Preparation method of azelnidipine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of azelnidipine. The preparation method of azelnidipine comprises the following steps: step 1, adding m-nitrobenzaldehyde and isopropyl acetoacetate into a solvent for reaction, and after the reaction is finished, obtaining a reaction solution containing an intermediate or separating the reaction solution to obtain the intermediate; and step 2, adding 1-benzhydryl-3-azetidinol amidino acetate acetate, an alkaline reagent and orthoester, and continuing to react with the intermediate to obtain azelnidipine. The orthoester dehydrating agent is added to catalyze the reaction, so that the target product can be obtained by adopting a post-treatment mode of adding water to crystallize after the reaction is finished, the reaction time is shortened, the impurity content in the system is reduced, and the reaction efficiency is improved; in addition, introduction of redundant organic solvents and inorganic salts is avoided, and the risks that API solvent residues exceed the standard and firing residues are unqualified are reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of azelnidipine. Background Art

[0002] Azelnidipine is a 1,4-dihydropyridine calcium channel blocker developed by Sankyo Co., Ltd. of Japan. It can selectively act on L-type calcium channels and does not affect kidney function when lowering blood pressure. It can be used clinically for hypertensive patients with impaired renal function. The structural formula of Azelnidipine is as follows:

[0003]

[0004] In the synthesis process of azelnidipine disclosed in the prior art, the processing steps after the reaction are relatively complicated and the production cycle is long. For example, the document (Mi Chunlai, Wei Shudong, Bian Yin, et al. Synthesis of Azelnidipine [J]. Chinese Journal of Pharmaceutical Industry, 2012, 43 (11): 885-887. DOI: 10.16522 / j.cnki.cjph.2012.11.024.) discloses a synthesis process of azelnidipine, in which m-nitrobenzaldehyde and isopropyl acetoacetate are first added to isopropanol, reacted under the action of piperidine acetate, and then crystallized and dried to obtain To obtain pure 2-(3-nitrobenzylidene)-isopropyl acetoacetate, and then to obtain azelnidipine crude product by cyclization reaction with amidinoacetic acid-1-diphenylmethylazetidin-3-yl acetate. During post-treatment, first concentrate to remove isopropanol to obtain an oily substance, dissolve in ethyl acetate / water, extract and wash, then dry with anhydrous sodium sulfate to remove water, then concentrate again to remove ethyl acetate, and then recrystallize from methanol and then recrystallize from dichloromethane / cyclohexane to obtain azelnidipine α-crystalline pure product. Part of the route for synthesizing azelnidipine in this document is as follows:

[0005]

[0006] Moreover, in the post-processing process of the document, a variety of organic solvents were introduced into the extraction process, which greatly increased the amount of waste liquid, was not conducive to green production, and increased the risk of residual solvents in azelnidipine (API). Inorganic salts were introduced into the drying and water removal process, which increased the risk of the ignition residue not meeting the standard and thus affecting the product quality.

[0007] Therefore, there is an urgent need to develop a synthesis process for azelnidipine that is lower in cost, more environmentally friendly, lower in risk and simpler in process. Summary of the invention

[0008] Technical problem solved by the present invention: In the synthesis process of azelnidipine disclosed in the prior art, it is impossible to use a simple post-treatment method of directly adding water for crystallization after the reaction is completed. The post-treatment steps used are concentration, extraction and drying, which are complicated, have a long production cycle, and greatly increase production costs. Moreover, during the extraction process, a variety of organic solvents are introduced, which greatly increases the amount of waste liquid, is not conducive to green production, and also increases the risk of solvent residues in the API; in addition, during the drying and dehydration process, inorganic salts are also introduced, which increases the risk of substandard ignition residues and thus affects product quality.

[0009] In view of the above problems, the object of the present invention is to provide a method for preparing azelnidipine.

[0010] Specifically, the present invention provides the following technical solutions:

[0011] In a first aspect, the present invention provides a method for preparing azelnidipine, comprising the following steps:

[0012] Step 1: adding m-nitrobenzaldehyde and isopropyl acetoacetate into a solvent for reaction, and after the reaction is completed, obtaining a reaction liquid containing an intermediate or separating the reaction liquid to obtain the intermediate;

[0013] Step 2: Add 1-benzhydryl-3-azetidinol amidino acetate, alkaline reagent and orthoester to continue reacting with the intermediate to obtain azelnidipine.

[0014] Preferably, in step 2, the orthoester includes orthoformate and / or orthoacetate; more preferably, in step 2, the orthoformate includes one or more selected from the group consisting of trimethyl orthoformate, triethyl orthoformate and tripropyl orthoformate; and / or, more preferably, the orthoacetate includes trimethyl orthoacetate; further preferably, the orthoester includes trimethyl orthoformate and / or triethyl orthoformate; further preferably, the orthoester includes trimethyl orthoformate.

[0015] And / or, preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-2; preferably, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-1.6.

[0016] And / or, preferably, in step 2, the orthoester is an orthoformate, and the molar ratio of the m-nitrobenzaldehyde to the orthoformate is 1:1 to 1.6; more preferably, the molar ratio of the m-nitrobenzaldehyde to the orthoformate is 1:1 to 1.5, and the orthoformate includes trimethyl orthoformate and / or triethyl orthoformate.

[0017] And / or, preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1-1.5; more preferably, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1-1.2; further preferably, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1.04-1.15.

[0018] And / or, preferably, in step 1, m-nitrobenzaldehyde and isopropyl acetoacetate are added to a solvent, the temperature is controlled at 15-30° C., and then an alkaline reagent and an acidic reagent are added.

[0019] More preferably, in step 1, the alkaline reagent includes one or more selected from the group consisting of pyridine, piperazine, methylpiperazine, N,N-diisopropylethylamine, triethylamine and piperidine; further preferably, in step 1, the alkaline reagent includes piperidine and / or pyridine.

[0020] And / or, more preferably, in step 1, the acidic reagent includes one or more selected from the group consisting of acetic acid, formic acid, propionic acid, oxalic acid and tartaric acid; further preferably, in step 1, the acidic reagent includes acetic acid and / or formic acid.

[0021] And / or, more preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.05-0.3; further preferably, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.05-0.2; further preferably, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.1-0.2; further preferably, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.10-0.13; most preferably, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.11-0.12.

[0022] And / or, more preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05-0.3; further preferably, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05-0.2; further preferably, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.08-0.2; further preferably, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.09-0.12; most preferably, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.1-0.11.

[0023] And / or, preferably, in step 1, the solvent includes one or more selected from the group consisting of isopropanol, anhydrous ethanol, n-propanol, n-butanol and tert-butanol; more preferably, the solvent includes isopropanol and / or tert-butanol.

[0024] And / or, preferably, in step 1, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5-15, wherein the unit of mass is g and the unit of solvent is mL; further preferably, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5-10, wherein the unit of mass is g and the unit of solvent is mL.

[0025] And / or, preferably, in step 1, the reaction temperature is 15-35°C; more preferably, in step 1, the reaction temperature is 20-30°C.

[0026] And / or, preferably, in step 1, the reaction time is 10 to 20 hours; more preferably, in step 1, the reaction time is 13 to 16 hours.

[0027] And / or, preferably, after the reaction in step 1 is completed, the intermediate is not isolated, and the 1-benzhydryl-3-azetidinol amidino acetate, alkaline reagent and orthoester described in step 2 are directly added to the reaction solution containing the intermediate for reaction.

[0028] And / or, preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9-1.5; more preferably, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9-1.2; further preferably, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:1-1.1.

[0029] And / or, preferably, in step 2, the alkaline reagent includes one or more selected from the group consisting of triethylamine, N,N-diethylpropylamine, pyridine and piperazine; more preferably, in step 2, the alkaline reagent includes triethylamine and / or N,N-diethylpropylamine.

[0030] And / or, preferably, in step 2, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9-1.5; more preferably, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9-1.1; further preferably, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.99-1.01.

[0031] And / or, preferably, in step 2, the reaction temperature is 45-65°C; more preferably, in step 2, the reaction temperature is 55-65°C.

[0032] And / or, preferably, in step 2, the reaction time is 1 to 3 h; more preferably, in step 2, the reaction time is 1.5 to 2.5 h; further preferably, in step 2, the reaction time is 1.5 to 2 h.

[0033] And / or, preferably, in step 2, water is added after the reaction to crystallize and separate the crude azelnidipine.

[0034] More preferably, in step 2, after the reaction is completed, the temperature is first lowered to 20-30° C., and then water is added for crystallization to separate and obtain the crude azelnidipine.

[0035] And / or, more preferably, in step 2, after the reaction is completed, water is added for crystallization, and the crude azelnidipine is separated, wherein the volume of the added water is 5 to 10 times the mass of the input m-nitrobenzaldehyde, wherein the unit of mass is g, and the unit of water is mL; further preferably, in step 2, the volume of the added water is 8 to 10 times the mass of the input m-nitrobenzaldehyde, wherein the unit of mass is g, and the unit of water is mL;

[0036] And / or, more preferably, in step 2, after the reaction is completed, water is added to crystallize for 5 to 9 hours to separate and obtain the crude azelnidipine; more preferably, in step 2, after the reaction is completed, water is added to crystallize for 6 to 8 hours to separate and obtain the crude azelnidipine;

[0037] And / or, more preferably, in step 2, water is added after the reaction is completed to crystallize, and then the temperature is lowered to 5-15°C for further crystallization to separate and obtain the crude azelnidipine; further preferably, in step 2, water is added after the reaction is completed to crystallize, and then the temperature is lowered to 5-15°C for further crystallization for 1-2h to separate and obtain the crude azelnidipine; most preferably, water is added after the reaction is completed to crystallize, and then the temperature is lowered to 5-15°C for further crystallization for 1.4-1.6h (for example, the temperature is further lowered to 5-15°C for further crystallization for 1.5h) to separate and obtain the crude azelnidipine.

[0038] And / or, more preferably, in step 2, the crude azelnidipine is recrystallized to obtain the refined azelnidipine. More preferably, in step 2, the reagent used for recrystallization is dichloromethane and / or cyclohexane.

[0039] In a second aspect, the present invention provides a method for separating azelnidipine from a reaction liquid after the reaction is completed by regulating the content of the orthoester in the preparation method. The method regulates the content of the orthoester in step 2 of the preparation method so that the reaction liquid after the reaction in step 2 does not need to be extracted, and azelnidipine can be precipitated by a post-treatment method of directly adding water.

[0040] Beneficial Effects of the Invention

[0041] (1) In the synthesis process of azelnidipine, the present invention adds an orthoester dehydrating agent to catalyze the reaction, so that after the reaction is completed, the target product can be obtained by adding water for crystallization, and the reaction time is shortened and the impurity content in the system is reduced, thereby improving the reaction efficiency.

[0042] (2) In the synthesis process of azelnidipine of the present invention, water is directly added for crystallization after the reaction is completed. The operation is simple and the process is greatly simplified. The introduction of excess organic solvents and inorganic salts is avoided, thereby reducing the risk of excessive API solvent residues and unqualified ignition residues. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the mass spectrum of 1-benzhydryl-3-azetidinol amidino acetate acetate prepared in Example 1.

[0044] Figure 2 The 1-benzhydryl-3-azetidinol amidino acetate prepared in Example 1 is 1 HNMR spectrum.

[0045] Figure 3 This is the mass spectrum of azelnidipine obtained in Example 3.

[0046] Figure 4 Azelnidipine obtained in Example 3 1 H NMR spectrum.

[0047] Figure 5 Azelnidipine obtained in Example 3 1 H NMR partial enlargement spectrum.

[0048] Figure 6 Azelnidipine prepared in Example 3 1 H NMR partial enlargement spectrum.

[0049] Figure 7 Azelnidipine obtained in Example 3 1 H NMR partial enlargement spectrum.

[0050] Figure 8 This is the HPLC spectrum of azelnidipine prepared in Example 3.

[0051] Fig. 9 This is the XRD pattern of the α-crystalline azelnidipine prepared in Example 3. DETAILED DESCRIPTION

[0052] At present, in the existing synthesis process of Azelnidipine, the post-processing procedures after the reaction are relatively cumbersome. It is necessary to first reduce pressure and concentrate to remove the reaction solvent, then add organic solvents such as ethyl acetate or dichloromethane for extraction, wash and separate the liquids several times, then add anhydrous sodium sulfate to dry, filter, concentrate, and finally add methanol for crystallization to obtain solidified Azelnidipine. In the actual production process, complicated procedures mean a longer production cycle, which will bring higher production costs. In the above-mentioned extraction process, organic solvents such as ethyl acetate or dichloromethane are introduced, which first increases the amount of waste liquid, which is not conducive to green production, and secondly increases the risk of solvent residues in API. In the above-mentioned drying and dehydration process, inorganic salts such as saturated salt water, anhydrous sodium sulfate or sodium bicarbonate are introduced, which also increases the risk of ignition residue not meeting the standard and thus affecting product quality. Moreover, the synthesis process of Azelnidipine disclosed in the prior art adopts the post-processing procedure of the present invention, that is, the obtained reaction solution is directly added with water for crystallization, and the precipitated substance is in a paste or agglomerated into a spherical viscous substance, which adheres to the inner wall of the reaction vessel and is difficult to disperse, and the target solid product Azelnidipine cannot be obtained.

[0053] As mentioned above, the purpose of the present invention is to provide a method for preparing azelnidipine. The present invention improves the synthesis process of azelnidipine, specifically as follows: First, an orthoester dehydrating agent is introduced, so that after the reaction is completed, a simple operation of adding water and crystallizing can be used to obtain the solid target product azelnidipine, which solves the technical problem that the water added after the reaction in the prior art is a paste-like substance that adheres to the inner wall of the reaction container and cannot be dispersed, so it is necessary to use a complex post-processing process of concentration, extraction and recrystallization; and the introduction of orthoester dehydrating agents greatly shortens the reaction time, and the impurities in the system are significantly reduced. Second, in the post-processing process after the reaction is completed, water is directly added to crystallize and separate to obtain the target solid product azelnidipine, which replaces the complicated operations of concentration, extraction and liquid separation, avoids the introduction of more organic solvents and inorganic salts, significantly shortens the production cycle, reduces production costs, and realizes green and efficient production.

[0054] Among them, in a specific embodiment of the present invention, a method for preparing azelnidipine is provided, comprising the following steps:

[0055] Step 1: adding m-nitrobenzaldehyde (1) and isopropyl acetoacetate into a solvent for reaction to obtain an intermediate or a reaction solution containing an intermediate (3);

[0056] Step 2: Add 1-benzhydryl-3-azetidinol amidinoacetic acid ester acetate (2), an alkaline reagent and an orthoester to continue reacting with the intermediate to obtain azelnidipine.

[0057] In the present invention, the synthetic route of azelnidipine is as follows:

[0058]

[0059] Preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-2. In some embodiments, the molar ratio of m-nitrobenzaldehyde to orthoester can be 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.2, 1:1.22, 1:1.24, 1:1.26, 1:1.28, 1:1.3, 1:1.32, 1:1.34, 1:1.36, 1:1.38, 1:1.4, 1:1.42, 1:1.44, 1:1.46, 1:1.48, 1:1.5, 1:1.52, 1:1.54, 1:1.56, 1:1.58, 1:1. 1:1.6, 1:1.62, 1:1.64, 1:1.66, 1:1.68, 1:1.7, 1:1.72, 1:1.74, 1:1.76, 1:1.78, 1:1.8, 1:1.82, 1:1.84, 1:1.86, 1:1.88, 1:1.9, 1:1.92, 1:1.94, 1:1.96, 1:1.98 or 1:2, or a molar ratio of m-nitrobenzaldehyde to the orthoester within a numerical range consisting of any two of the above specific values ​​as endpoints; more preferably, the orthoester includes orthoformate; further preferably, trimethyl orthoformate includes trimethyl orthoformate and / or triethyl orthoformate; and / or,

[0060] Preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1 to 1.5. In some embodiments, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate may be 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.2, 1:1.22, 1:1.24, 1:1.26, 1:1.28, 1:1.3, 1:1.32, 1:1.34, 1:1.36, 1:1.38, 1:1.4, 1:1.42, 1:1.44, 1:1.46, 1:1.48 or 1:1.5, or a molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate within a numerical range consisting of any two of the above specific numerical values ​​as endpoints; and / or

[0061] Preferably, in step 1, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.05-0.3. In some embodiments, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 1 can be 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.20, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29 or 1:0.3, or a molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 within a numerical range consisting of any two of the above specific numerical values ​​as endpoints; more preferably, the alkaline reagent used in step 1 includes triethylamine; and / or

[0062] Preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05-0.3. In some embodiments, the molar ratio of m-nitrobenzaldehyde to the acidic agent can be 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.2, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29 or 1:0.3, or a molar ratio of m-nitrobenzaldehyde to the acidic agent within a numerical range consisting of any two of the above specific values ​​as endpoints; more preferably, the acidic agent includes acetic acid; and / or

[0063] Preferably, in step 1, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5 to 15, wherein the unit of mass is g and the unit of the solvent is mL. In some embodiments, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5 or 1:15, or a ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent within a numerical range consisting of any two of the above specific numerical values ​​as endpoints; more preferably, the solvent comprises isopropanol; and / or

[0064] Preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9 to 1.5. In some embodiments, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9, 1:0.92, 1:0.94, 1:0.96, 1:0.98, 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.2, 1:1.22, 1:1. : 1.24, 1:1.26, 1:1.28, 1:1.3, 1:1.32, 1:1.34, 1:1.36, 1:1.38, 1:1.4, 1:1.42, 1:1.44, 1:1.46, 1:1.48 or 1:1.5, or a molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate acetate within a numerical range consisting of any two of the above specific numerical values ​​as endpoints; and / or

[0065] Preferably, in step 2, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9-1.5. In some embodiments, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9, 1:0.92, 1:0.94, 1:0.96, 1:0.98, 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.2, 1:1.24, 1:1.2 6, 1:1.28, 1:1.3, 1:1.32, 1:1.34, 1:1.36, 1:1.38, 1:1.4, 1:1.42, 1:1.44, 1:1.46, 1:1.48 or 1:1.5, or a molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 2 within a numerical range consisting of any two of the above specific numerical values ​​as endpoints; more preferably, the alkaline reagent used in step 2 comprises triethylamine; and / or

[0066] Preferably, in step 2, water is added after the reaction is completed for crystallization, and the crude azelnidipine is separated; more preferably, in step 2, the volume of water is 5 to 10 times the mass of m-nitrobenzaldehyde, wherein the unit of mass is g and the unit of water is mL. In some embodiments, the volume of water is 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 times the mass of m-nitrobenzaldehyde, or a multiple of the volume of water relative to the mass of m-nitrobenzaldehyde within a numerical range consisting of any two of the above specific values ​​as endpoints.

[0067] In a specific embodiment of the present invention, the specific steps are as follows:

[0068] Step 1: adding m-nitrobenzaldehyde and isopropyl acetoacetate into a solvent, then controlling the temperature within the range of 15 to 30° C., and then adding an alkaline reagent and an acidic reagent in turn for reaction, reacting for 10 to 20 hours at a temperature of 15 to 35° C. to obtain a reaction solution containing an intermediate; wherein the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1 to 1.5; the molar ratio of m-nitrobenzaldehyde to the alkaline reagent is 1:0.05 to 0.3; the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05 to 0.3; the ratio of the mass of m-nitrobenzaldehyde to the volume of the solvent is 1:5 to 15, wherein the unit of mass is g, and the unit of solvent is mL;

[0069] Step 2: Add 1-diphenylmethyl-3-azetidinol amidino acetate, alkaline reagent and orthoester to the reaction solution containing the intermediate obtained in step 1 to continue to react with the intermediate, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9-1.5, and the molar ratio of m-nitrobenzaldehyde to alkaline reagent is 1:0.9-1.5. The reaction is carried out at a temperature of 45-65° C. for 1-3 hours. After the reaction is completed, the temperature is first lowered to 20-30° C., and then water is added for crystallization. The volume of water added (unit: mL) is 5-10 times the mass of m-nitrobenzaldehyde (unit: g). Crystallization is carried out for 5-9 hours, and then the temperature is lowered to 5-15° C. for further crystallization for 1-2 hours to obtain azelnidipine crude product, which is then recrystallized with dichloromethane and / or cyclohexane to obtain azelnidipine fine product.

[0070] Preferably, the recrystallization comprises the following steps: adding the crude product of azelnidipine to a good solvent and heating it to 30-40°C until it is dissolved and clarified, then adding a poor solvent, cooling and crystallizing to obtain azelnidipine.

[0071] More preferably, the good solvent comprises dichloromethane.

[0072] And / or, more preferably, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the good solvent is 1-7:3-18, wherein the unit of mass is g and the unit of volume is mL;

[0073] And / or, more preferably, the poor solvent includes cyclohexane.

[0074] And / or, more preferably, the volume ratio of the good solvent to the poor solvent is 3-18:12-74.

[0075] And / or, more preferably, the temperature is lowered to 0-10°C for crystallization; further preferably, the temperature is lowered to 0-10°C for crystallization for 8-11 hours.

[0076] Unless otherwise specified, the raw materials used in the present invention are generally commercially available chemically pure reagents.

[0077] In the present invention, the mass spectrum testing instrument is Waters Acquity I-class UPLC / VionIMSQTofMS. 1 The HNMR spectrum was tested by Bruker Avance III-400 NMR. The XRD spectrum was tested by DX-2700 X-ray diffractometer; test method: tube voltage 40 kV, tube current 30 mA, graphite monochromator; wavelength: 1.54059A° (Cu / Kα1); scanning mode: θ / 2θ, step length 0.05° / 1s).

[0078] In order to better understand the technical solution of the present invention, the technical solution of the present invention is described in detail below in conjunction with specific embodiments.

[0079] Example 1

[0080] A method for preparing azelnidipine comprises the following steps:

[0081] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.5 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0082] Step 2: Without separating the intermediate, 25.4g of 1-benzhydryl-3-azetidinol amidoacetate acetate, 6.6g of triethylamine and 7.1g of trimethyl orthoformate were added, and the temperature was raised to 55-65°C and stirred for 1.5h. After the reaction was completed, 100mL of purified water was added dropwise at a temperature of 20-30°C, and the solid precipitated. The mixture was stirred for 6h at a temperature of 5-15°C and stirred for 1.5h. The crude product of Azelnidipine was obtained by filtration and drying. The dried crude product of Azelnidipine was added to 30mL of dichloromethane, heated to 30-40°C to dissolve, and then 120mL of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10°C for crystallization for 8h. The product was filtered and dried to obtain 34.54g of light yellow α-crystalline Azelnidipine, with a yield of 89.6%.

[0083] The preparation method of the 1-benzhydryl-3-azetidinol amidine acetate (also known as 3-amino-3-iminopropionic acid 1-(benzhydryl)-3-azetidinyl acetate) comprises the following steps:

[0084] Add 90 mL of dichloromethane and 41.1 g of anhydrous ethanol to the reaction container, and drip 61.5 g of acetyl chloride at -15 to 10 °C. After dripping, keep the temperature at -10 to 0 °C and stir for 10 to 20 minutes, then add 30.0 g of 1-diphenylmethyl-3-azetidine cyanoacetate (the 1-diphenylmethyl-3-azetidine cyanoacetate can be prepared by referring to the document "Mi Chunlai, Wei Shudong, Bian Yin, et al. Synthesis of Azelnidipine [J]. Chinese Journal of Pharmaceutical Industry, 2012, 43 (11): 885-887. DOI: 10.16522 / j.cnki.cjph.2012.11.024."). After the addition, control the temperature at 0 to 10 °C and react for 16 to 20 hours. Control the temperature at -15 to 20 °C and drip the above reaction solution into 135.0 g of ammonia water. After the addition is completed, control the temperature at 10-20°C and stir for 10-20 minutes, let it stand to separate the liquids, and collect the lower organic phase. Wash the organic phase with 60mL of 5% sodium chloride solution, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure to dry it. Add 30mL of ethyl acetate and 120mL of acetonitrile, raise the temperature to 45-55°C, and add 7.5g of ammonium acetate. After the addition is completed, control the temperature at 45-55°C to react for 4-6 hours, then lower the temperature to 0-10°C, and stir it for 1-2 hours. Centrifuge, wash, and dry to obtain 32.49g of 1-dibenzhydryl-3-azetidinol amidino acetate. The mass spectrum of the obtained 1-dibenzhydryl-3-azetidinol amidino acetate is shown in Figure 1 , MS-ESI[M+H] + :324.2. The obtained 1-diphenylmethyl-3-azetidinol amidino acetate acetate 1 HNMR spectrum see Figure 2 , 1 HNMR (400MHz, DMSO-d6): δ: 7.42 (d, J=7.2Hz, 4H), 7.26 (t, J=7.2Hz, 4H), 7.17 (t, J=7.2Hz, 2H), 5.97 (s , 2H), 4.88-4.85(m, 1H), 4.44(s, 1H), 3.82(s, 1H), 3.44-3.40(m, 2H), 2.86-2.83(m, 2H), 1.90(s, 3H).

[0085] Example 2

[0086] A method for preparing azelnidipine comprises the following steps:

[0087] Step 1: Add 7.5L isopropanol, 1.5kg m-nitrobenzaldehyde and 1.51kg isopropyl acetoacetate into a 30L glass reactor, control the temperature to 15-30°C, add 91g piperidine and 62g glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 14h, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0088] Step 2: Without separating the intermediate, 3.81 kg of 1-benzhydryl-3-azetidinol amidoacetic acid ester acetate, 1.01 kg of triethylamine and 1.08 kg of trimethyl orthoformate were added, and the temperature was raised to 55-65 ° C and stirred for 1.7 hours. After the reaction was completed, 7.5 L of purified water was added dropwise at a temperature of 20-30 ° C, and solids were precipitated. The mixture was stirred for 7 hours at a temperature of 5-15 ° C and stirred for 1.5 hours. The crude product of Azelnidipine was obtained by filtration and drying. The dried crude product of Azelnidipine was added to 5 L of dichloromethane, heated to 30-40 ° C to dissolve, and then 18 L of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10 ° C and crystallized for 10 hours. The product was filtered and dried to obtain 5.07 kg of light yellow α-crystalline Azelnidipine with a yield of 87.8%. Wherein, the preparation method of 1-diphenylmethyl-3-azetidinol amidino acetate is the same as that in Example 1.

[0089] Example 3

[0090] A method for preparing azelnidipine comprises the following steps:

[0091] Step 1: Add 60L isopropanol, 6.15kg m-nitrobenzaldehyde and 6.46kg isopropyl acetoacetate into a 200L enamel reactor, control the temperature to 20-30°C, add 375g piperidine and 255g glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 16h, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0092] Step 2: Without separating the intermediate, 15.62kg 1-benzhydryl-3-azetidinol amidoacetic acid ester acetate, 4.06kg triethylamine and 4.37kg trimethyl orthoformate were added, and the temperature was raised to 55-65℃ and stirred for 1.7h. After the reaction was completed, 60L of purified water was added dropwise at a temperature of 20-30℃, and the solid precipitated. The mixture was stirred for 8h at a temperature of 5-15℃ and stirred for 1.5h. The crude product of Azelnidipine was obtained by filtration and drying. The dried crude product of Azelnidipine was added to 18L of dichloromethane, heated to 30-40℃ to dissolve, and then 74L of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10℃ and the crystallization was carried out for 11h. The product was centrifuged and dried to obtain 21.35kg of light yellow α-crystalline Azelnidipine with a yield of 90.1%. Figure 3 The mass spectrum of azelnidipine obtained in Example 3, MS-ESI [M+H] + :583.2558. Figure 4 Azelnidipine prepared in Example 3 1 H NMR spectrum, Figure 5 , Figure 6 and Figure 7 Here is a partial enlarged picture. 1HNMR (d6-DMSO) δ: 8.81 (1H, s), 8.09 (1H, d), 8.05 (1H, s), 7.63 (1H, d), 7.58 (1 H, t), 7.37-7.22 (8H, m), 7.20-7.14 (2H, m), 6.77 (2H, brs), 4.88-4.83 (1H, m) ,4.81(1H,s),4.79-4.75(1H,m),4.16(1H,s),3.47-3.43(1H,m),3.29-3.25( 1H, m), 2.89-2.86 (1H, m), 2.29 (1H, m), 2.27 (3H, s), 1.18 (3H, d), 0.98 (3H, d); Figure 8 The HPLC spectrum of azelnidipine obtained in Example 3, the chromatographic peak with a retention time of 28.780 min is the chromatographic peak of azelnidipine, and the purity of azelnidipine is 99.94% according to the peak area calculation; Fig. 9 The XRD pattern of the α-crystalline azelnidipine prepared in Example 3. The preparation method of 1-dibenzhydryl-3-azetidinol amidinoacetate acetate is the same as that in Example 1.

[0093] Example 4

[0094] A method for preparing azelnidipine comprises the following steps:

[0095] Step 1: Add 150 mL of isopropanol, 20.0 g of m-nitrobenzaldehyde and 21.2 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 1.3 g of piperidine and 0.9 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0096] Step 2: Without separating the intermediate, 51.2g of 1-benzhydryl-3-azetidinol amidoacetate acetate, 13.3g of triethylamine and 21.5g of trimethyl orthoformate were added, and the temperature was raised to 55-65°C and stirred for 1.5h. After the reaction was completed, 150mL of purified water was added dropwise at a temperature of 20-30°C, and solids were precipitated. The mixture was stirred for 6h at a temperature of 5-15°C and stirred for 1.5h. The crude product of Azelnidipine was obtained by filtration and drying. The dried crude product of Azelnidipine was added to 60mL of dichloromethane, heated to 30-40°C to dissolve, and then 240mL of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10°C and the crystallization was carried out for 8h. The product was filtered and dried to obtain 66.07g of light yellow α-crystalline Azelnidipine, with a yield of 85.7%. Wherein, the preparation method of 1-diphenylmethyl-3-azetidinol amidino acetate is the same as that in Example 1.

[0097] Example 5

[0098] A method for preparing azelnidipine comprises the following steps:

[0099] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.5 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 14 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0100] Step 2: Without separating the intermediate, 25.3g of 1-benzhydryl-3-azetidinol amidoacetate acetate, 6.6g of triethylamine and 7.2g of trimethyl orthoformate were added, and the temperature was raised to 45-55°C and stirred for 2.5h. After the reaction was completed, 100mL of purified water was added dropwise at a temperature of 20-30°C, and solids were precipitated. The mixture was stirred for 7h at a temperature of 5-15°C and stirred for 1.5h. The crude azelnidipine was obtained by filtration and drying. The dried crude azelnidipine was added to 30mL of dichloromethane, heated to 30-40°C to dissolve, and then 120mL of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10°C for crystallization for 9h. The fine light yellow α-crystalline azelnidipine was obtained by filtration and drying, with a yield of 87.6%. Wherein, the preparation method of 1-diphenylmethyl-3-azetidinol amidino acetate is the same as that in Example 1.

[0101] Example 6

[0102] A method for preparing azelnidipine comprises the following steps:

[0103] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.5 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0104] Step 2: Without separating the intermediate, 25.5g of 1-benzhydryl-3-azetidinol amidoacetic acid ester acetate, 6.6g of triethylamine and 10.6g of triethyl orthoformate were added, and the temperature was raised to 55-65°C and stirred for 1.5h. After the reaction was completed, 100mL of purified water was added dropwise at a temperature of 20-30°C, and solids were precipitated. The mixture was stirred for 6h at a temperature of 5-15°C and stirred for 1.5h. The crude product of Azelnidipine was obtained by filtration and drying. The dried crude product of Azelnidipine was added to 30mL of dichloromethane, heated to 30-40°C to dissolve, and then 130mL of cyclohexane was slowly added dropwise, and the temperature was lowered to 0-10°C and the crystallization was carried out for 8h. The product was filtered and dried to obtain 33.82g of light yellow α-crystalline Azelnidipine, with a yield of 87.7%. Wherein, the preparation method of 1-diphenylmethyl-3-azetidinol amidino acetate is the same as that in Example 1.

[0105] Comparative Example 1

[0106] A method for preparing azelnidipine comprises the following steps:

[0107] Step 1: Place 40 mL of isopropanol, 9.6 g of isopropyl acetoacetate, 0.4 g of glacial acetic acid and 0.4 g of piperidine in a 100 mL reaction flask. Then add 10.0 g of m-nitrobenzaldehyde in batches and stir at 25°C for 16 h. Filter, wash the filter cake with 20 mL of isopropanol, recrystallize with 50 mL of anhydrous ethanol, filter and dry to obtain 15.13 g of a white solid with a yield of 82.5%.

[0108] Step 2: 15.0g of 1-benzhydryl-3-azetidinol amidino acetate, 10.9g of the above white solid, and 7mL of triethylamine were added to 60mL of isopropanol and reacted at 50-60°C for 7h. The solvent was evaporated to obtain a brown oily substance, 100mL of ethyl acetate was added to the oily substance, and the oily substance was washed twice with 50mL of water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the concentrate (oily substance) was added with 150mL of methanol for recrystallization, filtered and dried to obtain yellow crystals, which were then dissolved in 100mL of dichloromethane, and 200mL of cyclohexane was added dropwise at room temperature, and filtered and dried to obtain 18.73g of light yellow azelnidipine, with a yield of 82.2%, and a two-step yield of 67.8%. Among them, the preparation method of 1-benzhydryl-3-azetidinol amidino acetate is the same as that of Example 1.

[0109] Comparative Example 2

[0110] A method for preparing azelnidipine comprises the following steps:

[0111] In a 250 mL reaction flask, add 120 mL of isopropanol, 28.5 g of isopropyl acetoacetate, 1.3 g of glacial acetic acid and 1.2 g of piperidine. Then add 30.0 g of m-nitrobenzaldehyde in batches and stir at 25 °C for 16 h. Filter, wash the filter cake with 60 mL of isopropanol, recrystallize with 150 mL of anhydrous ethanol, filter and dry to obtain 46.40 g of a white solid with a yield of 84.3%.

[0112] 45.0 g of 1-benzhydryl-3-azetidinol amidinoacetate acetate, 32.6 g of the above white solid, and 21 mL of triethylamine were added to 180 mL of isopropanol and reacted at 50-60°C for 7 h. The solvent was evaporated under reduced pressure to obtain a brown oil. 180 mL of purified water was added to the oil, and it was observed that the oil aggregated into a spherical viscous substance, which was not dispersed and could not be filtered.

[0113] Comparative Example 3

[0114] A method for preparing azelnidipine comprises the following steps:

[0115] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.5 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 hours, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0116] Step 2: Without separating the intermediate, 25.4g 1-benzhydryl-3-azetidinol amidoacetate acetate and 6.6g triethylamine were added, and the temperature was raised to 55-65°C and stirred for 8h. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a brown oily substance, 100mL ethyl acetate was added to the oily substance, and it was washed twice with 50mL water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to evaporate the solvent, and the concentrate (oily substance) was added with 150mL methanol for recrystallization, filtered and dried to obtain yellow crystals, which were added to 30mL dichloromethane, heated to 30-40°C to dissolve, and then 120mL cyclohexane was slowly dripped, cooled to 0-10°C, and crystallized for 8h, filtered and dried to obtain 21.90g of light yellow α-crystalline azelnidipine fine product, with a yield of 56.8%.

[0117] Comparative Example 4

[0118] A method for preparing azelnidipine comprises the following steps:

[0119] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.6 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 hours, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0120] Step 2: Without isolating the intermediate, 25.6 g of 1-benzhydryl-3-azetidinol amidino acetate and 6.5 g of triethylamine were added, and the temperature was raised to 55-65°C and stirred for 8 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and 150 mL of purified water was added to the concentrate (brown oil). It was observed that the oil agglomerated into a spherical viscous substance, which was not dispersed and could not be filtered.

[0121] Comparative Example 5

[0122] A method for preparing azelnidipine comprises the following steps:

[0123] Step 1: Add 150 mL of isopropanol, 15.0 g of m-nitrobenzaldehyde and 15.9 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.9 g of piperidine and 0.6 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 16 hours, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0124] Step 2: Without isolating the intermediate, 38.2 g of 1-benzhydryl-3-azetidinol amidino acetate and 10.1 g of triethylamine were added, and the temperature was raised to 55-65°C and stirred for 8 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and 150 mL of purified water was added to the concentrate (brown oil). It was observed that the oil agglomerated into a spherical viscous substance, which was not dispersed and could not be filtered.

[0125] Comparative Example 6

[0126] A method for preparing azelnidipine comprises the following steps:

[0127] Step 1: Add 200 mL of isopropanol, 20.0 g of m-nitrobenzaldehyde and 21.1 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 1.3 g of piperidine and 0.8 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0128] Step 2: Without isolating the intermediate, 50.2 g of 1-benzhydryl-3-azetidinol amidinoacetate acetate and 13.5 g of triethylamine were added, and the temperature was raised to 55-65°C and stirred for 8 h. After the reaction was completed, 200 mL of purified water was added dropwise at a temperature of 20-30°C. A whole paste was observed to precipitate at the bottom, which adhered to the wall of the reaction bottle and was difficult to stir or filter.

[0129] Comparative Example 7

[0130] A method for preparing azelnidipine comprises the following steps:

[0131] Step 1: Add 200 mL of isopropanol, 20.0 g of m-nitrobenzaldehyde and 21.3 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 1.2 g of piperidine and 0.8 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 h. Monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0132] Step 2: Without isolating the intermediate, 50.5 g of 1-benzhydryl-3-azetidinol amidinoacetate acetate and 13.5 g of triethylamine were added, and the temperature was raised to 55-65°C and stirred for 1.5 h. 200 mL of purified water was added dropwise at a temperature of 20-30°C, and a viscous substance that agglomerated into a ball was observed to precipitate, which was not dispersed and could not be filtered.

[0133] Comparative Example 8

[0134] A method for preparing azelnidipine comprises the following steps:

[0135] Step 1: Add 150 mL of isopropanol, 15.0 g of m-nitrobenzaldehyde and 15.8 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.9 g of piperidine and 0.6 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 hours, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0136] Step 2: Without isolating the intermediate, 38.1 g of 1-benzhydryl-3-azetidinol amidinoacetate, 9.9 g of triethylamine and 11.1 g of trimethyl orthoformate were added, and the temperature was raised to 80-85°C and refluxed with stirring for 0.5 h. After the reaction was completed, 150 mL of purified water was added dropwise at a temperature of 20-30°C, and a viscous substance that agglomerated into a ball was observed to precipitate, which was not dispersed and could not be filtered.

[0137] Comparative Example 9

[0138] A method for preparing azelnidipine comprises the following steps:

[0139] Step 1: Add 100 mL of isopropanol, 10.0 g of m-nitrobenzaldehyde and 10.5 g of isopropyl acetoacetate into a 250 mL reaction flask, control the temperature to 15-30°C, add 0.6 g of piperidine and 0.4 g of glacial acetic acid in sequence, control the temperature to 20-30°C and stir for 13 hours, and monitor the reaction by HPLC to ensure complete conversion to the intermediate.

[0140] Step 2: Without separating the intermediate, 25.4g 1-benzhydryl-3-azetidinol amidino acetate acetate, 6.5g triethylamine and 7.2g trimethyl orthoformate were added, and the temperature was raised to 80-85°C and refluxed with stirring for 0.5h. After the reaction was completed, the solvent was evaporated, 100mL ethyl acetate was added to the concentrate (oil), washed twice with 50mL water, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to evaporate the solvent, and the concentrate (oil) was added with 150mL methanol for recrystallization, filtered and dried to obtain yellow crystals, and then the crystals were added to 30mL dichloromethane, heated to 30-40°C to dissolve, and then 120mL cyclohexane was slowly dripped, cooled to 0-10°C and kept warm for crystallization for 9h, filtered and dried to obtain 26.21g of light yellow α-crystalline azelnidipine fine product, with a yield of 67.9%.

[0141] The results of the synthesis process in the examples and comparative examples and the yield and purity of azelnidipine obtained are summarized in Tables 1 and 2 below.

[0142] Among them, the present invention 1The detection steps of H NMR spectrum refer to the general rule 0441 of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia. The detection steps of the ESI-MS spectrum of the present invention refer to the general rule 0431 of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia. The detection steps of the HPLC spectrum of the present invention refer to the general rule 0512 of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia. The inspection steps of the residue on ignition of the present invention refer to the general rule 0841 of the fourth volume of the 2020 edition of the Chinese Pharmacopoeia.

[0143] Table 1 Summary of post-treatment methods of the synthesis process of the embodiments and comparative examples

[0144]

[0145] Among them, "continuous addition" in Table 1 means that the intermediate obtained in step 1 is not separated, but the raw materials or reagents such as 1-dibenzhydryl-3-azetidinol amidino acetate acetate described in step 2 are directly added to the reaction solution containing the intermediate obtained after the reaction in step 1 is completed for the next reaction. "Two-step addition" means that the reaction solution containing the intermediate after the reaction in step 1 is separated and purified to obtain the intermediate, and then the obtained intermediate is used as the reaction raw material in step 2 for the next reaction.

[0146] Table 2 Yield and purity analysis of the synthetic process products of the embodiments and comparative examples

[0147]

[0148] From Table 1 and Table 2, we can see that:

[0149] The preparation method of Azelnidipine in Comparative Example 1 refers to the synthesis process of Azelnidipine disclosed in the prior art, and the total yield obtained is 67.8%, which is much lower than the total yield of Azelnidipine prepared in Examples 1-6 of the present invention, which is 85.7% to 90.1%. Comparative Example 2 is only to replace the extraction with ethyl acetate in the post-treatment process of Comparative Example 1 with first reducing pressure and concentrating to remove the solvent, and then adding water for crystallization. As a result, only a spherical viscous substance was precipitated, which was not dispersed and could not be filtered, and the solid product of Azelnidipine was not obtained.

[0150] It can be seen from the data of Comparative Examples 1 and 2 that in the synthesis process of azelnidipine disclosed in the prior art (i.e., Comparative Example 1), the azelnidipine solid can only be isolated by a complex post-treatment method of concentration, extraction, drying, filtration, re-concentration and two recrystallizations in sequence.

[0151] Comparative Example 3 is different from Example 1 in that trimethyl orthoformate is not added, and the post-processing method of step 2 is also different. It adopts a complex post-processing method of concentration, extraction, drying, filtration, re-concentration and two recrystallizations. The total yield obtained is 56.8%, which is much lower than the total yield of 85.7% to 90.1% of azelnidipine prepared in Examples 1-6 of the present invention. Comparative Example 4 is different from Comparative Example 3 in that only the post-processing method of step 2 is different. It adopts a post-processing method of directly adding water after concentrating to remove the solvent. As a result, only a viscous mass agglomerated into a ball is precipitated, which is not dispersed and cannot be filtered, and no azelnidipine solid is obtained.

[0152] From the data of Comparative Examples 3 and 4, it can be seen that without adding the orthoester, other processes for synthesizing azelnidipine using the present invention (excluding the post-treatment method) can only use a complex post-treatment method of concentration, extraction, drying, filtration, re-concentration and two recrystallizations in sequence to separate the azelnidipine solid. Adding water after concentration to remove the solvent cannot separate the azelnidipine solid.

[0153] Compared with Comparative Example 2, Comparative Example 5 is only that the intermediate generated in step 1 is not separated when the materials are added. After the reaction of step 1 is completely converted into the intermediate under HPLC monitoring, the intermediate is not separated, and then 1-diphenylmethyl-3-azetidinol amidine acetate is added. The results of Comparative Example 2 and Comparative Example 5 are similar. Only a viscous substance agglomerated into a ball can be precipitated, which is not dispersed and cannot be filtered, and no azelnidipine solid is obtained.

[0154] Compared with Comparative Example 4, Comparative Example 5 is different only in the reaction time in step 1, and other reaction conditions and post-treatment methods are the same. The results of Comparative Examples 4 and 5 show that even if the reaction time of step 1 is extended, a spherical viscous substance is still obtained, which is not dispersed and cannot be filtered, and the azelnidipine solid cannot be obtained.

[0155] Compared with Comparative Example 4, Comparative Example 6 does not concentrate and evaporate the solvent in the post-treatment process, but directly adds water. Its post-treatment method is the same as the post-treatment method of Examples 1-6. Under this post-treatment method, only a paste can be precipitated, which adheres to the wall of the reaction bottle and is difficult to stir and filter. Azelaic acid solid cannot be obtained.

[0156] Compared with Comparative Example 6, Comparative Example 7 is different only in the reaction time of step 2, and the other reaction conditions and post-treatment methods are the same. The results of Comparative Example 6 and Comparative Example 7 show that both comparative examples failed to produce azelnidipine solid, wherein Comparative Example 6 precipitated a paste after adding water, adhered to the wall of the reaction bottle, was difficult to stir, could not be filtered, and failed to obtain azelnidipine solid, and Comparative Example 7 precipitated a spherical viscous substance after adding water, which was not dispersed, could not be filtered, and failed to obtain azelnidipine solid. This shows that no orthoester is added in step 2, and even if the reaction time of step 2 is extended, the azelnidipine solid cannot be separated.

[0157] Compared with Example 1 of the present invention, Comparative Example 7 only did not add the dehydrating agent trimethyl orthoformate, and the other reaction conditions and post-treatment methods were the same. However, during the post-treatment of Comparative Example 7, a viscous substance that agglomerated into a ball was precipitated after adding water, which was not dispersed and could not be filtered, and no solid azelnidipine was obtained. However, Example 1 of the present invention can directly crystallize after adding water, and the crude azelnidipine can be obtained by filtration and drying. The azelnidipine obtained after recrystallization has a purity of 99.92% and a yield of 89.6%.

[0158] Compared with Example 1, in Comparative Example 8, only the reaction temperature in step 2 is increased to 80-85°C, and the reaction time of this step is adaptively shortened, and the feeding and other reaction conditions are the same. Both adopt the post-treatment method of adding water directly without concentration, but in Comparative Example 8, a viscous substance agglomerated into a ball is precipitated after adding water, which is not dispersed and cannot be filtered, and the solid Azelnidipine cannot be obtained. In Example 1, after adding water, crystallization can be directly performed, and the crude Azelnidipine can be obtained by filtering and drying, and the Azelnidipine obtained by recrystallization has a purity of 99.92% and a yield of 89.6%.

[0159] Compared with Comparative Example 8, Comparative Example 9 is different only in the post-treatment process. Comparative Example 9 adopts the post-treatment methods of concentration, extraction, drying, filtration, re-concentration and two recrystallizations in sequence to obtain the azelnidipine product, but the yield is only 67.9%, which is much lower than the total yield of 85.7% to 90.1% of azelnidipine prepared in Examples 1-6.

[0160] The above is a specific description of a feasible embodiment of the present invention, but the embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the technical spirit of the present invention should be included in the patent scope of the present invention.

Claims

1. A method for preparing azelnidipine, characterized in that: The following steps are involved: Step 1: adding m-nitrobenzaldehyde and isopropyl acetoacetate into a solvent for reaction, and after the reaction is completed, obtaining a reaction liquid containing an intermediate or separating the reaction liquid to obtain the intermediate; Step 2: Add 1-benzhydryl-3-azetidinol amidino acetate, alkaline reagent and orthoester to continue reacting with the intermediate to obtain azelnidipine.

2. The method for preparing azelnidipine according to claim 1, wherein: In step 2, the orthoester includes orthoformate and / or orthoacetate; preferably, in step 2, the orthoformate includes one or more selected from the group consisting of trimethyl orthoformate, triethyl orthoformate and tripropyl orthoformate; and / or, preferably, in step 2, the orthoacetate includes trimethyl orthoacetate; more preferably, in step 2, the orthoester includes trimethyl orthoformate and / or triethyl orthoformate; further preferably, in step 2, the orthoester includes trimethyl orthoformate; And / or, in step 2, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-2; preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-1.6; more preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to orthoester is 1:1-1.

2.

3. The method for preparing azelnidipine according to claim 2, wherein: In step 2, the orthoester is orthoformate, and the molar ratio of m-nitrobenzaldehyde to orthoformate is 1:1 to 1.6; Preferably, in step 2, the molar ratio of the m-nitrobenzaldehyde to the orthoformate is 1:1 to 1.5, and the orthoformate includes trimethyl orthoformate and / or triethyl orthoformate.

4. The method for preparing azelnidipine according to any one of claims 1 to 3, wherein: In step 1, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1-1.5; preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1-1.2; further preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to isopropyl acetoacetate is 1:1.04-1.

15.

5. The method for preparing azelnidipine according to any one of claims 1 to 4, wherein: In step 1, m-nitrobenzaldehyde and isopropyl acetoacetate are added to a solvent, the temperature is controlled at 15 to 30° C., and then an alkaline reagent and an acidic reagent are added; Preferably, in step 1, the alkaline reagent includes one or more selected from the group consisting of pyridine, piperazine, methylpiperazine, N,N-diisopropylethylamine, triethylamine and piperidine; More preferably, in step 1, the alkaline reagent includes piperidine and / or pyridine; And / or, preferably, in step 1, the acidic reagent includes one or more selected from the group consisting of glacial acetic acid, formic acid, propionic acid, oxalic acid and tartaric acid; more preferably, in step 1, the acidic reagent includes glacial acetic acid and / or formic acid.

6. The method for preparing azelnidipine according to claim 5, wherein: In step 1, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.05-0.3; preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.05-0.2; more preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.1-0.2; further preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the alkaline reagent used in step 1 is 1:0.1-0.13; And / or, in step 1, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05-0.3; preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.05-0.2; more preferably, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.08-0.2; further preferably, in step 1, the molar ratio of m-nitrobenzaldehyde to the acidic reagent is 1:0.09-0.

12.

7. The method for preparing azelnidipine according to any one of claims 1 to 6, wherein: In step 1, the solvent includes one or more selected from the group consisting of isopropanol, anhydrous ethanol, n-propanol, n-butanol and tert-butanol; preferably, the solvent includes isopropanol and / or tert-butanol; And / or, in step 1, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5-15, wherein the unit of mass is g and the unit of solvent is mL; preferably, in step 1, the ratio of the mass of the m-nitrobenzaldehyde to the volume of the solvent is 1:5-10, wherein the unit of mass is g and the unit of solvent is mL.

8. The method for preparing azelnidipine according to any one of claims 1 to 7, wherein: In step 1, the reaction temperature is 15 to 35°C; preferably, in step 1, the reaction temperature is 20 to 30°C; And / or, in step 1, the reaction time is 10 to 20 hours; preferably, in step 1, the reaction time is 13 to 16 hours.

9. The method for preparing azelnidipine according to any one of claims 1 to 8, wherein: In step 2, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9 to 1.5; preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:0.9 to 1.2; further preferably, in step 2, the molar ratio of m-nitrobenzaldehyde to 1-diphenylmethyl-3-azetidinol amidino acetate is 1:1 to 1.

1.

10. The method for preparing azelnidipine according to any one of claims 1 to 9, wherein: In step 2, the alkaline reagent includes one or more selected from the group consisting of triethylamine, N,N-diethylpropylamine, pyridine and piperazine; more preferably, in step 2, the alkaline reagent includes triethylamine and / or N,N-diethylpropylamine; And / or, in step 2, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9-1.5; preferably, in step 2, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.9-1.1; more preferably, in step 2, the molar ratio of the m-nitrobenzaldehyde to the alkaline reagent used in step 2 is 1:0.99-1.

01.

11. The method for preparing azelnidipine according to any one of claims 1 to 10, wherein: In step 2, the reaction temperature is 45 to 65°C; preferably, in step 2, the reaction temperature is 55 to 65°C; And / or, in step 2, the reaction time is 1 to 3 h; preferably, in step 2, the reaction time is 1.5 to 2.5 h; more preferably, in step 2, the reaction time is 1.5 to 2 h.

12. The method for preparing azelnidipine according to any one of claims 1 to 11, wherein: In step 2, after the reaction is completed, water is added for crystallization to separate and obtain azelnidipine crude product; Preferably, in step 2, after the reaction is completed, the temperature is first lowered to 20-30° C., and then water is added for crystallization; And / or, preferably, in step 2, the volume of water is 5 to 10 times the mass of m-nitrobenzaldehyde, wherein the unit of mass is g and the unit of water is mL; more preferably, in step 2, the volume of water is 8 to 10 times the mass of m-nitrobenzaldehyde, wherein the unit of mass is g and the unit of water is mL; More preferably, the crystallization is carried out for 5 to 9 hours after the addition of water; further preferably, the crystallization is carried out for 6 to 8 hours after the addition of water; Still more preferably, the temperature is further lowered to 5-15° C. for further crystallization; More preferably, the temperature is further lowered to 5-15° C. for further crystallization for 1-2 hours; Most preferably, the temperature is then lowered to 5-15°C for further crystallization for 1.4-1.6 hours.

13. The method for preparing azelnidipine according to claim 12, wherein: In step 2, the crude product of Azelnidipine is recrystallized to obtain the refined product of Azelnidipine; Preferably, in step 2, the reagent used for recrystallization is dichloromethane and / or cyclohexane.

14. A method for separating azelnidipine from a reaction solution after the reaction by regulating the content of the orthoester in the preparation method according to any one of claims 1 to 13, characterized in that: By adjusting the content of the orthoester in step 2 of the preparation method according to any one of claims 1 to 13, the reaction solution after the reaction in step 2 does not need to be extracted, and azelnidipine can be precipitated by directly adding water for post-treatment.

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