Process for the preparation of benzothiazepin-one derivatives

The object of the invention is a process for the preparation of the trans(-) (2R,3S) diastereoisomer of the glycidic esters of general formula: ##STR1## wherein a chlorohydrin of general formula: ##STR2## is reacted with a strong organic base in a suitable solvent and at a temperature between -10.degree. C. and room temperature. Another object of the invention is intermediate compounds cis(+) (2S,3S) 1,5-benzothiazepin-4-one.

In a general manner, the present invention relates to a new process for the 
preparation of glycidic esters, novel reaction intermediates as well as a 
new process for the preparation of benzothiazepin-one derivatives. 
In particular, the invention relates to a new process for the preparation 
of the trans(-)(2R,3S) diastereoisomer of the glycidic esters of formula: 
##STR3## 
in which Y denotes a C.sub.1 -C.sub.8 alkyl radical. 
By "C.sub.1 -C.sub.8 alkyl" radical is meant linear or branched saturated 
hydrocarbon residues such as, for example, methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl, n-heptyl or 
n-octyl. 
Y preferably represents the methyl radical. 
The trans(-)(2R,3S) diastereoisomers of formula I constitute intermediate 
compounds particularly useful for the preparation in particular of 
cis-(+)(2S,3S) 2-hydroxy 3-(4-methoxyphenyl) 3-(2-amino phenylthio) 
propionic acid. 
This acid, described in the patent FR-A-2 530 243, is a synthetic 
intermediate, the use of which according to the process of the French 
patent in question makes it possible to prepare cis(+)(2S,3S) 
diastereoisomeric derivatives of 1,5-benzothiazepin-4-one, known for their 
properties as calcium antagonists, hypotensives and coronary and cerebral 
vasodilators. 
Such derivatives may be represented by the general formula: 
##STR4## 
in which W.sub.1, W.sub.2 and W.sub.3, which are identical or different, 
each denotes a C.sub.1 -C.sub.4 alkyl radical, preferably methyl, and Z 
represents a C.sub.1 -C.sub.4 alkylene radical, preferably ethylene. 
The most interesting 1,5-benzothiazepin-4-one derivative of this series is 
unquestionably cis(+)(2S,3S) 3-acetoxy 5-(2-N,N-dimethylamino ethyl) 
2-(4-methoxyphenyl) 2,3-dihydro 1,5-benzothiazepin-4(5H)-one, commonly 
called diltiazem. 
Most of the compounds presently known for the preparation of this compound 
involve non-sterospecific synthesis. According to these processes, the 
correct configuration of the 2 and 3 carbon atoms of diltiazem is attained 
by an optical resolution of the final compound or of one of the 
intermediates leading to the final compound. Thus, the resolution of 
threo(2SR,3SR) 2-hydroxy 3-(2-amino phenylthio) 3-(4-methoxyphenyl) 
propionic acid by means of, for example, d-.alpha.-phenyl-ethylamine 
(patent application FR-A-2.530.243), lysine (patent application 
FR-A-2.534.579) or also d-p-tolylethylamine (patent application 
JP-A-85/243.062) has been considered. 
Similarly, the resolution of threo(2SR,3SR) 2-hydroxy 3-(2-nitrophenylthio) 
3-(4-methoxyphenyl) propionic acid and of threo(2SR,3SR) 2-hydroxy 
3-(2-dimethylaminoethylamino phenylthio) 3-(4-methoxyphenyl) propionic 
acid by means of cinchonidine have been described (patent applications 
JP-A-78/018038 and JP-A-83/ 110685). 
Finally, the optical separation of diltiazem itself by means of optically 
active mandelic acid (patent application JP-A-83/032873) or a chiral 
column (patent application JP-A-85/046111) has been performed. 
Such an optical resolution step has an unfavourable effect on the yields 
which fall, in consequence, by at least 50%, the final yield of diltiazem 
being 25% at the very most. 
Furthermore, these optical separations lead to an appreciable increase in 
the final cost of production of diltiazem since they are usually performed 
on quite complex intermediates in the context of the total synthesis. 
Moreover, a process for the preparation of diltiazem, starting from a 
(-)(2R,3S) glycidic ester, obtained by optical resolution of the 
(.+-.)(2RS,3SR) 2,3-epoxy 3-(4-methoxyphenyl) propionic acid with an 
optically active amine so as to recover an alkali metal salt of the 
trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) propionic acid which is 
esterified to give a (-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) propionic 
ester, has been described in the patent applications JP-A-86/145159, 
JP-A-86/145160 and JP-A-86/145173. 
This process, like its predecessors, also requires an optical resolution at 
the level of the glycidic intermediates. 
Consequently, it appears advantageous to have available an industrial 
process capable of supplying the trans(-)(2R,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionic esters of the patent application 
JP-A-61/145160 according to a stereospecific synthesis. 
A widely known and widely used method for the preparation of epoxides is 
based on the Darzens reaction which consists of the cyclization in basic 
medium of halohydrins obtained from an aldehyde and an .alpha.-halogenated 
derivate. 
Now, it is also well established that the step of either retroaldolization 
or cyclization of the halohydrins produced during this reaction is 
affected very considerably by the reaction medium and the reagents used 
such that is is impossible to predict with certainty the final result of 
such a reaction carried out starting from any halohydrin and a given basic 
reaction medium (J. Org. Chem., Vol. 34, No. 11, pp. 3600-3606). 
For example, a synthesis has been described in Tetrahedron Letters 27 pp. 
5397-5400 (1986) which enables a trans(2R,3S) diastereoisomer of a 
glycidic ester ultimately to be obtained. According to this process, the 
epoxidation of a mixture of optically active (2RS,3S) chlorohydrins, i.e. 
a mixture of (2RS,3S) ethyl 2-chloro 3-hydroxy butanoates, is carried out 
according to the Darzens reaction in order to produce an 85/15 mixture of 
ethyl trans/cis 2,3-epoxy butanoates, the reaction being performed in the 
presence of sodium ethylate in ethanol. The chemical yield of this 
reaction was found to be 84%. 
After removal of the cis epoxide by transitory conversion to the brucine 
salt of the corresponding butanoic acid, the optically pure trans(2R,3S) 
2-epoxy butanoic acid (enantiomeric excess&gt;99%) was recovered in a yield 
of only 37%, which would suggest, in view of the nature of the salt, a 
resolution of a mixture of trans diastereoisomers. 
Now, it has been found according to the invention that it is possible, 
starting from chlorohydrins in the form of a mixture of optically active 
(2RS,3S) diastereoisomers, to obtain trans(-)(2R,3S) diastereoisomers of 
4-methoxy phenylglycidic esters in very high chemical yield since the 
enantiomeric excess (ee) is higher than 85% and does not require the 
intermediary formation of a salt. 
According to the invention, the diastereoisomers of formula I are prepared 
by reacting a chlorohydrin of general formula: 
##STR5## 
in which Y has the same meaning as before, with an organic base and in a 
suitable solvent. 
A strong organic base, preferably 1,8-diazabicyclo [5,4,0] undec-7-ene, is 
usually used as base 
The solvent usually used is an apolar or slightly polar aprotic solvent 
such as dichloroethane, a polar aprotic solvent such as acetonitrile or 
even a polar protic solvent such as an alcohol, for example methanol. 
However, it is preferable to use a protic or aprotic polar solvent in which 
the diastereoselectivity of the conversion proves to be best. 
As for the reaction, it takes places at a temperature from -10.degree. C. 
to room temperature, and preferably at a temperature between -10.degree. 
C. and +10.degree. C., which allows maximal diastereoselectivity. 
The chlorohydrins of formula II may be in the form either of a mixture of 
anti(+)(2S,3S) and syn(-)(2R,3S) diastereoisomers, or the anti(+)(2S,3S) 
diastereoisomer, or the syn(-)(2R,3S) diastereoisomer. 
In the particular case of mixtures of methyl anti(+)(2S,3S) and 
syn(-)(2R,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionates, for 
example a 61/39 mixture, the formation of only the trans glycidic ester is 
observed in a chemical yield which may attain 100% and which exists 
predominantly in the form of the trans(-)(2R,3S) diastereoisomer since the 
enantiomeric excess is of the order of 86 to 88%. 
In view of the enantiomeric excess of the starting chloro-hydrins, this 
result attests to excellent optical retention. 
These results are all the more surprising since the bromo-hydrin analogues 
of the chlorohydrins of formula II were only able to provide the 
corresponding cis/trans mixture of epoxides of formula I, evidently 
without the occurrence of epimerization. 
Furthermore, it has been observed that the conversion, for example, into 
methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) propionate can be 
achieved by using methyl anti(+)(2S,3S) 2-chloro 3-hydroxy 
3-(4-methoxyphenyl) propionate in enantiomeric excess greater than 85% in 
order to give quantitatively and unequivocally the trans (-)(2R,3S) ester 
in question in an enantiomeric excess of 80 to 85%. 
Similarly, it is possible to prepare the same trans(-)(2R,3S) ester 
starting from methyl syn(-)(2R,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) 
propionate in enantiomeric excess of 80 to 85% in order to give the 
trans(-)(2R,3S) ester in question in a yield of the order of 90% and in an 
enantiomeric excess of about 85%. 
Consequently, these results demonstrate: 
retention of the absolute configuration at carbon atom 3 of the 
chlorohydrins of formula II, an observation which suggests that 
retrocondensation does not occur, 
the conversion of the syn(-)(2R,3S) chlorohydrin, after epimerization at 
carbon atom 2, into the trans(-)(2R,3S) glycidic ester at the expense of 
the cis(2S,3S) glycidic ester. 
This presupposes sufficiently different kinetics of cyclocondensation for 
the two diastereoisomeric chlorohydrins syn(-) (2R,3S) and anti(+)(2S,3S) 
and epimerization kinetics superior than those for the cyclocondensation 
into the cis epoxide. 
The chlorohydrins of formula II, whether they are in the form of a mixture 
(2RS,3S) or the separated diastereoisomers (2S,3S) and (2R,3S) 
consequently constitute particularly interesting novel intermediates since 
they can give rise easily and in high yield to the glycidic esters of 
formula I, which are themselves useful for the final synthesis of the 
compounds of formula Ia and, in particular, diltiazem. 
A second object of the invention consequently consists in the chlorohydrins 
of formula II in the form of anti(+)(2S,3S) diastereoisomers, 
syn(-)(2R,3S) diastereoisomers or in the form of their mixtures, as new 
intermediates which are useful in particular for the final preparation of 
the compounds of formula Ia and in particular diltiazem. 
In particular, the invention relates to the chlorohydrins of formula II 
below: 
Methyl anti(+)(2S,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionate 
Methyl syn(-)(2R,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionate, 
as well as their mixtures. 
The chlorohydrins of formula II can be obtained in the following manner: 
a) p-methoxyacetophenone is reacted at reflux in a suitable solvent such as 
an aprotic solvent, for example benzene, toluene or xylene, and in the 
presence of a basic agent such as an alkali metal hydride, for example 
sodium hydride, with a compound of general formula: 
##STR6## 
in which Y has the same meaning as before, which leads to the formation of 
a .beta.-ketoester of general formula: 
##STR7## 
in which Y has the same meaning as before, 
b) the .beta.-ketoester of formula IV is then treated with sulfuryl 
chloride at room temperature and in a suitable solvent, for example an 
aprotic solvent such as benzene, toluene or xylene, which leads to the 
formation of a .alpha.-chloro .beta.-ketoester of general formula: 
##STR8## 
in which Y has the same meaning as before 
c) a stereoselective reduction of the .alpha.-chloro .beta.-ketoester of 
formula V is then carried out according to the method described in J. 
Chem. Soc. Chem. Commun. (1985), pp. 138-139 and J. Organometallic Chem. 
(1985) 290 C23-C25, i.e. by treating the compound of formula V in question 
at a temperature between -70.degree. C. and -40.degree. C. with a mixture 
of (R,R) N,N'-dibenzoylcystine, tert.butanol and lithium borohydride in 
tetrahydrofuran, then by decomposing the complex formed by the addition of 
a strong acid such as hydrochloric acid, which leads to the formation of a 
mixture of about 50/50 of the syn and anti diastereoisomers of formula II 
in which the diastereoisomers syn(-)(2R,3S) very largely predominate. 
If necessary, this mixture of syn(-)(2R,3S) and anti(+)(2S,3S) 
diastereoisomers can be separated into its constituents according to known 
techniques, such as by chromatography. 
As for the the (R,R) N,N'-dibenzoylcystine, this latter can be prepared 
from (R)-cystine according to a protocol described in J. Med. Chem. (1969) 
pp. 950-953. 
As indicated previously, the trans(-)(2R,3S) diastereoisomers of formula I 
can be used for the final synthesis of the cis(+)(2S,3S) derivatives of 
formula Ia and, in particular, diltiazem. 
A third objective of the invention is consequently, a process for the 
preparation of the cis(+)(2S,3S) derivatives of formula Ia starting from 
the trans(-)(2R,3S) diastereoisomers of formula I, themselves obtained 
from the chlorohydrins of formula II according to the invention. 
For this purpose, the process consists of the following steps: 
a) the trans(-)(2R,3S) diastereoisomer of formula I obtained according to 
the invention from the chlorohydrins of formula II is reacted with 
2-aminothiophenol to give a cis(+)(2S,3S) 2-hydroxy 3-(4-methoxyphenyl) 
3-(2-amino phenylthio) propionic ester of general formula: 
##STR9## 
in which Y has the same meaning as before, 
b) the compound of formula VI is saponified by means of a basic agent such 
as an alkali metal hydroxide, for example sodium hydroxide or an alkali 
metal carbonate such as potassium carbonate, in order to form 
cis(+)(2S,3S) 2-hydroxy 3-(4-methoxyphenyl) 3-(2-amino phenylthio) 
propionic acid. 
c) the cis(+)(2S,3S) 2-hydroxy (3-(2-amino phenylthio) propionic acid thus 
obtained is cyclized by heating at a temperature between 100.degree. and 
140.degree. C. in an aromatic hydrocarbon, for example toluene, xylene or 
ethylbenzene, which leads to the formation of cis(+)(2S,3S) 3-hydroxy 
2-(4-methoxyphenyl) 2,3-dihydro 1,5-benzothiazepin-4(5H)-one of formula: 
##STR10## 
d) the cis(+)(2S,3S) derivative of formula VII is reacted with a halogen of 
general formula: 
##STR11## 
in which Hal denotes a halogen atom, for example chlorine, and W.sub.1, 
W.sub.2 and Z have the same meanings as before, or with a salt of this 
halogen, the halogen being preferably chlorine and the salt the 
hydrochloride, in the presence of a basic agent, for example potassium 
hydroxide, carbonate or bicarbonate and in a polar solvent, for example, 
formamide, acetamide, N,N-dimethylformamide or N,N-dimethylacetamide, in 
order to form the cis(+)(2S,3S) derivatives of 1,5-benzothiazepin-4-one of 
general formula: 
##STR12## 
in which W.sub.1, W.sub.2 and Z have the same meanings as before, 
e) the cis(+)(2S,3S) derivative of 1,5-benzothiazepin-4-one of formula IX 
is reacted in an aprotic solvent such as an aromatic hydrocarbon at reflux 
with a suitable acylating agent, for example an anhydride of general 
formula: 
##STR13## 
or an acid of formula: 
##STR14## 
in which W.sub.3 has the same meaning as before, in order to form the 
cis(+)(2S,3S) diastereoisomeric derivatives of 1,5-benzothiazepin-4-one of 
formula Ia in the form of the free base, the latter being allowed to 
react, if necessary, with a suitable inorganic or organic acid in order to 
form a pharmaceutically acceptable salt. 
The following non-limiting examples illustrate the invention:

PREATION 
Methyl anti(+)(2S,3S) and syn(-)(2R,3S) 2-chloro 3-hydroxy 
3-(4-methoxyphenyl) propionates. 
a) Methyl 3-(4-methoxyphenyl) 3-oxo propionate 
51 g (1.064 mole) of 50% sodium hydride (previously washed twice with 100 
ml of hexane), 340 ml of toluene and 90 ml (1.064 mole) of 
dimethylcarbonate are introduced under an argon atmosphere into a 21 
reactor equipped with a mechanical stirrer, a thermometer, a condenser and 
a dropping funnel. The reaction mixture is heated to reflux and then 80 g 
(0.532 mole) of p-methoxy-acetophrenone dissolved in 180 ml of toluene are 
added gradually during 2 hours. 
After the addition is complete, the reaction mixture is refluxed for a 
further 15 minutes, cooled and then 35 ml of acetic acid and 150 ml of 
water (pH=5) are added successively. After being left to stand and 
separation by decantation, the aqueous phase is again extracted with 80 ml 
of toluene. The organic phases are combined, washed with 50 ml of a 
saturated solution of sodium bicarbonate, dried over sodium sulfate, and 
then evaporated to dryness. A thick oil is thus obtained (54.3 g) which 
crystallizes when a seed of methyl 3-(4-methoxy-phenyl) 3-oxo propionate 
is added. 
In this manner, methyl 3-(4-methoxyphenyl) 3-oxo propionate is obtained in 
a yield of 98% and may be purified by passage through a column of silica. 
M.p.: 40.3.degree. C. 
Nuclear magnetic resonance spectrum (N.M.R.) (CDCl.sub.3): 7.9 ppm (d,2H); 
6.9 ppm (d,2H); 3.95 ppm (s,2H); 3.85 ppm (s,3H); 3.75 ppm (s,3H). 
b) Methyl 2-chloro 3-(4-methoxyphenyl) 3-oxo propionate 
24.96 g (0.12 mole) of methyl 3-(4-methoxyphenyl) 3-oxo propionate and 70 
ml of anhydrous toluene are introduced into a 250 ml round bottomed flask 
equipped with a stirrer, a thermometer and a condenser, under an 
atmosphere of argon. 10.19 ml (0.126 mole) of sulfuryl chloride are added 
with stirring during 10 minutes while the temperature is mainained at 
20.degree. C. After the reaction mixture has been stirred for an 
additional 30 minutes at 20.degree. C., 220 ml of a saturated aqueous 
solution of sodium bicarbonate (pH=7) are added, followed by 50 ml of 
toluene. 
After separation of the phases by decantation, the toluene phase is dried 
over sodium sulfate and then concentrated in a vacuum. 
In this manner, 28.24 g of methyl 2-chloro 3-(4-methoxyphenyl) 3-oxo 
propionate are obtained in a yield of 97% and can be purified by passage 
through a column of silica. 
n.sub.D.sup.20 =1.5630. 
N.M.R. spectrum (CDCl.sub.3): 8-7.95 ppm (d,2H); 6.95-6.90 ppm (d,2H); 5.60 
ppm (s,1H); 3.9 ppm (s,3H); 3.8 ppm (s,3H). 
c) Methyl anti(+)(2S,3S) and syn(-)(2R,3S) 2-chloro 3-hydroxy 
3-(4-methoxyphenyl) propionates 
2.87 g (6.43 mmoles) of (R,R) N,N'-dibenzoyl-cystine, 32 ml of anhydrous 
tetrahydrofuran, 0.634 g of tert.butanol dissolved in 32 ml of anhydrous 
tetrahydrofuran and 19.3 ml of a 1M solution of lithium borohydride in 
tetrahydrofuran are introduced under an argon atmosphere into a 250 ml 
round bottomed flask equipped with a mechanical stirrer, thermometer, 
dropping funnel and condenser. 
The white heterogeneous reaction mixture becomes homogeneous after being 
heated at reflux for 3 hours. The mixture is cooled to -70.degree. C. and 
a solution of 1.3 g(5.36 mmoles) of methyl 2-chloro 3-(4-methoxyphenyl) 
3-oxo propionate in 11 ml of tetrahydrofuran are added while the 
temperature of the reaction mixture is maintained at -70.degree. C. The 
temperature of the reaction mixture is then allowed to rise to -40.degree. 
C. and maintained there for 2 hours. Then 16.1 ml of 1N hydrochloric acid 
are added, causing the temperature to rise from -40.degree. C. to 
0.degree. C., followed by 60 ml of water and 80 ml of dichloromethane. 
After vigorous stirring of the mixture, the aqueous phase is isolated by 
decantation and extracted with 50 ml of methylene chloride. The organic 
phases are combined and then evaporated to dryness after being dried over 
sodium sulfate in order to obtain 3.60 g of a viscous product which is 
purified by rapid filtration through silica. 
In this manner, 1.02 g of methyl 2-chloro 3-hydroxy 3-(4-methoxyphenyl) 
propionate are added in a yield of 77.8%. Syn diastereoisomer/anti 
diastereoisomer: 50/50 
the diastereoisomeric excess of the product obtained is determined: 
a) by thin layer chromatography (dichloromethane/ethyl acetate: 95/5) or by 
high performance liquid chromatography (H.P.L.C.) (detection 230 nm; flow 
rate 1.8 ml/min. eluant: water/methanol/acetonitrile/tetrahydrofuran: 
770/50/180/10): 
syn diastereoisomer: 16.24 mn 
anti diastereoisomer: 25.56 mn 
b) by proton N.M.R: 
##STR15## 
syn diastereoisomer: 5.1 ppm (d,1H); 4.42 ppm (d,1H) 
anti diastereoisomer: 5 ppm (d,1H); 4.35 ppm (d,1H) 
The two diastereoisomers syn and anti were separated by preparative high 
performance liquid chromatography. The enantiomeric excess of the 
diastereoisomers isolated was determined on the --CHH--OH proton by proton 
N.M.R. in C.sub.6 D.sub.6 after addition of Eu (tfc).sub.3. The rotatory 
power was determined by polarimetry. 
1)syn diastereoisomer (-)(2R,3S) 
N.M.R.: two doublets located between 5.1 and 4.85.+-.0.5 ppm. 
ee: 84l %. 
.alpha..sub.D.sup.20 : 2.degree. C. (c=0.5, chloroform). 
2) anti diastereoisomer (+)(2S,3S) 
N.M.R.: two doublets located between 6.15 and 5.83.+-.ppm. 
ee: 88%. 
.alpha..sub.D.sup.20 : +36.degree. (c=0.5, chloroform). 
EXAMPLE 1 
Preparation of methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) 
propionate 
Under an atmosphere of argon, 0.305 g (1.25 mmole) of methyl anti(+)(2S,3S) 
2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionate previously obtained 
("Preparation") (ee=88%), 2.5 ml of dichloroethane and 0.2 ml (1.31 mmole) 
of 1,8-diazobicyclo [5.4.0] undec-7-ene are introduced into a 20 ml round 
bottomed flask, fitted with a thermometer, a condenser and a mechanical 
stirrer. A homogeneous reaction mixture is obtained. 
After the mixture has been stirred for 2 hours at 20.degree. C., the 
reaction is terminated. It is poured into 10 ml of a buffer solution 
(pH=7). After addition of 10 ml of dichloroethane, extraction and 
decantation, the organic phase is isolated and evaporated to dryness. 
In this manner, 0.250 g of methyl trans(-)(2R,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate are obtained in crystalline form in a yield 
of 94.7%. 
The presence of the cis epoxide was detected neither by N.M.R. nor by 
liquid chromatography. 
N.M.R. (in dimethylsulfoxide) 
##STR16## 
Trans diastereoisomer: 4.1 ppm (d,1H); 3.84 ppm (d,1H). 
Cis diastereoisomer: 4.35 ppm (d,1H); 4 ppm (d,1H). 
H. P. L. C. 
a) Cis epoxide: 22.28 mn 
Trans epoxide: 32,75 mn (detection: 230 nm; eluant: water: 770, methanol: 
50, acetonitrile: 180, tetrahydrofuran: 10; flow rate: 1.8 ml/mn). 
b) By means of liquid phase chromatography on a chiral column: 
Eluant: isopropanol/hexane 50/50 
Detection: 230 nm 
Flow rate: 0.9 ml/mn 
Trans(-) epoxide: 24.1 mn 
Trans(+) epoxide: 20.6 mn 
the enantiomeric excess of methyl trans(-)(2R.3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate formed was determined: 88%. 
Rotatory power 
.alpha..sub.D.sup.20 =-133.degree. (c=0.892, chloroform). 
Example 2 
Preparation of methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) 
propionate 
Under an argon atmosphere, 0.305 g (1.25 mmole) of syn(-)(2R,3S) 2-chloro 
3-hydroxy 3-(4-methoxyphenyl) propionate previously obtained 
("Preparation")(ee=84%), 2.5 ml of dichloroethane and 0.2 ml (1.31 mmole) 
of 1,8-diazobicyclo[5,4,0] undec-7-ene are introduced into a 20 ml round 
bottomed flask equipped with a thermometer, condenser and a mechanical 
stirrer. 
A homogeneous reaction mixture is obtained. After it has been stirred for 2 
hours at 20.degree. C., the reaction is terminated. The mixture is then 
poured into 10 ml of a buffer solution (pH=7). After addition of 10 ml of 
dichloroethane, extraction and decantation, the organic phase is isolated 
and evaporated to dryness. Thus are obtained 0.260 g (yield: 96%) of a 
crystalline product constituted, according to the N.M.R. and the H.P.L.C., 
of 13% of cis epoxide and 87% of trans epoxide. 
A separation by means of H.P.L.C. enabled methyl trans(-)(2R,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate to be isolated in the pure state. 
ee: 84% (H.P.L.C.). 
EXAMPLE 3 
Preparation of methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) 
propionate 
Under an atmosphere of argon, 0.78 of methyl syn(-)(2R,3S) 2-chloro 
3-hydroxy 3-(4-methoxyphenyl) propionate (ee=70%), 1.22 g of methyl 
anti(+)(2R,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionate 
(ee=100%), 4 ml of dichloroethane and 1.32 ml of 1.8-diazabicyclo[5,4,0] 
undec-7-ene are introduced into a 50 ml round bottomed flask equipped with 
a thermometer, a condenser and a mechanical stirrer. A homogeneous 
reaction mixture is obtained. After it has been stirred for 2 hours at 
20.degree. C., the reaction is terminated. The reaction mixture is poured 
into 50 ml of a buffered solution (pH=7). After addition of 40 ml of 
dichloroethane, extraction and decantation, the organic phase is isolated, 
dried over sodium sulfate then evaporated to dryness to give an oil (1.72 
g) which crystallizes (yield: 100%). 
This product is a mixture of methyl trans(-)(2R,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate and methyl cis(+)(2S,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate. 
Its diastereoisomeric composition was determined by proton N.M.R. and by 
H.P.L.C. 
Trans diastereoisomer/cis diastereoisomer: about 95/5 
A separation by means of H.P.L.C. enabled pure methyl trans (-)(23R,3S) 
2,3-epoxy 3-(4-methoxyphenyl) propionate to be isolated. Trans(-) 
diastereoisomer/trans(+) diastereoisomer: 93.3/6.7 (ee=86.6%) (H.P.L.C.) 
.alpha..sub.D.sup.23 : -130.degree.(c=0.9, chloroform) 
EXAMPLE 4 
Preparation of methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) 
propionate 
Under an atmosphere of argon, 0.39 g of methyl syn(-)(2R,3S) 2-chloro 
3-hydroxy 3-(4-methoxyphenyl) propionate (ee=70%) 0.610 g of methyl 
anti(+)(2S,3S) 2-chloro 3-hydroxy 3-(4-methoxyphenyl) propionate (ee=100% 
and 2 ml of methanol are introduced into a 50 ml round bottomed flask 
equipped with a thermometer and a mechanical stirrer. The mixture is 
cooled to -10.degree. C. and 0.66 ml of 1,8-diazobicyclo [5,4,0] 
undec-7-ene are added. After being stirred for 4 hours at -5.degree. C., 
the reaction mixture is evaporated to dryness. The oily residue is taken 
up in 25 ml of dichloroethane and the solution is washed with 25 of a 
buffered solution (pH=7). After extraction and decantation, the organic 
phase is isolated and evaporated to dryness to give 0.72 g of an oil which 
crystallizes (yield: 85%) 
This product is a mixture of methyl trans(-)(2R,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate and methyl cis(+)(2S,3S) 2,3-epoxy 
3-(4-methoxyphenyl) propionate. Its diastereoisomeric composition was 
determined by proton N.M.R. and by H.P.L.C. 
Trans diastereoisomer/cis diastereoisomer: about 99/1. 
A separation by means of H.P.L.C. enabled pure methyl trans(-) (2R,3S) 
2,3-epoxy 3-(4-methoxyphenyl) propionate to be isolated. Trans(-) 
diastereoisomer/trans(+) diastereoisomer: 94/6 (ee=88%) 
.alpha..sub.D.sup.23 : -133.degree. (c=0.9, chloroform). 
EXAMPLE 5 
Preparation of cis(+)(2S,3S) 3-acetoxy 5-(2-N,N-dimethylaminoethyl) 
2-(4-methoxyphenyl) 2,3-dihydro 1,5-benzothiazepin-4-(5H)one hydrochloride 
or diltiazem hydrochloride 
a) Methyl cis(+)(2S,3S) 2-hydroxy 3-(2-amino phenylthio) 
3-(4-methoxyphenyl) propionate 
Under an inert atmosphere, 13.875 g (0.111 mole) of o-amino-thiophenyl, 
20.8 g (0.1 mole) of methyl trans(-)(2R,3S) 2,3-epoxy 3-(4-methoxyphenyl) 
propionate and 100 ml of toluene are placed in a 250 ml reactor equipped 
with a heating-cooling system, a mechanical stirrer, a thermometer and a 
condenser. The mixture is refluxed for 2 hours, then the toluene is 
distilled so as to give 34 g of a solid residue (mass yield: 100%). 
In this manner, methyl cis(+)(2S,3S) 2-hydroxy 3-(2-amino phenylthio) 
3-(4-methoxyphenyl) propionate is obtained which can be used directly in 
the next step or can be recrystalled from a methanol/water mixture so as 
to give an analytically pure compound. 
b) Cis(+)(2S,3S) 2-hydroxy 3-(4-methoxyphenyl) 3-(2-amino phenylthio) 
propionic acid 
Under an inert atmosphere, 33.1 g (0.1 mole ) of crude methyl cis(+)(2S,3S) 
2-hydroxy 3-(2-amino phenylthio) 3-(4-methoxyphenyl) propionate and 160 ml 
of 5% sodium hydroxide are placed in a 250 ml round bottomed flask 
equipped with a heating-cooling system, a mechanical stirrer, a 
thermometer and a condenser. A mixture was heated to 50.degree. C. under 
vigorous stirring and maintained at that temperature for 2 hours. The 
reaction mixture is limpid and brown. After being cooled to room 
temperature, the mixture is poured into 82 ml of 9% hydrochloric acid, 
which leads to the precipitation of the expected product. It is filtered 
off and washed with water, then dried in an oven under vacuum at 
20.degree. C. 
In this manner, the cis(+)(2S,3S) 2-hydroxy 3-(4-methoxyphenyl) 3-(2-amino 
phenylthio) propionic acid is obtained in the crude state which can be 
purified by re-saponification in ethanol. 
M.p.: 138.degree. C. 
.alpha..sub.D.sup.20 : 346.degree.. 
c) Cis(+)(2S,3S) 2-hydroxy 2-(4-methoxyphenyl) 2,3-dihydro 
1,5-benzothiazepin-4(5H)-one 
Under an inert atmosphere, 50 g (0.156 mole) of cis(+)(2S,3S) 2-hydroxy 
3-(4-methoxyphenyl) 3-(2-amino phenylthio) propionic acid and 940 ml of 
xylene are placed in a 21 reactor equipped with a heating-cooling system, 
a mechanical stirrer, a thermometer, a condenser and a Dean-Stark system. 
The mixture is brought to reflux and maintained there for 8 hours. It is 
cooled to -10.degree. C., the solid is filtered off, washed with xylene 
and dried in a ventilated oven. 
In this manner, 43 g of cis(+)(2S,3S) 3-hydroxy 2-(4-methoxyphenyl) 
2,3-dihydro 1,5-benzothiazepin-4 (5H)-one. 
Yield: 91%. 
M.p.: 200.degree. C. 
.alpha..sub.D.sup.20 : +115.degree. C. 
The filtrate contains a further 6 to 7% of the desired product which can be 
recovered. 
d) Cis(+)(2S,3S) 3-hydroxy 5-(2-N,N-dimethylaminoethyl) 2-(4-methoxyphenyl) 
2,3-dihydro 1,5-benzothiazepin-4(5H)-one 
Under an inert atmosphere, 12 g (0.04 mole) of cis(+)(2S,3S) 3-hydroxy 
2-(4-methoxyphenyl) 2,3-dihydro 1,5-benzothiazepin-4(5H)-one and 60 ml of 
N,N-dimethylformamide are introduced into a 250 ml reactor equipped with a 
heating/cooling system, a mechanical stirrer, a thermometer and a 
condenser. The mixture is stirred and a limpid solution is obtained. Then 
16.6 g (0.12 mole of potassium carbonate and 6.9 g (0.048 mole) of 
2-dimethylamino 1-chloro-ethane hydrochloride are added. The mixture is 
heated at 60.degree. C. for 1 hour. After the mixture has been cooled to 
room temperature, the mineral salts are filtered off and the filtrate is 
concentrated in a vacuum. The oily residue obtained is taken up in 75 ml 
of dichloroethane and washed with water. The organic phase is concentrated 
and the residue is taken up in petroleum ether so as to give rise to the 
crystallization of the expected product. It is filtered off and dried in 
an oven under vacuum. 
In this manner, 13.65 g of cis(+)(2S,3S) 3-hydroxy 
5-(N,N-dimethylaminoethyl) 2-(4-methoxyphenyl) 2,3-dihydro 
1,5-benzothiazepin-4(5H)-one are obtained. 
Yield: 91.6%. 
M.p.: 86.degree.-87.degree. C. 
.alpha..sub.D.sup.20 : +168.8.degree. (c=0.25, methanol). 
e) Cis(+)(2S,3S) 3-acetoxy 5-(2-N,N-dimethylaminoethyl) 2-(4-methoxyphenyl) 
2,3-dihydro 1,5-benzothiazepin-4(5H)-one hydrochloride 
5.6 g (0.015 mole) of cis(+)(2S,3S) 3-hydroxy 5-(2-N,N-dimethylaminoethyl) 
2-(4-methoxyphenyl) 2,3-dihydro 1,5-benzothiazepin-4(5H)-one and 14 ml of 
anhydrous toluene are introduced into a 50 ml three-necked flask equipped 
with a heating/cooling system, a mechanical stirrer, a thermometer and a 
condenser. The mixture is stirred and 1.7 g (0.0165 mole) of acetic 
anhydride are added. The mixture is heated at the reflux temperature of 
toluene for 3 hours, then is cooled to room temperature and 3.4 ml of a 
4.8N ethanolic solution of hydrogen chloride are added. The mixture is 
cooled to 0.degree. C. and the precipitate obtained is filtered off. It is 
washed with toluene and dried. 
In this manner, 6.25 g of cis(+)(2S,3S) 3-acetoxy 
5-(2-N,N-dimethylaminoethyl) 2-(4-methoxyphenyl) 2,3-dihydro 
1,5-benzothiazepin-4(5H)-one hydrochloride are obtained. 
Yield: 92.4%. 
M.p. 210.degree. C. 
.alpha..sub.D.sup.20 : +116.5.degree. (c=1%, water).