IE61196B1

IE61196B1 - Process for preparing 1,5-benzothiazepine derivatives

Info

Publication number: IE61196B1
Application number: IE338788A
Authority: IE
Inventors: Hirozumi Inoue; Tsunehiro Harada; Masaaki Nagasawa
Original assignee: Tanabe Seiyaku Co
Priority date: 1987-11-13
Filing date: 1988-11-11
Publication date: 1994-10-19
Also published as: IT1230633B; DK631888D0; FI92393C; IL88296A0; FI885033A; JPH01128974A; IL88296A; FI885033A0; DK631888A; FR2623192A1; FI92393B; IE883387L; IT8822602A0; FR2623192B1; KR890008122A

Abstract

The invention relates to a process for preparing 1,5-benzothiazepine derivatives of formula: in which the symbols are defined, and their addition salts with pharmaceutically suitable acids, by intramolecular cyclisation of a propionic acid derviative of formula: in which the symbols are as defined above, or of a reactive derivative of the latter.

Description

Process for preparing 1,5-benzothiazepine derivatives This invention relates to a process for preparing le5-benzothiazepine derivatives» More particurallyc it relates to a process for preparing 1^5-benzothiazepine derivatives of the formulas 2 wherein R is a lower alkyl or lower alkoxy group; R is 4 hydrogen atom or a lower alkanoyl group; each of R and R o is a lower alkyl group; and one of R and R is halogen atom or a lower alkyl group and the other is hydrogen atom,and a pharmaceutically acceptable acid addition salt thereof.

The lt„ 5-benzothiazepine derivatives (I) and a pharmaceutically acceptable acid addition salt thereof are useful pharmaceutical compounds having an excellent hypotensive activity, cerebral or coronary vasodilating -iaactivity and/or platelet aggregation-inhibiting activity, . and among the compound (I), a compound in which R is hydrogen atom is also useful as an intermediate in the synthesis of other pharmaceutical compounds. It is hitherto known that the above-mentioned 1,5-benzothiazepine derivatives (I) can be prepared by reacting the corresponding N-unsubstituted-1,5-benzothiazepine derivatives with a di(lower alkyl)aminoethyl halide (Japanese Patent Publication (unexamined) Nos. 225174/1984 and 202871/1985).

As a result of various investigations, we have now found a novel and industrial process for preparing the 1,5-benzothiazepine derivative (I). Namely, according to the present invention, the 1,5-benzothiazepine derivatives (I) or a pharmaceutically acceptable acid addition salt thereof can be prepared by subjecting a propionic acid wherein the symbols are the same as defined above, or a reactive derivative thereof to intramolecular cyclization, and, if required, converting the product into a pharmaceutically acceptable acid addition salt thereof.

In the above-mentioned reaction, suitable examples of the reactive derivative of the compound (II) include the corresponding lower alkyl esters (e.g., methyl and ethyl -2ester), active esters (s.g.f p-nitrophenyl, 2,4dinitrophenyl, W-hydroxybenzotriazole, phthalimide, succimide, piperidine, 2-pyridine, 2-pyrrolidon-l-yl and diethylehlorophosphinate ester), mixed anhydrides (e.g., a mixed anhydride of the compound (II) with ethoxycarboxylie, t-butoxvcar boxy lie and benzyloxycarboxylic acid), acid halides (e.g., chloride and bromide), acid azide and acid amides (e.g., imidazole, I-substituted-imidazole and triazole amide).

The cyclization reaction of the present invention can be carried out in the presence or absence of a condensing agent or an acid acceptor. For example, when the free propionic acid compound (II) or a lower alkyl ester thereof is used as a starting compound, said intramolecular cyclization may be carried out under heating in an inert solvent. The compound (II) or an lower alkyl ester thereof may be used in the free form or in the form of a salt thereof. Examples of such salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, perchlorate, phosphate; organic acid addition salts such as acetate, oxalate, fumarate, maleate; and the like. Organic solvents of high boiling point such as xylene, toluene, acetic acid, diphenyl ether and the like may be preferably used as the solvent. It is preferred to carry out the reaction at a temperature between 100 and 180 °C. Further, when a propionic acid compound (II) is used as a starting compound, it may also be carried out in the presence of a condensing agent in an inert solvent. -3Examples of such condensing agent include a carbodiimide compound such as N,NB-dicyclohexylcarbodiimide, N,NS10 diisopropylcarbodiimide; carbonyldiimidazole; l-methyl-2~ chloropyridinium iodide; ethoxyacetylene; a mixture of 2,2-dipyridyl-disulfide and triphenylphosphine; a dimethylprop-2-inylsulfonium halide such as dimethylprop2-inylsufonium chloride; and the like. Organic solvents such as chloroform, methylene chloride, chlorobenzene, tetrahydrofuran, diethyl ether, methylethyl ether, dioxane, ethyl acetate, benzene, toluene, dimethylformamide, diethylformamide, N-formylmorpholine, dimethylacetamide, acetonitrile, dimethylsulfoxide and the like may be used as the solvent. It is preferred to carry out the reaction at the temperature between the temperature of ice-cooling and 150fC.

On the other hand, the intramolecular cyclization of an active ester, an acid anhydride or an acid halide of the compound (II) may be carried out in an inert solvent. The solvents which are employed in carring out the cyclisation in the presence of a condensing agent are also available in this reaction. It is preferred to carry out the reaction at a temperature between -50 and 60 ®C. Further, when an acid halide is used as the reactive derivative of the compound (II), it is preferred to carried out the reaction in the presence of an acid acceptor at a temperature of -30 to 50 fC. Examples of the acid acceptor include organic bases such as pyridine, collidine, lutidine, triethylamine, N-methylmorpholine and the like; and inorganic bases such -4as alkali metal carbonate (e.g., sodium carbonate, etc»), alkali metal bicarbonate (e.g., sodium bicarbonate, etc) and the like» The thus-obtained 1,5-benzothiazepine derivative (I) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt thereof, for example, by treating the compound with an acid. Examples of the pharmaceutically acceptable acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, and the like; organic acid addition salts such as oxalate, maleate, tartrate, methanesulfonate, and so forth» Since the above-mentioned reaction of the present invention proceeds without racemization, the compound (I) can be obtained in an optical form by the use of an optically active compound (IX).

According to the present invention as mentioned above, the 1,5-benzothiazepine derivative (I) can be obtained in a high yield by a single procedure. Thus, the preferred examples of the 1,5-benzothiazepine derivative obtained in the present invention include the compounds of the formula 1 (I) in which R is an alkyl or alkoxy group of one to 6 2 carbon atoms; R is hydrogen atom or an alkanoyl group of 2 3 a . to β carbon atoms; each of R and R is an alkyl group or one to 6 carbon atoms; and one of R^ and is halogen atom or an alkyl group of one fo 6 carbon atoms and the other is hydrogen atom. 5More preferred examples include those of the formula (I) in which JR1 is an alkyl or alkoxy group of one to 4 2 carbon atoms? R is hydrogen atom or an alkanoyl group of 2 3 λ to 4 carbon atoms; each of R and R‘ is an alkyl group of 5 6 one to 4 carbon atoms? and one of R and R is chlorine atom or an alkyl group of one to 4 carbon atoms and the other is hydrogen atom.

While the compound (I) can exist in the form of cis or trans isomer or optical isomer (e.g., (+)-cis, (-)-cis, (+)-trans and (-)-trans) due to the two asymmetric carbon atoms involved therein, all of these isomers or a mixture thereof are included within the scope of the invention. Among these isomers, however, the cis isomer of the compound (I) is preferred for medicinal use.

The starting compound (II) of the present invention is prepareds for example, by (A) reacting the compound of the formula: (III) wherein X is hydrogen atom or a conventional protecting 15 6 group, R , R and R are the same as defined above, with a di(lower alkyl)aminoethyl halide, (3) if required, reacting the product with a lower alkanoic acid or a reactive derivative thereof, and (C) when X is a conventional protecting group, further removing it from the resulting product.

Example 1 (1) 10.49g of (-r)-threo~3~(4-methoxyphenyl)-3-(2amino-5-chlorophenyl)thio-2-hydroxypropionic acid are dissolved in an aqueous solution containing 1.2g of sodium hydroxide, and ether is added thereto. A diethyl ether solution containing 9.21g of henzyloxycarbonyl chloride and an aqueous solution containing 2.16g of sodium hydroxide are added dropwise to the mixture at the same time at a temperature of 4 to 10 PC, and the mixture is stirred at the same temperature for 3.5 hours. The reaction mixture is poured into hydrochloric acid and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is recrystallized from isopropanol to give 12.Og of (t)-threo-3-(4-methoxyphenyl )3(2-(henzyloxycarbonyl) amino-5-chlorophenyl)thio2-hydroxypropionic acid. m.p. 159 to 162 °C (2) 0„76g of potassium hydroxide is added to a dimethyl sulfoxide solution containing 1.9g of the product obtained above, and 0.67g of 2-(dimethylamino)ethylchloride hydrochloride is further added thereto. After stirred overnight, the reaction mixture is poured into ice-water and acidified with hydrochloric acid. The mixture is washed with ether and adjusted at pH 4 to 5. Then, the mixture is extracted with chloroform, and the extract is washed with water, dried and evaporated to remove the solvent to give 1.81g of (t)threo-3~(4-methoxyphenyl)-3-f Nujol .

IRV (cm ): 3400, 2700-2400, 1700, 1610 Max (3) A mixture of 6.90g of the product obtained above, 5ml of acetic anhydride and 15ml of pyridine is stirred at room temperature for 2 hours,. The reaction mixture is poured into ice-water and extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent. Diethyl ether is added to the residue, and the crystalline precipitates are collected by filtration to give 7»Olg of (+)-threo-3-(4-methoxyphenyl)3~'(2~{N"bensyloxycarbonyl-N- (2- (dimethylamino) ethyl) amino^· -5-chlorophenylJ.thio-2-acetoxypropionic acid.

Nujol Ί IRU (cm ): 3420, 2720-2400, 1740(weak), 1710, 1610 Max (4) 2„10g of the product obtained above are dissolved in 10ml of acetic acid. 15ml of 25% hydrobromic acid acetic acid solution and 0„2ml of anisole are added thereto under ice cooling. After the mixture is stirred at room temperature for 2.5 hours, it is condensed under reduced pressure, and ice-water is added to the residue. The mixture is adjusted af pH 4 to 5 with an aqueous sodium bicarbonate solution, and then extracted with methylene chloride. The extract is washed with a saturated aqueous sodium chloride solution, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of isopropyl alcohol and diethyl ether to give 1.51g of -8(+)-threo-3-(4-methoxyphenyl)-3-(2-(2-(dimethylamino)ethyl)amino-5-chloroph£nyl}thio-2"acetoxypropionic acid acetate. m.p. 150 to 153 °C (decomp.) Hydrochloride: CHCl., » IRV (cm"*): 3370, 2700-2460, 1740, 1600, 1580 max (5) The product obtained above (hydrochloride) is converted into the free base in a conventional manner, and 2„0g of the thus-obtained compound are dissolved in 70ml of xylene. After the mixture is refluxed for 20 hours, it is condensed under reduced pressure. The residue (oil) is converted into maleate in a conventional manner and recrystallized from ethanol to give 2„lg of (+)-cis-2-(4methoxyphenyl)-3-acetoxy~5-(2-(dimethylamino) ethyl)-8chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one maleate. Yield: 86.8% m.p. 158 to 160 .°C Example 2 (1) 1.0Ig of ( + )-threo-3-(4-methoxyphenyl )-3-»j 2~£n~ benzyloxycarbonyl-N-(2-(dimethylamino)ethyl)aminoj-5ii % chlorophenyl?», thio-2-hydroxypropionic acid is added to 8ml J of a 25% hydrogen chloride-methanol solution, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is condensed under reduced pressure to give methyl ( + )-threo-3-(4-methoxyphenyl)-3-j*2"{N~ benzyloxycarbonyl-N-(2-(dimethylamino)ethyl)amino|-5chlorophenylJthio-2-hydroxypropionate hydrochloride in quantitative yield. -9CHC1 IRV icin'1): 3520, 1740, 1700 Max (2) The product obtained above is treated in the same '1 manner as described in Example 1-(3) to give 980mg of methyl (+)threo-3-(4-methoxyphenyl)-3-^2-|N5 benzyloxycarbonyl-M-(2-(dimethylamino) ethyl)aminoj-5chlorophenyl^ thio-2-acetoxypropionate.

Liquid η IRV (cin ): 1750, 1730, 1700 Max (3) The product obtained above (hydrochloride) is treated in the same manner as described in Example 1-(4) to give methyl (+)-threo-3-(4-methoxyphenyl)-3-^2-(2(dimethylamino)ethyl)amino-5-chlorophenyljthio-2-acetoxypropionate.

Oxalate l/2hydrate: Nujol .

IRV (cm1): 3370, 2700-2400, 1750 max 15 MS (m/e): 480 (M/) (4) The product obtained above is treated in the same manner as described in Example 1-(5) to give (+)-cis-2-(4methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino) ethyl)-8chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.

Maleate of this product exhibits the same physicochemical properties as the product obtained in Example 1-10 Example 3 6„0g of N,N8-dicyclohexylcarbodiimide are added to a mixture of 5.0g of (+)"threo-3-(4-methoxyphenyl)-3-^2-(2(dimethylamino) ethyl)amino-5-chlorophenylJthio"2"acetoxypropionic acid hydrochloride, 200mg of N-hydroxy- Q benzotriazole, lOOmg of methylene chloride and 500ml of dimethylformamide under ice-cooling. After the mixture is stirred at room temperature for 17 hours, water is added thereto. Then, the mixture is stirred for another 1 hour, and 5¾ aqueous sodium bicarbonate solution and ethyl acetate are further added thereto. Insoluble materials are filtered off, and the filtrate is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is converted into maleate in a conventional manner and recrystallized from ethanol to give 4.48g of (+ )-cis-2-(4-methoxyphenyl)-3~acetoxy-5"(2(dimethylamino) ethyl) -8-chloro~2,3-dihydro-l,5benzothiazepin~4(5H)-one maleate. Yields 79.8% The thus-obtained product exhibits the same physicochemical properties as the product obtained in Example 1(5).

Example 4 7.55g of ( + )"threo-3-(4~methoxyphenyl)-3--^2-(2(dimethylamino) ethyl) amino-5-chlorophenylj· thio-2-acetoxy- , propionic acid hydrochloride are dissolved in 100ml of methylene chloride. 8ml of pyridine are added thereto at a temperature not higher than 10.°C, and then 3.56 g of -11benzyloxycarbonyl chloride are further added. After stirred for 2 hours, the reaction mixture is poured into 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate» The extract is washed, dried and evaporated to remove the solvent, After toluene is added to the residue, pyridine is removed as a toluene azeotrope therefrom. The residue is converted into maleate in a conventional manner and recrystallized from ethanol to give 6„12g of ( + )"-cis-2-(4-methoxyphenyl)3-acetoxy-5-(2™ (dimethylamino) ethyl)-8-chloro-2,3-dihydro-l,5benzothiazepin-4(5H)-one maleate. Yield: 72.2S The thus-obtained product exhibits the same physicochemical properties as the product obtained in Example 1(5) .

Example 5 l.Og of (+)-threo-3-(4-methoxyphenyl)-3-^2-(2(dimethylamino) ethyl) amino-5-chiorophenyl|thio-2-acetoxy~ propionic acid hydrochloride is dissolved in 5ml of methylene chloride, and 2ml of thionyl chloride are added thereto. After stirred for 2 hours, the reaction mixture is condensed under reduced pressure, and the residue is dissolved in 50ml of methylene chloride. Said solution is added to a mixture of 1ml of pyridine and 20ml of methylene chloride, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate and alkalized with 5% aqueous sodium bicarbonate solution. Then, the mixture is washed, dried and -12The residue is evaporated to remove the solvent, converted into maleate in a conventional manner and recrystallized from ethanol to give 970mg of (+)-cis-2"(4= < methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl)-8chloro -2,3-dihydro-l, 5-benzothiazepin-4 (5H)-one maleate.

The thus-obtained product exhibits the same physicochemical properties as the product obtained in Example 1(5) .

Examples 6 to 12 Corresponding starting materials are treated in the same manner as described in either one of Examples 1 to 5 to give the following compounds. (6) ( + )-cis-2-(4-methoxyphenyl)-3~hydroxy-5-(2(dimethylamino) ethyl)-8~chloro~2f3-dihydro-l,5benzothiazepin-4(5H)-one m.p. 122 to 124 °C (decomp.) (7) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2(dimethylamino) ethyl)-9-chloro-2,3-dihydro-l,5benzothiasepin-4(5H)-one perchlorate l/4hydrate m.p. 190 to 192 °C (8) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5~(2- . (dimethylamino) ethyl) -9-chloro-2 „ 3-dihydro-l, 5I. benzothiazepin-4(5H)-one hydrochloride hydrate m.p. 140 to 143 °C (9) (±J-cis-2-(4-methylphenyl)-3-hydroxy-5-(2(dimethylamino)ethyl)~8-methyl-2,3-dihydro-l,5benzothiazepin-4(5H)-one m.p. 142 to 143 °C (recrystallized from ethyl acetate) (10) (+J-cis-2-(4-methylphenyl)-3-acetoxy~5-(2(dimetyhlamino)ethyl)-8-methyl-2,3-dihydro-l,5benzothiazepin-4(5H)-one hydrochloride m.p. 184 to 186 °C (recrystallized from a mixture of isopropyl alcohol and ether) m.p. 190 to 192 °C (recrystallized from a mixture of acetone and isopropyl ether) Fumarate: m.p. 196.5 to 198.5 °C (decomp., recrystallized from isopropyl alcohol) Maleate ; m.p. 173.5 to 175.5 °C (decomp., recrystallized from ethanol) m.p. 172.5 to 174 °C (recrystallized from methanol) m.p. 191.5 °C (recrystallized from water) Methanesulfonate: m.p. 124 to 128 °C (recrystallized from isopropyl alcohol) (11) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5"(2(dimethylamino) ethyl)-8-methyl-2,3-dihydro-l,5benzothiazepin-4(5H)-one maleate -14m.p. 194 to 197 °C (decomp., recrystallized from ethanol) Ca)p° +83.7° (c=0.362, methanol) Oxalate: m.p. 179 to 180 °C (recrystallized from ethanol) (a)2° -:-88,2° (c=0.288, methanol) (12) (-)-cis-2-(4-methylphenyl)"3-acetoxy-5-(2(dimethylamino) ethyl)-8-methyl-2,3-dihydro-l,5henzothiazepin-4(5H) - one oxalate m.p. 179.5 to 181 °C (decomp., recrystallized from ethanol) (α)2θ -83„8° (c=0.333, methanol) Maleate: m.p. 195 to 197.5 °C (decomp., recrystallized from ethanol) (a)2° -83.6° (c=0.50, methanol) Fumalate: m.p. 210.5 to 212.5 °C (decomp., recrystallized from ethanol) Ca)^° -91.3° (c=0.323, methanol) L- (+) -tartrate : m.p. 140 to 143 °C (recrystallized from a mixture of ethanol and ether)

Claims

1. What is claimd is

2. A process for preparing a 1,5-benzothiazepine

3.JR is hydrogen atom or a lower alkanoyl group; each of JR •

4. 5 6 and R' is a lower alkyl group; and one of R and R is halogen atom or a lower alkyl group and the other is hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof, which comprises subjecting a propionic acid derivative of the formula; CH 2 CH 2\ r 4 (II) wherein symbols are the same as defined above, or a reactive derivative thereof to intramolecular cyclization, and, if required, converting the product into a pharmaceutically acceptable acid addition salt thereof» 2. The process according to Claim 1, wherein the reactive derivative of the compound (II) is selected from a lower alkyl ester, an active ester, an mixed anhydride and an acid halide. -163. The process according to Claim 2, wherein the propionic acid compound (II) or the lower alkyl ester thereof is subjected to the intramolecular cyclization at a temperature between 100 and 180 9 C.

5. 4. The process according to Claim 2, wherein the «1 propionic acid compound (II) is subjected to the j intramolecular cyclization in the presence of a condensing agent at a temperature between the temperature of icecooling and 150 °C » 10 5» The process according to Claim 2, wherein the active ester, the mixed anhydride or the acid halide of the compound (II) is subjected to the intramolecular cyclization in the presence or absence of an acid acceptor at a temperature between -50 and 60 °C» 15

6. , The process according to either one of Claims 1 through 5, wherein the 1,5-benzothiazepine derivative is 2-(4-methoxyphenyl)~3-acetoxy-5-(2-(dimethylamino)ethyl)S-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.

7. The process according to either one of Claims 1 20 through 5, wherein the 1,5-benzothiazepine derivative is 2-(4-methylphenyl)-3-acetoxy-5-(2-(dimethylamino) ethyl)-8methyl-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.

8. A process for the preparation of compounds of Formula (I) as defined in Claim 1 9 substantially as hereinbefore described by wav/ of Example.

9. Compounds of the Formula (I) as defined in Claim 1, whenever prepared by a process as claimed in any of Claims 1 to 8. Dated this the 11th day of Novembers 1988.