CA2056129C - Process for preparing 1,5-benzothiazepine derivative - Google Patents
Process for preparing 1,5-benzothiazepine derivativeInfo
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- CA2056129C CA2056129C CA002056129A CA2056129A CA2056129C CA 2056129 C CA2056129 C CA 2056129C CA 002056129 A CA002056129 A CA 002056129A CA 2056129 A CA2056129 A CA 2056129A CA 2056129 C CA2056129 C CA 2056129C
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- acetic acid
- hydroxy
- compound
- methoxyphenyl
- ethyl
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Control Of Driving Devices And Active Controlling Of Vehicle (AREA)
- Control Of Vehicle Engines Or Engines For Specific Uses (AREA)
- Combined Controls Of Internal Combustion Engines (AREA)
Abstract
A process for preparing hydrochloride of 3-acetoxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)- 1, 5-benzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2, 3-dihydro-5-[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride. According to the process, hydrochloride of 3-acetoxy-2, 3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzo-thiazepin-4(5H)-one is readily obtained in one step.
Description
1 - 20~6129 PROCESS FOR PREPARING 1,5-BENZOTHIAZEPIN_ DERIVATIVE
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-5 benzothiazepin-4(5H)-one which is useful as a medicinal compound.
Hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethyl~mi no)ethyl]-2-(p-methoxyphenyl)- 1,5-benzothiazepin-4(5H)-one (hereinafter referred to as 10 desired compound), particularly, d-cis form thereof is a medicinal compound useful as a coronary vasodilator and an anti-hypertensive agent. Hitherto, there have been known some processes for preparing the desired compound.
Examples of these processes are, for instance, (1) a 15 process wherein 3-hydroxy-2,3-dihydlo 5-[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1,5-~enzothiazepin-4(5H)-one (hereinafter referred to as 3-hydroxy compound) is reacted with an acetylating agent such as acetic anhydride with heating to give 3-acetoxy-2,3-dihydro-20 5-[2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to 3-acetoxy compound) according to a conventional method and then the resulting 3-acetoxy compound is treated with ethanolic hydrogen chloride (or methanolic hydrogen 25 chloride) (see Japanese Fx~mined Patent Publication No.
813/1972 and No. 18038/1978), (2) a process wherein the 3-hydroxy compound is reacted with acetic anhydride in the presence of hydrochloric acid in one step (see Japanese Un~x~mine-l Patent Publication No. 132876/1987) and the 30 like.
However, in the process (1), two steps, namely, a step for the acetylation and a step for the formation of hydrochloride, are required to ~e carried out separately, although the acetylation can be suitably carried out in 35 the absence of water. On the other hand, in the process (2), hydrochloric acid must be at first added with cooling '~
20~6129 and then the acetylation is carried out with heating, since heat is generated on the addition of hydrochloric acid (aqueous solution of hydrogen chloride) used as a supplier of hydrogen chloride. The operations in the 5 method (2) are, therefore, complicated. Further, it is always required in the method (2) to use a large exess of acetic anhydride for removing water existing in the reaction system, which is introduced on the addition of hydrochloric acid, since the acetylation cannot be 10 completed in the presence of water.
An object of the invention is to provide a process for simply preparing the desired compound from the 3-hydroxy compound in one step without cooling the reaction system or using a large excess of an acetylating 15 agent.
This and the other objects of the present invention will become apparent from the description hereinafter.
It has now been found that a process for preparing hydrochloride of 3-acetoxy-2, 3-dihydro-5-[ 2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-l, 5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride overcomes the defects of the above-mentioned conventional processes.
DETAILED DESCRIPTION
The above-mentioned process of the present invention is estaUished based upon a novel knowledge that acetyl chloride acts as not only an acetylating agent for 35 the 3-hydroxy compound but also a supplier of hydrogen chloride, resulting in giving the desired compound.
According to the process of the present invention, therefore, the desired compound can be prepared quantitatively without supplying hydrogen chloride separately, using a large excess of an acetylating agent or cooling the reaction system which are needed in conventional processes.
In the process of the present invention, acetic acid or a mixed solvent of acetic acid and acetic anhydride can be suitably used as a solvent. As to the mi xi ng ratio of the mixed solvent, the amount of acetic anhydride may be about one-tenth of the amount of acetic 10 acid or may be increased to several times of the amount of acetic acid. The mixing ratio of the mixed solvent can be appropriately selected according to the reaction temperature or a desired reaction time. The amount of the solvent to be used is not particularly limited and, 15 for example, the amount is sufficiently from about 1 to about 5 parts by weight per part by weight of the 3-hydroxy compound. Suitable amount of acetyl chloride to be used may vary according to the solvent, but are usually within 1 to 20 moles per mole of the 3-hydroxy compound.
20 For example, when only acetic acid is used as the solvent, it is preferred to use acetyl chloride in an amount of more than 1 mole, preferably 1.01 to 10 moles, more preferably 1.05 to 1.5 moles, per mole of the 3-hydroxy compound. On the other hand, when a mixture of acetic 25 acid and acetic anhydride is used as the solvent, it is preferred to use acetyl chloride in an amount of not less than 1 mole, preferably 1 to 5 moles, more preferably 1 to 1.5 moles, per mole of the 3-hydroxy compound.
The process of the present invention can be 30 carried out at from a low temperature with cooling, for instance 5C, to a high temperature with heating, for instance 130C, preferaUy from the room temperature to a refluxing temperature. Especially, when only acetic acid is used as the solvent, it is preferred to carry out the 35 process at 10 to 110C, more preferably 40 to 80C. On the other hand, when a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to carry out the process at 5 to 130C, more preferably 10 to In case that a mixed solvent of acetic acid and acetic anhydride is used in the present invention, the reaction is accelarated and the solvent is prevented from 5 freezing when temperature lowering.
With respect to the 3-hydroxy compound which is the starting material of the present invention, there are four stereoisomers owing to asymmetric carbon atoms at the 2-position and the 3-position. Since the process of the 10 present invention can be carried out without racemization, the desired compound having an optical activity can be obtained from the 3-hydroxy compound having the corresponding optical activity.
Isolation of the desired compound after the 15 completion of the reaction can be easily carried out according to the conventional methods such as recrystallization after distilling the reaction solvent away.
As indicated in the following Examples, 20 according to the process of the present invention, the desired compound can be obtained in a high yield in one step without carrying out another step to obtain the hydrochloride after the acetylation or ~ ling hydrochloric acid to a reaction system, since acethyl chloride acts as 25 not only an acetylating agent but also a supplier of hydrogen chloride.
The process of the present invention, therefore, has an industrially excellent advantage that the desired compound can be obtained by a simple operation in a high 30 yield, compared with other conventional methods. For example, while two steps, namely a step for the acetylation and a step for the formation of the hydrochloride, are required to be carried out separetely in the process ( 1) described in Japanese F.x~min~l Patent 35 Publication No. 813/1972 and No. 13038/1978, the desired compound can be obtained in one step in the present invention. Further, while a large excess of acetic anhydride is required to be used in order to remove water existing in the reaction system, which is intruduced on the addition of hydrochloric acid (aqueous solution of hydrogen chloride), from the reaction system in the process (2) described in Japanese Unex~mine-l Patent 5 Publication No. 132876/1987, only 1 mole or a little more than 1 mole of acetyl chloride per mole of the 3-hydroxy compound may be sufficiently used in the present invention, which does not require the addition of hydrochloric acid with cooling, to obtain the desired 10 compound in a high yield.
The present invention is more specifically described and explained by means of the following Experimental ~mples and Examples. It is to be understood that the present invention is not limited to 15 the Ex~mples, and various changes and modifications may be made in the invention without departing from the sprit and scope thereof.
Experimental Example 1 [ Effect of a solvent for the acetylation on conversion 20 rate]
In 200 ml of each solvent described in Table 1 were mixed 25 g of the d-cis-3-hyd~o~y compound and 5.8 g of acetyl chloride ( 1.1 moles per mole of the d-cis-3-hydroxy compound) and each mixture was stirred at 30C for 2 5 2 hours. Conversion rate to the desired compound was determined by high performance liquid chromatography. The results are shown in the following Table 1. When acetic acid or a mixed solvent of acetic acid and acetic anhydride was used, the desired compound was obtained in a 3 o significantly high conversion rate compared with those in case of using other solvents.
Table 1 Solvent Conversion rate to the desired compound Solvents used Acetic acid 95 %
in the present invention Mixed solvent A 99.98 % ~2) Mixed solvent B 100 % ~2) Acetic anhydride 33 % ~2) Other Chloroform 78 %
solvents (Reference) Methylene chloride 70 %
Dichloroethane 77 %
Acetone 51 %
Trichloroethane 66 %
Toluene 78 %
Mixed solvent A: acetic acid: acetic anhydride = 1: 1 Mixed solvent B: acetic acid: acetic anhydride = 1: 3 ~2) The used amount of acetyl chloride was 1.2 moles per mole of the d-cis-3-hydroxy compound and the reaction system was stirred at 60C for 3 hours.
Example 1 In 15 ml of acetic acid was dissolved 7.45 g (0.02 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[ 2-35 (dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-thiazepin-4(5H)-one with heating. Then thereto was added 1.71 g (0.022 mole) of acetyl chloride at 20C and the mixture was stirred at room temperature for 72 hours.
After the reaction, acetic acid was distilled away and the residue was recrystallized from ethanol to give 7.53 g of hydrochloride of d-cis-3-acetoxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-thiazepin-4(5H)-one.
yield: 83 %
m.p.: 213 - 214~C
Example 2 The procedure of Example 1 was repeated except that the reaction was carried out at 70 - 80 C for 3 hours with stirring and 97 % ethanol was used for the recrystallization to give 8. 4 5 g of hydrochloride of the d-cis-3-acetoxy compound.
yield: 9 4 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
F.Y~mrle 3 The procedure of Example 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2, 3-dih~ o 5~ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one and 12. 7 25 g (0.16 mole) of acetyl chloride were used. The reaction was carried out at 60~ for 3 hours with stirring in a mixed solvent of 81 ml of acetic acid and 19 ml of acetic anhydride and 97 % ethanol was used for the recrystallization. Thus 55.9 g of the hydrochloride of 30 the d-cis-3-acetoxy compound was obt~ine i yield: 92 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1 Example 4 The procedure of FY~mple 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of 20561~9 d-cis-3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 10.8 g (0.13 mole) of acetyl chloride were used. The reaction was carried out at 100 - 110C for 6 hours with stirring 5 in a mixed solvent of 50 ml of acetic acid and 50 ml of acetic anhydride and 9 7 % ethanol was used for the recrystallization. Thus 53.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
yield: 89 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
Example 5 The procedure of Example 1 was repeated except for followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acethyl chloride were used. The reaction 20 was carried out at 60C for 3 hours with stirring in a mixed solvent of 25 ml of acetic acid and 75 ml of acetic anhydride and 9 7 % ethanol was used for the recrystallization. Thus 54.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
yield: 90.4 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-5 benzothiazepin-4(5H)-one which is useful as a medicinal compound.
Hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethyl~mi no)ethyl]-2-(p-methoxyphenyl)- 1,5-benzothiazepin-4(5H)-one (hereinafter referred to as 10 desired compound), particularly, d-cis form thereof is a medicinal compound useful as a coronary vasodilator and an anti-hypertensive agent. Hitherto, there have been known some processes for preparing the desired compound.
Examples of these processes are, for instance, (1) a 15 process wherein 3-hydroxy-2,3-dihydlo 5-[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1,5-~enzothiazepin-4(5H)-one (hereinafter referred to as 3-hydroxy compound) is reacted with an acetylating agent such as acetic anhydride with heating to give 3-acetoxy-2,3-dihydro-20 5-[2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to 3-acetoxy compound) according to a conventional method and then the resulting 3-acetoxy compound is treated with ethanolic hydrogen chloride (or methanolic hydrogen 25 chloride) (see Japanese Fx~mined Patent Publication No.
813/1972 and No. 18038/1978), (2) a process wherein the 3-hydroxy compound is reacted with acetic anhydride in the presence of hydrochloric acid in one step (see Japanese Un~x~mine-l Patent Publication No. 132876/1987) and the 30 like.
However, in the process (1), two steps, namely, a step for the acetylation and a step for the formation of hydrochloride, are required to ~e carried out separately, although the acetylation can be suitably carried out in 35 the absence of water. On the other hand, in the process (2), hydrochloric acid must be at first added with cooling '~
20~6129 and then the acetylation is carried out with heating, since heat is generated on the addition of hydrochloric acid (aqueous solution of hydrogen chloride) used as a supplier of hydrogen chloride. The operations in the 5 method (2) are, therefore, complicated. Further, it is always required in the method (2) to use a large exess of acetic anhydride for removing water existing in the reaction system, which is introduced on the addition of hydrochloric acid, since the acetylation cannot be 10 completed in the presence of water.
An object of the invention is to provide a process for simply preparing the desired compound from the 3-hydroxy compound in one step without cooling the reaction system or using a large excess of an acetylating 15 agent.
This and the other objects of the present invention will become apparent from the description hereinafter.
It has now been found that a process for preparing hydrochloride of 3-acetoxy-2, 3-dihydro-5-[ 2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-l, 5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride overcomes the defects of the above-mentioned conventional processes.
DETAILED DESCRIPTION
The above-mentioned process of the present invention is estaUished based upon a novel knowledge that acetyl chloride acts as not only an acetylating agent for 35 the 3-hydroxy compound but also a supplier of hydrogen chloride, resulting in giving the desired compound.
According to the process of the present invention, therefore, the desired compound can be prepared quantitatively without supplying hydrogen chloride separately, using a large excess of an acetylating agent or cooling the reaction system which are needed in conventional processes.
In the process of the present invention, acetic acid or a mixed solvent of acetic acid and acetic anhydride can be suitably used as a solvent. As to the mi xi ng ratio of the mixed solvent, the amount of acetic anhydride may be about one-tenth of the amount of acetic 10 acid or may be increased to several times of the amount of acetic acid. The mixing ratio of the mixed solvent can be appropriately selected according to the reaction temperature or a desired reaction time. The amount of the solvent to be used is not particularly limited and, 15 for example, the amount is sufficiently from about 1 to about 5 parts by weight per part by weight of the 3-hydroxy compound. Suitable amount of acetyl chloride to be used may vary according to the solvent, but are usually within 1 to 20 moles per mole of the 3-hydroxy compound.
20 For example, when only acetic acid is used as the solvent, it is preferred to use acetyl chloride in an amount of more than 1 mole, preferably 1.01 to 10 moles, more preferably 1.05 to 1.5 moles, per mole of the 3-hydroxy compound. On the other hand, when a mixture of acetic 25 acid and acetic anhydride is used as the solvent, it is preferred to use acetyl chloride in an amount of not less than 1 mole, preferably 1 to 5 moles, more preferably 1 to 1.5 moles, per mole of the 3-hydroxy compound.
The process of the present invention can be 30 carried out at from a low temperature with cooling, for instance 5C, to a high temperature with heating, for instance 130C, preferaUy from the room temperature to a refluxing temperature. Especially, when only acetic acid is used as the solvent, it is preferred to carry out the 35 process at 10 to 110C, more preferably 40 to 80C. On the other hand, when a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to carry out the process at 5 to 130C, more preferably 10 to In case that a mixed solvent of acetic acid and acetic anhydride is used in the present invention, the reaction is accelarated and the solvent is prevented from 5 freezing when temperature lowering.
With respect to the 3-hydroxy compound which is the starting material of the present invention, there are four stereoisomers owing to asymmetric carbon atoms at the 2-position and the 3-position. Since the process of the 10 present invention can be carried out without racemization, the desired compound having an optical activity can be obtained from the 3-hydroxy compound having the corresponding optical activity.
Isolation of the desired compound after the 15 completion of the reaction can be easily carried out according to the conventional methods such as recrystallization after distilling the reaction solvent away.
As indicated in the following Examples, 20 according to the process of the present invention, the desired compound can be obtained in a high yield in one step without carrying out another step to obtain the hydrochloride after the acetylation or ~ ling hydrochloric acid to a reaction system, since acethyl chloride acts as 25 not only an acetylating agent but also a supplier of hydrogen chloride.
The process of the present invention, therefore, has an industrially excellent advantage that the desired compound can be obtained by a simple operation in a high 30 yield, compared with other conventional methods. For example, while two steps, namely a step for the acetylation and a step for the formation of the hydrochloride, are required to be carried out separetely in the process ( 1) described in Japanese F.x~min~l Patent 35 Publication No. 813/1972 and No. 13038/1978, the desired compound can be obtained in one step in the present invention. Further, while a large excess of acetic anhydride is required to be used in order to remove water existing in the reaction system, which is intruduced on the addition of hydrochloric acid (aqueous solution of hydrogen chloride), from the reaction system in the process (2) described in Japanese Unex~mine-l Patent 5 Publication No. 132876/1987, only 1 mole or a little more than 1 mole of acetyl chloride per mole of the 3-hydroxy compound may be sufficiently used in the present invention, which does not require the addition of hydrochloric acid with cooling, to obtain the desired 10 compound in a high yield.
The present invention is more specifically described and explained by means of the following Experimental ~mples and Examples. It is to be understood that the present invention is not limited to 15 the Ex~mples, and various changes and modifications may be made in the invention without departing from the sprit and scope thereof.
Experimental Example 1 [ Effect of a solvent for the acetylation on conversion 20 rate]
In 200 ml of each solvent described in Table 1 were mixed 25 g of the d-cis-3-hyd~o~y compound and 5.8 g of acetyl chloride ( 1.1 moles per mole of the d-cis-3-hydroxy compound) and each mixture was stirred at 30C for 2 5 2 hours. Conversion rate to the desired compound was determined by high performance liquid chromatography. The results are shown in the following Table 1. When acetic acid or a mixed solvent of acetic acid and acetic anhydride was used, the desired compound was obtained in a 3 o significantly high conversion rate compared with those in case of using other solvents.
Table 1 Solvent Conversion rate to the desired compound Solvents used Acetic acid 95 %
in the present invention Mixed solvent A 99.98 % ~2) Mixed solvent B 100 % ~2) Acetic anhydride 33 % ~2) Other Chloroform 78 %
solvents (Reference) Methylene chloride 70 %
Dichloroethane 77 %
Acetone 51 %
Trichloroethane 66 %
Toluene 78 %
Mixed solvent A: acetic acid: acetic anhydride = 1: 1 Mixed solvent B: acetic acid: acetic anhydride = 1: 3 ~2) The used amount of acetyl chloride was 1.2 moles per mole of the d-cis-3-hydroxy compound and the reaction system was stirred at 60C for 3 hours.
Example 1 In 15 ml of acetic acid was dissolved 7.45 g (0.02 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[ 2-35 (dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-thiazepin-4(5H)-one with heating. Then thereto was added 1.71 g (0.022 mole) of acetyl chloride at 20C and the mixture was stirred at room temperature for 72 hours.
After the reaction, acetic acid was distilled away and the residue was recrystallized from ethanol to give 7.53 g of hydrochloride of d-cis-3-acetoxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-thiazepin-4(5H)-one.
yield: 83 %
m.p.: 213 - 214~C
Example 2 The procedure of Example 1 was repeated except that the reaction was carried out at 70 - 80 C for 3 hours with stirring and 97 % ethanol was used for the recrystallization to give 8. 4 5 g of hydrochloride of the d-cis-3-acetoxy compound.
yield: 9 4 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
F.Y~mrle 3 The procedure of Example 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2, 3-dih~ o 5~ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one and 12. 7 25 g (0.16 mole) of acetyl chloride were used. The reaction was carried out at 60~ for 3 hours with stirring in a mixed solvent of 81 ml of acetic acid and 19 ml of acetic anhydride and 97 % ethanol was used for the recrystallization. Thus 55.9 g of the hydrochloride of 30 the d-cis-3-acetoxy compound was obt~ine i yield: 92 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1 Example 4 The procedure of FY~mple 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of 20561~9 d-cis-3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 10.8 g (0.13 mole) of acetyl chloride were used. The reaction was carried out at 100 - 110C for 6 hours with stirring 5 in a mixed solvent of 50 ml of acetic acid and 50 ml of acetic anhydride and 9 7 % ethanol was used for the recrystallization. Thus 53.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
yield: 89 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
Example 5 The procedure of Example 1 was repeated except for followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acethyl chloride were used. The reaction 20 was carried out at 60C for 3 hours with stirring in a mixed solvent of 25 ml of acetic acid and 75 ml of acetic anhydride and 9 7 % ethanol was used for the recrystallization. Thus 54.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
yield: 90.4 %
Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
Claims (5)
1. A process for preparing hydrochloride of 3-acetoxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)- 1, 5-benzothiazepine-4 ( 5H)-one which comprises reacting 3-hydroxy-2, 3-dihydro-5-[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride.
2. The process of Claim 1, wherein 1 to 20 moles of acetyl chloride is used per mole of a 3-hydroxy-1,5-benzothiazepine derivative which is a starting material.
3. The process of claim 1, wherein the reaction is carried out in acetic acid by using 1.01 to 10 moles of acetyl chloride per mole of a 3-hydroxy-1, 5-benzothiazepine derivative which is a starting material.
4. The process of claim 1, wherein the reaction is carried out in a mixed solvent of acetic acid and acetic anhydride by using 1 to 5 moles of acetyl chloride per mole of a 3-hydroxy-1, 5-benzothiazepine derivative which is a starting material.
5. The process of Claim 1, 2, 3 or 4 wherein d-cis form of 3-hydroxy- 1, 5-benzothiazepine derivative is used as a starting material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2326010A JPH04197837A (en) | 1990-11-29 | 1990-11-29 | Event-driven type computer for controlling vehicle |
| JP336010/1990 | 1990-11-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2056129A1 CA2056129A1 (en) | 1992-05-30 |
| CA2056129C true CA2056129C (en) | 1996-10-15 |
Family
ID=18183089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002056129A Expired - Lifetime CA2056129C (en) | 1990-11-29 | 1991-11-28 | Process for preparing 1,5-benzothiazepine derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH04197837A (en) |
| CA (1) | CA2056129C (en) |
-
1990
- 1990-11-29 JP JP2326010A patent/JPH04197837A/en active Pending
-
1991
- 1991-11-28 CA CA002056129A patent/CA2056129C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04197837A (en) | 1992-07-17 |
| CA2056129A1 (en) | 1992-05-30 |
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