WO2020259366A1 - 一种凝血因子XIa抑制剂的晶型及其制备方法 - Google Patents

一种凝血因子XIa抑制剂的晶型及其制备方法 Download PDF

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WO2020259366A1
WO2020259366A1 PCT/CN2020/096572 CN2020096572W WO2020259366A1 WO 2020259366 A1 WO2020259366 A1 WO 2020259366A1 CN 2020096572 W CN2020096572 W CN 2020096572W WO 2020259366 A1 WO2020259366 A1 WO 2020259366A1
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crystal form
compound
peaks
ray powder
powder diffraction
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PCT/CN2020/096572
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English (en)
French (fr)
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张�杰
董吉川
黄河
雷鑫
陈勇
王仲清
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080042070.7A priority Critical patent/CN114040908A/zh
Publication of WO2020259366A1 publication Critical patent/WO2020259366A1/zh

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    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a crystal form of a blood coagulation factor XIa inhibitor and a preparation method thereof.
  • BMS-262084 (CAS number: 253174-92-4), the chemical name is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonoyl]-3-[3- (Diaminomethylamino)propyl]-4-cyclopropanamide-2-carboxylic acid, also called compound (1) in the present invention, is developed by BMS (Bristol-Myers-Squibb) for the treatment of cardiovascular diseases
  • the drug as an oral factor XIa inhibitor for thrombus, has the advantage of significantly reducing the risk of bleeding, and its structure is shown in formula (1):
  • Patent application WO 9967215A1 discloses the BMS-262084 compound, but the specific molecular formula of the solid substance obtained by the disclosed preparation process is C 18 H 31 N 7 O 5 ⁇ 1.56H 2 O, which is similar to the crystal of BMS-262084 described in this application. Type and amorphous water have different molecular weights.
  • crystal form of the drug is an important factor affecting the quality of the drug.
  • Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug
  • the present invention provides a new crystal form of compound (1) and a preparation method and composition thereof.
  • the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2 ⁇ angles of 6.9 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form comprises at least one peak or at least two peaks or three peaks among the diffraction peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.5 ⁇ 0.2°; or the crystal
  • the type X-ray powder diffraction pattern does not include at least one peak or at least two peaks or three peaks among the diffraction peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, and 19.5 ⁇ 0.2°.
  • the differential scanning calorimetry curve of the crystal form has an endothermic peak at 122°C to 126°C, or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 128°C to 132°C.
  • the crystal form is monohydrate or 1.5 hydrate.
  • the crystal form is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-(diaminomethylamino ) Propyl]-4-cyclopropanamide-2-carboxylic acid monohydrate.
  • the crystal form is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-(diaminomethylamino ) Propyl]-4-cyclopropanamide-2-carboxylic acid 1.5 hydrate.
  • the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° diffraction peaks.
  • the crystal form provided by the invention has better performance and high stability, and can be used for preparing pharmaceutical preparations for treating cardiovascular diseases.
  • a method for preparing the crystal form comprises: dissolving or suspending the raw material compound (1) (BMS-262084) in a solvent, wherein the completely dissolved solution is volatilized and dried to obtain the crystal form; The dissolved solid-liquid mixture is suspended, filtered and dried to obtain the crystal form.
  • the present invention also provides a composition comprising the aforementioned crystal form of compound (1).
  • the crystal form is at least 90% of the compound (1), or the crystal form does not exceed 0.5% to 5% of the compound (1).
  • crystal form is used to describe the state of existence of a solid compound, describing a collection of multiple parameters of the ion, atomic or molecular composition, symmetry properties, and periodic arrangement rules inside the crystal.
  • relative intensity refers to the ratio of the intensity of other peaks to the intensity of the first peak when the intensity of the first peak in a set of diffraction peaks belonging to a certain crystal form is defined as 100%.
  • substantially as shown in the figure means that at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.
  • the 2 ⁇ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
  • the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
  • the X-ray powder diffraction peak of the crystal form, the 2 ⁇ or diffraction peak measurement of the X-ray powder diffraction pattern has experimental errors, between one machine and another machine and between one sample and another sample ,
  • the measurement of 2 ⁇ or diffraction peaks of X-ray powder diffraction patterns may be slightly different, and the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units Therefore, the value of the 2 ⁇ or diffraction peaks cannot be regarded as absolute.
  • the differential scanning calorimetry curve (DSC) of the crystal form has experimental errors.
  • the position and peak of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample.
  • Difference, experimental error or difference value may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak The value of cannot be regarded as absolute.
  • thermogravimetric analysis (TGA) of the crystal form has experimental errors. Between one machine and another machine and between one sample and another sample, the weight loss temperature and the weight loss amount may be slightly different, the experimental error Or the value of the difference may be about +/-0.1 units, about +/-0.05 units, or about +/-0.01 units, so the values of the weight loss temperature and the weight loss amount cannot be regarded as absolute.
  • Root temperature refers to a temperature of about 15°C-32°C or about 20°C-30°C or about 23°C-28°C or about 28°C.
  • High temperature refers to a temperature of about 40°C to 100°C or about 50°C to 70°C or about 60°C.
  • the solid when the solid is dried, the solid is dried to a constant weight.
  • the inventor developed the crystal form of compound (1) and its preparation method through research.
  • the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystal form of the compound (1) of the present invention that is, the new crystal form, including crystal form I or crystal form II, has good performance, high solubility, and high bioavailability; or/and good stability , Is conducive to storage, thereby meeting the requirements of drug stability; low hygroscopicity, or/and good performance in terms of static electricity, low static electricity, which is conducive to operation in the production process; and as an oral clotting factor XIa inhibitor for thrombus , Has the effect of reducing the risk of bleeding.
  • the crystalline form of compound (1) has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks with 2 ⁇ angles of 6.9 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2°.
  • the crystal form of the compound (1) has the following characteristics: the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystal form of the compound (1) has the following characteristics: the X-ray powder diffraction pattern of the crystal form includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 19.5 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, Diffraction peaks at 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2°.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystal form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.4 ⁇ 0.2°, 32.3 ⁇ 0.2°, 35.1 ⁇ 0.2° and 36.3 ⁇ 0.2° Diffraction peaks.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern does not include at least one of the peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.5 ⁇ 0.2° one. In some embodiments, the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern does not include peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.5 ⁇ 0.2°.
  • the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes at least one of the peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.5 ⁇ 0.2° One. In some embodiments, the crystalline form of the compound (1) has the following characteristics: its X-ray powder diffraction pattern includes peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.5 ⁇ 0.2°.
  • the crystal form of the compound (1) in the X-ray powder diffraction pattern 2 ⁇ angle does not contain at least one of the diffraction peaks of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, 19.5 ⁇ 0.2°, is called “Form I"; otherwise, it is called “Form II”.
  • the crystalline form I of compound (1) has an X-ray powder diffraction pattern including those with 2 ⁇ angles of 6.9 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° Diffraction peak; or its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peak; or its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks; or its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°,
  • the crystalline form I of compound (1) has an X-ray powder diffraction pattern that does not include at least one of the diffraction peaks of 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, and 19.5 ⁇ 0.2° or At least two peaks or three peaks.
  • the crystalline form I of compound (1) has an X-ray powder diffraction pattern that does not include at least one of the diffraction peaks of 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, and 19.5 ⁇ 0.2° or At least two peaks or three peaks; and: its X-ray powder diffraction pattern contains diffraction peaks with 2 ⁇ angles of 6.9 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2°; or Its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° Diffraction peak; or its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.
  • the X-ray powder diffraction pattern of the crystalline form I of compound (1) is basically as shown in FIG. 3, wherein the relative intensity of the peak with a diffraction angle 2 ⁇ of 15.9 ⁇ 0.2° is greater than 50%, or greater than 60 %, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystalline form II of compound (1) has an X-ray powder diffraction pattern comprising at least one of diffraction peaks or at least one of diffraction peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, and 19.5 ⁇ 0.2° Two peaks or three peaks.
  • the crystalline form II of compound (1) has an X-ray powder diffraction pattern comprising at least one of diffraction peaks or at least one of diffraction peaks with 2 ⁇ angles of 7.5 ⁇ 0.2°, 17.0 ⁇ 0.2°, and 19.5 ⁇ 0.2° Two peaks or three peaks; and its X-ray powder diffraction pattern includes diffraction with 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° Peak; or its X-ray powder diffraction pattern contains 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.7 ⁇ 0.2° and 28.2 ⁇ 0.2° diffraction peaks; or its X-ray powder diffraction pattern includes 2 ⁇ angles of 6.9 ⁇ 0.2°, 7.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 14.3
  • the X-ray powder diffraction pattern of the crystalline form II of compound (1) is basically shown in Figure 7, wherein the relative intensity of the peak with a diffraction angle 2 ⁇ of 15.9 ⁇ 0.2° is greater than 50%, or greater than 60 %, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystal form of the compound (1) also has the following characteristics: its differential scanning calorimetry (DSC) has an endothermic peak at 75°C to 175°C.
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry (DSC) of the crystalline form I of compound (1) has an endothermic peak at 100°C to 140°C. In a specific embodiment, the differential scanning calorimetry (DSC) of the crystalline form I of compound (1) has an endothermic peak at 120°C-128°C. In a specific embodiment, the differential scanning calorimetry (DSC) of the crystalline form I of compound (1) has an endothermic peak at 122°C-126°C. In a specific embodiment, the differential scanning calorimetry curve (DSC) of the crystalline form I of compound (1) has an endothermic peak at 122°C-126°C, and the peak top value of the endothermic peak is 124°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form I of compound (1) is shown in FIG. 4.
  • the differential scanning calorimetry (DSC) of the crystalline form II of compound (1) has an endothermic peak at 110°C to 150°C. In a specific embodiment, the differential scanning calorimetry (DSC) of the crystalline form II of compound (1) has an endothermic peak at 126°C-134°C. In a specific embodiment, the differential scanning calorimetry (DSC) of the crystalline form II of compound (1) has an endothermic peak at 128°C-132°C. In a specific embodiment, the differential scanning calorimetry curve (DSC) of the crystalline form II of compound (1) has an endothermic peak at 128°C-132°C, and the peak top value of the endothermic peak is 130°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form II of compound (1) is shown in FIG. 8.
  • the crystal form of the compound (1) also has the following characteristics: the thermogravimetric analysis curve (TGA) of the crystal form of the compound (1) shows that the crystal form I of the compound (1) has a weight loss at 30°C-150°C. About 3.5%-7.5%.
  • TGA thermogravimetric analysis curve
  • thermogravimetric analysis curve (TGA) of the crystalline form I of compound (1) shows a weight loss between 30°C and 150°C, which is about 4.0%.
  • thermogravimetric analysis curve (TGA) of the crystalline form I of compound (1) is shown in FIG. 5.
  • thermogravimetric analysis curve (TGA) of the crystalline form II of compound (1) shows a weight loss between 30°C and 150°C, and the weight loss is about 6.0%.
  • thermogravimetric analysis graph (TGA) of the crystalline form II of compound (1) is shown in FIG. 9.
  • the crystal form of the compound (1) is hydrate or hydrate. In some embodiments, the water content of the crystal form of the compound (1) is about 4.0%. In some embodiments, the water content of the crystal form of the compound (1) is about 6.0%.
  • the crystal form of the compound (1) is monohydrate. In some embodiments, the crystal form of the compound (1) is 1.5 hydrate. In some embodiments, the crystal form is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-(diaminomethylamino ) Propyl]-4-cyclopropanamide-2-carboxylic acid monohydrate.
  • the crystal form is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-(diaminomethylamino ) Propyl]-4-cyclopropanamide-2-carboxylic acid 1.5 hydrate.
  • the crystalline form I of the compound (1) is a hydrate or a hydrate. In some embodiments, the water content of the crystalline form I of the compound (1) is about 4.0%. In some embodiments, the crystalline form I of the compound (1) is a monohydrate.
  • the water content of the crystalline form II of the compound (1) is about 6.0%. In some embodiments, the crystal form II of the compound (1) is 1.5 hydrate.
  • the crystalline form I of compound (1) also has the following characteristics: its dynamic adsorption equilibrium curve has as the humidity increases, the greater the hygroscopicity of the product, and when the humidity reaches 95.0%, the moisture content is 1.6%, that is, the moisture gain is 1.6%.
  • the crystal form I of the compound (1) also has the following characteristics: its dynamic moisture adsorption (DVS) isotherm diagram is shown in FIG. 6.
  • the crystal form II of compound (1) also has the following characteristics: its dynamic adsorption equilibrium curve has, as the humidity increases, the greater the hygroscopicity of the product, and when the humidity reaches 95.0%, the crystal form II The moisture content of the moisture absorption is 5.7%, that is, the moisture gain is 5.7%.
  • the crystal form II of the compound (1) also has the following characteristics: its dynamic moisture adsorption (DVS) isotherm diagram is shown in FIG. 10.
  • the crystal form I of compound (1) also has the following characteristics: the aforementioned crystal form I is at least 90%, or at least 95%, of the compound (1). In some embodiments, the aforementioned crystalline form I is at least 98% or at least 99% of the compound (1).
  • the crystalline form II of compound (1) also has the following characteristics: the aforementioned crystalline form II is at least 90%, or at least 95%, of the compound (1). In some embodiments, the aforementioned crystalline form II is at least 98% or at least 99% of compound (1).
  • the crystal form I has better stability and fluidity, lower hygroscopicity, is conducive to material transfer in the production process, is conducive to the use and stability of raw materials in pharmaceutical preparations, and is conducive to The preparation and quality of pharmaceutical preparations are stable.
  • the crystal form II has good stability and fluidity, relatively low hygroscopicity, and can be used for the preparation of pharmaceutical preparations.
  • the present invention provides a method for preparing the crystal form of the compound (1).
  • the preparation method of the crystal form of the compound (1) in the present invention is simple, convenient to operate, mild conditions, high yield and high purity, and is suitable for industrial production.
  • a method for preparing the crystal form of the compound (1) includes: dissolving or suspending the raw material compound (1) (BMS-262084) in a solvent, wherein the completely dissolved solution is volatilized and dried to a constant weight to obtain The crystal form; the incompletely dissolved solid-liquid mixture is suspended, filtered and dried to constant weight to obtain the crystal form.
  • a method for preparing the crystal form of the compound (1) includes: dissolving or suspending the raw material compound (1) (BMS-262084) in a solvent, wherein the completely dissolved solution is volatilized and dried To a constant weight to obtain the crystal form; the incompletely dissolved solid-liquid mixture is suspended, filtered, and dried to a constant weight to obtain the crystal form; the solvent includes selected from water, isopropanol, n-propanol, methanol, At least one of ethylene glycol dimethyl ether, tetrahydrofuran and dioxane.
  • a method for preparing the crystalline form of the compound (1) comprises: dissolving the raw material compound (1) (BMS-262084) in isopropanol, n-propanol, methanol, dioxane or its combination In the mixed solvent of water, the solution formed by completely dissolving at room temperature is volatilized and dried to obtain the crystal form.
  • a method for preparing the crystal form of the compound (1) includes: suspending the raw material compound (1) (BMS-262084) in water, ethylene glycol dimethyl ether, tetrahydrofuran or a mixed solvent thereof A solid-liquid mixture is formed, and the solid-liquid mixture is suspended at room temperature, filtered, and dried to obtain the crystal form.
  • a method for preparing the crystal form of the compound (1) includes: dissolving or suspending the raw material compound (1) (BMS-262084) in a solvent, wherein the completely dissolved solution is volatilized and dried To a constant weight to obtain the crystal form; the incompletely dissolved solid-liquid mixture is suspended, filtered and dried to a constant weight to obtain the crystal form; the solvent is selected from water, isopropanol, ethylene glycol dimethyl ether and At least one of tetrahydrofuran; the crystal form is crystal form I.
  • a method for preparing the crystalline form I of the compound (1) includes: dissolving the raw material compound (1) in a mixed solvent of isopropanol and water, and completely dissolving the resulting solution at room temperature, After volatilization and drying, the crystal form I is obtained.
  • a method for preparing the crystalline form I of the compound (1) includes: suspending the raw material compound (1) in water at a high temperature to form a mixed solution, and the mixed solution is suspended at a high temperature or at room temperature. , Then filtered and dried to obtain the crystal form I.
  • a method for preparing the crystalline form I of the compound (1) includes: suspending the raw material compound (1) in a mixed solvent of ethylene glycol dimethyl ether and water or a mixture of tetrahydrofuran and water In the solvent, a solid-liquid mixture is formed, and the solid-liquid mixture is suspended at room temperature, filtered, and dried to obtain the crystal form I.
  • a method for preparing the crystalline form I of the compound (1) includes: suspending the raw material compound (1) in a mixed solvent of ethylene glycol dimethyl ether and water or tetrahydrofuran and water at room temperature. In the mixed solvent of, a solid-liquid mixture is formed, and the solid-liquid mixture is suspended at room temperature, filtered, and dried to obtain the crystal form I.
  • a method for preparing the crystal form of the compound (1) includes: dissolving or suspending the raw material compound (1) (BMS-262084) in a solvent, wherein the completely dissolved solution is volatilized and dried To constant weight to obtain the crystal form; the incompletely dissolved solid-liquid mixture is suspended, filtered, and dried to constant weight to obtain the crystal form; the solvent is selected from water, n-propanol, methanol and dioxane At least one of; the crystal form is crystal form II.
  • a method for preparing the crystalline form II of the compound (1) comprises: dissolving the raw material compound (1) in n-propanol, methanol or dioxane, or in n-propanol at room temperature. In a mixed solvent of alcohol, methanol or dioxane and water, the solution formed by completely dissolving at room temperature is volatilized and dried to obtain the crystal form II.
  • a method for preparing the crystalline form II of the compound (1) includes: suspending the raw material compound (1) in water at room temperature to form a solid-liquid mixture, and suspending the solid-liquid mixture at room temperature, Filter and dry to obtain the crystal form II.
  • the suspension time may be 4 hours to 120 hours, or 4 hours to 96 hours, or 4 hours to 72 hours, or 4 hours to 36 hours, or 24 hours to 48 hours, or 36 hours to 72 hours, or 8 hours to 36 hours, or 12 hours to 36 hours, or 12 hours to 24 hours.
  • the suspension time does not exceed 48 hours to obtain the crystal form I.
  • the suspension time is not less than 48 hours to obtain crystal form II.
  • the present invention also provides a composition comprising the aforementioned crystal form of compound (1).
  • the crystal form is at least 90% of the compound (1), or the crystal form does not exceed 0.5% to 5% of the compound (1).
  • a composition in terms of mass ratio, in some embodiments, includes the crystal form of the aforementioned compound (1), wherein the crystal form is at least 90% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form of the aforementioned compound (1), wherein the crystal form is at least 95%, or at least 99%, of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form of the aforementioned compound (1), wherein the crystal form is at least 0.5%-5% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form of the aforementioned compound (1), wherein the crystal form is at least 5% of the compound (1).
  • a composition in terms of mass ratio, in some embodiments, includes the crystal form of the aforementioned compound (1), wherein the crystal form does not exceed 0.5%-5% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form of the aforementioned compound (1), wherein the crystal form does not exceed 5% of the compound (1).
  • a composition comprises the crystal form of the aforementioned compound (1), and the crystal form is crystal form I and/or crystal form II. In some embodiments, a composition comprises crystal form I and/or crystal form II of the aforementioned compound (1).
  • a composition in terms of mass ratio, in some embodiments, includes the crystal form I of the aforementioned compound (1), wherein the crystal form I is at least 90% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form I of the aforementioned compound (1), wherein the crystal form I is at least 95%, or at least 99%, of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystalline form I of the aforementioned compound (1), wherein the crystalline form I is at least 0.5%-5% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystalline form I of the aforementioned compound (1), wherein the crystalline form I is at least 5% of the compound (1).
  • a composition in terms of mass ratio, in some embodiments, includes the crystal form I of the aforementioned compound (1), wherein the crystal form I does not exceed 0.5% to 5% of the compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystalline form I of the aforementioned compound (1), wherein the crystalline form I does not exceed 5% of the compound (1).
  • a composition comprises the aforementioned crystal form II of the compound (1), wherein the crystal form II is at least 90% of the compound (1). In terms of mass ratio, in some embodiments, a composition comprises the aforementioned crystal form II of compound (1), wherein the crystal form II is at least 95%, or at least 99%, of the compound (1). In terms of mass ratio, in some embodiments, a composition comprises the aforementioned crystal form II of compound (1), wherein the crystal form II is at least 0.5%-5% of compound (1). In terms of mass ratio, in some embodiments, a composition comprises the aforementioned crystalline form II of the compound (1), wherein the crystalline form II is at least 5% of the compound (1).
  • a composition in terms of mass ratio, in some embodiments, includes the aforementioned crystal form II of compound (1), wherein the crystal form II does not exceed 0.5% to 5% of compound (1). In terms of mass ratio, in some embodiments, a composition includes the crystal form II of the aforementioned compound (1), wherein the crystal form II does not exceed 5% of the compound (1).
  • composition may also include pharmaceutically acceptable excipients or carriers, such as fillers, diluents, lubricants and the like.
  • composition further includes a pharmaceutically acceptable excipient or carrier, and the pharmaceutically acceptable excipient or carrier includes a lubricant.
  • the lubricant is magnesium stearate.
  • composition can be prepared into any suitable pharmaceutical preparations, such as tablets, capsules, granules, suspensions, or injections.
  • Figure 1 shows the X-ray powder diffraction pattern (XRPD) of compound (1) crystal form A;
  • Figure 2 shows the X-ray powder diffraction pattern (XRPD) of Compound (1) Form B;
  • Figure 3 shows the X-ray powder diffraction pattern (XRPD) of compound (1) crystalline form I;
  • FIG. 4 shows the differential scanning calorimetry (DSC) of compound (1) crystalline form I;
  • FIG. 5 shows the thermogravimetric analysis curve (TGA) of compound (1) crystal form I;
  • Figure 6 shows a dynamic moisture adsorption (DVS) isotherm diagram of compound (1) crystal form I;
  • Figure 7 shows the X-ray powder diffraction pattern (XRPD) of compound (1) crystal form II;
  • Figure 8 shows the differential scanning calorimetry (DSC) of compound (1) crystalline form II
  • FIG. 9 shows the thermogravimetric analysis curve (TGA) of compound (1) crystal form II
  • Figure 10 shows the dynamic moisture adsorption (DVS) isotherm diagram of compound (1) crystal form II;
  • Figure 11 shows the X-ray powder diffraction pattern (XRPD) of the amorphous form of compound (1)
  • Figure 12 shows the isotherm diagram of the compound (1) amorphous dynamic moisture adsorption (DVS).
  • the reagents used in the present invention can all be purchased from the market or can be prepared by prior art methods or prepared by the methods described in the present invention.
  • °C means degrees Celsius
  • mg means milligrams
  • mL means milliliter
  • h means hour
  • mm means millimeter
  • the hydrate is calculated according to the molar ratio.
  • (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-( The molar ratio of diaminomethylamino)propyl]-4-cyclopropanamide-2-carboxylic acid and water is 1:1; in 1.5 water, (2S,3R)-1-[4-(tert-butyl The molar ratio of carbamoyl)piperazine-1-carbo]-3-[3-(diaminomethylamino)propyl]-4-cyclopropanamide-2-carboxylic acid and water is 1:1.5.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , 1.540598; 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • X-ray beam divergence that is, the effective size of X-ray confinement on the sample, is 10mm using ⁇ - ⁇ continuous Scanning mode to obtain an effective 2 ⁇ range of 3° ⁇ 60°.
  • thermogravimetric analyzer Q500 is used for thermogravimetric analysis. Place an appropriate amount of sample in a platinum sample pan, and in a nitrogen atmosphere, the temperature is increased at a rate of 60°C/min, and the temperature range is 30 to 300°C.
  • the abscissa represents temperature (Temperature, °C), and the ordinate represents mass percentage (Weight, %).
  • DVS test isotherm adsorption equilibrium curve test method, instrument: DVS-INTRINSIC, with relative humidity (0%-95.0%-0%) at 25.0°C, starting from 0% relative humidity, with 5% relative humidity step The change reaches 95% relative humidity, and then a 5% relative humidity step change to 0% relative humidity.
  • the absolute value of the sample weight change dm/dt per unit time is less than 0.5% under a certain relative humidity condition, it is considered that the equilibrium is reached, and the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions.
  • Ethanol solvent volatilization at room temperature 50mg BMS-262084 (amorphous) is added to 1.0mL ethanol solvent and completely dissolved at room temperature (about 25°C). After volatilizing at room temperature for two days, the solid product is obtained and its crystal form is tested. It is crystal form A, as shown in Figure 1. It is believed that it contains a small amount of amorphous; but it is unstable and will undergo crystal transformation at room temperature. After being left for one day, the XRPD was tested, and it was found that it was converted to a mixture containing crystal form A, other crystal forms and amorphous forms.
  • High temperature test Take appropriate amounts of BMS-262084 crystal form I, II, and amorphous samples, and place them in a weighing bottle, place them in a constant temperature and humidity box at 60 ⁇ 5°C, RH75 ⁇ 5%, and then place them at 5, 10 At 15 days, about 10 mg of the above sample was taken to test the X-ray powder diffraction pattern.
  • High humidity test Take appropriate amounts of BMS-262084 crystal forms I, II, and amorphous samples, and place them flat in a weighing bottle. Place them in a constant temperature and humidity box at 25°C, RH 92.5 ⁇ 5%, and then place them in 5, 10 At 15 days, about 10 mg of the above sample was taken to test the X-ray powder diffraction pattern.
  • the test results show that the X-ray powder diffraction patterns of crystal form I and crystal form II are consistent with the patterns shown in Figs. 3 and 7 respectively. Both crystal form I and crystal form II are stable under high temperature, high humidity and light conditions, and the crystal form remains unchanged.
  • the X-ray powder diffraction pattern of the amorphous form is consistent with that shown in Figure 7 under high temperature and high humidity conditions, but the X-ray powder diffraction pattern of the amorphous form is consistent with that shown in Figure 11 under light conditions.
  • the amorphous form is only in light conditions. It is stable under high temperature and high humidity, and transforms into crystal form II under high temperature and high humidity.
  • BMS-262084 crystal form I, II, and amorphous samples Take proper amounts of BMS-262084 crystal form I, II, and amorphous samples to test their moisture absorption, and use DVS (model: DVS-INTRINSIC) to test their dynamic adsorption equilibrium curves. See Figure 6, Figure 10, and Figure 12. 25.0 With the range of humidity (0%-95.0%) at °C, as the humidity increases, the hygroscopicity of the product is greater. When the humidity reaches 95.0%, the moisture content of BMS-262084 crystal form I is at least about 1.6%; the moisture content of crystal form II is about 5.7%; the moisture content of amorphous is about 12.0%. Compared with the amorphous form, the crystal form of the present invention has significantly lower hygroscopicity, especially the crystal form I.

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Abstract

一种凝血因子XIa抑制剂的晶型及其制备方法，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。所述晶型具有较好的性能，稳定性高，可用于制备治疗心血管疾病的药物制剂。

Description

一种凝血因子XIa抑制剂的晶型及其制备方法 技术领域
本发明涉及药物化学领域，具体地，本发明涉及一种凝血因子XIa抑制剂的晶型及其制备方法。
背景技术
BMS-262084(CAS号：253174-92-4)，化学名称为(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸，本发明中也称为化合物(1)，是BMS(百时美-施贵宝)公司开发用于治疗心血管疾病药物，其作为血栓的口服凝血因子XIa抑制剂，具有显著降低出血风险的优势，其结构如式(1)所示：
Figure PCTCN2020096572-appb-000001
专利申请WO 9967215A1公开了BMS-262084化合物，但其公开的制备工艺得到的固体物质的具体分子式为C 18H 31N 7O 5·1.56H 2O，与本申请所述的BMS-262084的晶型和无定型的水分子量不同。
《A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor》(文献来源：有机化学期刊，2002，67(11)：3595-3600；Journal of Organic Chemistry,2002,67(11):3595-3600)中提到BMS-262084的制备方法是中性条件下的氢解消除了苯和Cbz保护组，并得到了BMS-262084(熔点213-215℃)。发明人根据该文献公开的部分内容进行试验，试验结果得到了晶型A和晶型B，其的X-射线粉末衍射图分别见图1、图2。
因药物的晶型是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于药物制剂的晶型，需要对药物的结晶行为进行深入探索探究，以得到满足生产要求的晶型。
发明内容
发明概述
本发明提供了化合物(1)的新晶型及其制备方法和组合物。
所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。所述晶型的X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰；或者所述晶型的X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
所述晶型的差示扫描量热曲线在122℃-126℃处具有吸热峰，或者所述晶型的差示扫描量热曲线在128℃-132℃处具有吸热峰。
所述晶型为一水物或者1.5水物。在一些实施方式中，所述晶型为(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸一水物。在一些实施方式中，所述晶型为(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸1.5水物。
在一些实施方式中，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。在一些实施方式中，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。在一些实施方式中，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
本发明提供的晶型具有较好的性能，稳定性高，可用于制备治疗心血管疾病的药物制剂。
一种制备所述晶型的方法，包括：将原料化合物(1)(BMS-262084)溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥得到所述晶型。
本发明还提供一种组合物，所述组合物包含前述的化合物(1)的晶型。按照质量比计，所述晶型为化合物(1)的至少90％，或者所述晶型不超过化合物(1)的0.5％-5％。
术语定义
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“晶型”用来描述固体化合物的存在状态，描述晶体内部的离子、原子或分子组成、对称性质与周 期排列规律的多种参量集合体。
术语“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的强度与第一强峰的强度的比值。
术语“基本上如图所示”是指X-射线粉末衍射图中至少90％，或至少95％，或至少99％的峰显示在其图中。
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。
所述晶型的差示扫描量热曲线(DSC)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
所述晶型的热重分析(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，失重温度和失重的量可能会略有差别，实验误差或差别的数值可能是大约+/-0.1个单位，大约+/-0.05个单位，或者大约+/-0.01个单位，因此所述失重温度和失重的量的数值不能视为绝对的。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。
“室温”是指温度在大约15℃-32℃或大约20℃-30℃或大约23℃-28℃或大约28℃。
“高温”是指温度在大约40℃-100℃或大约50℃-70℃或大约60℃。
本发明中，涉及到固体干燥时，固体干燥至恒重。
发明详述
发明人通过研究开发了化合物(1)的晶型及其制备方法。
第一方面，本发明研究过程中意外发现了化合物(1)的新晶型，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
本发明所述的化合物(1)的晶型，即所述新晶型，包括晶型I或晶型Ⅱ，具有良好的性能，溶解度高，生物利用度高；或/和在稳定性方面良好，有利于储存，从而符合药物稳定性的要求；吸湿性低，或/和在静 电性方面具有良好的性能，静电性低，有利于生产工艺中操作；并且作为血栓的口服凝血因子XIa抑制剂，具有降低出血风险的作用。
化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，15.9±0.2°，17.0±0.2°，19.5±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，15.9±0.2°，17.0±0.2°，17.5±0.2°，19.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°， 7.5±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.0±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，19.5±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，24.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.0±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，19.5±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，24.4±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的峰中的至少之一。在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的峰。
在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的峰中的至少之一。在一些实施方式中，所述化合物(1)的晶型，具有如下特性：其X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的峰。
在本申请中，将化合物(1)的晶型在X射线粉末衍射图2θ角不包含7.5±0.2°，17.0±0.2°，19.5±0.2°，中的至少之一衍射峰的晶型称为“晶型I”；反之，称为“晶型Ⅱ”。
在一些实施方式中，化合物(1)的晶型I，其X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
在一些实施方式中，化合物(1)的晶型I，其X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°，和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些实施方式中，化合物(1)的晶型I，其X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°，和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰；且：其X射线粉末衍射图包含2θ角为 6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
一些实施例中，化合物(1)的晶型I的X-射线粉末衍射图基本上如图3所示，其中衍射角2θ为15.9±0.2°度的峰的相对强度大于50％，或者大于60％，或者大于70％，或者大于80％，或者大于90％，或者大于99％。
在一些实施方式中，化合物(1)的晶型Ⅱ，其X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°，和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些实施方式中，化合物(1)的晶型Ⅱ，其X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°，和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰；且其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者其X射线粉末衍射图包含2θ角为6.9±0.2°，7.5±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
一些实施例中，化合物(1)的晶型Ⅱ的X-射线粉末衍射图基本上如图7所示，其中衍射角2θ为15.9±0.2°度的峰的相对强度大于50％，或者大于60％，或者大于70％，或者大于80％，或者大于90％，或者大于99％。
所述化合物(1)的晶型，还具有如下特性：其差示扫描量热曲线(DSC)在75℃-175℃处具有吸热峰。
在一具体实施方案中，化合物(1)的晶型I的差示扫描量热曲线(DSC)在100℃-140℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型I的差示扫描量热曲线(DSC)在120℃-128℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型I的差示扫描量热曲线(DSC)在122℃-126℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型I的差示扫描量热曲线(DSC)在122℃-126℃处具有吸热峰，吸热峰峰顶值为124℃。在一些实施方案中，化合物(1)的晶型Ⅰ的差示扫描量热曲线(DSC)如图4所示。
在一具体实施方案中，化合物(1)的晶型Ⅱ的差示扫描量热曲线(DSC)在110℃-150℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型Ⅱ的差示扫描量热曲线(DSC)在126℃-134℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型Ⅱ的差示扫描量热曲线(DSC)在128℃-132℃处具有吸热峰。在一具体实施方案中，化合物(1)的晶型Ⅱ的差示扫描量热曲线(DSC)在128℃-132℃处具有吸热峰，吸热峰峰顶值为130℃。在一些实施方案中，化合物(1)的晶型Ⅱ的差示扫描量热曲线(DSC)如图8所示。
所述化合物(1)的晶型，还具有如下特性：化合物(1)的晶型的热重分析曲线(TGA)显示化合物(1)的晶型Ⅰ在30℃-150℃有失重，失重量约为3.5％-7.5％。
在一具体实施方案中，化合物(1)的晶型I的热重分析曲线(TGA)显示在30℃-150℃有失重，失重量约为4.0％。在一具体实施方案中，化合物(1)的晶型I的热重分析曲线图(TGA)如图5所示。
在一具体实施方案中，化合物(1)的晶型Ⅱ的热重分析曲线(TGA)显示在30℃-150℃有失重，失重量约为6.0％。在一具体实施方案中，化合物(1)的晶型Ⅱ的热重分析曲线图(TGA)如图9所示。
在一些实施方式中，所述化合物(1)的晶型为含水物或水合物。在一些实施方式中，所述化合物(1)的晶型含水量为约4.0％。在一些实施方式中，所述化合物(1)的晶型含水量为约6.0％。
在一些实施方式中，所述化合物(1)的晶型为一水物。在一些实施方式中，所述化合物(1)的晶型为1.5水物。在一些实施方式中，所述晶型为(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸一水物。在一些实施方式中，所述晶型为(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸合1.5水物。
在一些实施方式中，所述化合物(1)的晶型I为含水物或水合物。在一些实施方式中，所述化合物(1)的晶型I含水量为约4.0％。在一些实施方式中，所述化合物(1)的晶型I为一水物。
在一些实施方式中，所述化合物(1)的晶型Ⅱ含水量为约6.0％。在一些实施方式中，所述化合物(1)的晶型Ⅱ为1.5水物。
在一具体实施方案中，化合物(1)的晶型I，还具有如下特性：其动态吸附平衡曲线具有随着湿度的增加，产品的吸湿性越大，湿度达到95.0％时，吸湿水分量为1.6％，即水分增重1.6％。在一具体实施方案中，所述化合物(1)的晶型I，还具有如下特性：其动态水分吸附仪(DVS)等温线图如图6所示。在一具体实施方案中，化合物(1)的晶型Ⅱ，还具有如下特性：其动态吸附平衡曲线具有，随着湿度的增加，产品的吸湿性越大，湿度达到95.0％时，晶型Ⅱ的吸湿水分量为5.7％，即水分增重5.7％。在一具体实施方案中，所述化合物(1)的晶型Ⅱ，还具有如下特性：其动态水分吸附仪(DVS)等温线图如图10所示。
在一些实施方式中，化合物(1)的晶型I，还具有如下特性：前述的晶型I为化合物(1)的至少90％，或者至少95％。在一些实施方式中，前述的晶型I为化合物(1)的至少98％或者至少99％。
在一些实施方式中，化合物(1)的晶型Ⅱ，还具有如下特性：前述的晶型Ⅱ为化合物(1)的至少90％，或 者至少95％。在一些实施方式中，前述的晶型Ⅱ为化合物(1)的至少98％或者至少99％。
根据本发明的一些实施例，所述晶型I具有较好的稳定性和流动性，较低的吸湿性，有利于生产过程中物料转移，有利于药物制剂中原料的使用和稳定，有利于药物制剂的制备和质量稳定。
根据本发明的一些实施例，所述晶型Ⅱ具有较好的稳定性和流动性，相对较低的吸湿性，可以用于药物制剂的制备。
第二方面，本发明提供了所述化合物(1)的晶型的制备方法。
本发明中所述化合物(1)的晶型的制备方法简单、操作方便，条件温和，收率高，纯度高，适用于工业化生产。
一种制备所述化合物(1)的晶型方法包括：将原料化合物(1)(BMS-262084)溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥至恒重，得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥至恒重，得到所述晶型。一些实施方式中，一种制备所述化合物(1)的晶型方法包括：将原料化合物(1)(BMS-262084)溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥至恒重，得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥至恒重，得到所述晶型；溶剂包括选自水，异丙醇、正丙醇、甲醇、乙二醇二甲醚，四氢呋喃和二氧六环中的至少一种。
一些实施方式中，一种制备所述化合物(1)的晶型方法包括：将原料化合物(1)(BMS-262084)溶解于异丙醇、正丙醇、甲醇、二氧六环或其与水的混合溶剂中，室温下完全溶解形成的溶液经过挥发，干燥得到所述晶型。一些实施方式中，一种制备所述化合物(1)的晶型的方法包括：将原料化合物(1)(BMS-262084)混悬于水、乙二醇二甲醚、四氢呋喃或其混合溶剂中形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型。
一些实施方式中，一种制备所述化合物(1)的晶型方法包括：将原料化合物(1)(BMS-262084)溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥至恒重，得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥至恒重，得到所述晶型；溶剂选自水，异丙醇、乙二醇二甲醚和四氢呋喃中的至少一种；所述晶型为晶型I。
在一具体实施方案中，一种制备所述化合物(1)的晶型I的方法包括：将原料化合物(1)溶解于异丙醇与水的混合溶剂中，室温下完全溶解形成的溶液，经过挥发，干燥，得到所述晶型I。
在一具体实施方案中，一种制备所述化合物(1)的晶型I的方法包括：高温下将原料化合物(1)混悬于水形成混合液，高温下或室温下混合液经过混悬，然后过滤，干燥得到所述晶型I。
在一些具体实施方案中，一种制备所述化合物(1)的晶型I的方法包括：将原料化合物(1)混悬于乙二醇二甲醚与水的混合溶剂或四氢呋喃与水的混合溶剂中，形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型I。在一些具体实施方案中，一种制备所述化合物(1)的晶型I的方法包括：室温下 将原料化合物(1)混悬于乙二醇二甲醚与水的混合溶剂或四氢呋喃与水的混合溶剂中，形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型I。
一些实施方式中，一种制备所述化合物(1)的晶型方法包括：将原料化合物(1)(BMS-262084)溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥至恒重，得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥至恒重，得到所述晶型；溶剂选自水、正丙醇、甲醇和二氧六环中的至少一种；所述晶型为晶型Ⅱ。
在一具体实施方案中，一种制备所述化合物(1)的晶型Ⅱ的方法包括：室温下将原料化合物(1)溶解于正丙醇、甲醇或二氧六环，或溶解于正丙醇、甲醇或二氧六环与水的混合溶剂中，室温下完全溶解形成的溶液，经过挥发，干燥得到所述晶型Ⅱ。
在一具体实施方案中，一种制备所述化合物(1)的晶型Ⅱ的方法包括：室温下将原料化合物(1)混悬于水中形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型Ⅱ。
所述制备晶型的方法中，混悬的时间可以为4小时-120小时，或者4小时-96小时，或者4小时-72小时，或者4小时-36小时，或者24小时-48小时，或者36小时-72小时，或者8小时-36小时，或者12小时-36小时，或者12小时-24小时。
在一些实施方式中，所述制备晶型的方法中，混悬的时间不超过48小时，得到晶型I。
在一些实施方式中，所述制备晶型的方法中，混悬的时间不低于48小时，得到晶型Ⅱ。
另一方面，本发明还提供一种组合物，所述组合物包含前述的化合物(1)的晶型。
按照质量比计，所述晶型为化合物(1)的至少90％，或者所述晶型不超过化合物(1)的0.5％-5％。
按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型为化合物(1)的至少90％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型为化合物(1)的至少95％，或者至少99％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型为化合物(1)的至少0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型为化合物(1)的至少5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型不超过化合物(1)的0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型，其中，所述晶型不超过化合物(1)的5％。
在一些实施方式中，一种组合物，包含前述的合物(1)的晶型，所述晶型为晶型I和/或晶型Ⅱ。在一些实施方式中，一种组合物，包含前述的合物(1)的晶型I和/或晶型Ⅱ。
按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中，晶型I为化合物(1)的至少90％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中， 晶型I为化合物(1)的至少95％，或者至少99％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中，晶型I为化合物(1)的至少0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中，晶型I为化合物(1)的至少5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中，晶型I不超过化合物(1)的0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型I，其中，晶型I不超过化合物(1)的5％。
按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ为化合物(1)的至少90％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ为化合物(1)的至少95％，或者至少99％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ为化合物(1)的至少0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ为化合物(1)的至少5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ不超过化合物(1)的0.5％-5％。按照质量比计，在一些实施方式中，一种组合物，包含前述化合物(1)的晶型Ⅱ，其中，晶型Ⅱ不超过化合物(1)的5％。
所述的组合物，还可以包括药学上可接受的辅料或载体，如填充剂，稀释剂，润滑剂等。在一些实施方式中，所述组合物还包含药学上可接受的辅料或载体，所述药学上可接受的辅料或载体包括润滑剂。在一些实施方式中，所述润滑剂为硬脂酸镁。
所述的组合物可制备成任何适宜的药物制剂，如片剂，胶囊剂，颗粒剂，混悬剂，或注射剂等。
附图说明
图1示化合物(1)晶型A的X-射线粉末衍射图(XRPD)；
图2示化合物(1)晶型B的X-射线粉末衍射图(XRPD)；
图3示化合物(1)晶型I的X-射线粉末衍射图(XRPD)；
图4示化合物(1)晶型I的差示扫描量热曲线图(DSC)；
图5示化合物(1)晶型I的热重分析曲线图(TGA)；
图6示化合物(1)晶型I的动态水分吸附仪(DVS)等温线图；
图7示化合物(1)晶型Ⅱ的X-射线粉末衍射图(XRPD)；
图8示化合物(1)晶型Ⅱ的差示扫描量热曲线图(DSC)；
图9示化合物(1)晶型Ⅱ的热重分析曲线图(TGA)；
图10示化合物(1)晶型Ⅱ的动态水分吸附仪(DVS)等温线图；
图11示化合物(1)无定型的X-射线粉末衍射图(XRPD)；
图12示化合物(1)无定型的动态水分吸附仪(DVS)等温线图。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过现有技术的方法制备或者通过本发明所描述的方法制备而得。
本发明中，℃表示摄氏度，mg表示毫克，mL表示毫升，h表示小时，mm表示毫米。
本发明中，水合物按照摩尔比计算，一水物中，(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸与水的摩尔比为1:1；1.5水物中，(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸与水的摩尔比为1:1.5。
仪器参数
除非参数中另行规定，以下所有分析都在室温下进行。
X-射线粉末衍射(XRPD)
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，
Figure PCTCN2020096572-appb-000002
1.540598；
Figure PCTCN2020096572-appb-000003
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm采用θ-θ连续扫描模式，得到3°～60°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0167°的扫描步长在3～60°2θ±0.2°范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。在X-射线粉末衍射图中，纵坐标为用计数(counts)表示的衍射强度，横坐标为用度(°)表示的衍射角2θ。
差示扫描量热法(DSC)
使用TA Instruments差示扫描量热计Q2000进行差示扫描量热法(DSC)。将样品(约1mg～3mg)放入铝盘中并精确记录重量。该盘用盖子覆盖，然后压接，并将样品转移至仪器中进行测量。将样品池在30下平衡并在氮气吹扫下以50℃/min的速率加热至300℃的最终温度。在DSC图中，横坐标表示温度(Temperature,℃)，纵坐标表示单位质量的物质放出的热流量(Heat Flow,W/g)。
热重分析法(TGA)
使用热重分析仪Q500进行热重分析，将适量样品放置在铂样品盘中，在氮气氛下，以60℃/分钟速率 升温，温度范围为30至300℃。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示质量百分数(Weight,％)。
动态蒸汽吸附分析仪DVS
DVS测试等温吸附平衡曲线测试方法，仪器：DVS-INTRINSIC，25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以5％的相对湿度阶梯变化到达95％相对湿度，然后再以5％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.5％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。
实施例1
《A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor》(文献来源：有机化学期刊，2002，67(11)：3595-3600；Journal of Organic Chemistry,2002,67(11):3595-3600)文献中只提到了乙醇溶剂。由于没有具体提供结晶精制工艺，从而仅利用乙醇溶剂进行部分实验。
1)乙醇溶剂的室温挥发：50mg BMS-262084(无定型)加入到1.0mL乙醇溶剂中，室温(约25℃)条件下完全溶解。敞口进行室温挥发两天，得到固体产品检测其晶型情况，为晶型A，见图1，认为其含有少量无定型；但其不稳定，室温条件下会发生转晶，在室温条件下放置一天后检测XRPD，发现其转为含有晶型A、其他晶型和无定型的混合物。
2)乙醇溶剂的高温挥发：50mg BMS-262084加入到1.0mL乙醇溶剂中，高温(约60℃)条件下完全溶解，敞口进行高温挥发，得到固体产品，检测其晶型情况，为晶型B(含大量无定型)，见图2。
实施例2
5mL EP管中加入50.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下固液混合物搅拌约24h后仍然无法溶清，关闭加热保持搅拌自然降温至室温(约28℃)，并室温搅拌混悬约1天，过滤、真空50℃干燥24h得到白色固体约20.0mg，进行固态分析检测，得到晶型I，参见图3至图6。
实施例2-02
5mL EP管中加入50.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下无法完全溶解。固液混合物高温(约60℃)、磁力搅拌200rpm条件下混悬约1天，高温过滤、真空50℃干燥24h得到白色固体约20.0mg，进行固态分析检测，为晶型I，与图3至图6一致。
实施例3
5mL EP管中加入100.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下固液混合物搅拌约24h后仍然无法溶清，关闭加热保持搅拌自然降温至室温(约28℃)，并室温搅拌混悬约1天，过滤、真空50℃干燥24h得到白色固体约55.0mg，进行固态分析检测，为晶型I，与图3至图6一致。
实施例3-02
5mL EP管中加入100.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下无法完全溶解。固液混合物高温(约60℃)、磁力搅拌200rpm条件下混悬约1天，高温过滤、真空50℃干燥24h得到白色固体约55.0mg，进行固态分析检测，为晶型I，与图3至图6一致。
实施例4
5mL EP管中加入200.0mg BMS-262084和2.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下固液混合物搅拌约24h后仍然无法溶清，关闭加热保持搅拌自然降温至室温(约28℃)，并室温搅拌混悬约3天，过滤、真空50℃干燥24h得到白色固体约105mg，进行固态分析检测，为晶型I，与图3至图6一致。
实施例4-02
5mL EP管中加入200.0mg BMS-262084和2.0mL纯化水，磁力搅拌200rpm，高温(约60.0℃)下无法完全溶解。固液混合物高温(约60℃)、磁力搅拌200rpm条件下混悬约1天，高温过滤、真空50℃干燥24h得到白色固体约105mg，进行固态分析检测，为晶型I，与图3至图6一致。
实施例5
5mL EP管中加入50.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，室温(约28.0℃)下无法完全溶解。固液混合物室温(约28.0℃)、磁力搅拌200rpm条件下混悬约3天，过滤、真空50℃干燥24h得到白色固体约25.0mg，进行固态分析检测，得到晶型Ⅱ，参见图7至图10。
实施例6
5mL EP管中加入100.0mg BMS-262084和1.0mL纯化水，磁力搅拌200rpm，室温(约28.0℃)下无法完全溶解。固液混合物室温(约28.0℃)、磁力搅拌200rpm条件下混悬约3天，过滤、真空50℃干燥24h得到白色固体约65.0mg，进行固态分析检测，为晶型Ⅱ，与图7至图10一致。
实施例7
5mL EP管中加入200.0mg BMS-262084和2.0mL纯化水，磁力搅拌200rpm，室温(约28.0℃)下无法完全溶解。固液混合物室温(约28.0℃)、磁力搅拌200rpm条件下混悬约3天，过滤、真空50℃干燥24h得到白色固体约135mg，进行固态分析检测，为晶型Ⅱ，与图7至图10一致。
实施例8
50mL烧瓶中加入2.00g BMS-262084和50.0mL甲醇溶剂，磁力搅拌200rpm，室温(约28.0℃)下完全溶解。溶液采用旋蒸方式去除溶剂，真空50℃干燥24h得到白色固体约1.90g，进行固态分析检测，确定为无定型，参见图11、图12。
实施例9
5mL EP管中加入30mg BMS-262084(无定型)、0.5mL有机溶剂和0.5mL纯化水，磁力搅拌2小时，200rpm。其中完全溶清形成的溶液采用室温挥发的方式筛选，未完全溶清的固液混合物采用室温混悬的方式筛选，混悬及挥发时间均为三天；最后过滤，所得固体进行固态分析检测，结果见表1。
表1
Figure PCTCN2020096572-appb-000004
注：Y：表示完全溶解；N：表示未完全溶解。
实施例10
高温试验：分别取BMS-262084晶型I、Ⅱ、无定型样品适量，平铺置称量瓶中，在60±5℃、RH75±5％恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试X-射线粉末衍射图谱。
高湿试验：分别取BMS-262084晶型I、Ⅱ、无定型样品适量，平铺置称量瓶中，在25℃、RH 92.5±5％恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试X-射线粉末衍射图谱。
光照试验：分别取BMS-262084晶型I、Ⅱ、无定型样品适量，平铺至称量瓶中，在可见光4500Lux±500 Lux、紫外光1.7W*h/m2的恒温恒湿箱(25℃、RH60±5％)条件下放置，然后分别于5、10和15天取上述样品约10mg，测试X-射线粉末衍射图谱。
试验结果表明晶型I和晶型Ⅱ的X-射线粉末衍射图谱分别与图3、图7所示图谱一致。晶型I和晶型Ⅱ在高温、高湿、光照条件下均稳定，晶型不变。无定型在高温、高湿条件下其X-射线粉末衍射图谱与图7所示图谱一致，但在光照条件下其X-射线粉末衍射图谱与图11所示图谱一致，无定型仅在光照条件下稳定，高温和高湿条件下均转化为晶型Ⅱ。
实施例11
取分别取BMS-262084晶型I、Ⅱ、无定型样品适量测试其引湿性情况，利用DVS(型号：DVS-INTRINSIC)测试其动态吸附平衡曲线，分别参见图6、图10、图12。25.0℃下随着湿度(0％～95.0％)的变化范围，随着湿度的增加，产品的吸湿性越大。湿度达到95.0％时，其中BMS-262084晶型I的吸湿水分量最少仅约为1.6％；晶型Ⅱ的吸湿水分量约为5.7％；无定型的吸湿水分量约为12.0％。相对于无定型，本发明所述晶型具有明显的较低吸湿性，尤其是晶型I。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (12)

  1. 化合物(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸的晶型，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，15.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰。
  2. 根据权利要求1所述的晶型，其中，所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，15.9±0.2°，17.5±0.2°，20.2±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，23.7±0.2°和28.2±0.2°的衍射峰；或者所述晶型的X射线粉末衍射图包含2θ角为6.9±0.2°，11.2±0.2°，13.9±0.2°，14.3±0.2°，15.6±0.2°，15.9±0.2°，17.5±0.2°，18.2±0.2°，18.8±0.2°，20.2±0.2°，20.9±0.2°，21.8±0.2°，22.4±0.2°，23.7±0.2°，27.4±0.2°，28.2±0.2°，29.4±0.2°，32.3±0.2°，35.1±0.2°和36.3±0.2°的衍射峰。
  3. 根据权利要求1或2所述的晶型，所述晶型为一水物或者1.5水物。
  4. 根据权利要求1-3任一所述的晶型，其中，所述晶型的差示扫描量热曲线在122℃-126℃处具有吸热峰，或者所述晶型的差示扫描量热曲线在128℃-132℃处具有吸热峰。
  5. 根据权利要求1-4任一所述的晶型，所述晶型的X射线粉末衍射图包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰；或者所述晶型的X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
  6. 根据权利要求1-5任一所述的晶型，其中，所述晶型的X-射线粉末衍射图基本上如图3所示，或者所述晶型的X-射线粉末衍射图基本上如图7所示。
  7. 根据权利要求1-4任一所述的晶型，所述晶型的X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
  8. 一种制备权利要求1-7任一项所述的晶型的方法，包括：将原料溶解或混悬于溶剂中，其中，完全溶解形成的溶液经过挥发，干燥至恒重，得到所述晶型；未完全溶解的固液混合物经过混悬，过滤、干燥至恒重，得到所述晶型；溶剂包括选自水，异丙醇、正丙醇、甲醇、乙二醇二甲醚，四氢呋喃和二氧六环中的至少一种。
  9. 根据权利要求8所述的方法，包括：将原料溶解于异丙醇与水的混合溶剂中，室温下完全溶解形成的溶液，经过挥发，干燥，得到所述晶型；或者高温下将原料混悬于水形成混合液，高温下或室温下混合液经过混悬，然后过滤，干燥得到所述晶型；或者室温下将原料混悬于乙二醇二甲醚与水的混合溶剂或四氢呋喃与水的混合溶剂中，形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型。
  10. 根据权利要求8所述的方法，包括：室温下将原料溶解于正丙醇、甲醇或二氧六环，或溶解于正丙醇、甲醇或二氧六环与水的混合溶剂中，室温下完全溶解形成的溶液，经过挥发，干燥得到所述晶型；或 者室温下将原料混悬于水中形成固液混合物，室温下固液混合物经过混悬，过滤，干燥得到所述晶型。
  11. 一种组合物，包含权利要求1-7任一项所述的晶型和药学上可接受的辅料或载体；其中，按照质量比计，所述晶型为化合物(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸的至少90％，或者所述晶型不超过化合物(2S,3R)-1-[4-(叔丁基氨甲酰基)哌嗪-1-碳酰基]-3-[3-(二氨甲基氨基)丙基]-4-环丙酰胺-2-羧酸的0.5％-5％。
  12. 根据权利要求11所述的组合物，其中，所述晶型的X射线粉末衍射图不包含2θ角为7.5±0.2°，17.0±0.2°和19.5±0.2°的衍射峰中的至少一个峰或至少两个峰或三个峰。
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