CA1239400A - 1,5-benzothiazepine derivatives and processes for preparing the same - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

This invention provides novel 9-chloro-1,5-benzothiazepine derivatives of the formula:

(I) wherein R1 is hydrogen or lower alkanoyl, or a salt thereof.
These derivatives (I) and their salts are useful as an intermediate in the synthesis of novel 5-alkyl-9-chloro-1,5-benzothiazepine derivatives which show potent hypotensive activity and potent cerebral or coronary vasodilating activity.

Description

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~

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

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 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~

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:

(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

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~

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)-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~

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~

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 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 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

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 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.

Claims (12)

Claims:

1. A process for preparing a 9-chloro-1,5-benzothiazepine derivative of the formula:

(I) wherein R1 is hydrogen or lower alkanoyl, or a salt thereof, which comprises the step(s) of:
(A)-a) reacting 2-amino-6-chlorothiophenol (II) with a glycidic ester of the formula:

(III) wherein R2 is lower alkyl, to give a compound of the formula:

(I-a) or -b) subjecting a propionic acid compound of the formula:

(IV) wherein R3 is hydrogen or lower alkyl, to intramolecular cyclization to give the compound (I-a), and (B) optionally acylating the compound (I-a) with a lower alkanoic acid of the formula:
R4COOH (V) wherein R4 is lower alkyl, or a reactive derivative thereof to give a compound of the formula:

(I-b) wherein R4 is the same as defined above, and (C) if required, further converting the resultant compound to a salt thereof.

2. A process according to claim 1 for producing a compound of formula (I) in which R1 is hydrogen or alkanoyl of 2 to 5 carbon atoms, which comprises carrying out step (A) of claim 1, or step (B) employing a compound of formula (V) in which R4 is an alkyl group having 2 to 5 carbon atoms.

3. A process according to claim 2 for producing a compound of formula (I) in which R1 is hydrogen, which comprises carrying out step (A) of claim 1.

4. A process according to claim 1 for produc-ing a cis isomer of the compound of formula (I), which comprises carrying out step (A), step (B) or step (C) of claim 1 using an appropriate isomer of the starting material or isolating the cis stereo isomer from the product.

5. A process according to claim 1 for producing a (+)-cis isomer of the compound of formula (I), which comprises carrying out step (A), or step (B) or step (C) of claim 1 using an appropriate isomer of the starting material or step (A), isolating the (+)-cis optical isomer from the product.

6. A process according to claim 1 for producing (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one or a salt thereof, which comprises carrying out step (A) or step (C) of claim 1 using an appropriate isomer of the starting material or isolating the (+)-cis optical isomer from the product.

7. A 9-chloro-1,5-benzothiazepine derivative of the formula (I) wherein R1 is hydrogen or lower alkanoyl, or a salt thereof.

8. A derivative according to claim 7 wherein R1 is hydrogen or an alkanoyl of 2 to 5 carbon atoms.

9. A derivative according to claim 7 wherein R1 is hydrogen.

10. A cis isomer of the derivative according to claim 7.

11. A (+)-cis isomer of the derivative according to claim 7.

12. (+)-Cis-2-(4-methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one or a salt thereof.