Process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones

The invention relates to a process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones of formula I by the kinetic resolution of racemates, characterized in that racemic I is dissolved in an inert solvent or solvent mixture and acylated with a chiral acid chloride. The resulting mixture of diastereoisomers is reacted with an amine or alcohol, thereby achieving a complete resolution of one of the diastereoisomers and a very slight or partial resolution of the other diastereoisomer into the enantiomers on which they are based, the resolution products are then separated off and the remaining pure diastereoisomer is converted to the corresponding pure enantiomer by reaction with an amine or an alcohol.

SUMMARY OF THE INVENTION 
The invention relates to a process for the resolution of enantiomers of 
5-heteroaryl-1,3,4-thiadiazinones of formula I: 
##STR1## 
wherein R.sup.1 is A, 
R.sup.2 and R.sup.3 are each H or A, 
R.sup.4 is H, A or acyl having 1-15 C atoms, 
A is alkyl having 1-8 C atoms and 
n is 1, 2 or 3. 
Thiadiazinone derivatives of formula I are known from European patent 0 294 
647 and have the meanings indicated therein as preferred. 
Above and below, R.sup.1 to R.sup.4 and A are as defined for formula I, 
unless expressly indicated otherwise. 
In the formulae, alkyl is preferably unbranched, has preferably 1, 2 or 3 C 
atoms and is preferably methyl, or preferably ethyl or propyl, or else 
preferably isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl or 
isopentyl. 
Acyl is the acid radical of a carboxylic or sulfonic acid, preferably 
alkanoyl having 1-10 or especially 1, 2, 3, 4 or 5 C atoms, specifically 
preferably acetyl, or preferably formyl, propionyl, butyryl, isobutyryl, 
valeryl, isovaleryl or pivaloyl (trimethylacetyl), or else preferably 
substituted or unsubstituted aroyl having 7-15 C atoms, possible 
substituents being especially 1-3 or preferably one of the following 
groups: alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each 
having 1-3 or preferably 1 or 2 C atoms, methylenedioxy and also OH, F, 
Cl, Br, I, NO.sub.2, NH.sub.2 and alkylamino or dialkylamino each having 
1-3 or preferably 1 or 2 C atoms in the alkyl group. Specific preferred 
aroyl radicals are benzoyl, o-, m- or p- toluyl, o-, m- or 
p-methoxybenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 
2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxybenzoyl, o-, m- 
or p-methylthiobenzoyl, o-, m- or p-methylsulfinylbenzoyl, o-, m- or 
p-methylsulfonylbenzoyl, 2,3- or 3,4-methylenedioxybenzoyl and 1- or 
2-naphthoyl. Acyl can also be heteroarylcarbonyl having 2-10 C atoms, such 
as 2- or 3-furoyl, 2- or 3-thenoyl, picolinoyl, nicotinoyl or 
isonicotinoyl, or else arylalkanoyl such as phenylacetyl, o-, m- or 
p-methoxyphenylacetyl, 2- or 3-phenylpropionyl or 2-, 3- or 
4-phenylbutyryl, cycloalkylcarbonyl such as cyclohexylcarbonyl, 
alkylsulfonyl such as methyl-, ethyl-, propyl- or butyl-sulfonyl, or 
arylsulfonyl such as benzenesulfonyl, o-, m- or p- toluenesulfonyl, o-, m- 
or p-methoxybenzenesulfonyl or 1- or 2-naphthalenesulfonyl. 
Resolution of the racemate into the respective enantiomers has hitherto 
been possible only by means of expensive HPLC processes. 
An object of the invention s to provide a process for the resolution of 
enantiomers of formula I which avoids an expensive HPLC resolution with a 
small through-put of substance, but simultaneously produces a high 
enantiomeric purity in satisfactory amounts of substances. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects are achieved by the discovery of the present process, namely 
the kinetic resolution of racemates, in respect of the resolution of 
enantiomers of 5-heteroaryl-1,3,4-thiadiazinones. 
The invention accordingly relates to a process for the resolution of 
enantiomers of Formula I, characterized in that racemic I is dissolved in 
an inert solvent or solvent mixture and acylated with a chiral acid 
chloride, the resulting mixture of diastereoisomers is reacted with an 
amine or alcohol, thereby achieving a complete resolution of one of the 
diastereoisomers and possibly a very slight or partial resolution of the 
other diastereoisomer into the enantiomers on which they are based, the 
resolution products are then separated off and the remaining pure 
diastereoisomer is converted to the corresponding pure enantiomer by 
reaction with an amine or an alcohol. 
If a partial resolution of the other diastereoisomer occurs, such a partial 
resolution can amount to, for example, 0.01-0.99% of the total of the 
other diastereoisomer. 
Racemic I refers to a racemic mixture of enantiomers of Formula I. 
The process of the kinetic resolution of racemates does not normally 
produce a satisfactory enantiomeric purity and has to be supplemented by 
additional processes. 
It is therefore surprising that this process can be applied successfully in 
the case of compounds of Formula I and produces an enantiomeric purity of 
more than 99% in all Examples without the use of supplementary methods. 
Suitable solvents are preferably ethers such as tetrahydrofuran (THF), 
dioxane or methyl tert.-butyl ether, hydrocarbons such as hexane, 
cyclohexane, benzene, toluene, xylenes or mesitylene, glycol dialkyl 
ethers such as glycol dimethyl or diethyl ether, amides such as 
dimethylformamide (DMF), halogenated hydrocarbons such as methylene 
chloride, chlorobenzene or trichloroethylene, and mixtures of these 
solvents. 
Methylene chloride and THF are particularly preferred. 
Examples of suitable optically active acid chlorides are 
tetrahydro-5-oxofuran-2-carboxylic acid chloride, o-acetylmandelic acid 
chloride, campholic acid chloride or, particularly preferably, camphanic 
acid chloride. 
Specifically, racemic I is dissolved or suspended in one of said solvents 
or a solvent mixture, a base is conveniently added and the acid chloride, 
dissolved in one of said solvents or in the pure form, is added. Examples 
of suitable bases are alkali metal or alkaline earth metal hydroxides, 
carbonates and alcoholates, but especially secondary or tertiary amines 
such as, for example, triethylamine or pyridine. The reaction mixture is 
then stirred for 1-48 hours at temperatures of between -20.degree. and the 
boiling point of the solvent, preferably in the range from -10.degree. to 
+30.degree., and the mixture of diastereoisomers is isolated. To resolve 
the mixture of diastereoisomers, said mixture is redissolved in one of 
said solvents, treated with an amine or an alcohol and again stirred for 
1-48 hours at 0.degree.-50.degree., preferably at 0.degree.-30.degree., or 
simply left to stand. 
It is equally possible to dissolve the mixture of diastereoisomers directly 
in a suitable alcohol without using an additional solvent. 
Examples of suitable alcohols are lower alcohols having 1-8 C atoms, 
especially methanol, ethanol or isopropanol, but also mixtures thereof. 
Suitable amines are inter alia piperidine, pyrrolidine, morpholine or else 
ethylamine. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. 
In the foregoing and in the following examples, all temperatures are set 
forth uncorrected in degrees Celsius and unless otherwise indicated, all 
parts and percentages are by weight. 
The entire disclosures of all applications, patents and publications, cited 
above and below, and of corresponding application German P 41 29 062.3, 
filed Sep. 2, 1991, are hereby incorporated by reference.

EXAMPLES 
In the following Examples, which serve to illustrate the invention in 
greater detail, all temperatures are given in .degree. C., as in the 
preceding text. "Conventional working-up" means that water or dilute 
sodium hydroxide solution is added if necessary, the mixture is extracted 
with an organic solvent such as ethyl acetate, chloroform or methylene 
chloride, the organic phase is separated off, dried over Na.sub.2 SO.sub.4 
or MgSO.sub.4, filtered and evaporated and the residue is additionally 
purified by chromatography or crystallization if appropriate. The 
enantiomeric purity can be determined for example by HPLC or differential 
scanning calorimetry (DSC). The abbreviations HPLC and ee stand for high 
pressure liquid chromatography and enantiomeric excess. 
EXAMPLES 
Example 1 
A solution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene 
chloride is added dropwise at 0.degree., with stirring, to a suspension of 
48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- 
yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene 
chloride to which 20 ml of triethylamine have been added, and the reaction 
mixture is stirred for 4 hours. It is then washed with dilute hydrochloric 
acid and subsequently with bicarbonate solution. The organic phase is 
separated off and worked up in conventional manner to give 
3-[(-)-camphanoyl]-5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 4- 
tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as 
a mixture of diastereoisomers, m.p. 216.degree.-217.degree. . 
Example 2 
48 g of the mixture of diastereoisomers of Example 1 are dissolved in 800 
ml of tetrahydrofuran, 3.6 ml of morpholine are added and the reaction 
mixture is left to stand for 14 hours at 25.degree.. It is concentrated, 
aqueous ethyl acetate is added and the mixture is worked up in 
conventional manner. The (-)-enantiomer obtained by resolution, which is 
contaminated with small amounts of (+)-enantiomer, is separated from the 
bulk of the unresolved diastereoisomer by chromatography. The small amount 
of (+)-enantiomer present is removed from the (-)-enantiomer as the 
racemate by recrystallization from ethanol. Concentration of the mother 
liquor and crystallization gives (-)-5-[1-(3,4- 
methylenedioxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]- 6-methyl-3, 
6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 180.degree.; 
[.alpha.].sub.D.sup.20 =-534.2.degree.; ee&gt;99% (HPLC). 
Example 3 
20 g of the unresolved diastereoisomer of Example 2 are dissolved in THF, 3 
ml of morpholine are added and the mixture is processed further 
analogously to Example 2. After removal of the solvent, the residue is 
recrystallized from ethanol to give (+)-5-[1- 
(3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- 
yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 181.degree.; 
[.alpha.].sub.D.sup.20 =++541.5.degree.; ee&gt;99%. 
Example 4 
20 g of the unresolved diastereoisomeric compound of Example 2 are 
dissolved in 400 ml of methanol and boiled for 24 hours. After removal of 
the solvent, the residue is recrystallized from ethanol to give (+)- 
5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 
4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, 
m.p. 181.degree.; [.alpha.].sub.D.sup.20 =++541.5.degree.; ee&gt;99%. 
Example 5 
Analogously to Example 1, the racemic mixture of 
5-[1-methyl-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-t 
hiadiazin-2 H-1,3,4-thiadiazin-2-one (m.p. 177.degree.) is reacted with 
(+)-camphanic acid chloride to give 3- [(+)-camphanoyl]-5-(1-methyl-1,2,3, 
4-tetrahydroquinol-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one as 
a mixture of diastereoisomers. 
Example 6 
The mixture of diastereoisomers of Example 5 is reacted with morpholine 
analogously to Example 2 to give 
(+)-5-(1-methyl-1,2,3,4-tetrahydroquinol-6-yl)-6- 
methyl-3,6-dihydro-2H-1,3, 4-thiadiazin-2-one and the corresponding 
unresolved diastereoisomer, the further processing of which is described 
in Example 7. 
Example 7 
The unresolved diastereoisomer of Example 6 is dissolved in methanol and 
boiled for 20 hours, analogously to Example 4. After removal of the 
solvent, the residue is recrystallized from ethanol to give 
(-)-5-(1-methyl-1,2,3,4-tetrahydroquinol-6-yl)-6-methyl-3,6-dihydro-2H-1,3 
, 4-thiadiazin-2-one. 
Example 8 
Analogously to Example 1, the racemate of 
5-[1-(3,4,5-trimethoxybenzyl)-1,2,3, 
4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one is 
reacted with (-)-camphanic acid chloride to give 
3-[(+)-camphanoyl]-5-[1-(3,4, 5-trimethoxybenzoyl)- 
1,2,3,4,-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H- 1,3, 
4-thiadiazin-2-one as a mixture of diastereoisomers. 
3-[(+)-Camphanoyl]-5-[1-isonicotinoyl-2,3,4, 
5-tetrahydro-1H-1-benzazepin-7-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazi 
n-2-one as a mixture of diastereomers is obtained analogously. 
Example 9 
The mixture of diastereoisomers of Example 8 is reacted with morpholine 
analogously to Example 2 to give (-)-5- [1- 
(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3, 
6-dihydro-2H-1,3,4-thiadiazin-2-one and the corresponding unresolved 
diastereoisomer, the further processing of which is described in Example 
10. 
(-)-5-[1-Isonicotinoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]-6-methyl-3, 
6-dihydro-2H-1,3,4-thiadiazin-2-one is obtained analogously. 
Example 10 
Analogously to Example 3, (+)-5-[1-(3,4,5-trimethoxybenzoyl)-1,2,3, 
4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, 
[.alpha.].sub.D.sup.20 =+476.2.degree., is obtained starting from the 
unresolved diastereoisomer of Example 9. 
(+)-5-[1-Isonicotinoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]-6-methyl-3, 
6-dihydro-2H-1,3,4-thiadiazin-2-one, [.alpha.].sub.D.sup.20 
=+478.2.degree., is obtained analogously. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.