Preparation method of diltiazem hydrochloride

Abstract

The invention relates to the field of medicine preparation, in particular to a diltiazem hydrochloride preparation method which comprises the following steps: S1, contacting a compound as shown in a formula 1, a compound as shown in a formula 2 and an alkaline compound to obtain a compound as shown in a formula 3; s2, contacting the compound as shown in the formula 3 with an alcoholic solution containing hydrochloric acid to obtain a compound as shown in a formula 4; and S3, carrying out acetylation reaction on the compound as shown in the formula 4 to obtain a compound as shown in a formula 5. The method is high in yield, low in cost and easy to implement, and industrialization of diltiazem hydrochloride is facilitated.

Description

Technical Field

[0001] The invention relates to the field of drug preparation, and in particular to a method for preparing diltiazem hydrochloride. Background Art

[0002] Diltiazem hydrochloride, chemical name is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-keto hydrochloride is a calcium channel blocker, and its action is related to inhibiting the influx of calcium ions during the depolarization of myocardial and vascular smooth muscle. It acts on the calcium ion channels in the myocardium, coronary vessels, smooth muscles of peripheral blood vessels, and atrioventricular node, inhibiting the transmembrane influx of calcium ions from the extracellular to the intracellular, reducing the concentration of intracellular calcium ions, but without changing the serum calcium concentration, thereby relieving and preventing the contraction of myocardial and vascular smooth muscle cells, and has the effects of dilating coronary arteries and peripheral blood vessels, improving myocardial hypertrophy, and prolonging the conduction time of the atrioventricular node.

[0003] At present, the preparation method of diltiazem hydrochloride mainly includes the following steps: using p-methoxybenzaldehyde and methyl chloroacetate as raw materials, and undergoing 8 steps of Darzens condensation, thiolation, hydrolysis, splitting, cyclization, N-alkylation, O-acetylation, and salt formation to obtain the target compound diltiazem hydrochloride. The specific steps are as follows: Darzens condensation: using p-methoxybenzaldehyde and methyl chloroacetate as raw materials, Darzens condensation reaction is carried out to obtain the intermediate dl-trans-(4-methoxyphenyl)-2,3-epoxypropionic acid methyl ester; thiolation reaction: the intermediate reacts with o-aminothiophenol to prepare the intermediate dl-cis-3-(4-methoxyphenyl)-3-(2-aminophenylthio)-2-hydroxypropionic acid methyl ester; hydrolysis reaction: the intermediate is hydrolyzed under alkaline conditions to prepare the intermediate dl-cis-3-(4-methoxyphenyl)-3-(2-aminophenylthio)-2-hydroxypropionic acid methyl ester. The invention relates to a method for preparing diltiazem hydrochloride, wherein the intermediate is subjected to an N-substitution reaction with N,N-dimethylethyl chloride hydrochloride to produce d-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine; a step of splitting: using L-lysine as a splitting agent to split the intermediate to obtain d-cis-3-(4-methoxyphenyl)-3-(2-aminophenylthio)-2-hydroxypropionic acid; a step of cyclization ...hydroxy-2,3-dihydro-1,5-benzothiazepine; a step of esterification: using the intermediate to undergo an esterification reaction with acetic anhydride to produce diltiazem; a step of salt formation: dissolving diltiazem in a methanol solution of HCl to produce the final diltiazem hydrochloride form. However, this method has problems such as low atomic utilization, low yield, high reaction cost and complexity, which limits the widespread application of diltiazem hydrochloride.

[0004] Therefore, it is urgent to provide a preparation method of diltiazem hydrochloride to overcome the above technical problems. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art to at least a certain extent. To this end, the present invention provides a preparation method of diltiazem hydrochloride, which has high yield, low cost, is easy to implement, and is conducive to the industrialization of diltiazem hydrochloride.

[0006] To this end, the present invention provides a method for preparing diltiazem hydrochloride, comprising the following steps:

[0007] S1: contacting the compound represented by Formula 1, the compound represented by Formula 2, and a basic compound to obtain a compound represented by Formula 3;

[0008] S2: contacting the compound represented by Formula 3 with an alcohol solution containing hydrochloric acid to obtain a compound represented by Formula 4;

[0009] S3: subjecting the compound of formula 4 to an acetylation reaction to obtain a compound of formula 5;

[0010]

[0011] Wherein, R is a halogen.

[0012] According to an embodiment of the present invention, in step S1, the alkaline compound includes at least one of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium phosphate, preferably potassium carbonate.

[0013] According to an embodiment of the present invention, the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 is 1:(1.0-1.3), preferably 1:(1.05-1.2).

[0014] According to an embodiment of the present invention, the molar ratio of the compound represented by Formula 1 to the basic compound is 1:(1.2-2.2), preferably 1:(1.8-2.2).

[0015] According to an embodiment of the present invention, the compound represented by Formula 1, the compound represented by Formula 2, and the basic compound are contacted in a first solvent, and the first solvent includes at least one of dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, toluene, and acetonitrile, preferably at least one of tetrahydrofuran and acetonitrile.

[0016] According to an embodiment of the present invention, the reaction temperature of step S1 is 55-85°C, preferably 70-85°C.

[0017] According to an embodiment of the present invention, the reaction time of step S1 is 1-4 hours, preferably 4 hours.

[0018] According to an embodiment of the present invention, R is chlorine or bromine.

[0019] According to an embodiment of the present invention, in step S2, the alcohol solution includes at least one of ethanol, methanol, isopropanol, n-butanol, and tert-butanol, preferably at least one of ethanol, isopropanol, n-butanol, and tert-butanol.

[0020] According to an embodiment of the present invention, the mass volume ratio of the compound represented by Formula 3 to the hydrochloric acid alcohol solution is 1 g: (2.0-3.2) mL.

[0021] According to an embodiment of the present invention, the reaction temperature of step S2 is 10-30°C, preferably 10-20°C.

[0022] According to an embodiment of the present invention, the reaction time of step S2 is 0.5-2h.

[0023] According to an embodiment of the present invention, in step S3, the acetylation reaction further comprises contacting the compound represented by formula 4 with acetic anhydride to obtain the compound represented by formula 5.

[0024] According to an embodiment of the present invention, the acetylation reaction is carried out under the action of a catalyst.

[0025] According to an embodiment of the present invention, the catalyst includes at least one of DMAP, imidazole, triphenylphosphine oxide, mercaptopropionic acid, and n-methylmorpholine, preferably at least one of DMAP, imidazole, and triphenylphosphine oxide.

[0026] According to an embodiment of the present invention, the acetylation reaction is carried out in a second solvent, and the second solvent includes at least one of DCM, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile, preferably at least one of DCM, tetrahydrofuran, dioxane, and acetonitrile.

[0027] According to an embodiment of the present invention, the molar ratio of the compound represented by Formula 4 to acetic anhydride and the catalyst is 1:(1.8-2.7):(0.3-0.5), preferably 1:(2.1-2.7):(0.3-0.5).

[0028] According to an embodiment of the present invention, the temperature of the acetylation reaction is 10-40°C, preferably 40°C.

[0029] According to an embodiment of the present invention, the acetylation reaction time is 1-3 hours.

[0030] According to an embodiment of the present invention, step S3 further comprises: purifying the product of the acetylation reaction to obtain the compound represented by formula 5.

[0031] According to an embodiment of the present invention, the purification treatment includes recrystallizing the product of the acetylation reaction using dichloromethane-n-hexane to obtain the compound represented by Formula 5.

[0032] 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

[0033] 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:

[0034] Figure 1 The NMR spectrum of diltiazem hydrochloride prepared in Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] According to an embodiment of the present invention, the present invention provides a method for preparing diltiazem hydrochloride, comprising the following steps:

[0042] S1: contacting the compound represented by Formula 1, the compound represented by Formula 2, and a basic compound to obtain a compound represented by Formula 3;

[0043]

[0044] Wherein, R is a halogen.

[0045] In this step, the compound represented by Formula 1 and the compound represented by Formula 2 undergo N-alkylation reaction under the action of a basic compound to obtain a compound represented by Formula 3.

[0046] According to a specific embodiment of the present invention, the type of the alkaline compound is not particularly limited. As some specific examples, the alkaline compound includes but is not limited to potassium carbonate, sodium carbonate, sodium hydroxide, potassium phosphate, preferably potassium carbonate.

[0047] According to a specific embodiment of the present invention, the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 is 1:(1.0-1.3), and the molar ratio of the compound represented by Formula 1 to the basic compound is 1:(1.2-2.2), thereby making full use of the raw materials and improving the yield. Specifically, the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 can be 1:1.0, 1:1.1, 1:1.2, 1:1.3, etc., preferably 1:(1.05-1.2); the molar ratio of the compound represented by Formula 1 to the basic compound can be 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, etc., preferably 1:(1.8-2.2).

[0048] According to a specific embodiment of the present invention, the compound represented by Formula 1, the compound represented by Formula 2, and the alkaline compound are contacted in a first solvent, and the type of the first solvent is not particularly limited, including but not limited to dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, toluene, acetonitrile, preferably at least one of tetrahydrofuran and acetonitrile, and more preferably an aqueous solution of acetonitrile.

[0049] According to a specific embodiment of the present invention, the temperature and time of this step are not particularly limited. As some specific examples, the reaction temperature of step S1 is 55-85°C, and the reaction time is 1-4h. Specifically, the reaction temperature of step S1 can be 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, etc., preferably 70-85°C; the reaction time can be 1h, 2h, 3h, 4h, etc., preferably 4h.

[0050] According to a specific embodiment of the present invention, in the compound structure shown in Formula 2, R is a halogen, including but not limited to chlorine and bromine. When R is chlorine, the compound shown in Formula 2 is N,N-dimethylaminoethyl chloride hydrochloride; when R is bromine, the compound shown in Formula 2 is N,N-dimethylaminoethyl bromide hydrobromide.

[0051] S2: contacting the compound represented by Formula 3 with an alcohol solution containing hydrochloric acid to obtain a compound represented by Formula 4;

[0052]

[0053] In the prior art, the intermediate salt-forming step is mostly carried out by directly contacting with hydrochloric acid, but the reaction stability is poor, and the stability and yield of the obtained salt-forming compound are also affected. Here, the compound represented by formula 3 is contacted with an alcohol solution containing hydrochloric acid to obtain a more stable salt-forming compound and improve the reaction yield.

[0054] According to a specific embodiment of the present invention, the type of the alcohol solution is not particularly limited, including but not limited to ethanol, methanol, isopropanol, n-butanol, tert-butanol, preferably at least one of ethanol, isopropanol, n-butanol, tert-butanol.

[0055] According to a specific embodiment of the present invention, the mass volume ratio of the compound represented by Formula 3 to the hydrochloric acid alcohol solution is 1 g: (2.0-3.2) mL, thereby further improving the reaction stability and yield.

[0056] According to a specific embodiment of the present invention, the temperature and time of this step are not particularly limited. As some specific examples, the reaction temperature of step S2 is 10-30°C, and the reaction time is 0.5-2h. Specifically, the reaction temperature of step S2 can be 10°C, 15°C, 20°C, 25°C, 30°C, etc., preferably 10-20°C; the reaction time can be 0.5h, 1h, 1.5h, 2h, etc.

[0057] S3: subjecting the compound of formula 4 to an acetylation reaction to obtain a compound of formula 5;

[0058]

[0059] According to a specific embodiment of the present invention, the acetylation reaction further comprises contacting the compound represented by Formula 4 with acetic anhydride to obtain the compound represented by Formula 5.

[0060] According to a specific embodiment of the present invention, the acetylation reaction is carried out under the action of a catalyst, and the type of the catalyst is not particularly limited. As some specific examples, they include but are not limited to DMAP (4-dimethylaminopyridine), imidazole, triphenylphosphine oxide, mercaptopropionic acid, and n-methylmorpholine, preferably at least one of DMAP, imidazole, and triphenylphosphine oxide.

[0061] According to a specific embodiment of the present invention, the acetylation reaction is carried out in a second solvent, and the type of the second solvent is not particularly limited. As some specific examples, it includes but is not limited to DCM (dichloromethane), ethyl acetate, toluene, tetrahydrofuran, dioxane, acetonitrile, preferably at least one of DCM, tetrahydrofuran, dioxane, and acetonitrile.

[0062] According to a specific embodiment of the present invention, the molar ratio of the compound shown in Formula 4 to acetic anhydride and the catalyst is 1: (1.8-2.7): (0.3-0.5), thereby further improving the reaction yield. Specifically, the molar ratio of the compound shown in Formula 4 to acetic anhydride and the catalyst can be 1: 1.8: 0.3, 1: 1.8: 0.4, 1: 1.8: 0.5, 1: 2: 0.3, 1: 2.5: 0.4, 1: 2.7: 0.3, 1: 2.7: 0.5, etc., preferably 1: (2.1-2.7): (0.3-0.5).

[0063] According to a specific embodiment of the present invention, the temperature and time of this step are not particularly limited. As some specific examples, the temperature of the acetylation reaction is 10-40°C, and the reaction time is 1-3h. Specifically, the temperature of the acetylation reaction can be 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc., preferably 40°C; the reaction time can be 1h, 1.5h, 2h, 2.5h, 3h, etc.

[0064] According to a specific embodiment of the present invention, this step further comprises: purifying the product of the acetylation reaction to obtain the compound represented by Formula 5. The purification process includes but is not limited to recrystallizing the product of the acetylation reaction using dichloromethane-n-hexane to obtain purified diltiazem hydrochloride.

[0065] 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.

[0066] Example 1

[0067] (1) Add 3.01 g of the compound of formula 1, 2.56 g of N,N-dimethylaminoethyl bromide hydrobromide, 2.76 g of potassium carbonate, 50 mL of acetonitrile, and 1 mL of water into a three-necked flask, and react at 85° C. for 4 h. After the reaction is completed, filter the mixture by suction, dry the filtrate, and spin dry to obtain a precipitate. The yield is 85% and the purity is 98.9%.

[0068] (2) Add 10 mL of ethanolic hydrochloric acid solution and 40 mL of methanol to a flask containing 3.17 g of the above precipitate, react at 10°C for 0.5 h, and separate the precipitate. The yield is 93% and the purity is 98.5%;

[0069] (3) 3.23 g of the above precipitate, 2.02 g of acetic anhydride, 0.29 g of DMAP, and 30 mL of DCM were added to a flask in sequence, and the mixture was reacted at 40° C. for 3 h to obtain a crude diltiazem hydrochloride product, which was recrystallized using dichloromethane-n-hexane to obtain a finished diltiazem hydrochloride product with a yield of 85% and a purity of 98.9%.

[0070] Example 2 Selection of the amount of reaction raw materials

[0071] The compound of formula 3 was prepared according to the method of Example 1. Compared with Example 1, the only difference was that the molar ratio of the compound of formula 1 and the compound of formula 2 was changed. The yield and purity of the prepared compound of formula 3 are shown in Table 1:

[0072] Table 1 Selection results of reaction raw material dosage

[0073]

[0074] Example 3 Selection of basic compounds

[0075] The compound of formula 3 was prepared according to the method of Example 1, and the only difference from Example 1 was that the type of the basic compound was changed. The yield and purity of the prepared compound of formula 3 are shown in Table 2:

[0076] Table 2 Selection results of basic compounds

[0077]

[0078] Example 4 Selection of the amount of reaction raw materials and basic compounds

[0079] The compound of formula 3 was prepared according to the method of Example 1. Compared with Example 1, the only difference was that the molar ratio of the compound of formula 1 and the basic compound was changed. The yield and purity of the prepared compound of formula 3 are shown in Table 3:

[0080] Table 3 Selection results of reaction raw materials and basic compound dosage

[0081]

[0082] Example 5 Selection of solvent type

[0083] The compound of formula 3 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 compound of formula 3 were shown in Table 4:

[0084] Table 4 Results of solvent type selection

[0085]

[0086] Example 6 Selection of reaction time and temperature

[0087] The compound of formula 3 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 compound of formula 3 prepared were shown in Table 5:

[0088] Table 5 Selection results of reaction time and temperature

[0089]

[0090]

[0091] Example 7 Selection of the amount of reactants

[0092] The compound of formula 4 was prepared according to the method of Example 1. Compared with Example 1, the only difference was that the mass volume ratio of the compound of formula 3 to the hydrochloric acid alcohol solution was changed. The yield and purity of the prepared compound of formula 4 are shown in Table 6:

[0093] Table 6 Results of selection of reactant dosage

[0094]

[0095] Example 8 Selection of the type of alcohol in the hydrochloric acid alcohol solution

[0096] The compound of formula 4 was prepared according to the method of Example 1. The only difference from Example 1 was that the type of alcohol in the hydrochloric acid alcohol solution was changed. The yield and purity of the prepared compound of formula 4 are shown in Table 7:

[0097] Table 7 Selection results of the types of alcohol in the hydrochloric acid alcohol solution

[0098]

[0099] Example 9 Selection of reaction time and temperature

[0100] The compound of formula 4 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 compound of formula 4 are shown in Table 8:

[0101] Table 8 Selection results of reaction time and temperature

[0102]

[0103]

[0104] Example 10 Selection of the amount of reaction raw materials

[0105] The compound of Formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference was that the molar ratio of the compound of Formula 4 and acetic anhydride was changed. The yield and purity of the prepared compound of Formula 5 are shown in Table 9:

[0106] Table 9 Selection results of reaction raw material dosage

[0107]

[0108] Example 11 Selection of Catalyst

[0109] The compound of Formula 5 was prepared according to the method of Example 1, and the only difference from Example 1 was that the type of catalyst was changed. The yield and purity of the prepared compound of Formula 5 are shown in Table 10:

[0110] Table 10 Catalyst selection results

[0111]

[0112] Example 12 Selection of the second solvent type

[0113] The compound of Formula 5 was prepared according to the method of Example 1. The only difference from Example 1 was that the type of the second solvent in the reaction was changed. The yield and purity of the prepared compound of Formula 5 are shown in Table 11:

[0114] Table 11 Selection results of the second solvent type

[0115]

[0116] Example 13 Selection of reaction raw materials and catalyst dosage

[0117] The compound of Formula 5 was prepared according to the method of Example 1. The only difference from Example 1 was that the molar ratio of the compound of Formula 4, acetic anhydride and the catalyst was changed. The yield and purity of the prepared compound of Formula 5 are shown in Table 12:

[0118] Table 12 Selection results of reaction raw materials and catalyst dosage

[0119]

[0120] Example 14 Selection of acetylation reaction time and temperature

[0121] The compound of Formula 5 was prepared according to the method of Example 1. The only difference from Example 1 was that the time and temperature of the acetylation reaction were changed. The yield and purity of the prepared compound of Formula 5 are shown in Table 13:

[0122] Table 13 Selection results of acetylation reaction time and temperature

[0123]

[0124] Comparative Example 1

[0125] (1) Add 3.01 g of the compound of formula 1, 2.56 g of N,N-dimethylamino bromoethane hydrobromide, 2.24 g of potassium tert-butoxide, 50 mL of acetonitrile, and 1 mL of water into a three-necked flask, and react at 85° C. for 4 h. After the reaction is completed, filter the mixture by suction, dry the filtrate, and spin-dry to obtain a precipitate. The yield is 45% and the purity is 24.2%;

[0126] (2) Add 5 mL of ethanolic hydrochloric acid solution and 40 mL of methanol to a flask containing 1.68 g of the above precipitate, react at 10°C for 0.5 h, and separate the precipitate. The yield is 93% and the purity is 98.5%;

[0127] (3) 1.71 g of the above precipitate, 1.07 g of acetic anhydride, 0.15 g of DMAP, and 30 mL of DCM were added to a flask in sequence, and the mixture was reacted at 40° C. for 3 h to obtain a crude diltiazem hydrochloride product, which was recrystallized using dichloromethane-n-hexane to obtain a finished diltiazem hydrochloride product with a yield of 85% and a purity of 98.9%.

[0128] Comparative Example 2

[0129] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0130] Step (2): Add 10 mL of hydrochloric acid solution and 40 mL of methanol to a flask containing 3.17 g of the above precipitate, react at 10° C. for 0.5 h, and separate the precipitate. The yield of this step is 53% and the purity is 87%.

[0131] Comparative Example 3

[0132] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0133] In step (1), acetonitrile is replaced with acetone. The yield of this step is 50% and the purity is 72%.

[0134] Comparative Example 4

[0135] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0136] In step (1), acetonitrile is replaced with tert-butyl alcohol. The yield of this step is 73% and the purity is 81%.

[0137] Comparative Example 5

[0138] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0139] The raw materials in step (1) also include 0.15 g of FeCl2. The yield of this step is 70% and the purity is 89%.

[0140] Comparative Example 6

[0141] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0142] The molar ratio of the compound represented by formula 1 and the basic compound in step (1) is changed to 1:1. The yield of this step is 50% and the purity is 85%.

[0143] Comparative Example 7

[0144] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0145] The reaction temperature in step (1) was changed to 100° C. The yield of this step was 60% and the purity was 82%.

[0146] Comparative Example 8

[0147] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0148] The mass volume ratio of the compound represented by formula 3 to the hydrochloric acid alcohol solution in step (2) was changed to 1:1.0. The yield of this step was 55% and the purity was 88%.

[0149] Comparative Example 9

[0150] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0151] Step (2): Add 40 mL of methanol to a flask containing 3.17 g of the above precipitate, and continue to introduce dry hydrogen chloride gas, react at 10° C. for 0.5 h, and separate the precipitate. The yield of this step is 48% and the purity is 65%.

[0152] Comparative Example 10

[0153] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0154] The reaction temperature of step (2) was changed to 50° C. The yield of this step was 74% and the purity was 92%.

[0155] Comparative Example 11

[0156] The compound of formula 3 was prepared according to the method of step (1) in Example 1, and then 30 mL of DCM and 10 mL of acetyl chloride were added to a flask containing 3.17 g of the above precipitate to obtain the compound of formula 5. The yield was 40% and the purity was 68%.

[0157] Comparative Example 12

[0158] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0159] The molar ratio of the compound represented by formula 4 and acetic anhydride in step (3) was changed to 1:4. The yield of this step was 60% and the purity was 83%.

[0160] Comparative Example 13

[0161] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0162] The molar ratio of the compound represented by formula 4, acetic anhydride and catalyst in step (3) is changed to 1:1:1. The yield of this step is 50% and the purity is 80%.

[0163] Comparative Example 14

[0164] The compound of formula 5 was prepared according to the method of Example 1. Compared with Example 1, the only difference is that:

[0165] The acetylation reaction temperature in step (3) was changed to 50° C. The yield of this step was 55% and the purity was 82%.

[0166] 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.

[0167] 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: The following steps are involved: S1: contacting the compound represented by Formula 1, the compound represented by Formula 2, and a basic compound to obtain a compound represented by Formula 3; S2: contacting the compound represented by Formula 3 with an alcohol solution containing hydrochloric acid to obtain a compound represented by Formula 4; S3: subjecting the compound of formula 4 to an acetylation reaction to obtain a compound of formula 5; Wherein, R is a halogen.

2. The preparation method according to claim 1, characterized in that: In step S1, the alkaline compound includes at least one of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium phosphate, preferably potassium carbonate; Optionally, the molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 is 1:(1.0-1.3), preferably 1:(1.05-1.2); Optionally, the molar ratio of the compound represented by Formula 1 to the basic compound is 1:(1.2-2.2), preferably 1:(1.8-2.2); Optionally, the compound represented by Formula 1, the compound represented by Formula 2, and the basic compound are contacted in a first solvent, and the first solvent includes at least one of dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, toluene, and acetonitrile, preferably at least one of tetrahydrofuran and acetonitrile.

3. The preparation method according to claim 1, characterized in that: The reaction temperature of step S1 is 55-85°C, preferably 70-85°C; Optionally, the reaction time of step S1 is 1-4 h, preferably 4 h.

4. The preparation method according to claim 1, characterized in that: The R is chlorine or bromine.

5. The preparation method according to claim 1, characterized in that: In step S2, the alcohol solution includes at least one of ethanol, methanol, isopropanol, n-butanol, and tert-butanol, preferably at least one of ethanol, isopropanol, n-butanol, and tert-butanol; Optionally, the mass volume ratio of the compound represented by Formula 3 to the hydrochloric acid alcohol solution is 1 g: (2.0-3.2) mL.

6. The preparation method according to claim 1, characterized in that: The reaction temperature of step S2 is 10-30°C, preferably 10-20°C; Optionally, the reaction time of step S2 is 0.5-2h.

7. The preparation method according to claim 1, characterized in that: In step S3, the acetylation reaction further comprises contacting the compound represented by formula 4 with acetic anhydride to obtain the compound represented by formula 5; Optionally, the acetylation reaction is carried out under the action of a catalyst; Optionally, the catalyst comprises at least one of DMAP, imidazole, triphenylphosphine oxide, mercaptopropionic acid, and n-methylmorpholine, preferably at least one of DMAP, imidazole, and triphenylphosphine oxide; Optionally, the acetylation reaction is carried out in a second solvent, and the second solvent includes at least one of DCM, ethyl acetate, toluene, tetrahydrofuran, dioxane, and acetonitrile, preferably at least one of DCM, tetrahydrofuran, dioxane, and acetonitrile; Optionally, the molar ratio of the compound represented by formula 4 to acetic anhydride and the catalyst is 1:(1.8-2.7):(0.3-0.5), preferably 1:(2.1-2.7):(0.3-0.5).

8. The preparation method according to claim 1, characterized in that: The temperature of the acetylation reaction is 10-40°C, preferably 40°C; Optionally, the acetylation reaction time is 1-3 hours.

9. The preparation method according to claim 1, characterized in that: Step S3 further includes: purifying the product of the acetylation reaction to obtain the compound represented by Formula 5.

10. The preparation method according to claim 9, characterized in that: The purification treatment includes recrystallizing the product of the acetylation reaction using dichloromethane-n-hexane to obtain the compound represented by Formula 5.

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