(+)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid esters, method of preparation and use

The invention discloses (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid esters and a process for their preparation. The process provides the dextrorotatory isomers substantially free from the corresponding levorotatory isomers. Antihypertensive pharmaceutical compositions comprising the dextrorotatory esters and methods for using said compositions are also disclosed.

BACKGROUND OF THE INVENTION 
Ethyl (3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
(etozoline) is a known compound [see Liebigs Ann. Chem., 665, 150(1963)] 
and its diuretic action has also already been described. 
This compound contains an asymmetric carbon atom in the 5-position; thus, 
etozoline is a racemate. Because of the particular structural 
characteristics of etozoline, the separation of the racemate into its 
optically active isomers has hitherto not been carried out for certain 
technical reasons. Etozoline is a very weak base which does not form salts 
with the usual chiral acids, for example (+)-tartaric acid, 
(+)-dibenzoyltartaric acid and (+)-camphorsulphonic acid. Thus, this 
racemate has not been separated by known methods. 
Esterification of the known, optically-active 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)-acetic acid 
[(+)-ozolinone (see Federal Republic of Germany Patent Specification No. 
26 58 858)] also cannot be carried out with agents which can be used on a 
large scale because it racemizes under the esterification conditions. 
Thus, for example, (+)-ozolinone racemizes to an extent of 15% in 0.1N 
hydrochloric acid in less than 1 hour. Even in chloroform, in the same 
period of time, the degree of racemization which occurs is about 10%. 
We have now surprisingly found that (+)-ozolinone can be esterified without 
racemization via the acid chloride. Thus, pure (+)-etozoline is obtained 
when a solution of the free (+)-carboxylic acid [(+)-ozolinone] is quickly 
mixed at a low temperature with an excess of a compound chosen from among 
thionyl chloride phosphorous oxychloride, phosphorous pentachloride and 
phosphorous trichloride; thereafter anhydrous ethanol, also in excess, is 
added thereto. In the case of this method of esterification, surprisingly, 
no racemization takes place and pure (+)-etozoline is obtained. 
The method according to the present invention has also proved to be useful 
for the preparation of other optically pure esters of ozolinone and 
permits the large scale preparation of these optically-active compounds in 
an especially favorable one-pot process. 
SUMMARY OF THE INVENTION 
The present invention relates to the dextrorotatory isomer, substantially 
free from the levorotatory isomer, of an optically-active compound of the 
general formula I: 
##STR1## 
in which R is a straight- or branched-chain alkyl group containing from 1 
to 4 carbon atoms and *C denotes an asymmetric carbon atom. 
The invention also relates to a process for the preparation of the 
optically-active dextrorotatory isomer I, substantially free from the 
corresponding levorotatory isomer, wherein (+)-ozolinone of formula II: 
##STR2## 
is rapidly mixed, in a solvent which is inert under the reaction 
conditions with regard to racemization, at a temperature of from about 
-10.degree. C. to about 40.degree. C. with an excess of a compound chosen 
from among thionyl chloride, phosphorous oxychloride, phosphorous 
pentachloride, and phosphorous trichloride and after a reaction period of 
about 10 to about 60 minutes, an excess of an alcohol of the general 
formula III: 
EQU R--OH (III) 
in which R has the same meaning as above, is added thereto, the reaction 
mixture is allowed to react, optionally with slight cooling, whereafter 
the desired product is isolated. 
The invention also relates to pharmaceutical compositions which comprise an 
antihypertensive-effective amount of a dextrorotatory isomer of a compound 
of the formula I. 
The invention also relates to a method for treating hypertension in a 
mammal which method comprises administering to a mammal in need thereof an 
antihypertensive effective amount of a dextrorotary isomer of a compound 
of formula I. 
DESCRIPTION OF THE INVENTION 
The dextrorotatory isomers of the compounds of formula I are prepared, 
substantially free from the corresponding levorotatory isomers, in the 
following manner: 
The dextrorotatory isomer of the compound of formula II [(+)-ozolinone] is 
first dissolved in a solvent. The solvents used for the reaction can be 
all solvents which are inert under the reaction conditions with regard to 
racemization, especially preferred are chlorinated hydrocarbons, such as 
dichloromethane and chloroform. The addition of a dipolar, aprotic 
solvent, such as hexamethylphosphoric acid triamide, has also proved to be 
useful. The dissolved carboxylic acid is mixed at a temperature of from 
about -10.degree. C. to about 40.degree. C. and preferably at ambient 
temperature, optionally with cooling, with an excess of a compound chosen 
from among thionyl chloride, phosphorous oxychloride, phosphorous 
pentachloride and phosphorous trichloride. Thereafter, the reaction is 
allowed to continue for 15 to 60 minutes. Subsequently, a comparatively 
large excess (up to 50 equivalents) of the alcohol component of general 
formula III is added thereto; and the reaction mixture is then allowed to 
stir for about 30 minutes at 10.degree. C. to 25.degree. C. 
The reaction mixture is then extracted with cold dilute ammonia solution in 
order to remove inorganic acids, alcohol and unreacted starting carboxylic 
acid. The organic phase is subsequently dried, the solvent is distilled 
off and the residue is crystallized, by means of the addition of a solvent 
in which the dextrorotatory isomers of the compounds of general formula I 
are sparingly soluble, for example benzene or cyclohexane. 
This process can, of course, be modified with regard to the reaction 
conditions but the above-described embodiment of the process has proved to 
be especially advantageous. 
The pharmacological investigation of the alkyl esters of (+)-ozolinone 
according to the present invention gave completely unexpected results in 
that the diuretic activity present in the racemate is not present in the 
pure dextrorotatory isomers. However, the pure dextrorotatory isomers 
nevertheless were surprisingly found to possess a strong antihypertensive 
action. Hitherto, even in potent diuretics, a more or less strongly 
antihypertensive action has admittedly been found. This antihypertensive 
effect is generally regarded as a causal consequence of the anti-edematous 
properties of potent diuretics normalizing the electrolyte equilibrium. It 
has also previously been observed in the case of etozoline that, even at 
subdiuretic doses, an antihypertensive effect occurs (cf. Federal Republic 
of Germany Patent Specification No. 25 32 180). However, from these 
findings, it could only have been concluded that, even in the case of pure 
optical isomers, both directions of activity would still be present. 
Conclusions regarding separately present mechanisms were hitherto not 
possible. 
The finding according to the present invention is not only scientifically 
interesting and without parallel in the prior art but also opens up a way 
to a completely new type of antihypertensively-acting compounds which are 
characterized by no longer possessing diuretic side effects. The previous 
risks which regularly accompanied the treatment of hypertension with 
potent diuretics, namely, electrolyte imbalance, heartcirculation 
stressing or hemoconcentration, can now be completely avoided by the use 
of the compounds according to the present invention. 
According to the present invention, it is now possible for the first time 
to separate the antihypertensive component of the activity profile of a 
potent class of diuretics and to make it useful in pure form. This advance 
is all the more valuable since previous attempts to influence the activity 
profile of racemic diuretics by racemate splitting did not produce any 
significant results. Therefore, they were regarded as being unimportant in 
practice [see Arzneimittelforschung, 17, 657(1967)]. 
The present invention provides a solution to a long existing problem and 
thus provides the possibility for the therapy of various forms of 
hypertension with a new type of antihypertensive medicament which is free 
from the side effects of the known diuretics [cf. Drugs, 14, 446(1977)]. 
Since the medicinal therapy of high blood pressure is planned for very 
long periods of time and, not unusually, must be carried out for many 
years, it is particularly important to employ medicaments without side 
effects. Only in this way can it be ensured that the treatment can be 
carried out without interruption and free of disturbance. Therefore, the 
exclusively antihypertensively-acting dextrorotatory isomers of the 
compounds of general formula I represent a significant technical advance. 
The following pharmacological investigations show the exclusive 
antihypertensive properties of the pure dextrorotatory isomers of the 
compounds according to the present invention: 
Pharmacological investigations 
The racemic compounds of general formula I showed, in the case of 
pharmacological testing, strong diuretic and saluretic properties and had 
a good antihypertensive activity. These findings have already been 
published for the compound in which R is ethyl (etozolin) [see 
Arzneimittelforschung/Drug Research, (II), No. 9a, 1745(1977)]. 
The diuretic action of the compounds of formula I is completely limited to 
the levorotatory enantiomers, the dextrorotatory enantiomers being 
completely inactive with regard to diuresis. Indeed, the dextrorotatory 
enantiomers even exhibit a furosemide antagonistic action to the kidneys. 
In the case of rats with renovascular high blood pressure, the levorotatory 
enantiomers, in the diuretically effective dosage range, lower somewhat, 
as is to be expected, the average blood pressure of the hypertensive 
animals because of the saluretic action. 
However, the diuretically absolutely ineffective pure dextrorotatory 
enantiomers possess a considerably stronger antihypertensive action. 
Thus, with the pure dextrorotatory enantiomers of general formula I, there 
is provided a completely new principle for the treatment of hypertension 
which, due to the low toxicity and the absence of side effects, possesses 
a great degree of therapeutic certainty. 
1. Acute toxicity 
(a) Methodology 
The experimental animals used were male and female rats of the SIV 50 
strain with a body weight of 115 to 170 g and of 100 to 160 g, 
respectively. All the animals were fasted for 20 hours before the 
commencement of the experiments, water was available ad libitum. There 
were 10 animals in each dosage group. The test substances were 
administered intragastrally with a metal probe in the form of 1% 
tragacanth slurry suspensions (4 ml/100 g of body weight). 
The animals were observed over a period of time of 7 days. For the 
calculation of the LD.sub.50 with the related confidence limits, use was 
made of Weber's probit analysis (see Grundriss der Biologischen Statistik, 
pub. Gustav Fischer Verlag, Jena, 1-72). 
(b) Results 
The following compounds were investigated or compared on the basis of 
values published in the literature: 
Compound A: ethyl 
(.+-.)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
(etozolin) 
Compound B: ethyl 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
Compound C: ethyl 
(-)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
Compound D: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 
1,1-dioxide (hydrochlorothiazide) 
Compound E: 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic 
acid (furosemide) 
Compound F: [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy]acetic acid 
(ethacrynic acid) 
Compound G: 6-phenyl-2,4,7-pteridinetriamine (triamterene). 
The LD.sub.50 values of Compounds A and B are summarized in the following 
Table I; 
TABLE I 
______________________________________ 
confidence limits 
LD.sub.50 mg/kg 
Sex mg/kg p = 0.05 
Compound (rat) intragastral 
lower upper 
______________________________________ 
A male 11,040 9,380 13,000 
female 10,250 9,260 11,350 
B male 3,646 3,083 4,161 
female 4,227 3,590 5,192 
______________________________________ 
For the purpose of comparison, the literature values (cf. Meng-Loew, 
Diuretika, pub. Georg Thieme Verlag, Stuttgart, 1974, p. 177) for the 
known diuretic compounds D to G are set out in the following Table II: 
TABLE II 
______________________________________ 
Sex LD.sub.50 
Compound (mice) mg/kg 
______________________________________ 
D male 3,080 
E male 4,600 
F male 600 
G male 450 
______________________________________ 
As can be seen from Table I, Compound B is more toxic than Compound A but, 
nevertheless, since it has an LD.sub.50 greater than 2 g/kg body weight, 
it is extraordinarily nontoxic. 
2. Diuresis in awake rats 
(a) Methodology 
The experimental animals used were male rats of the SIV 50 strain which 
were kept under constant conditions. Feed was removed 36 hours before the 
commencement of the experiments but water was available until just before 
the commencement of the experiment. 
The test substances were administered intragastrally as suspensions in 1% 
tragacanth slurry which has been prepared with a 0.2% sodium chloride 
solution (1 ml/100 g body weight). In addition, the animals were given 
intragastrally 4 ml/100 g body weight a 0.2% sodium chloride solution. The 
animals were kept individually in metabolic cages in order to determine 
the urine volumes within the first 4 hours. 
(b) Results 
In the FIG. 2, there are graphically illustrated the urine-time volumes, 
the average value with standard deviations of 88 control animals being 
shown parallel to the abscissae: 
It can be seen from the Figure that Compounds A and C are diuretically 
effective in a dosage dependent manner and that Compound B does not 
possess any diuretic action at all. 
3. Renovascular high blood pressure 
(a) Methodology 
The antihypertensive properties were investigated in rats which, after 
experimental ligature of the kidney blood flow, had developed a 
renovascular high blood pressure. 
The experimental animals used were male rats of the SIV 50 strain which, 
under ether narcosis, had been monolaterally nephrectomised and the 
contralateral renal arteries of which had been stenosed 2 days later with 
the help of silver clips. After 6 to 8 weeks, these animals developed a 
high blood pressure. The blood pressure measurement took place bloodlessly 
on the root of the tail of the animals. 
The test substances were administered intragastrally once daily as 
tragacanth slurry suspensions for 33 days. 
(b) Results 
In the following Table III, there are given the average blood pressure 
values before, during and after the treatment: 
TABLE III 
______________________________________ 
Renovascular high blood pressure 
______________________________________ 
100 mg/kg i.g. control A C B 
______________________________________ 
before treatment 
190 197 191 189 
6th day of treatment 
183 187 177 170 
13th day of treatment 
195 175 173 169 
20th day of treatment 
207 175 176 164 
2nd day after treatment 
197 195 201 190 
______________________________________ 
200 mg/kg i.g. control A C B 
______________________________________ 
before treatment 
185 187 192 185 
10th day of treatment 
185 171 178 159 
17th day of treatment 
188 182 176 150 
33rd day of treatment 
196 174 164 156 
8th day after treatment 
182 182 190 182 
______________________________________ 
It can be seen from Table III that, for example, the diuretically inactive 
Compound B possesses the strongest antihypertensive action and that this 
effect is dosage dependent. 
The present invention also provides pharmaceutical compositions containing 
at least one dextrorotatory isomer of a compound of general formula I, in 
admixture with a solid or liquid pharmaceutical diluent or carrier. 
The dextrorotatory isomers of the compounds of general formula I can be 
administered in liquid or solid form. Liquid forms are, in particular, 
prepared on an aqueous basis and contain conventional additives, such as 
stabilizing agents, solubilizing agents and/or buffers. Examples of such 
additives include ethanol, complex formers (such as 
ethylenediaminetetraacetic acid and the nontoxic salts thereof), tartrate 
and citrate buffers and high molecular weight polymers (for example liquid 
polyethylene oxide) for viscosity regulation. Solid carrier materials 
include, for example, starch, lactose, mannitol, methyl cellulose, talc, 
highly dispersed silicic acids, high molecular weight fatty acids (for 
example stearic acid), gelatine, agar-agar, calcium phosphate, magnesium 
stearate, animal and vegetable fats and solid high molecular weight 
polymers (such as polyethylene glycols). Compositions suitable for oral 
administration can, if desired, contain flavoring and/or sweetening 
materials. 
The dosage depends upon the nature and severity of the disease to be 
treated. Generally, the individual dose is from 20 to 400 mg of the pure 
dextrorotatory isomer of a compound of formula I.

The following Examples are given for the purpose of illustrating the 
present invention: 
EXAMPLE 1 
Ethyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
25.6 g (0.1 mol) 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid is 
dissolved in a mixture of 500 ml chloroform and 100 ml 
hexamethylphosphoric acid triamide (HMPT). Then, with the exclusion of 
moisture, at ambient temperature and with efficient and rapid stirring, 
23.8 g (0.2 mol) thionyl chloride is added thereto and, after 15 minutes, 
36.8 g (0.8 mol) anhydrous ethanol is also added thereto. After a further 
30 minutes, 500 ml dilute aqueous ammonia solution is added. The 
chloroform phase is then separated and extracted four times with 500 ml 
amounts of dilute aqueous ammonia solution. The chloroform phase is dried 
with 50 g anhydrous magnesium sulphate, evaporated on a rotary evaporator 
and the residue crystallized by the addition of 200 ml petroleum ether. 
The crystals are filtered with suction and recrystallized from 200 ml 
cyclohexane. The almost colorless crystals obtained are dried at 
50.degree. C. There is obtained 19.5 g (69% of theory) ethyl 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate; mp 
131.degree. C. [.alpha.].sub.D.sup.23 =+224.degree. (c=0.5 in chloroform). 
EXAMPLE 2 
Ethyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
768 g (3 mol) (+)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidine)acetic 
acid is dissolved in 7 liters dichloromethane. 428 g (3.6 mol) Thionyl 
chloride (262 ml) is allowed to run all at once into this solution, while 
stirring. The temperature thereby increases from 18.degree. C. to 
27.degree. C. The reaction mixture is cooled to 20.degree. C. and stirred 
for 30 minutes at this temperature. Subsequently, 2760 g (60 mol) 
anhydrous ethanol (3500 ml) is allowed to run in all at once, the 
temperature thereby increasing to 26.degree. C. The reaction mixture is 
again cooled to 20.degree. C. and stirred for 30 minutes. Subsequently, 
the reaction mixture is extracted once with 9 liters of a mixture of 1.5 
liters concentrated aqueous ammonia solution, 3 kg ice and 4.5 liters 
water and four times with 4 liter amounts of water. The dichloromethane 
phase is dried with 200 g magnesium sulphate, filtered and evaporated on a 
rotary evaporator. The addition of 6 liters of petroleum ether causes the 
product to crystallize. The crystals are filtered with suction, thereafter 
washed with 500 ml benzene and dried at 45.degree. C. There is obtained 
528 g (62.1% of theory) ethyl 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate; mp 
130.8.degree. C.; [.alpha.].sub.D.sup.23 =+226.5.degree. (c=1 in 
chloroform). 
The following compounds are obtained in an analogous manner: 
n-propyl (+)-(3-methyl-4-oxo-5N-piperidino-thiazolidin-2-ylidene)acetate 
isopropyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
n-butyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
isobutyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
t-butyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate. 
EXAMPLE 3 
Methyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
153 g (0.6 mol) 
(+)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid is 
dissolved in 1.53 liters dichloromethane and mixed all at once, while 
stirring, with 107 g (0.9 mol) thionyl chloride (about 66 ml, d=1.63). The 
reaction mixture is stirred for 30 minutes at 20.degree. C. and then 768 g 
(24 mol) methanol (967 ml) is added all at once. The reaction mixture is 
then stirred for 30 minutes at 20.degree. C. The organic phase is 
subsequently washed with 2.5 liters dilute aqueous ammonia solution (300 
ml concentrated ammonium hydroxide in water) and then washed three times 
with 2.5 liter amounts of water. The dichloromethane phase is dried with 
anhydrous sodium sulphate, evaporated in a rotary evaporator and the 
residue obtained is crystallized from 1 liter cyclohexane. The crystals 
are filtered with suction and dried at 60.degree. C. There is obtained 124 
g (76.7% of theory) methyl (+)-( 
3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate; mp 126.1.degree. 
C.; [.alpha.].sub.D.sup.23 =+239.degree. (c=0.5 in chloroform). 
EXAMPLE 4 
Methyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
30 g (0.117 mol) 
(+)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid is 
dissolved in a mixture of 600 ml dichloromethane and 120 ml 
hexamethylphosphoric acid triamide and, while stirring at 20.degree. C., 
is mixed all at once with 27.8 g (0.234 mol) thionyl chloride (d=1.63; 
about 17.1 ml). The temperature thereby increasing to 26.degree. C. The 
reaction mixture is cooled to 20.degree. C., stirred for 30 minutes and 
then mixed with 37.5 g (1.17 mol) anhydrous methanol and again cooled to 
20.degree. C. After 30 minutes, the reaction mixture is extracted once 
with 1 liter dilute aqueous ammonia solution (100 ml concentrated ammonium 
hydroxide and water) and five times with 1 liter amounts of water. The 
dichloromethane phase is dried with anhydrous sodium sulphate, evaporated 
in a rotary evaporator and the residue crystallized from 300 ml petroleum 
ether. There is obtained 25.8 g (81.6% of theory) methyl 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)-acetate; mp 
125.8.degree. C.; [.alpha.].sub.D.sup.23 =+239.degree. (c=0.5 in 
chloroform). 
EXAMPLE 5 
Ethyl (-)-(3-methyl-4-oxo-5N-piperidinothiazolidin- 2-ylidene)acetate 
25.6 g. (0.1 mol) 
(-)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid is 
dissolved in a mixture of 500 ml dichloromethane and 100 ml 
hexamethylphosphoric acid triamide. With the exclusion of moisture and at 
ambient temperature and with efficient rapid stirring, 23.8 g (0.2 mol) 
thionyl chloride is added thereto and, after 15 minutes, 36.8 g (0.8 mol) 
anhydrous ethanol is also added. After a further 30 minutes, 500 ml dilute 
aqueous ammonia solution is added and the phases are separated. The 
dichloromethane phase is further extracted four times with 500 ml amounts 
of dilute aqueous ammonia solution, dried with 50 g anhydrous magnesium 
sulphate and evaporated on a rotary evaporator. The residue is 
crystallized by the addition of 200 ml petroleum ether. The crystals are 
filtered with suction and recrystallized from cyclohexane. The almost 
colorless crystals are dried at 50.degree. C. There is obtained 19.5 g 
(69% of theory) ethyl 
(-)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate; mp 
130.degree. C.; [.alpha.].sub.D.sup.23 =-229.8.degree. (c=0.5 in 
chloroform). 
EXAMPLE 6 
Ethyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
25.6 g (0.1 mol) 
(+)-(3-Methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetic acid is 
dissolved in 228 ml dichloromethane with stirring. 22.8 g (0.11 mol) 
phosphorous pentachloride in 256 ml dichloromethane is allowed to run 
rapidly into this solution while stirring. The temperature is maintained 
at 30.degree. C. The mixture is then cooled to 20.degree. C. and stirred 
for 30 minutes at this temperature. Subsequently, 291 ml (5 mol) anhydrous 
ethanol is allowed to run in at once, the temperature thereby increases to 
28.degree. C. The reaction mixture is again cooled to 20.degree. C. and is 
stirred for 30 minutes. Subsequently, the reaction mixture is extracted 
once with 200 ml aqueous ammonia and four times with 200 ml amounts of 
water. The dichloromethane phase is dried with sodium sulfate and then 
evaporated. The residue is recrystallized from 200 ml petroleum ether. 
There is obtained 24.0 g (84.4% of theory) ethyl (+)-(3-methyl-4 
-oxo-5N-piperidinothiazolidin-2-ylidene)-acetate; mp 129.4.degree. C.; 
[.alpha.].sub.D.sup.RT =+226.1.degree. (c=1 in chloroform). 
EXAMPLE 7 
Ethyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
The reaction of Example 6 is carried out with 0.01 mol phosphorus 
oxychloride under exactly the same reaction conditions. There is obtained 
710 mg (25% of theory) ethyl 
(+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate, mp 
107.5.degree. C.; [.alpha.].sub.D.sup.RT =+208.degree. (c=1 in 
Chloroform). This product contains impurities consisting of the anhydride. 
EXAMPLE 8 
Ethyl (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate 
The reaction of Example 6 is carried out with 0.01 mol phosphorous 
trichloride under exactly the same reaction conditions. There is obtained 
110 mg (3.8% of theory); mp 120.6.degree. C.; [.alpha.].sub.D.sup.RT 
=+211.degree. (c=1 in chloroform).