Nicardipine hydrochloride crystal form as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a nicardipine hydrochloride crystal form and a preparation method and application thereof. The nicardipine hydrochloride crystal form I has characteristic peaks at 10.6 + / -0.2 degrees, 11.3 + / -0.2 degrees, 18.8 + / -0.2 degrees and 25.9 + / -0.2 degrees in an X-ray powder diffraction pattern which is radiated by Cu-Ka and is expressed by a 2 theta angle. According to the nicardipine hydrochloride crystal form II, Cu-Ka radiation is adopted, and an X-ray powder diffraction pattern represented by a 2 theta angle has characteristic peaks at 9.99 + / -0.2 degrees, 17.9 + / -0.2 degrees, 23.9 + / -0.2 degrees and 24.2 + / -0.2 degrees. The crystal forms I and II are good in stability, the preparation method is simple, and the obtained product is high in purity. The invention also provides application of the nicardipine hydrochloride crystal form I or the nicardipine hydrochloride crystal form II, namely preparation of the nicardipine hydrochloride crystal form alpha. The preparation method is simple to operate, high in product purity, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to two new crystal forms of nicardipine hydrochloride, a preparation method thereof, and uses thereof. Among them, an important use of the new crystal form of nicardipine hydrochloride is to be used for preparing medicinal nicardipine hydrochloride. Background Art

[0002] Nicardipine hydrochloride, with the English name Nicardipine Hydrochloride, has the chemical name: 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride. Nicardipine hydrochloride belongs to the second-generation dihydropyridine calcium antagonists and has the advantages of rapid onset, long duration, wide indications, and few side effects. The structural formula of nicardipine hydrochloride is as follows.

[0003]

[0004] Patent CN105061297A describes the crystal form characterization data and preparation methods of crystal form α and crystal form β of nicardipine hydrochloride. For the α crystal form of nicardipine hydrochloride recorded in this patent document, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angle has a very strong absorption peak at 22±0.2, and has relatively strong characteristic peaks at 8±0.2, 14±0.2, 16±0.2, 18±0.2, 26±0.2, and has relatively weak characteristic peaks at 12±0.2, 15±0.2, 20.5±0.2, 21±0.2, 23±0.2, 27±0.2, 29±0.2, 30±0.2, 32±0.2. For the β crystal form of nicardipine hydrochloride recorded in this patent document, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angle has a very strong characteristic peak at 22±0.2, has a relatively strong characteristic peak at 20.5±0.2, and has relatively weak characteristic peaks at 8±0.2, 14±0.2, 16±0.2, 16±0.2, 19±0.2, 32±0.2.

[0005] The relevant properties of crystal form α and crystal form β are as follows:

[0006]

[0007] The Chinese Pharmacopoeia CP2020 edition standard records that the melting point of nicardipine hydrochloride is 179-185°C, indicating that the α crystal form of nicardipine hydrochloride can be used as a medicinal crystal form.

[0008] Combined with the relevant descriptions of the embodiments in patents CN105061297A, US4769465A, and CN113072483A, it can be seen that the preparation of nicardipine hydrochloride requires first obtaining nicardipine hydrochloride oily substance and then refining it, which undoubtedly increases the complexity of the process, and lacks further purification process, resulting in a high impurity content in the product. Summary of the invention

[0009] The purpose of the present invention is to provide, based on the prior art, a crystalline form I and a crystalline form II of nicardipine hydrochloride and a preparation method thereof. Both crystalline form I and crystalline form II have good stability and mild preparation conditions, and can be used to prepare a non-solvate of nicardipine hydrochloride.

[0010] In the process of preparing nicardipine hydrochloride, the inventor unexpectedly discovered new crystal forms of nicardipine hydrochloride, which are crystal form I and crystal form II. Both crystal forms are solvates. The chemical name of crystal form I is acetonitrile complex of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride. The chemical name of crystal form II is 1 / 2 ethyl acetate complex of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride. The structural formulas are as follows:

[0011]

[0012] The properties of Form I, Form II, Form α and Form β are compared as follows:

[0013]

[0014] The first aspect of the present invention provides a nicardipine hydrochloride crystal form I, wherein the crystal form I is a nicardipine hydrochloride acetonitrile complex, and using Cu-Ka radiation, an X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 10.6±0.2°, 11.3±0.2°, 18.8±0.2° and 25.9±0.2°.

[0015] The nicardipine hydrochloride crystal form I of the present invention, specifically, uses Cu-Ka radiation, and the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 10.6±0.2°, 11.3±0.2°, 17.6±0.2°, 18.8±0.2° and 25.9±0.2°.

[0016] Nicardipine hydrochloride polymorph I of the present invention, more specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.9±0.2°, 10.6±0.2°, 11.3±0.2°, 17.6±0.2°, 18.8±0.2°, 24.1±0.2°, 24.9±0.2° and 25.9±0.2°.

[0017] Nicardipine hydrochloride polymorph I of the present invention, further specifically, said polymorph I has an X-ray powder diffraction pattern substantially consistent with that Figure 1 shown.

[0018] The second aspect of the present invention provides a nicardipine hydrochloride polymorph II, said polymorph II being a 1 / 2 ethyl acetate complex of nicardipine hydrochloride, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.99±0.2°, 17.9±0.2°, 23.9±0.2° and 24.2±0.2°.

[0019] Nicardipine hydrochloride polymorph II of the present invention, specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.5±0.2°, 9.99±0.2°, 17.9±0.2°, 23.9±0.2° and 24.2±0.2°.

[0020] Nicardipine hydrochloride polymorph II of the present invention, more specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.5±0.2°, 9.99±0.2°, 11.2±0.2°, 17.9±0.2°, 20.0±0.2°, 20.5±0.2°, 23.9±0.2° and 24.2±0.2°.

[0021] Nicardipine hydrochloride polymorph II of the present invention, further specifically, said polymorph II has an X-ray powder diffraction pattern substantially consistent with that Figure 2 shown.

[0022] The third aspect of the present invention provides a method for preparing the above-mentioned nicardipine hydrochloride polymorph I or polymorph II, comprising the following steps:

[0023] Reacting 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate with methyl β-aminocrotonate to obtain nicardipine hydrochloride polymorph I or polymorph II:

[0024]

[0025] The present invention provides a method for preparing nicardipine hydrochloride polymorphic form I or polymorphic form II as described above. In some preferred embodiments, the method comprises the following steps:

[0026] (1) An organic solvent is added to 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate. After mixing evenly, methyl β-aminocrotonate and trimethylchlorosilane are added, and the temperature is raised and maintained until the reaction ends.

[0027] (2) The temperature is lowered for crystallization, and filtration is carried out by suction to obtain solid 1.

[0028] (3) Solid 1 is added to ethyl acetate, and an alkaline aqueous solution is added. Stir until there are no obvious particles in the system, let it stand for layering, and separate to obtain the organic phase.

[0029] (4) A hydrogen chloride solution is added to the organic phase. After stirring until a solid precipitates, the temperature is lowered for crystallization, and filtration is carried out by suction to obtain solid 2.

[0030] (5) Solid 2 is slurried with a solvent and dried to obtain a solvate of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride.

[0031] In some preferred embodiments, the temperature after the temperature increase in step (1) is 30°C to 80°C; the temperature after the temperature decrease in step (2) is 0 to 30°C; the temperature after the temperature decrease in step (4) is -10°C to 20°C.

[0032] In the method for preparing nicardipine hydrochloride polymorphic form I or polymorphic form II of the present invention, in some preferred embodiments, the organic solvent in step (1) is selected from a mixed solvent of a good solvent and a non-good solvent.

[0033] Wherein the good solvent is selected from one or more of DMF, DMA, and DMSO; preferably DMF and / or DMA; most preferably DMF.

[0034] The non-good solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropanol, ethanol, tetrahydrofuran, and acetonitrile; preferably ethyl acetate and / or isopropyl acetate; most preferably isopropyl acetate.

[0035] The base in the alkaline aqueous solution in step (3) can be any inorganic base. In some preferred embodiments, the base in the alkaline aqueous solution in step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0036] The method for preparing nicardipine hydrochloride polymorphic form I or polymorphic form II of the present invention, in some preferred embodiments, the slurrying solvent used for solid 2 in step (5) is selected from acetonitrile or ethyl acetate:

[0037] When the slurrying solvent used for solid 2 is acetonitrile, the solvate of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride is the acetonitrile complex of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride, that is, polymorphic form I.

[0038] When the slurrying solvent used for solid 2 is ethyl acetate, the solvate of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride is the 1 / 2 ethyl acetate complex of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride, that is, polymorphic form II.

[0039] The fourth aspect of the present invention provides a method for preparing nicardipine hydrochloride polymorphic form α using nicardipine hydrochloride polymorphic form I or polymorphic form II as described in any one of the above, comprising the following steps:

[0040] (1) Add acetone to nicardipine hydrochloride polymorphic form I or polymorphic form II, heat to 35°C - 60°C, stir until completely dissolved, filter to obtain a filtrate,

[0041] (2) Add nicardipine hydrochloride α seed crystals to the filtrate obtained in step (1), cool to 0 - 30°C, keep warm and stir for 1 h - 20 h, filter with suction to obtain a filter cake,

[0042] (3) Wash the filter cake obtained in step (2) with acetone and dry to obtain nicardipine hydrochloride polymorphic form α.

[0043] Wherein, in some preferred embodiments, the mass ratio of acetone to nicardipine hydrochloride polymorphic form I or polymorphic form II in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1.

[0044] In some other preferred embodiments, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

[0045] The method for preparing nicardipine hydrochloride polymorph α using nicardipine hydrochloride polymorph I or polymorph II as described in any one of the above, in some preferred embodiments, comprises the following steps:

[0046] (1) Add acetone to nicardipine hydrochloride polymorph I or polymorph II, heat to 40°C - 55°C, stir until completely dissolved, filter to obtain a filtrate.

[0047] (2) Add nicardipine hydrochloride α seed crystals to the filtrate obtained in step (1), cool to 5°C - 20°C, keep warm and stir for 9h - 15h, filter by suction to obtain a filter cake.

[0048] (3) Wash the filter cake obtained in step (2) with acetone and dry to obtain nicardipine hydrochloride polymorph α.

[0049] Wherein, in some preferred embodiments, the mass ratio of acetone to nicardipine hydrochloride polymorph I or polymorph II in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1.

[0050] In some other preferred embodiments, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

[0051] The fifth aspect of the present invention provides the use of nicardipine hydrochloride polymorph I or polymorph II as described in any one of the above for preparing nicardipine hydrochloride polymorph α. In some preferred embodiments, the use is to prepare nicardipine hydrochloride polymorph α according to the method described in the fourth aspect.

[0052] The beneficial technical effects of the present invention:

[0053] 1. New polymorphs of nicardipine hydrochloride are provided, namely polymorph I and polymorph II, and nicardipine hydrochloride polymorph α can be stably prepared.

[0054] 2. The preparation reaction system of nicardipine hydrochloride polymorph I and polymorph II selects a mixed solvent of a good solvent and a non - good solvent, and trimethylchlorosilane is added to the reaction system. After the reaction is completed, crystallization can be directly carried out by filtration to obtain a solid, avoiding repeated extraction and washing operations, and at the same time, the purity is greatly improved.

[0055] 3. Nicardipine hydrochloride polymorph I and polymorph II have higher solubility in acetone compared with nicardipine hydrochloride non - solvate, reducing the difficulty of dissolving solids in acetone in the refining step. The method for preparing nicardipine hydrochloride α polymorph from polymorph I or polymorph II is simple in operation, low in cost, the obtained nicardipine hydrochloride has a purity ≥ 99.9%, a high yield, and is more suitable for commercial production. Description of the Drawings

[0056] Figure 1It is the X-ray powder diffraction pattern of the acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0057] Figure 2 It is the X-ray powder diffraction pattern of the 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0058] Figure 3 It is the TGA-DSC thermal pattern of the acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0059] Figure 4 It is the TGA-DSC thermal pattern of the 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0060] Figure 5 It is the X-ray powder diffraction pattern of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (α crystal form).

[0061] Figure 6 It is the X-ray powder diffraction pattern of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (α crystal form + β crystal form). Detailed implementation manners

[0062] The above content of the present invention will be further described in detail through specific implementation manners below, but this should not be construed as any limitation to the protection subject matter of the present invention. Any technical solutions implemented based on the above content of the present invention fall within the scope of the present invention.

[0063] In the following text, if not otherwise specified, the operations carried out in the present invention are carried out at room temperature, and the room temperature refers to 20 to 35 °C, preferably 20 to 30 °C, more preferably 25 to 30 °C.

[0064] Example 1 Preparation of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate

[0065] 6 L of ethyl acetate and 3 kg of N-benzyl-N-methylethanolamine were added to a reaction tank, stirring was started, and a solution of 1.8 kg of diketene dissolved in 3 L of ethyl acetate was added. The temperature was raised to 45 °C, and after holding the reaction for 1.5 h, the temperature was lowered to 25 ± 5 °C to obtain a reaction solution of 2-(benzylmethylamino)ethyl acetoacetate for standby.

[0066] 21 L of ethyl acetate was added to a reaction tank, 462 g of piperidine and 227 g of glacial acetic acid were added, stirring was started, 9 kg of molecular sieve, 3.12 kg of m-nitrobenzaldehyde and the above-mentioned reaction solution of 2-(benzylmethylamino)ethyl acetoacetate were added. The temperature was controlled at 25 ± 5 °C, and after holding the reaction for 2 h, filtration was carried out. A solution of 3.0 kg of oxalic acid dissolved in 23.7 kg of isopropanol was added to the organic phase, and crystallization was carried out at room temperature for 2 h, suction filtration was carried out, and drying was carried out at 50 °C for 2.5 h to obtain 7.3 kg of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate oxalate, with a yield of 85.1% and a purity of 98%.

[0067] Example 2 Preparation of Acetonitrile Complex (Nicardipine Hydrochloride Polymorph I) of 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic Acid, 3-[β-(N-Benzyl-N-methyl)amino]ethyl Ester-5-methyl Ester Hydrochloride

[0068] 6.87 kg of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate oxalate was added to a reaction tank, 26.2 L of N,N-dimethylformamide and 44 L of isopropyl acetate were added, and stirring was started. 2.18 kg of methyl β-aminocrotonate and 2.26 kg of trimethylchlorosilane were added, the temperature was raised to 55 ± 5 °C, and after holding the reaction for 4 h, the temperature was lowered to 10 ± 5 °C, and crystallization was carried out for 2.5 h, suction filtration was carried out. The wet product was added to 61.8 kg of ethyl acetate, stirring was started, a solution of 4.88 kg of sodium bicarbonate dissolved in 55 kg of purified water was added, and stirring was carried out for 1 h, and then layering was carried out. The organic phase was washed with 55 kg of purified water again. 2.08 kg of 28% hydrogen chloride isopropanol solution was added to the organic phase at room temperature, and stirring was carried out for 1 h. The temperature was lowered to 15 ± 5 °C, and crystallization was carried out for 2 h, suction filtration was carried out. The wet product was added to 40.5 kg of acetonitrile, and stirring was carried out for 2.5 h, suction filtration was carried out, and drying was carried out at 40 °C for 3.5 h to obtain 6.2 kg of acetonitrile complex of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride, with a yield of 76.5%.

[0069] Data Detection Results

[0070] The nifedipine hydrochloride polymorph I prepared in Example 1 was subjected to relevant data detection, and the results are shown in Table 1 below.

[0071] Table 1 Data Results of Nifedipine Hydrochloride Polymorph I

[0072]

[0073] It can be seen from the above experiments that under the conditions of light protection and sealed storage, the purity, properties, acetonitrile content, and crystal form of the nifedipine hydrochloride polymorph I prepared in the present invention have not changed, indicating that the nifedipine hydrochloride polymorph I provided by the present invention is stable and has good chemical stability.

[0074] Example 3 Preparation of 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nifedipine hydrochloride polymorph II)

[0075] 2.34 kg of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate was added to the reaction kettle, 8 L of N,N-dimethylformamide and 16 L of ethyl acetate were added, and stirring was started. 0.74 kg of methyl β-aminocrotonate and 770 g of trimethylchlorosilane were added, the temperature was raised to 55 ± 5 °C, and the reaction was carried out for 4 h while maintaining the temperature. Then the temperature was lowered to 10 ± 5 °C, and crystallization was carried out for 2.5 h while maintaining the temperature. The product was filtered by suction, and the wet product was added to 21 kg of ethyl acetate, and stirring was started. A solution of 1.66 kg of sodium bicarbonate dissolved in 19 kg of purified water was added, and stirring was carried out for 45 min. Then the layers were separated, and the organic phase was washed with 18.7 kg of purified water again. At room temperature, 2.5 kg of 8% hydrochloric acid ethyl acetate solution was added to the organic phase, and stirring was carried out for 1 h while maintaining the temperature. The temperature was lowered to 15 ± 5 °C, and crystallization was carried out for 2 h while maintaining the temperature. The product was filtered by suction, the wet product was added to 13.8 kg of ethyl acetate, and stirring was carried out for 2 h while maintaining the temperature. Then the product was filtered by suction and dried at 45 °C for 4 h to obtain 2.05 kg of 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 73.9%.

[0076] Data Detection Results

[0077] The nifedipine hydrochloride polymorph II prepared in Example 2 was subjected to relevant data detection, and the results are shown in Table 2 below.

[0078] Table 2 Data Results of Nifedipine Hydrochloride Polymorph II

[0079]

[0080] As can be seen from the above experiments, under the conditions of light shielding and sealed storage, the purity, properties, ethyl acetate content, and crystal form of the nicardipine hydrochloride crystal form II prepared by the present invention have not changed, indicating that the nicardipine hydrochloride crystal form I provided by the present invention is stable and has good chemical stability.

[0081] Example 4 Preparation of nicardipine hydrochloride crystal form I to nicardipine hydrochloride crystal form α

[0082] 5.67 kg of acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride crystal form I) and 40.3 kg of acetone were added to a reaction kettle, the temperature was controlled at 45 ± 5 °C, stirred until dissolved, filtered, nicardipine hydrochloride α seed crystals were added, the temperature was lowered to 15 ± 5 °C, kept warm and stirred for 12 h, suction filtered, washed with acetone, and dried at 55 °C for 5.5 h to obtain 5.0 kg of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 95.2% and a purity of 99.9% crystal form α. The X-ray powder diffraction pattern of the obtained nicardipine hydrochloride is shown in Figure 5 .

[0083] Example 5 Preparation of nicardipine hydrochloride crystal form II to nicardipine hydrochloride crystal form α

[0084] 1.56 kg of 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride crystal form II) and 11.1 kg of acetone were added to a reaction kettle, the temperature was controlled at 45 ± 5 °C, stirred until dissolved, suction filtered, nicardipine hydrochloride α seed crystals were added to the filtrate, slowly cooled to 15 ± 5 °C, kept warm and stirred for 12 h, suction filtered, washed with acetone, and dried at 65 °C for 6 h to obtain 1.35 kg of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 93.9% and a purity of 99.9%, crystal form α.

[0085] Comparative Example 1 Preparation of nicardipine hydrochloride non-solvate to nicardipine hydrochloride crystal form α

[0086] 10 g of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride was added to 70 ml of ethanol. The mixture was heated to dissolve and then cooled to room temperature. α-seeds of nicardipine hydrochloride were added, and n-heptane was slowly added. After the addition was complete, the mixture was stirred overnight, filtered by suction, washed with n-heptane, and dried at 55 °C for 6 h to obtain 8.2 g of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 82.0% and a purity of 99.4%, which was a mixed crystal of crystal form α and crystal form β. The X-ray powder diffraction pattern of the obtained nicardipine hydrochloride is shown in Figure 6 .

[0087] It can be seen from Comparative Example 1 that due to the dissolution characteristics of the nicardipine hydrochloride non-solvate itself, alcohols are usually selected as solvents for purification, and it is easy to obtain mixed crystals.

[0088] Comparative Example 2 Preparation of nicardipine hydrochloride crystal form α from nicardipine hydrochloride non-solvate

[0089] 10 g of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride was added to 70 ml of methanol and stirred to dissolve. The solvent was distilled off under reduced pressure to obtain an oily substance. The oily substance was added to 100 ml of acetone, heated to reflux, stirred to dissolve, cooled, α-seeds of nicardipine hydrochloride were added, and crystallization was carried out with stirring for 4 h. The mixture was filtered by suction, washed with acetone, and dried at 55 °C for 6 h to obtain 9.1 g of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 91.0% and a purity of 99.5%, which was crystal form α.

[0090] It can be seen from Comparative Example 2 that the purification of nicardipine hydrochloride non-solvate has a relatively cumbersome operation process compared to Examples 3 and 4, and the operation is complex. The residual methanol from the reduced-pressure distillation is introduced into the crystallization system, resulting in a relatively low yield.

Claims

1. Nicardipine Hydrochloride Polymorph I, characterized in that, The crystalline form I is nicardipine hydrochloride acetonitrile complex. Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 10.6±0.2°, 11.3±0.2°, 18.8±0.2° and 25.9±0.2°. Specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 10.6±0.2°, 11.3±0.2°, 17.6±0.2°, 18.8±0.2° and 25.9±0.2°. More specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.9±0.2°, 10.6±0.2°, 11.3±0.2°, 17.6±0.2°, 18.8±0.2°, 24.1±0.2°, 24.9±0.2° and 25.9±0.2°. Further specifically, the crystalline form I has an X-ray powder diffraction pattern substantially consistent with that shown in Figure 1.

2. Nicardipine Hydrochloride Polymorph Ⅱ, characterized in that, The crystalline form II is nicardipine hydrochloride 1 / 2 ethyl acetate complex. Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.99±0.2°, 17.9±0.2°, 23.9±0.2° and 24.2±0.2°. Specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.5±0.2°, 9.99±0.2°, 17.9±0.2°, 23.9±0.2° and 24.2±0.2°. More specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.5±0.2°, 9.99±0.2°, 11.2±0.2°, 17.9±0.2°, 20.0±0.2°, 20.5±0.2°, 23.9±0.2° and 24.2±0.2°. Further specifically, the crystalline form II has an X-ray powder diffraction pattern substantially consistent with that shown in Figure 2.

3. A method for preparing the crystalline form I or crystalline form II of nicardipine hydrochloride according to any one of claims 1-2, comprising the following steps: 2-[Benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate reacts with methyl β-aminocrotonate to obtain the crystalline form I or crystalline form II of nicardipine hydrochloride:

4. A method for preparing the crystalline form I or crystalline form II of nicardipine hydrochloride according to any one of claims 1-2, comprising the following steps: (1) Add an organic solvent to 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate. After mixing evenly, add methyl β-aminocrotonate and trimethylchlorosilane, raise the temperature, and keep warm until the reaction ends. (2) Cool down for crystallization, filter by suction to obtain solid 1. (3) Add solid 1 to ethyl acetate, add an alkaline aqueous solution, stir until there are no obvious particles in the system, let it stand for layering, and separate to obtain the organic phase. (4) Add a hydrochloric acid solution to the organic phase, stir until a solid precipitates, then cool down for crystallization, and filter by suction to obtain Solid 2. (5) Slurry Solid 2 with a solvent and dry it to obtain a solvate of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

5. The preparation method according to claim 4, wherein in step (1), the organic solvent is selected from a mixed solvent of a good solvent and a non-good solvent. The good solvent is selected from one or more of DMF, DMA, and DMSO; preferably DMF and / or DMA; most preferably DMF. The non-good solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropanol, ethanol, tetrahydrofuran, and acetonitrile; preferably ethyl acetate and / or isopropyl acetate; most preferably isopropyl acetate. Preferably, in step (3), the base in the alkaline aqueous solution is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

6. The preparation method according to claim 4, wherein the slurry solvent used for Solid 2 in step (5) is selected from acetonitrile or ethyl acetate. When the slurry solvent used for Solid 2 is acetonitrile, the solvate of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride is an acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, namely Crystal Form I. When the slurry solvent used for Solid 2 is ethyl acetate, the solvate of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride is a 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, namely Crystal Form II.

7. A method for preparing nifedipine hydrochloride polymorph α using nifedipine hydrochloride polymorph I or polymorph II according to any one of claims 1-2, characterized in that, Comprising the following steps: (1) Add acetone to nicardipine hydrochloride Crystal Form I or Crystal Form II, heat up to 35°C - 60°C, stir until completely dissolved, filter to obtain a filtrate. (2) Add nicardipine hydrochloride α-seed crystals to the filtrate obtained in step (1), cool down to 0 - 30°C, keep stirring for 1 h - 20 h, and filter by suction to obtain a filter cake. (3) Wash the filter cake obtained in step (2) with acetone and dry it to obtain nicardipine hydrochloride Crystal Form α. Preferably, the mass ratio of acetone to nicardipine hydrochloride Crystal Form I or Crystal Form II in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:

1. Preferably, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

8. A method for preparing nifedipine hydrochloride polymorph α using nifedipine hydrochloride polymorph I or polymorph II according to any one of claims 1-2, characterized in that, Comprising the following steps: (1) Add acetone to nicardipine hydrochloride polymorph I or polymorph II, heat up to 40°C - 55°C, stir until completely dissolved, filter to obtain a filtrate. (2) Add nicardipine hydrochloride α seed crystal to the filtrate obtained in step (1), cool down to 5°C - 20°C, keep the temperature and stir for 9h - 15h, filter by suction to obtain a filter cake. (3) Wash the filter cake obtained in step (2) with acetone and dry it to obtain nicardipine hydrochloride polymorph α. Preferably, the mass ratio of the acetone to nicardipine hydrochloride polymorph I or polymorph II in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:

1. Preferably, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

9. Use of nicardipine hydrochloride polymorph I or polymorph II according to any one of claims 1 - 2 for preparing nicardipine hydrochloride polymorph α; preferably, the use is to prepare nicardipine hydrochloride polymorph α according to the method according to any one of claims 8 - 9.

Images