WO2017177781A1 - Formes cristallines d'ahu377, leur procédé de préparation et leur utilisation - Google Patents

Formes cristallines d'ahu377, leur procédé de préparation et leur utilisation Download PDF

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Publication number
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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Prior art keywords
ahu377
crystal form
solvent
toluene
form iii
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PCT/CN2017/076451
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English (en)
Chinese (zh)
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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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Publication of WO2017177781A1 publication Critical patent/WO2017177781A1/fr

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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:

Abstract

La présente invention concerne des formes cristallines d'AHU377, un procédé de préparation de celles-ci et leur utilisation. L'invention concerne des formes cristallines III et IV d'AHU377 ; lesdites formes cristallines III et IV présentant une bonne stabilité, une faible hygroscopicité, une capacité élevée d'élimination des impuretés, un bon effet de purification, et ont une valeur économique très élevée.
PCT/CN2017/076451 2016-04-15 2017-03-13 Formes cristallines d'ahu377, leur procédé de préparation et leur utilisation WO2017177781A1 (fr)

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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

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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

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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
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WO2016029828A1 (fr) * 2014-08-27 2016-03-03 上海翰森生物医药科技有限公司 Acide crystallin libre, sel hemicalcique et sel d'alpha-phényléthylamine de ahu-377 et son procédé de préparation et son application
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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 (fr) * 2014-12-08 2016-03-31 Crystal Pharmatech Inc. Formes cristallines de complexe supramoléculaire de trisodium comprenant du valsartan et ahu-377 ainsi que procédés associés
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 (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

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