 3 pH 7 and 0.25 g of ammonium iodide.
The reaction mixture, stirred by means of a bar magnetic coated with polytetrafluoroethylene, is deoxygenated by bubbling a stream of nitrogen. We ~ ix the potential of the working electrode at +0.8 v relative to the electrode at saturated calomel (which we note: ~ 0.8 v / DHW). The stream crossing the cell decreases from 700 mA to 150 mA.
During electrolysis, an aqueous solution is added of ammonia about 5N in order to maintain the pH at a similar value or greater than 7. Electrolysis is stopped when the quantity of electricity that passed through the cell is equal to 8 54 ~ 4 Coulombs, or 7.15 Faradays per mole of product to be oxidized.
The reaction mixture is then concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). The residue is extracted 3 times with 50 cm3 in total of ethyl ether; the phases are washed twice with 30 cm3 of distilled water and eliminated.
The aqueous phases are combined and extracted 10 times with 300 cm3 in total ethyl acetate to remove non-byproducts polar. The organic phases are washed 5 times with SO cm3 distilled water.
The aqueous phases are combined and extracted 3 times per 150 cm3 in total of butanol-l. The organic phases are combined, dried over sodium sulfate, filtered and concentrated dry under reduced pressure (20 mm of mercury; 2.7 kPa) at 30C.
850 mg of a crude product are thus obtained which is purified by preparative chromatography on a thin layer of silica gel (eluent: ethyl acetate / methanol 70/30 by volume). After scratching the area containing the product (marked with W), it is desorbed with a mixture of ethyl acetate and methanol (50/50 by volume). 392 mg of N-methyl (3-pyridyl) -2 are thus obtained.
tetrahydrothiopyrannecarbothioamide-2 oxide-l trans form fondant 228C.
CRf = 0.24; thin layer gel chromatography silica; solvent: ethyl acetate-methanol (75-25 in volumes V
N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothio-amide-2 can be prepared as described in the patent application European publication number 0046 417.

Claims (7)

The embodiments of the invention, concerning the-what an exclusive property right or lien is claimed, are defined as follows: 1. Process for the preparation of sulfoxides thioformamide derivatives of general formula:

in which R represents a hydrogen atom or a radical cal alkyl containing 1 to 4 carbon atoms in chain straight or branched, Het represents a heterocyclic radical aromatic in nature containing one or two nitrogen atoms chosen from pyridyle-3 unsubstituted or substituted by a alkyl radical containing 1 to 4 carbon atoms in chain straight or branched or with a halogen atom, quinolyl-3, pyridazinyl-4, pyrimidinyl-5, thiazolyl-5, thieno [2,3-b]
pyridyle-5 and thieno [3,2-b] pyridyle-6 and Y represents a valence bond or a methylene radical, characterized in what we electrochemically oxidize products of general formula:

in which the symbols R, Het and Y are defined as above by operating in an electrolyte with a high content of water, at a pH between 7 and 7.5 in the presence of an agent specific oxidation X? obtained in situ electronically chemical from an X halide? working at a imposed electrode potential close to the oxidation potential of X?, then isolates the product thus obtained. 2. Method according to claim 1, characterized in that the oxidizing agent X? is obtained from a ammonium halide. 3. Method according to claim 2, characterized in that the ammonium halide is ammonium iodide. 4. Method according to claim 2, characterized in that the ammonium halide is triethyl iodide n-propylammonium. 5. Method according to claim 1, characterized in that the imposed electrode potential is between 0.6 and 0.8 v compared to a saturated calomel electrode. 6. Method according to claim 1, characterized in that the high water electrolyte contains a organic solvent miscible with water. 7. Method according to claim 6, characterized in that the water-miscible organic solvent is aceto-nitrile.