Preparation method of diltiazem hydrochloride

Abstract

The invention belongs to the technical field of compound synthesis, and particularly relates to a preparation method of diltiazem hydrochloride. The invention provides a preparation method of diltiazem hydrochloride, which comprises the following steps: reacting d-cis-2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine-4 (5H)-ketone and dimethylaminoethanol serving as initiators, and extracting, separating liquid, filtering and the like for many times under the catalytic action of triphenylphosphine and diethyl azodicarboxylate to obtain the diltiazem hydrochloride. The diltiazem hydrochloride is obtained by salifying hydrochloric acid and ethanol, and the diltiazem hydrochloride is further obtained through esterification reaction. According to the preparation method provided by the invention, the yield of diltiazem hydrochloride is improved, and the preparation cost is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a method for preparing diltiazem hydrochloride. Background Art

[0002] Diltiazem hydrochloride, the main ingredient and its chemical name are: cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride, which can effectively dilate the epicardial and subendocardial coronary arteries, relieve spontaneous angina pectoris or angina pectoris caused by coronary artery spasm induced by ergonovine; by slowing down the heart rate and lowering blood pressure, it reduces myocardial oxygen demand, increases exercise tolerance and relieves exertional angina pectoris. It can relax vascular smooth muscle, reduce peripheral vascular resistance, and lower blood pressure; the extent of its blood pressure reduction is related to the degree of hypertension, and only slightly reduces blood pressure in people with normal blood pressure. It has a negative inotropic effect and can slow down the conduction of the sinoatrial node and atrioventricular node.

[0003] At present, the chemical preparation of diltiazem hydrochloride mainly includes splitting method and asymmetric preparation method. The splitting method first used cinchonidine to split the product diltiazem, but it had the disadvantages of large waste of raw materials and high cost. Later, ephedrine or lysine was used for splitting, but the splitting effect of ephedrine was not good. Tartaric acid can also be used to split diltiazem, but the reagents are expensive and the industrial significance is not great; the asymmetric preparation method has the disadvantages of long reaction time and low yield.

[0004] Therefore, it is urgent to develop a method for high-yield diltiazem hydrochloride. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, one object of the present invention is to provide a method for preparing diltiazem hydrochloride, wherein d-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and dimethylaminoethanol starting materials are reacted, and under the catalysis of triphenylphosphine and diethyl azodicarboxylate, hydrochloric acid ethanol is used to form salts through multiple extraction-liquid separation-filtration operations to obtain deacetyl diltiazem hydrochloride, and further diltiazem hydrochloride is obtained through esterification reaction. The preparation method provided by the present invention improves the yield of diltiazem hydrochloride and reduces the preparation cost.

[0006] To this end, the first aspect of the present invention provides a method for preparing diltiazem hydrochloride. In some embodiments of the present invention, the preparation method comprises:

[0007] S1: contacting the compound represented by Formula 1 with the compound represented by Formula 2 to cause a photoreaction to obtain a compound represented by Formula 3;

[0008] S2: The compound shown in Formula 3 is subjected to an esterification reaction to obtain a compound shown in Formula 4.

[0009]

[0010] Wherein, step S1 further comprises:

[0011] (1) stripping the product of the reaction between the compound of Formula 1 and the compound of Formula 2 using an acidic solution for at least ten times to obtain an aqueous solution;

[0012] (2) extracting the aqueous phase solution with dichloromethane and collecting the organic phase;

[0013] (3) Concentrating the organic phase under reduced pressure, and contacting the concentrated product with ethanol hydrochloride to obtain the compound represented by Formula 3.

[0014] The preparation method of diltiazem hydrochloride provided by the present invention has high yield, low cost and is easy to implement, and is conducive to realizing large-scale production of diltiazem hydrochloride.

[0015] In some embodiments of the present invention, in step S1, the Mitsunobu reaction uses triphenylphosphine and diethyl azodicarboxylate as catalysts.

[0016] In some embodiments of the present invention, the molar ratio of the compound represented by Formula 1, the compound represented by Formula 2, triphenylphosphine, and diethyl azodicarboxylate is (2-2.5):1:2:2.

[0017] In some embodiments of the present invention, in step S1, the Mitsunobu reaction uses ethanol hydrochloride to form a salt so as to obtain deacetyl diltiazem hydrochloride. Using ethanol hydrochloride to form a salt can obtain a more stable salt compound and can improve the reaction yield.

[0018] In some embodiments of the present invention, in step S1, the Mitsunobu reaction is contacted in a first solvent, and the first solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile.

[0019] In some embodiments of the present invention, in step S1, the reaction temperature of the Mitsunobu reaction is 0-10°C, and the reaction time is 3-5h.

[0020] In some embodiments of the present invention, in step S2, the esterification reaction uses acetic anhydride and 4-dimethylaminopyridine as catalysts.

[0021] In some embodiments of the present invention, the molar ratio of the compound represented by Formula 3, acetic anhydride and 4-dimethylaminopyridine is 1:(2.1-2.7):(0.3-0.5).

[0022] In some embodiments of the present invention, in step S2, the esterification reaction is contacted in a second solvent, and the second solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile.

[0023] In some embodiments of the present invention, the reaction temperature of the esterification reaction is 10-40° C., and the reaction time is 1-4 h.

[0024] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. 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 synthetic route for preparing diltiazem hydrochloride of the present invention is shown;

[0027] Figure 2 The NMR spectrum of diltiazem hydrochloride prepared in Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0028] 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 construed as limiting the present invention.

[0029] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[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 order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0032] 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.

[0033] 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.

[0034] According to a specific embodiment of the present invention, the present invention provides a method for preparing diltiazem hydrochloride, comprising:

[0035] S1: contacting the compound represented by Formula 1 with the compound represented by Formula 2 to cause a photoreaction to obtain a compound represented by Formula 3;

[0036] S2: The compound shown in Formula 3 is subjected to an esterification reaction to obtain a compound shown in Formula 4.

[0037]

[0038] Wherein, step S1 further comprises:

[0039] (1) stripping the product of the reaction between the compound of Formula 1 and the compound of Formula 2 using an acidic solution for at least ten times to obtain an aqueous solution;

[0040] (2) extracting the aqueous phase solution with dichloromethane and collecting the organic phase;

[0041] (3) Concentrating the organic phase under reduced pressure, and contacting the concentrated product with ethanol hydrochloric acid to obtain the compound represented by Formula 3.

[0042] It should be noted that the number of back extractions can be 10 times, 11 times, 12 times or 15 times, etc. When the reactants after the reaction of the compound of Formula 1 and the compound of Formula 2 are back extracted at least 10 times using an acidic solution, the yield of the compound represented by Formula 3 can be improved.

[0043] According to a specific embodiment of the present invention, in step S1, the Mitsunobu reaction uses triphenylphosphine and diethyl azodicarboxylate as catalysts, thereby making full use of the raw materials and improving the product yield.

[0044] The synthetic route for preparing diltiazem hydrochloride provided by the present invention is as follows: Figure 1 According to a specific embodiment of the present invention, the molar ratio of the compound represented by Formula 1, the compound represented by Formula 2, triphenylphosphine, and diethyl azodicarboxylate is (2-2.5):1:2:2. Within this molar ratio range, the raw materials can be fully utilized, the reaction efficiency can be improved, and the product yield can be increased.

[0045] According to a specific embodiment of the present invention, in step S1, the Mitsunobu reaction uses ethanol hydrochloride to form a salt so as to obtain deacetyl diltiazem hydrochloride. Using ethanol hydrochloride to form a salt can obtain a more stable salt compound and can improve the reaction yield. Using other salt-forming reagents, for example, using methanol to form a salt, the yield of deacetyl diltiazem hydrochloride is low.

[0046] According to a specific embodiment of the present invention, in step S1, the Mitsunobu reaction is contacted in a first solvent, and the first solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile. The Mitsunobu reaction is contacted in a first solvent, and the first solvent includes but is not limited to dichloromethane, and can also be other organic reagents, preferably dichloromethane.

[0047] According to a specific embodiment of the present invention, the acidic solution may be, for example, a hydrochloric acid solution.

[0048] According to a specific embodiment of the present invention, the above-mentioned back extraction process can be multiple times, for example, five times, ten times, etc., the aqueous phases obtained by multiple back extractions are combined, and the aqueous phase is further extracted multiple times with DCM to collect the organic phase.

[0049] According to a specific embodiment of the present invention, in step S1, the reaction temperature of the Mitsunobu reaction is 0-10°C, and the reaction time is 3-5h.

[0050] According to a preferred embodiment of the present invention, in step S1, the reaction temperature of the Mitsunobu reaction is 5° C., and the reaction time is 5 h.

[0051] According to a specific embodiment of the present invention, in step S2, the esterification reaction uses acetic anhydride and 4-dimethylaminopyridine as catalysts, thereby making full use of the raw materials and improving the product yield.

[0052] According to a specific embodiment of the present invention, the molar ratio of the compound shown in Formula 3, acetic anhydride, and 4-dimethylaminopyridine is 1:(2.1-2.7):(0.3-0.5). Within this ratio range, the raw materials can be fully utilized and the product yield can be improved.

[0053] According to a specific embodiment of the present invention, in step S2, the esterification reaction is contacted in a second solvent, and the second solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile. The esterification reaction is contacted in the second solvent, and the second solvent includes but is not limited to dichloromethane, and can also be other organic reagents, preferably dichloromethane.

[0054] The scheme of the present disclosure will be explained below in conjunction with the examples. Those skilled in the art will appreciate that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific techniques or conditions are not indicated in the examples, the techniques or conditions described in the literature in this area or the product instructions are used. Where the manufacturers of reagents or instruments are not indicated, they are all conventional products that can be obtained commercially.

[0055] Example 1 Preparation method of diltiazem hydrochloride

[0056] 1. Preparation of Deacetyl Diltiazem Hydrochloride

[0057] The preparation process of deacetyl diltiazem hydrochloride is as follows:

[0058] (1) 3.01 g DH-SM2, 1.78 g DH-SM1, 5.25 g PPh3, and 15 mL DCM were added to a three-necked flask and stirred at 5°C. Then 3.48 g DEAD was added dropwise to the system and reacted for 5 h.

[0059] (2) After the reaction, the reaction solution was filtered, rinsed with 50 mL of DCM and the filtrate was collected. The filtrate was then back-extracted with 50 mL of 1 M HCl ten times. The aqueous phases were combined and the pH was adjusted to 7-8 with NaCO3. The aqueous phase was extracted three times with 100 mL of DCM, the organic phase was collected and concentrated under reduced pressure, and placed in a refrigerator for crystallization. 10 mL of DCM was added to the precipitated solid, filtered, and the filtrate was concentrated under reduced pressure.

[0060] (3) Add 35 mL of hydrochloric acid ethanol to the concentrate, a large amount of solid precipitates, and filter, the filter cake is DH-1. It has been determined that triphenylphosphine can be removed well in the above preparation method.

[0061] 2. Preparation of Diltiazem Hydrochloride

[0062] The preparation process of diltiazem hydrochloride is as follows:

[0063] Add 5g DH-1, 0.45g DMAP, 15mL DCM to a three-necked flask, stir to dissolve. Then add 3.12g Ac2O, reflux at 40°C for 4h, after the reaction is completed, concentrate the reaction solution under reduced pressure and dry to obtain crude diltiazem hydrochloride (DH-CP), the product yield is 85%, the purity is 98.9%; add 15mL ethanol to the above DH-CP, stir to dissolve at 80°C, then cool to 5°C and keep warm for 1h for crystallization, filter, and the filter cake is diltiazem hydrochloride. Figure 2 The figure is the nuclear magnetic resonance spectrum of diltiazem hydrochloride prepared by the method of this embodiment.

[0064] Example 2 Selection of the amount of reaction raw materials

[0065] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the molar ratio of DH-SM1, DH-SM2, PPh3 and DEAD was changed. The yield and purity of the prepared DH-1 are shown in Table 1:

[0066] Table 1 Selection results of reaction raw material dosage

[0067]

[0068] The results in Table 1 above show that in the process of preparing DH-1, the molar ratio of DH-SM1, DH-SM2, PPh3 and DEAD is in the range of (2-2.5):1:2:2, and the yield and purity of DH-1 are high.

[0069] Example 3 Selection of solvent type

[0070] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the type of solvent used in the reaction was changed. The yield and purity of the prepared DH-1 are shown in Table 2:

[0071] Table 2 Results of solvent type selection

[0072]

[0073] The results in Table 2 above show that in the process of preparing DH-1, the Mitsunobu reaction occurs in dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane or acetonitrile solvent, and the yield and purity of DH-1 are relatively high.

[0074] Example 4 Selection of reaction time and temperature

[0075] DH-1 was prepared according to the method of Example 1, and the only difference from Example 1 was that the reaction time and temperature were changed. The yield and purity of the prepared DH-1 are shown in Table 3:

[0076] Table 3 Selection results of reaction time and temperature

[0077]

[0078] The results in Table 3 above show that in the process of preparing DH-1, the reaction temperature of the Mitsunobu reaction is 0-10°C, the reaction time is 3-5h, and the yield and purity of DH-1 are high.

[0079] Example 5 Selection of stripping times

[0080] DH-1 was prepared according to the method of Example 1. The only difference from Example 1 was that the number of back extraction operations in step (2) was changed. The yield and purity of the prepared DH-1 are shown in Table 4:

[0081] Table 4 Results of selection of back extraction times

[0082]

[0083] The results in Table 4 above show that in the process of preparing DH-1, the number of back-extraction operations affects the yield of DH-1. When the back-extraction operation reaches ten times, the yield of DH-1 is higher.

[0084] Example 6 Selection of the amount of reactants

[0085] 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, acetic anhydride and 4-dimethylaminopyridine was changed. The yield and purity of the prepared DH-CP are shown in Table 5:

[0086] Table 5 Results of selection of reactant dosage

[0087]

[0088] The results in Table 5 above show that in the process of preparing DH-CP, 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 higher.

[0089] Example 7 Selection of the second solvent type

[0090] 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 of the reaction was changed. The yield and purity of the prepared DH-CP are shown in Table 6:

[0091] Table 6 Selection results of the second solvent type

[0092]

[0093]

[0094] The results in Table 6 above show that in the process of preparing DH-CP, the esterification reaction occurs in dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane or acetonitrile solvent, and the yield and purity of DH-CP are high.

[0095] Example 8 Selection of reaction time and temperature

[0096] 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 were changed. The yield and purity of the prepared DH-CP are shown in Table 7:

[0097] Table 7 Selection results of reaction time and temperature

[0098]

[0099] The results in Table 7 above show that in the process of preparing DH-CP, the reaction temperature of the esterification reaction is 10-40°C, the reaction time is 1-4h, and the yield and purity of DH-CP are high.

[0100] Comparative Example 1

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

[0102] Table 8 Selection results of extraction solvent dosage

[0103]

[0104]

[0105] Comparative Example 2

[0106] DH-1 was prepared according to the method of Example 1, and the only difference from Example 1 was that the type of salt-forming reagent in step (3) was changed. The yield and purity of the prepared DH-1 are shown in Table 9:

[0107] Table 9 Selection results of salt-forming reagent types

[0108]

[0109] Comparative Example 3

[0110] DH-CP was prepared according to the method of Example 1. Compared with Example 1, the only difference was that the molar ratio of DH-1, acetic anhydride and 4-dimethylaminopyridine was 1:1.8:0.3. The preparation process of DH-CP was as follows:

[0111] Add 5g DH-1, 0.45g DMAP, 15mL DCM to a three-necked flask, stir to dissolve. Then add 2.25g Ac2O, reflux at 40°C for 4h, after the reaction is completed, concentrate the reaction solution under reduced pressure and dry to obtain crude diltiazem hydrochloride (DH-CP), the product yield is 65%, the purity is 80.5%; add 15mL ethanol to the above DH-CP, stir to dissolve at 80°C, then cool to 5°C and keep warm for 1h for crystallization, filter, and the filter cake is diltiazem hydrochloride.

[0112] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", "some implementation schemes" 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, unless they are contradictory.

[0113] 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 the compound represented by Formula 1 with the compound represented by Formula 2 to cause a photoreaction to obtain a compound represented by Formula 3; S2: The compound shown in Formula 3 is subjected to an esterification reaction to obtain a compound shown in Formula 4. Wherein, step S1 further comprises: (1) stripping the product of the reaction between the compound of Formula 1 and the compound of Formula 2 using an acidic solution for at least ten times to obtain an aqueous solution; (2) extracting the aqueous phase solution with dichloromethane and collecting the organic phase; (3) Concentrating the organic phase under reduced pressure, and contacting the concentrated product with ethanol hydrochloric acid to obtain the compound represented by Formula 3.

2. The preparation method according to claim 1, characterized in that: In step S1, the Mitsunobu reaction uses triphenylphosphine and diethyl azodicarboxylate as catalysts; Optionally, the molar ratio of the compound represented by Formula 1, the compound represented by Formula 2, triphenylphosphine, and diethyl azodicarboxylate is (2-2.5):1:2:

2.

3. The preparation method according to claim 2, characterized in that: In step S1, the Mitsunobu reaction uses hydrochloric acid ethanol to form a salt so as to obtain deacetyl diltiazem hydrochloride.

4. The preparation method according to claim 1, characterized in that: In step S1, the Mitsunobu reaction is carried out in a first solvent, and the first solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile.

5. The preparation method according to claim 1, characterized in that: In step S1, the reaction temperature of the Mitsunobu reaction is 0-10°C, and the reaction time is 3-5h.

6. The preparation method according to claim 1, characterized in that: In step S2, the esterification reaction uses acetic anhydride and 4-dimethylaminopyridine as catalysts; Optionally, the molar ratio of the compound represented by Formula 3, acetic anhydride and 4-dimethylaminopyridine is 1:(2.1-2.7):(0.3-0.5).

7. The preparation method according to claim 6, characterized in that: In step S2, the esterification reaction is carried out in a second solvent, and the second solvent includes any one of dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile.

8. The preparation method according to claim 1, characterized in that: The reaction temperature of the esterification reaction is 10-40° C., and the reaction time is 1-4 hours.

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