The present invention relates to a process for the preparation of (1R,2R)-N-methyl -2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 1-oxide of formula: ##STR1## which is particularly useful as an antihypertensive and as a cardioprotective agent.

This application is a continuation-in-part of co-pending PCT Serial No. 
FR94/00221, filed Feb. 28, 1994, designating the United States. 
BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a process for the preparation of 
(1R,2R)-N-methyl -2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 
1-oxide of formula: 
##STR2## 
which is particularly useful as an antihypertensive and as a 
cardioprotective agent. 
2. Reported Developments 
European Patent EP 0,097,584 has described thioamide derivatives of general 
formula: 
##STR3## 
in which R represents a hydrogen atom or an alkyl radical containing 1 to 
4 carbon atoms, Het represents a heterocyclic radical of aromatic 
character and Y represents a valency bond or a methylene radical. 
The presence of two asymmetric centres leads to 4 stereoisomers which may 
optionally be separated into two cis and trans racemic pairs. 
The product of general formula (II) for which R represents a methyl 
radical, Het represents a 3-pyridyl radical and Y represents a methylene 
group, in the form of the trans racemic mixture which may be represented 
in the following way: 
##STR4## 
is valuable as an antihypertensive (EP-0,097,584) and, particularly the 
(1R,2R) isomer, as a cardioprotective agent (EP-0,429,324) at doses for 
which the antihypertensive effect is not exhibited. 
(1 R,2R)-N-Methyl-2-(3-pyridyl)tetrahydro-thiopyran-2-carbothloamide 
1-oxide may be isolated from a mixture of the (1R,2R) and (1 S,2S) forms, 
in particular from the racemic mixture, by chiral-phase chromatography 
(EP-0,097,584), or may be prepared by stereoselective methods 
(EP-0,426,557). These processes make it necessary to use large quantities 
of solvents or else to perform a large number of steps. 
SUMMARY OF THE INVENTION 
The subject of the present invention is directed to 
(1R,2R)-N-methyl-2-(3-pyridyl) tetrahydrothiopyran-2-carbothioamide 
1-oxide from a salt of the mixture of (1R,2R)- and (1S,2S)-trans isomers, 
and in particular from the racemic mixture, with an optically active acid. 
DETAILED DESCRIPTION 
More particularly, the process according to the invention consists in 
selectively precipitating a salt of the (1R,2R)-trans isomer with an 
optically active acid in a suitable solvent, and then in liberating the 
(1R,2R)-trans isomer from its salt. 
For the implementation of the process according to the invention, it is 
particularly advantageous to use an optically active acid chosen from 
(-)-camphanic acid and (+)-3-bromo-10-camphorsulphonic acid. 
The solvents which are particularly suitable for the selective 
crystallization of the salt of the (1R,2R)-trans isomer with an optically 
active acid are preferably chosen from water, aliphatic alcohols 
containing I to 4 carbon atoms such as methanol, ethanol or isopropanol, 
and aqueous-alcoholic mixtures. 
(1 R,2R)-N-Methyl-2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 1-oxide 
is liberated from its salt by means of an inorganic or organic base, the 
procedure being carried out in water or in a mixture consisting of water 
and an immiscible solvent in which the (1R,2R)-trans isomer is soluble. 
Alkali metal carbonates or hydroxides (sodium hydroxide, potassium 
hydroxide or sodium carbonate) are preferably used as inorganic base. 
Tertiary aliphatic amines (triethylamine) or pyridine, whose basicity is 
sufficiently great to liberate the optically active acid from its salt, 
may be used as organic base. Preferably, potassium hydroxide is used in an 
aqueous-organic medium such as a water/halogenated aliphatic hydrocarbon 
mixture such as water/methylene chloride: in this way, the (1R,2R)-trans 
isomer dissolves in the organic solvent as it is being formed, with the 
salt of the optically active acid remaining in aqueous solution. 
(1 R,2R)-N-Methyl-2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 1-oxide 
is separated from its solution according to the usual methods and it may 
be purified according to known techniques, for example by crystallization. 
The mixture of the (1R,2R)- and (1S,2S)-trans isomers of 
N-methyl-2-(3-pyridyl) tetrahydrothiopyran-2-carbothioamide 1-oxide, and 
more particularly the racemic mixture, may be prepared under the 
conditions described in European Patent EP-0,097,584. 
The examples which follow illustrate the present invention.

EXAMPLE 1 
1900 cm.sup.3 of ethanol, 165 g of the trans racemic mixture of 
N-methyl-2-(3-pyridyl) tetrahydrothiopyran-2-carbothioamide 1-oxide and 
121.9 g of (-)-camphanic acid are introduced into a 2-liter reactor. The 
suspension is heated to 65.degree. C. until complete dissolution is 
obtained. After cooling to 45.degree. C., crystallization is initiated 
with 100 mg of the salt of (1R,2R)-N-methyl-2-(3-pyridyl) 
tetrahydrothiopyran-2-carbothothiomide 1-oxide with (-)-camphanic acid. 
The suspension is cooled over a period of 2 hours to a temperature in the 
region of 20.degree. C. and then stirred for 30 minutes at this 
temperature. The crystals are separated off by filtration, then washed 
with twice 150 cm.sup.3 of ethanol and finally dried under reduced 
pressure at 40.degree. C. 95.76 g of a white powder containing 57.7% of 
(1R,2R)-N-methyl-2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 1-oxide 
are thus obtained. 
The enantiomeric excess is in the region of 100%. 
The yield is 33.4%. 
EXAMPLE 2 
940 cm.sup.3 of methylene chloride, 188 g of the salt of (1R,2R)-N-methyl 
-2-(3-pyridyl)tetrahydrothiopyran-2-carbothioamide 1-oxide with 
(-)-camphanic acid and 880 cm.sup.3 of demineralized water are introduced 
into a 2-liter reactor. To the stirred suspension are added 68.6 g of 30% 
(w/w) aqueous potassium hydroxide solution over a period of 10 minutes. 
Stirring is carried out for 15 minutes. After settling has taken place, 
the organic phase is separated off and washed with 188 cm.sup.3 of 
distilled water and then dried. After evaporation of the solvent, 90.5 g 
of pure (1R,2R)-N-methyl-2-(3-pyridyl) 
tetrahydrothiopyran-2-carbothio-amide 1-oxide are obtained, with a yield 
of 83.7%. 
The enantiomeric excess is in the region of 100%.