WO2021043200A1 - Procédé de préparation d'un dérivé de quinazoline et cristallisation de ce dernier - Google Patents

Procédé de préparation d'un dérivé de quinazoline et cristallisation de ce dernier Download PDF

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WO2021043200A1
WO2021043200A1 PCT/CN2020/113178 CN2020113178W WO2021043200A1 WO 2021043200 A1 WO2021043200 A1 WO 2021043200A1 CN 2020113178 W CN2020113178 W CN 2020113178W WO 2021043200 A1 WO2021043200 A1 WO 2021043200A1
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optionally
compound
reducing agent
preparation
acid
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PCT/CN2020/113178
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English (en)
Chinese (zh)
Inventor
汤松
刘飞
朱益忠
赵玮
朱波
王路路
王璇
项立伟
魏强强
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
首药控股(北京)有限公司
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Priority to CN202080057886.7A priority Critical patent/CN114401957B/zh
Publication of WO2021043200A1 publication Critical patent/WO2021043200A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This application relates to the field of drug synthesis, in particular to a preparation method and crystallization of quinazoline derivatives.
  • Epidermal growth factor receptor is a tyrosine kinase receptor, which is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells.
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Loss of function of protein tyrosine kinases such as EGFR or abnormal activity or cell localization of key factors in related signal pathways can cause tumors, diabetes, immunodeficiency and cardiovascular diseases.
  • WO201615340A1 discloses a related compound.
  • Example 1 discloses the synthesis of a compound of formula (I). The method is obtained by reacting a synthesized compound of formula (I-1) with tert-butyl 4-oxopiperidine-1-carboxylate The compound of formula (I-2) is deprotected from the compound of formula (I-2) to obtain the compound of formula (I-3), which is then reacted with acryloyl chloride to obtain the compound of formula (I),
  • Steps 1-5 of Example 1 disclose the synthesis method of the compound of formula (I-1).
  • the method disclosed in WO201615340A1 first introduces the protective group of the 3,4-dimethoxybenzyl group, then introduces the protective group of the tert-butoxycarbonyl group, then removes the protective group, and finally connects the 1-acryloyl group to obtain the target
  • the preparation method is complicated, the yield is low, and it is difficult to meet the requirements of industrial production. Therefore, there is still a need for a better preparation method of the compound of formula (I).
  • the drug has excellent properties in the following aspects: drug activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, ease of preparation, etc., so as to meet the requirements of drug production, storage and Therefore, there is also a need to develop crystals of the compound of formula (I).
  • this application provides a method for preparing a compound of formula (I), which comprises reacting compound A and compound B in the presence of a reducing agent to obtain a compound of formula (I)
  • the molar ratio of reducing agent to compound A is 1 to 5:1. In some embodiments, the molar ratio of reducing agent to compound A is 1.5-3:1. In some embodiments, the molar ratio of reducing agent to compound A is 2:1.
  • the reducing agent is selected from sodium triacetoxyborohydride or sodium cyanoborohydride. In some embodiments, the reducing agent is sodium triacetoxyborohydride.
  • the molar ratio of compound B to compound A is 0.5-2:1. In some embodiments, the molar ratio of compound B to compound A is 0.8 to 1.5:1. In some embodiments, the molar ratio of compound B to compound A is 1.1 to 1.3:1. In some embodiments, wherein the molar ratio of compound B to compound A is 1.2:1. In some embodiments, wherein the molar ratio of compound B to compound A is 1.3:1.
  • the above preparation method reaction further includes an acid.
  • the acid is selected from trifluoroacetic acid, acetic acid, hydrochloric acid, or sulfuric acid. In some embodiments, the acid is selected from trifluoroacetic acid or acetic acid. In some embodiments, the acid is selected from trifluoroacetic acid.
  • the molar ratio of acid to compound A is 1-10:1. In some embodiments, the molar ratio of acid to compound A is 2-5:1. In some embodiments, the molar ratio of acid to compound A is 2.5 to 4.5:1. In some embodiments, wherein the molar ratio of acid to compound A is 4.3:1. In some embodiments, wherein the molar ratio of acid to compound A is 2.8:1.
  • the reducing agent in the above preparation method, is added to the reaction system at one time or divided into multiple times. In some embodiments, the reducing agent is divided into multiple parts (for example, each part has the same weight) and then added to the reaction system separately. In some embodiments, the reducing agent is divided into 2-10 parts and then added to the reaction system respectively. For example, the reducing agent is divided into 2, 3, 4, 5 or 6 parts and then added to the reaction system respectively. In some embodiments, the reducing agent is divided into 5 or 6 parts and then added to the reaction system separately. In some embodiments, the reducing agent is divided into 6 parts and then added to the reaction system separately.
  • the reducing agent is divided into 6 parts and then added to the reaction system, wherein 5 parts (for example, each part has the same weight) are added separately in 5 times (for example, 1 hour in total), and then reacted for a period of time (for example, 3 parts). ⁇ 6 hours, 4 ⁇ 5 hours or 4 hours), and then add the sixth part of the reducing agent to the reaction system.
  • the reaction is carried out in the presence of a solvent.
  • the solvent is selected from a mixture of one or more of 1,2-dichloroethane, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, or ethanol.
  • the solvent in the above preparation method, is selected from one of 1,2-dichloroethane or dichloromethane or a mixture thereof.
  • the solvent is selected from 1,2-dichloroethane.
  • the solvent is selected from dichloromethane.
  • the reaction in the above preparation method, is performed at 10-50°C. In some embodiments, the above reaction is carried out at 20-30°C. In some embodiments, the above reaction is carried out at 20-30°C. In some embodiments, the above-mentioned reactions are reacted under room temperature conditions.
  • the reaction time of the reaction is 1-12 hours. In some embodiments, the reaction time of the above reaction is 4-10 hours. In some embodiments, the reaction time of the above reaction is 7-9 hours. In some embodiments, the reaction time of the above reaction is 6-8 hours.
  • the reaction time of the reaction is: adding a reducing agent to react for 1 to 6 hours, and then adding a reducing agent to react for 1 to 6 hours. In some embodiments, the reaction time of the above-mentioned reaction is: after adding a reducing agent to react for 2 to 5 hours, then adding a reducing agent to react for 2 to 5 hours. In some embodiments, the reaction time of the above reaction is: adding a reducing agent to react for 4 to 5 hours, and then adding a reducing agent to react for 2 to 4 hours. In some embodiments, the reaction time of the above reaction is 4 hours after the addition of the reducing agent is completed, and 2 to 4 hours after the addition of the reducing agent is completed.
  • the above-mentioned preparation method further includes the step of adding an organic solvent to dilute after the completion of the reaction, and then adding an alkali treatment.
  • the above-mentioned organic solvent is selected from water-immiscible organic solvents or a mixed organic solvent of water-immiscible organic solvents and methanol.
  • the above organic solvent is selected from a mixed organic solvent of one or more of 1,2-dichloroethane, dichloromethane, chloroform, or methanol.
  • the above preparation method further includes the step of adding an organic solvent immiscible with water to dilute after the completion of the reaction, and then adding an alkali treatment.
  • the above-mentioned preparation method further includes a step of adding a mixed organic solvent to dilute after the completion of the reaction, and then adding an alkali treatment.
  • the method of adding alkali treatment is: adding alkali in the form of an aqueous solution, and then separating the organic layer.
  • the base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, or potassium bicarbonate.
  • the base is sodium bicarbonate.
  • the method of adding alkali treatment is: adding alkali in the form of saturated sodium bicarbonate aqueous solution, and then separating the organic layer.
  • the water-immiscible organic solvent is selected from a mixture of one or more of 1,2-dichloroethane, dichloromethane, or chloroform. In some embodiments, the water-immiscible organic solvent is dichloromethane. In some embodiments, in the above preparation method, after adding water-immiscible organic solvent for dilution, water may be further added for mixing, and then the organic layer may be separated.
  • a saturated aqueous sodium chloride solution may be further added for mixing, and then the organic layer may be separated.
  • the mixed organic solvent is selected from a mixed organic solvent of one or more of 1,2-dichloroethane, dichloromethane, or chloroform and methanol.
  • the organic solvent added after the reaction is completed is selected from a mixed organic solvent of dichloromethane and methanol.
  • a saturated aqueous sodium chloride solution can be further added for mixing, and then the organic layer is separated.
  • the above preparation method includes the step of purifying the compound of formula (I) with isopropyl ether.
  • the above preparation method includes the step of separating the compound of formula (I) from isopropyl ether.
  • the above-mentioned preparation method includes after the reaction is completed, the reaction solution after alkali treatment is concentrated, optionally dried before concentration, and then isopropyl ether is added, and after isopropyl ether is added, optionally, Heating at 40-60°C, or heating and stirring at 50 ⁇ 2°C (for example, beating).
  • the above-mentioned preparation method after the above-mentioned preparation method has completed the reaction and treated with a base, it further includes dissolving the compound of formula (I) in an organic solvent, then adding the base, and stirring the reaction under heating.
  • the above-mentioned organic solvent is selected from tetrahydrofuran or acetone.
  • the above-mentioned organic solvent is selected from tetrahydrofuran.
  • the aforementioned base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, or potassium bicarbonate.
  • the aforementioned base is selected from potassium carbonate.
  • the above-mentioned stirring is under the condition of heating to 40-80°C; in some embodiments, the above-mentioned stirring is under the condition of heating to 60°C.
  • the organic layer is separated after cooling and concentrated to dryness. Further, the obtained concentrate is mixed with methanol with one or more of 1,2-dichloroethane, dichloromethane or chloroform, and the obtained solution is washed with water. In some embodiments, the resulting concentrate is added to a mixture of dichloromethane and methanol, and the resulting solution is washed with water.
  • the compound A of the present application can be obtained commercially, or can be prepared by a method of the prior art.
  • Compound A of the present application is prepared by the following method:
  • the method for preparing compound A described above, wherein the reducing agent is FeCl 3 and hydrazine hydrate.
  • the method for preparing compound A described above, wherein the reducing agent is Raney nickel/hydrogen.
  • the preparation method of compound A described above, wherein the reaction is carried out in the presence of ammonium chloride is carried out in the presence of ammonium chloride.
  • the compound B of the present application can be obtained commercially, or can be prepared by the method of the prior art.
  • Compound B of the present application is prepared by the following method:
  • this application also provides a type A crystal of the compound of formula (I), which is characterized in that in the X-ray powder diffraction pattern of Cu K ⁇ radiation, the 2 ⁇ value is expressed as 11.01° ⁇ 0.2°, 11.78° ⁇ There are diffraction peaks at 0.2°, 19.57° ⁇ 0.2°, 20.32° ⁇ 0.2°, 22.08° ⁇ 0.2°, and 23.27° ⁇ 0.2°; in some embodiments, it is characterized by using Cu K ⁇ radiation X-ray powder In the diffraction pattern, the 2 ⁇ values are expressed in 7.39° ⁇ 0.2°, 11.01° ⁇ 0.2°, 11.78° ⁇ 0.2°, 16.17° ⁇ 0.2°, 16.66° ⁇ 0.2°, 19.35° ⁇ 0.2°, 19.57° ⁇ 0.2° There are diffraction peaks at 20.32° ⁇ 0.2°, 20.59° ⁇ 0.2°, 21.52° ⁇ 0.2°, 22.08° ⁇ 0.2°, 22.34° ⁇ 0.2°, 23.27° ⁇ 0.2° and 24.57° ⁇ 0.2
  • the XRPD pattern of the type A crystal of the compound of formula (I) is shown in FIG. 1.
  • this application also provides the B-type crystal of the compound of formula (I), which is characterized in that the X-ray powder diffraction pattern of Cu K ⁇ radiation is represented by the 2 ⁇ value at 10.15° ⁇ 0.2°, 20.65° ⁇ There are diffraction peaks at 0.2°, 21.43° ⁇ 0.2° and 22.47° ⁇ 0.2°; in some embodiments, it is characterized in that in the X-ray powder diffraction pattern using Cu K ⁇ radiation, the 2 ⁇ value is expressed at 9.59° ⁇ 0.2°, 10.15° ⁇ 0.2°, 10.69° ⁇ 0.2°, 13.85° ⁇ 0.2°, 17.09° ⁇ 0.2°, 17.38° ⁇ 0.2°, 19.53° ⁇ 0.2°, 20.65° ⁇ 0.2°, 21.43° ⁇ 0.2° There are diffraction peaks at 22.47° ⁇ 0.2° and 27.85 ⁇ 0.2°; in some embodiments, it is characterized in that in the X-ray powder diffraction pattern using Cu K ⁇ radiation, the 2 ⁇ value is expressed at 9.
  • the XRPD pattern of the type B crystal of the compound of formula (I) is shown in FIG. 2.
  • the instrument model for X-ray powder diffraction spectrometry is Bruker D2 X-ray diffractometer, light tube: Cu, K-Alpha, (u, ).
  • this application provides a method for preparing the type A crystal of the compound of formula (I): including the step of precipitating the type A crystal of the compound of formula (I) in a mixed solvent of ethyl acetate and ethanol.
  • the type A crystal of the compound of formula (I) of the present application is prepared by the following method:
  • the volume ratio of ethanol to ethyl acetate is 10-1:1, preferably 5-2:1, and most preferably 3:1.
  • the crystallization in step (2) is performed at 20-30°C.
  • the present application provides a method for preparing the type B crystal of the compound of formula (I): comprising precipitating the type A crystal of the compound of formula (I) in a mixed solvent of N,N-dimethylformamide and acetonitrile A step of.
  • the type B crystal of the compound of formula (I) of the present application is prepared by the following method:
  • the volume ratio of acetonitrile to N,N-dimethylformamide is 5 to 0.5:1, preferably 3 to 1:1, most preferably 2:1.
  • the crystallization in step (2) is performed at 20-30°C.
  • the present application provides a crystalline composition comprising the type A crystal or the type B crystal of the compound of formula I, wherein the type A crystal or the type B crystal of the compound of formula I accounts for 50% of the weight of the crystalline composition Above, it is preferably at least 80%, more preferably at least 90%, most preferably at least 95%.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of the type A crystal or type B crystal of the compound of formula I described herein, or the type A crystal or type B crystal of the compound of formula I described herein.
  • Type crystal crystalline composition The pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the present application provides a crystal composition of a type A crystal or a type B crystal of a compound of formula I, a crystal composition of a type A crystal or a type B crystal of a compound of formula I, or a pharmaceutical composition thereof in preparation for treatment and/or prevention. Use in tumor medicine.
  • the relative intensity of diffraction peaks can be changed due to the preferred orientation caused by factors such as crystal morphology, which is well known in the field of crystallography. Where there is the influence of the preferred orientation, the peak intensity is changed, but the position of the diffraction peak of the crystal form cannot be changed.
  • there may be a slight error in the position of the peak which is also well known in the field of crystallography. For example, due to temperature changes during sample analysis, sample movement, or instrument calibration, etc., the peak position can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2 degrees. Therefore, those skilled in the art are well-known in determining each crystal When constructing, this error should be taken into account.
  • the method for preparing the compound of formula (I) provided in the present application reacts compound A and compound B in one step to obtain the target compound, does not require the steps of introducing and removing protective groups, is simple in operation, and has a significantly improved yield, which can meet the requirements of industrial production.
  • Fig. 2 The crystal XRPD pattern of the compound of formula (I) prepared in Example 4.
  • HPLC conditions According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) test, octadecylsilane bonded silica gel is used as filler (Waters XBridge Shield RP18, 150 ⁇ 4.6mm, 3.5 ⁇ m or equivalent chromatogram Column); Use 0.01mol/L ammonium formate buffer (take 0.63g of ammonium formate, add 1000ml of water to dissolve, add 1ml of formic acid, adjust the pH to 7.4 with triethylamine) as mobile phase A, and acetonitrile as mobile phase B.
  • the detection wavelength is 260nm.
  • the compound of formula (I) (65.4 g) and absolute ethanol (654 mL) were sequentially added to the reaction flask, the stirring was turned on, the temperature was raised to 80° C., ethyl acetate (218 mL) was added, and the mixture was stirred until it was clear. After the solution is clear, the temperature starts to cool naturally, and the mixture is stirred and crystallized for 20-24 hours, and then filtration is started. The filter cake is washed with absolute ethanol (50 mL) and dried under vacuum at 60° C. for 12 hours.
  • the compound of formula (I) (55.6 g, yield 85%) was obtained as a light yellow solid powder, and its X-ray powder diffraction pattern using Cu K ⁇ radiation is shown in FIG. 1.
  • the compound of formula (I) (41g) and N,N-dimethylformamide (82mL) were sequentially added to the reaction flask, the stirring was turned on, the temperature was raised to 80° C., and the mixture was stirred until the solution was clear. After dissolving, add acetonitrile (164mL) and start to cool down naturally, stir and crystallize for 8-12 hours, then start to filter, the filter cake is washed with a small amount of acetonitrile, and vacuum dried at 60°C for 12 hours.
  • the compound of formula (I) (35.5 g, yield 86.6%) was obtained as a light yellow solid powder, and its X-ray powder diffraction pattern using Cu K ⁇ radiation is shown in FIG. 2.

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Abstract

La présente invention concerne le domaine de la synthèse de médicaments et se rapporte spécifiquement à un procédé de préparation d'un dérivé de quinazoline et la cristallisation de celui-ci, et plus spécifiquement un procédé de préparation d'un composé représenté par la formule (I) et sa cristallisation. Le procédé décrit est facile à mettre en oeuvre, a un rendement significativement accru, et peut satisfaire aux exigences de la production industrielle.
PCT/CN2020/113178 2019-09-04 2020-09-03 Procédé de préparation d'un dérivé de quinazoline et cristallisation de ce dernier WO2021043200A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN107556295A (zh) * 2013-09-28 2018-01-09 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
CN107892684A (zh) * 2013-07-18 2018-04-10 锦州奥鸿药业有限责任公司 喹唑啉衍生物及其药物组合物，以及作为药物的用途
WO2018103058A1 (fr) * 2016-12-09 2018-06-14 Janssen Pharmaceutica Nv Inhibiteurs de tyrosine kinase de bruton et leurs procédés d'utilisation
CN107406430B (zh) * 2015-03-20 2019-04-26 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法

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JO3793B1 (ar) * 2015-12-10 2021-01-31 Janssen Pharmaceutica Nv مثبطات تيروزين كاينيز بروتون وأساليب استخدامها

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CN107892684A (zh) * 2013-07-18 2018-04-10 锦州奥鸿药业有限责任公司 喹唑啉衍生物及其药物组合物，以及作为药物的用途
CN107556295A (zh) * 2013-09-28 2018-01-09 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
CN107406430B (zh) * 2015-03-20 2019-04-26 正大天晴药业集团股份有限公司 喹唑啉衍生物的盐及其制备方法
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HAMMILL JARED T., SCOTT DANIEL C., MIN JAEKI, CONNELLY MICHELE C., HOLBROOK GLORIA, ZHU FANGYI, MATHENY AMY, YANG LEI, SINGH BHUVA: "Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 7, 16 March 2018 (2018-03-16), pages 2680 - 2693, XP055787832, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01277 *

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