A preparation method of large-particle azelnidipine

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing azelnidipine with large particle size. The method comprises the following steps: step 1: adding azelnidipine crude product to a good solvent, heating to 30-40°C; step 2: cooling, adding a poor solvent, and performing the first crystallization; step 3: heating to 28-33°C, adding a poor solvent, and performing the second crystallization; step 4: cooling to 18-23°C, and performing the third crystallization; step 5: continuing to cool to 8-12°C, and performing the fourth crystallization; step 6: further cooling to 0-5°C, and performing the fifth crystallization, and separating and obtaining azelnidipine; wherein, in step 1, the good solvent is dichloromethane; in steps 2 and 3, the poor solvent is n-heptane. The D90 particle size of the azelnidipine obtained by the present invention is above 110 μm, which can realize the efficient separation of azelnidipine, reduce the production energy consumption, and the yield and purity of the obtained azelnidipine are high, which is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing large-particle azelnidipine. Background Art

[0002] Azelnidipine is a third-generation DHP calcium antagonist. It mainly works by reversibly inhibiting the voltage-dependent calcium influx of L-type calcium channels on the cell membrane, dilating peripheral blood vessels and thus lowering blood pressure. It can be used to treat mild, moderate and severe essential hypertension. It can also be used for hypertensive patients with diseases such as diabetes and renal dysfunction, as well as patients with severe hypertension. While controlling blood pressure, it has relatively little adverse effect on concomitant diseases. It can play a certain auxiliary therapeutic role in improving myocardial blood supply and relieving angina pectoris by dilating coronary arteries. At the same time, the effect on cardiac function is relatively mild and is not easy to cause adverse reactions such as reflex tachycardia. The structural formula of azelnidipine is as follows:

[0003]

[0004] In the synthesis process of azelnidipine disclosed in the prior art, the particle size of azelnidipine precipitated after the reaction is too small. In order to efficiently separate it from impurities, it is necessary to use a filter medium with a smaller pore size and / or a centrifuge with a higher centrifugal speed for separation. However, the pore size of the filter medium is too small, which is not conducive to the rapid separation of solids and liquids, resulting in more impurities in the product; and each step of the centrifugal speed of the centrifuge increases the equipment and technical requirements, and greatly increases the production cost. In general, the filtration and washing of small-particle azelnidipine particles have high requirements for the filter medium and / or centrifuge, and are time-consuming and costly, which significantly increases the production cost and is not conducive to industrial production. Japanese patent JP2010083888A (Japanese Patent 2010-83888) prepared azelnidipine in α-crystal form by direct crystallization using a solvent method. Generally, direct crystallization using a solvent method will cause the crystal nucleus to form rapidly, inhibit crystal growth, and thus make the resulting crystal form smaller in particle size; even through multiple recrystallizations, it is difficult to obtain an ideal large-particle size crystal form. Therefore, how to prepare azelnidipine with larger particles that are easier to separate is of great research significance. Summary of the invention

[0005] The technical problem solved by the present invention is as follows: the particle size of the azelnidipine product obtained by the synthesis process of azelnidipine disclosed in the prior art is relatively small, and a filter medium with a smaller pore size and / or a centrifuge with a higher centrifugal speed is required, which has the technical problems of long time consumption and large loss, significantly increases the production cost, and is not conducive to industrial production.

[0006] In view of the above problems, the present invention aims to provide a method for preparing large-particle azelnidipine.

[0007] Specifically, the present invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides a method for preparing azelnidipine, comprising the following steps:

[0009] Step 1: Add crude azelnidipine to a good solvent and heat to 30-40°C;

[0010] Step 2: Cooling, adding a poor solvent, and performing the first crystallization;

[0011] Step 3: Raise the temperature to 28-33°C, add a poor solvent, and perform a second crystallization;

[0012] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0013] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0014] Step 6: further cooling to 0-5°C, performing a fifth crystallization to separate and obtain azelnidipine;

[0015] Wherein, in step 1, the good solvent is dichloromethane; in steps 2 and 3, the poor solvent is n-heptane; and the D90 particle size of the azelnidipine obtained in step 6 is above 110 μm.

[0016] Preferably, in step 1, the volume of the good solvent is 2 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 1, the volume of the good solvent is 3 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; further preferably, in step 1, the volume of the good solvent is 3.5 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g. And / or

[0017] Preferably, in step 1, the reaction time is 10 to 30 minutes; more preferably, the reaction time is 25 to 30 minutes. And / or

[0018] Preferably, in step 2, the temperature is lowered to 20-25°C. And / or

[0019] Preferably, in step 2, the volume of the poor solvent is 5 to 9 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 2, the volume of the poor solvent is 6.5 to 7.5 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; further preferably, in step 2, the volume of the poor solvent is 6.8 to 7.2 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g. And / or

[0020] Preferably, in step 2, the first crystallization is static crystallization; more preferably, in step 2, the crystallization time is 30 to 60 minutes; further preferably, in step 2, the crystallization time is 30 to 35 minutes.

[0021] and / or

[0022] Preferably, in step 3, the volume of the poor solvent is 3 to 5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 3, the volume of the poor solvent is 3.5 to 4.5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; further preferably, in step 3, the volume of the poor solvent is 3.8 to 4.2 times the mass of azelnidipine, wherein the unit of volume is mL and the unit of mass is g. And / or

[0023] Preferably, in step 3, the second crystallization is stirring crystallization; more preferably, in step 3, the crystallization time is 20 to 40 minutes; further preferably, in step 3, the crystallization time is 28 to 32 minutes.

[0024] and / or

[0025] Preferably, in step 4, the third crystallization is static crystallization; more preferably, in step 4, the crystallization time is 30 to 60 minutes; further preferably, in step 4, the crystallization time is 58 to 60 minutes.

[0026] and / or

[0027] Preferably, in step 5, the cooling rate is 1-2°C / min. and / or

[0028] Preferably, in step 5, the fourth crystallization is stirring crystallization; more preferably, in step 5, the crystallization time is 1 to 2 hours; further preferably, in step 5, the crystallization time is 1.5 to 2 hours. And / or

[0029] Preferably, in step 6, the fifth crystallization is stirring crystallization; more preferably, in step 6, the crystallization time is 3 to 5 hours; further preferably, in step 6, the crystallization time is 3.5 to 4.5 hours. And / or

[0030] Preferably, in step 1, the crystal form of the crude azelnidipine is α-crystal form. And / or

[0031] Preferably, the crystal form of the azelnidipine obtained in step 6 is an α-crystal form. And / or

[0032] Preferably, the D90 particle size of the azelnidipine obtained in step 6 is 120 to 250 μm; more preferably, the D90 particle size of the azelnidipine obtained in step 6 is 160 to 250 μm. And / or

[0033] Preferably, step 6 further comprises a step of cooling and crystallizing after cooling and crystallizing.

[0034] In a second aspect, the present invention provides a method for regulating the particle size of azelnidipine by adjusting the ratio of dichloromethane as a good solvent and n-heptane as a poor solvent, the dissolution temperature and the gradient cooling crystallization conditions in the preparation method of azelnidipine, comprising the following steps:

[0035] Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 2-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0036] Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0037] Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 3-5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0038] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0039] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0040] Step 6: Further cool the mixture to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is greater than 110 μm; preferably, the D90 particle size of the azelnidipine is 120-250 μm; more preferably, the D90 particle size of the azelnidipine is 160-250 μm.

[0041] Preferably, the method comprises the following steps:

[0042] Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0043] Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 6.8 to 7.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0044] Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 3.8-4.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0045] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0046] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0047] Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 235-240 μm.

[0048] Or, preferably, the method comprises the following steps:

[0049] Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0050] Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 5.8 to 6.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0051] Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 2.8-3.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0052] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0053] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0054] Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 163-167 μm.

[0055] Or, preferably, the method comprises the following steps:

[0056] Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0057] Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 8.5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0058] Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 4.6-5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0059] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0060] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0061] Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 169-173 μm.

[0062] Beneficial Effects of the Invention

[0063] (1) The present invention adjusts the type and ratio of good solvent and poor solvent, dissolution temperature, and gradient temperature rise and fall process and conditions to obtain α-crystalline azelnidipine with a D90 particle size of more than 110 μm, which can achieve efficient separation of azelnidipine, reduce production energy consumption, and be more conducive to industrial production. At the same time, the product purity of azelnidipine obtained by the preparation method of azelnidipine of the present invention reaches more than 99.5%.

[0064] (2) The preparation method of large-particle azelnidipine of the present invention is simple to operate, the product quality is controllable, and it is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 This is the particle size distribution diagram of azelnidipine prepared in Example 1.

[0066] Figure 2 This is the HPLC chart of azelnidipine prepared in Example 1.

[0067] Figure 3 This is the XRD pattern of azelnidipine prepared in Example 1.

[0068] Figure 4 This is the particle size distribution diagram of azelnidipine prepared in Example 2.

[0069] Figure 5 This is the HPLC chart of azelnidipine prepared in Example 2.

[0070] Figure 6 This is the particle size distribution diagram of azelnidipine prepared in Example 3.

[0071] Figure 7 This is the HPLC chart of azelnidipine prepared in Example 3.

[0072] Figure 8 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 1.

[0073] Fig. 9 This is the HPLC chart of azelnidipine prepared in Comparative Example 1.

[0074] Fig.10 This is the HPLC chart of azelnidipine prepared in Comparative Example 2.

[0075] Fig.11 This is the HPLC chart of azelnidipine prepared in Comparative Example 3.

[0076] Fig.12 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 4.

[0077] Fig.13 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 6.

[0078] Fig.14 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 8.

[0079] Fig.15 This is the HPLC chart of azelnidipine prepared in Comparative Example 8.

[0080] Fig.16 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 9.

[0081] Fig.17 This is the particle size distribution diagram of azelnidipine prepared in Comparative Example 10. DETAILED DESCRIPTION

[0082] For the crystallization of azelnidipine, recrystallization is the most ideal separation and purification method. Through solid-liquid separation, azelnidipine and impurities are effectively separated, so that a high-purity azelnidipine product can be obtained. However, if the particle size of the azelnidipine solid particles precipitated in the recrystallization is too small, in order to separate the impurities and the azelnidipine product as much as possible, it is necessary to use a filter medium with a smaller pore size and a high-speed centrifuge for centrifugation. The pore size of the filter medium is too small, which is not conducive to the rapid separation of solids and liquids, resulting in more impurities in the product; and each increase in the centrifugal speed of the centrifuge poses a huge challenge to the equipment and technical requirements, and the cost will increase significantly. Therefore, the filtration and washing of small-size particles have high requirements for the centrifuge, and are time-consuming and costly, resulting in a significant increase in production costs, which is not conducive to industrial production requirements.

[0083] In view of the above technical problems, the purpose of the present invention is to provide a method for preparing large-particle azelnidipine. The method for preparing large-particle azelnidipine of the present invention, by regulating the type, proportion, dissolution temperature of the solvent used for crystallization of the azelnidipine product and the conditions of crystallization using gradient cooling, has simple process operation and controllable product quality, so that the particle size of the obtained azelnidipine reaches more than 110 microns, reducing production energy consumption. At the same time, the product purity of azelnidipine can also reach more than 99.5%.

[0084] In the present invention, D50 represents the particle size corresponding to the cumulative particle size distribution volume percentage of a sample reaching 50%. Its physical meaning is that particles with a particle size larger than it account for 50% of the total particle volume, and particles with a particle size smaller than it also account for 50% of the total particle volume. D50 is also called the median diameter or median particle size. D90 represents the particle size corresponding to the cumulative particle size distribution volume percentage of a sample reaching 90%. Its physical meaning is that particles with a particle size less than or equal to it account for 90% of the total particle volume.

[0085] The first object of the present invention is to provide a method for preparing azelnidipine, comprising the following steps:

[0086] Step 1: Add crude azelnidipine into dichloromethane and heat to 30-40°C;

[0087] Step 2: Cooling the solution, adding n-heptane to the solution obtained in step 1, and performing the first crystallization;

[0088] Step 3: Raise the temperature to 28-33°C, continue to add n-heptane, and perform a second crystallization;

[0089] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0090] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0091] Step 6: Further cool the mixture to 0-5°C and perform the fifth crystallization to separate and obtain azelnidipine, the particle size of which is above 110 μm.

[0092] The second object of the present invention is to provide a method for regulating the particle size of azelnidipine by adjusting the ratio of dichloromethane as a good solvent and n-heptane as a poor solvent, the dissolution temperature and the gradient cooling crystallization conditions in the preparation method of azelnidipine, the method comprising the following steps:

[0093] Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 2-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0094] Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0095] Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 3-5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g;

[0096] Step 4: Cooling to 18-23°C and performing the third crystallization;

[0097] Step 5: Continue to cool to 8-12°C and perform the fourth crystallization;

[0098] Step 6: Further cool the mixture to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is greater than 110 μm; preferably, the D90 particle size of the azelnidipine is 120-250 μm; more preferably, the D90 particle size of the azelnidipine is 160-250 μm.

[0099] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 1, the volume of the good solvent is 2 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g. In some embodiments, the volume of the good solvent is 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4 times the quality of the crude azelnidipine, or the multiple of the volume of the good solvent within the numerical range consisting of any two of the above specific numerical values ​​as endpoints relative to the quality of the crude azelnidipine; and / or,

[0100] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 1, the reaction time is 10 to 30 minutes. In some embodiments, the reaction time is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 minutes, or the reaction time within the numerical range consisting of any two of the above specific values ​​as endpoints; and / or,

[0101] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of dichloromethane as a good solvent and n-heptane as a poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 2, the volume of the poor solvent is 5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g. In some embodiments, the volume of the poor solvent is 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9 or 9 times the quality of the crude azelnidipine, or the volume of the poor solvent within the numerical range consisting of any two of the above specific numerical values ​​as endpoints relative to the quality of the crude azelnidipine; and / or,

[0102] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 2, the time for the first crystallization is 30 to 60 minutes. More preferably, the first crystallization is static crystallization. In some embodiments, the time for the first crystallization is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes, or the first crystallization time is within the numerical range consisting of any two of the above specific values ​​as endpoints, more preferably the first static crystallization time; and / or,

[0103] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 3, the volume of the poor solvent is 3 to 5 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g. In some embodiments, the volume of the poor solvent is 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 times the quality of the crude azelnidipine, or the multiple of the volume of the poor solvent within the numerical range consisting of any two of the above specific numerical values ​​as endpoints relative to the quality of the crude azelnidipine; and / or,

[0104] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 3, the time of the second crystallization is 20 to 40 minutes. More preferably, the second crystallization is stirring crystallization. In some embodiments, the time of the second crystallization is 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 minutes, or the time of the second crystallization is within the numerical range consisting of any two of the above specific values ​​as endpoints, more preferably the time of the second stirring crystallization; and / or,

[0105] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 4, the time for the third crystallization is 30 to 60 minutes. More preferably, the third crystallization is static crystallization. In some embodiments, the time for the third crystallization is 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes, or the time for the third crystallization is within the numerical range consisting of any two of the above specific values ​​as endpoints, more preferably the time for the third static crystallization; and / or,

[0106] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 5, the time for the fourth crystallization is 1 to 2 hours. Preferably, the fourth crystallization is stirring crystallization. In some embodiments, the time for the fourth crystallization is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 hours, or the time for the fourth crystallization is within the numerical range consisting of any two of the above specific numerical values ​​as endpoints, more preferably the time for the fourth stirring crystallization; and / or,

[0107] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 6, the time for the fifth crystallization is 3 to 5 hours. Preferably, the fifth crystallization is stirring crystallization. In some embodiments, the time for the fifth crystallization is 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 hours, or the time for the fifth crystallization is within the numerical range consisting of any two of the above specific numerical values ​​as endpoints, more preferably the time for the fifth stirring crystallization; and / or,

[0108] Preferably, in the method for preparing azelnidipine or the method for regulating the particle size of azelnidipine by adjusting the ratio of the dichloromethane as the good solvent and the n-heptane as the poor solvent in the method for preparing azelnidipine, the dissolution temperature and the gradient cooling crystallization conditions, in step 6, the D90 particle size of the azelnidipine obtained is 120 to 250 μm. In some embodiments, the D90 particle size of the azelnidipine is 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 μm, or the D90 particle size of azelnidipine within the numerical range consisting of any two of the above specific values ​​as endpoints.

[0109] Unless otherwise specified, the raw materials used in the present invention are generally chemically pure reagents commonly sold on the market. In the present invention, the XRD spectrum test instrument is a DX-2700 ray diffractometer; the test method is: tube voltage 40kV, tube current 30mA, graphite monochromator; wavelength: 1.54059A° (Cu / Kα1); scanning mode: θ / 2θ, step length 0.05° / 1s).

[0110] 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.

[0111] Example

[0112] Preparation of crude azelnidipine

[0113] A method for preparing azelnidipine crude product, the synthesis route of which is as follows:

[0114]

[0115] Wherein, the preparation method of the crude azelnidipine comprises the following steps:

[0116] Step 1: Preparation of 1-diphenylmethyl-3-azetidinol (Compound 4)

[0117] Add 21.85g (120mmol) of benzhydrylamine (compound 2) and 11g (120mmol) of epichlorohydrin (compound 3) to a reaction flask, add 80mL of methanol, stir at 45°C in the dark for 10h, and reflux for 12h. Evaporate the solvent under reduced pressure, wash the residue with acetone, and set aside the solid after washing. Evaporate the solvent in the washing liquid, dissolve the residue in 50mL of methanol, and reflux for 12h. Evaporate the solvent under reduced pressure, combine the residue with the above solid, add 90mL of dichloromethane, stir for 15min, wash with saturated sodium bicarbonate solution, separate the organic layer, and dry over anhydrous magnesium sulfate. Evaporate the solvent under reduced pressure to obtain a colorless crystalline solid, namely 1-benzhydryl-3-azetidinol (compound 4).

[0118] Step 2: Preparation of 1-benzhydryl-3-azetidinium cyanoacetate (Compound 5)

[0119] 6.8 g (80 mmol) of nitrile acetic acid and 19.39 g (80 mmol) of compound 4 were added to a reaction flask, 150 mL of tetrahydrofuran was added, stirred to dissolve, and then 20.3 g (100 mmol) of N, N-dicyclohexylcarbodiimide (DCC) was added, and stirred at 55 ° C for 11 h. The reactants were cooled, filtered, the filter cake was rinsed with a small amount of tetrahydrofuran, the filtrate was combined, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a viscous liquid product, that is, nitrile acetic acid-1-diphenylmethyl-3-azetidinium ester (compound 5), which was directly used in the next step without purification.

[0120] Step 3: Preparation of 3-amino-3-iminopropionic acid 1-(diphenylmethyl)-3-azetidinium acetate (Compound 6)

[0121] 23.99g (78mmol) of compound 5 and 3.59g (78mmol) of ethanol were added to a reaction flask, and 550mL of chloroform was added. The mixture was stirred and dissolved in an ice-salt bath. Hydrogen chloride gas was introduced into the reaction solution for 30min and placed in an ice-salt bath for 24h. The mixture was naturally warmed to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in 300mL of chloroform. Ammonia gas was introduced into the solution under ice-salt bath conditions for 1h, and the precipitated salt was filtered off. The solvent was evaporated under reduced pressure, and the residue was dissolved in 80mL of acetonitrile. 6.01g (78mmol) of ammonium acetate was added under stirring, and the temperature was raised to 55°C and kept warm for 1h. The unreacted ammonium acetate was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate and dried in vacuo to obtain colorless crystals, i.e., 3-amino-3-iminopropionic acid 1-(diphenylmethyl)-3-azetidinium acetate acetate (compound 6).

[0122] Step 4: Preparation of isopropyl 2-(3-nitrobenzylidene)acetoacetate (Compound 9)

[0123] 11.2 g (100 mmol) of isopropyl acetoacetate (Compound 7) and 25.92 g (180 mmol) of m-nitrobenzaldehyde (Compound 8) were added to a reaction bottle with a water separator, 30 mL of dry toluene was added, 0.2 g (3.3 mmol) of glacial acetic acid and 0.28 g (3.3 mmol) of piperidine were added dropwise, and the mixture was refluxed for 3.5 h. After cooling, the reaction solution was washed with water, sodium bicarbonate solution, water, and saturated brine in sequence, and dried. The solvent was evaporated under reduced pressure, and the obtained oil was recrystallized with 90% by volume ethanol aqueous solution to obtain 2-(3-nitrobenzylidene) isopropyl acetoacetate (Compound 9).

[0124] Step 5: Preparation of crude azelnidipine

[0125] 24.38g (63.6mmol) of compound 6 and 17.62g (63.6mmol) of compound 9 were added to a reaction flask, 300mL of isopropanol was added, stirred to dissolve, and then 3.45g (64mmol) of sodium methoxide was added and refluxed for 2h. Cooled to room temperature, filtered, concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate to obtain crude azelnidipine (compound 1). The crude azelnidipine obtained was detected by nuclear magnetic resonance spectroscopy, NMR spectrum (CDCl3), δ: 1.07 (3H, d, J = 5.9Hz), 1.25 (3H, d, J = 5.9Hz), 2.35 (3H, s), 2.67-2.84 (1H, br), 3.13-3.27 (1H, br), 3.57-3.68 (1H, br) , 3.68-3.83 (1H, br), 4.32-4.44 (1H, br), 4.86-5.12 (3H, m), 6.08-6.36 (3H, br), 7.12-7.55 (11H, m), 7.60 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 8.1 Hz), 8.17 (1H, s). The NMR spectrum proved that the α-crystalline crude azelnidipine had been successfully synthesized.

[0126] Example 1

[0127] A method for preparing azelnidipine comprises the following steps:

[0128] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0129] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0130] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0131] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0132] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0133] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 99.69% (based on the mass of the crude Azelnidipine), and the HPLC purity is 99.95%. The particle size distribution is shown in the figure Figure 1 As shown, from Figure 1 It can be seen that the D50 of the finished product of azelnidipine is 114 μm and the D90 is 238 μm. Figure 3 This is the XRD diagram of the α-crystalline product of Azelaic Acid obtained in Example 1.

[0134] HPLC chart of azelnidipine Figure 2 As shown, from Figure 2 It can be seen that the information of the chromatographic peak is shown in Table 1. The chromatographic peak with a retention time of 36.830 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 99.95%.

[0135] Table 1 HPLC chromatogram analysis data of azelnidipine obtained in Example 1

[0136]

[0137] Example 2

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

[0139] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0140] Step 2: Cool down to 20-25°C, add 60 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0141] Step 3: Stir and heat to 28-33°C, add 30 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0142] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0143] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0144] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 95.66% (based on the mass of the crude Azelnidipine), and the HPLC purity is 96.86%. The particle size distribution diagram is as follows Figure 4 As shown, from Figure 4 It can be seen that the D50 of the finished azelnidipine product is 37.9 μm and the D90 is 165 μm.

[0145] HPLC chart of azelnidipine Figure 5 As shown, from Figure 5 It can be seen that the information of the chromatographic peak is shown in Table 2. The chromatographic peak with a retention time of 36.776 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 96.86%.

[0146] Table 2 HPLC chromatogram analysis data of azelnidipine obtained in Example 2

[0147]

[0148]

[0149] Example 3

[0150] A method for preparing azelnidipine comprises the following steps:

[0151] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystal of azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution:

[0152] Step 2: Cool down to 20-25°C, add 90 mL of n-heptane dropwise, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0153] Step 3: Stir and heat to 28-33°C, add 50 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0154] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0155] Step 4: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0156] Step 5: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 96.13% (based on the mass of the crude Azelnidipine), and the HPLC purity is 96.41%. The particle size distribution diagram is as follows Figure 6 As shown, from Figure 6 It can be seen that the D50 particle size of the finished azelnidipine product is 39 μm, and the D90 particle size is 171 μm.

[0157] HPLC chart of azelnidipine Figure 7 As shown, from Figure 7 It can be seen that the information of the chromatographic peak is shown in Table 3. The chromatographic peak with a retention time of 36.764 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 96.41%.

[0158] Table 3 HPLC chromatogram analysis data of azelnidipine obtained in Example 3

[0159]

[0160]

[0161] Comparative Example 1

[0162] A method for preparing azelnidipine comprises the following steps:

[0163] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 50-65° C. and stir for 30 minutes to obtain a clear solution.

[0164] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0165] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0166] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0167] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0168] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 90.65% (based on the mass of the crude Azelnidipine), and the HPLC purity is 89.72%. The particle size distribution diagram is as follows Figure 8 As shown, from Figure 8 It can be seen that the D50 particle size of the finished azelnidipine product is 26.3 μm, and the D90 particle size is 88.4 μm.

[0169] HPLC chart of azelnidipine Fig. 9 As shown, from Fig. 9 It can be seen that the information of the chromatographic peak is shown in Table 4. The chromatographic peak with a retention time of 36.736 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 89.72%.

[0170] Table 4 HPLC chromatogram analysis data of azelnidipine obtained in Comparative Example 1

[0171]

[0172]

[0173] Comparative Example 2

[0174] A method for preparing azelnidipine comprises the following steps:

[0175] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0176] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0177] Step 3: Stir and heat to 35-45°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0178] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0179] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0180] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline finished product of Azelnidipine. The yield of Azelnidipine is 91.34% (based on the mass of the crude Azelnidipine), and the HPLC purity is 90.87%. The D90 particle size of the finished Azelnidipine is 86.8 μm.

[0181] HPLC chart of azelnidipine Fig.10 As shown, from Fig.10 It can be seen that the information of the chromatographic peak is shown in Table 5. The chromatographic peak with a retention time of 39.752 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 90.87%.

[0182] Table 5 HPLC chromatogram analysis data of azelnidipine obtained in Comparative Example 2

[0183]

[0184]

[0185] Comparative Example 3

[0186] A method for preparing azelnidipine comprises the following steps:

[0187] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0188] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0189] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0190] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0191] Step 5: Cool the system to 13-16°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0192] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline finished product of Azelnidipine. The yield of the finished product of Azelnidipine is 90.98% (based on the mass of the crude product of Azelnidipine), and the HPLC purity is 91.46%. The D90 particle size of the finished product of Azelnidipine is 90.6 μm.

[0193] HPLC chart of azelnidipine Fig.11 As shown, from Fig.11 It can be seen that the information of the chromatographic peak is shown in Table 6. The chromatographic peak with a retention time of 39.663 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 91.46%.

[0194] Table 6 HPLC chromatogram analysis data of azelnidipine obtained in Comparative Example 3

[0195]

[0196] Comparative Example 4

[0197] A method for preparing azelnidipine comprises the following steps:

[0198] Step 1: Add 40 mL of ethyl acetate and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40°C and stir for 30 minutes to obtain a clear solution;

[0199] Step 2: Cool down to 20-25°C, add 70 mL of cyclohexane dropwise, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0200] Step 3: Stir and heat to 28-33°C, add 40 mL of cyclohexane dropwise, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0201] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0202] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0203] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of cyclohexane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 91.67% (based on the mass of the crude Azelnidipine), and the HPLC purity is 90.98%. The particle size distribution is shown in the figure Fig.12 As shown, from Fig.12 It can be seen that the D50 particle size of the finished product of azelnidipine is 20.4 μm, and the D90 particle size is 80.5 μm.

[0204] Comparative Example 5

[0205] A method for preparing azelnidipine comprises the following steps:

[0206] Step 1: Add 40 mL of ethyl acetate and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40°C and stir for 30 minutes to obtain a clear solution;

[0207] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0208] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0209] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0210] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0211] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline finished product of Azelnidipine. The yield of the finished product of Azelnidipine is 92.45% (based on the mass of the crude product of Azelnidipine), and the HPLC purity is 91.33%. The D90 particle size of the finished product of Azelnidipine is 89.9 μm.

[0212] Comparative Example 6

[0213] A method for preparing azelnidipine comprises the following steps:

[0214] Step 1: Add 40 mL of tetrahydrofuran and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0215] Step 2: Cool down to 20-25°C, add 70 mL of cyclohexane dropwise, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0216] Step 3: Stir and heat to 28-33°C, add 40 mL of cyclohexane dropwise, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0217] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0218] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0219] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of cyclohexane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of the Azelnidipine product is 91.11% (based on the mass of the crude Azelnidipine), and the HPLC purity is 91.21%. The particle size distribution is shown in the figure Fig.13 As shown, from Fig.13 It can be seen that the D50 particle size of the finished product of azelnidipine is 6.60 μm, and the D90 particle size is 71.1 μm.

[0220] Comparative Example 7

[0221] A method for preparing azelnidipine comprises the following steps:

[0222] Step 1: Add 40 mL of tetrahydrofuran and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0223] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0224] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0225] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0226] Step 5: Cool the system to 8-12°C at a cooling rate of 1-2°C / min, and stir to crystallize for 2 hours (the fourth crystallization);

[0227] Step 6: Continue to cool to 0-5°C, stir and crystallize for 4 hours (the fifth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline finished product of Azelnidipine. The yield of the finished product of Azelnidipine is 91.39% (based on the mass of the crude product of Azelnidipine), and the HPLC purity is 92.26%. The D90 particle size of the finished product of Azelnidipine is 93.8 μm.

[0228] Comparative Example 8

[0229] A method for preparing azelnidipine comprises the following steps:

[0230] Step 1: Add 40 mL of dichloromethane and 10.0 g of crude α-crystalline azelnidipine into a 500 mL reaction flask, heat to 30-40° C. and stir for 30 minutes to obtain a clear solution;

[0231] Step 2: Cool down to 20-25°C, add 70 mL of n-heptane, stop stirring after the addition is complete, and let stand for crystallization for 30 minutes (first crystallization);

[0232] Step 3: Stir and heat to 28-33°C, add 40 mL of n-heptane, and after the addition is complete, stir and crystallize for 30 minutes (second crystallization);

[0233] Step 4: Cool down to 18-23°C, stop stirring, and let stand for crystallization for 60 minutes (third crystallization);

[0234] Step 5: Cool the system to 0-5°C at a cooling rate of 1-2°C / min, stir and crystallize for 4 hours (the fourth crystallization), centrifuge, rinse the filter cake with a small amount of n-heptane, and dry to obtain the α-crystalline product of Azelnidipine. The yield of Azelnidipine is 95.45% (based on the mass of the crude Azelnidipine), and the HPLC purity is 96.68%. The particle size distribution diagram is shown in FIG. Fig.14 As shown, from Fig.14 It can be seen that the D50 particle size of the finished azelnidipine product is 4.73 μm, and the D90 particle size is 94.5 μm.

[0235] HPLC chart of azelnidipine Fig.15 As shown, from Fig.15 It can be seen that the information of the chromatographic peak is shown in Table 7. The chromatographic peak with a retention time of 37.104 min corresponds to azelnidipine, and the purity of azelnidipine calculated by the percentage of the peak area is 96.68%.

[0236] Table 7 HPLC chromatogram analysis data of azelnidipine obtained in Comparative Example 8

[0237]

[0238]

[0239] Comparative Example 9

[0240] At room temperature and nitrogen atmosphere, 3.8 g of azelnidipine β crystal was dissolved in 8 mL of acetone, and the obtained solution was added dropwise to 40 mL of cyclohexane and stirred for 1 hour. The precipitate of the crystalline product was filtered, washed with cyclohexane and dried in an oven at a temperature of 65-70°C for 24 hours to completely remove the cyclohexane. Thus, azelnidipine α crystals were obtained. The yield of azelnidipine α crystals was 91.90%, and the HPLC purity was 90.17%. The particle size distribution diagram is shown as follows Fig.16 As shown, from Fig.16 It can be seen that the D50 of the azelnidipine α crystal is 3.28 μm, and the D90 is 10.1 μm (the preparation steps of the azelnidipine α crystal in Comparative Example 9 are the same as those in Example 3 of patent application No. JP2010083888A).

[0241] Comparative Example 10

[0242] At room temperature and nitrogen atmosphere, 1.0 g of azelnidipine β crystal was dissolved in 2 mL of methyl ethyl ketone, and the obtained solution was added dropwise to 10 mL of hexane and stirred for 1 hour. The precipitate of the crystalline product was filtered, washed with hexane and dried in an oven at 65-70°C for 24 hours to completely remove the hexane. Thus, azelnidipine α crystals were obtained. The yield of azelnidipine α crystals was 90.90%, and the HPLC purity was 91.24%. The particle size distribution diagram is shown in the figure. Fig.17 As shown, from Fig.17 It can be seen that the D50 of the azelnidipine α crystal is 2.298 μm, and the D90 is 8.887 μm (the preparation steps of the azelnidipine α crystal in Comparative Example 10 are the same as those in Example 9 in Patent Publication No. JP2010083888A).

[0243] Comparative Example 11

[0244] At room temperature and nitrogen atmosphere, 1.0 g of azelnidipine β crystal was dissolved in 2 mL of ethyl acetate, and the obtained solution was added dropwise to 10 mL of heptane and stirred for 1 hour. The precipitate of the crystallized product was filtered, washed with heptane and dried in an oven at a temperature of 65-70°C for 24 hours to completely remove the heptane. Thus, azelnidipine α crystals were obtained. The yield of azelnidipine α crystals was 92.60%, and the HPLC purity was 90.56%. The D50 of azelnidipine α crystals was 3.17 μm, and the D90 was 9.87 μm (the preparation steps of the azelnidipine α crystals in Comparative Example 11 are the same as Example 8 in Patent Publication No. JP2010083888A).

[0245] Among them, the detection steps of the particle size distribution diagram of the present invention refer to the general rules 0982 of the fourth volume of the 2020 edition of the "Chinese Pharmacopoeia", and the detection steps of the HPLC spectrum of the present invention refer to the general rules 0512 of the fourth volume of the 2020 edition of the "Chinese Pharmacopoeia". The detection steps of the NMR data of the present invention refer to the general rules 0441 of the fourth volume of the 2020 edition of the "Chinese Pharmacopoeia".

[0246] The results of the yield, purity and particle size of azelnidipine obtained in Examples and Comparative Examples 1-8 are summarized in Table 8 below.

[0247] Table 8 Yield, purity and D90 particle size of azelnidipine α crystals obtained in Examples and Comparative Examples 1-8

[0248] project Yield (%) purity(%) D90(μm) Example 1 99.69 99.95 238 Example 2 95.66 96.86 165 Example 3 96.13 96.41 171 Comparative Example 1 90.65 89.72 88.4 Comparative Example 2 91.34 90.87 86.8 Comparative Example 3 90.98 91.46 90.6 Comparative Example 4 91.67 90.98 80.5 Comparative Example 5 92.45 91.33 89.9 Comparative Example 6 91.11 91.21 71.1 Comparative Example 7 91.39 92.26 93.8 Comparative Example 8 95.45 96.68 94.5

[0249] As can be seen from Table 8, relative to Example 1, in step 1 of Comparative Example 1, after adding dichloromethane, the temperature was raised to 50-65°C, and the other conditions were the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystal product were significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystal product was 88.4 μm, which was significantly lower than the D90 particle size of 165-238 μm of Examples 1-3.

[0250] Relative to Example 1, step 3 of Comparative Example 2 is heated to 35-45°C, and the other conditions are the same as those of Example 1. The yield and purity of the obtained azelnidipine α-crystal finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystal finished product is 86.8 μm, which is significantly lower than the D90 particle size of 165-238 μm of Examples 1-3.

[0251] Relative to Example 1, step 5 of Comparative Example 3 is cooled to 13-16°C, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystal finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystal finished product is 90.6 μm, which is significantly lower than the D90 particle size of 165-238 μm of Examples 1-3.

[0252] Relative to Example 1, the good solvent dichloromethane in step 1 of Comparative Example 4 is replaced by ethyl acetate, and the poor solvent n-heptane in steps 2 and 3 is replaced by cyclohexane, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystalline finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystalline finished product is 80.5 μm, which is significantly lower than the D90 particle size of 165 to 238 μm of the particle size 1-3 of Examples.

[0253] In Comparative Example 5, relative to Example 1, the good solvent dichloromethane in step 1 is replaced by ethyl acetate, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystal finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystal finished product is 89.9 μm, which is significantly lower than the D90 particle size of 165 to 238 μm of Examples 1-3.

[0254] Relative to Example 1, the good solvent dichloromethane in step 1 of Comparative Example 6 is replaced by tetrahydrofuran, and the poor solvent n-heptane in steps 2 and 3 is replaced by cyclohexane, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystalline finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystalline finished product is 71.1 μm, which is significantly lower than the D90 particle size of 165 to 238 μm of Examples 1-3.

[0255] Relative to Example 1, the good solvent dichloromethane in step 1 of Comparative Example 7 is replaced by tetrahydrofuran, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystalline finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystalline finished product is 93.8 μm, which is significantly lower than the D90 particle size of 165 to 238 μm of Examples 1-3.

[0256] In Comparative Example 8, relative to Example 1, the crystallization step at 8-12°C in Step 5 is omitted, and the other conditions are the same as those in Example 1. The yield and purity of the obtained azelnidipine α-crystal finished product are significantly lower than those of Examples 1-3, and the D90 particle size of the obtained azelnidipine α-crystal finished product is 94.5 μm, which is significantly lower than the D90 particle size of 165-238 μm of Examples 1-3.

[0257] It can be seen from the examples and comparative examples 1-8 that only by adopting the specific preparation process defined in the present invention, i.e., a specific dissolution temperature, gradient cooling conditions and a specific solvent system, can the D90 particle size of the prepared azelaic acid α-crystal finished product be higher, with the D90 particle size being as high as 165 μm or more.

[0258] The results of the yield, purity and particle size of azelnidipine obtained in Examples and Comparative Examples 9-11 are summarized in Table 9 below.

[0259] Table 9 Analysis of the yield, purity and particle size of azelnidipine obtained in Examples and Comparative Examples 9-11

[0260] project Yield (%) purity(%) D50(μm) D90(μm) Example 1 99.69 99.95 114 238 Example 2 95.66 96.86 37.9 165 Example 3 96.13 96.41 39.0 171 Comparative Example 9 91.9 90.17 3.28 10.1 Comparative Example 10 90.9 91.24 2.298 8.887 Comparative Example 11 92.6 90.56 3.17 9.87

[0261] It can be seen from Table 9 that compared with Examples 1-3, the yield and purity of the finished α-crystal azelnidipine obtained in Comparative Example 9 are significantly lower than those of Examples 1-3; the D50 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 9 is 3.28 μm, which is much lower than the D50 particle size of 37.9 to 114 μm of Examples 1-3; the D90 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 9 is 10.1 μm, which is also much lower than the D90 particle size of 165 to 238 μm of Examples 1-3.

[0262] Compared with Examples 1-3, the yield and purity of the finished α-crystal azelnidipine obtained in Comparative Example 10 are significantly lower than those of Examples 1-3; the D50 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 10 is 2.298 μm, which is much lower than the D50 particle size of 37.9 to 114 μm of Examples 1-3; the D90 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 10 is 8.887 μm, which is also much lower than the D90 particle size of 165 to 238 μm of Examples 1-3.

[0263] Compared with Examples 1-3, the yield and purity of the finished α-crystal azelnidipine obtained in Comparative Example 11 are significantly lower than those in the Examples; the D50 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 11 is 3.17 μm, which is much lower than the D50 particle size of 37.9 to 114 μm in Examples 1-3; the D90 particle size of the finished α-crystal azelnidipine obtained in Comparative Example 11 is 9.87 μm, which is also much lower than the D90 particle size of 165 to 238 μm in Examples 1-3.

[0264] It can be seen from the examples and comparative examples 9-11 that the D50 particle size and D90 particle size of the finished α-crystal form of azelaic acid obtained by the preparation method of the present invention are both larger, and are significantly higher than those of the prior art.

[0265] 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 steps include: Step 1: Add crude azelnidipine to a good solvent and heat to 30-40°C; Step 2: Cooling, adding a poor solvent, and performing the first crystallization; Step 3: Raise the temperature to 28-33°C, add a poor solvent, and perform a second crystallization; Step 4: Cooling to 18-23°C and performing the third crystallization; Step 5: Continue to cool to 8-12°C and perform the fourth crystallization; Step 6: further cooling to 0-5°C, performing a fifth crystallization to separate and obtain azelnidipine; Wherein, in step 1, the good solvent is dichloromethane; in steps 2 and 3, the poor solvent is n-heptane; and the D90 particle size of the azelnidipine obtained in step 6 is above 110 μm.

2. The method for preparing azelnidipine according to claim 1, wherein: In step 1, the volume of the good solvent is 2 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; preferably, in step 1, the volume of the good solvent is 3 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 1, the volume of the good solvent is 3.5 to 4 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; And / or, in step 1, the reaction time is 10 to 30 min; preferably, the reaction time is 25 to 30 min.

3. The method for preparing azelnidipine according to claim 1 or 2, wherein: In step 2, the temperature is lowered to 20-25°C; And / or, in step 2, the volume of the poor solvent is 5 to 9 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; preferably, in step 2, the volume of the poor solvent is 6.5 to 7.5 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 2, the volume of the poor solvent is 6.8 to 7.2 times the quality of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; And / or, in step 2, the first crystallization is static crystallization; preferably, in step 2, the crystallization time is 30 to 60 minutes; more preferably, in step 2, the crystallization time is 30 to 35 minutes.

4. The method for preparing azelnidipine according to any one of claims 1 to 3, wherein: In step 3, the volume of the poor solvent is 3 to 5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; preferably, in step 3, the volume of the poor solvent is 3.5 to 4.5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; more preferably, in step 3, the volume of the poor solvent is 3.8 to 4.2 times the mass of azelnidipine, wherein the unit of volume is mL and the unit of mass is g; And / or, in step 3, the second crystallization is stirring crystallization; preferably, in step 3, the crystallization time is 20 to 40 minutes; more preferably, in step 3, the crystallization time is 28 to 32 minutes.

5. The method for preparing azelnidipine according to any one of claims 1 to 4, wherein: In step 4, the third crystallization is static crystallization; preferably, in step 4, the crystallization time is 30 to 60 minutes; more preferably, in step 4, the crystallization time is 58 to 60 minutes.

6. The method for preparing azelnidipine according to any one of claims 1 to 5, wherein: In step 5, the cooling rate is 1-2°C / min; And / or, in step 5, the fourth crystallization is stirring crystallization; preferably, in step 5, the crystallization time is 1 to 2 hours; more preferably, in step 5, the crystallization time is 1.5 to 2 hours.

7. The method for preparing azelnidipine according to any one of claims 1 to 6, wherein: In step 6, the fifth crystallization is stirring crystallization; preferably, in step 6, the crystallization time is 3 to 5 hours; more preferably, in step 6, the crystallization time is 3.5 to 4.5 hours.

8. The method for preparing azelnidipine according to any one of claims 1 to 7, wherein: In step 1, the crystal form of the crude azelnidipine is α-crystalline; Preferably, the crystal form of the azelnidipine obtained in step 6 is an α-crystal form; And / or, preferably, the D90 particle size of the azelnidipine obtained in step 6 is 120 to 250 μm; more preferably, the D90 particle size of the azelnidipine obtained in step 6 is 160 to 250 μm.

9. The method for preparing azelnidipine according to any one of claims 1 to 8, wherein: Step 6 includes a further cooling and crystallization step after cooling and crystallization.

10. A method for regulating the particle size of azelnidipine by adjusting the ratio of dichloromethane as a good solvent to n-heptane as a poor solvent, the dissolution temperature and the gradient cooling crystallization conditions in the method for preparing azelnidipine according to any one of claims 2 to 9, characterized in that: The method comprises the following steps: Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 2-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 3-5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 4: Cooling to 18-23°C and performing the third crystallization; Step 5: Continue to cool to 8-12°C and perform the fourth crystallization; Step 6: Further cool the mixture to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is greater than 110 μm; preferably, the D90 particle size of the azelnidipine is 120-250 μm; more preferably, the D90 particle size of the azelnidipine is 160-250 μm.

11. The method according to claim 10, wherein: The method comprises the following steps: Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 6.8 to 7.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 3.8-4.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 4: Cooling to 18-23°C and performing the third crystallization; Step 5: Continue to cool to 8-12°C and perform the fourth crystallization; Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 235-240 μm.

12. The method according to claim 10, wherein: The method comprises the following steps: Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 5.8 to 6.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 2.8-3.2 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 4: Cooling to 18-23°C and performing the third crystallization; Step 5: Continue to cool to 8-12°C and perform the fourth crystallization; Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 163-167 μm.

13. The method according to claim 10, wherein: The method comprises the following steps: Step 1: Add the crude azelnidipine to dichloromethane as a good solvent and heat it to 30-40° C.; the volume of the good solvent is 3.5-4 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 2: cooling, adding n-heptane as a poor solvent, and performing the first crystallization; the volume of the poor solvent is 8.5 to 9 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 3: Raise the temperature to 28-33° C., add n-heptane as a poor solvent, and perform a second crystallization; the volume of the poor solvent is 4.6-5 times the mass of the crude azelnidipine, wherein the unit of volume is mL and the unit of mass is g; Step 4: Cooling to 18-23°C and performing the third crystallization; Step 5: Continue to cool to 8-12°C and perform the fourth crystallization; Step 6: Further cool down to 0-5°C, perform the fifth crystallization, and separate azelnidipine; the D90 particle size of the azelnidipine is 169-173 μm.

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