CA2015182C - Processes for preparing 1,5-benzothiazepine derivatives - Google Patents
Processes for preparing 1,5-benzothiazepine derivativesInfo
- Publication number
- CA2015182C CA2015182C CA 2015182 CA2015182A CA2015182C CA 2015182 C CA2015182 C CA 2015182C CA 2015182 CA2015182 CA 2015182 CA 2015182 A CA2015182 A CA 2015182A CA 2015182 C CA2015182 C CA 2015182C
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- preparing
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- benzothiazepine
- formula
- iii
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There is disclosed a process for preparing 1,5-benzothiaze-pine derivatives represented by the formula:
(I) wherein R is a lower alkyl group, which comprises subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group.
(I) wherein R is a lower alkyl group, which comprises subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group.
Description
Process for preparing 1,5-benzothiazepine derivatives BACKGROUND OF THE INVENTION
This invention relates to a novel process for preparing 1,5-benzothiazepine derivatives represented by the formula:
~ OR
OH (I) H O
wherein R represents a lower alkyl group.
The above 1,5-benzothiazepine derivatives (I) are useful compounds as an intermediate for the synthesis of medical compounds, for example, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(~-dimethylaminoethyl)-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one (generic name: Diltiazem) having excellent coronary vasodilating activity.
Heretofore, as a process for preparing 1,5-benzothiazepine derivatives (I), for example, the method in which 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid is ~.
20151~2 subjected to intramolecular ring closing reaction in xylene under reflux (Japanese Patent Publication No.
18038/1978) has been known. However, this method is disadvantageous in that a long time (12 hours in Examples of the above publication) is required for completing the reaction.
SUMMARY OF THE INVENTION
The present inventors have studied various research and as a result, they have found that, when the intramolecular ring closing reaction of a specific propionic acid com-pound (II) is carried out in the presence of a specific sulfonic acid compound, the reaction time can be remark-ably shortened and the compound (I) can be prepared ingood yield.
That is, according to the process of the present inven-tion, the desired product represented by the formula (I) can be prepared by subjecting a propionic acid derivative represented by the formula (II):
~ OR
~ ~ (II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
RlSO3H (III) wherein Rl represents a lower alkyL group or a sub-stituted or unsubstituted phenyl group.
20151~2 DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of the sulfonic acid compound (III) to be used in the intramolecular ring closing reaction of the present invention include, for example, the compounds wherein in the formula (III) is an alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group or butyl group or a phenyl group which may be substi-tuted by at least one of these alkyl groups. Of these, more preferred are methanesulfonic acid and p-toluenesul-fonic acid. An amount of the said sulfonic acid is not particularly limited but generally, it is preferably used at an amount of 0.5 to 10 w/w ~, more preferably about 1 to 6 w/w ~ based on the compound (II).
The above reaction is preferably carried out in a high boiling point solvent such as xylene, toluene, etc. under reflux.
The desired compound (I) formed can be isolated as a pure product containing no sulfonic acid compound (III) by simple and easy operations as, for example, cooling the reaction mixture, collecting precipitated crystals by filtration, and washing them with a suitable solvent (e.g.
ethanol, aqueous ethanol, etc.).
The thus obtained compound (I) can be converted to the corresponding 3-acetoxy-5-(~-dimethylaminoethyl)-1,5-benzo-thiazepine derivatives represented by the formula:
~ OR
OCOCH3 (IV) \CH3 wherein R has the same meaning as defined above, or a pharmaceutically acceptable salt thereof in a known method, for example, in a method described in Japanese Patent Publications (examined) No. 18038/1978 and No. -43785/1971 and U.S. Patents No. 3,562,257 and No.
4,438,035.
According to the process of the present invention as mentioned above, a time required for the intramolecular ring closing reaction can be markedly shortened and the desired compound can be obtained in high yield and high purity. Therefore, the process of the present invention is extremely excellent as the industrial process.
Throughout the specification and claims, the term "lower alkyl" should be interpreted as referring to an alkyl having one to four carbon atoms.
Experimental example For forming (I)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-di-hydro-1,5-benzothiazepin-4(5H)-one by refluxing by heating 12.75 g of (~)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid in 52 ml of xylene or toluene, under continuous removal of formed water, the effects of presence of a sulfonic acid compound in the reaction system were examined. The results are shown in Tables 1 and 2.
In the tables, the amount of the sulfonic acid compound is based on the starting compound, and p-toluenesulfonic acid is used as a monohydrate.
X
Table 1 (in xylene) SulfonicAmount . Yield of Reactlon deslred acld used time product 5.4 30 min 94 p-Toluene- 2.7 60 min 93.9 Process Of thiS acid 1.1 1 hr & 95.5 lnven- 15 mln tion 0.6 15 min 95.4 fonic acid 5-4 45 min 93 Con- 12 hrs 82.2 *: Control is Example described in Japanese Patent Publication No. 18038/1978 Table 2 (in toluene) Sulfonic Amount Reaction desired acld used time product compound (w/w %) Process p-Toluenesul- 5 4 5 hrs 92 inven- Methanesul- 5.4 5 hrs 92 tion fonic acld trol 7 hrs < 50 As seen from the above Table 1 and Table 2, it can be understood that by the existance of p-toluenesulfonic acid or methanesulfonic acid in the reaction system, the desir-ed product can be obtained within extremely short time in good yield.
Example 1 A mixture of 12.75 g of (~)-threo-2-hydroxy-3-(2-amino-phenylthio)-3-(4-methoxyphenyl)propionic acid, 140 mg of p-toluenesulfonic acid monohydrate and 52 ml of xylene is refluxed by heating for about 1 hour and 15 minutes.
During the reaction, water formed is continuously removed.
After cooling, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11.5 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Yield: 95.5 %
m.p.: 203 to 204 C
[a]Do + 116 (c = 0.5, dimethylformamide) Example 2 A mixture of 12.75 g of (+)-threo-2-hydroxy-3-(2-amino-phenylthio)-3-(4-methoxyphenyl)propionic acid, 690 mg of p-toluenesulfonic acid monohydrate and 52 ml of toluene is refluxed by heating for about 5 hours. During the reac-tion, water formed is continuously removed. After cool-ing, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Yield: 92 ~
m.p.: 203 to 204.5 C
[alD + 118 (c = 0.5, dimethylformamide)
This invention relates to a novel process for preparing 1,5-benzothiazepine derivatives represented by the formula:
~ OR
OH (I) H O
wherein R represents a lower alkyl group.
The above 1,5-benzothiazepine derivatives (I) are useful compounds as an intermediate for the synthesis of medical compounds, for example, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(~-dimethylaminoethyl)-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one (generic name: Diltiazem) having excellent coronary vasodilating activity.
Heretofore, as a process for preparing 1,5-benzothiazepine derivatives (I), for example, the method in which 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid is ~.
20151~2 subjected to intramolecular ring closing reaction in xylene under reflux (Japanese Patent Publication No.
18038/1978) has been known. However, this method is disadvantageous in that a long time (12 hours in Examples of the above publication) is required for completing the reaction.
SUMMARY OF THE INVENTION
The present inventors have studied various research and as a result, they have found that, when the intramolecular ring closing reaction of a specific propionic acid com-pound (II) is carried out in the presence of a specific sulfonic acid compound, the reaction time can be remark-ably shortened and the compound (I) can be prepared ingood yield.
That is, according to the process of the present inven-tion, the desired product represented by the formula (I) can be prepared by subjecting a propionic acid derivative represented by the formula (II):
~ OR
~ ~ (II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
RlSO3H (III) wherein Rl represents a lower alkyL group or a sub-stituted or unsubstituted phenyl group.
20151~2 DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of the sulfonic acid compound (III) to be used in the intramolecular ring closing reaction of the present invention include, for example, the compounds wherein in the formula (III) is an alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group or butyl group or a phenyl group which may be substi-tuted by at least one of these alkyl groups. Of these, more preferred are methanesulfonic acid and p-toluenesul-fonic acid. An amount of the said sulfonic acid is not particularly limited but generally, it is preferably used at an amount of 0.5 to 10 w/w ~, more preferably about 1 to 6 w/w ~ based on the compound (II).
The above reaction is preferably carried out in a high boiling point solvent such as xylene, toluene, etc. under reflux.
The desired compound (I) formed can be isolated as a pure product containing no sulfonic acid compound (III) by simple and easy operations as, for example, cooling the reaction mixture, collecting precipitated crystals by filtration, and washing them with a suitable solvent (e.g.
ethanol, aqueous ethanol, etc.).
The thus obtained compound (I) can be converted to the corresponding 3-acetoxy-5-(~-dimethylaminoethyl)-1,5-benzo-thiazepine derivatives represented by the formula:
~ OR
OCOCH3 (IV) \CH3 wherein R has the same meaning as defined above, or a pharmaceutically acceptable salt thereof in a known method, for example, in a method described in Japanese Patent Publications (examined) No. 18038/1978 and No. -43785/1971 and U.S. Patents No. 3,562,257 and No.
4,438,035.
According to the process of the present invention as mentioned above, a time required for the intramolecular ring closing reaction can be markedly shortened and the desired compound can be obtained in high yield and high purity. Therefore, the process of the present invention is extremely excellent as the industrial process.
Throughout the specification and claims, the term "lower alkyl" should be interpreted as referring to an alkyl having one to four carbon atoms.
Experimental example For forming (I)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-di-hydro-1,5-benzothiazepin-4(5H)-one by refluxing by heating 12.75 g of (~)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid in 52 ml of xylene or toluene, under continuous removal of formed water, the effects of presence of a sulfonic acid compound in the reaction system were examined. The results are shown in Tables 1 and 2.
In the tables, the amount of the sulfonic acid compound is based on the starting compound, and p-toluenesulfonic acid is used as a monohydrate.
X
Table 1 (in xylene) SulfonicAmount . Yield of Reactlon deslred acld used time product 5.4 30 min 94 p-Toluene- 2.7 60 min 93.9 Process Of thiS acid 1.1 1 hr & 95.5 lnven- 15 mln tion 0.6 15 min 95.4 fonic acid 5-4 45 min 93 Con- 12 hrs 82.2 *: Control is Example described in Japanese Patent Publication No. 18038/1978 Table 2 (in toluene) Sulfonic Amount Reaction desired acld used time product compound (w/w %) Process p-Toluenesul- 5 4 5 hrs 92 inven- Methanesul- 5.4 5 hrs 92 tion fonic acld trol 7 hrs < 50 As seen from the above Table 1 and Table 2, it can be understood that by the existance of p-toluenesulfonic acid or methanesulfonic acid in the reaction system, the desir-ed product can be obtained within extremely short time in good yield.
Example 1 A mixture of 12.75 g of (~)-threo-2-hydroxy-3-(2-amino-phenylthio)-3-(4-methoxyphenyl)propionic acid, 140 mg of p-toluenesulfonic acid monohydrate and 52 ml of xylene is refluxed by heating for about 1 hour and 15 minutes.
During the reaction, water formed is continuously removed.
After cooling, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11.5 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Yield: 95.5 %
m.p.: 203 to 204 C
[a]Do + 116 (c = 0.5, dimethylformamide) Example 2 A mixture of 12.75 g of (+)-threo-2-hydroxy-3-(2-amino-phenylthio)-3-(4-methoxyphenyl)propionic acid, 690 mg of p-toluenesulfonic acid monohydrate and 52 ml of toluene is refluxed by heating for about 5 hours. During the reac-tion, water formed is continuously removed. After cool-ing, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Yield: 92 ~
m.p.: 203 to 204.5 C
[alD + 118 (c = 0.5, dimethylformamide)
Claims (8)
1. A process for preparing 1,5-benzothiazepine deriva-tives represented by the formula:
(I) wherein R is a lower alkyl group, which comprises subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group.
(I) wherein R is a lower alkyl group, which comprises subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group.
2. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 1, wherein R1 in the the sulfonic acid compound (III) is methyl group, ethyl group, propyl group, butyl group or phenyl group which may be substi-tuted by at least one group selected from methyl group, ethyl group, propyl group and butyl group.
3. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 2, wherein the sulfonic acid compound (III) is methanesulfonic acid or p-toluenesul-fonic acid.
4. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the reaction is carried out in a high boiling point solvent at the reflux temperature of the solvent.
5. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 4, wherein the solvent is selected from xylene, toluene, dichlorobenzene and a mixture thereof.
6. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 1, wherein the sulfonic acid (III) is used at an amount of 0.5 to 10 w/w % based on the compound (II).
7. A process for preparing 1,5-benzothiazepine deriva-tives according to Claim 6, wherein the sulfonic acid (III) is used at an amount of 1 to 6 w/w % based on the propionic acid compound (II).
8. A process for preparing 3-acetoxy-5-(.beta.-dimethylamino-ethyl)-1,5-benzothiazepine derivatives represented by the formula: -(IV) wherein R is a lower alkyl group, or a pharmaceutically acceptable salt thereof which com-prises the sptes of:
subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group, to give a compound represented by the formula:
(I) wherein R has the same meaning as defined above, and converting the compound (I).to the corresponding 3-acetoxy-5-(.beta.-dimethylaminoethyl)-1,5-benzothiazepine derivative by N-.beta.-dimethylaminoethylation and O-acetylation, and if necessary, followed by converting the product into a pharmaceutically acceptable salt thereof.
subjecting a propionic acid compound represented by the formula:
(II) wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula:
R1SO3H (III) wherein R1 represents a lower alkyl group or a sub-stituted or unsubstituted phenyl group, to give a compound represented by the formula:
(I) wherein R has the same meaning as defined above, and converting the compound (I).to the corresponding 3-acetoxy-5-(.beta.-dimethylaminoethyl)-1,5-benzothiazepine derivative by N-.beta.-dimethylaminoethylation and O-acetylation, and if necessary, followed by converting the product into a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP109795/1989 | 1989-04-28 | ||
| JP1109794A JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
| JP1109795A JPH0798813B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2015182A1 CA2015182A1 (en) | 1990-10-28 |
| CA2015182C true CA2015182C (en) | 1996-12-10 |
Family
ID=26449514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2015182 Expired - Lifetime CA2015182C (en) | 1989-04-28 | 1990-04-23 | Processes for preparing 1,5-benzothiazepine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2015182C (en) |
-
1990
- 1990-04-23 CA CA 2015182 patent/CA2015182C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2015182A1 (en) | 1990-10-28 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |