CA1337346C - Process for preparing 1,5-benzothiazepine derivatives - Google Patents
Process for preparing 1,5-benzothiazepine derivativesInfo
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- CA1337346C CA1337346C CA000571438A CA571438A CA1337346C CA 1337346 C CA1337346 C CA 1337346C CA 000571438 A CA000571438 A CA 000571438A CA 571438 A CA571438 A CA 571438A CA 1337346 C CA1337346 C CA 1337346C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
There is disclosed a process for preparing 1,5-benzothiaze-pine derivatives represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, and X1 is a reactive residue, with an amine represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meanings as defined above, and X1 is a reactive residue, with an amine represented by the formula:
Description
1 3373~
Process for preparing 1,5-benzothiazepine derivatives SUMMARY OF THE INVENTION
This invention relates to a process for preparing 1,5-benzothiazepine derivatives and a pharmaceutically accept-able salt thereof which is useful as a pharmaceuticalcompound and represented by the formula:
R4 ~ Rl ~ ; ~ oR2 (I) CH2CH2N~
wherein Rl is a lower alkyl group or a lower alkoxy group, R is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group.
The 1,5-benzothiazepine derivatives (I) and a pharmaceuti-cally acceptable acid addition salt thereof are useful pharmaceutical compounds having an excellent hypotensive - - 2 - 1 33 7 3 ~ 6 activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among the compound (I), a compound wherein R2 is hydrogen atom is also useful of as an intermediate for synthesis of pharmaceuticals.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of the compound (I) of the present invention may include compounds in which Rl is a lower alkyl group, or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, either one of R3 or R4 is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R and R6 is a lower alkyl group.
In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group, the lower alkoxy group, and the lower alkanoyl group include an alkyl group of one to six carbon atoms, an alkoxy group of one to six carbon atoms and an alkanoyl group of two to six carbon atoms, respectively.
Preferred examples of these groups are an alkyl group of one to four carbon atoms, an alkoxy group of one to four carbon atoms and an alkanoyl group of two to five carbon atoms.
According to the present invention, the compound (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting a compound represented by the formula:
R4 ~ Rl OR (II) wherein Xl is a reactive residue and Rl, R2, R3 and R4 have the same meanings as defined above, with an amine represented by the formula:
HN \ (III) wherein R5 and R6 have the same meanings as defined above, or a salt thereof, and if necessary convert it to a salt thereof.
The reaction of the compound (II) and the amine (III) or a salt thereof may be carried out in a suitable solvent in the presence or absence of base. In the compound (II), examples of the reactive residue represented by Xl may include halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom, an alkylsulfonyloxy group such as methylsulfonyloxy group, and a substituted or unsubstituted phenylsulfonyloxy group such as tosyloxy group. Also, the amine (III) can be used in the state of free or as a salt thereof to the above reaction. Examples of such a salt may include conventional acid addition salt such as hydrochloride, hydrobromide, sulfate, nitrate, etc. As the base, there may be suitably mentioned alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine, etc., and also the - 4 - l 3 3 7 3 4 6 amine (III) may be used to this purpose. The present reaction is preferably carried out in a suitable solvent (for example, dimethylformamide, diethylformamide, di-methylacetamide, N-formylmorpholine, N-acetylmorpholine, dimethylsulfoxide, diglyme, diethylether, tetrahydrofuran, dimethoxyethane, dioxane, pyridine, alkanol, acetonitrile, acetone, methyl ethyl ketone, ethylacetate, methylacetate, methylpropionate, ethylpropionate, benzene, xylene, tolu-ene, etc.) at the temperature between 0 C and 150 C.
The compound (I) thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, for example, by treating with an acid, if necessary. Examples of such pharmaceutically acceptable acid addition salts may include inorganic acid addition salts such as hydro-chloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as oxalate, maleate, tartrate, methanesulfonate, etc.
Since the reaction of the present invention as mentioned above proceeds without accompanying any racemization, by using an optically active compound (II) as the starting material, the compound (I) can be obtained as an optically active compound.
The 1,5-benzothiazapine derivatives (I) or pharmaceuti-cally acceptable acid addition salts thereof of the pre-sent invention have excellent hypotensive activity, cere-bral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity as mentioned above, and can be used for therapy and prevention of brain diseases such as cerebrovascular contraction, cerebral ischemia, cerebral infarction, etc., or cardiac diseases such as stenocardia, cardiac infarction, etc. Also, among the compound (I), the compound wherein R2 is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R2 is a lower Al~noyl group.
The comro~nA (II) of the ~ nt invention can be proAl~Ge~ by reacting the compound represented by the formula:
4 ~ Rl (IV) wherein R1, R3 and R4 have the same meAn;n~s as defined above, which can be obt~;neA in accordance with the method as described, for example, in JArAn~ce Provisional Patent Publication No. 225174/1984, published December 18, 1984 (which co~ ponA~ to U.S. Patent No. 4,567,175, issued January 28, 1986) with the compo~nA ~e~-e~ented by the formula:
X1 _ CH2CH2 - x2 (V) wherein x2 is a reactive residue and X1 has the same meAn;~ as defined above, in a suitable solvent (for example, dimethylsulfoxide) in the preC~nce of base (for example, alkali metal hydroxide, alkali metal hydride), and further the product is carried out condensation reaction with a reactive derivative (for example, acid anhydride, acid halide) of a lower aliphatic acid, if required.
~ ~
Also, the compound (I) of the present invention and the compolln~ (II) include either two kinds of stereoisomers (that is, cis and trans-isomers) or four kinds of optical isomers (that is, (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) and mixtures thereof based on asym-metric carbon atoms (two) in the molecule.
Example 1 (1) In 50 ml of dimethylsulfoxide containing 590 mg of potassium hydroxide was dissolved 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one, and the solution was stirred at room temperature for 30 minutes. Then, 1.75 g of 1-chloro-2-methanesulfonyloxyethane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, insoluble starting materials were removed by filtration.
The filtrate was condensed to remove the solvent. Oily products obtained were purified by silica gel column chromatography (eluent: chloroform : ethyl acetate = 20 :
1), and recrystallized from ethanol to give 1.05 g of a mixture (9 : 1) of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methanesulfonyloxy)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.
mp. 125 to 128 C.
MS (m/e): 365, 363 (M+ - CH3SO2) (2) This product (1.03 g) was dissolved in 10 ml of dimethylformamide, and 90 mg of a 51 % dimethylamine-toluene solution was added to the solution and the mixture was stirred at room temperature for 62 hours. Further, 180 mg of a 51 % dimethylamine-toluene solution was added to the mixture and the mixture was stirred at room tempera-- 7 - 1 33 73 ~6 ture. After completion of the reaction, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform : ethanol = 95 : 5) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 6~7 mg of (+~-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(di-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
- mp. 122 to 124 C (decomposed).
Example 2 (1) In 150 ml of dimethylsulfoxide containing 1.77 g of potassium hydroxide was dissolved 10.08 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one and the solution was stirred at room temperature for 30 minutes. Subse~uently, 4.70 g of l-bromo-2-chloroel.hane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, precipitated starting material was removed by filtration. The filtrate was condensed to distill off most of the solvent. The residue was allowed to stand and precipitated crystals were collected bv filtration to obtain crude product (594 mg). The filtrate was applied to a silica gel column chromatography (eluent: chloroform : ethyl acetate = 20 : 1) and the crude product obtained was combined with the crude product obtained above, and they were recrystallized from ethanol to give 7.94 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
IR vNu~ol~ -1 max (cm ): 3460, 1660, 1590.
MS (m/e): 399, 397 (M ).
(2) This product, a 51 ~ dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
mp. 122 to 124 C (decomposed).
Example 3 (1) To a mixture of 3 ml of acetic anhydride and 2 ml of acetic acid was added 484 mg of (+)-cis-2-(4-methoxy-phenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the mixture was stirred at 110 C. After completion of the reaction, the mixture was condensed under reduced pressure to distill off the solvent. After the residue was dissolved in toluene, it was condensed to dryness under reduced pressure to give 535 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as oily product.
IR vmaxq (cm 1): 1740, 1680, 1600, 1580.
MS (m/e): 439, 441 (M ).
(2) This product, a 51 % dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Maleate of this product:
mp. 158 to 160 C (recrystallized from ethanol).
Examples 4 to 9 By treating corresponding starting materials in the same manner as in Examples 1 to 3, the following compounds can be obtained.
(4) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.perchlorate.~hydrate mp. 190 to 192 C.
(5) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride.monohydrate mp. 140 to 143 C.
(6) (+)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one mp. 142 to 143 C (recrystallized from ethyl acetate).
(7) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride mp. 184 to 186 C (recrystallized from a mixed solventof isopropanol and ether).
This product, when recrystallized from a mixed solvent of acetone and isopropyl ether, exhibits a melting point of - lo - 1 3 3 73 4 6 190 to 192 C, thus having the properties of crystals polymorphism.
Fumarate of this product:
mp. 196.5 to 198.5 C (decomposed) (recrystallized from isopropanol).
Maleate of this product:
mp. 173.5 to 175.5 C (decomposed) (recrystallized from ethanol).
This product, when recrystallized from methanol, exhibits a melting point of 172.5 to 174 C and, when recrystal-lized from water, gives crystals exhibiting a melting point of 191.9 C, thus having the properties of crystals polymorphism.
Methanesulfonate of this product:
mp. 124 to 128 C (recrystallized from isopropanol).
(8) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate mp. 194 to 197 C (decomposed) (recrystallized from ethanol).
[~]20 + 83.7 (c=0.362, methanol).
Oxalate of this product:
mp. 179 to 180 C (recrystallized from ethanol).
[~]D + 88.2 (c=0.288, methanol).
(9) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.oxalate mp. 179.5 to 181 C (decomposed) (recrystallized from ethanol).
[~]D0 _ 83.8 (c=0.333, methanol).
Maleate of this product:
mp. 195 to 197.5 C (decomposed) (recrystallized from ethanol).
[~]D - 83.6 (c=0.50, methanol).
Fumarate of this product:
mp. 210.5 to 212.5 C (decomposed) (recrystallized from ethanol).
[~]D0 _ 91.3 (c=0.323, methanol).
L-(+)-tartrate of this product:
mp. 140 to 143 C (recrystallized from a mixed solvent of ethanol and ether).
Process for preparing 1,5-benzothiazepine derivatives SUMMARY OF THE INVENTION
This invention relates to a process for preparing 1,5-benzothiazepine derivatives and a pharmaceutically accept-able salt thereof which is useful as a pharmaceuticalcompound and represented by the formula:
R4 ~ Rl ~ ; ~ oR2 (I) CH2CH2N~
wherein Rl is a lower alkyl group or a lower alkoxy group, R is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each of R5 and R6 is a lower alkyl group.
The 1,5-benzothiazepine derivatives (I) and a pharmaceuti-cally acceptable acid addition salt thereof are useful pharmaceutical compounds having an excellent hypotensive - - 2 - 1 33 7 3 ~ 6 activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among the compound (I), a compound wherein R2 is hydrogen atom is also useful of as an intermediate for synthesis of pharmaceuticals.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of the compound (I) of the present invention may include compounds in which Rl is a lower alkyl group, or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, either one of R3 or R4 is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R and R6 is a lower alkyl group.
In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group, the lower alkoxy group, and the lower alkanoyl group include an alkyl group of one to six carbon atoms, an alkoxy group of one to six carbon atoms and an alkanoyl group of two to six carbon atoms, respectively.
Preferred examples of these groups are an alkyl group of one to four carbon atoms, an alkoxy group of one to four carbon atoms and an alkanoyl group of two to five carbon atoms.
According to the present invention, the compound (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting a compound represented by the formula:
R4 ~ Rl OR (II) wherein Xl is a reactive residue and Rl, R2, R3 and R4 have the same meanings as defined above, with an amine represented by the formula:
HN \ (III) wherein R5 and R6 have the same meanings as defined above, or a salt thereof, and if necessary convert it to a salt thereof.
The reaction of the compound (II) and the amine (III) or a salt thereof may be carried out in a suitable solvent in the presence or absence of base. In the compound (II), examples of the reactive residue represented by Xl may include halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom, an alkylsulfonyloxy group such as methylsulfonyloxy group, and a substituted or unsubstituted phenylsulfonyloxy group such as tosyloxy group. Also, the amine (III) can be used in the state of free or as a salt thereof to the above reaction. Examples of such a salt may include conventional acid addition salt such as hydrochloride, hydrobromide, sulfate, nitrate, etc. As the base, there may be suitably mentioned alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine, etc., and also the - 4 - l 3 3 7 3 4 6 amine (III) may be used to this purpose. The present reaction is preferably carried out in a suitable solvent (for example, dimethylformamide, diethylformamide, di-methylacetamide, N-formylmorpholine, N-acetylmorpholine, dimethylsulfoxide, diglyme, diethylether, tetrahydrofuran, dimethoxyethane, dioxane, pyridine, alkanol, acetonitrile, acetone, methyl ethyl ketone, ethylacetate, methylacetate, methylpropionate, ethylpropionate, benzene, xylene, tolu-ene, etc.) at the temperature between 0 C and 150 C.
The compound (I) thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, for example, by treating with an acid, if necessary. Examples of such pharmaceutically acceptable acid addition salts may include inorganic acid addition salts such as hydro-chloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as oxalate, maleate, tartrate, methanesulfonate, etc.
Since the reaction of the present invention as mentioned above proceeds without accompanying any racemization, by using an optically active compound (II) as the starting material, the compound (I) can be obtained as an optically active compound.
The 1,5-benzothiazapine derivatives (I) or pharmaceuti-cally acceptable acid addition salts thereof of the pre-sent invention have excellent hypotensive activity, cere-bral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity as mentioned above, and can be used for therapy and prevention of brain diseases such as cerebrovascular contraction, cerebral ischemia, cerebral infarction, etc., or cardiac diseases such as stenocardia, cardiac infarction, etc. Also, among the compound (I), the compound wherein R2 is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R2 is a lower Al~noyl group.
The comro~nA (II) of the ~ nt invention can be proAl~Ge~ by reacting the compound represented by the formula:
4 ~ Rl (IV) wherein R1, R3 and R4 have the same meAn;n~s as defined above, which can be obt~;neA in accordance with the method as described, for example, in JArAn~ce Provisional Patent Publication No. 225174/1984, published December 18, 1984 (which co~ ponA~ to U.S. Patent No. 4,567,175, issued January 28, 1986) with the compo~nA ~e~-e~ented by the formula:
X1 _ CH2CH2 - x2 (V) wherein x2 is a reactive residue and X1 has the same meAn;~ as defined above, in a suitable solvent (for example, dimethylsulfoxide) in the preC~nce of base (for example, alkali metal hydroxide, alkali metal hydride), and further the product is carried out condensation reaction with a reactive derivative (for example, acid anhydride, acid halide) of a lower aliphatic acid, if required.
~ ~
Also, the compound (I) of the present invention and the compolln~ (II) include either two kinds of stereoisomers (that is, cis and trans-isomers) or four kinds of optical isomers (that is, (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) and mixtures thereof based on asym-metric carbon atoms (two) in the molecule.
Example 1 (1) In 50 ml of dimethylsulfoxide containing 590 mg of potassium hydroxide was dissolved 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one, and the solution was stirred at room temperature for 30 minutes. Then, 1.75 g of 1-chloro-2-methanesulfonyloxyethane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, insoluble starting materials were removed by filtration.
The filtrate was condensed to remove the solvent. Oily products obtained were purified by silica gel column chromatography (eluent: chloroform : ethyl acetate = 20 :
1), and recrystallized from ethanol to give 1.05 g of a mixture (9 : 1) of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methanesulfonyloxy)ethyl]-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one.
mp. 125 to 128 C.
MS (m/e): 365, 363 (M+ - CH3SO2) (2) This product (1.03 g) was dissolved in 10 ml of dimethylformamide, and 90 mg of a 51 % dimethylamine-toluene solution was added to the solution and the mixture was stirred at room temperature for 62 hours. Further, 180 mg of a 51 % dimethylamine-toluene solution was added to the mixture and the mixture was stirred at room tempera-- 7 - 1 33 73 ~6 ture. After completion of the reaction, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform : ethanol = 95 : 5) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 6~7 mg of (+~-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(di-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
- mp. 122 to 124 C (decomposed).
Example 2 (1) In 150 ml of dimethylsulfoxide containing 1.77 g of potassium hydroxide was dissolved 10.08 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one and the solution was stirred at room temperature for 30 minutes. Subse~uently, 4.70 g of l-bromo-2-chloroel.hane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, precipitated starting material was removed by filtration. The filtrate was condensed to distill off most of the solvent. The residue was allowed to stand and precipitated crystals were collected bv filtration to obtain crude product (594 mg). The filtrate was applied to a silica gel column chromatography (eluent: chloroform : ethyl acetate = 20 : 1) and the crude product obtained was combined with the crude product obtained above, and they were recrystallized from ethanol to give 7.94 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
IR vNu~ol~ -1 max (cm ): 3460, 1660, 1590.
MS (m/e): 399, 397 (M ).
(2) This product, a 51 ~ dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
mp. 122 to 124 C (decomposed).
Example 3 (1) To a mixture of 3 ml of acetic anhydride and 2 ml of acetic acid was added 484 mg of (+)-cis-2-(4-methoxy-phenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the mixture was stirred at 110 C. After completion of the reaction, the mixture was condensed under reduced pressure to distill off the solvent. After the residue was dissolved in toluene, it was condensed to dryness under reduced pressure to give 535 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as oily product.
IR vmaxq (cm 1): 1740, 1680, 1600, 1580.
MS (m/e): 439, 441 (M ).
(2) This product, a 51 % dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Maleate of this product:
mp. 158 to 160 C (recrystallized from ethanol).
Examples 4 to 9 By treating corresponding starting materials in the same manner as in Examples 1 to 3, the following compounds can be obtained.
(4) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.perchlorate.~hydrate mp. 190 to 192 C.
(5) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride.monohydrate mp. 140 to 143 C.
(6) (+)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one mp. 142 to 143 C (recrystallized from ethyl acetate).
(7) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride mp. 184 to 186 C (recrystallized from a mixed solventof isopropanol and ether).
This product, when recrystallized from a mixed solvent of acetone and isopropyl ether, exhibits a melting point of - lo - 1 3 3 73 4 6 190 to 192 C, thus having the properties of crystals polymorphism.
Fumarate of this product:
mp. 196.5 to 198.5 C (decomposed) (recrystallized from isopropanol).
Maleate of this product:
mp. 173.5 to 175.5 C (decomposed) (recrystallized from ethanol).
This product, when recrystallized from methanol, exhibits a melting point of 172.5 to 174 C and, when recrystal-lized from water, gives crystals exhibiting a melting point of 191.9 C, thus having the properties of crystals polymorphism.
Methanesulfonate of this product:
mp. 124 to 128 C (recrystallized from isopropanol).
(8) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.maleate mp. 194 to 197 C (decomposed) (recrystallized from ethanol).
[~]20 + 83.7 (c=0.362, methanol).
Oxalate of this product:
mp. 179 to 180 C (recrystallized from ethanol).
[~]D + 88.2 (c=0.288, methanol).
(9) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethyl-amino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.oxalate mp. 179.5 to 181 C (decomposed) (recrystallized from ethanol).
[~]D0 _ 83.8 (c=0.333, methanol).
Maleate of this product:
mp. 195 to 197.5 C (decomposed) (recrystallized from ethanol).
[~]D - 83.6 (c=0.50, methanol).
Fumarate of this product:
mp. 210.5 to 212.5 C (decomposed) (recrystallized from ethanol).
[~]D0 _ 91.3 (c=0.323, methanol).
L-(+)-tartrate of this product:
mp. 140 to 143 C (recrystallized from a mixed solvent of ethanol and ether).
Claims (8)
1. A process for preparing 1,5-benzothiazepine derivatives represented by the formula:
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each or R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meaning as defined above, and X1 is a halogen atom, an alkylsulfonyloxy group, or a substituted or unsubstituted phenylsulfonyloxy group, with an amine represented by the formula:
(III) wherein R5 and R6 have the same meanings as defined above, or a salt thereof, and if necessary convert it to a pharmaceutically acceptable acid addition salt thereof.
(I) wherein R1 is a lower alkyl group or a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a lower alkyl group or halogen atom, and the other is hydrogen, and each or R5 and R6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound represented by the formula:
(II) wherein R1, R2, R3 and R4 have the same meaning as defined above, and X1 is a halogen atom, an alkylsulfonyloxy group, or a substituted or unsubstituted phenylsulfonyloxy group, with an amine represented by the formula:
(III) wherein R5 and R6 have the same meanings as defined above, or a salt thereof, and if necessary convert it to a pharmaceutically acceptable acid addition salt thereof.
2. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the reaction is carried out in a solvent in the presence or absence of base at the temperature between 0°C and 150°C.
3. A process for preparing 1,5-benzothiazepine derivatives according to Claim 2, wherein said base is alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate or tertiary amine.
4. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein said salt of the amine is hydrochloride, hydrobromide, sulfate or nitrate of the amine.
5. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein said compound represented by the formula (II) is prepared by reacting the compound represented by the formula:
(IV) wherein R1, R3 and R4 have the same meanings as defined in Claim 1, with the compound represented by the formula:
X1 - CH2CH2 - X2 (V) wherein X1 and X2, independently, are as defined in Claim 1 for X1, in a solvent in the presence of base, and further the product is carried out condensation reaction with a reactive derivative of a lower aliphatic acid, if required.
(IV) wherein R1, R3 and R4 have the same meanings as defined in Claim 1, with the compound represented by the formula:
X1 - CH2CH2 - X2 (V) wherein X1 and X2, independently, are as defined in Claim 1 for X1, in a solvent in the presence of base, and further the product is carried out condensation reaction with a reactive derivative of a lower aliphatic acid, if required.
6. A process for preparing 1,5-benzothiazepine derivatives according to Claim 5, wherein said reactive derivative of a lower aliphatic acid is acid anhydride or acid halide.
7. The process claimed in Claim 1, in which one of R3 and R4 is a lower alkyl group and the other is hydrogen atom.
8. The process claimed in Claim 1, in which one of R3 and R4 is halogen atom and the other is hydrogen atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62202027A JPS6445376A (en) | 1987-08-12 | 1987-08-12 | Production of 1,5-benzothiazepine derivative |
| JP202027/1987 | 1987-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1337346C true CA1337346C (en) | 1995-10-17 |
Family
ID=16450708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000571438A Expired - Fee Related CA1337346C (en) | 1987-08-12 | 1988-07-07 | Process for preparing 1,5-benzothiazepine derivatives |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS6445376A (en) |
| KR (1) | KR890003722A (en) |
| CN (1) | CN1030570C (en) |
| AT (1) | AT395010B (en) |
| BG (1) | BG50501A3 (en) |
| CA (1) | CA1337346C (en) |
| ES (1) | ES2007990A6 (en) |
| FI (1) | FI883115A (en) |
| GR (1) | GR1000385B (en) |
| IE (1) | IE61168B1 (en) |
| IL (1) | IL86978A0 (en) |
| NO (1) | NO170017C (en) |
| PT (1) | PT88250B (en) |
| SU (1) | SU1709908A3 (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1236467A (en) * | 1967-10-28 | 1971-06-23 | Tanabe Seiyaku Co | Benzothiazepine derivatives |
| US3895006A (en) * | 1974-04-19 | 1975-07-15 | Squibb & Sons Inc | 5-(Substituted amino)alkyl)-2-aryl-3-halo-1,5-benzothiazepin-4(5H)-ones |
| SE449611B (en) * | 1982-07-09 | 1987-05-11 | Tanabe Seiyaku Co | SET TO MAKE 1,5-BENZOTIAZEPINE DERIVATIVES |
| US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
| GB8315364D0 (en) * | 1983-06-03 | 1983-07-06 | Tanabe Seiyaku Co | 8-chloro-1 5-benzothiazepine derivatives |
| GB8406318D0 (en) * | 1984-03-10 | 1984-04-11 | Tanabe Seiyaku Co | 1 5-benzothiazepine derivatives |
| JPS60204776A (en) * | 1984-03-30 | 1985-10-16 | Roller Japan Kk | 1,5-benzothiazepine derivative |
| JPS61103877A (en) * | 1984-10-24 | 1986-05-22 | Tanabe Seiyaku Co Ltd | Benzothiazepine derivative and its preparation |
-
1987
- 1987-08-12 JP JP62202027A patent/JPS6445376A/en active Pending
-
1988
- 1988-06-27 IE IE194988A patent/IE61168B1/en not_active IP Right Cessation
- 1988-06-29 FI FI883115A patent/FI883115A/en not_active Application Discontinuation
- 1988-07-04 IL IL86978A patent/IL86978A0/en not_active IP Right Cessation
- 1988-07-07 CA CA000571438A patent/CA1337346C/en not_active Expired - Fee Related
- 1988-07-11 CN CN88104387A patent/CN1030570C/en not_active Expired - Fee Related
- 1988-08-02 BG BG085116A patent/BG50501A3/en unknown
- 1988-08-04 GR GR880100515A patent/GR1000385B/en unknown
- 1988-08-09 NO NO883525A patent/NO170017C/en unknown
- 1988-08-10 KR KR1019880010209A patent/KR890003722A/en not_active Application Discontinuation
- 1988-08-11 SU SU884356317A patent/SU1709908A3/en active
- 1988-08-11 PT PT88250A patent/PT88250B/en not_active IP Right Cessation
- 1988-08-11 ES ES8802522A patent/ES2007990A6/en not_active Expired
- 1988-08-11 AT AT0202388A patent/AT395010B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATA202388A (en) | 1992-01-15 |
| NO883525D0 (en) | 1988-08-09 |
| ES2007990A6 (en) | 1989-07-01 |
| GR880100515A (en) | 1989-05-25 |
| JPS6445376A (en) | 1989-02-17 |
| GR1000385B (en) | 1992-06-30 |
| PT88250A (en) | 1989-06-30 |
| PT88250B (en) | 1995-03-01 |
| FI883115A (en) | 1989-02-13 |
| CN1030570C (en) | 1995-12-27 |
| AT395010B (en) | 1992-08-25 |
| CN1031229A (en) | 1989-02-22 |
| SU1709908A3 (en) | 1992-01-30 |
| NO170017B (en) | 1992-05-25 |
| FI883115A0 (en) | 1988-06-29 |
| IL86978A0 (en) | 1988-12-30 |
| IE61168B1 (en) | 1994-10-05 |
| IE881949L (en) | 1989-02-12 |
| KR890003722A (en) | 1989-04-17 |
| BG50501A3 (en) | 1992-08-14 |
| NO883525L (en) | 1989-02-13 |
| NO170017C (en) | 1992-09-02 |
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