JPH0354939B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula () (2S,3S)-3-acetoxy-5-(N,N-
The present invention relates to a new method for producing dimethylamino-ethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)one and its acid addition salt. The compound of formula () by its generic name diltiazem is a cardiac drug with calcium antagonist activity. In many methods of producing diltiazem known in the art, it is produced in more reaction steps by the reaction of 2-amino-thiophenol and transmethyl 3-(4-methoxyphenyl)-oxirane-2-carboxylate. expression () (2S,3S)-3-(2-aminophenyl-thio)
-2-hydroxy-3-(4-methoxyphenyl)
-propionic acid or the formula prepared from it () (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is used as starting material. According to certain methods of preparing compounds of formula (), for example Hungarian Patent No. 159671 (Belgium Patent No. 723035) and the publication Pharmaceutical Journal
93, 729 (1973) and Helv. Chim. Acta 67 , 916 (1984), the racemate of the compound of formula () is first treated with an alkali metal hydride, preferably sodium hydride. The resulting salt is converted into a 2-dimethylaminoethyl halide, preferably 2-dimethylaminoethyl chloride.
Alkylated with dimethyl-aminoethyl and then obtained as a racemic compound of formula () 5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-
ion was acetylated with acetic anhydride. According to the example,
The yield of the alkylation step varies over a wide range (12.4% to 84%
%) and its technical realization was accompanied by many difficulties. Equimolar amounts of sodium hydride are required to bring the compound of formula () into the anionic form and to bind the chloride ion. Because of its flammability, sodium hydride can be mixed with mineral oil (40% to 50%
%) stored under. The presence of traces of mineral oil in the reaction mixture is therefore unavoidable. Traces of oil are present in the resulting 5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3
-dihydro-1,5-benzothiazepine-4
The (5H)-one can only be removed by introducing it into the aqueous phase in the form of its salt. Another disadvantage of the reaction is the use of 2-dimethylaminoethyl chloride in the alkylation step, which is added to an anhydrous organic solution due to the aforementioned properties of sodium hydride. 2-dimethylaminoethylethyl chloride is
They are known to be prone to self-quaternization (during "head-to-tail" reactions), which poses a difficult problem on a large scale. This is because the products of the quaternization reaction precipitate from solutions prepared with ether solutions or other inert solvents, thereby shifting the reaction towards by-product formation. As mentioned above and according to the above reference, the compound of formula () is converted to the final product of formula () with acetic anhydride at 90° to 100°C. Although this process appears to be without any difficulties, the yields obtained are only 80%-84%, and problems with regeneration of reactants used in excess are made more difficult by the presence of acetic acid. It can be seen from this that even this process does not fully meet the requirements of the developed industrially applicable operation. Compounds of formula () are also used as starting materials in European Patent Application No. 81234. In the first step, a compound of formula () was reacted with acetyl chloride in pyridine. The reaction time is long (one night), and the formula () 3-acetoxy-2(4-methoxyphenyl)-
2,3-dihydro-1,5-benzothiazepine-
4(5H)-one was formed in 71% yield. The desired final product was then prepared by alkylation of the latter compound with 2-dimethylaminoethyl chloride hydrochloride in acetone in the presence of potassium carbonate. The disadvantage of this procedure is that the acetylation is carried out in pyridine, an expensive and toxic solvent, and the reaction time is rather long. Furthermore, the use of highly hygroscopic 2-dimethylaminoethyl chloride hydrochloride would cause many technical problems, such as inaccuracies in the weighing of reactants. Propionic acid derivatives of formula () or their salts formed with pyridine, tertiary amines, alkali metals or alkaline earth metals can be prepared in the process disclosed in published Japanese Patent Application No. 571,365-81. It was used as a starting material. More specifically, acetylation of any of the above salts with acetic anhydride in dimethylformamide gave an acetyl derivative of formula (), which was then purified by chromatography. The intermediate of formula () is then converted to the final product of formula () by an ethereal solution of 2-dimethylaminoethyl chloride in dimethyl sulfoxide in the presence of sodium hydride and silica gel in a yield of 77.
Converted in %. In addition to the chromatographic purification, further disadvantages of this method are the use of hazardous substances (pyridine, dimethyl sulfoxide, sodium hydride) and solvent mixtures. The object of the present invention is (2S,3S)-3-acetoxy-5-(N,N-dimethylaminoethyl)-2-
(4-methoxy-phenyl)-2,3-dihydro-
The object of the present invention is to provide a new method for the preparation of 1,5-benzothiazepin-4(5H)-one and its acid addition salts, preferably its hydrochloride, by which these compounds can be prepared using easily obtainable materials, less hazardous reactants, and in better yields without the problems mentioned with respect to the operation. The inventors have determined that both the compound of formula () and the compound of formula () can be prepared by simply using 2-dimethylaminoethanol mesylate hydrochloride as the alkylating agent, as described above with respect to previously known alkylation operations. It has been experimentally found that the alkylation can be carried out without difficulty and in excellent yields. This compound was prepared using methanesulfonic acid chloride from 2-dimethylamino-ethanol, which is more readily and safely available than 2-dimethylaminoethyl chloride hydrochloride, following procedures known in the art for its preparation. , can be manufactured [see Organic Synthesis [Org. Synt.] 31 37 (151)]. Dimethylaminoethanol mesylate hydrochloride is prepared by methods known in the art [J.Med.Chem. 9 , 344 (1966)], but by
However, they are prepared in ethereal solvents, such as diethyl ether, diisopropyl ether or tetrahydrofuran. This is because dimethylaminoethanol mesylate hydrochloride can be obtained with higher purity in this method. A further advantage is that this dimethylaminoethanol mesylate hydrochloride is not hygroscopic and therefore its storage and handling is easier than with alkylating agents known in the art. Furthermore, the inventors have found that the drawbacks associated with previously known acetylation reactions can be avoided by using isopropenyl acetate as the acetylating agent in the presence of an acid catalyst. By using this reactant, the corresponding acetyl derivatives can be prepared virtually quantitatively in a very short time from both compounds of formula () and compounds of formula (). The invention is therefore characterized in that the following alkylation is carried out with 2-dimethylaminoethanol mesylate hydrochloride and/or the following acetylation is carried out with isopropenyl acetate: a) In any order, the formula ( ) (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5
-benzothiazepine-4(5H)-one is alkylated and acetylated, or b) formula () of 3-acetoxy-2-(4-methoxy-phenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and, if desired, the resulting formula () By converting the compound of formula () into its acid addition salt (2S,3S)-3-acetoxy-5-(N,N
-Dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its acid addition salt. According to a preferred embodiment of the process of the invention, a compound of formula () is prepared starting from a compound of formula () and in the alkylation step 2
-Dimethylaminoethanol mesylate hydrochloride is used as alkylating agent, while acetylation is carried out with isopropenyl acetate in the presence of an acid catalyst. According to a variant of this procedure in the first step, the alkylation is carried out with the abovementioned reactants and the compound obtained is then acetylated with isopropenyl acetate or in the presence of an acid catalyst of the formula ( )
The compound is first acetylated with isopropenyl acetate and then the resulting compound is further reacted with 2-dimethylaminoethanol mesylate hydrochloride. As acid catalyst it is possible to use, for example, sulfonic acids, preferably methanesulfonic acid or p-toluene-sulfonic acid. The present invention enables O-
It is based on the discovery that acetylation can be carried out using isopropenyl acetate, the enol acetate of acetone. Furthermore, it has been found that the N,N-dimethylaminoethyl group can be easily formed with 2-dimethylaminoethanol mesylate hydrochloride, which is easy to prepare and has no unpleasant properties. The yield of the reaction is high. According to a particularly preferred embodiment of the reaction, 1 mol of a compound of formula () is alkylated with 1.2 mol to 2 mol of 2-dimethyl-aminoethanol mesylate hydrochloride in acetone in the presence of potassium carbonate under reflux. Thereafter, the inorganic substances and acetone are removed and a chlorinated hydrocarbon, preferably dichloroethane, is prepared in the presence of methanesulfonic acid or p-toluene-sulfonic acid, preferably using 1 molar equivalent of the latter compound. The compound of formula () obtained in solution was added to isopropenyl acetate 2
mol ~ 3.2 mol, acetylates. the product,
It is isolated as its hydrochloride salt. According to another particularly preferred embodiment of the process according to the invention, 1 mole of a compound of formula Acetylation occurs between 2 mol and 2.2 mol. The solvent is removed and the product obtained is then treated with concentrated ammonium hydroxide. The resulting compound of formula () is then alkylated with 1.2 to 2 moles of 2-dimethylaminoethanol mesylate hydrochloride as described above. The product is isolated in its hydrochloride form. The most important advantages of the method according to the invention are: - No special equipment is required. - The final product is obtained in high purity with good yield using simple techniques and readily available reactants. - There is no need to isolate intermediates during the reaction. - When carrying out the reaction, no hazardous reactants or solvents with unpleasant properties are used. Further details of the method according to the invention are illustrated by the following non-limiting examples. Example 1 1.5 g (0.005 mol) of (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one was added to a 50 cm ³ weighed into a round bottom flask and then dissolved in 15 cm ³ of dioxane, followed by 0.15 g of p-toluene-sulfonic acid and 1.1 g of isopropenyl acetate (1.2
cm ³ , 0.011 mol) is added to the solution. The reaction mixture is
While stirring, reflux for 1 hour, evaporate in vacuo,
The residue was then diluted with 5 cm ³ of concentrated ammonium hydroxide aqueous solution.
Grind with. The obtained (2S,3S)-3-acetoxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was filtered off and neutralized. Wash with water and then dry. Yield: 1.71g (99%) Melting point: 150℃~152℃ Example 2 (2S,3S)-3-acetoxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine -4(5H)-one 1.70 g (0.005 mol) was dissolved in 50 cm ³ of acetone and 1.52 g of 2-dimethylaminoethanol mesylate hydrochloride
(0.0075 mol) and potassium carbonate 2.08 g (0.015 mol)
mol) to the solution. The resulting suspension is refluxed for 12 hours with stirring. The insoluble salts which separated out from the reaction mixture on cooling are filtered off and the filtrate is then evaporated. Dissolve the residue in 20 cm ³ of chloroform and add the calculated amount of hydrochloric acid in ethanol to the solution.
The solution is evaporated in vacuo and the residue is crystallized from 15 cm ³ of isopropanol. The crystalline diltiazem hydrochloride is filtered off and then dried. Yield: 1.8g (79.92%) Melting point: 206℃~207℃ Example 3 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine 4.5 g (0.015 mol) of -4(5H)-one were dissolved in 80 cm ³ of acetone and 4.58 g of 2-dimethylaminoethanol mesylate hydrochloride
(0.0225 mol) and potassium carbonate 6.25 g (0.045
mol) to the solution. 12 while stirring the suspension
Reflux for an hour, cool to room temperature and filter off the insoluble material. Evaporate the filtrate and chloroform the residue.
Dissolve in 25 cm ³ and acidify the solution with the calculated amount of hydrochloric acid solution in ethanol. After evaporation, the residue was crystallized from 20 cm ³ of isopropanol to give the crystalline form (2S,3S)-5-(2-dimethylaminoethyl)-
3-hydroxy-2-(4-methoxyphenyl)-
2,3-dihydro-1,5-benzothiazepine-
4(5H)-one hydrochloride is produced. The crystals are then filtered and then dried. Yield: 5.25g (85.68%) Melting point: 225°C to 227°C [α] ²⁰ _D = +176.5° (c = 0.7; chloroform) Example 4 (2S,3S)-5-(2-dimethyl-aminoethyl) 4.08 g (0.01 mol) of -3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride was dissolved in 60 cm ³ of chloroform. , then 3.0 g (3.3 cm ³ , 0.3 mol) of isopropenyl acetate and 2.88 g (1.97 cm ³ , 0.03 mol) of methanesulfonic acid are added to the solution. The solution was then refluxed for 45 minutes, cooled to room temperature,
Then, extract with 31 cm ³ of 1N aqueous sodium hydroxide solution. Dry the organic phase, add the calculated amount of hydrochloric acid solution in ethanol and evaporate the mixture. The residue is crystallized from 20 cm ³ of isopropanol. The precipitated diltiazem hydrochloride crystals are filtered and dried. Yield: 4.0g (88.8%) Melting point: 206°C to 207°C [α] ²⁰ _D = +96° (c = 0.5, methanol) Example 5 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl )-2,3-dihydro-1,5-benzothiazepine-4(5H)-one 3.0 g (0.01 mol)
was dissolved in 80 cm ³ of acetone, then 3.05 g of 2-dimethylaminoethanol mesylate hydrochloride
(0.015 mol) and 4.17 g (0.03 mol) of potassium carbonate are added to the solution. The resulting suspension is refluxed for 12 hours with stirring. After cooling, the insoluble material is filtered off and the filtrate is then evaporated in vacuo. The residual oil is dissolved in 30 cm ³ of dichloroethane and 2.2 g (2.42 cm ³ , 0.022 mol) of isopropenyl acetate and 2.11 g (1.42 cm ³ , 0.022 mol) of methanesulfonic acid are added to the solution. Boil the solution for 45 minutes, cool, and add 1n
Extract with 22 cm ³ of aqueous sodium hydroxide solution. The organic phase is dried, evaporated and the residue is crystallized from 20 cm ³ of isopropanol. The precipitated diltiazem hydrochloride crystals are filtered and then dried. Yield: 3.21g (71.3%) Melting point: 210°C to 211°C [α] ²⁰ _D = +95.81° (c = 0.4, methanol) Example 6 Production of 2-dimethylaminoethanol mesylate hydrochloride 2-dimethylaminoethanol 8.9g ( ^10.2cm3 ,
0.1 mol) in 100 cm ³ of diisopropyl ether and then, with stirring, 12.68 g (8 cm ³ , 0.11 mol) of methanesulfonic acid chloride at a temperature of 0°C to 5°C.
mol) dropwise into the solution. After stirring for a further 10 minutes, the product is filtered off. The wet material is recrystallized from 25 cm ³ of ethanol and dried at room temperature. Yield: 14.5g (72.74%) Melting point: 126℃~127℃

Claims (1)

[Scope of Claims] 1. characterized in that the following alkylation is carried out with 2-dimethylamino-ethanol mesylate hydrochloride and/or the following acetylation is carried out with isopropenyl acetate, a) in any order of the formula () (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5
-benzo-thiazepin-4(5H)-one is alkylated and acetylated, or b) formula () of 3-acetoxy-2-(4-methoxy-phenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and, if desired, the resulting formula () By converting the compound into its acid addition salt, the formula () (2S,3S)-3-acetoxy-5-(N,N
A method for producing -dimethylaminoethyl)-2-(4-methoxy-phenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its acid addition salt. 2 A compound of formula () is alkylated with 2-dimethylaminoethanol mesylate hydrochloride, and the resulting formula () 2. A method according to claim 1, characterized in that the compound is reacted with an acetylating agent. 3. Alkylating a compound of formula () with a reactive derivative of 2-dimethylaminoethanol and acetylating the resulting compound of formula () with isopropenyl acetate in the presence of an acid catalyst, A method according to claim 1. 4. Claim 1, characterized in that the compound of formula () is reacted with an acetylating agent and the resulting compound of formula () is alkylated with 2-dimethylaminoethanol mesylate hydrochloride.
The method described in section. 5. Acetylation of a compound of formula () with isopropenyl acetate in the presence of an acid catalyst, and then alkylation of the resulting compound of formula () with a reactive derivative of 2-dimethylamino-ethanol, A method according to claim 1. 6. Claims characterized in that the compound of formula () is alkylated with 2-dimethylaminoethanol mesylate hydrochloride and the compound of formula () obtained in the presence of an acid catalyst is acetylated with isopropenyl acetate. The method described in item 1 of the scope. 7. Acetylating a compound of formula () with isopropenyl acetate in the presence of an acid catalyst, and then alkylating the resulting compound of formula () with 2-dimethylaminoethanol mesylate hydrochloride, A method according to claim 7. 8 1 mole of the compound of formula () is alkylated with 1.2 to 2 moles of 2-dimethylaminoethanol mesylate hydrochloride and in the presence of an acid catalyst, preferably methane-sulfonic acid or p-toluene-sulfonic acid, the obtained 7. The method according to claim 1, wherein the compound of formula () is acetylated with 2 to 3.2 mol of isopropenyl acetate. 9 In the presence of an acid catalyst, preferably methane-sulfonic acid or p-toluene-sulfonic acid, the formula ()
1 mole of the compound is converted into 2 moles of isopropenyl acetate ~
Acetylated with 2.2 mol and then the resulting formula ()
6. Process according to claim 1, characterized in that the compound of 2-dimethylamino-ethanol mesylate hydrochloride is alkylated with 1.2 to 2 mol of 2-dimethylamino-ethanol mesylate hydrochloride.