CN117567358A - Nicardipine hydrochloride ethyl semiacetate compound crystal and preparation method and application thereof - Google Patents
Nicardipine hydrochloride ethyl semiacetate compound crystal and preparation method and application thereof Download PDFInfo
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- CN117567358A CN117567358A CN202311458299.0A CN202311458299A CN117567358A CN 117567358 A CN117567358 A CN 117567358A CN 202311458299 A CN202311458299 A CN 202311458299A CN 117567358 A CN117567358 A CN 117567358A
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- nicardipine hydrochloride
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- 229960002289 nicardipine hydrochloride Drugs 0.000 title claims abstract description 260
- 239000013078 crystal Substances 0.000 title claims abstract description 159
- 150000001875 compounds Chemical class 0.000 title claims abstract description 92
- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- AIKVCUNQWYTVTO-UHFFFAOYSA-N nicardipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 AIKVCUNQWYTVTO-UHFFFAOYSA-N 0.000 claims abstract description 204
- 239000002904 solvent Substances 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 147
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 84
- 238000001816 cooling Methods 0.000 claims description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 238000002425 crystallisation Methods 0.000 claims description 55
- 230000008025 crystallization Effects 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000012046 mixed solvent Substances 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 28
- 238000002844 melting Methods 0.000 claims description 26
- 230000008018 melting Effects 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 17
- 238000002441 X-ray diffraction Methods 0.000 claims description 15
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
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- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims description 2
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- IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 claims 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- JPXPPUOCSLMCHK-UHFFFAOYSA-N 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 JPXPPUOCSLMCHK-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical compound [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
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- 229960005070 ascorbic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
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- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
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- 230000002040 relaxant effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
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- 229940054967 vanquish Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Crystallography & Structural Chemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a nicardipine hydrochloride ethyl semiacetate compound crystal, and a preparation method and application thereof. The novel crystal form of nicardipine hydrochloride, namely the nicardipine hydrochloride ethyl semiacetate compound crystal, has characteristic peaks at the positions of 17.80, 20.43, 23.85 and 24.15 of 2 theta values in an XRD diffraction spectrum, and the error range of the 2 theta values is 0.2. The alpha crystal form nicardipine hydrochloride crystal is prepared by recrystallising the nicardipine hydrochloride ethyl semiacetate compound, the required solvent consumption is less, the yield is higher, and the method is more beneficial to industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a nicardipine hydrochloride ethyl semiacetate compound crystal, and a preparation method and application thereof.
Background
The nicardipine hydrochloride (Nicardipine Hydrochloride) is a 2 nd-generation dihydropyridine calcium antagonist, can inhibit the inflow of calcium ions, selectively inhibit phosphodiesterase of brain and coronary artery to ensure that CAMP rises in cells, thereby relaxing vascular smooth muscle, generating obvious vascular dilation effect, having the characteristics of high selectivity, low cardiac toxicity and good curative effect, being widely used for treating hypertension and angina clinically, and being a first-line medicament for emergency treatment of abnormal hypertension and hypertension emergency during operation. The structural formula of nicardipine hydrochloride is as follows:
Example 29 of US patent 3985758 discloses a preparation method of nicardipine hydrochloride, which adopts a compound I and a compound II as raw materials, and the raw materials are subjected to reflux reaction in isopropanol, and then are acidified by hydrochloric acid, concentrated and crystallized by ethyl acetate to obtain a crude product, and the crude product is dissolved by methanol, concentrated and crystallized by acetone to obtain an alpha crystal form, wherein the yield is 42%. The scheme is complex to operate, has low yield and has transesterification risk. The reaction equation is as follows:
chinese patent CN105061297a discloses a method for synthesizing nicardipine hydrochloride. The preparation method of the nicardipine hydrochloride alpha crystal form and the nicardipine hydrochloride beta crystal form is related. The method comprises the steps of taking a compound I and a compound II as raw materials, completely reacting in an inert solvent, decoloring and filtering, concentrating filtrate to be sticky, adding a crystallization solvent, decoloring by active carbon, cooling to a proper temperature, and crystallizing by hydrochloride formation to obtain high-purity alpha crystal form or beta crystal form nicardipine hydrochloride. The invention improves and optimizes the synthesis process of the nicardipine hydrochloride, provides a preparation method of the nicardipine hydrochloride with simple operation, cost saving, convenient mass production and simple and convenient obtaining of the alpha crystal form and the beta crystal form with high purity and high yield. The reaction equation is as follows:
Journal literature (Polymorphs and Solvates of Nicardipine hydrochloride.selective Stabilization of Different Diastereomeric Racemates, moreno-Calvo E et al, molecular pharmaceutics,2011,8 (2): 395-404) discloses that nicardipine hydrochloride is a polymorphic compound, having five crystalline forms, including the alpha, beta and three solvates, wherein the three solvates are dihydrate, hemitoluene and chloroform, respectively, and discloses a molecular understanding of nicardipine hydrochloride.
The nicardipine hydrochloride preparation is developed in Japan at the earliest time, and then is marketed in the United states and Europe, and according to the specifications of the medicines of the nicardipine hydrochloride preparation marketed in Japan, the United states, europe and other countries, the melting points of the used raw medicines are 169-171 ℃, which indicates that the original ground products are all beta crystal form raw materials.
Disclosure of Invention
The technical problems solved by the invention are as follows: the system for preparing the alpha crystal form nicardipine hydrochloride crystal by the crude nicardipine hydrochloride product in the prior art has extremely poor impurity removal effect and difficult quality research; moreover, the dissolution of the nicardipine hydrochloride crystal of the alpha crystal form in acetone is low, a large amount of solvent is needed, equipment is limited, and the three wastes are extremely large, so that the method is not beneficial to industrial production.
Aiming at the technical problems, the invention provides a nicardipine hydrochloride ethyl semiacetate compound crystal, and a preparation method and application thereof.
Specifically, the invention provides the following technical scheme:
in a first aspect, the present invention provides a crystalline nicardipine hydrochloride ethyl semiacetate compound, wherein the molecular structural formula is shown in the following formula (I):
preferably, in the XRD diffractogram, there are characteristic peaks at values of 2θ of 17.80, 20.43, 23.85 and 24.15, where the error range of 2θ values is 0.2.
More preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.98, 11.16, 16.98, 17.80, 20.01, 20.43, 22.90, 23.85, 24.15 and 27.40, where the 2 theta value error range is 0.2.
Further preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.09, 9.98, 11.16, 11.45, 16.98, 17.80, 20.01, 20.43, 20.89, 22.90, 23.85, 24.15, 25.35, 27.40, 28.05 and 31.61, wherein the error range of 2 theta values is 0.2.
Preferably, the melting point of the nicardipine hydrochloride ethyl semiacetate compound is 148 ℃, and the error range of the melting point is 2 ℃.
In a second aspect, the invention provides a preparation method of the nicardipine hydrochloride ethyl hemiacetate compound crystal, which comprises the following steps:
Adding a solvent into the crude nicardipine hydrochloride, and heating and refluxing to dissolve the crude nicardipine hydrochloride; then cooling and crystallizing for the first time; then cooling and crystallizing for the second time; and removing the solvent and drying to obtain the nicardipine hydrochloride ethyl semiacetate compound.
Preferably, the volume of the solvent is 10-20 times of the mass of the crude nicardipine hydrochloride; wherein, the volume unit is mL, and the mass unit is g.
More preferably, the volume of the solvent is 10-15 times of the mass of the crude nicardipine hydrochloride; wherein, the volume unit is mL, and the mass unit is g.
Preferably, the solvent is a mixed solution containing a good solvent and ethyl acetate, wherein the good solvent is selected from one or more of dichloromethane, methanol, ethanol and isopropanol.
More preferably, the solvent is a mixed solution of dichloromethane and ethyl acetate.
Further preferably, the volume ratio of dichloromethane to ethyl acetate is 1:1 to 1:3.
Still more preferably, the volume ratio of dichloromethane to ethyl acetate is 1:1.5 to 1:2.5.
Preferably, the temperature is raised to 40-65 ℃.
More preferably, the temperature is raised by heating the solvent to 40 to 60 ℃.
Preferably, the reflux time is 30min to 60min.
Preferably, the cooling crystallization is a direct crystallization method or a seed crystal induced crystallization method.
More preferably, the cooling crystallization is a direct crystallization method.
Preferably, in the first cooling crystallization process, the temperature is reduced to 20-40 ℃; and/or the crystallization time is 2-24 h.
More preferably, the temperature is reduced to 20-30 ℃ in the first cooling crystallization process; and/or the crystallization time is 3-24 h.
Preferably, in the second cooling crystallization process, the temperature is reduced to 0-10 ℃; and/or the crystallization time is 1-5 h.
More preferably, in the second cooling crystallization process, the temperature is reduced to 2-8 ℃; and/or the crystallization time is 3-5 h.
Preferably, drying is performed after removing the solvent to obtain the nicardipine hydrochloride ethyl semiacetate compound crystal.
Preferably, it is washed with ethyl acetate before drying.
Preferably, the drying mode is vacuum drying.
More preferably, the drying temperature is 40 to 60 ℃; and/or drying for 2-24 hours.
Still more preferably, the temperature of drying is 45-55 ℃; and/or drying for 11-17 hours.
Preferably, the nicardipine hydrochloride crystal is prepared by the preparation method of the nicardipine hydrochloride ethyl hemiacetate compound crystal.
In a third aspect, the present invention provides a pharmaceutical composition, wherein the crystalline nicardipine hydrochloride ethyl hemiacetate compound is used as an active ingredient.
Preferably, the pharmaceutical composition is any clinically acceptable pharmaceutical dosage form.
More preferably, the formulation comprises a tablet, pill, capsule, granule, injection, suspension or emulsion.
In a third aspect, the invention provides an application of the nicardipine hydrochloride ethyl hemiacetate compound crystal or the pharmaceutical composition in preparing a medicine for treating cardiovascular or cerebrovascular diseases.
Preferably, the application in preparing the medicine for treating cardiovascular diseases is the application in preparing the medicine for resisting hypertension, angina pectoris or treating ischemic and hemorrhagic cerebrovascular accident sequelae.
In a fourth aspect, the invention provides a preparation method of an α -crystal form of nicardipine hydrochloride crystal, which comprises the following steps: the nicardipine hydrochloride ethyl semiacetate compound crystal is prepared by recrystallization.
Preferably, the nicardipine hydrochloride semi-acetate compound is added into a recrystallization solvent, and the nicardipine hydrochloride semi-acetate compound is dissolved by heating and refluxing; then cooling and crystallizing for the first time; then cooling and crystallizing for the second time; and removing the solvent and drying to obtain the nicardipine hydrochloride crystal of the alpha crystal form.
Preferably, the temperature is raised to 40-65 ℃;
and/or, refluxing for 10-30 min;
preferably, the volume of the recrystallization solvent is 6-15 times of the mass of the nicardipine hydrochloride ethyl semiacetate compound; wherein, the volume unit is mL, and the mass unit is g.
More preferably, the volume of the recrystallization solvent is 8-12 times of the mass of the nicardipine hydrochloride ethyl semiacetate compound; wherein, the volume unit is mL, and the mass unit is g.
More preferably, the solvent for recrystallization is a mixed solvent of acetone and ethanol.
Further preferably, the volume ratio of the acetone to the ethanol is 1-3:0.5-2.
Still more preferably, the ethanol is absolute ethanol.
Preferably, after the reflux is finished, the solution is subjected to cooling crystallization, wherein the cooling crystallization is selected from a direct crystallization method or a seed crystal induced crystallization method.
Preferably, the cooling crystallization is a seed crystal induced crystallization method, and the added seed crystal is alpha-crystal nicardipine hydrochloride.
More preferably, the mass of the nicardipine hydrochloride in the alpha crystal form is 0.1% of the feeding amount of the nicardipine hydrochloride ethyl semiacetate compound crystal.
And/or, in the first cooling crystallization process, cooling the solution to 10-40 ℃; and/or the crystallization time is 2-24 h.
And/or, in the second cooling crystallization process, cooling the solution to 0-10 ℃; and/or the crystallization time is 1-5 h.
Preferably, after crystallization, removing the solvent, washing with acetone, and drying to obtain the nicardipine hydrochloride crystal of the alpha crystal form.
Preferably, the drying is vacuum drying.
The beneficial effects of the invention are that
(1) The invention prepares a new nicardipine hydrochloride crystal form: the nicardipine hydrochloride ethyl acetate compound has good storage stability under the room temperature condition.
(2) The alpha crystal form nicardipine hydrochloride crystal is prepared by recrystalizing the nicardipine hydrochloride semi-ethyl acetate compound crystal, so that the impurity removal capability of finished product refining can be obviously improved, the purity of the finished product is improved, the crystallization difficulty of the finished product is reduced, and the quality research is simplified.
(3) Compared with other intermediate crystal forms, the solubility of the novel crystal form of the nicardipine hydrochloride ethyl hemiacetate compound is obviously improved, the solvent consumption is obviously reduced when the crystalline form of the nicardipine hydrochloride is recrystallized into a medicinal alpha crystal form, the yield is higher, and the industrial production is facilitated.
Drawings
Fig. 1 is an XRD pattern of the nicardipine hydrochloride ethyl semiacetate compound prepared in example 1 of the present invention.
Fig. 2 is an HPLC diagram of the nicardipine hydrochloride ethyl semiacetate compound prepared in example 1 of the present invention.
FIG. 3 is a photograph showing the nicardipine hydrochloride ethyl semiacetate compound prepared in example 1 of the present invention 1 H NMR spectrum.
FIG. 4 is a DSC/TGA spectrum of the nicardipine hydrochloride ethyl semiacetate compound prepared in example 1 of the present invention.
Detailed Description
As described above, the present invention aims to provide a nicardipine hydrochloride ethyl semiacetate compound crystal, and a preparation method and application thereof.
Terminology:
the cooling crystallization means: and cooling the reaction system by means of ice water bath cooling, self-heating cooling or cooling by using refrigeration equipment and the like, so that crystals in the reaction system are separated out.
The direct crystallization method means: and directly cooling the reaction system to a certain temperature range, and preserving heat until the target crystal is separated out.
The seed crystal induced crystallization method refers to: and adding a target seed crystal into the reaction system to induce precipitation of the target seed crystal.
The first object of the invention is to provide a nicardipine hydrochloride ethyl semiacetate compound crystal with a molecular formula of C 28 H 34 ClN 3 O 7 The structural formula is as follows:
XRD diffractograms with characteristic peaks at values of 17.80, 20.43, 23.85 and 24.15, wherein the error range of 2 theta values is 0.2; the peak height of the characteristic peak is more than 45 percent, and the peak height of the characteristic peak at the 2 theta of 23.85 plus or minus 0.2 degrees is 100 percent;
Preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.98, 11.16, 16.98, 17.80, 20.01, 20.43, 22.90, 23.85, 24.15 and 27.40, where the 2 theta value error range is 0.2; the peak height of the characteristic peak is more than 19 percent, and the peak height of the characteristic peak at the 2 theta of 23.85 plus or minus 0.2 degrees is 100 percent;
preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.09, 9.98, 11.16, 11.45, 16.98, 17.80, 20.01, 20.43, 20.89, 22.90, 23.85, 24.15, 25.35, 27.40, 28.05 and 31.61, wherein the 2 theta values range from 0.2; the peak height of the characteristic peak is more than 12%, and the peak height of the characteristic peak at the 2 theta of 23.85 plus or minus 0.2 degrees is 100%.
The second object of the invention is to provide a preparation method of a nicardipine hydrochloride ethyl semiacetate compound crystal, which comprises the following steps:
adding the nicardipine hydrochloride crude product into a mixed solvent of dichloromethane and ethyl acetate, and heating to dissolve; then cooling and crystallizing for the first time, cooling to 20-40 ℃ and crystallizing for 2-24 hours; then cooling and crystallizing for the second time, cooling to 0-10 ℃, and crystallizing for 3-5 hours; filtering to remove the solvent, washing with ethyl acetate, and drying at 40-60 ℃ for 2-24 h to obtain the nicardipine hydrochloride ethyl semiacetate compound.
The crude nicardipine hydrochloride is one or a mixture of more than two of alpha crystal form, beta crystal form, amorphous form and solvate of the nicardipine hydrochloride which is not purified;
preferably, the nicardipine hydrochloride crude product is prepared by reacting 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid with 2- (benzyl (methyl) amino) ethane-1-ol.
According to the invention, through regulating specific preparation conditions, such as regulating crystallization temperature or time and the like, and crystallization times, the obtained nicardipine hydrochloride ethyl semiacetate compound has higher crystal purity and higher yield.
The third object of the invention is to provide a pharmaceutical composition containing the nicardipine hydrochloride ethyl semiacetate compound crystal.
Preferably, the pharmaceutical composition can be prepared into any clinically acceptable dosage form suitable for raw materials, including injection, transdermal administration, respiratory administration, mucosal administration in the lumen and other parts of the body, protein-binding targeting preparation and other parenteral administration forms. Further preferably, the pharmaceutically acceptable dosage form comprises one or more of a tablet, pill, capsule, granule, injection, suspension and emulsion.
Preferably, the nicardipine hydrochloride semi-acetate compound crystal can be prepared into a pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients, or the α crystal form or the β crystal form of the nicardipine hydrochloride crystal prepared from the nicardipine hydrochloride semi-acetate compound crystal can be prepared into a pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutically acceptable carrier or excipient may be selected from one or more of the following: water for injection, mannitol, lactose, polyethylene glycol, tween-80, propylene glycol, tartaric acid, citric acid, ascorbic acid, disodium edentate, calcium sodium edentate, sodium bisulphite, glucose, sodium chloride, albumin, soybean oil, soybean lecithin, egg yolk phospholipid, distearoyl phosphatidylethanolamine, dextran, glycine, and glycerol.
The fourth object of the invention is to provide a preparation method of a nicardipine hydrochloride crystal of alpha crystal form, which comprises the following steps:
adding the nicardipine hydrochloride ethyl acetate compound into a mixed solvent of acetone and absolute ethyl alcohol, and heating and refluxing to dissolve the nicardipine hydrochloride ethyl acetate compound; then cooling and crystallizing for the first time, cooling the solution to 10-40 ℃, adding seed crystal, and crystallizing for 2-24 hours; then cooling and crystallizing for the second time, and cooling the solution to 0-10 ℃ for 1-5 h; filtering, washing the filter cake with acetone, vacuum drying for 2-20 hours, cooling and collecting the material to obtain an alpha crystal form nicardipine hydrochloride finished product.
The alpha crystal form, beta crystal form, dihydrate, hemitoluene compound and chloroform compound of the nicardipine hydrochloride prepared by the invention are confirmed to be consistent with the crystal forms reported in the literature through melting points and XRD patterns.
The various reagents/instruments used in the examples and comparative examples of the present invention are conventional commercial products unless otherwise specified. The experimental materials and instrument information used in the invention are shown in the following table:
table 1 laboratory apparatus and manufacturer
| Instrument for measuring and controlling the intensity of light | Model number | Production/vending machine |
| Thermogravimetric analysis and differential thermal analyzer | TGA/DSC2LF/1100/155 | Meite Teler |
| X-ray diffractometer | DX-2700 | Dandonghaoyuan |
| Liquid chromatograph | VanquishcDuo | Siemens fly |
| Nuclear magnetic resonance spectrometer | AvanceⅢ-400NMR | Bruker |
| Microcomputer melting point instrument | WRS-2 | Electric object light |
The X-ray diffraction detection method comprises the following steps: an X-ray powder diffractometer of Dandong Haoyuan is adopted, the model is DX-2700, and the measurement conditions are as follows: cu-K alpha radiation, the wavelength diverges from the slit by 1 degree, the voltage of the X-ray light tube is 40kV, the current of the X-ray light tube is 30mA, the scanning range is 3-53 degrees (2 theta), the step length is 0.05 degrees, and the scanning speed is 3 degrees/min. The data acquisition software DX-2700 system controls 2.1, and the data viewing software JADE 9.
Wherein, the HPLC detection condition of the invention: the detection method adopts a liquid chromatograph of the Siemens flight, the model is Vanquish c Duo, and the detection method comprises the following steps: the sample is precisely weighed, dissolved and diluted by a diluent to prepare a solution containing about 2mg per 1 ml. Performing gradient elution by using octadecylsilane chemically bonded silica as filler (Ultimate XB-C18,4.6mm×150mm,5 μm or chromatographic column with equivalent efficacy), acetonitrile as mobile phase A, and 1.5g/L perchloric acid aqueous solution as mobile phase B; the column temperature is 25 ℃; the flow rate is 1.5ml per minute; the detection wavelength is 237nm and 215nm; the sample volume was 20. Mu.L.
Wherein the invention 1 The H NMR detection steps were as follows: the detection steps are carried out by using Bruker nuclear magnetic resonance spectrum model Avance III-400 NMR: about 10mg of the sample is taken and dissolved in about 0.6mL of deuterated reagent, transferred into a 5mm nuclear magnetic tube for sealing, placed into an instrument for setting parameters, locked, tuned, homogenized, and finally data acquisition and processing are carried out.
Wherein, the TGA/DSC detection steps of the invention are as follows: the thermogravimetric analysis and differential thermal analyzer of the type TGA/DSC 2LF/1100/155 was used to determine the conditions: the sample vessel type was Al40uL, the initial temperature was 40 ℃, the end temperature was 350 ℃, the heating rate was 10 ℃/min, and the nitrogen purge flow rate was 50.0mL/min.
Wherein, the melting point detection steps of the invention are as follows: microcomputer melting point instrument of the electric object light is adopted, the model is WRS-2, and the measuring conditions are as follows: the initial temperature was 100deg.C and the heating rate was 2.0deg.C/min.
In order to better understand the technical scheme of the present invention, the following describes the technical scheme of the present invention in detail with reference to specific embodiments.
Example 1: preparation of nicardipine hydrochloride ethyl semiacetate compound
The nicardipine hydrochloride crude product is prepared by the following process: 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid (10 g) was added to a mixed solution of dichloromethane (20 mL) and N, N-dimethylformamide (5 mL), and thionyl chloride (3.6 g) was added dropwise thereto at a temperature of 0.+ -. 5 ℃ to react for 3 hours. Then, a solution of 2- (benzyl (methyl) amino) ethan-1-ol (4.9 g) in methylene chloride (60 mL) was added dropwise thereto at a temperature of 5.+ -. 5 ℃ to react for 1 hour. The organic phase was washed twice with water (50 mL) and concentrated to dryness to give crude nicardipine hydrochloride.
The crude nicardipine hydrochloride (1.1 kg) is added into a mixed solvent of 13.2L of dichloromethane and ethyl acetate, wherein the volume ratio of the dichloromethane to the ethyl acetate is 1:2, the volume (unit is mL) of the mixed solvent is 12 times of the mass (unit is g) of the nicardipine hydrochloride crude product, the temperature is raised to 40 ℃, the mixture is refluxed, and the mixture is stirred for 30 minutes until the system is dissolved. The system is cooled, the temperature is controlled to 25 ℃, stirred and crystallized for 4 hours, then cooled to 5 ℃, stirred for 4 hours continuously, reduced pressure and suction filtration are carried out, filter cakes are washed by ethyl acetate, and the filter cakes are dried for 14 hours at the temperature of 50 ℃ to obtain 1.0kg of the product, namely the nicardipine hydrochloride ethyl semiacetate compound, the purity of which is 99.92% and the mass yield of which is 91% as measured by HPLC.
The XRD pattern of the nicardipine hydrochloride ethyl semiacetate compound is shown in figure 1, the peak position with the peak height of 100 percent is 2θ=23.85+ -0.2 DEG,The XRD pattern data are shown in table 2.
TABLE 2 XRD pattern data for nicardipine hydrochloride ethyl hemiacetate compounds
And (3) notes: intensity=count, 2θ (0) =0.0 (degrees), wavelength for calculating d value= 1.54059 angstroms (Cu/kα1)
Wherein, the HPLC chart of the nicardipine hydrochloride ethyl semiacetate compound is shown in figure 2, the purity is 99.92%, the yield is 91%, and the HPLC chart data is shown in the following table 3.
TABLE 3 HPLC profile data for nicardipine hydrochloride ethyl hemiacetate compound
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 1.456 | 0.089 | 2.906 | 0.03 |
| 2 | 9.672 | 0.152 | 0.605 | 0.05 |
| 3 | 22.562 | 306.746 | 219.044 | 99.92 |
Wherein, the nicardipine hydrochloride is the ethyl acetate compound 1 H NMR is shown in FIG. 3. 1 H NMR(400MHz，CDCl3)：δ12.59(s,1H),8.05-8.04(m,1H),7.96–7.94(m,1H),7.61(t,1H),7.57–7.523(m,2H),7.46–7.27(m,4H),7.20(d,J＝8.0Hz,1H),5.30(s,1H),5.063–5.056(m,2H),4.66–4.61(m,1H),4.23–4.19(q,J＝4.8Hz,1H),4.18–3.90(m,1H),3.65(d,J＝1.6Hz,3H),3.0–3.35(m,1H),3.20–3.14(m,1H),2.66–2.56(dd,J1＝4.8Hz,J2＝5.2Hz,3H),2.42–2.38(dd,J1＝3.2Hz,J2＝2.0Hz,6H),2.05(s,1.5H),1.26(t,J＝7.2Hz,1.5H)。
Wherein, delta 4.18-3.90,1H, multiple peaks (characteristic peak of methylene hydrogen); 2.05,1.5H, monomodal (characteristic peak for methyl hydrogen); 1.26,1.5H, a triplet (characteristic peak for methylene paracymethyl hydrogen), the three characteristic peaks are characteristic peaks for half molecular ethyl acetate. The nuclear magnetic data show that the mol ratio of the ethyl acetate molecules to the nicardipine hydrochloride molecules is 0.5:1, and the nicardipine hydrochloride semi-ethyl acetate compound simultaneously contains semi-molecular ethyl acetate and one molecule of nicardipine hydrochloride.
Wherein the DSC/TGA spectrum of the nicardipine hydrochloride ethyl semiacetate compound is shown in figure 4. As can be seen from FIG. 4, there is an endothermic peak at 148.+ -. 3 ℃ in the DSC chart at a heating rate of 10 ℃/min, indicating that the melting point of the compound is around 148 ℃. In thermogravimetric analysis TGA profile, nicardipine hydrochloride ethyl acetate compound has about 7.9% of theoretical weight loss in the range of 120-160 ℃, corresponding to the weight loss of half molecular ethyl acetate, the weight loss of about 7.9% of half molecular ethyl acetate can be changed within the error range of a measuring instrument, and the weight loss of half molecular ethyl acetate is 7.7778% through experimental measurement. From the following components 1 The H NMR spectrum and DCS/TGA spectrum confirmed that the crystals obtained in example 1 were nicardipine hydrochloride ethyl semiacetate.
Example 2: preparation of nicardipine hydrochloride ethyl semiacetate compound
The preparation of crude nicardipine hydrochloride was the same as in example 1.
The crude nicardipine hydrochloride (100 g) is added into a mixed solvent of 1000mL of dichloromethane and ethyl acetate, wherein the volume ratio of the dichloromethane to the ethyl acetate is 1:1.5, the volume (unit is mL) of the mixed solvent is 10 times of the mass (unit is g) of the crude nicardipine hydrochloride, the temperature is raised to 40 ℃ for reflux, and the mixed solvent is stirred for 30 minutes until the system is dissolved. The system is cooled, the temperature is controlled to 25 ℃, crystallization is carried out for 2 hours, the temperature is further cooled to 5 ℃, stirring is continued for 3 hours, decompression and suction filtration are carried out, filter cakes are washed by ethyl acetate, drying is carried out for 10 hours at the temperature of 50 ℃, 89.4g of product is obtained, the mass yield is 89.4%, and the purity of the compound is 99.85% as measured by HPLC.
Example 3: preparation of nicardipine hydrochloride ethyl semiacetate compound
The preparation of crude nicardipine hydrochloride was the same as in example 1.
The crude nicardipine hydrochloride (120 g) was added to 1440mL of a mixed solvent of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate is 1:3, the volume (unit is mL) of the mixed solvent is 12 times of the mass (unit is g) of the nicardipine hydrochloride crude product, the temperature is raised to 40 ℃ for reflux, and the mixed solvent is stirred for 30 minutes until the system is dissolved. The system is cooled, the temperature is controlled to 25 ℃, crystallization is carried out for 24 hours, the temperature is further cooled to 5 ℃, stirring is continued for 5 hours, decompression and suction filtration are carried out, filter cakes are washed by ethyl acetate, drying is carried out for 10 hours at the temperature of 50 ℃, 111.4g of product is obtained, the mass yield is 92.8%, and the purity of the compound is 93.22% measured by HPLC.
Example 4: preparation of nicardipine hydrochloride ethyl semiacetate compound
The preparation of crude nicardipine hydrochloride was the same as in example 1.
The crude nicardipine hydrochloride (150 g) is added into 2400mL of mixed solvent of dichloromethane and ethyl acetate, wherein the volume ratio of the dichloromethane to the ethyl acetate is 1:3, the volume (unit is mL) of the mixed solvent is 16 times of the mass (unit is g) of the nicardipine hydrochloride crude product, the temperature is raised to 40 ℃ for reflux, and the mixed solvent is stirred for 30 minutes until the system is dissolved. The system is cooled, the temperature is controlled to 25 ℃, crystallization is carried out for 2 hours, the temperature is further cooled to 5 ℃, stirring is continued for 3 hours, decompression and suction filtration are carried out, filter cakes are washed by ethyl acetate, drying is carried out for 10 hours at the temperature of 50 ℃, 136.5g of product is obtained, the mass yield is 91.0%, and the purity of the compound is 99.12% as measured by HPLC.
Example 5: preparation of nicardipine hydrochloride ethyl semiacetate compound
The preparation of crude nicardipine hydrochloride was the same as in example 1.
The crude nicardipine hydrochloride (100 g) is added into 2000mL of mixed solvent of dichloromethane and ethyl acetate, wherein the volume ratio of the dichloromethane to the ethyl acetate is 1:3, the volume (unit is mL) of the mixed solvent is 20 times of the mass (unit is g) of the nicardipine hydrochloride crude product, the temperature is raised to 65 ℃ for reflux, and the mixed solvent is stirred for 30 minutes until the system is dissolved. The system is cooled, the temperature is controlled to 20 ℃, crystallization is carried out for 2 hours, the temperature is reduced to 0 ℃, stirring is continued for 1 hour, decompression and suction filtration are carried out, filter cakes are washed by ethyl acetate, drying is carried out for 24 hours at the temperature of 40 ℃, 92.4g of product is obtained, the mass yield is 92.4%, and the purity of the compound is 98.78% measured by HPLC.
Example 6: preparation of nicardipine hydrochloride ethyl semiacetate compound
The preparation of crude nicardipine hydrochloride was the same as in example 1.
The crude nicardipine hydrochloride (100 g) is added into 2000mL of mixed solvent of dichloromethane and ethyl acetate, wherein the volume ratio of the dichloromethane to the ethyl acetate is 1:1, the volume (unit is mL) of the mixed solvent is 20 times of the mass (unit is g) of the nicardipine hydrochloride crude product, the temperature is raised to 40 ℃ for reflux, and the mixture is stirred for 60 minutes until the system is dissolved. The system is cooled, the temperature is controlled to be 40 ℃, crystallization is carried out for 24 hours, the temperature is reduced to be 10 ℃, stirring is continued for 5 hours, decompression and suction filtration are carried out, a filter cake is washed by ethyl acetate, and drying is carried out for 2 hours at the temperature of 60 ℃, so that 93.3g of product is obtained, the mass yield is 93.3%, and the purity of the compound is 99.51% by HPLC.
Example 7: preparation of alpha crystal nicardipine hydrochloride finished product
Preparing an alpha crystal form nicardipine hydrochloride seed crystal: the crude nicardium hydrochloride product (20 g) prepared in example 1 is added into methanol (100 mL) to be stirred and dissolved, the mother liquor is filtered, decompressed and evaporated to be foaming at 40 ℃, the mixed solvent (1:9, 100 mL) of acetone and absolute ethanol is added, and stirring and heating are started until the mother liquor is dissolved. Stirring at 40deg.C for 24 hr, cooling to 5deg.C, and stirring for 5 hr. The resulting solid was filtered and dried to give 15.8g of the product in a mass yield of 79%. The melting point is measured to be 179-188 ℃, and the crystal seed crystal of the nicardipine hydrochloride in the alpha crystal form is obtained.
Nicardipine hydrochloride ethyl semiacetate (10 g, prepared in example 3) was added to a mixed solvent of acetone and absolute ethanol (2:1, 80 mL), and the mixture was stirred and heated to 65 ℃ with stirring for 30 minutes. Then cooling to 40 ℃, adding 0.1% of alpha crystal form nicardipine hydrochloride crystal seed, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 9.0g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 90%. The melting point is measured to be 179-184 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product.
Wherein, the HPLC profile data of the nicardipine hydrochloride ethyl acetate compound is shown in the following table 4, wherein the retention time is 21.505min, which is the chromatographic peak of the nicardipine hydrochloride ethyl acetate compound, and the relative peak area is 93.22%.
TABLE 4 HPLC profile data for nicardipine hydrochloride ethyl hemiacetate compound
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HPLC profile data of the finished product of the alpha-crystalline form of nicardipine hydrochloride is shown in the following table 5, wherein the retention time is 21.807min, and the chromatographic peak of the alpha-crystalline form of nicardipine hydrochloride is 99.94% of the relative peak area.
Table 5 HPLC profile data for crystalline nicardipine hydrochloride product
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 1.458 | 0.14 | 4.659 | 0.04 |
| 2 | 9.531 | 0.056 | 0.242 | 0.02 |
| 3 | 21.807 | 313.404 | 230.917 | 99.94 |
Example 8: preparation of alpha crystal nicardipine hydrochloride finished product
Nicardipine hydrochloride ethyl acetate compound (10 g, prepared in example 3) was added to a mixed solvent of acetone and absolute ethanol (2:1, 120 mL), and the temperature was raised to 40 ℃ with stirring, and stirred for 30 minutes. Then cooling to 10 ℃, adding the crystal seed of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 24 hours, cooling to 0 ℃, and stirring for 1 hour. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting 8.9g of alpha crystal form nicardipine hydrochloride finished product, wherein the quality yield is 89%, and the purity is 99.97%. The melting point is measured to be 181-184 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product.
Example 9: preparation of alpha crystal nicardipine hydrochloride finished product
Nicardipine hydrochloride ethyl acetate compound (10 g, prepared in example 3) was added to a mixed solvent of acetone and absolute ethanol (2:1, 80 mL), and the temperature was raised to 65 ℃ with stirring, and stirred for 10 minutes. Then cooling to 10 ℃, adding the crystal seed of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 2 hours, cooling to 0 ℃ and stirring for 5 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 8.8 g of alpha crystal form nicardipine hydrochloride finished product, wherein the quality yield is 88%, and the purity is 99.95%. Measured melting point is 179-184 ℃, and the alpha crystal nicardipine hydrochloride finished product is indicated
Comparative example 1: preparation of alpha crystal nicardipine hydrochloride finished product
(1) Preparation of nicardipine hydrochloride chloroform compound (intermediate crystal form)
The crude nicardipine hydrochloride (20 g) prepared in example 1 was dissolved in chloroform (800 mL) at 40 ℃; then the reaction solution is rapidly cooled to-20 ℃, diethyl ether (200 mL) is added dropwise under stirring, the temperature is kept and the stirring is carried out for 3 hours, the obtained solid is filtered, and the product is dried to obtain 18.6g, and the mass yield is 93%. The melting point was measured at 108-110℃and was consistent with literature (Moreno-Calvo E, munt. TM., wurst K, et a1.Polymorphs and solvates ofnicardipine hydro-selective stabilization of different diastereomeric racemates [ J ]. Molecular pharmaceutics,2011,8 (2): 395-404.), indicating a chloroform compound, to obtain nicardipine hydrochloride chloroform compound.
(2) Preparation of alpha crystal nicardipine hydrochloride finished product
Nicardipine hydrochloride chloroform compound (8 g) was added to a mixed solvent of acetone and absolute ethanol (2:1, 96 mL), and the temperature was raised to 65 ℃ with stirring for 30 minutes. Then cooling to 40 ℃, adding the crystal seed crystal of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 6.6g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 83%. The melting point is measured to be 179-183 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product. The HPLC data of the chloroform compound of nicardipine hydrochloride are shown in the following Table 6, wherein the retention time is 22.273min, which is the chromatographic peak of the chloroform compound of nicardipine hydrochloride, and the relative peak area is 94.86%.
TABLE 6 HPLC profile data for nicardipine hydrochloride chloroform compounds
HPLC profile data of the finished product of the alpha-crystalline form of nicardipine hydrochloride is shown in the following table 7, wherein the retention time is 22.325min, and the chromatographic peak of the alpha-crystalline form of nicardipine hydrochloride is 98.49% of the relative peak area.
Table 7 HPLC profile data for crystalline nicardipine hydrochloride product
Comparative example 2: preparation of alpha crystal nicardipine hydrochloride finished product
(1) Preparation of nicardipine hydrochloride hemitoluene (intermediate crystal form)
The crude nicardipine hydrochloride (10 g) prepared in example 1 was dissolved in toluene/methanol (ratio 3:1) mixed solvent (400 mL) at 40 ℃; the reaction mixture was heated at 60℃to remove methanol until crystals were formed. The suspension was cooled to 0-5℃with rapid stirring, the resulting solid was filtered after 5 hours and dried to give 9.1g of product with a mass yield of 91%. The melting point was measured at 114-115℃and was consistent with the literature (Moreno-Calvo E, munt. TM., wurstK, et al a1.Polymorphs and solvates of nicardipine hydrochloride.selective stabilization of different diastereomeric racemates [ J ]. Molecular pharmaceutics,2011,8 (2): 395-404.), indicating a hemitoluene compound, thus obtaining nicardipine hydrochloride hemitoluene compound.
(2) Preparation of alpha crystal nicardipine hydrochloride finished product
Nicardipine hydrochloride hemitoluene (8 g) was added to a mixed solvent of acetone and absolute ethanol (2:1, 160 mL), and the temperature was raised to 65 ℃ with stirring for 30 minutes. Then cooling to 40 ℃, adding the crystal seed crystal of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 6.0g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 75%. The melting point is measured to be 179-185 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product. The HPLC profile data of the nicardipine hydrochloride toluene compound is shown in the following table 8, wherein the retention time is 22.075min, which is a chromatographic peak of the nicardipine hydrochloride toluene compound, and the relative peak area is 94.58%.
TABLE 8 HPLC profile data for nicardipine hydrochloride toluene compound
HPLC profile data of the finished product of the alpha-crystalline form of nicardipine hydrochloride is shown in the following table 9, wherein the retention time is 22.623min, and the chromatographic peak of the alpha-crystalline form of nicardipine hydrochloride is 98.71% of the relative peak area.
Table 9 HPLC profile data for crystalline nicardipine hydrochloride product
Comparative example 3: preparation of alpha crystal nicardipine hydrochloride finished product
(1) Preparation of nicardipine hydrochloride dihydrate (intermediate form)
The nicardipine hydrochloride chloroform compound (10 g) prepared in comparative example 1 was added to diethyl ether (100 mL), followed by addition of water (5 mL); the reaction solution was stirred at 10℃for 5 days, the resulting solid was filtered and dried to give 8.7g of a product with a mass yield of 87%. Melting point 136-137℃was measured and consistent with literature (Moreno-Calvo E, munt. M, wurst K, et a1.Polymorphs and solvates of nicardipine hydro-selective stabilization of different diastereomeric racemates [ J ]. Molecular pharmaceutics,2011,8 (2): 395-404.), indicating dihydrate, to obtain nicardipine hydrochloride dihydrate.
(2) Preparation of alpha crystal nicardipine hydrochloride finished product
Nicardipine hydrochloride dihydrate (8 g) was added to a mixed solvent of acetone and absolute ethanol (2:1, 320 mL), and the temperature was raised to 65 ℃ with stirring for 30 minutes. Then cooling to 40 ℃, adding alpha crystal form seed crystal, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 3.6g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 45%. The melting point is measured to be 180-185 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product. The HPLC profile data of nicardipine hydrochloride dihydrate is shown in table 10 below, wherein retention time is 22.254min, which is a chromatographic peak of nicardipine hydrochloride dihydrate, and the relative peak area is 93.79%.
Table 10 HPLC profile data for nicardipine hydrochloride dihydrate
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HPLC profile data of the finished product of the alpha-crystalline form of nicardipine hydrochloride is shown in the following table 11, wherein the retention time is 22.565min, and the chromatographic peak of the alpha-crystalline form of nicardipine hydrochloride is 99.15% of the relative peak area.
Table 11 HPLC profile data for crystalline nicardipine hydrochloride product
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 5.585 | 0.064 | 0.363 | 0.04 |
| 2 | 6.027 | 0.068 | 0.461 | 0.04 |
| 3 | 9.478 | 0.484 | 1.992 | 0.31 |
| 4 | 11.974 | 0.095 | 0.316 | 0.06 |
| 5 | 12.643 | 0.08 | 0.185 | 0.05 |
| 6 | 14.532 | 0.103 | 0.209 | 0.07 |
| 7 | 17.88 | 0.229 | 0.499 | 0.14 |
| 8 | 22.565 | 157.076 | 153.027 | 99.15 |
| 9 | 36.308 | 0.154 | 0.185 | 0.1 |
| 10 | 44.153 | 0.075 | 0.093 | 0.05 |
Comparative example 4: preparation of alpha crystal nicardipine hydrochloride finished product
The crystalline form α nicardipine hydrochloride seed crystal (i.e., intermediate crystal form, 10 g) prepared in example 7 was added to a mixed solvent of acetone and absolute ethanol (2:1, 350 mL), and the temperature was raised to 65 ℃ with stirring, and stirred for 30 minutes. Then cooling to 40 ℃, adding the crystal seed crystal of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 6.8g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 68%. The melting point is measured to be 179-185 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product. The HPLC profile data of the α crystalline form of nicardipine hydrochloride (intermediate form) are shown in table 12 below, wherein the retention time is 24.393min, which is a chromatographic peak of the α crystalline form of nicardipine hydrochloride (intermediate form), and the relative peak area is 96.07%.
Table 12 HPLC profile data for the intermediate crystalline form of nicardipine hydrochloride form alpha
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 1.45 | 1.722 | 57.733 | 1.06 |
| 2 | 3.12 | 0.915 | 12.249 | 0.56 |
| 3 | 4.248 | 0.507 | 5.553 | 0.31 |
| 4 | 4.885 | 2.123 | 19.08 | 1.31 |
| 5 | 13.934 | 0.152 | 0.462 | 0.09 |
| 6 | 14.852 | 0.671 | 1.339 | 0.41 |
| 7 | 18.723 | 0.293 | 0.722 | 0.18 |
| 8 | 24.393 | 156.135 | 175.06 | 96.07 |
HPLC profile data of the finished product of the α -crystalline form of nicardipine hydrochloride is shown in the following Table 13, wherein the retention time is 21.041min, which is chromatographic peak of the α -crystalline form of nicardipine hydrochloride, and the relative peak area is 98.64%.
HPLC profile data of crystalline form 13 alpha of nicardipine hydrochloride finished product
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 1.506 | 0.057 | 1.142 | 0.02 |
| 2 | 2.812 | 0.096 | 1.568 | 0.04 |
| 3 | 4.537 | 0.132 | 0.812 | 0.05 |
| 4 | 5.035 | 0.061 | 0.449 | 0.02 |
| 5 | 5.423 | 0.083 | 0.631 | 0.03 |
| 6 | 5.839 | 0.164 | 1.087 | 0.07 |
| 7 | 6.371 | 0.213 | 0.661 | 0.09 |
| 8 | 6.805 | 0.025 | 0.175 | 0.01 |
| 9 | 9.659 | 0.963 | 4.065 | 0.38 |
| 10 | 11.52 | 0.229 | 0.628 | 0.09 |
| 11 | 12.558 | 0.069 | 0.249 | 0.03 |
| 12 | 14.362 | 0.065 | 0.198 | 0.03 |
| 13 | 14.815 | 0.136 | 0.389 | 0.05 |
| 14 | 17.401 | 0.396 | 1.052 | 0.16 |
| 15 | 21.041 | 246.723 | 197.871 | 98.64 |
| 16 | 34.751 | 0.283 | 0.352 | 0.11 |
| 17 | 45.223 | 0.162 | 0.131 | 0.06 |
| 18 | 53.703 | 0.26 | 0.088 | 0.1 |
Comparative example 5: preparation of alpha crystal nicardipine hydrochloride finished product
(1) Preparation of beta-crystalline form of nicardipine hydrochloride (intermediate form)
Adding the nicardium hydrochloride crude product (20 g) prepared in the example 1 into methanol (100 mL) to stir and dissolve, filtering, evaporating the mother liquor to be foaming under reduced pressure, and adding acetone (80 mL) to stir and dissolve; the reaction solution was rapidly cooled to-40℃and stirred for 13 hours, the resulting solid was filtered and dried to give 16.7g of the product in 83.5% yield. The melting point was measured at 166-168℃and was consistent with the literature (Moreno-Calvo E, munt. TM., wurst K, et a1.Polymorphs and solvates ofnicardipine hydro-crystalline stabilization of different diastereomeric racemates [ J ]. Molecular pharmaceutics,2011,8 (2): 395-404.), indicating a beta crystalline form, thus obtaining nicardipine hydrochloride in the beta crystalline form.
(2) Preparation of alpha crystal nicardipine hydrochloride finished product
Beta-crystalline form nicardipine hydrochloride (10 g) was added to a mixed solvent of acetone and absolute ethanol (2:1, 600 mL), and the temperature was raised to 65 ℃ with stirring for 30 minutes. Then cooling to 40 ℃, adding the crystal seed crystal of the alpha crystal form nicardipine hydrochloride, preserving heat and stirring for 24 hours, cooling to 5 ℃ and stirring for 4 hours. Filtering, and washing the filter cake with acetone. Vacuum drying for 16 hours, cooling and collecting to obtain 6.1g of alpha crystal form nicardipine hydrochloride finished product, and the mass yield is 61%. The melting point is measured to be 179-184 ℃, and the product is indicated to be the alpha crystal form nicardipine hydrochloride finished product. The HPLC profile data of the beta-crystalline form of nicardipine hydrochloride is shown in table 14 below, wherein the retention time is 23.797min, which is a chromatographic peak of the beta-crystalline form of nicardipine hydrochloride, and the relative peak area is 95.83%.
Table 14 HPLC profile data for crystalline form β nicardipine hydrochloride
| Sequence number | Retention time/min | Peak area/mAU min | Peak height/mAU | Relative peak area/% |
| 1 | 1.446 | 1.855 | 62.78 | 0.76 |
| 2 | 3.111 | 1.672 | 22.603 | 0.69 |
| 3 | 4.214 | 0.702 | 7.943 | 0.29 |
| 4 | 4.858 | 3.306 | 30.058 | 1.36 |
| 5 | 5.808 | 0.125 | 0.821 | 0.05 |
| 6 | 13.687 | 0.272 | 0.811 | 0.11 |
| 7 | 14.758 | 0.619 | 1.13 | 0.25 |
| 8 | 15.845 | 0.06 | 0.116 | 0.02 |
| 9 | 17.9 | 0.048 | 0.175 | 0.02 |
| 10 | 18.543 | 1.064 | 2.242 | 0.44 |
| 11 | 23.797 | 232.896 | 229.94 | 95.83 |
| 12 | 56.503 | 0.411 | 0.33 | 0.17 |
HPLC profile data of the finished product of the alpha-crystalline form of nicardipine hydrochloride is shown in the following table 15, wherein the retention time is 20.411min, and the chromatographic peak of the alpha-crystalline form of nicardipine hydrochloride is 98.77% of the relative peak area.
Table 15 HPLC profile data for crystalline nicardipine hydrochloride product
The data of the finished product of nicardipine hydrochloride of alpha crystal form obtained by recrystallizing nicardipine hydrochloride of different intermediate crystal forms in examples 7 to 9 and comparative examples 1 to 5 are summarized in the following table 16.
Table 16 data for the preparation of nicardipine hydrochloride product of alpha form from intermediate form
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Note that: the intermediate forms in the tables refer to the recrystallization starting materials used to prepare the finished product of nicardipine hydrochloride in the alpha form in example 7 and comparative examples 1-5; wherein, the intermediate crystal form in example 7 refers to nicardipine hydrochloride ethyl acetate, the intermediate crystal form in comparative example 1 refers to nicardipine hydrochloride chloroform, the intermediate crystal form in comparative example 2 refers to nicardipine hydrochloride hemitoluene, the intermediate crystal form in comparative example 3 refers to nicardipine hydrochloride dihydrate, the intermediate crystal form in comparative example 4 refers to nicardipine hydrochloride in alpha crystal form, and the intermediate crystal form in comparative example 5 refers to nicardipine hydrochloride in beta crystal form. The final product is the obtained alpha crystal form nicardipine hydrochloride final product. The solvent used for recrystallization is a mixed solvent of acetone and ethanol in a volume ratio of 2:1.
As can be obtained from table 16, the yield of the α -crystalline nicardipine hydrochloride product prepared using the nicardipine hydrochloride ethyl acetate compound obtained in example 1 as a raw material is higher than the yields of the nicardipine hydrochloride chloroform compound, the nicardipine hydrochloride hemitoluene compound, the nicardipine hydrochloride dihydrate, the α -crystalline nicardipine hydrochloride and the β -crystalline nicardipine hydrochloride as raw materials. The nicardipine hydrochloride ethyl acetate compound is more soluble in the recrystallization solvent, the amount of the solvent used is less, and the cost is saved. In addition, the report limit of impurities in bulk drugs in ICH guidelines is 0.05%, the alpha crystal form nicardipine hydrochloride finished product prepared from the nicardipine hydrochloride semi-acetate compound does not contain impurities higher than the report limit, the maximum unknown single impurity content is only 0.04%, and the impurity report limit is lower than 0.05%, namely, the purity of the alpha crystal form nicardipine hydrochloride finished product prepared from the nicardipine hydrochloride semi-acetate compound is higher, can reach more than 99.9%, and has remarkable advantages. In addition, the nicardipine hydrochloride semi-acetate compound has higher melting point, more regular grains and better stability, and generally, the melting point is increased to lower the solubility in a solvent, but the nicardipine hydrochloride semi-acetate compound prepared by the method has higher melting point and higher solubility in a solvent used for recrystallization.
While the foregoing describes the embodiments of the present invention, it is not intended to limit the scope of the present invention, and on the basis of the technical solutions of the present invention, various modifications or variations may be made by those skilled in the art without the need for inventive labor.
Claims (18)
1. The nicardipine hydrochloride ethyl hemiacetate compound crystal is characterized in that the molecular structural formula is shown in the following formula (I):
2. the crystalline nicardipine hemiacetate hydrochloride according to claim 1, characterized by characteristic peaks in XRD diffractogram at values of 17.80, 20.43, 23.85 and 24.15, wherein the error range of 2 theta values is 0.2;
preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.98, 11.16, 16.98, 17.80, 20.01, 20.43, 22.90, 23.85, 24.15 and 27.40, where the 2 theta value error range is 0.2;
more preferably, in the XRD diffractogram, there are characteristic peaks at values of 7.50, 9.09, 9.98, 11.16, 11.45, 16.98, 17.80, 20.01, 20.43, 20.89, 22.90, 23.85, 24.15, 25.35, 27.40, 28.05 and 31.61, wherein the error range of 2 theta values is 0.2.
3. The crystalline nicardipine hydrochloride ethyl semiacetate compound according to claim 1 or 2, wherein the melting point of the nicardipine hydrochloride ethyl semiacetate compound is 148 ℃ and the error range of the melting point is 2 ℃.
4. A process for the preparation of crystalline nicardipine hydrochloride ethyl hemiacetate according to any one of claims 1 to 3, comprising the steps of:
adding a solvent into the crude nicardipine hydrochloride, and heating and refluxing to dissolve the crude nicardipine hydrochloride; then cooling and crystallizing for the first time; then cooling and crystallizing for the second time; and removing the solvent and drying to obtain the nicardipine hydrochloride ethyl semiacetate compound.
5. The preparation method of the nicardipine hydrochloride ethyl acetate compound crystal according to claim 4, wherein the volume of the solvent is 10-20 times of the mass of the crude nicardipine hydrochloride, preferably the volume of the solvent is 10-15 times of the mass of the crude nicardipine hydrochloride; wherein, the volume unit is mL, and the mass unit is g;
preferably, the solvent is a mixed solution containing a good solvent and ethyl acetate, wherein the good solvent is selected from one or more of dichloromethane, methanol, ethanol and isopropanol;
More preferably, the solvent is a mixed solution of dichloromethane and ethyl acetate;
further preferably, the volume ratio of dichloromethane to ethyl acetate is 1:1 to 1:3, preferably the volume ratio of dichloromethane to ethyl acetate is 1:1.5 to 1:2.5.
6. The process for preparing a crystalline nicardipine hydrochloride ethyl hemiacetate compound according to claim 4 or 5, wherein the heating is to heat the solvent to 40 ℃ to 65 ℃, preferably the heating is to heat the solvent to 40 ℃ to 60 ℃;
and/or, the reflux time is 30 min-60 min.
7. The preparation method of the nicardipine hydrochloride ethyl hemiacetate compound crystal according to any one of claims 4 to 6, wherein the cooling crystallization is a direct crystallization method or a seed crystal induced crystallization method;
preferably, the cooling crystallization is a direct crystallization method;
and/or, in the first cooling crystallization process, the temperature is reduced to 20-40 ℃, preferably to 20-30 ℃; and/or the crystallization time is 2-24 hours, preferably 3-24 hours;
and/or, in the second cooling crystallization process, the temperature is reduced to 0-10 ℃, preferably to 2-8 ℃; and/or the time of crystallization is 1 to 5 hours, preferably 3 to 5 hours.
8. The preparation method of the nicardipine hydrochloride ethyl acetate compound crystal according to any one of claims 4 to 7, wherein the nicardipine hydrochloride ethyl acetate compound crystal is obtained by drying after removing the solvent;
preferably, it is washed with ethyl acetate before drying;
and/or, preferably, the drying mode is vacuum drying;
more preferably, the drying temperature is 40 to 60 ℃; and/or drying for 2-24 hours;
still more preferably, the temperature of drying is 45-55 ℃; and/or drying for 11-17 hours.
9. A crystalline nicardipine hydrochloride, characterized in that it is prepared by the preparation method of crystalline nicardipine hydrochloride ethyl hemiacetate compound according to any one of claims 4 to 8.
10. A pharmaceutical composition characterized by comprising the crystalline nicardipine hydrochloride hemiacetate compound according to any one of claims 1 to 3 or claim 9 as an active ingredient.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in any clinically acceptable pharmaceutical dosage form.
12. Use of the crystalline nicardipine hydrochloride ethyl hemiacetate compound of any one of claims 1-3 or claim 9, or the pharmaceutical composition of claim 10 or 11, for the preparation of a medicament for the treatment of cardiovascular or cerebrovascular diseases;
Preferably, the application in preparing the medicine for treating cardiovascular diseases is the application in preparing the medicine for resisting hypertension, angina pectoris or treating ischemic and hemorrhagic cerebrovascular accident sequelae.
13. The preparation method of the nicardipine hydrochloride crystal of the alpha crystal form is characterized by comprising the following steps:
crystalline nicardipine hydrochloride ethyl semiacetate compound according to any one of claims 1 to 3 or 9, which is prepared by recrystallization.
14. The preparation method of claim 13, wherein nicardipine hydrochloride ethyl acetate compound is added into the recrystallization solvent, and the nicardipine hydrochloride ethyl acetate compound is dissolved by heating and refluxing; then cooling and crystallizing for the first time; then cooling and crystallizing for the second time; and removing the solvent and drying to obtain the nicardipine hydrochloride crystal of the alpha crystal form.
15. The production method according to claim 13 or 14, wherein the temperature increase is to increase the temperature of the solution to 40 to 65 ℃;
and/or, the reflux time is 10-30 min.
16. The preparation method according to any one of claims 13 to 15, wherein the volume of the recrystallization solvent is 6 to 15 times the mass of the nicardipine hydrochloride ethyl semiacetate compound; wherein, the volume unit is mL, and the mass unit is g;
Preferably, the volume of the recrystallization solvent is 8-12 times of the mass of the nicardipine hydrochloride ethyl semiacetate compound;
more preferably, the solvent for recrystallization is a mixed solvent of acetone and ethanol;
further preferably, the volume ratio of the acetone to the ethanol is 1-3:0.5-2;
still more preferably, the ethanol is absolute ethanol.
17. The production method according to any one of claims 13 to 16, wherein after the completion of the reflux, the solution is subjected to cooling crystallization selected from direct crystallization or seed crystal induced crystallization;
preferably, the cooling crystallization is a seed crystal induced crystallization method, and the added seed crystal is nicardipine hydrochloride of alpha crystal form;
and/or, in the first cooling crystallization process, cooling the solution to 10-40 ℃; and/or the crystallization time is 2-24 hours;
and/or, in the second cooling crystallization process, cooling the solution to 0-10 ℃; and/or the crystallization time is 1-5 h.
18. The preparation method of any one of claims 13-17, wherein after crystallization, removing the solvent, washing with acetone, and drying to obtain crystalline nicardipine hydrochloride crystals of alpha crystal form;
preferably, the drying is vacuum drying.
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