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WO2017177781A1 - Ahu377的晶型及其制备方法与用途 - Google Patents

Ahu377的晶型及其制备方法与用途 Download PDF

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WO2017177781A1
WO2017177781A1 PCT/CN2017/076451 CN2017076451W WO2017177781A1 WO 2017177781 A1 WO2017177781 A1 WO 2017177781A1 CN 2017076451 W CN2017076451 W CN 2017076451W WO 2017177781 A1 WO2017177781 A1 WO 2017177781A1
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ahu377
crystal form
solvent
toluene
form iii
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PCT/CN2017/076451
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English (en)
French (fr)
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陈敏华
张炎锋
杨朝惠
陆飞
张良
张晓宇
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苏州晶云药物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • 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 belongs to the field of chemical medicine, and particularly relates to a crystal form of AHU377, a preparation method and use thereof.
  • Patent US5354892A discloses for the first time the preparation of the AHU377 structure and its sodium salt; however, the AHU377 crystal form is not involved in this patent.
  • Patent CN102702119A discloses a dual-acting complex LCZ696 having the structural formula shown in formula (II).
  • the complex has AHU377 and valsartan as active ingredients, and the two active ingredients are connected by hydrogen bonding.
  • the patent also discloses a method for preparing LCZ696 using AHU377 or a salt thereof.
  • LCZ696 has been clinically proven to be useful in the treatment of a variety of cardiovascular and/or renal diseases. Clinical data suggest that LCZ696 is expected to be the drug of choice for anti-heart failure treatment.
  • AHU377 exists in the form of a thick substance at room temperature.
  • the transfer and quantification of the thick AHU377 raw material has insurmountable operational difficulties.
  • the prior art can only achieve the purpose of material transfer and accurate quantification by preparing AHU377 as a solid salt first, but the subsequent preparation of LCZ696 still needs to break the salt into AHU377 free acid.
  • the existing process is not only cumbersome to operate, but also introduces a large amount of impurity ions, which is not conducive to process quality control.
  • the technical problem to be solved by the present invention is to provide a new crystal form of AHU377 suitable for pharmaceutical research and industrial production.
  • the present invention adopts the following technical solutions:
  • the X-ray powder diffraction pattern of the crystal form III measured by CuK ⁇ ray has a characteristic peak at a 2theta value of 6.1 ° ⁇ 0.2 °, 13.2 ° ⁇ 0.2 °, and 19.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form III measured by CuK ⁇ ray is also one of 2theta values of 12.3° ⁇ 0.2°, 21.1° ⁇ 0.2°, 19.2° ⁇ 0.2°. There are characteristic peaks at or at multiple locations.
  • the X-ray powder diffraction pattern of the crystalline form III measured by CuK ⁇ ray has a characteristic peak at 2theta values of 12.3° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form III measured by CuK ⁇ ray is also in the 2theta value of 9.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, 19.8° ⁇ 0.2°.
  • One or more points have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form III measured by CuK ⁇ ray has a characteristic peak at 2theta values of 9.6° ⁇ 0.2°, 25.4° ⁇ 0.2°, and 19.8° ⁇ 0.2°.
  • the crystalline form III is an X-ray powder diffraction pattern measured by CuK ⁇ ray. It also has characteristic peaks at 2theta values of 12.3 ° ⁇ 0.2 °, 21.1 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 9.6 ° ⁇ 0.2 °, 25.4 ° ⁇ 0.2 °, and 19.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form III is substantially identical to that of FIG.
  • the crystalline form III is a hemi-toluene solvate.
  • the hemi-toluene solvate means that the number of moles of toluene participating in the crystal lattice is 0.5 times the number of moles of the compound of the formula (I).
  • said Form III has a weight loss gradient of about 9.6% when heated to around 150 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • said Form III begins to exhibit an endothermic peak near heating to about 48 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • a second object of the present invention is to provide a process for preparing the AHU377 crystal form III, which comprises starting from a product solution for synthesizing AHU377, which comprises AHU377 and a reaction for synthesizing AHU377. a solvent, the method comprising the steps of:
  • the anti-solvent may be, for example, a combination of one or more selected from the group consisting of n-heptane, mixed heptane, and cyclohexane.
  • the reaction solvent has a boiling point lower than the boiling point of toluene.
  • Commonly used reaction solvents such as dichloromethane, acetone, ethyl acetate and the like.
  • the step (a) after adding the anti-solvent, the mixture is aged for more than 8 hours, filtered, and rinsed with an anti-solvent to obtain a solid wet product, the method further comprising performing the step (a) once. And after (b), one or more crystallizations are repeated, the crystallization is obtained by heating and dissolving the dried product obtained in the previous step in toluene, cooling to room temperature or less, adding an anti-solvent to crystallization, and finally filtering the precipitated crystal. Rinse with anti-solvent and dry.
  • the vacuum distillation is carried out at 45 to 55 °C.
  • crystallization is carried out at 10 to 25 °C.
  • a third object of the present invention is to provide an AHU377 Form IV,
  • the X-ray powder diffraction pattern of the Form IV measured by CuK ⁇ ray has a characteristic peak at a 2theta value of 11.6° ⁇ 0.2°, 5.7° ⁇ 0.2°, and 17.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV measured by CuK ⁇ ray is also one of 2theta values of 23.1° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 21.2° ⁇ 0.2°. There are characteristic peaks at or at multiple locations.
  • the X-ray powder diffraction pattern of the Form IV measured by CuK ⁇ ray has a characteristic peak at 2theta values of 23.1° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 21.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form IV measured by CuK ⁇ ray is also in the 2theta value of 19.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 14.5° ⁇ 0.2°.
  • One or more points have characteristic peaks.
  • the X-ray powder diffraction pattern of the Form IV measured by CuK ⁇ ray has a characteristic peak at 2theta values of 19.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV measured by CuK ⁇ ray is also 2theta value of 23.1° ⁇ 0.2°, 24.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 19.9° ⁇ There are characteristic peaks at 0.2°, 9.6° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV is substantially identical to that of FIG.
  • the crystalline form IV is a mono-toluene solvate.
  • the mono-toluene solvate means that the number of moles of toluene participating in the crystal lattice is equal to the number of moles of the compound of the formula (I).
  • said Form IV has a weight loss gradient of about 17.8% when heated to around 180 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • said Form IV begins to exhibit an endothermic peak near heating to about 48 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • a fourth object of the present invention is to provide a method for preparing the AHU377 Form IV, which comprises the method (1) or the method (2) or the method (3):
  • the method (2) comprises starting a product solution of AHU377, wherein the synthetic AHU377 product solution comprises AHU377 and a reaction solvent used in synthesizing AHU377, and the method comprises the following steps:
  • Toluene is added to the product solution, followed by distillation under reduced pressure to remove the reaction solvent in the system as much as possible, and then toluene is selectively added to the system, and the temperature is lowered to below room temperature, and the anti-solvent is added to perform crystallization and separation.
  • the product solution of the AHU377 is distilled under reduced pressure to remove the reaction solvent to obtain an oil, and then adding toluene to the oil and heating to dissolve the oil, and then dropping to room temperature or lower, and finally adding the The anti-solvent is subjected to crystallization and separation to obtain a solid wet product which is directly used as a final product without drying, or is further subjected to one or more crystallizations to obtain a final product which is obtained by drying the solid wet product. Heating and dissolving in toluene, then falling below room temperature, adding anti-solvent for crystallization;
  • Method (3) preparing a toluene solution of AHU377, stirring at room temperature or lower, adding a seed crystal of Form IV, depositing a solid, and then selectively adding an anti-solvent to obtain the crystal form IV.
  • the method for preparing Form IV comprises the method (1) and further comprises preparing the Form III using the above-described preparation method of Form III of the present invention.
  • the anti-solvent may be a combination of one or more selected from the group consisting of n-heptane, mixed heptane, and cyclohexane.
  • the reaction solvent has a boiling point lower than the boiling point of toluene. Commonly used reaction solvents such as dichloromethane, acetone, ethyl acetate and the like.
  • the vacuum distillation is carried out at 45 to 55 °C.
  • crystallization is carried out at 10 to 25 °C.
  • the anti-solvent is added dropwise, after the addition is completed, the ripening is carried out, and finally, the product is centrifuged to obtain a final product.
  • the invention also provides a further preparation method of AHU377 crystal form III, which comprises the step of drying AHU377 crystal form IV at 40 ° C or lower.
  • a fifth object of the present invention is to provide a use of the above-described Form III or Form IV as described above or any ratio thereof in the preparation of AHU377 and valsartan complex.
  • a sixth object of the present invention is to provide a process for producing a composite of AHU377 and valsartan which is formed by mixing crystal form III as described above or form IV or valsartan as described above or any ratio thereof. Anti-heart failure drugs.
  • the present invention has the following advantages compared with the prior art:
  • the crystal form III and the crystal form IV of the AHU377 prepared by the invention have good stability, low wettability, strong impurity removal ability, good purification effect and strong economic value.
  • Form III and Form IV of AHU377 prepared by the present invention can be used for the preparation of anti-heart failure drug LCZ696.
  • the difficulty in transferring and accurately quantifying the use of AHU377 thick material as a starting material in the prior art is overcome, and the process flow is simplified, which is of great significance for industrial production and quality control of LCZ696.
  • Example 1 is an XRPD pattern of Form III prepared in Example 1;
  • Example 2 is a TGA diagram of Form III prepared in Example 1;
  • Figure 5 is an XRPD pattern of Form IV prepared in Example 4.
  • Figure 6 is a TGA diagram of Form IV prepared in Example 4.
  • Figure 7 is a DSC chart of Form IV prepared in Example 4.
  • Figure 8 is a 1 H NMR chart of Form IV prepared in Example 4.
  • Figure 9 is a PLM diagram of Form IV prepared in Example 4.
  • the test temperature is at a normal temperature, such as 25 ° C.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dried solid was placed in a 20 L jacketed reaction vessel, 8.5 L of toluene was added, and the mixture was warmed to 50 ° C and then cooled to 20 ° C. Adding 1.36 L of n-heptane appeared turbid, adding 200 mL of toluene and re-raising to 50 ° C to dissolve, and cooling to 20 ° C spontaneous crystallization. 5 L of n-heptane was added dropwise to the kettle at a rate of 8 mL/min, and the mixture was aged overnight. Filtration and leaching with 1.5 L of n-heptane gave a wet product which was dried at 40 ° C under vacuum to give a solid product.
  • the solid product obtained in this example was Form III, and the X-ray powder diffraction data thereof is shown in Table 1. Its XRPD diagram is shown in Figure 1, its TGA diagram is shown in Figure 2, its DSC diagram is shown in Figure 3, and its nuclear magnetic diagram is shown in Figure 4.
  • Example 1 100 mg of the solid of Form III obtained in Example 1 was added to 1 mL of a mixed solution of n-heptane and toluene in a volume ratio of 1:1, stirred at room temperature overnight, and centrifuged to obtain a solid product.
  • a product solution of 3.39 kg of synthetic AHU377 was weighed (the product solution contained about 726 g of AHU377 and the solvent was dichloromethane). 7.5 L of toluene was added, and the mixture was distilled under reduced pressure to 50 ° C to a remaining volume of 5 L, and the temperature was lowered to room temperature, and 2.5 L of toluene was added. 1.2 L of n-heptane was added, and after solids were precipitated, 4.8 L of n-heptane was added dropwise to the kettle. It was stirred and aged overnight, filtered and rinsed with 1 L of n-heptane and dried under vacuum at 40 °C.
  • the dried solid was placed in a 20 L jacketed reaction vessel, 8.5 L of toluene was added, and the mixture was warmed to 50 ° C and then cooled to 20 ° C. Adding 1.36 L of n-heptane appeared turbid, adding 200 mL of toluene and re-raising to 50 ° C to dissolve, and cooling to 20 ° C spontaneous crystallization. 5 L of n-heptane was added dropwise to the kettle at a rate of 8 mL/min, and the mixture was aged overnight. Filtration and rinsing with 1.5 L of n-heptane gave the wet solid product. Upon examination, the wet product obtained in this example was in the same crystal form as the crystal form obtained in Example 2, that is, Form IV.
  • AHU377 methanol solution (concentration: 31.9%, obtained from a batch of AHU377 Form III dissolved in methanol) was weighed and placed under reduced pressure at 50 ° C, and concentrated to dryness. 1 L of toluene was added, the solution was dissolved, and concentrated under reduced pressure to a volume of about 800 mL, cooled to room temperature and stirred overnight. AHU377 Form IV seed crystals (obtained according to the method of Example 3) were added to rapidly precipitate the solid. 500 mL of n-heptane was added using a metering pump at a drop rate of 3 mL/min. After the addition was completed, the ripening was continued and centrifugation gave a solid product.
  • the solid product obtained in this example was Form IV, and its X-ray powder diffraction data is shown in Table 3. Its XRPD diagram is shown in Fig. 5. Its TGA diagram is shown in Fig. 6, its DSC diagram is shown in Fig. 7, and nuclear magnetic diagram is shown in Fig. 8.
  • the AHU377 crystal form IV obtained in Example 1 of the present invention was subjected to a polarizing microscope photograph, as shown in FIG. From the results of the polarizing microscope, the AHU377 crystal form IV of the present invention is in the form of a sheet, has a good crystal form, and has a distinct crystal form advantage over the prior art oil.
  • AHU377 Form IV can serve as a purification agent for the drug substance. As shown in Preparation Example 4 of Form IV, the purity was improved from 96.05% to 99.13% by HPLC purity test, and the purification effect was remarkable, as shown in Table 6:

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Abstract

本发明涉及一种AHU377的晶型及其制备方法与用途。本发明提供了AHU377的晶型III和晶型IV，并且晶型III和晶型IV的稳定性好，引湿性低，除杂能力强，提纯效果好，具有很强的经济价值。

Description

AHU377的晶型及其制备方法与用途 技术领域
本发明属于化学医药领域，特别涉及AHU377的晶型及其制备方法与用途。
背景技术
AHU377，化学名称为(2R,4S)-5-联苯-4-基-4-(3-羧基-丙酰基氨基)-2-甲基-戊酸乙酯，其结构式如式(I)：
Figure PCTCN2017076451-appb-000001
专利US5354892A首次公开了AHU377结构及其钠盐的制备方法；但该专利中并未涉及AHU377晶型。
专利CN102702119A公开了一种双重作用的复合物LCZ696，结构式如式(II)所示。该复合物以AHU377和缬沙坦为活性成分，两种活性成分之间通过氢键连接。专利也公开了AHU377或其盐用于制备LCZ696的方法。LCZ696临床证实可用于治疗多种心血管和/或肾脏疾病，临床数据表明LCZ696有望成为抗心衰治疗的首选药物。
Figure PCTCN2017076451-appb-000002
发明人总结现有技术，发现室温下AHU377是以稠状物形式存在，在工业化生产LCZ696过程中，稠状物AHU377原料的转移和定量具有难以克服的操作困难。现有技术只能通过先将AHU377制备成固体盐来达成物料转移和精确定量的目的，但后续制备LCZ696仍需破盐成AHU377游离酸。现有工艺不但操作繁琐，也引入了大量杂质离子，不利于工艺质量控制。
基于现有技术的问题，寻找到AHU377的固体形式，便于LCZ696制备工艺中精确定量和转移、避免引入杂质离子以及简化工艺过程具有重要意义。
发明内容
本发明所要解决的技术问题是提供一种适于药物研究和工业化生产的AHU377的新晶型。
为解决以上技术问题，本发明采用如下技术方案：
本发明的一个目的是提供一种AHU377晶型III，
Figure PCTCN2017076451-appb-000003
所述的晶型III以CuKα射线测得的X射线粉末衍射图在2theta值为6.1°±0.2°,13.2°±0.2°,19.0°±0.2°处具有特征峰。
根据本发明的一个具体方面，所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为12.3°±0.2°,21.1°±0.2°,19.2°±0.2°中的一处或多处具有特征峰。优选地，所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为12.3°±0.2°,21.1°±0.2°,19.2°±0.2°处均具有特征峰。
根据本发明的另一个具体方面，所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为9.6°±0.2°,25.4°±0.2°,19.8°±0.2°中的一处或多处具有特征峰。优选地，所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为9.6°±0.2°,25.4°±0.2°,19.8°±0.2°处均具有特征峰。
根据一个最优选地方面，所述的晶型III以CuKα射线测得的X射线粉末衍射图 还在2theta值为12.3°±0.2°,21.1°±0.2°,19.2°±0.2°，9.6°±0.2°,25.4°±0.2°,19.8°±0.2°处均具有特征峰。在根据该方案的一个具体实施方式中，晶型III的X射线粉末衍射图基本上与图1一致。
本发明中，所述的晶型III为半甲苯溶剂合物。其中，所述的半甲苯溶剂合物是指参与构成晶体晶格的甲苯的摩尔数为式(I)化合物的摩尔数的0.5倍。
还优选地，所述的晶型III在被加热至150℃附近时，具有约9.6％的重量损失梯度，其热重分析图基本如图2所示。
还优选地，所述的晶型III在被加热至48℃附近开始出现吸热峰，其差示扫描量热分析图基本如图3所示。
本发明的第二个目的是提供一种所述的AHU377晶型III的制备方法，该方法以合成AHU377的产物溶液为起始物，所述合成AHU377产物溶液包含AHU377和合成AHU377时使用的反应溶剂，所述方法包括以下步骤：
(a)向所述产物溶液中加入甲苯，然后进行减压蒸馏以尽可能除去体系中的所述反应溶剂，然后选择性地向体系中加入甲苯，降至室温以下，再加入反溶剂，进行析晶并分离得到固体湿品；或者，直接对所述AHU377的产物溶液进行减压蒸馏除去反应溶剂得到油状物，再向油状物中加入甲苯并加热使油状物溶解，最后降至室温以下，加入所述反溶剂，进行析晶并分离得到固体湿品；
(b)将固体湿品置于温度40℃以下进行干燥以得到所述AHU377晶型III。
进一步地，所述的反溶剂可以为例如选自正庚烷、混合庚烷、环己烷中的一种或多种的组合。
优选地，所述的反应溶剂的沸点低于甲苯的沸点。常用的反应溶剂如二氯甲烷，丙酮，乙酸乙酯等。
根据本发明的一个具体方面，步骤(a)中，加入反溶剂后，搅拌熟化8小时以上，过滤，用反溶剂淋洗，得到固体湿品，所述方法还包括在实施一次步骤(a)和(b)之后，再重复进行一次或多次结晶，所述结晶是将前一步获得的干燥产物加热溶解于甲苯中，然后冷却至室温以下，加入反溶剂进行析晶，最后将析出晶体过滤后用反溶剂淋洗，干燥。
优选地，在45～55℃下进行所述减压蒸馏。
优选地，在10～25℃下进行析晶。
本发明的第三个目的是提供一种AHU377晶型IV，
Figure PCTCN2017076451-appb-000004
所述的晶型IV以CuKα射线测得的X射线粉末衍射图在2theta值为11.6°±0.2°,5.7°±0.2°,17.8°±0.2°处具有特征峰。
根据本发明的一个具体方面，所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为23.1°±0.2°,24.9°±0.2°,21.2°±0.2°中的一处或多处具有特征峰。优选地，所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为23.1°±0.2°,24.9°±0.2°,21.2°±0.2°处均具有特征峰。
根据本发明的另一个具体方面，所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为19.9°±0.2°,9.6°±0.2°,14.5°±0.2°中的一处或多处具有特征峰。优选地，所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为19.9°±0.2°,9.6°±0.2°,14.5°±0.2°处均具有特征峰。
根据一个最优选地方面，所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为23.1°±0.2°,24.9°±0.2°,21.2°±0.2°，19.9°±0.2°,9.6°±0.2°,14.5°±0.2°处均具有特征峰。在根据该方案的一个具体实施方式中，所述的晶型IV的X射线粉末衍射图基本上与图5一致。
本发明中，所述的晶型IV为单甲苯溶剂合物。其中，所述的单甲苯溶剂合物是指参与构成晶体晶格的甲苯的摩尔数与式(I)化合物的摩尔数相等。
还优选地，所述的晶型IV在被加热至180℃附近时，具有约17.8％的重量损失梯度，其热重分析图基本如图6所示。
还优选地，所述的晶型IV在被加热至48℃附近开始出现吸热峰，其差示扫描量热分析图基本如图7所示。
本发明的第四个目的是提供一种所述的AHU377晶型IV的制备方法，所述的晶型IV的制备方法包括方法(1)或方法(2)或方法(3)：
方法(1)、将本发明所述的晶型III在正庚烷和甲苯的混合溶液中搅拌以得到所 述的晶型IV；
方法(2)、所述方法以合成AHU377的产物溶液为起始物，所述合成AHU377产物溶液包含AHU377和合成AHU377时使用的反应溶剂，所述方法包括以下步骤：
向所述产物溶液中加入甲苯，然后进行减压蒸馏以尽可能除去体系中的所述反应溶剂，然后选择性地向体系中加入甲苯，降至室温以下，加入反溶剂，进行析晶并分离得到固体湿品；或者，直接对所述AHU377的产物溶液进行减压蒸馏除去反应溶剂得到油状物，再向油状物中加入甲苯并加热使油状物溶解，然后降至室温以下，最后加入所述反溶剂，进行析晶并分离得到固体湿品，所述固体湿品不经干燥直接作为终产物，或者再重复进行一次或多次结晶，得到终产物，所述结晶是将固体湿品干燥后加热溶解于甲苯中，然后降至室温以下，加入反溶剂进行析晶；
方法(3)、配制AHU377的甲苯溶液，并于室温以下搅拌，加入晶型IV的晶种，有固体析出，再选择性地滴加反溶剂，得到所述晶型IV。
根据本发明的一个方面，所述的晶型IV的制备方法包括方法(1)且还包括采用本发明上述的晶型III的制备方法来制备晶型III。
进一步地，方法(2)中，所述的反溶剂可以为选自正庚烷、混合庚烷、环己烷中的一种或多种的组合。优选地，所述的反应溶剂的沸点低于甲苯的沸点。常用的反应溶剂如二氯甲烷，丙酮，乙酸乙酯等。优选地，在45～55℃下进行所述减压蒸馏。优选地，在10～25℃下进行析晶。
优选地，在加入晶型IV的晶种后，以滴加方式加入反溶剂，滴加完毕后，进行熟化，最后离心，离心产物作为终产物。
本发明还提供又一种AHU377晶型III的制备方法，其包括将AHU377晶型IV置于40℃以下进行干燥的步骤。
鉴于本发明的AHU377晶型III和AHU377晶型IV之间的转化关系，因此，可以合理预测某些条件下实际得到的产物中既包含AHU377晶型III也包含AHU377晶型IV。
本发明的第5个目的是提供一种如上所述的晶型III或如上所述的晶型IV或其任意比例混合在制备AHU377与缬沙坦复合物中的用途。
本发明的第6个目的是提供一种AHU377与缬沙坦复合物的制备方法，其通过将如上所述的晶型III或如上所述的晶型IV或缬沙坦或其任意比例混合形成抗心衰药物。
由于上述技术方案的运用，本发明与现有技术相比具有如下优点：
本发明制备的AHU377的晶型III和晶型IV的稳定性好，引湿性低，除杂能力强，提纯效果好，具有很强的经济价值。
本发明制备的AHU377的晶型III和晶型IV可用于抗心衰药物LCZ696的制备。克服了现有技术中采用AHU377稠状物为起始物质导致难以转移和精确定量的困难，也简化了工艺流程，对于LCZ696的工业化生产和质量控制具有重大的意义。
附图说明
图1为实施例1制得的晶型III的XRPD图；
图2为实施例1制得的晶型III的TGA图；
图3为实施例1制得的晶型III的DSC图；
图4为实施例1制得的晶型III的1H NMR图；
图5为实施例4制得的晶型IV的XRPD图；
图6为实施例4制得的晶型IV的TGA图；
图7为实施例4制得的晶型IV的DSC图；
图8为实施例4制得的晶型IV的1H NMR图；
图9为实施例4制得的晶型IV的PLM图。
具体实施方式
以下结合具体实施例对本发明做进一步详细说明。应理解，这些实施例是用于说明本发明的基本原理、主要特征和优点，而本发明不受以下实施例的限制。实施例中采用的实施条件可以根据具体要求做进一步调整，未注明的实施条件通常为常规实验中的条件。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：液态核磁
PLM：偏光显微镜
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍 射仪上采集，测试温度采用常规温度，例如25℃。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Kα1
Figure PCTCN2017076451-appb-000005
1.540598；Kα2
Figure PCTCN2017076451-appb-000006
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q200上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min；
保护气体：氮气。
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min；
保护气体：氮气。
实施例1：AHU377晶型III的制备：
称取3.39kg合成AHU377的产物溶液(该产物溶液溶液中含有AHU377约726g，溶剂为二氯甲烷)于20L夹套反应釜中。加入7.5L甲苯，升至50℃，减压蒸馏至剩余5L体积，降至室温，补加2.5L甲苯，加入1.2L正庚烷，待有固体析出后，再将4.8L正庚烷滴加到釜中。搅拌熟化过夜，过滤并用1L正庚烷淋洗并于40℃真空干燥。将干燥得到的固体加入20L夹套反应釜中，加入8.5L甲苯，升至50℃溶清后降温至20℃。加入1.36L正庚烷出现浑浊，补加200mL甲苯并重新回升到50℃溶清，降温至20℃自发析晶。将5L正庚烷以8mL/min的速度滴加到釜中，搅拌熟化过夜。过滤并用1.5L正庚烷淋洗得到湿品，将湿品固体放置于40℃真空干燥，得到固体产物。
晶型III的核磁数据如下：1H NMR(400MHz,DMSO)δ12.09(s,1H),7.76(d,J＝8.4Hz,1H),7.67–7.63(m,2H),7.58(d,J＝8.2Hz,2H),7.45(t, J＝7.6Hz,2H),7.34(t,J＝7.3Hz,1H),7.25(dd,J＝7.8,3.7Hz,3H),7.15(dd,J＝15.5,7.4Hz,1H),4.04–3.85(m,3H),2.76–2.61(m,2H),2.38(t,J＝6.9Hz,2H),2.35–2.20(m,4H),1.76(ddd,J＝13.7,9.8,3.9Hz,1H),1.43–1.33(m,1H),1.11(t,J＝7.1Hz,3H),1.05(d,J＝7.1Hz,3H).
经检测，本实施例得到固体产物为晶型III，其X射线粉末衍射数据如表1所示。其XRPD图如图1，其TGA图如图2，其DSC图如图3，核磁如图4。
表1
theta d间隔 强度％
4.71 18.77 1.99
6.11 14.45 100.00
7.70 11.48 1.30
9.57 9.25 6.65
10.55 8.39 0.87
11.48 7.71 3.20
12.33 7.18 12.03
13.2 6.69 17.51
14.39 6.16 2.05
15.79 5.61 4.29
17.99 4.93 2.68
19.03 4.66 14.54
19.84 4.47 2.80
20.41 4.35 1.53
21.06 4.22 11.59
22.03 4.03 0.65
22.80 3.90 0.80
23.62 3.77 2.79
25.43 3.50 4.57
26.85 3.32 3.46
28.19 3.17 0.51
29.15 3.06 0.51
30.14 2.96 0.25
30.62 2.92 0.25
31.10 2.88 0.11
32.02 2.80 0.28
32.99 2.72 1.42
34.13 2.63 0.27
34.89 2.57 0.24
36.48 2.46 0.28
37.32 2.41 0.39
37.83 2.38 0.31
39.01 2.31 0.43
实施例2：晶型IV晶种的制备
将100mg实施例1制得的晶型III固体加入1mL正庚烷和甲苯体积比为1:1的混合溶液，室温搅拌过夜，离心得到固体产物。
经检测，本实施例得到固体产物为晶型IV，其X射线粉末衍射数据如表2所示。
表2
theta d间隔 强度％
5.75 15.38 87.56
9.60 9.21 92.32
11.60 7.63 87.80
14.49 6.11 40.80
15.11 5.86 39.24
17.36 5.11 59.16
17.81 4.98 96.99
18.31 4.85 67.58
20.03 4.43 96.99
21.21 4.19 100.00
23.23 3.83 83.08
24.96 3.57 41.91
27.77 3.21 20.06
29.09 3.07 10.55
实施例3：AHU377晶型IV的制备
称取3.39kg合成AHU377的产物溶液(该产物溶液中含有AHU377约726g，溶剂为二氯甲烷)。加入7.5L甲苯，升至50℃减压蒸馏至剩余5L体积，降至室温，补加2.5L甲苯。加入1.2L正庚烷，待析出固体后，将4.8L正庚烷滴加到釜中。搅拌熟化过夜，过滤并用1L正庚烷淋洗并于40℃真空干燥。将干燥得到的固体加入20L夹套反应釜中，加入8.5L甲苯，升至50℃溶清后降温至20℃。加入1.36L正庚烷出现浑浊，补加200mL甲苯并重新回升到50℃溶清，降温至20℃自发析晶。将5L正庚烷以8mL/min的速度滴加到釜中，搅拌熟化过夜。过滤并用1.5L正庚烷淋洗，得湿品固体产物。经检测，本实施例得到湿品固体产物与实施例2所得晶型为同一晶型，即晶型IV。
实施例4：AHU377晶型IV的制备
称取255.0g AHU377甲醇溶液(浓度为31.9％，由某批次制备的AHU377晶型III溶解于甲醇中得到)放置在50℃下减压蒸馏，浓缩至干。加入1L甲苯，搅拌溶清，减压浓缩至体积约为800mL，降温至室温，搅拌过夜。加入AHU377晶型IV晶种(可按照实施例3的方法获得)，快速浑浊析出固体。用计量泵加入500mL正庚烷，滴加速度为3mL/min。滴加完毕，继续熟化，离心得到固体产物。
核磁数据如下：1H NMR(400MHz,DMSO)δ12.09(s,1H),7.76(d,J＝8.4Hz,1H),7.67–7.62(m,2H),7.58(d,J＝8.2Hz,2H),7.45(t,J＝7.6Hz,2H),7.34(t,J＝7.3Hz,1H),7.28–7.22(m,5H),7.16(dd,J＝15.2,7.2Hz,4H),4.07–3.82(m,3H),2.77–2.60(m,2H),2.38(t,J＝6.8Hz,2H),2.32–2.24(m,6H),1.76(ddd,J＝13.8,9.8,4.1Hz,1H),1.43–1.34(m,1H),1.25(s,1H),1.11(t,J＝7.1Hz,3H),1.05(d,J＝7.1Hz,3H),0.86(t,J＝6.9Hz,0H).
经检测，本实施例得到固体产物为晶型IV，其X射线粉末衍射数据如表3所示。其XRPD图如图5，其TGA图如图6，其DSC图如图7，核磁如图8。
表3
theta d间隔 强度％
5.70 15.49 84.94
9.61 9.20 15.32
10.41 8.50 2.39
11.60 7.63 100.00
13.20 6.71 3.65
14.53 6.10 12.61
15.17 5.84 7.21
15.82 5.60 3.63
16.85 5.26 5.89
17.83 4.97 59.58
18.85 4.71 8.03
19.55 4.54 15.97
19.94 4.45 12.17
21.24 4.18 26.57
21.92 4.05 11.80
23.09 3.85 39.69
24.33 3.66 6.74
24.99 3.56 38.08
26.51 3.36 5.37
27.81 3.21 5.30
28.64 3.12 7.82
29.95 2.98 6.27
30.66 2.92 9.06
31.16 2.87 2.30
32.70 2.74 1.54
34.38 2.61 5.87
36.51 2.46 1.68
39.24 2.30 1.58
实施例5以AHU377晶型III为原料制备LCZ696的实施例
将24.3mg的AHU377晶型III与23.2mg的缬沙坦放置于玻璃小瓶中，再加入6.3mg NaOH，然后加2.0mL的丙酮，放置于室温下搅拌过夜，分离固体得到LCZ696。
实施例6以AHU377晶型IV为原料制备LCZ696的实施例
将26.2mg的AHU377晶型IV与23.0mg的缬沙坦放置于玻璃小瓶中，再加入 6.2mg NaOH，然后加2.0mL的丙酮，放置于室温下搅拌过夜，分离固体得到LCZ696。
实施例7AHU377晶型IV的PLM
将本发明实施例1得到的AHU377晶型IV进行偏光显微镜拍摄，如图9所示。从偏光显微镜的拍摄结果看，本发明的AHU377晶型IV呈片状，结晶形态良好，比现有技术的油状物具有明显的晶体形态优势。
实施例8AHU377晶型IV的提纯作用
AHU377晶型IV的制备能起到原料药提纯的作用。如晶型IV制备实施例4所示，通过HPLC纯度测试，纯度由96.05％提升至99.13％，提纯效果显著，如表6所示：
表4晶型IV提纯前后纯度对比
  起始原料 晶型IV
相对保留时间 面积(％) 面积(％)
0.64(杂质) 0.05 0.05
0.85(杂质) 0.05 0.03
1.00(AHU377) 96.05 99.13
1.24(杂质) 3.79 0.79
2.84(杂质) 0.05 \
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (22)

  1. AHU377晶型III，AHU377结构式如式(I)所示：
    Figure PCTCN2017076451-appb-100001
    其特征在于：所述的晶型III以CuKα射线测得的X射线粉末衍射图在2theta值为6.1°±0.2°,13.2°±0.2°,19.0°±0.2°处具有特征峰。
  2. 根据权利要求1所述的AHU377晶型III，其特征在于：所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为12.3°±0.2°,21.1°±0.2°,19.2°±0.2°中的一处或多处具有特征峰。
  3. 根据权利要求1或2所述的AHU377晶型III，其特征在于：所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为9.6°±0.2°,25.4°±0.2°,19.8°±0.2°中的一处或多处具有特征峰。
  4. 根据权利要求1所述的AHU377晶型III，其特征在于：所述的晶型III以CuKα射线测得的X射线粉末衍射图还在2theta值为12.3°±0.2°,21.1°±0.2°,19.2°±0.2°，9.6°±0.2°,25.4°±0.2°,19.8°±0.2°处具有特征峰。
  5. 根据权利要求1至4中任一项所述的AHU377晶型III，其特征在于：所述的晶型III为半甲苯溶剂合物。
  6. 一种如权利要求1至5中任一项所述的AHU377晶型III的制备方法，其特征在于：所述方法以合成AHU377的产物溶液为起始物，所述合成AHU377产物溶液包含AHU377和合成AHU377时使用的反应溶剂，所述方法包括以下步骤：
    (a)向所述产物溶液中加入甲苯，然后进行减压蒸馏以尽可能除去体系中的所述反应溶剂，然后选择性地向体系中加入甲苯，降至室温以下，再加入反溶剂，进行析晶并分离得到固体湿品；或者，直接对所述AHU377的产物溶液进行减压蒸馏除去反应溶剂得到油状物，再向油状物中加入甲苯并加热使油状物溶解，最后降至室温以下，加入所述反溶剂，进行析晶并分离得到固体湿品；
    (b)将固体湿品置于温度40℃以下进行干燥以得到所述AHU377晶型III。
  7. 根据权利要求6所述的AHU377晶型III的制备方法，其特征在于：所述的反溶剂为选自正庚烷、混合庚烷、环己烷中的一种或多种的组合。
  8. 根据权利要求6所述的AHU377晶型III的制备方法，其特征在于：所述的反应溶剂的沸点低于甲苯的沸点。
  9. 根据权利要求6至8中任一项所述的AHU377晶型III的制备方法，其特征在于：步骤(a)中，加入反溶剂后，搅拌熟化8小时以上，过滤，用反溶剂淋洗，得到固体湿品，所述方法还包括在实施一次步骤(a)和(b)之后，再重复进行一次或多次结晶，所述结晶是将前一步获得的干燥产物加热溶解于甲苯中，然后冷却至室温以下，加入反溶剂进行析晶，最后将析出晶体过滤后用反溶剂淋洗，干燥。
  10. AHU377晶型IV，AHU377的结构式如式(I)所示：
    Figure PCTCN2017076451-appb-100002
    其特征在于：所述的晶型IV以CuKα射线测得的X射线粉末衍射图在2theta值为11.6°±0.2°,5.7°±0.2°,17.8°±0.2°处具有特征峰。
  11. 根据权利要求10所述的AHU377晶型IV，其特征在于：所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为23.1°±0.2°,24.9°±0.2°,21.2°±0.2°中的一处或多处具有特征峰。
  12. 根据权利要求10或11所述的AHU377晶型IV，其特征在于：所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为19.9°±0.2°,9.6°±0.2°,14.5°±0.2°中的一处或多处具有特征峰。
  13. 根据权利要求10所述的AHU377晶型IV，其特征在于：所述的晶型IV以CuKα射线测得的X射线粉末衍射图还在2theta值为23.1°±0.2°,24.9°±0.2°,21.2°±0.2°，19.9°±0.2°,9.6°±0.2°,14.5°±0.2°处均具有特征峰。
  14. 根据权利要求10至13中任一项所述的AHU377晶型IV，其特征在于：所述的晶型IV为单甲苯溶剂合物。
  15. 一种如权利要求12至18中任一项所述的AHU377晶型IV的制备方法，其特征在于：所述的晶型IV的制备方法包括方法(1)或方法(2)或方法(3)：
    方法(1)、将权利要求1至5中任一项所述的晶型III在正庚烷和甲苯的混合溶液中搅拌以得到所述的晶型IV；
    方法(2)、所述方法以合成AHU377的产物溶液为起始物，所述合成AHU377产物溶液包含AHU377和合成AHU377时使用的反应溶剂，所述方法包括以下步骤：
    向所述产物溶液中加入甲苯，然后进行减压蒸馏以尽可能除去体系中的所述反应溶剂，然后选择性地向体系中加入甲苯，降至室温以下，加入反溶剂，进行析晶并分离得到固体湿品；或者，直接对所述AHU377的产物溶液进行减压蒸馏除去反应溶剂得到油状物，再向油状物中加入甲苯并加热使油状物溶解，然后降至室温以下，最后加入所述反溶剂，进行析晶并分离得到固体湿品，所述固体湿品不经干燥直接作为终产物，或者再重复进行一次或多次结晶，得到终产物，所述结晶是将固体湿品干燥后加热溶解于甲苯中，然后降至室温以下，加入反溶剂进行析晶；
    方法(3)、配制AHU377的甲苯溶液，并于室温以下搅拌，加入晶型IV的晶种，有固体析出，再选择性地滴加反溶剂，得到所述晶型IV。
  16. 根据权利要求15所述的AHU377晶型IV的制备方法，其特征在于：所述的晶型IV的制备方法包括方法(1)且还包括采用要求8至11中任一项所述的晶型III的制备方法来制备晶型III。
  17. 根据权利要求15所述的AHU377晶型IV的制备方法，其特征在于：方法(2)中，所述的反溶剂为选自正庚烷、混合庚烷、环己烷中的一种或多种的组合。
  18. 根据权利要求15所述的AHU377晶型IV的制备方法，其特征在于：方法(2)中，所述的反应溶剂的沸点低于甲苯的沸点。
  19. 根据权利要求15至18任一项所述的AHU377晶型IV的制备方法，其特征在于：在加入晶型IV的晶种后，以滴加方式加入反溶剂，滴加完毕后，进行熟化，最后离心，离心产物作为终产物。
  20. 一种如权利要求1至5中任一项所述的AHU377晶型III的制备方法，其特征在于：其包括将如权利要求10至14中任一项所述的AHU377晶型IV置于40℃以下进行干燥的步骤。
  21. 一种如权利要求1至5中任一项所述的晶型III或如权利要求10至14中任一项所述的晶型IV或其任意比例混合在制备AHU377与缬沙坦复合物中的用途。
  22. 一种AHU377与缬沙坦复合物的制备方法，其特征在于：其通过将如权利要求1至5中任一项所述的晶型III或如权利要求10至14中任一项所述的晶型IV或其任意比例混合与缬沙坦复合形成抗心衰药物。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110563607A (zh) * 2019-10-25 2019-12-13 许昌远志生物科技有限公司 一种mk-2866的精制方法
CN115315299A (zh) * 2020-07-13 2022-11-08 日本碍子株式会社 精制方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753733B (zh) * 2016-04-15 2019-06-18 苏州晶云药物科技股份有限公司 Ahu377的晶型及其制备方法与用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
CN105367438A (zh) * 2014-08-27 2016-03-02 上海翰森生物医药科技有限公司 AHU-377α-苯乙胺盐多晶型及其制备方法和应用
WO2016049663A1 (en) * 2014-12-08 2016-03-31 Crystal Pharmatech Inc. Crystalline forms of trisodium supramolecular complex comprising valsartan and ahu-377 and methods thereof
CN105753733A (zh) * 2016-04-15 2016-07-13 苏州晶云药物科技有限公司 Ahu377的晶型及其制备方法与用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230865B (zh) * 2013-06-13 2018-01-09 上海翰森生物医药科技有限公司 联芳基取代的4‑氨基丁酸衍生物及其制备方法和用途
CN106458857A (zh) * 2014-08-27 2017-02-22 上海翰森生物医药科技有限公司 AHU‑377结晶型游离酸、半钙盐、α﹣苯乙胺盐及其制备方法和应用
CN104557600B (zh) * 2015-01-26 2016-05-04 苏州明锐医药科技有限公司 沙库比曲的制备方法
AU2016236659B9 (en) * 2015-03-20 2019-05-02 Crystal Pharmatech Co., Ltd. AHU377 crystal form, preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
CN105367438A (zh) * 2014-08-27 2016-03-02 上海翰森生物医药科技有限公司 AHU-377α-苯乙胺盐多晶型及其制备方法和应用
WO2016049663A1 (en) * 2014-12-08 2016-03-31 Crystal Pharmatech Inc. Crystalline forms of trisodium supramolecular complex comprising valsartan and ahu-377 and methods thereof
CN105753733A (zh) * 2016-04-15 2016-07-13 苏州晶云药物科技有限公司 Ahu377的晶型及其制备方法与用途

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110563607A (zh) * 2019-10-25 2019-12-13 许昌远志生物科技有限公司 一种mk-2866的精制方法
CN115315299A (zh) * 2020-07-13 2022-11-08 日本碍子株式会社 精制方法
CN115315299B (zh) * 2020-07-13 2024-06-04 日本碍子株式会社 精制方法

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