Note: Descriptions are shown in the official language in which they were submitted.
I
1,5-Benzothiazepine derivati us and processes for
no arid the same
P P . q _ _
This invention relates to novel 9-chloro-1,5-benzothi-
aspen derivatives and to processes for preparing the same.
US. Patent 3,562,257 discloses various benzothiazepine
derivatives including 7-chloro-1,5-benzothiazepine don-
natives such as 2-(4-methoxyphenyl)-3~hydroxy (or Aztecs)-
5-~2~(dimethylamino)ethyl]-7-chloro-2,3-dihydro-1,buoyancy-
thiazepin-4(5H)-one This US. Patent also discloses that
these benzothiazepine derivatives show anti depressive,
tranquilizing Andre coronary vasodilating activities.
lo As a result of various investigations, we have now
found that the compounds (I) as defined below or the
salts thereof are useful as an intermediate in the
I`
synthesis of 5-alkyl-9-chloro-1,5-benzothiazepine don-
natives which show potent hypotensive and/or cerebral or
coronary vasodilating activities and are claimed ill our
related Canadian patent application Serial No. 495,576
filed on November 18, 1985, of which the present apply
cation is a division.
According to the present invention there is provided
a compound of the formula:
Of OOZE
or
wherein R is hydrogen or lower alkanoyl or a salt
thereof.
Representative examples of the compounds of the
present invention include those of the formula I) in
which Al is hydrogen or lower alklanoyl of 2 to 5 car-
bun atoms such as acutely, propionyl, bitterly or Valery.
Among the compounds of the present invention, a preferred
subgenus is those of the formula (I) in which Al is
hydrogen or acutely.
On the other hand, suitable examples of the salt of
the compound (I) include, for example, alkali metal salts
(e.g., sodium salt or potassium salt) and alkaline earth
metal salts (e.g., calcium salt or barium salt). Such
~23~
-- 3
salts are readily obtained by treating the compound (I)
with, for example, alkali metal hydroxide or alkaline
earth metal hydroxide in a solvent.
Whiz e ho compound (I) of the preset invention can
exist in the form of two stereo isomers it is and trays
isomers) or four optical isomers it is, is,
trueness and -trays isomers) due to the two asymmetric
carbon atoms involved therein, all of these optical isomers
or a mixture thereof are included within the scope of the
LO invention.
According to thy prevent invention, the compound (I)
is novel and can be prepared by the step(s) of:
-c) reacting 2-amino-6-chlorothiophenol with a
glycidic ester of the formula:
o
SHEA- OH - SHAKER (III)
wherein is lower alkyd, to give a compound of the formula:
Of OUCH
OH (I-a)
or
-by subjecting a prop ionic acid compound of the
I formula:
~2~3~
Of Ho
S (It)
COO
wherein R3 is hydrogen or lower alkyd, to intramolecular
cyclization to give the compound It r and
(By optionally assaulting the compound a) with a
lower alkanoic acid of the formula:
R COO (V)
wherein R4 is lower alkyd, or a reactive derivative
thereof to give a compound of the formula:
Of ooze
N It
HI O
wherein R4 is the same as defined above.
The reaction of the 2-amino-6 chlorothiophenol~ith
the glycidic ester (III) may be accomplished by heating a
mixture of these compounds at a temperature of 130 to 180C.
The reaction may be carried out either in a solvent (e.g.,
zillion, diphenyl ether or p-cymene) or without solvent.
when the reaction product thus obtained is a mixture of the
compound (I-a) and the prop ionic acid compound (IVY lR3 =
lower alkyd) or a mixture of two stereoisamers (i.e., is
I
and trays immures of the compound I they may be
separated from each other by their difference in volubility
in a solvent such as lower alkanol (e.g., ethanol) and/or by
column chromatography.
S The intramolecular cycliza~ion of the prop ionic acid
compound (IV) can be carried out by heating it either in a
solvent or without solvent. Zillion, toluene,_diphenyl
ether, p-cymene and acetic acid are suitable as the solvent.
It is preferred to carry out the reaction at a temperature
ox 110 to 160C, especially under refluxing. Alternatively,
the intramolecular cyclizaion of the prop ionic acid compound
(IV) (R3 = lower alkyd) may be carried out at 0 to 30C in
the presence of methylsulfinylcarbanion (C~3SCCH2 ) (prepared
from dimethylsulfoxide and sodium hydrides in a solvent
(eye., dimethylsulfoxide). Moreover, the intramolecular
cyclization of the prop ionic acid compound (IV) (R
hydrogen) may be carried out in the presence of a condensing
agent. Dicyclohexylcarbodiimide is used alone as the
condensing agent or in combination with 1-hydroxybenzo-
Russell, 4-dimethylaminopyridine, N-hydroxyphthalimide,
N-hydroxysucCinimide, trichlorophenol, p-nitrophenol or
3-hydroxy 4-oxo-3,4 dihydro-1,2,3-benzotriazine. Carbonyl-
diimidazole, athoxyacethylene and l-methyl-2-halopyridinium
halide ego., l-methyl-2-chloropyridinium iodide or 1-methyl-
2-bromopyri~inium iodide) are also used as the condensing
I
-- 6
agent.. 1-Methyl-2-halopyridi~iu~ halide, the condensing
agent, may be used in combination with a base such as triethyl-
amine or tri~utylaminev Chloroform, dimethylformamide,
carbon tetrachloride, dichloromethane, 1,2-dichloroethane,
ethyl acetate, and Dixon are suitable as the solvent.
It is preferred to carry out the reaction at a temperature
ox -10 to 70C.
If required, the rhizomic modification of the compound
It thus-obtained may be resolved into each optical
lo enantiomers thereof by using an optically active 1-(2-naphthyl-
sulfonyl)pyrroliAine-2-carbonyl chloride as a resolving
agent, for example, by the steps of reacting the compound
(I-a) with (S) 1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl
chloride to give a pair of diastereoisomers, separating said
diastereoisomers from each other by selective crystallization
or column chromatography, and then hydrolyzing each of
diastereoisomers to give the optically active compound
(I-a). When a mixture of the optically active compound
(I-a) and the optically active compound (IV) (R3 = H) is
produced by the hydrolysis of the diastereoisomer, they may
be separated from Peck other by taking advantage of the
dourness in solubilities thereof.
The optional acylation of the compound (I-a) or a salt
thereof with the reactive derivative of the lower alkanolic
acid (V) can be conducted in a solvent in the presence or
absence of an acid acceptor. The reactive derivative of
the lower alkanolic acid (V) includes, for example, lower
-- 7 --
alkanoic acid android (e.g., acetic android, prop ionic
android) and lower al~anoyl halide (e.g., acutely chloride,
propionyl chloride, bitterly chloride, Valery chloride).
The acid acceptor includes, for example, pardon, triethylamine,
S N-methylpiperidine, N-methylmorpholine, ~-me1thylpyrrolidine and
N~ethyl-N,N-diisopropylami~e. Acetic acid, chloroform, dichloro-
methane, dimethylformamide and tetrahydrofuran are suitable
as the solvent. When an Swiss amount of acetic android
is used as the reactive derivative of the lower al~anoic
lo acid (V), it is not always necessary to use the solvent
because said acetic android serves as the solvent. It is
preferred to carry out the reaction at a temperature of -10
to 140C; e.g., at a temperature of 20 to L40C if the
lower alkanoic acid android is used as the reactive derivative
of the lower alkanoic acid (Al; or at a temperature of -10
to 100C if the lower alkanoic acid halide is used as the
reactive derivative.
On the other hand, the acylation of the compound (I-a)
or a salt thereof with the lower alkanoic acid (V) may be
carried out in a solvent in the presence of a condensing
agent. The condensing agent includes, for example, duskily-
hexylcar~odiimide, N,N'-carbonyldiimidazole, methyl-
halapyridinium iodide (e.g., 1-methyl-2-bromopyridinium
iodide), methoxyacetylene and (C6~5)3p-CC14. Ethylene
chloride, 1,2-dichloroethane, chloroform, Bunsen, Tulane,
12'3~
-- 8
tetrahydrofuran and Dixon are suitable as the solvent.
It is preferred to carry out the reaction at a temperature
of I to 50C, especially at 0 to SKYE.
the starting compound (IV) of the present invention
involves four optical isomers due to the two asymmetric
carbon atoms at 2- and 3-position of the prop ionic acid
(IV). However, since the above-mentioned reactions
according to the invention can be carried out without
racemization, the compound (I) of the present invention
in an optically active form can be readily obtained from
the corresponding optically active isomer of the compound
(IV).
The starting compound (IV) used in the above mentioned
reaction can be prepared, for example, according to the
methods described in Japanese Patent Publication (examined)
Nos. 9383/1970, 8982/1971, 36221/1974 or 24954/1975, or
Japanese Patent Publication (unexamined) Nos. 142963/1982,
176951/1982 or 193449/1982.
The compound (I) of the present invention is useful
as an intermediate in the synthesis of novel alkali-
chloro-1,5-benzothiazepine derivative of the following
formula:
1 OUCH
(VI)
SHOESHINE \ R6
I
I
g
wherein each of R5 and R6 is lower alkyd and Al is the same
as defined above.
The compound (VI) may be prepared from the compound (I)
of the present invention, for example, by condensing the
compound (I) or a salt thereof with amino alkyd compound
of the formula:
x-CH2cH2N \~R6 (VII)
wherein X is halogen and R5 and R6 are the same as defined
above, or a salt thereof (e.g., hydrochloride or hydrobromide)
in the presence or absence of an alkali agent such as alkali
metal hydroxide (ego potassium hydroxide or sodium hydrox-
ire?, alkali metal carbonate (e.g., potassium carbonate or
sodium carbonate) and alkali metal hydrides (e.g., sodium
hydrides in a solvent (e.g., acetone, ethyl acetate, dim ethyl-
formamide, acetonitrile, tetrahydrofuran, Dunn, aqueous acetone and aqueous ethyl acetate) and when Al is hydrogen,
if required, condensing the resulting product with the
compound (V) or a reactive derivative thereof in the same
manner as the condensation of the compound (I-a) with the
compound TV) or a reactive derivative thereof.
As mentioned herein before, the thus obtained compound
(VI) has a potent hypotensive activity, a potent cerebral
or coronary vasodilating activity, and a potent platelet
aggregation-inhibiting activity. Therefore, the come
pound (VI) is useful for the treatment, amelioration or
I
-- 10 --
prophylaxis of hypertension; cerebral diseases such as
cerebral vapospasm or cerebral infarction; and heart
diseases such as angina pocketers, arrhythmias or coronary
or cardiac infarction in a warm-blooded animal including
human being. Especially, since the compound VOW) of the
present invention shows stronger and longer-lasting there-
peptic effects Leo hypotensive, cerebral and coronary
vasodilating activities) as compared Wyeth sheller-
derivative (e.g., ~+)-cis-2-(4-methoxyphenyl)-3-acetoxy-
5-[2-(dimethylamino)ethyl]-7-chloro-2,3-dihydro-1,buoyancy-
thiazepin-4~5H)-one) of US. Patent No. 3,562,257, the
compound (VI) of the present invention is much more useful
as a hypotensive agent or a cerebral or coronary voiced-
later than the above-mentioned 7-chloro-derivative.
US Practically and presently preferred embodiments of the
present invention are illustratively shown in the following
lines Throughout the specification and claims, the terms
"lower alkyd n slower alkanoyl n and "lower alkanoic acid"
should be interpreted as referring to straight or branched
alkyd of one to 4 carbon atoms, straight or branched alkanoyl
of 2 to 5 carbon atoms and straight or branched alkanoic
acid of 2 to 5 carbon atoms, respectively.
Concomitantly, throughout the specification and claims,
I
the term thrown means that the hydroxy and 2-aminc-6-chloro-
phenylthio (or 2-chloro-6-nitrophenylthio) groups substituted
at the 2 and 3-positions of prop ionic acid hove threo-type
configuration (i.e., said two groups are placed on opposite
side of the central bond in the Fisher's projection formula.
Example l
(1) A mixture of OWE g of 2-chloro-6-nitro~hiopheno~,
60.15 g of methyl trans-3-14~methoxypheny~)glycidate, 1 g of
lo zinc acetate dehydrate and 410 ml of Tulane is stirred at
rove temperature for 3 hours under argon atmosphere. The
reaction mixture is evaporated under reduced pressure to
remove Tulane. Isopropyl ether is added to the residue
and the precipitated crystals are collected by filtration.
The crystals are recrystallized from a mixture of ethyl
acetate and hexane (the filtrate is hereinafter referred to
as smother liquor It). 62.37 g of methyl threo~2-hydroxy-
3-(2-chloro-6-nitrophenylthio)-3-(4-methoxyphenyl)preappoint
are obtained.
Mop. 110 - 111.5C
me mother liquor I is subjected to silica gel chromatography
(Solvent: benzene-ethyl acetate ~20 : l)), whereby 2.93 g of
methylthreo-2-hydroxy-3-(2-chloro-6-nitrophenylthio)-3-((4-
methoxyphenyl)propionate are further obtained.
Mop. 109.5 - 111C
I A mixture of 62 g of methyl threo-2-hydroxy-3-(2-
chloro-5~nitrophenylthio)-3-(4-methoxyphenyl)propiinnate, 7 g
~23~
- 12 -
of lo % palladium-charcoal, 500 ml of acetic acid and 500 ml
of ethanol is shaken at room temperature in hydrogen gas
atmosphere for Lo hours under an atmospheric pressure.
Insoluble materials are removed by filtration. The filtrate
is evaporated under reduced pressure to remove solvent and
the residue is recrystallized from a mixture of ethyl acetate
and hexane. 51.74 g of methyl threo-2-hydroxy-3-(2-amino-6-
chloro~henylthio)-3-(4-methoxyphenyl)propionate are obtained
Mop. 114 - 116C
(3) 84 my of sodium hydrides ( 60 % oil dispersion) are
added to 2 ml of dimethylsulfoxide, and the mixture is
stirred at 70C or 40 minutes under argon atmosphere.
After cooling the mixture, a solution of 0.368 g of methyl
threo-2-hydroxy-3-(2-amino-6-chlorophenylthio)-3-((4-methoxy-
phenyl)propionate in 1 ml of dimethylsulfoxide is added
thereto, and the mixture is stirred at room temperature for
40 minutes. Then, the reaction mixture is poured into a
mixture of ice and acetic acid and the precipitated crystals
are collected by filtration. Said crystals are washed with
water, dried and recrystallized from a mixture of chloroform
and ethanol. 0.163 g of (~)-cis-2-(4-methoxyphenyl)-3-hydroxy-
9-~hloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
Mop. 249 - 252C (decomp.)
Example 2
(1) A mixture of 18.39 g of methyl ~hreo-2-hydroxy-3-(2-
I
amino-6-chlorophenylthi Q 1-3-(4-methoxyphPnyl~propionate, 90
ml of 10 % sodium hydroxide 200 ml of methanol and 90 ml of
water is stirred at room temperature for 4 hours. The
reaction mixture is adjusted to a pi of about 2 under ice-cooling
and is stirred at room temperature overnight. The precipitated
crystals are collected by filtration, washed with water and
dried. 16~77 g of threo-2-hydroxy-3-~2-amino-6-chlorophenyl
thio)-3-t4-methoxyphenyl)propionic acid hemihydrate are
obtained.
lo pi 108 - 110C (recrystallized from a mixture ox
ethanol and water)
(2) A mixture of 15.77 g of threo-2-hydroxy Amman-
chlorophenylthio)-3-(4-methoxyphenyl)propionic acid hemihydrat2
and 630 ml of ~ylene is reflexed or 18 hours while removing
the resulting water by a dehydration apparatus. After
cooling the reaction mixture, the precipitated crystals are
collected by filtration. 10.44 g of (+)-cis-2-(4-methoxyphenyl~-
3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin--one
are obtained.
Mop. 24g - 251C ~decomp.)
When the product is recrystallized from a mixture of
dimethylformamide and isopropyl ether, said product shows
mop. 247 - 250C (decomp.)
Exam 3
I A mixture of 22.39 g of (~)-cis-2-~4-methoxyphenyl)-
- 14 -
3-hydroxy-9-chloro-2,3-dihydro~ benzothiazepin-4(5Hl-one,
60 ml of pardon is cooled with ice-water, and 2804 g of
(S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride
(prepared from -l ~2-naphthylsulfonyl~pyl-rolidine-2-car~o~ylic
acid and oxalyl chloride in an hydrous benzerle) are added
thereto. The mixture is stirred at room temperature for 18
hours. Water and a mixture of ethyl acetate and chloroform
(1 13 are added lo the reaction mixture. The organic
layer is collected therefrom and washed with 10 hydrochloric
lo acid, water, an aqueous 5 sodium bicarbonate solution and
water, successively. The solution is dried and the evaporated.
ale residue it chromatographed on silica gel solvent:
benzene-ethyl acetate I : lo), whereby 18.22 g of the
product "A" (oil, [~20 -113.2
I - 0~326, chloroform)) and 17.01 g of the product "B"
(crystalline product, Mop. 106 - 123C, [DOW 22.8 (C =
0.324, chloroform)) are obtained.
(2-a) A mixture of 17~46 of the product "A"
obtained in paragraph (1), 41 y of potassium carbonate, 100
I ml of water and 200 ml of methanol is stirred at room temperature
for 19 hours. After the reaction, the precipitated crystals
(needles) are collected by filtration and recrystallized
from aqueous methanol. 7.85 g of optically active Swiss-
methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5--benzothiazepin-
4(5~ one this product is referred to as "lactam Aye are
~235~
- 15 -
obtained Yield: 83.4 %
Mop. 188 - 189C
Do 0 (C = n. 275~ dLmethylfomamide)
(2-b) A mixture of 12.75 g of the product B obtained
in paragraph (11, 30 g of potassium carbonate, 75 ml of
water and 150 ml of methanol is stirred at room temperature
for 20 hours After the reaction, thy precipitated crystals
(needles) are collected by filtration and recrystallized
from aqueous methanol. 6.01 g of optically active Swiss-
methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5--benzothiazepin-
Ann (this product is referrer to as "lactam B") are
obtained. Yield: 91.3
Mop. 188 - L89C
COO 0 (C = 0.477, dLmethylformamide~
Example 4
A mixture of 2.27 9 of the product "s" obtained in
Example 3-(1~, 40 ml of an aqueous 5 sodium hydroxide
solution and 40 ml ox methanol is stirred at room temperature
for 18 hours. After the reaction is completed, the mixture
is diluted with water and then extracted with chloroform
The extract is washed with water, dried and evaporated to
remove solvent. The residue is recrystallized from aqueous
methanol, whereby 287 Jug of optically active cis-2-(4-methoxy-
phenyl~3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiiazepin-
ennui (lactam By are obtained.
~39~
- 16 -
On the other hand, the aqueous layer is adjusted to pi
3 - 4 with 10 % hydrochloric acid and then extracted with
chloroform. The extract is washed with water, dried and
evaporated to remove solvent. The residue (oil, 1.7 g ) it
dissolved in benzene-ether, and then extracted with Cook-
hydrochloric acid. The hydrochloric acid layer is adjusted
to pi 4 with potassium carbonate and then extracted with
chloroform. The extract is washed with water, dried and
evaporated to remove solvent. 640 my of threo-2-hydroxy-
3(2-amino-6-chlorophenylthio)-3-(4-methoxyphenyl~prropionic
acid are obtained as an oil.
Do -15~ (C = 0.520, chloroform)
Example 5
600 my of (-)-threo-2-hydroxy-3-(2-amino~6-chlorophenyl-
thioj-3-~4-methoxyphenyl)propionic acid are dissolved in a
mixture of 2 ml of dimethylformamide and 5 ml of dichloromethane.
150 my of 1-hydroxybenzotriazole and 550 my of dicyclohexyl-
carbodiLmide are added to the solution. Then, the precipitated
dicyclohexyl~rea (270 my) is removed by filtration, and the
filtrate is evaporated under reduced pressure to remove
solvent The residue is dissolved in ethyl acetate, and
the solution it washed with an aqueous 5 % sodium bicarbonate
solution and water, successively. The washed solution is
dried and evaporated to remove ethyl acetate. The residue
is recrystal lived from aqueous methanol . 414 my of optical lye
- 17 -
active Swiss ~4-methoxyphenyl~-3 hydroxy-9-chloro-2,3-dihydro-
1,5-~enzothiazepin-4(5~)-one (lactam By are obtained
Yield: 72.6 %
Mop. 188 - 189C
Example 6
220 my of (~)-cis-2-(4-methoxyphenyl)-3--hydroxy-9-chloro-
2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in
1.5 ml of pardon, and 61 my of acutely chloride are added
thereto under ice-coolingO The mixture is stirred at room
lo temperature for one hour. The reaction mixture is evaporated
under reduced pressure to remove solvent. The residue is
dissolved in ethyl acetate, and the solution is washed with
10 % hydrochloric acid, water an aqueous 5 Sydney bicarbonate
solution and water, successively. The washed solution is
dried and evaporated to remove solvent. The residue is
recrystallized from ethyl acetate, whereby 206 my of -is-
2-(4-methoxyphenyl)-3-acetoxy-9-chloro-2,3-dihydroo-1,5-
benzothiazepin-4(5a)-one are obtained. Yield: 83.4
Mop. 217 219C
Reference Example _
A mixture of 2.01 g of (~)-cis-2-(4-methoxyphenyl)-3-
hydroxy-9-chloro-273-dihydro-l,S-benzothiazepin-4((one,
0.95 g of 2-(dimethylaminolethyl chloride hydrochloride,
2.49 g of powdered potassium carbonate, 60 ml of acetone and
0.6 ml of water is reflexed for 23 hours. After the reaction
- 18 -
is completed, insoluble materials are removed by filtration.
The filtrate is evaporated to remove solvent. The residue
is digested with isopropyl ether and the resultant crystals
are collected by filtration and recrystallized from ethyl
acetate. 1.84 g of (+)-cis-2-(4-methoxypheny)-3-hydroxy-5
~2-(dimethylamino)ethyl~ -9-chloro~2,3-dihydro-l,S-benzo-
thiazepin-4(S~)-one are obtained.
My 143 - 144C
Hydrochloride hydrate :
Mop. 228 - 230~C (decomp.) (turbid melt at 143C)
(recrystallized from methanol)
Reference Example 2
A mixture of OOZE g of (+)-cis-Z-(4-methoxyphenyl)-3-hydroxy-
5-(2-(dimethylamino)ethyl~ -9-chloro-2,3-dihydro-l,S-benzothiazepin-
one hydrochloride hydrate, 10 ml of acetic android
and 10 ml of acetic acid is stirred at 110C for 6.5 hours.
After the reaction is completed, the reaction mixture is
evaporated under reduced pressure to remove solvent.
Tulane is added to the residue, and the mixture is evaporated
under reduced pressure to remove solvent. The residue is
recrystallized from a mixture of methanol and ether. 0.93
g of -Swiss (4-methoxyphenyl)-3-acetoxy-5-~Z-(dimethyl-
amino)ethyl)-9-chloro-2,3-dihydro-l,S-benzothiazeppinion
hydrochloride hydrate is obtained.
I
-- 19 --
Mop. lB5 - 189C (turbid melt at at about 150C)
Reference Example 3
mixture of 4.00 g of optically active cis-2-(4-methoxy-
phenolhydroxy-9-chloro-2,3-dihy~ro-1,5-~nzothiazepin-4~5one
like lactum A obtained in Example aye)), 1.80 g of
2-(dimethylamino)ethyl chloride hydrochloride, 5.7 g of
powdered potassium carbonate and 150 ml of acetone is ruffled
for 20 hours. After the reaction is completed, insoluble
materials are removed by filtration. The filtrate is
lo evaporated to remove solvent. The residue is converted to
its per chlorate and recrystallized from methanol. 4.63 g of
(+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-~2-(dimet::hylamino~-
ethyl-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5~)-onee
per chlorate 1/4 hydrate are obtained.
Mop. 190 - 192C
Do ~10.2 (C=0.334, dimethylformamideJ
Reference Example 4
A mixture of 2.84 g of (~)-cis-2-(4-methoxyphenyl)-3-
hydroxy-5-~2-~dimethylamino)ethyl~-9-chloro-2,3-diihydro-1,5-
benzothiazepin-4(5H~-one, 30 ml of acetic android and 30
drops of pardon is stirred at 100C for 4 hours. After
the reaction is completed, the reaction mixture is evaporate
under reduced pressure to remove solvent. Tulane is added
Tao residue, and the mixture is evaporated under reduced
pressure to remove silent The residue is converted to
-- 20 --
its hydrochloris3e and recrystal lived from a mixture of
ethanol and ether. 3. 02 g of ( + Swiss ( 4 methoxyphenyl I
acetoxy-5-~2-(dLmethylamino)ethyl~-9-chloro-2,3-diihydro-1,5-
benzothiazepin-4(5~)-one hydrochloride hydrate are obtained.
Mop. 140 - 143C
[I D +13.0 (C= 0.347, methanol)
Reference Example 5
A mixture of 2.00 9 of optically active Swiss-
methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5--buoyancy-
thiazepin-4(5H)-one (the lactam B obtained in Example
3-(2-b)), 0.90 g of 2-(dimethylamino)ethyl chloride hydra-
chloride, 2.89 ox powdered potassium carbonate and 100
ml of acetone is treated in the same manner as described
in Reference example 3. 2.68 9 of (-)-cis-2-(4-methoxy-
phenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chllore-
2,3-dihydro-1,5-benzothiazepin-4(5H)-one per chlorate 1/4
hydrate are obtained.
Mop. 190 - 192C
Do -10.3~ (C-0.321 dimethylformamide)
Reference Exam e 6
A mixture of 1.27 g of (-)-cis-2-(4-methoxyphenyl)-3-
hydroxy-5-(2-tdLmethylamino)ethyl)-9-chloro~2,3-diihydro-1,5-
benzothiazepin-4tS~)-one, 15 ml of acetic android and 15
drops of pardon is treated in the same manner as described
in example 4. 1.40 g of (-)-cis-2-(4-me~hoxyphenyl~-3-
I
` I
Aztecs S~2-(dimethylamino)ethylJ-9~chloro-2,3-dihydro-1,5--
benzo-thiazepin-4~5H~-one hydrochloride hydrate are obtained.
Mop. 139 - 142C
Do -13.0 (C= 0.348, methanol
Reference Example 7
A mixture of 200 my of (~-cis-2-(4-methoxypheny:L~-3-
acetoxy-9-chlcro-2,3 dihydro-l,S-benzothiazepin-4(5H)-one,
84 go of 2-(dimethylamino)ethyl chloride hydrochloride, 220
my of powdered potassium carbonate and 10 Al of acetone is
reflexed for 20 hours. After the reaction is completed,
insoluble materials are removed by filtration. The filtrate
is evaporated to remove solvent. The residue is converted
to its hydrochloride and then recrystallized from methanol.
226 my of(~)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethHal-
amino)ethyl)-9-chloro-2,3-dihydro-1,5-benzothiazeppinion
hydrochloride hydrate are obtained.
The phvsico-chemical properties of the product are
identical with the product obtained in Reference Example 2.
