WO2018141276A1 - Forme cristalline a de l'intermédiaire de brivaracétam et son procédé de préparation, forme cristalline c de brivaracétam et son procédé de préparation - Google Patents

Forme cristalline a de l'intermédiaire de brivaracétam et son procédé de préparation, forme cristalline c de brivaracétam et son procédé de préparation Download PDF

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WO2018141276A1
WO2018141276A1 PCT/CN2018/075177 CN2018075177W WO2018141276A1 WO 2018141276 A1 WO2018141276 A1 WO 2018141276A1 CN 2018075177 W CN2018075177 W CN 2018075177W WO 2018141276 A1 WO2018141276 A1 WO 2018141276A1
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solvent
compound
crystal form
preparation
mixed system
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PCT/CN2018/075177
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English (en)
Chinese (zh)
Inventor
李丕旭
王鹏
魏强
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苏州鹏旭医药科技有限公司
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Priority claimed from CN201710064673.7A external-priority patent/CN106866483A/zh
Priority claimed from CN201710118467.XA external-priority patent/CN107056643A/zh
Application filed by 苏州鹏旭医药科技有限公司 filed Critical 苏州鹏旭医药科技有限公司
Publication of WO2018141276A1 publication Critical patent/WO2018141276A1/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
    • A61K31/40—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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystalline form A of a basixamine intermediate, a preparation method thereof and a crystalline form C of bovistam and a preparation method thereof.
  • Epilepsy is a common disease of the nervous system. The incidence rate in the population is 0.6% to 1.1%, and 60% to 70% of patients still have seizures when taking anti-epileptic drugs, causing some patients to stop taking drugs themselves. At present, there are about 6 million epilepsy patients in China, and 650,000 to 700,000 new epilepsy patients each year, and about 25% are refractory epilepsy. Although the current diagnosis and treatment of epilepsy has made great progress, the number of patients with refractory epilepsy is increasing.
  • Generalized refractory epilepsy refers to the use of current anti-epileptic drugs (AEDs) to treat epilepsy and epilepsy syndrome that cannot be terminated or has been clinically proven to be refractory.
  • AEDs anti-epileptic drugs
  • Bovasitan English name: Brivaracetam
  • the structural formula is: Bovasistatin is a novel high-affinity synaptophysin 2A ligand that inhibits neuronal voltage-dependent sodium channels and is used to treat partial seizures of refractory epilepsy.
  • Phase II, phase III clinical trials of bovistam have a good effect. The incidence of major adverse events was similar to that of the placebo group, with mild to moderate fatigue, headache, nasopharyngitis, nausea, lethargy, and dizziness. No patients discontinued treatment due to adverse events.
  • the results indicate that bovistam tablets are effective and well tolerated in the adjuvant treatment of patients with refractory epilepsy with a prevalence of 16 to 65 years of age.
  • bovistam is a third-generation anti-epileptic drug with very good prospects after levetiracetam. It was approved for listing in the United States in February 2016.
  • Chiral HPLC purity separation requires expensive equipment and consumables and is not suitable for large scale production.
  • chiral HPLC purity separation if the yield is to be increased and the cost is reduced, it will inevitably lead to the collection of more isomer components, and the quality will be reduced.
  • the presence of a large amount of chiral impurities may cause adverse drug reactions and influence.
  • the safety of the drug In addition, the patent CN104892483A reports a method of asymmetric catalytic hydrogenation, but in which an expensive chiral ligand is used, the route is uneconomical.
  • CN106279074A, CN106365986A, CN106432030A and CN105646319A report the synthesis of bovistam from a chiral raw material which is readily available at low cost, the route does not involve expensive chiral catalysts or ligands, and does not require chiral HPLC purity separation and purification of the final product, Among them, compound I is an intermediate for the synthesis of bovistam, which is essential for the successful synthesis of high purity, high chiral purity of bovistam.
  • the structural formula of Compound I is:
  • the polymorph of a drug means that two or more different crystalline form states exist in the drug
  • the polymorph of the compound means that two or more different crystalline form states exist in the compound.
  • Polymorphism is widespread in drugs and organic compounds. Different crystal forms of the same drug or the same compound have significant differences in solubility, melting point, density, stability, etc., thereby affecting the stability and uniformity of the drug or compound to varying degrees, and affecting the drug for the drug. Bioavailability, efficacy and safety.
  • the research on the crystal form and purification process of the drug intermediate compound is beneficial to reduce the production cost of the active ingredient of the drug, improve the quality of the active ingredient of the drug, and ensure the quality and safety of the drug preparation. Therefore, in drug development, comprehensive systematic polymorph screening of drugs and drug intermediates, and selection of the most suitable crystal form, is one of the important research contents that cannot be ignored.
  • the invention provides a new crystal form of the bovastatin intermediate compound I, named as the crystal form A, and the crystal form A provided by the invention has the significant improvement effect on the purification of the compound I, and has good stability and process development.
  • the preparation method of crystal form A is simple and low in cost, and has important value for the production, purification and quality control of compound I, and is essential for obtaining bovastatin bulk drug of high purity and high chiral purity. .
  • the invention also provides a new crystal form of basistatin, named as crystal form C, and the crystal form C provided by the invention has favorable properties such as good stability, process development and easy handling, and the preparation method is simple and the cost is Low cost and valuable for the development and formulation optimization of bovistam.
  • the present invention adopts the following technical solutions:
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.4 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, 28.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 14.0 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, and 36.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is also 2theta value of 17.4 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, 28.1 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 ° , with characteristic peaks at 36.5 ° ⁇ 0.2 °.
  • its X-ray powder diffraction pattern is substantially identical to that of FIG.
  • the content of the enantiomer and the diastereomer are not more than 2.5%.
  • Diastereomers of Compound I include those represented by the following structural formula:
  • the content of both the enantiomeric and diastereomers is not more than 1.0%.
  • the content of both the enantiomeric and diastereomers is not more than 0.5%.
  • the content of both enantiomers and diastereomers is not more than 0.15%.
  • Another object of the present invention is to provide a process for the preparation of Form A of Compound I, which comprises adding a powder of Compound I to a mixed system of one or more solvents for crystallization.
  • the crystallization method includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is a mixed system of an ether solvent and an aliphatic hydrocarbon solvent, preferably a mixed system of tetrahydrofuran and n-heptane.
  • the method of crystallization is a heating and cooling method, and the specific process comprises: adding the compound I powder to the first solvent, raising the temperature to 50 to 60 ° C, stirring, and then adding the second solvent. Cooling to 0-10 ° C, filtration, the obtained filter cake is dried to obtain the crystal form A, wherein the first solvent is water, alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogen a mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, an aliphatic hydrocarbon solvent; the second solvent is water, an alcohol, an ether, a ketone, an ester, an aromatic hydrocarbon, a halogen A mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, and an aliphatic hydrocarbon solvent.
  • the first solvent is water, alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogen a mixed system of one or more of a
  • the first solvent and the second solvent are different solvents.
  • the first solvent is a mixed system of one or more of an ether, a ketone, and a nitrile; and the second solvent is an aliphatic hydrocarbon, an ether, or one of water or Several hybrid systems.
  • the first solvent is a mixed system of one or more of tetrahydrofuran, acetone, acetonitrile;
  • the second solvent is n-heptane, methylcyclohexane, methyl t-butyl A mixed system of one or more of ether and water.
  • a third object of the present invention is to provide a use of the crystalline form A of the compound I as an intermediate for the synthesis of bovistam.
  • a fourth object of the present invention is to provide a crystalline form C of bovistam with an X-ray powder diffraction pattern having a value of 15.7 ° ⁇ 0.2 °, 17.4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 26.9 °. There is a characteristic peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 8.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, and 21.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.0 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 °, and 25.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is also 2theta values of 8.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 ° , with characteristic peaks at 25.0 ° ⁇ 0.2 °.
  • its X-ray powder diffraction pattern is substantially identical to that of FIG.
  • a fifth object of the present invention is to provide a process for preparing bovistam form C, which comprises adding bovistam powder to a mixed system of one or more solvents for crystallization.
  • the method of crystallization includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.
  • the solvent is one selected from the group consisting of an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent. Mixed system of one kind or several kinds.
  • the solvent is methyl tert-butyl ether.
  • a sixth object of the present invention is to provide a pharmaceutical composition comprising an effective amount of said crystalline form C of bovistam and a pharmaceutically acceptable excipient.
  • a seventh object of the present invention is to provide the use of said crystalline form C of bovistam or said pharmaceutical composition for the preparation of a pharmaceutical preparation for the treatment of epilepsy.
  • the new crystalline form (crystal form A) of the bovastatin intermediate compound I provided by the invention has remarkable purification effect and good stability;
  • the crystallization method of the crystal form A provided by the present invention can effectively control the enantiomeric and diastereomers in the compound I to 2.5% or less, further, 1.0% or less, further, 0.5% or less, further, 0.15. %the following;
  • the high chiral purity compound I obtained by the crystallization method provided by the invention can be used to produce bovastatin with high chiral purity, improve the chiral purity of the final active ingredient of the drug, and reduce the potential adverse reaction caused by chiral impurities. Thereby improving the safety of the drug;
  • the preparation method of the crystal form A provided by the invention is simple and reproducible, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.
  • the novel crystalline form of Bevastatin (Form C) provided by the present invention is better than the crystalline forms A and B of Bovaciltam disclosed by U.S. Patent No. 6,784,197. Stability, suitable for long-term storage and industrial production, to provide more and better choice for the subsequent development of drugs.
  • the crystallization method of the crystal form C provided by the invention can effectively control the impurities to be less than 0.10%;
  • the crystallization of the process provided by the patent US 6,784,197 is carried out using isopropyl ether, which presents a potential hazard in industrial scale-up.
  • the preparation method of the crystal form C provided by the invention is simple and reproducible, avoids the use of dangerous solvents, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.
  • Example 2 is a TGA chart and a DSC chart overlay of Compound I Form A of Example 1.
  • Figure 3 is an XRPD pattern of the Bovaxitan Form C.
  • test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the method of WO2016191435.
  • the X-ray powder diffraction pattern of the present invention was collected on a PANalytical Empyrean X-ray diffraction powder diffractometer.
  • 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) of the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme cristalline d'un composé (I) qui est un intermédiaire de brivaracétam et son procédé de préparation, ainsi qu'une nouvelle forme cristalline de brivaracétam et son procédé de préparation. L'invention concerne particulièrement, une forme cristalline A du composé I et une forme cristalline C de brivaracétam. La forme cristalline A selon la présente invention, présente des propriétés bénéfiques telle qu'une bonne stabilité, une propriété développée de manière technologique et une facilité de traitement; en outre, la forme cristalline A de la présente invention, possède la particularité d'un procédé de préparation simple et à faibles coûts, et présente une valeur significative pour la production, la purification et le contrôle de qualité des principes actifs du médicament. La forme cristalline C selon la présente invention, présente des propriétés bénéfiques telle qu'une bonne stabilité, une propriété développée de manière technologique et une facilité de traitement; en outre, la forme cristalline C de la présente invention, possède la particularité d'un procédé de préparation simple et à faibles coûts, et présente une valeur significative pour la production, la purification et le contrôle de qualité des principes actifs du médicament.
PCT/CN2018/075177 2017-02-05 2018-02-03 Forme cristalline a de l'intermédiaire de brivaracétam et son procédé de préparation, forme cristalline c de brivaracétam et son procédé de préparation WO2018141276A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710064673.7 2017-02-05
CN201710064673.7A CN106866483A (zh) 2017-02-05 2017-02-05 布瓦西坦的晶型c及其制备方法
CN201710118467.X 2017-03-01
CN201710118467.XA CN107056643A (zh) 2017-03-01 2017-03-01 一种化合物的晶型a及其制备纯化方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020148787A1 (fr) * 2019-01-17 2020-07-23 Clininvent Research Pvt. Ltd. Synthèse énantiosélective de brivaracétam et de ses intermédiaires
CN111943880A (zh) * 2019-05-14 2020-11-17 浙江京新药业股份有限公司 一种布瓦西坦晶体及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1404469A (zh) * 2000-02-23 2003-03-19 Ucb公司 2－氧代－1－吡咯烷衍生物、其制备方法和用途
WO2016191435A1 (fr) * 2015-05-25 2016-12-01 Peng Wang Procédés de production du brivaracetam
CN106866483A (zh) * 2017-02-05 2017-06-20 苏州鹏旭医药科技有限公司 布瓦西坦的晶型c及其制备方法
CN107056643A (zh) * 2017-03-01 2017-08-18 苏州鹏旭医药科技有限公司 一种化合物的晶型a及其制备纯化方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1404469A (zh) * 2000-02-23 2003-03-19 Ucb公司 2－氧代－1－吡咯烷衍生物、其制备方法和用途
WO2016191435A1 (fr) * 2015-05-25 2016-12-01 Peng Wang Procédés de production du brivaracetam
CN106866483A (zh) * 2017-02-05 2017-06-20 苏州鹏旭医药科技有限公司 布瓦西坦的晶型c及其制备方法
CN107056643A (zh) * 2017-03-01 2017-08-18 苏州鹏旭医药科技有限公司 一种化合物的晶型a及其制备纯化方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020148787A1 (fr) * 2019-01-17 2020-07-23 Clininvent Research Pvt. Ltd. Synthèse énantiosélective de brivaracétam et de ses intermédiaires
CN111943880A (zh) * 2019-05-14 2020-11-17 浙江京新药业股份有限公司 一种布瓦西坦晶体及其制备方法和应用

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