Method for preparing diltiazem hydrochloride by one-pot method

Abstract

The invention provides a method for preparing diltiazem hydrochloride by a one-pot process, which comprises the following steps: S1, thionyl chloride, dimethylaminoethanol and d-cis-2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine-4 (5H)-ketone are contacted, and an N-alkylation reaction is carried out, so that deacetyldiltiazem hydrochloride is obtained; s2, enabling a catalyst, an acylating agent and the deacetyldiltiazem hydrochloride to be in contact, and carrying out esterification reaction, so as to obtain diltiazem hydrochloride. According to the preparation method disclosed by the invention, dimethylaminoethanol, thionyl chloride and d-cis-2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine-4 (5H)-ketone are taken as initial raw materials, and meanwhile, the preparation method has the advantages of simplicity in operation, few synthesis steps, mild operation conditions, high synthesis efficiency and the like, and is wide in application range; the method is suitable for large-scale industrial synthesis of diltiazem hydrochloride.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing diltiazem hydrochloride by a one-pot process. Background Art

[0002] As an important drug intermediate, the traditional synthesis method of diltiazem hydrochloride usually involves multi-step reactions, mainly using p-methoxybenzaldehyde and methyl chloroacetate as raw materials, and completing the synthesis of diltiazem hydrochloride through Darzens condensation, thiolation, hydrolysis, splitting, cyclization, N-alkylation, O-acetylation, salt formation and other steps. However, the traditional synthesis process of diltiazem has problems such as many synthesis steps, low yield, many by-products, great environmental impact, high cost and harsh reaction conditions, which limits its possibility of large-scale production and application.

[0003] Therefore, there is an urgent need to develop a method for preparing diltiazem hydrochloride that is simple to operate, has few synthetic steps, mild operating conditions, high synthetic efficiency, and is suitable for large-scale industrial production, so as to meet the needs of large-scale industrial production of diltiazem hydrochloride. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a method for preparing diltiazem hydrochloride by a one-pot method. The preparation method of the present invention has the advantages of simple operation, fewer synthesis steps, mild operating conditions, high synthesis efficiency, etc., and has a wide range of applications, and is suitable for large-scale industrial synthesis of diltiazem hydrochloride.

[0005] The present invention provides a method for preparing diltiazem hydrochloride. According to an embodiment of the present invention, the method comprises:

[0006] S1: contacting thionyl chloride, dimethylaminoethanol and the compound represented by formula 1 to cause N-alkylation reaction to obtain deacetyl diltiazem hydrochloride;

[0007] S2: contacting the catalyst, the acylating agent and the deacetyl diltiazem hydrochloride to cause an esterification reaction to obtain diltiazem hydrochloride,

[0008]

[0009] The preparation method of the invention uses dimethylaminoethanol, thionyl chloride and the compound shown in Formula 1 as starting materials, and has the advantages of simple operation, fewer synthesis steps, mild operation conditions, high synthesis efficiency, etc., and has a wide application range and is suitable for large-scale industrial synthesis of diltiazem hydrochloride.

[0010] According to an embodiment of the present invention, the above method for preparing diltiazem hydrochloride may also have the following additional technical features:

[0011] According to an embodiment of the present invention, in step S1, the N-alkylation reaction uses a hydrochloric acid alcohol solution to form a salt so as to obtain deacetyl diltiazem hydrochloride.

[0012] According to an embodiment of the present invention, the alcohol hydrochloric acid solution includes ethanol hydrochloric acid and / or methanol hydrochloric acid.

[0013] According to an embodiment of the present invention, the temperature of the salt formation using the hydrochloric acid alcohol solution is -8 to 8° C. and the time is 1 to 4 hours.

[0014] According to an embodiment of the present invention, the catalyst is 4-dimethylaminopyridine and / or 4-pyrrolidinopyridine.

[0015] According to an embodiment of the present invention, the acylating agent includes one or more of anhydride, acyl chloride and α-keto acid.

[0016] According to an embodiment of the present invention, in step S1, the N-alkylation reaction is carried out in a first organic solvent.

[0017] According to an embodiment of the present invention, in step S2, the esterification reaction is carried out in a second organic solvent.

[0018] According to an embodiment of the present invention, the first organic solvent and the second organic solvent include one or more of dichloromethane, ethyl acetate, toluene, tetrahydrofuran and acetonitrile.

[0019] According to an embodiment of the present invention, the molar ratio of the thionyl chloride, the dimethylaminoethanol and the compound represented by Formula 1 is 1.05:(0.5-1.3):(0.1-0.5).

[0020] According to an embodiment of the present invention, the molar ratio of the diltiazem hydrochloride deacetylate, the acylating agent and the catalyst is 1:(1.8-2.7):(0.3-0.5).

[0021] According to an embodiment of the present invention, the temperature of the N-alkylation reaction is 30-60° C., and the time is 0.5-6 hours.

[0022] According to an embodiment of the present invention, the temperature of the esterification reaction is 5 to 50° C., and the time is 0.5 to 6 hours.

[0023] According to an embodiment of the present invention, the method further comprises concentrating and crystallizing the diltiazem hydrochloride;

[0024] According to an embodiment of the present invention, the temperature of the crystallization treatment is 0-10°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0026] Figure 1 The overall synthetic route design diagram of diltiazem hydrochloride in Example 1 of the present invention;

[0027] Figure 2 It is the chemical reaction formula for the overall synthesis of diltiazem hydrochloride in Example 1 of the present invention.

[0028] Figure 3 This is the NMR result of diltiazem hydrochloride prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0029] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0030] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0031] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0032] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0033] The present invention provides a method for preparing diltiazem hydrochloride. According to an embodiment of the present invention, the method comprises:

[0034] S1: contacting thionyl chloride, dimethylaminoethanol and the compound represented by formula 1 to cause N-alkylation reaction to obtain deacetyl diltiazem hydrochloride;

[0035] S2: contacting the catalyst, the acylating agent and the deacetyl diltiazem hydrochloride to cause an esterification reaction to obtain diltiazem hydrochloride,

[0036]

[0037] The preparation method of the invention uses dimethylaminoethanol, thionyl chloride and the compound shown in Formula 1 as starting materials, and has the advantages of simple operation, fewer synthesis steps, mild operation conditions, high synthesis efficiency, etc., and has a wide application range and is suitable for large-scale industrial synthesis of diltiazem hydrochloride.

[0038] According to an embodiment of the present invention, in step S1, the N-alkylation reaction uses a hydrochloric acid alcohol solution to form a salt so as to obtain deacetyl diltiazem hydrochloride. Thus, the solubility and purity of deacetyl diltiazem hydrochloride can be improved by forming a salt with a hydrochloric acid alcohol solution, which is convenient for subsequent separation and purification steps, and further improves the yield and purity of the product, so as to obtain deacetyl diltiazem hydrochloride with a higher yield and purity.

[0039] According to an embodiment of the present invention, the alcoholic hydrochloride solution includes ethanolic hydrochloride and / or methanolic hydrochloride. Thus, using ethanolic hydrochloride and / or methanolic hydrochloride as the alcoholic hydrochloride solution can provide a suitable acidic environment to promote the salt-forming reaction, and the alcoholic solvent helps to dissolve and purify the product, so as to obtain deacetyl diltiazem hydrochloride with higher yield and purity.

[0040] According to an embodiment of the present invention, the temperature of the salt formation using the hydrochloric acid alcohol solution is -8 to 8°C, and the time is 1 to 4 hours. The salt is formed within the temperature and time range, the salt formation efficiency is improved, and deacetyl diltiazem hydrochloride with a higher yield and purity is obtained. Exemplarily, the temperature of the salt formation using the hydrochloric acid alcohol solution is -8°C, -4°C, 0°C, 4°C, 8°C, preferably -4 to 4°C, more preferably 0°C; the time of the salt formation using the hydrochloric acid alcohol solution is 1h, 2h, 3h, 4h, preferably 2h.

[0041] According to an embodiment of the present invention, the catalyst is 4-dimethylaminopyridine and / or 4-pyrrolidinylpyridine. Thus, the esterification reaction is accelerated, the time of the entire diltiazem hydrochloride synthesis process is shortened, and the preparation efficiency is improved.

[0042] According to an embodiment of the present invention, the acylating agent comprises one or more of anhydride, acyl chloride and α-keto acid. Thus, an acyl group is provided to synthesize the target product diltiazem hydrochloride.

[0043] According to an embodiment of the present invention, in step S1, the N-alkylation reaction is carried out in a first organic solvent. Thus, with the assistance of the organic solvent, the reactants are fully contacted, the reaction is promoted, the preparation efficiency is improved, and the target product with higher yield and purity is obtained.

[0044] According to an embodiment of the present invention, in step S2, the esterification reaction is carried out in a second organic solvent. Thus, with the assistance of the organic solvent, the reaction substances are fully contacted, the reaction is promoted, the preparation efficiency is improved, and the target product with higher yield and purity is obtained.

[0045] According to an embodiment of the present invention, the first organic solvent and the second organic solvent include one or more of dichloromethane, ethyl acetate, toluene, tetrahydrofuran and acetonitrile. Thus, the first organic solvent and the second organic solvent are variously selected, and different organic solvents are selected according to different application scenarios to promote the reaction, improve the preparation efficiency, and obtain the target product with higher yield and purity.

[0046] According to an embodiment of the present invention, the molar ratio of the thionyl chloride, the dimethylaminoethanol and the compound shown in Formula 1 is 1.05: (0.5-1.3): (0.1-0.5). Thus, by precisely controlling the molar ratio of the reactants, the efficiency of the N-alkylation reaction and the yield of the product are optimized, the stoichiometric control of the reaction and the completeness of the reaction are ensured to obtain a high yield and purity of diltiazem hydrochloride. Exemplarily, the molar ratio of the thionyl chloride, the dimethylaminoethanol and the compound shown in Formula 1 is 1.05: 0.5: 0.3, 1.05: 0.7: 0.3, 1.05: 0.9: 0.3, 1.05: 1.1: 0.3, 1.05: 1.3: 0.3, preferably 1.05: (0.75-1): (0.2-0.5), more preferably 1.05: 1: 0.3. According to an embodiment of the present invention, the molar ratio of diltiazem hydrochloride deacetyl, the acylating agent and the catalyst is 1: (1.8-2.7): (0.3-0.5). Thus, by accurately controlling the addition amount of the acylating agent and the catalyst, the selectivity and efficiency of the esterification reaction can be improved, the side reactions can be reduced, and the purity and yield of the target product can be improved to obtain diltiazem hydrochloride with higher yield and purity. Exemplarily, the molar ratio of diltiazem hydrochloride deacetyl, the acylating agent and the catalyst is 1: 1.8: 0.3, 1: 2.4: 0.3, 1: 2.7: 0.3, 1: 1.8: 0.4, 1: 2.4: 0.4, 1: 2.7: 0.4, 1: 1.8: 0.5, 1: 2.4: 0.5, 1: 2.7: 0.5, preferably 1: (1.8-2.7): (0.3-0.5), more preferably 1: 2.5: 0.3.

[0047] According to an embodiment of the present invention, the temperature of the N-alkylation reaction is 30 to 60°C, and the time is 0.5 to 6h. Thus, the N-alkylation reaction is carried out within the temperature range and time range, which can ensure the mildness and efficiency of the reaction, avoid the occurrence of overreaction or side reactions, and ensure the stability and yield of the product to obtain deacetyl diltiazem hydrochloride with higher yield and purity. Exemplarily, the temperature of the N-alkylation reaction is 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, preferably 40 to 50°C, more preferably 45°C; the time of the N-alkylation reaction is 0.5h, 1h, 2h, 3h, 4h, 5h, preferably 1 to 4h, more preferably 4h.

[0048] According to an embodiment of the present invention, the temperature of the esterification reaction is 5 to 50°C, and the time is 0.5 to 6h. Thus, the esterification reaction is carried out within the temperature range and time range, which can ensure the mildness and efficiency of the reaction, avoid the occurrence of overreaction or side reactions, ensure the stability and yield of the product, and obtain a higher yield of diltiazem hydrochloride. Exemplarily, the temperature of the esterification reaction is 5°C, 10°C, 20°C, 30°C, 35°C, 40°C, 45°C, 50°C, preferably 10 to 40°C, more preferably 40°C; the time of the esterification reaction is 0.5h, 1h, 2h, 3h, 4h, 5h, preferably 1 to 4h, more preferably 4h.

[0049] According to an embodiment of the present invention, the method further comprises concentrating and crystallizing the diltiazem hydrochloride. Thus, the diltiazem hydrochloride is further refined through concentration and crystallization to obtain diltiazem hydrochloride with higher purity.

[0050] According to an embodiment of the present invention, the temperature of the crystallization treatment is 0-10°C. Therefore, performing the crystallization treatment within the temperature range can control the crystallization rate and the crystal size, and improve the purity and stability of the diltiazem hydrochloride product. Exemplarily, the temperature of the crystallization treatment is 0°C, 2°C, 5°C, 7°C, 10°C, preferably 5°C;

[0051] As used herein, "DH-SM2" refers to d-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.

[0052] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0053] Example 1: Preparation of diltiazem hydrochloride

[0054] The inventor prepared diltiazem hydrochloride in the following specific steps:

[0055] 1) Add 8.5 mL of thionyl chloride (SOCl2) to a 100 mL three-necked flask, cool to about 0°C, add 10 g of dimethylaminoethanol (DMEA) to the flask using a dropping funnel, add 30 mL of the first organic solvent DCM (dichloromethane) and 5 mL of water after the addition is complete, then add 10 g of d-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one (DH-SM2), heat to 45°C and reflux for 4 hours. After the reaction is complete, separate the liquids to obtain an organic phase. Concentrate the organic phase under reduced pressure, add about 30 mL of methanol to dissolve the concentrate, then drop about 20 mL of ethanolic hydrochloric acid, cool to 0°C, crystallize for about 2 hours, and filter to obtain a white solid, which is deacetyl diltiazem hydrochloride (DH-1).

[0056] 2) Take another 100 mL three-necked flask, add 5 g of DH-1, 0.45 g of catalyst 4-dimethylaminopyridine (DMAP), and 15 mL of the second organic solvent DCM, and stir until dissolved. Then add 3.12 g of acylating agent acetic anhydride (Ac2O), reflux and stir at 40°C for 4 h to obtain a diltiazem hydrochloride (DH-CP) solution.

[0057] 3) The diltiazem hydrochloride solution obtained in step 2) was concentrated under reduced pressure and dried, 15 mL of ethanol was added, and stirred at 80° C. until the solution was clear. The temperature was lowered to 5° C. and the temperature was maintained for 1 hour for crystallization. The diltiazem hydrochloride solid was separated by suction filtration, and the filter cake obtained by suction filtration was the pure diltiazem hydrochloride.

[0058] The overall synthetic route design of diltiazem hydrochloride is shown in Figure 1 .

[0059] The chemical reaction formula for the overall synthesis of diltiazem hydrochloride is shown in Figure 2 .

[0060] The NMR results of the prepared diltiazem hydrochloride are shown in Figure 3 .

[0061] The results show:

[0062] (1) When the molar ratio of DMEA, SOCl2 and DH-SM2 is 1:1.05:0.3, the first organic solvent is dichloromethane, the reaction temperature of step 1) is 45°C, the reaction time of step 1) is 4h, the hydrochloric acid alcohol solution is ethanolic hydrochloric acid, the DH-1 crystallization treatment temperature is 0°C, and the DH-1 crystallization treatment time is 2h, the yield of DH-1 is 84% ​​and the purity is 98.1%.

[0063] (2) When the molar ratio of DH-1, acylating agent and catalyst is 1:2.5:0.3, the acylating agent is acetic anhydride, the catalyst is 4-dimethylaminopyridine, the second organic solvent is dichloromethane, the reaction temperature of step 2) is 40° C., and the reaction time of step 2) is 4 h, the yield of DH-CP is 85% and the purity is 98.9%.

[0064] Example 2 Selection of reactant dosage

[0065] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the molar ratio of DMEA, SOCl2, and DH-SM2 in step 1) was changed. The yield and purity of the prepared DH-1 are shown in Table 1:

[0066] Table 1 Results of selection of reactant dosage

[0067]

[0068]

[0069] The results showed that when the molar ratio of DMEA, SOCl2 and DH-SM2 was (0.75-1.3):1.05:0.3, the yield and purity of the product were high, while when the molar ratio of DMEA, SOCl2 and DH-SM2 was 0.5:1.05:0.3, the reaction yield was poor; based on the experimental results, the preferred molar ratio of DMEA, SOCl2 and DH-SM2 was 1:1.05:0.3.

[0070] Example 3 Selection of the first organic solvent type

[0071] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the type of the first organic solvent in step 1) was changed. The yield and purity of the prepared DH-1 are shown in Table 2:

[0072] Table 2 Selection results of the first organic solvent type

[0073]

[0074] The results show that the target product DH-1 can be obtained by using dichloromethane, ethyl acetate, toluene, tetrahydrofuran, and acetonitrile as the first reaction solvent. However, when dichloromethane is used as the first reaction solvent, the yield and purity of the product obtained are higher than those when ethyl acetate, toluene, tetrahydrofuran, and acetonitrile are used as the first reaction solvent. Therefore, dichloromethane is preferred in the selection of the first reaction solvent.

[0075] Example 4 Selection of N-alkylation reaction time and temperature

[0076] DH-1 was prepared according to the method of Example 1, and the only difference from Example 1 was that the time and temperature of the N-alkylation reaction in step 1) were changed. The yield and purity of the prepared DH-1 are shown in Table 3:

[0077] Table 3 Selection results of reaction time and temperature

[0078]

[0079] The results show that during the reaction, as the reaction time increases, the yield of the product increases to a certain extent. When the reaction temperature is 45°C and the reaction time is 4h, the yield and purity of the product are the best. This reaction temperature and time are preferred.

[0080] Example 5 Selection of hydrochloric acid alcohol solution type

[0081] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the type of alcohol solvent in the hydrochloric acid alcohol solution in step 1) was changed. The yield and purity of the prepared DH-1 are shown in Table 4:

[0082] Table 4 Selection results of the type of alcohol in hydrochloric acid alcohol solution

[0083]

[0084] The results show that the target product DH-1 can be obtained by using ethanol hydrochloride and methanol hydrochloride as the reaction salt-forming reagent. However, when ethanol hydrochloride is used as the reaction salt-forming reagent, the yield and purity of the product obtained are higher than those when methanol hydrochloride is used as the reaction salt-forming reagent. Therefore, ethanol hydrochloride is preferred in the selection of reaction catalyst.

[0085] Example 6 Selection of DH-1 crystallization treatment temperature

[0086] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the temperature of the crystallization treatment in step 1) was changed. The yield and purity of the prepared DH-1 are shown in Table 5:

[0087] Table 5 Results of selection of crystallization temperature

[0088]

[0089] The results showed that the target product DH-1 could be obtained in good yield when the crystallization temperature was -4 to 4°C, but when the crystallization temperature was 0°C, the yield and purity of the product were optimal. Therefore, 0°C was the preferred crystallization temperature for DH-1.

[0090] Example 7 Selection of the amount of reactants

[0091] DH-CP was prepared according to the method of Example 1, and the only difference from Example 1 was that the molar ratio of DH-1, acylating agent and catalyst in step 2) was changed. The yield and purity of the prepared DH-CP are shown in Table 6:

[0092] Table 6 Results of selection of reactant dosage

[0093]

[0094] The results show that when the molar ratio of DH-1, acetic anhydride and 4-dimethylaminopyridine is in the range of 1:(2.1-2.7):(0.3-0.5), the yield and purity of DH-CP are high; while when the molar ratio of DH-1, acetic anhydride and 4-dimethylaminopyridine is 1:1.8:0.3, the reaction yield is poor; based on the experimental results, the preferred molar ratio of DH-1, acetic anhydride and 4-dimethylaminopyridine is 1:2.5:0.3.

[0095] Example 8 Selection of acylating agent

[0096] DH-CP was prepared according to the method of Example 1. The only difference from Example 1 was that the acylating agent used in step 2) was changed. The yield and purity of the prepared DH-CP are shown in Table 7:

[0097] Table 7 Selection results of acylating agents

[0098]

[0099] The results show that the target product DH-CP can be obtained by using acyl chloride, acetic anhydride and α-keto acid as the reaction acylating agent. However, when acetic anhydride is used as the reaction acylating agent, the yield and purity of the product obtained are higher than those when acyl chloride and α-keto acid are used as the reaction acylating agent. Therefore, acetic anhydride is preferred in the selection of the reaction acylating agent.

[0100] Example 9 Selection of Catalyst

[0101] DH-CP was prepared according to the method of Example 1. The only difference from Example 1 was that the catalyst used in the step 2) was changed. The yield and purity of the prepared DH-CP are shown in Table 8:

[0102] Table 8 Catalyst selection results

[0103]

[0104] The results show that the target product DH-CP can be obtained by using 4-dimethylaminopyridine and 4-pyrrolidinylpyridine as reaction catalysts. However, when 4-dimethylaminopyridine is used as the reaction catalyst, the yield and purity of the product obtained are higher than those when 4-pyrrolidinylpyridine is used as the reaction catalyst. Therefore, 4-dimethylaminopyridine is preferred in the selection of reaction catalysts.

[0105] Example 10 Selection of the second solvent type

[0106] DH-CP was prepared according to the method of Example 1, and the only difference from Example 1 was that the type of the second solvent in step 2) was changed. The yield and purity of the prepared DH-CP are shown in Table 9:

[0107] Table 9 Selection results of the second solvent type

[0108]

[0109] The results show that the target product DH-CP can be obtained by using dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile as the second reaction solvent. However, when dichloromethane is used as the second reaction solvent, the yield and purity of the obtained product are higher than those when ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile are used as the second reaction solvent. Therefore, dichloromethane is preferred in the selection of the second reaction solvent.

[0110] Example 11 Selection of esterification reaction time and temperature

[0111] DH-CP was prepared according to the method of Example 1. The only difference from Example 1 was that the time and temperature of the esterification reaction in step 2) were changed. The yield and purity of the prepared DH-CP are shown in Table 10:

[0112] Table 10 Selection results of reaction time and temperature

[0113]

[0114]

[0115] The results show that during the esterification reaction, as the reaction temperature increases and the reaction time prolongs, the yield of the product increases to a certain extent. When the reaction temperature is 40°C and the reaction time is 4h, the yield and purity of the product are the best, and this reaction temperature and time are preferred.

[0116] Example 12 Selection of DH-CP crystallization treatment temperature

[0117] DH-CP was prepared according to the method of Example 1, and the only difference from Example 1 was that the temperature of the crystallization treatment in step 3) was changed. The yield and purity of the prepared diltiazem hydrochloride are shown in Table 11:

[0118] Table 11 Selection results of crystallization temperature

[0119]

[0120] The results showed that the target product diltiazem hydrochloride can be obtained with a good yield when the crystallization temperature of diltiazem hydrochloride is 0-10°C, but when the crystallization temperature is 5°C, the yield and purity of the product are optimal. Therefore, 5°C is preferred for the selection of the crystallization temperature of diltiazem hydrochloride.

[0121] Comparative Example 1

[0122] DH-1 was prepared according to the method of Example 1, the only difference from Example 1 being that the solvent used in the reaction of step (1) was changed.

[0123] Add 8.5 mL of thionyl chloride to a 100 mL three-necked flask, cool to about 0°C, add 10 g of dimethylaminoethanol to the flask using a dropping funnel, add 30 mL of dioxane and 5 mL of water after the addition is complete, and then add about 10 g of DH-SM2, heat to 45°C and reflux for 4 hours. After the reaction is complete, separate the liquids to obtain an organic phase. Concentrate the organic phase under reduced pressure, add about 30 mL of methanol to dissolve the concentrate, then drop in about 20 mL of hydrochloric acid ethanol, cool to 0°C, crystallize for about 2 hours, and filter to obtain a white solid, which is DH-1.

[0124] The results showed that the yield of DH-1 was 49% and the purity was 70.8%.

[0125] Comparative Example 2

[0126] DH-1 was prepared according to the method of Example 1, with the only difference from Example 1 being that the solvent used to dissolve the concentrate was changed to ethanol.

[0127] Add 8.5 mL of thionyl chloride to a 100 mL three-necked flask, cool to about 0°C, add 10 g of dimethylaminoethanol to the flask using a dropping funnel, add 30 mL of DCM and 5 mL of water after the addition is complete, and then add about 10 g of DH-SM2, heat to 45°C and reflux for 4 hours. After the reaction is complete, separate the liquids to obtain an organic phase. Concentrate the organic phase under reduced pressure, add about 30 mL of ethanol to dissolve the concentrate, then drop about 20 mL of hydrochloric acid ethanol, cool to 0°C, crystallize for about 2 hours, and filter to obtain a white solid, which is DH-1.

[0128] The results showed that the yield of DH-1 was 55% and the purity was 95.5%.

[0129] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0130] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing diltiazem hydrochloride, characterized in that: include: S1: contacting thionyl chloride, dimethylaminoethanol and the compound represented by formula 1 to cause N-alkylation reaction to obtain deacetyl diltiazem hydrochloride; S2: contacting the catalyst, the acylating agent and the deacetyl diltiazem hydrochloride to cause an esterification reaction to obtain diltiazem hydrochloride, 2. The method according to claim 1, characterized in that In step S1, the N-alkylation reaction uses a hydrochloric acid alcohol solution to form a salt so as to obtain deacetyl diltiazem hydrochloride; Optionally, the alcoholic hydrochloric acid solution comprises ethanolic hydrochloric acid and / or methanolic hydrochloric acid; Optionally, the temperature of the salt formation using the hydrochloric acid alcohol solution is -8 to 8°C and the time is 1 to 4 hours.

3. The method according to claim 1, characterized in that The catalyst is 4-dimethylaminopyridine and / or 4-pyrrolidinopyridine.

4. The method according to claim 1, characterized in that: The acylating agent includes one or more of anhydrides, acid chlorides and α-keto acids.

5. The method according to claim 1, characterized in that In step S1, the N-alkylation reaction is carried out in a first organic solvent; Optionally, in step S2, the esterification reaction is carried out in a second organic solvent; The first organic solvent and the second organic solvent include one or more of dichloromethane, ethyl acetate, toluene, tetrahydrofuran and acetonitrile.

6. The method according to claim 1, characterized in that The molar ratio of the thionyl chloride, the dimethylaminoethanol and the compound represented by Formula 1 is 1.05:(0.5-1.3):(0.1-0.5).

7. The method according to claim 1, characterized in that The molar ratio of the diltiazem hydrochloride deacetylate, the acylating agent and the catalyst is 1:(1.8-2.7):(0.3-0.5).

8. The method according to claim 1, characterized in that The temperature of the N-alkylation reaction is 30-60° C. and the time is 0.5-6 hours.

9. The method according to claim 1, characterized in that: The temperature of the esterification reaction is 5 to 50° C., and the time is 0.5 to 6 hours.

10. The method according to claim 1, characterized in that The method further comprises concentrating and crystallizing the diltiazem hydrochloride; Optionally, the temperature of the crystallization treatment is 0-10°C.

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