WO2019001414A1 - Benzodiazepine compound solid forms, and preparation methods therefor and applications thereof - Google Patents

Benzodiazepine compound solid forms, and preparation methods therefor and applications thereof Download PDF

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Publication number
WO2019001414A1
WO2019001414A1 PCT/CN2018/092820 CN2018092820W WO2019001414A1 WO 2019001414 A1 WO2019001414 A1 WO 2019001414A1 CN 2018092820 W CN2018092820 W CN 2018092820W WO 2019001414 A1 WO2019001414 A1 WO 2019001414A1
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Prior art keywords
drying
methyl
benzodiazepine
chloro
oxadiazol
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PCT/CN2018/092820
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French (fr)
Chinese (zh)
Inventor
周新波
朱建荣
谢作念
任小娟
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浙江京新药业股份有限公司
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Publication of WO2019001414A1 publication Critical patent/WO2019001414A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a solid form of a benzodiazepine compound and a preparation method and application thereof, in particular to 7-chloro-3-(5-dimethylaminomethyl-[1, 2, 4]oxadiazole -3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine-6-one (Formula I) Amorphous morphology, and methods of preparation and the use of such morphologies in the preparation of a medicament. Background technique
  • WO 2000/069858 describes that Formula I has valuable pharmacodynamic properties, exhibits high in vitro and in vivo activity of bound benzodiazepine receptors, and exhibits such indications as anxiety disorders, insomnia, affective disorders, Rapid onset and powerful therapeutic effects in psychotic symptoms and disorders.
  • WO 2000/069858 also discloses a process for the preparation of the formula I.
  • these processes are disclosed in terms of a manufacturing process for the purpose of increasing the yield and chemical purity, and there is no description of the solid form of the drug at all.
  • the solid form of the drug compound can be divided into three states, gp, global ordered state crystalline solid matter; global disordered amorphous solid matter, partially ordered and partially disordered crystalline and amorphous solid matter.
  • changes in the solid form of the drug may affect various physical and chemical properties that may have benefits or drawbacks to mechanical properties, stability, solubility and bioavailability, as well as other important pharmaceutical properties
  • the preparation and selection of solid forms is complex.
  • the discovery of new polymorphs of the drug expands all the constituents of the material, making it necessary for the formulation scientist to use this component to design the target release characteristics. Or other pharmaceutical pharmaceutical dosage form of the desired characteristics. Summary of the invention
  • the present invention provides the chemical name 7-chloro-3-(5-dimethylaminomethyl-[1, 2,4]oxadiazol-3-yl)-5-methyl-4, 5-
  • the new crystal form which is referred to herein as crystal form 8, crystal form B, and its amorphous form.
  • Another object of the present invention is to provide 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5 -
  • Yet another object of the present invention is to provide 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4, 5- One or more of the crystalline form A, the crystalline form B and the amorphous form of dihydro-imidazo[1,5-][l,4]benzodiazepine-6-one Use in the preparation of a pharmaceutical composition for use as an anxiolytic and/or anticonvulsant and/or non-sedative hypnotic.
  • the present invention provides a crystal of formula I (Form A).
  • Form A of formula I can be characterized by X-ray powder diffraction analysis.
  • the crystal form A of the formula I is in the X-ray powder diffraction pattern measured by Cu- ⁇ ray, at least at the following diffraction angles 2 ⁇ of 6.62 ⁇ 0.1°, 9.12+0.1°, 12.56 ⁇ 0.1°, 12.98+0.1 14.70 ⁇ 0.1°, 15.94+0.1 16.96 ⁇ 0.1 °, 18.48+0.1 19.66+0.1 19.80+0.1 20.04+0.1 21 ⁇ 02 ⁇ 0 ⁇ 1 ⁇ , 22.66+0.1 23 ⁇ 70 ⁇ 0 ⁇ 1 ⁇ and 24.56 ⁇ 0.1° Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form is substantially as shown in FIG.
  • Form A of Formula I is a single crystal that can be characterized by X-ray single crystal diffraction analysis.
  • the X-ray powder diffraction analysis of Form A of Formula I was matched to X-ray single crystal diffraction analysis.
  • Form A of Formula I can be characterized by thermal analysis. Typical of Form A of Formula I
  • the DSC chart is shown in Figure 4.
  • the endothermic peak peak value of about 155.5 °C
  • the melting endothermic peak of the crystal form A is included, which is the melting endothermic peak of the crystal form A. From the TGA chart of Form A, no loss of mass was observed from room temperature to 150 ° C, indicating that Form A did not contain a large amount of water or other solvent in the crystal lattice. Form A is unsolvated. Form A is anhydrous.
  • a typical TGA pattern for Form A of Formula I is shown in FIG.
  • Form A of Formula I can be characterized by Raman spectroscopy.
  • a typical Raman plot for Form A of Formula I is shown in Figure 5.
  • Form A is characterized by having 403 ⁇ 2cm—i, 447 ⁇ 2cm—i, 566 ⁇ 2cm- 1 , 653 ⁇ 2cm- 1 , 742 ⁇ 2cm- 1 , 784 ⁇ 2cm- 1 , 850 included in 325 ⁇ 2cm.
  • Form A of Formula I can be characterized by its stability characteristics.
  • Form A is stable and its PXRD pattern remains substantially unchanged. For example, after a week of exposure to an environment of about 100 ° C, Form A is stable.
  • Form A is stable after exposure to an environment of about 40 ° C and an environment of about 75% RH for 6 months.
  • Form A is stable after exposure to an environment of about 30 ° C and an environment of about 75% RH for 12 months.
  • the invention also provides a process for the preparation of pure Form A of Formula I, which comprises the steps of:
  • the organic solvent is preferably isopropyl acetate.
  • the anti-solvent may be an organic solvent having poor solubility to the compound of the formula I, preferably including but not limited to cyclohexyl hydrazine, n-hexyl hydrazine, n-glyoxime and methyl tert-butyl ether.
  • organic solvent having poor solubility to the compound of the formula I preferably including but not limited to cyclohexyl hydrazine, n-hexyl hydrazine, n-glyoxime and methyl tert-butyl ether.
  • One or more, more preferably methyl tert-butyl ether is preferably methyl tert-butyl ether.
  • Form B of Formula I can be characterized by X-ray powder diffraction analysis.
  • Form B of Formula I is in the X-ray powder diffraction pattern measured by Cu- ⁇ ray, at least at the following diffraction angles 2 ⁇ of 4.48 ⁇ 0.1°, 6.36+0.1 ° , There are characteristic peaks at 21.96 ⁇ 0.1 °, 22.42 + 0.1 22.82 ⁇ 0.1 ° and 24.16 ⁇ 0.1 °.
  • the X-ray powder diffraction pattern of the crystalline form is substantially as shown in FIG.
  • the crystalline form of Formula I can be characterized by thermal analysis.
  • a typical DSC plot of Form I of Formula I is shown in Figure 8. In the DSC chart, the endothermic peak at about 56 ° C to 85 ° C (the peak value is about 76 ° C) and the exothermic peak at about 114 ° C to 130 ° C (the peak value is about 122). °C). From the TGA pattern of Form B of Formula I, it is shown that from room temperature to 100 ° C, there is a loss of about 4-6%, indicating that Form B contains a portion of water or other solvent in the crystal lattice. A typical TGA plot for Form B of Formula I is shown in Figure 7.
  • Form B contains water molecules in the crystal lattice.
  • Form B is a hydrate.
  • Form B of Formula I can be characterized by Raman spectroscopy. A typical Raman plot for Form B of Formula I is shown in Figure 9.
  • Form B is characterized by having a range of 442 ⁇ 2 cm - 644 ⁇ 2 cm - 745 ⁇ 2 cm - 784 ⁇ 2 cm - 822 ⁇ 2 cm - 1091 ⁇ 2 cm - 1239 ⁇ 2 cm - 1392 ⁇ 2 cm - 1492 ⁇ 2 cm - 1564 ⁇ 2 cm - 1630 A peak of the wavenumber of ⁇ 2 cm- 1 .
  • Form B of Formula I can be characterized by its stability characteristics.
  • Form B is stable and its PXRD pattern remains substantially unchanged. For example, after a week of exposure to an environment of about 45 ° C, Form B is stable. However, when exposed to an environment of about 70 ° C, Form B is converted to amorphous.
  • the invention also provides a method for preparing a pure Form B of Formula I, which is Method 1 or Method 2;
  • the method 1 comprises the following steps:
  • the method 2 includes the following steps:
  • the crystal form A is mixed with water or a mixed solvent of water and an organic solvent at room temperature, stirred, filtered, washed, and dried at 50 ° C or lower.
  • a mixed solvent of water and an organic solvent at room temperature, stirred, filtered, washed, and dried at 50 ° C or lower.
  • the organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran;
  • the methods and conditions for filtration, washing and drying are all conventional in the art.
  • the drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 ° ( .
  • the organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone, and tetrahydrofuran;
  • the suspension time is preferably 8 to 48 hours
  • the methods and conditions for filtration, washing and drying are all routine in the art.
  • the drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 ° (.
  • the present invention also provides a 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydrol - an amorphous form of imidazo[1,5-][l,4]benzodiazepine-6-one having no characteristic peak in an X-ray powder diffraction pattern measured using Cu- ⁇ ray .
  • the X-ray powder diffraction pattern of the amorphous material is substantially as shown in Fig. 10.
  • the invention also provides a preparation method of the amorphous substance, which comprises the method 1 or the method 2; the method 1 comprises the following steps:
  • the method 2 includes the following steps:
  • the crystal form B is heat-treated at 70 to 80 ° C to obtain.
  • the organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran;
  • the methods and conditions for filtration, washing and drying are all conventional in the art.
  • the drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 70 to 80 °C.
  • the heat treatment time is generally from 1 to 3 hours.
  • the present invention also provides the compound 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro- One or more of the crystalline form A, the crystalline form B and the amorphous form of imidazo[1,5-][l,4]benzodiazepine-6-one, Use in the preparation of a medicament for use as an anxiolytic and/or anticonvulsant and/or non-sedative hypnotic.
  • the crystalline form A, the crystalline form B and the amorphous form of the present invention can be used as a single component or as a mixture of other crystalline forms or amorphous forms for the preparation of a pharmaceutical composition suitable for treating anxiety disorders, Patients with insomnia, affective disorder, psychotic symptoms and disorders.
  • crystal form is understood not only as “crystal type” or “crystal structure”; in the technical solution, “crystal form” is more understood as “substance having a specific crystal structure” or “crystal of a specific crystal type” ".
  • “Form A of Formula I” can be understood as “Formula I having a specific crystal structure” or “Crystal of Formula I of a specific crystal type”.
  • amorphous matter may be referred to as “amorphous state” or “amorphous form” and the like.
  • both the "crystalline form” and “amorphous form” are confirmed by the X-ray diffraction pattern characterization shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with the conditions of the instrument.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.1° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • any crystal form having the same or similar features as the characteristic peaks in the map of the present invention is within the scope of the present invention.
  • the error of the DSC test is also taken into account, and the measurement of the peak value usually allows an error of ⁇ 1 °C.
  • the "room temperature” is a room temperature in the conventional sense of the art, and is generally 10 30 V.
  • the preparation method of the invention is simple in operation, good in reproducibility, and stable in obtaining the target crystal form.
  • Figure 1 is an X-ray powder diffraction (PXRD) pattern of Compound Form I Form A (abscissa: diffraction angle)
  • Figure 2 is an ORTEP (single crystal structure analysis) diagram of the formula I crystal form A
  • FIG 3 is a thermogravimetric analysis (TG) of Compound I Form A (abscissa: temperature (V); ordinate: weight (%))
  • Figure 4 is a differential scanning analysis (DSC) diagram of the compound Form I Form A (abscissa: temperature (°C); ordinate: heat flow (W/g))
  • Figure 5 is a Raman spectrum of the formula I crystal form A (abscissa: Raman shift (cm- 1 ); ordinate: relative intensity (counts))
  • Figure 6 is an X-ray powder diffraction (PXRD) pattern of Form I Form B (abscissa: diffraction angle 2 ⁇ (°); ordinate: relative intensity (CPS))
  • FIG. 7 is a thermogravimetric analysis (TG) of Compound Formula I Form B (abscissa: temperature (V); ordinate: weight (%))
  • Figure 8 is a differential scanning analysis (DSC) chart of the compound Form B (abstraction: temperature (°C); ordinate: heat flow (W/g))
  • Figure 9 is a Raman spectrum of Compound Formula B Form B (abscissa: Raman shift (cm" 1 ); ordinate: relative intensity (counts))
  • Figure 10 is an X-ray powder diffraction (PXRD) pattern of the amorphous form of the compound Formula I (abscissa: diffraction angle 2 ⁇ (°); ordinate: relative intensity (CPS))
  • the apparatus for detecting the structure and properties of the polymorph of the drug in the present invention is as follows:
  • Powder X-ray diffraction (XRD) Characterization Instrument: Rigaku D/Max-2550 PC, CuKa radiation, power 40kVx250mA, scanning range 2 ⁇ 3 ⁇ 40°, step width 0.02°, scanning speed 5°/min.
  • Thermogravimetric analysis (TG) characterization Instrument: TA company SDT Q600, purge gas: nitrogen 120 mL/min, heating rate: 10 °C / min, temperature range: room temperature ⁇ 380 ° (.
  • DSC Differential Scanning Calorimetry Characterization: Instrument: TA Company DSC Q100, Purge Gas: Nitrogen 50 mL/min, Heating Rate: 10 °C /min, Temperature Range: Room Temperature ⁇ 200 ° (.
  • Raman characterization Instrument: Horiba Lab RAMHR Evolution, Light wavelength 633nm, laser power 100%, excitation time 30s, cumulative test times 2 times, grating 600gr/mm.
  • % in the mixed solvent means a volume percentage
  • 5-Dihydro-imidazo[l,5-a][l,4]benzodiazepine-6-one was added to 70 mL of isopropyl acetate, and dissolved by heating under reflux. At a temperature of 70 ° C, methyl tert-butyl ether was added, and the solid precipitated in the process was cooled, suction filtered, washed twice with cold isopropyl acetate, and dried under vacuum drying at 50 ° C to obtain a product.
  • Example 3 Preparation of Form A
  • Example 4 Preparation of Form B
  • Example 8 Preparation of amorphous material

Abstract

Disclosed are novel solid forms of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one, comprising crystalline form A, crystalline form B and an amorphous form. Also disclosed are preparation methods for the solid forms, and applications of the solid forms in the preparation of anxiolytics and/or anticonvulsants and/or non-sedative hypnotics.

Description

一种苯并二氮杂草化合物的固态形式及其制备方法和应用 技术领域  Solid form of benzodiazepine compound and preparation method and application thereof
本发明涉及一种苯并二氮杂草化合物的固态形式及其制备方法和应用， 具体涉及 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮 （式 I ) 的多晶形和非晶态形 态， 及制备方法和包括这些形态在制备药物中的应用。 背景技术  The invention relates to a solid form of a benzodiazepine compound and a preparation method and application thereof, in particular to 7-chloro-3-(5-dimethylaminomethyl-[1, 2, 4]oxadiazole -3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine-6-one (Formula I) Amorphous morphology, and methods of preparation and the use of such morphologies in the preparation of a medicament. Background technique
7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢- 咪唑 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮对应于式 I 的化合物：  7-Chloro-3-(5-dimethylaminomethyl-[1, 2,4]oxadiazol-3-yl)-5-methyl-4, 5-dihydro-imidazole [1, 5- a] [l, 4] benzodiazepine-6-one corresponds to the compound of formula I:
Figure imgf000002_0001
Figure imgf000002_0001
C I )  C I )
WO2000/069858描述式 I是具备有价值的药效特性， 表现出高的结合苯 并二氮杂草受体的体内外活性，并且表现出在此类适应症如焦虑障碍、失眠、 情感障碍、 精神病症状和障碍中快速起效和强大的治疗效应。  WO 2000/069858 describes that Formula I has valuable pharmacodynamic properties, exhibits high in vitro and in vivo activity of bound benzodiazepine receptors, and exhibits such indications as anxiety disorders, insomnia, affective disorders, Rapid onset and powerful therapeutic effects in psychotic symptoms and disorders.
WO2000/069858同时公开了式 I 的制备方法， 然而， 这些制造方法是以 提高产量和化学纯度为目的的制造方法的公开， 完全没有对于药物固态形式 方面的记载。药物化合物的固态形式可分为 3种状态， gp，全局有序状态 晶态固体物质； 全局无序状态 无定形态固体物质， 部分有序与部分无序 状态 晶态与无定形态固体物质。 考虑到药物固态形式的变化可能影响各 种物理和化学性质， 而这些性质可能会对机械性质、 稳定性、 溶解性和生物 利用度， 以及其他的重要的药物特性产生益处或弊端， 因此药物化合物的固 态形式的制备和选择是复杂的。 另外， 药物的新的多晶型的发现扩大了材料 的所有组成成分， 使得制剂科学家必须采用该成分以设计具有目标释放特性 或其它所需特征的药物制药剂型。 发明内容 WO 2000/069858 also discloses a process for the preparation of the formula I. However, these processes are disclosed in terms of a manufacturing process for the purpose of increasing the yield and chemical purity, and there is no description of the solid form of the drug at all. The solid form of the drug compound can be divided into three states, gp, global ordered state crystalline solid matter; global disordered amorphous solid matter, partially ordered and partially disordered crystalline and amorphous solid matter. Considering that changes in the solid form of the drug may affect various physical and chemical properties that may have benefits or drawbacks to mechanical properties, stability, solubility and bioavailability, as well as other important pharmaceutical properties, The preparation and selection of solid forms is complex. In addition, the discovery of new polymorphs of the drug expands all the constituents of the material, making it necessary for the formulation scientist to use this component to design the target release characteristics. Or other pharmaceutical pharmaceutical dosage form of the desired characteristics. Summary of the invention
本发明提供的是符合对化学名称 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4] 噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的 化合物 （式 I ) 的固态形式的需求的实施方案， 现己惊奇地发现了式 I 的新 晶型， 该新晶型在此记作晶型八、 晶型 B， 以及其非晶态形态。  The present invention provides the chemical name 7-chloro-3-(5-dimethylaminomethyl-[1, 2,4]oxadiazol-3-yl)-5-methyl-4, 5- An embodiment of the desired form of the solid form of a compound of formula (Formula I) of dihydro-imidazo[1,5-a][l,4]benzodiazepine-6-one, has now surprisingly found Formula I The new crystal form, which is referred to herein as crystal form 8, crystal form B, and its amorphous form.
本发明的一个目的是， 提供了 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁 二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮 （式 I ) 的化合物的 2种新晶型（晶型 A、 晶型 B)， 及其非晶态形态。  It is an object of the present invention to provide 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4, 5- Two new crystalline forms of the compound of dihydro-imidazo[1,5-a][l,4]benzodiazepine-6-one (formula I) (Form A, Form B), and Its amorphous form.
本发明的另一个目的是， 提供了 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4] 噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮 （式 I ) 的新晶型及非晶态形态的制备方法。  Another object of the present invention is to provide 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5 - A process for the preparation of new crystalline forms and amorphous forms of dihydro-imidazo[1,5-a][l,4]benzodiazepine-6-one (formula I).
本发明的又一个目的是， 提供 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁 二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的所 述晶型 A、 所述晶型 B 和非晶态形态中的一种或多种在制备用作抗焦虑和 / 或抗惊厥和 /或非镇静性安眠药的药物组合物中的应用。  Yet another object of the present invention is to provide 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4, 5- One or more of the crystalline form A, the crystalline form B and the amorphous form of dihydro-imidazo[1,5-][l,4]benzodiazepine-6-one Use in the preparation of a pharmaceutical composition for use as an anxiolytic and/or anticonvulsant and/or non-sedative hypnotic.
为解决上述技术问题， 本发明提供的技术方案如下：  In order to solve the above technical problems, the technical solution provided by the present invention is as follows:
本发明提供了一种式 I 的结晶 （晶型 A) 。 式 I 的晶型 A可以通过 X- 射线粉末衍射分析来表征。 式 I 的晶型 A在使用 Cu-Κα射线进行测定的 X- 射线粉末衍射图谱中， 至少在下述衍射角 2Θ 为 6.62±0.1 °、 9.12+0.1° , 12.56±0.1°、 12.98+0.1 14.70±0.1°、 15.94+0.1 16.96±0.1 °、 18.48+0.1 19.66+0.1 19.80+0.1 20.04+0.1 21 ·02±0·1 ο、 22.66+0.1 23·70±0·1ο和 24.56±0.1°处有特征峰。 较佳地， 所述晶型 Α的 X-射线粉末衍射图谱基本上 如图 1所示。 The present invention provides a crystal of formula I (Form A). Form A of formula I can be characterized by X-ray powder diffraction analysis. The crystal form A of the formula I is in the X-ray powder diffraction pattern measured by Cu-Κα ray, at least at the following diffraction angles 2Θ of 6.62±0.1°, 9.12+0.1°, 12.56±0.1°, 12.98+0.1 14.70± 0.1°, 15.94+0.1 16.96±0.1 °, 18.48+0.1 19.66+0.1 19.80+0.1 20.04+0.1 21 ·02±0·1 ο , 22.66+0.1 23·70±0·1 ο and 24.56±0.1° Characteristic peaks. Preferably, the X-ray powder diffraction pattern of the crystalline form is substantially as shown in FIG.
进一步地， 在某些实施方案中， 式 I 的晶型 A为单晶， 其可以通过 X- 射线单晶衍射分析来表征。式 I 的晶型 A的最小不对称单元由 1个式 I分子 构成， 所述的晶体属于正交晶系， Pbca空间群， 晶胞参数为 a=14.0911(6)A， b=9.6006(4)A，c=26.6704(9)A，晶胞体积 V=3608.1 (2)A3，晶胞内分子数 Z=8。 式 I 的晶型 A的 X-射线粉末衍射分析与 X-射线单晶衍射分析相匹配。  Further, in certain embodiments, Form A of Formula I is a single crystal that can be characterized by X-ray single crystal diffraction analysis. The smallest asymmetric unit of Form A of Formula I consists of one molecule of Formula I, which belongs to the orthorhombic system, the Pbca space group, and the unit cell parameters are a=14.0911(6)A, b=9.6006(4) A, c = 26.6704 (9) A, unit cell volume V = 3608.1 (2) A3, number of molecules in the unit cell Z = 8. The X-ray powder diffraction analysis of Form A of Formula I was matched to X-ray single crystal diffraction analysis.
进一步地， 式 I 的晶型 A可以通过热分析来表征。式 I 的晶型 A的典型 的 DSC图在图 4中显示。 DSC图中， 包含在约 153.5~ 158 °C处的吸热峰 （峰 顶值约 155.5 °C ) ， 为晶型 A的熔融吸热峰。 从晶型 A的 TGA图可知， 当从 室温至 150°C范围内， 没有显示质量损失， 表明晶型 A在晶格中不包含大量 的水或其他溶剂。 晶型 A是未溶剂化的。 晶型 A是无水的。 式 I 的晶型 A 的典型的 TGA图在图 3中显示。 Further, Form A of Formula I can be characterized by thermal analysis. Typical of Form A of Formula I The DSC chart is shown in Figure 4. In the DSC chart, the endothermic peak (peak value of about 155.5 °C) at about 153.5 to 158 °C is included, which is the melting endothermic peak of the crystal form A. From the TGA chart of Form A, no loss of mass was observed from room temperature to 150 ° C, indicating that Form A did not contain a large amount of water or other solvent in the crystal lattice. Form A is unsolvated. Form A is anhydrous. A typical TGA pattern for Form A of Formula I is shown in FIG.
进一步地， 式 I 的晶型 A可以通过拉曼光谱来表征。式 I 的晶型 A的典 型的 Raman 图在图 5 中显示。 晶型 A 的特征是具有包括在 325±2cm人 403±2cm— i、 447±2cm— i、 566±2cm— 1、 653±2cm— 1、 742±2cm— 1、 784±2cm— 1、 850±2cm— 91 1 ±2cm— 936±2cm— 961 ±2cm— 1057±2cm— 1084±2cm— 1 158±2cm— 1240±2cm— 1265±2cm— 13 16±2cm— 1400±2cm— 1451 ±2cm— 1495±2cm" 1577±2cm— 1禾卩 1627±2cm— 1的波数的峰。 Further, Form A of Formula I can be characterized by Raman spectroscopy. A typical Raman plot for Form A of Formula I is shown in Figure 5. Form A is characterized by having 403±2cm—i, 447±2cm—i, 566±2cm- 1 , 653±2cm- 1 , 742±2cm- 1 , 784±2cm- 1 , 850 included in 325±2cm. ±2cm—91 1 ±2cm— 936±2cm— 961 ±2cm— 1057±2cm— 1084±2cm— 1 158±2cm—1240±2cm—1265±2cm— 13 16±2cm— 1400±2cm—1451 ±2cm— The peak of the wave number of 1495±2cm" 1577±2cm- 1 and 1627±2cm- 1 .
进一步地， 式 I 的晶型 A可以通过其稳定性特征来表征。 在本发明的一 些具体实施方案中， 晶型 A是稳定的， 其 PXRD图基本保持不变。 例如， 暴 露于约 100°C环境一个星期后， 晶型 A 是稳定的。 暴露于约 40°C环境和约 75%RH环境 6个月后， 晶型 A是稳定的。 暴露于约 30°C环境和约 75%RH 环境 12个月后， 晶型 A是稳定的。  Further, Form A of Formula I can be characterized by its stability characteristics. In some embodiments of the invention, Form A is stable and its PXRD pattern remains substantially unchanged. For example, after a week of exposure to an environment of about 100 ° C, Form A is stable. Form A is stable after exposure to an environment of about 40 ° C and an environment of about 75% RH for 6 months. Form A is stable after exposure to an environment of about 30 ° C and an environment of about 75% RH for 12 months.
本发明还提供了制备纯的式 I 的晶型 A的方法， 其包括下述步骤： The invention also provides a process for the preparation of pure Form A of Formula I, which comprises the steps of:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 - [ 1， 2 , 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [ 1， 5-a] [ l， 4]苯并二氮杂草 -6-酮加热溶解于有机溶剂； 所述有 机溶剂为甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2-丁醇、 丙酮、 甲酸乙酯、 甲基乙基酮、 乙酸异丙酯、 二氯甲垸、 三氯甲垸、 甲苯和二甲苯中的一种或 者多种； (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [ 1, 5-a] [ l, 4 ] benzodiazepine-6-one is dissolved in an organic solvent by heating; the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, 2 - one or more of butanol, acetone, ethyl formate, methyl ethyl ketone, isopropyl acetate, chloroform, chloroform, toluene and xylene;
(b)将热溶液冷却析晶， 或加入反溶剂析晶； 所述反溶剂为有机溶剂； (b) cooling the crystallization of the hot solution, or adding anti-solvent crystallization; the anti-solvent is an organic solvent;
(c)过滤， 洗涤后， 干燥， 即得。 (c) Filtration, washing, and drying, that is.
步骤 (a)中， 所述的有机溶剂优选乙酸异丙酯。  In the step (a), the organic solvent is preferably isopropyl acetate.
步骤 (b)中， 所述的反溶剂可为对式 I化合物溶解能力差的有机溶剂， 较 佳地包括但不限于环己垸、正己垸、正庚垸和甲基叔丁基醚中的一种或多种， 更优选甲基叔丁基醚。  In the step (b), the anti-solvent may be an organic solvent having poor solubility to the compound of the formula I, preferably including but not limited to cyclohexyl hydrazine, n-hexyl hydrazine, n-glyoxime and methyl tert-butyl ether. One or more, more preferably methyl tert-butyl ether.
步骤 (c)中， 所述过滤、 洗涤和干燥的方法和条件均为本领域常规。 所述 干燥较佳地为常压干燥或减压干燥， 所述干燥的温度较佳地为 40~60 °C， 例 如 50 ° ( 。 本发明还提供了另一种式 I 的结晶 （晶型 B ) 。 式 I 的晶型 B可以通过 X-射线粉末衍射分析来表征。 式 I 的晶型 B 在使用 Cu-Κα射线进行测定的 X-射线粉末衍射图谱中， 至少在下述衍射角 2Θ 为 4.48±0.1°、 6.36+0.1 ° ,
Figure imgf000005_0001
21.96±0.1°、 22.42+0.1 22.82±0.1°和 24.16±0.1°处有特征峰。 较佳地， 所述晶型 Β的 X- 射线粉末衍射图谱基本上如图 6所示。 In the step (c), the methods and conditions for filtration, washing and drying are all conventional in the art. The drying is preferably atmospheric drying or reduced pressure drying, and the drying temperature is preferably 40 to 60 ° C, for example, 50 ° (. The invention also provides another crystal of formula I (Form B). Form B of Formula I can be characterized by X-ray powder diffraction analysis. Form B of Formula I is in the X-ray powder diffraction pattern measured by Cu-Κα ray, at least at the following diffraction angles 2Θ of 4.48±0.1°, 6.36+0.1 ° ,
Figure imgf000005_0001
There are characteristic peaks at 21.96 ± 0.1 °, 22.42 + 0.1 22.82 ± 0.1 ° and 24.16 ± 0.1 °. Preferably, the X-ray powder diffraction pattern of the crystalline form is substantially as shown in FIG.
进一步地， 式 I 的晶型 Β可以通过热分析来表征。 式 I 的晶型 Β的典型 的 DSC图在图 8中显示。 DSC图中， 包含在约 56°C ~85 °C处的吸热峰（峰顶 值约 76°C ) ， 以及在约 114°C ~130°C处的放热峰 （峰顶值约 122 °C ) 。 从式 I 的晶型 B的 TGA图可知， 当从室温至 100°C范围内， 有显示约 4-6%质量 损失， 表明晶型 B在晶格中包含部分水或其他溶剂。 式 I 的晶型 B的典型的 TGA图在图 7中显示。  Further, the crystalline form of Formula I can be characterized by thermal analysis. A typical DSC plot of Form I of Formula I is shown in Figure 8. In the DSC chart, the endothermic peak at about 56 ° C to 85 ° C (the peak value is about 76 ° C) and the exothermic peak at about 114 ° C to 130 ° C (the peak value is about 122). °C). From the TGA pattern of Form B of Formula I, it is shown that from room temperature to 100 ° C, there is a loss of about 4-6%, indicating that Form B contains a portion of water or other solvent in the crystal lattice. A typical TGA plot for Form B of Formula I is shown in Figure 7.
进一步优选地， 晶型 B在晶格中包含的是水分子。 晶型 B是水合物。 进一步地， 式 I 的晶型 B可以通过拉曼光谱来表征。 式 I 的晶型 B的典 型的 Raman 图在图 9 中显示。 晶型 B 的特征是具有包括在 442±2cm- 644±2cm— 745±2cm— 784±2cm— 822±2cm— 1091±2cm— 1239±2cm— 1392±2cm— 1492±2cm— 1564±2cm— 1630±2cm— 1的波数的峰。 Further preferably, Form B contains water molecules in the crystal lattice. Form B is a hydrate. Further, Form B of Formula I can be characterized by Raman spectroscopy. A typical Raman plot for Form B of Formula I is shown in Figure 9. Form B is characterized by having a range of 442 ± 2 cm - 644 ± 2 cm - 745 ± 2 cm - 784 ± 2 cm - 822 ± 2 cm - 1091 ± 2 cm - 1239 ± 2 cm - 1392 ± 2 cm - 1492 ± 2 cm - 1564 ± 2 cm - 1630 A peak of the wavenumber of ±2 cm- 1 .
进一步地， 式 I 的晶型 B可以通过其稳定性特征来表征。 在本发明的一 些具体实施方案中， 晶型 B是稳定的， 其 PXRD图基本保持不变。 例如， 暴 露于约 45°C环境一个星期后， 晶型 B是稳定的。 但是， 暴露于约 70°C环境 中， 晶型 B转变成无定形。  Further, Form B of Formula I can be characterized by its stability characteristics. In some embodiments of the invention, Form B is stable and its PXRD pattern remains substantially unchanged. For example, after a week of exposure to an environment of about 45 ° C, Form B is stable. However, when exposed to an environment of about 70 ° C, Form B is converted to amorphous.
本发明还提供了制备纯的式 I 的晶型 B的方法， 其为方法一或方法二； 所述方法一包括下述步骤：  The invention also provides a method for preparing a pure Form B of Formula I, which is Method 1 or Method 2; The method 1 comprises the following steps:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加热溶解于水或水和有机溶剂 的混合溶剂中；  (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one is dissolved in water or a mixed solvent of water and an organic solvent;
(b)将该热溶液冷却至室温后， 析出固体；  (b) after cooling the hot solution to room temperature, a solid is precipitated;
(c)过滤， 洗涤后， 在 50°C以下进行干燥， 即得；  (c) filtration, after washing, drying at 50 ° C or lower, that is, obtained;
所述方法二包括下述步骤：  The method 2 includes the following steps:
将所述晶型 A与水或水和有机溶剂的混合溶剂在室温下混悬， 搅拌， 过 滤， 洗涤后， 在 50°C以下进行干燥， 即得。 所述方法一中： The crystal form A is mixed with water or a mixed solvent of water and an organic solvent at room temperature, stirred, filtered, washed, and dried at 50 ° C or lower. In the method one:
步骤 (a)中， 所述的有机溶剂较佳地包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2-丁醇、 丙酮和四氢呋喃的一种或者多种；  In the step (a), the organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran;
步骤 (c)中， 所述过滤、 洗涤和干燥的方法和条件均为本领域常规。 所述 干燥较佳地为常压干燥或减压干燥， 所述干燥的温度较佳地为 40~50° ( 。  In the step (c), the methods and conditions for filtration, washing and drying are all conventional in the art. The drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 ° ( .
所述方法二中：  In the second method:
所述的有机溶剂较佳地包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正 丁醇、 2-丁醇、 丙酮和四氢呋喃的一种或者多种；  The organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone, and tetrahydrofuran;
所述混悬的时间较佳地为 8~48小时；  The suspension time is preferably 8 to 48 hours;
所述过滤、 洗涤和干燥的方法和条件均为本领域常规。 所述干燥较佳地 为常压干燥或减压干燥， 所述干燥的温度较佳地为 40~50° ( 。  The methods and conditions for filtration, washing and drying are all routine in the art. The drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 ° (.
本发明还提供了一种 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的无定形物， 其 在使用 Cu-Κα射线进行测定的 X-射线粉末衍射图谱中无特征峰。  The present invention also provides a 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydrol - an amorphous form of imidazo[1,5-][l,4]benzodiazepine-6-one having no characteristic peak in an X-ray powder diffraction pattern measured using Cu-Κα ray .
较佳地， 所述无定形物的 X-射线粉末衍射图谱基本上如图 10所示。 本发明还提供了所述无定形物的制备方法， 其包括方法一或方法二； 所述方法一包括下述步骤：  Preferably, the X-ray powder diffraction pattern of the amorphous material is substantially as shown in Fig. 10. The invention also provides a preparation method of the amorphous substance, which comprises the method 1 or the method 2; the method 1 comprises the following steps:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加热溶解于水和有机溶剂的混 合溶剂中；  (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one is heated and dissolved in a mixed solvent of water and an organic solvent;
(b)将该热溶液冷却至室温后， 析出固体；  (b) after cooling the hot solution to room temperature, a solid is precipitated;
(c)过滤， 洗涤后， 在 70°C以上进行干燥， 即得；  (c) filtration, after washing, drying at 70 ° C or higher, that is, obtained;
所述方法二包括下述步骤：  The method 2 includes the following steps:
将所述晶型 B于 70~80°C下进行热处理， 即得。  The crystal form B is heat-treated at 70 to 80 ° C to obtain.
所述方法一中：  In the method one:
步骤 (a)中， 所述的有机溶剂较佳地包括但不限于甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2-丁醇、 丙酮和四氢呋喃的一种或者多种；  In the step (a), the organic solvent preferably includes, but is not limited to, one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran;
步骤 (c)中， 所述过滤、 洗涤和干燥的方法和条件均为本领域常规。 所述 干燥较佳地为常压干燥或减压干燥， 所述干燥的温度较佳地为 70~80°C。  In the step (c), the methods and conditions for filtration, washing and drying are all conventional in the art. The drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 70 to 80 °C.
所述方法二中：  In the second method:
所述热处理的时间一般为 l~3h。 本发明还提供了化合物 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3- 基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的所述晶型 A、 所述晶型 B和所述无定形物中的一种或多种，在制备用作抗焦虑和 /或抗惊厥 和 /或非镇静性安眠药的药物中的应用。 The heat treatment time is generally from 1 to 3 hours. The present invention also provides the compound 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro- One or more of the crystalline form A, the crystalline form B and the amorphous form of imidazo[1,5-][l,4]benzodiazepine-6-one, Use in the preparation of a medicament for use as an anxiolytic and/or anticonvulsant and/or non-sedative hypnotic.
本发明的晶型 A、 晶型 B和无定形物可以作为单一组分或作为于其他晶 型或非晶态形态的混合物使用， 用于制备药物组合物， 其适用于治疗患有焦 虑障碍、 失眠、 情感障碍、 精神病症状和障碍患者。  The crystalline form A, the crystalline form B and the amorphous form of the present invention can be used as a single component or as a mixture of other crystalline forms or amorphous forms for the preparation of a pharmaceutical composition suitable for treating anxiety disorders, Patients with insomnia, affective disorder, psychotic symptoms and disorders.
本发明中， "晶型 "一词不仅理解为"晶体类型"或"晶体结构"； 在技术方 案中， "晶型 "更理解为"具有特定晶体结构的物质"或"特定晶体类型的晶体"。 例如，在技术方案中， "式 I 的晶型 A"可以理解为"具有特定晶体结构的式 I " 或"特定晶体类型的式 I 的晶体"。  In the present invention, the term "crystal form" is understood not only as "crystal type" or "crystal structure"; in the technical solution, "crystal form" is more understood as "substance having a specific crystal structure" or "crystal of a specific crystal type" ". For example, in the technical solution, "Form A of Formula I" can be understood as "Formula I having a specific crystal structure" or "Crystal of Formula I of a specific crystal type".
本发明中， "无定形物"又可以被称为 "非晶态"或"非晶态形态"等类似术 语。  In the present invention, "amorphous matter" may be referred to as "amorphous state" or "amorphous form" and the like.
本发明中， 所述"晶型"、 "无定形物"均被所示的 X射线衍射图表征所证 实。 本领域技术人员能够理解， 其中的实验误差取决于仪器的条件、 样品的 准备和样品的纯度。 特别是， 本领域技术人员公知， X射线衍射图通常会随 着仪器的条件而有所改变。 另外， 峰角度的实验误差通常在 5%或更少， 这 些角度的误差也应该被考虑进去， 通常允许有 ±0.1°的误差。 另外， 由于样品 高度等实验因素的影响， 会造成峰角度的整体偏移， 通常允许一定的偏移。 因而， 本领域技术人员可以理解的是， 任何具有和本发明图谱中的特征峰相 同或相似的图的晶型均属于本发明的范畴之内。  In the present invention, both the "crystalline form" and "amorphous form" are confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will appreciate that the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with the conditions of the instrument. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.1° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that any crystal form having the same or similar features as the characteristic peaks in the map of the present invention is within the scope of the present invention.
本发明中， 按本领域常识， DSC测试的误差也被考虑进去， 通常峰值的 测量允许有 ±1 °C的误差。  In the present invention, as is common in the art, the error of the DSC test is also taken into account, and the measurement of the peak value usually allows an error of ±1 °C.
本发明中， 所述"室温"为本领域常规意义上的室温温度， 一般为 10 30 V。  In the present invention, the "room temperature" is a room temperature in the conventional sense of the art, and is generally 10 30 V.
本发明的积极进步效果在于：  The positive effects of the present invention are:
本发明涉及的制备方法操作简单， 重现性好， 可以稳定获得目标晶型。 附图说明  The preparation method of the invention is simple in operation, good in reproducibility, and stable in obtaining the target crystal form. DRAWINGS
图 1是化合物式 I 晶型 A的 X-射线粉末衍射 (PXRD)图 (横坐标：衍射角 Figure 1 is an X-ray powder diffraction (PXRD) pattern of Compound Form I Form A (abscissa: diffraction angle)
2Θ(° ); 纵坐标： 相对强度 (CPS) ) 图 2 是化合物式 I 晶型 A的 ORTEP( 单晶结构分析） 图 2Θ(°) ; ordinate: relative intensity (CPS) Figure 2 is an ORTEP (single crystal structure analysis) diagram of the formula I crystal form A
图 3是化合物式 I 晶型 A的热重分析 (TG)图 (横坐标： 温度 ( V ) ； 纵坐 标： 重量（％ ))  Figure 3 is a thermogravimetric analysis (TG) of Compound I Form A (abscissa: temperature (V); ordinate: weight (%))
图 4是化合物式 I 晶型 A的差示扫描分析 (DSC)图 (横坐标： 温度（°C ) ; 纵坐标： 热流 (W/g))  Figure 4 is a differential scanning analysis (DSC) diagram of the compound Form I Form A (abscissa: temperature (°C); ordinate: heat flow (W/g))
图 5 是化合物式 I 晶型 A 的拉曼光谱 (Raman) 图（横坐标： 拉曼位移 (cm—1) ; 纵坐标： 相对强度 (counts)) Figure 5 is a Raman spectrum of the formula I crystal form A (abscissa: Raman shift (cm- 1 ); ordinate: relative intensity (counts))
图 6是化合物式 I 晶型 B的 X-射线粉末衍射 (PXRD)图 (横坐标： 衍射角 2Θ(° ) ； 纵坐标： 相对强度 (CPS) )  Figure 6 is an X-ray powder diffraction (PXRD) pattern of Form I Form B (abscissa: diffraction angle 2 Θ (°); ordinate: relative intensity (CPS))
图 7是化合物式 I 晶型 B的热重分析 (TG)图 (横坐标： 温度 ( V ) ； 纵坐 标： 重量（％ ))  Figure 7 is a thermogravimetric analysis (TG) of Compound Formula I Form B (abscissa: temperature (V); ordinate: weight (%))
图 8是化合物式 I 晶型 B 的差示扫描分析 (DSC)图 (横坐标： 温度（°C ) ; 纵坐标： 热流 (W/g))  Figure 8 is a differential scanning analysis (DSC) chart of the compound Form B (abstraction: temperature (°C); ordinate: heat flow (W/g))
图 9 是化合物式 I 晶型 B 的拉曼光谱 (Raman) 图（横坐标： 拉曼位移 (cm"1) ; 纵坐标： 相对强度（counts)) Figure 9 is a Raman spectrum of Compound Formula B Form B (abscissa: Raman shift (cm" 1 ); ordinate: relative intensity (counts))
图 10是化合物式 I非晶态形态的 X-射线粉末衍射 (PXRD)图 (横坐标： 衍射角 2Θ(° ) ； 纵坐标： 相对强度 (CPS) ) 具体实施方式  Figure 10 is an X-ray powder diffraction (PXRD) pattern of the amorphous form of the compound Formula I (abscissa: diffraction angle 2 Θ (°); ordinate: relative intensity (CPS))
本发明中检测药物多晶型结构及性能的仪器如下：  The apparatus for detecting the structure and properties of the polymorph of the drug in the present invention is as follows:
单晶衍射： Rigaku R-AXIS-RAPID单晶衍射仪，采用 ΜοΚα( λ=0.71073Α) 射线， 用 SHELXS97和 SHELXL97进行结构解析和修正。 使用 Diamond和 Mercury软件获得结构图。  Single crystal diffraction: Rigaku R-AXIS-RAPID single crystal diffractometer with ΜοΚα (λ=0.71073Α) ray, structural analysis and correction with SHELXS97 and SHELXL97. Get the structure diagram using Diamond and Mercury software.
粉末 X射线衍射 （XRD ) 表征： 仪器： Rigaku D/Max-2550 PC , CuKa 辐射， 功率 40kVx250mA， 扫描范围 2Θ 3〜40°， 步宽（step width) 0.02°, 扫 描速度 5°/min。  Powder X-ray diffraction (XRD) Characterization: Instrument: Rigaku D/Max-2550 PC, CuKa radiation, power 40kVx250mA, scanning range 2Θ 3~40°, step width 0.02°, scanning speed 5°/min.
热重分析 (TG)表征:仪器： TA公司 SDT Q600 ,吹扫气：氮气 120 mL/min, 升温速度： 10 °C /min， 温度范围： 室温〜 380° ( 。  Thermogravimetric analysis (TG) characterization: Instrument: TA company SDT Q600, purge gas: nitrogen 120 mL/min, heating rate: 10 °C / min, temperature range: room temperature ~ 380 ° (.
差示扫描量热分析 (DSC)表征 ： 仪器： TA公司 DSC Q100 ， 吹扫气： 氮气 50 mL/min, 升温速度： 10 °C /min， 温度范围： 室温〜 200° ( 。  Differential Scanning Calorimetry (DSC) Characterization: Instrument: TA Company DSC Q100, Purge Gas: Nitrogen 50 mL/min, Heating Rate: 10 °C /min, Temperature Range: Room Temperature ~ 200 ° (.
拉曼光谱 （Raman ) 表征： 仪器： Horiba公司 Lab RAMHR Evolution, 激 光波长 633nm， 激光功率 100%， 激发时间 30s， 累计测试次数 2 次， 光栅 600gr/mm。 Raman characterization: Instrument: Horiba Lab RAMHR Evolution, Light wavelength 633nm, laser power 100%, excitation time 30s, cumulative test times 2 times, grating 600gr/mm.
下述实施例中， 混合溶剂中的"％ "指的是体积百分比。  In the following examples, "%" in the mixed solvent means a volume percentage.
实施例 1: 晶型 A的制备  Example 1: Preparation of Form A
将 10g的 7-氯 -3- (5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 10 g of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,
5-二氢-咪唑并 [l，5-a][l，4]苯并二氮杂草 -6-酮加入至 70mL的乙酸异丙酯中， 加热回流溶解。 在 70°C温度下， 加入甲基叔丁基醚， 过程中析出的固体， 降 温， 抽滤， 用冷的乙酸异丙酯洗涤 2次后， 在 50°C真空干燥下干燥， 获得的 产物是 7-氯 -3- (5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二 氢-咪唑并 [1， 5-a][l， 4]苯并二氮杂草 -6-酮的晶型 A。 5-Dihydro-imidazo[l,5-a][l,4]benzodiazepine-6-one was added to 70 mL of isopropyl acetate, and dissolved by heating under reflux. At a temperature of 70 ° C, methyl tert-butyl ether was added, and the solid precipitated in the process was cooled, suction filtered, washed twice with cold isopropyl acetate, and dried under vacuum drying at 50 ° C to obtain a product. Is 7-chloro-3-(5-dimethylaminomethyl-[1, 2, 4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1, Form A of 5-a][l,4]benzodiazepine-6-one.
将按以上制备得到的 7-氯 -3- (5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a][l， 4]苯并二氮杂草 -6-酮的晶型 A， 经由 空间群 Pbca的正交晶系来鉴别，通过 296K下用 X-射线单晶衍射分析测定得 到下述参数： a=14.0911(6)， b=9.6006(4)， c=26.6704(9)， V=3608.1(2)， 晶胞 内分子数 Z=8; 原子坐标见表 1。 它的特征 X射线粉末衍射图为图 1所示， 特征谱线见表 2， 单晶结构分析 （ORTEP) 图见图 2。 获得的晶型 A的热分 析 （见图 3和图 4) 进一步表征其不含溶剂， 熔点峰为 155.5° ( 。 特征拉曼光 谱图为图 5所示。  7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro- as prepared above Crystalline form A of imidazo[1,5-][l,4]benzodiazepine-6-one, identified by orthorhombic system of space group Pbca, by X-ray single crystal at 296K The following parameters were obtained by diffraction analysis: a=14.0911(6), b=9.6006(4), c=26.6704(9), V=3608.1(2), number of molecules in the unit cell Z=8; atomic coordinates are shown in Table 1. . Its characteristics X-ray powder diffraction pattern is shown in Figure 1, the characteristic line is shown in Table 2, and the single crystal structure analysis (ORTEP) chart is shown in Figure 2. The obtained thermal analysis of Form A (see Fig. 3 and Fig. 4) further characterized that it contained no solvent and the melting point peak was 155.5° (the characteristic Raman spectrum is shown in Fig. 5.
表 1 式 I的晶型 A各原子的原子坐标和温度因子  Table 1 Formula I Form I atomic coordinates and temperature factors of each atom
原子 X Y Z U(eq)  Atom X Y Z U(eq)
C11 0.07686(8) 0.73143(13) 0.38620(4) 0.0838(4) C11 0.07686(8) 0.73143(13) 0.38620(4) 0.0838(4)
01 0.07904(16) 0.7852(2) 0.49603(10) 0.0663(7)01 0.07904(16) 0.7852(2) 0.49603(10) 0.0663(7)
02 0.2702(3) 0.2120(5) 0.69905(13) 0.1222(14)02 0.2702(3) 0.2120(5) 0.69905(13) 0.1222(14)
N1 0.09725(17) 0.5722(3) 0.53013(10) 0.0550(7)N1 0.09725(17) 0.5722(3) 0.53013(10) 0.0550(7)
N2 0.3882(2) 0.4909(3) 0.59216(12) 0.0665(8)N2 0.3882(2) 0.4909(3) 0.59216(12) 0.0665(8)
N3 0.30664(17) 0.5521(3) 0.52424(10) 0.0536(7)N3 0.30664(17) 0.5521(3) 0.52424(10) 0.0536(7)
N4 0.1767(2) 0.3038(4) 0.64323(12) 0.0754(9)N4 0.1767(2) 0.3038(4) 0.64323(12) 0.0754(9)
N5 0.3294(3) 0.2924(5) 0.66654(17) 0.1165(16)N5 0.3294 (3) 0.2924 (5) 0.66654 (17) 0.1165 (16)
N6 0.1102(4) 0.1707(6) 0.76158(16) 0.1336(18)N6 0.1102(4) 0.1707(6) 0.76158(16) 0.1336(18)
C1 0.1979(2) 0.6437(3) 0.45958(12) 0.0548(8)C1 0.1979(2) 0.6437(3) 0.45958(12) 0.0548(8)
C2 0.1194(2) 0.6716(3) 0.49676(12) 0.0525(8) /s/u/ O iiisld 3ϊοο6ϊοίAV7 C2 0.1194(2) 0.6716(3) 0.49676(12) 0.0525(8) /s/u/ O iiisld 3ϊοο6ϊοίAV7
Figure imgf000010_0001
Figure imgf000010_0001
21.02 4.22 28.4021.02 4.22 28.40
22.66 3.92 10.6022.66 3.92 10.60
22.84 3.89 7.2022.84 3.89 7.20
23.40 3.80 6.7023.40 3.80 6.70
23.70 3.75 35.0023.70 3.75 35.00
24.56 3.62 9.9024.56 3.62 9.90
27.38 3.25 8.10 实施例 2: 晶型 A的制备 27.38 3.25 8.10 Example 2: Preparation of Form A
将 300mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加入至 2mL 的丙酮中， 加热溶解。 将溶解液冷却到室温后， 过滤取得析出的固体， 用冷的丙酮洗涤 2次后， 在 50°C真空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂 草 -6-酮的晶型 A。  300 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one was added to 2 mL of acetone and dissolved by heating. After cooling the solution to room temperature, the precipitated solid was collected by filtration, washed twice with cold acetone, and dried under vacuum drying at 50 ° C to give the product 7-chloro-3-( 5-dimethylaminomethyl) -[1, 2, 4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine Form A of the -6-ketone.
经检测， X-射线粉末衍射的特征衍射谱线等均与实施例 1 相同。 实施例 3: 晶型 A的制备  The characteristic diffraction lines and the like of the X-ray powder diffraction were examined and found to be the same as in Example 1. Example 3: Preparation of Form A
将 600mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加入至 3mL 的四氢呋喃 中， 加热溶解。 逐滴加入甲基叔丁基醚， 过程中开始有大量固体析出， 过滤 取得析出的固体，用冷的甲基叔丁基醚洗涤 2次后，在 50°C真空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 A。  600 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one was added to 3 mL of tetrahydrofuran and dissolved by heating. Methyl tert-butyl ether was added dropwise, and a large amount of solids began to precipitate. The precipitated solid was obtained by filtration, washed twice with cold methyl tert-butyl ether, and dried under vacuum at 50 ° C to obtain a product. Is 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1, 5-a] [l, 4] benzodiazepine-6-one crystal form A.
经检测， X-射线粉末衍射的特征衍射谱线等均与实施例 1 相同。 实施例 4: 晶型 B的制备  The characteristic diffraction lines and the like of the X-ray powder diffraction were examined and found to be the same as in Example 1. Example 4: Preparation of Form B
将 600mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4，5-二氢-咪唑并[1，5-&] [1，4]苯并二氮杂草-6-酮加入至 70mL的纯化水中， 加热溶解。 将溶解液冷却到室温后， 过滤取得析出的固体， 用纯化水洗涤 2 次后，在 45 °C真空干燥下干燥，获得的产物是 7-氯 -3-( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6- 酮的晶型 B。 600 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1,5- & ] [1,4]benzodiazepine-6-one was added to 70 mL of purified water, and dissolved by heating. After cooling the solution to room temperature, the precipitated solid was collected by filtration, washed twice with purified water, and dried under vacuum at 45 ° C to give the product 7-chloro-3-(5-dimethylaminomethyl). -[1, 2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a] [l, 4]benzodiazepine-6-one Form B.
它的特征 X射线粉末衍射图为图 6所示， 特征谱线见表 3。 获得的晶型 B的 TG图如图 7所示， 表明含有约 6%的水； DSC图 （图 8 ) 显示其脱水温 度在约 76° ( 。 特征拉曼光谱图为图 9所示。  Its characteristic X-ray powder diffraction pattern is shown in Figure 6, and the characteristic line is shown in Table 3. The TG pattern of Form B obtained is shown in Figure 7, which indicates that it contains about 6% water; the DSC chart (Figure 8) shows that the dehydration temperature is about 76° (the characteristic Raman spectrum is shown in Figure 9.
表 3 式 I的晶型 B特征谱线  Table 3 Form I Form B Characteristic line
Figure imgf000012_0001
实施例 5: 晶型 B的制备
Figure imgf000012_0001
Example 5: Preparation of Form B
将 600mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加入至 20mL 50%的甲醇 -水中， 加热溶解。 将溶解液冷却到室温后， 过滤取得析出的固体， 用纯化水 洗涤 2次后， 在 45 °C真空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基 甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二 氮杂草 -6-酮的晶型 8。  600 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one was added to 20 mL of 50% methanol-water and dissolved by heating. After cooling the solution to room temperature, the precipitated solid was collected by filtration, washed twice with purified water, and dried under vacuum at 45 ° C to give 7-chloro-3-(5-dimethylaminomethyl). -[1, 2, 4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine- Form 6 of 6-ketone.
经检测， X- 射线粉末衍射的特征衍射谱线等均与实施例 4 相同。 实施例 6: 晶型 B的制备 The characteristic diffraction lines and the like of the X-ray powder diffraction were examined to be the same as in Example 4. Example 6: Preparation of Form B
将 600mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加入至 40mL 30%的乙醇 -水中， 加热溶解。 将溶解液冷却到室温后， 过滤取得析出的固体， 用纯化水 洗涤 2次后， 在 45 °C真空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基 甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二 氮杂草 -6-酮的晶型 8。  600 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one was added to 40 mL of 30% ethanol-water and dissolved by heating. After cooling the solution to room temperature, the precipitated solid was collected by filtration, washed twice with purified water, and dried under vacuum at 45 ° C to give 7-chloro-3-(5-dimethylaminomethyl). -[1, 2, 4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine- Form 6 of 6-ketone.
经检测， X-射线粉末衍射的特征衍射谱线等均与实施例 4相同。 实施例 7: 晶型 B的制备  The characteristic diffraction lines and the like of the X-ray powder diffraction were examined and found to be the same as in Example 4. Example 7: Preparation of Form B
将 500mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 A加入至 5mL 30% 的乙醇-水中室温搅拌 24h， 过滤取得固体， 用纯化水洗涤 2次后， 在 45 °C真 空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 B。  500 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one form A was added to 5 mL of 30% ethanol-water at room temperature for 24 h, filtered to obtain a solid, and washed twice with purified water. Drying under vacuum drying at 45 ° C gave the product 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl- Form B of 4,5-dihydro-imidazo[1,5-][l,4]benzodiazepine-6-one.
经检测， X-射线粉末衍射的特征衍射谱线等均与实施例 4相同。 实施例 8: 无定形物的制备  The characteristic diffraction lines and the like of the X-ray powder diffraction were examined and found to be the same as in Example 4. Example 8: Preparation of amorphous material
将 600mg的 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加入至 20ml 30%的丙酮- 水中， 加热溶解。 将溶解液冷却到室温后， 过滤取得析出的固体， 用纯化水 洗涤 2次后， 在 70°C真空干燥下干燥， 获得的产物是 7-氯 -3- ( 5-二甲基氨基 甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二 氮杂草 -6-酮的非晶态形态。  600 mg of 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[ 1, 5-a] [l, 4] benzodiazepine-6-one was added to 20 ml of 30% acetone-water and dissolved by heating. After cooling the solution to room temperature, the precipitated solid was collected by filtration, washed twice with purified water, and dried under vacuum at 70 ° C to give the product 7-chloro-3-(5-dimethylaminomethyl). -[1, 2, 4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine- The amorphous form of 6-ketone.
经检测， 其特征 X-射线粉末衍射图为图 10所示。 实施例 9: 无定形物的制备  Upon examination, the characteristic X-ray powder diffraction pattern is shown in Fig. 10. Example 9: Preparation of amorphous material
将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二 氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 B， 在 70°C真空干燥下干 燥 lh， 获得的产物是 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5- 甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的无定形物。 经检测， X-射线粉末衍射的特征衍射谱线等均与实施例 8相同。 效果实施例： 根据晶型的溶解性实验 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1, Form B of 5-a] [l, 4]benzodiazepine-6-one, dried under vacuum drying at 70 ° C for 1 h, the product obtained is 7-chloro-3-( 5-dimethyl Aminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][l,4]benzodiazepine An amorphous form of weed-6-ketone. The characteristic diffraction lines and the like of the X-ray powder diffraction were examined and found to be the same as in Example 8. Effect example: Solubility test according to crystal form
根据晶型八、 晶型 B在 37 °C水中的溶解性， 采用 HPLC法计算出两种晶 型的饱和溶液溶度。 结果显示， 晶型 A在 37 °C水中的溶解度为 4.5mg/mL; 晶型 B 在 37°C水中的溶解度为 6.9mg/mL; 无定形在 37 °C水中的溶解度为
Figure imgf000014_0001
According to the solubility of Form No. 8 and Form B in water at 37 ° C, the solubility of the saturated solution of the two crystal forms was calculated by HPLC method. The results showed that the solubility of Form A in water at 37 °C was 4.5 mg/mL; the solubility of Form B in water at 37 °C was 6.9 mg/mL; the solubility of amorphous in water at 37 °C was
Figure imgf000014_0001

Claims

权 利 要 求 Rights request
1、 一种 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 A， 其特征在于， 其 在使用 Cu-Κα射线进行测定的 X-射线粉末衍射图谱中，至少在下述衍射角 2Θ 为 6.62+0.1 9.12+0.1 12.56+0.1 12.98+0.1 14.70+0.1 15.94±0.1 °、 16.96+0.1 18.48+0.1 19.66+0.1 19·80±0· 1 °、 20.04+0.1 21.02+0.1 22.66+0.1 23.70±0.1。和 24.56±0.1。处有特征峰。 1. A 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one crystal form A, characterized in that it is at least in an X-ray powder diffraction pattern measured using Cu-Κα ray The diffraction angle 2 下述 is 6.62+0.1 9.12+0.1 12.56+0.1 12.98+0.1 14.70+0.1 15.94±0.1 °, 16.96+0.1 18.48+0.1 19.66+0.1 19·80±0·1 °, 20.04+0.1 21.02+0.1 22.66+0.1 23.70±0.1. And 24.56 ± 0.1. There are characteristic peaks.
2、 如权利要求 1所述的晶型 Α， 其特征在于， 所述晶型 Α为单晶， 所 述的晶体属于正交晶系， Pbca 空间群， 晶胞参数为 a=14.091 1 (6)A， b=9.6006(4)A，c=26.6704(9)A，晶胞体积 V=3608.1 (2)A3，晶胞内分子数 Z=8。 2. The crystalline germanium according to claim 1, wherein the crystalline germanium is a single crystal, the crystal belongs to an orthorhombic system, a Pbca space group, and the unit cell parameter is a=14.091 1 (6) A, b = 9.6006 (4) A, c = 26.6704 (9) A, unit cell volume V = 3608.1 (2) A 3 , number of molecules in the unit cell Z = 8.
3、 如权利要求 1或 2所述的晶型 A， 其特征在于， 所述晶型 A的 X-射 线粉末衍射图谱基本上如图 1所示；  The crystal form A according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form A is substantially as shown in Fig. 1;
和 /或， 所述晶型 A的 DSC图中， 包含在约 153.5 °C ~158 °C处的吸热峰； 和 /或， 所述晶型 A 的 Raman 图具有包括在 325±2cm- 403±2cm- And/or, the DSC pattern of the crystal form A includes an endothermic peak at about 153.5 ° C to 158 ° C; and/or the Raman map of the crystal form A has a photo included at 325 ± 2 cm - 403 ±2cm-
447±2cm— i、 566±2cm— 1、 653±2cm— 1、 742±2cm— 1、 784±2cm— 1、 850±2cm— 1、 91 1±2cm— 936±2cm— 961±2cm— 1057±2cm— 1084±2cm— 1 158±2cm— 1240±2cm— 1265±2cm— 1316±2cm— 1400±2cm— 1451 ±2cm— 1495±2cm— 1577±2cm— 1和 1627±2cm— 1的波数的峰。 447±2cm—i, 566±2cm— 1 , 653±2cm— 1 , 742±2cm— 1 , 784±2cm— 1 , 850±2cm— 1 , 91 1±2cm—936±2cm—961±2cm—1057 ±2cm— 1084±2cm—1 158±2cm—1240±2cm—1265±2cm— 1316±2cm— 1400±2cm—1451±2cm—1495±2cm—1577±2cm— 1 and 1627±2cm— 1 wavenumber peak.
4、一种制备如权利要求 1-3任一项所述的晶型 A的方法，其特征在于， 其包括下述步骤：  A method of preparing a crystalline form A according to any one of claims 1 to 3, which comprises the steps of:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加热溶解于有机溶剂； 所述的 有机溶剂为甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2-丁醇、 丙酮、 甲酸乙 酯、 甲基乙基酮、 乙酸异丙酯、 二氯甲垸、 三氯甲垸、 甲苯和二甲苯中的一 种或者多种；  (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one is dissolved in an organic solvent by heating; the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, One or more of 2-butanol, acetone, ethyl formate, methyl ethyl ketone, isopropyl acetate, dichloromethane, chloroform, toluene and xylene;
(b)将热溶液冷却析晶， 或加入反溶剂析晶； 所述反溶剂为有机溶剂； (b) cooling the crystallization of the hot solution, or adding anti-solvent crystallization; the anti-solvent is an organic solvent;
(c)过滤， 洗涤后， 干燥， 即得； (c) filtration, washing, drying, that is;
其中， 步骤 (b)中， 所述的反溶剂较佳地包括环己垸、 正己垸、 正庚垸和 甲基叔丁基醚中的一种或多种； 和 /或， 步骤 (c)中， 所述干燥较佳地为常压干 燥或减压干燥， 所述干燥的温度较佳地为 40~60° ( 。 Wherein, in the step (b), the anti-solvent preferably comprises one or more of cyclohexanyl, n-hexyl, n-heptane and methyl tert-butyl ether; and/or, step (c) Wherein the drying is preferably atmospheric drying Drying or drying under reduced pressure, the drying temperature is preferably 40 to 60 ° (.
5、 一种 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的晶型 B， 其特征在于， 其在 使用 Cu-Κα射线进行测定的 X-射线粉末衍射图谱中， 至少在下述衍射角 2Θ 为 4.48+0.1 6.36+0.1 8.96+0.1 10.00+0.1 12.92+0.1 13·68±0· 1 ο、 17.88+0.1 21.96+0.1 22.42+0.1 22.82±0.1。和 24.16±0.1。处有特征峰。 5. A 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one crystal form B, characterized in that it is at least in an X-ray powder diffraction pattern measured using Cu-Κα ray The diffraction angle 2 下述 is 4.48 + 0.1 6.36 + 0.1 8.96 + 0.1 10.00 + 0.1 12.92 + 0.1 13 · 68 ± 0 · 1 ο , 17.88 + 0.1 21.96 + 0.1 22.42 + 0.1 22.82 ± 0.1. And 24.16 ± 0.1. There are characteristic peaks.
6、 如权利要求 5所述的晶型 Β， 其特征在于， 所述晶型 Β的 X-射线粉 末衍射图谱基本上如图 6所示；  6. The crystalline germanium according to claim 5, wherein the X-ray powder diffraction pattern of the crystalline germanium is substantially as shown in FIG. 6;
和 /或， 所述晶型 Β 的 DSC图中， 包含在约 56 °C ~85 °C处有的吸热峰， 以及在约 1 14°C ~ 130°C处的放热峰；  And/or, the DSC pattern of the crystalline form 包含 includes an endothermic peak at about 56 ° C to 85 ° C, and an exothermic peak at about 1 14 ° C to 130 ° C;
和 /或， 所述晶型 B 的 TGA图中， 从室温至 100°C范围内， 所述晶型 B 有 4-6%质量损失；  And/or, in the TGA diagram of Form B, the Form B has a 4-6% mass loss from room temperature to 100 °C;
和 /或， 所述晶型 B 的 Raman 图具有包括在 土 ^！！人 όΑΑΐ ^!!-1 745±2cm— 784±2cm— 822±2cm— 1091±2cm— 1239±2cm— 1392±2cm— 1492±2cm— 1564±2cm— 1630±2cm— 1的波数的峰。 And/or, the Raman diagram of Form B has been included in the soil ^! ! Person όΑΑΐ ^!! - 1 745 ± 2cm - 784 ± 2cm - 822 ± 2cm - 1091 ± 2cm - 1239 ± 2cm - 1392 ± 2cm - 1492 ± 2cm - 1564 ± 2cm - 1630 ± 2cm - 1 wavenumber peak.
7、 一种制备如权利要求 5或 6所述的晶型 B 的方法， 其特征在于， 其 为方法一或方法二；  A method for preparing a crystal form B according to claim 5 or 6, which is a method 1 or a method 2;
所述方法一包括下述步骤：  The method 1 includes the following steps:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加热溶解于水或水和有机溶剂 的混合溶剂中；  (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one is dissolved in water or a mixed solvent of water and an organic solvent;
(b)将该热溶液冷却至室温后， 析出固体；  (b) after cooling the hot solution to room temperature, a solid is precipitated;
(c)过滤， 洗涤后， 在 50°C以下进行干燥， 即得；  (c) filtration, after washing, drying at 50 ° C or lower, that is, obtained;
所述方法二包括下述步骤：  The method 2 includes the following steps:
将如权利要求 1-3任一项所述的晶型 A与水或水和有机溶剂的混合溶剂 在室温下混悬， 搅拌， 过滤， 洗涤后， 在 50°C以下进行干燥， 即得；  The crystal form A according to any one of claims 1 to 3 and water or a mixed solvent of water and an organic solvent are suspended at room temperature, stirred, filtered, washed, and dried at 50 ° C or lower, that is, obtained;
所述方法一中：  In the method one:
步骤 (a)中， 所述的有机溶剂包括甲醇、 乙醇、正丙醇、异丙醇、正丁醇、 2-丁醇、 丙酮和四氢呋喃的一种或者多种； 和 /或， 步骤 (c)中， 所述干燥较佳 地为常压干燥或减压干燥， 所述干燥的温度较佳地为 40~50°C ;  In the step (a), the organic solvent comprises one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran; and/or, step (c) The drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 ° C;
所述方法二中： 所述的有机溶剂较佳地包括甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2- 丁醇、 丙酮和四氢呋喃的一种或者多种； 所述混悬的时间较佳地为 8~48 小 时； 和 /或， 所述干燥较佳地为常压干燥或减压干燥， 所述干燥的温度较佳地 为 40~50°C。 In the second method: The organic solvent preferably includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran; the suspension time is preferably 8~48 hours; and/or, the drying is preferably dry under normal pressure or dried under reduced pressure, and the drying temperature is preferably 40 to 50 °C.
8、 一种 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2， 4]噁二唑 -3-基） -5-甲基 -4， 8. A 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,
5-二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮的无定形物， 其特征在于， 其在使用 Cu-Κα射线进行测定的 X-射线粉末衍射图谱中无特征峰。 An amorphous form of 5-dihydro-imidazo[1,5-][l,4]benzodiazepine-6-one, characterized in that it is X-measured using Cu-Κα ray There are no characteristic peaks in the ray powder diffraction pattern.
9、 一种制备如权利要求 8 所述的无定形物的方法， 其包括方法一或方 法二；  9. A method of preparing an amorphous material according to claim 8 comprising a method one or method two;
所述方法一包括下述步骤：  The method 1 includes the following steps:
(a)将 7-氯 -3- ( 5-二甲基氨基甲基 -[1， 2, 4]噁二唑 -3-基） -5-甲基 -4， 5- 二氢-咪唑并 [1， 5-a] [l， 4]苯并二氮杂草 -6-酮加热溶解于水和有机溶剂的混 合溶剂中；  (a) 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazole [1, 5-a] [l, 4] benzodiazepine-6-one is heated and dissolved in a mixed solvent of water and an organic solvent;
(b)将该热溶液冷却至室温后， 析出固体；  (b) after cooling the hot solution to room temperature, a solid is precipitated;
(c)过滤， 洗涤后， 在 70°C以上进行干燥， 即得；  (c) filtration, after washing, drying at 70 ° C or higher, that is, obtained;
所述方法二包括下述步骤：  The method 2 includes the following steps:
将所述晶型 B于 70~80°C下进行热处理， 即得；  The crystal form B is heat-treated at 70 to 80 ° C, that is, obtained;
所述方法一中：  In the method one:
步骤 (a)中， 所述的有机溶剂较佳地包括甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 2-丁醇、 丙酮和四氢呋喃的一种或者多种； 和 /或， 步骤 (c)中， 所述 干燥较佳地为常压干燥或减压干燥， 所述干燥的温度较佳地为 70~80°C； 所述方法二中：  In the step (a), the organic solvent preferably comprises one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetone and tetrahydrofuran; and/or In the step (c), the drying is preferably dry at normal pressure or dried under reduced pressure, and the drying temperature is preferably 70 to 80 ° C;
所述热处理的时间一般为 l~3h。  The heat treatment time is generally from 1 to 3 hours.
10、 如权利要求 1-3任一项所述的晶型 A、 如权利要求 5或 6所述的晶 型 B 和如权利要求 8所述的无定形物中的一种或多种在制备用作抗焦虑和 / 或抗惊厥和 /或非镇静性安眠药的药物中的应用。  10. One or more of the crystalline form A according to any one of claims 1 to 3, the crystalline form B according to claim 5 or 6, and the amorphous material according to claim 8 Use as a drug for anti-anxiety and / or anticonvulsant and / or non-sedative sleeping pills.
PCT/CN2018/092820 2017-06-27 2018-06-26 Benzodiazepine compound solid forms, and preparation methods therefor and applications thereof WO2019001414A1 (en)

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Publication number Priority date Publication date Assignee Title
CN1350538A (en) * 1999-05-12 2002-05-22 弗·哈夫曼-拉罗切有限公司 Imiadazodiazepine derivative
US20090054412A1 (en) * 2007-08-20 2009-02-26 John Alan Kemp Treatment of Sleep Disorders
CN101426771A (en) * 1999-05-12 2009-05-06 弗·哈夫曼-拉罗切有限公司 Process for manufacturing diazepine derivatives

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Publication number Priority date Publication date Assignee Title
CN1350538A (en) * 1999-05-12 2002-05-22 弗·哈夫曼-拉罗切有限公司 Imiadazodiazepine derivative
CN101426771A (en) * 1999-05-12 2009-05-06 弗·哈夫曼-拉罗切有限公司 Process for manufacturing diazepine derivatives
US20090054412A1 (en) * 2007-08-20 2009-02-26 John Alan Kemp Treatment of Sleep Disorders

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