WO2022199576A1 - Procédé de préparation de midostaurine de haute pureté - Google Patents

Procédé de préparation de midostaurine de haute pureté Download PDF

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WO2022199576A1
WO2022199576A1 PCT/CN2022/082265 CN2022082265W WO2022199576A1 WO 2022199576 A1 WO2022199576 A1 WO 2022199576A1 CN 2022082265 W CN2022082265 W CN 2022082265W WO 2022199576 A1 WO2022199576 A1 WO 2022199576A1
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Prior art keywords
midostaurin
formula
solvent
preparation
reaction
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PCT/CN2022/082265
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English (en)
Chinese (zh)
Inventor
张富昌
郭万成
段永立
信铭雁
王国平
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扬州联澳生物医药有限公司
奥锐特药业(天津)有限公司
扬州奥锐特药业有限公司
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Publication of WO2022199576A1 publication Critical patent/WO2022199576A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8624—Detection of slopes or peaks; baseline correction
    • G01N30/8631—Peaks
    • G01N30/8637—Peak shape
    • 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
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of high-purity midostaurin.
  • Midostaurin is an oral PKC inhibitor from Novartis. The FDA approved it on April 28, 2017, in combination with chemotherapy for newly diagnosed FLT3-positive acute myeloid leukemia (AML). Its structural formula is as follows:
  • WO2006048296 The preparation method disclosed in WO2006048296 is shown in the following route 2.
  • This route uses benzoic anhydride to condense at a high temperature in a mixed solvent of ethanol and water, and the yield is only about 82%, and may require multiple purifications, and the relevant impurities are unknown;
  • the preparation method disclosed in WO2019215759 is shown in the following route 5.
  • the condensation reaction of this route 5 uses an expensive and explosive condensing agent HBTU, and the yield is only 70%.
  • WO2020200945A1 pointed out that after a long-term stability test in a pressurized air environment, the oxidized impurities of midostaurin were significantly increased.
  • This patent discloses that after purifying the crude product midostaurin with a purity of 99.08% in a yield of 95%, the product midostaurin with a yield of 99.69% is finally obtained in a yield of 85%. It can be seen that a slight increase in the purity of midostaurin will lead to a significant decrease in its yield.
  • the technical problem to be solved by the present invention is that the preparation method of midostaurin in the prior art has the defects of high environmental hazard, many impurities, unbalanced yield and purity, and unfavorable industrial production, and provides a high-purity rice
  • the preparation method of dostaurin does not need to use toxic and expensive reagents, and the reaction conditions are mild, the obtained product has high yield and high purity, and is suitable for industrial production.
  • a preparation method of high-purity midostaurin comprising the steps:
  • the base is an inorganic base.
  • the base (such as an inorganic base) is selected from the group consisting of alkali metal carbonate, alkali metal phosphate, alkali metal hydrogen carbonate, alkali metal hydrogen phosphate, or a combination thereof .
  • the alkali metals are each independently selected from the group consisting of lithium, sodium, potassium or cesium.
  • the alkali metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof.
  • the alkali metal phosphate is potassium phosphate.
  • the alkali metal bicarbonate is selected from the group consisting of sodium hydrogen phosphate, potassium hydrogen phosphate, or a combination thereof.
  • the base eg, inorganic base
  • the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, or a combination thereof.
  • the molar ratio of the base to the compound represented by formula N-1 is (1.5-5):1; preferably, (2-3):1.
  • the pyrrolidone-based solvent is NMP (N-methylpyrrolidone).
  • the amount of the pyrrolidone-based solvent used is 3-20 mL/g.
  • the molar ratio of benzoyl chloride to the compound represented by formula N-1 is (1-3):1.
  • reaction temperature of the reaction is -10 to 10°C.
  • reaction time of the reaction is 1-4 hours.
  • the method further includes a post-processing step for separating and/or purifying midostaurin.
  • the preparation method includes:
  • (S2) A post-processing step for isolating and/or purifying midostaurin.
  • the post-processing step includes:
  • step (2) (2) converting the solvate obtained in step (1) to form midostaurin.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof.
  • step (1) relative to the mass of the compound represented by formula N-1, the amount of the alcohol solvent used is 1.0-3.0 mL/g.
  • step (1) the volume ratio of water to the alcohol solvent is (8.0-12.0):1.
  • step (1) a mixed solvent composed of an alcohol solvent and water is added at 0-10°C.
  • step (2) comprises the steps:
  • step (2.2) Mix the mixture obtained in step (2.1) with water, collect the solid therein, and dry to obtain midostaurin.
  • step (2.1) the mixture of the solvate and DMF is a solution of the solvate in DMF.
  • step (2) relative to the mass of the compound represented by formula N-1, the amount of the DMF used is 1.0-3.0 mL/g.
  • step (2) relative to the mass of the compound represented by formula N-1, the amount of water used is 8.0-12.0 mL/g.
  • the preparation method comprises the steps:
  • step (S1) in the reaction system that step (S1) obtains, add the mixed solvent that alcoholic solvent and water form, collect wherein solid, optional drying, thereby obtain the solvate of midostaurin and pyrrolidone solvent;
  • step (S2.2) converting the solvate obtained in step (S2.1) to form midostaurin.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, or a combination thereof.
  • step (S2.1) relative to the mass of the compound represented by formula N-1, the amount of the alcohol solvent used is 1.0-3.0 mL/g.
  • step (S2.1) the volume ratio of water to the alcohol solvent is (8.0-12.0):1.
  • step (S2.1) a mixed solvent composed of an alcohol solvent and water is added at 0-10°C.
  • step (S2.2) includes the steps:
  • step (S2.2.2) Mix the mixture obtained in step (S2.2.1) with water, collect the solid therein, and dry to obtain midostaurin.
  • step (S2.2) relative to the mass of the compound represented by formula N-1, the amount of the DMF used is 1.0-3.0 mL/g.
  • step (S2.2) relative to the mass of the compound represented by formula N-1, the amount of the water used is 8.0-12.0 mL/g.
  • the impurity reference substance is a control bottle used in the quality control of the midostaurin API and/or the pharmaceutical composition containing midostaurin.
  • composition comprising midostaurin with HPLC purity > 99.5% (preferably, HPLC purity > 99.6%).
  • the content of any single impurity in the composition is ⁇ 0.15, preferably ⁇ 0.10%.
  • the midostaurin is midostaurin prepared by the preparation method described in the first aspect.
  • an NMP solvate of midostaurin is provided.
  • a pyrrolidone-based solvent as the solvent of the reaction system can not only provide a reaction system that enables the compound of formula N-1 and benzoyl chloride to efficiently react, but also the solvent will not participate in the reaction to generate additional Impurities, and the formation of midostaurin in the reaction system can be directly obtained after simple treatment in the form of a solvate (ie a solvate with a pyrrolidone solvent) that has excellent impurity removal ability and is easily converted into midostaurin get.
  • a solvate ie a solvate with a pyrrolidone solvent
  • the inventors also found that the use of inorganic bases such as potassium phosphate, potassium carbonate and other inorganic bases for the reaction can also significantly reduce the amount of impurities generated in the reaction and improve the purity of the product. Based on this, the inventors have completed the present invention.
  • the technical problem to be solved by the present invention is that the preparation method of midostaurin in the prior art has the defects of high environmental hazard, many impurities, unbalanced yield and purity, and unfavorable industrial production, and provides a high-purity rice
  • the preparation method of dostaurin does not need to use toxic and expensive reagents, and the reaction conditions are mild, the obtained product has high yield and high purity, and is suitable for industrial production.
  • the present invention provides a preparation method of high-purity midostaurin, which comprises the following steps: in a pyrrolidone solvent, under the action of a base (such as an inorganic base), the compound shown in formula N-1 is mixed with benzene Formyl chloride carries out the following reaction to obtain midostaurin;
  • the pyrrolidone-based solvent is N-methylpyrrolidone.
  • the amount of the pyrrolidone solvent can be the conventional capacity for this type of reaction in the art, and the volume-to-mass ratio of the pyrrolidone solvent to the compound represented by formula N-1 is preferably 3 to 20 mL/g, more preferably 3 to 10 mL/g. g, for example, about 10 mL/g, about 9, 8, 7, 6, 5 mL/g, or about 4 mL/g.
  • Described inorganic base can be the conventional inorganic base that this area carries out this kind of reaction, is preferably a kind of in the carbonate of alkali metal, the phosphate of alkali metal, the bicarbonate of alkali metal and the hydrogen phosphate of alkali metal or more.
  • the alkali metal is preferably lithium, sodium, potassium or cesium.
  • the alkali metal carbonate is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate.
  • the alkali metal phosphate is preferably potassium phosphate.
  • the alkali metal bicarbonate is preferably sodium bicarbonate and/or potassium bicarbonate.
  • the alkali metal hydrogen phosphate is preferably sodium hydrogen phosphate and/or potassium hydrogen phosphate.
  • the amount of the inorganic base () can be the conventional amount used in this field for such reactions, and the molar ratio of the inorganic base to the compound represented by formula N-1 is preferably 1.5 to 5, more preferably 2 to 3, for example, 3.0 or 2.0.
  • the consumption of the described benzoyl chloride can be the conventional consumption in this field to carry out this type of reaction, and the molar ratio of the benzoyl chloride to the compound represented by formula N-1 is preferably 1 to 3, more preferably 1.1 to 2.0, and most preferably 1 to 3. 1.4 to 1.6, for example, 1.4 or 1.5.
  • the addition rate and/or manner of benzoyl chloride is not particularly limited as long as the reaction conditions can be maintained, for example, the temperature of the reaction system can be maintained at the desired reaction temperature (eg, at -10-10°C).
  • the addition method of benzoyl chloride is dropwise.
  • the speed of the dropwise addition is not particularly limited, as long as the temperature of the reaction system is -10 to 10°C.
  • the temperature of the reaction may be the conventional temperature for such reactions in the art, preferably -10 to 10°C, more preferably -5 to 5°C, for example, 0 to 5°C.
  • the monitoring method of the reaction can be a conventional monitoring method (for example, TLC, HPLC or NMR) that can be used for such reactions in the art, preferably the content of the compound represented by formula N-1 no longer changes as the end point of the reaction .
  • the reaction time of the described reaction can be the conventional time for such reactions in the art, preferably 1 to 4 hours, for example, 2 hours.
  • the post-treatment of the reaction can be a conventional post-treatment method for such reactions in the art, preferably it includes the following steps: (1) after the reaction is completed, optionally at 0 to 10 ° C, add alcohol to the reaction system and water, filter and dry to obtain a solvate of midostaurin and a pyrrolidone-based solvent; (2) convert the solvent into midostaurin under suitable conditions, for example, by converting the solvate into The mixture with DMF is mixed with water, filtered and dried to obtain midostaurin.
  • the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.
  • the consumption of the alcoholic solvent can be the conventional consumption for such post-treatment in the art, and the volume-to-mass ratio of the alcoholic solvent to the compound shown in formula N-1 is preferably 1.0 to 3.0 mL/g, for example, 2.0 mL/g. g.
  • the amount of the water used can be the conventional amount used for such post-treatment in the art, and the volume ratio of the water to the methanol is preferably 8.0 to 12.0, for example, 10.0.
  • the consumption of described DMF can be the conventional consumption of this type of post-treatment in the field, preferably the volume-to-mass ratio of the compound shown in formula N-1 is 1.0 ⁇ 3.0mL/g, for example , 2.0mL/g.
  • the amount of water used can be the conventional amount used for such post-treatment in the art, and the volume-to-mass ratio of the water to the compound represented by formula N-1 is preferably 8.0-12.0 mL/g, for example, 10.0 mL/g.
  • the present invention also provides a composition comprising midostaurin, wherein the HPLC purity of the midostaurin is greater than or equal to 99.5%; preferably, it is greater than or equal to 99.6%.
  • the content of any single impurity in the composition comprising midostaurin is less than or equal to 0.15%, preferably less than or equal to 0.10%.
  • the present invention also provides a kind of midostaurin impurity, and its structure is as follows:
  • the impurity reference substance can be used for quality control of midostaurin raw materials and/or pharmaceutical compositions containing midostaurin.
  • DMF is N,N-dimethylformamide
  • NMP is N-methylpyrrolidone
  • the content of impurities refers to HPLC purity.
  • the operating temperature is not limited, it is all carried out at room temperature.
  • the room temperature is 0°C to 35°C, preferably 20°C to 30°C.
  • the reagents and raw materials used in the present invention are commercially available.
  • reaction basically does not produce difficult-to-remove impurities, and the amount of solvent required for post-treatment is small.
  • the raw materials used in the examples were provided by Yangzhou Branch of Orient Pharmaceutical Co., Ltd., and were prepared by biological fermentation with reference to EP296110B1.
  • the compound represented by formula N-1 (5.0 g, 10.72 mmol) was added to 50 mL of NMP, and the temperature was lowered to 0-5 °C. Potassium phosphate (6.8 g, 32.15 mmol) was added, and benzoyl chloride (2.26 g, 16.08 mmol) was added dropwise. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0-10° C., and the NMP solvate of midostaurin (determined by nuclear magnetic resonance) was obtained by filtration and drying, and the HPLC purity was 99.50%.
  • the compound represented by formula N-1 (5.0 g, 10.72 mmol) was added to 20 mL of NMP, and the temperature was lowered to 0-5 °C. Potassium phosphate (4.6 g, 21.44 mmol) was added, and benzoyl chloride (2.10 g, 15.01 mmol) was added dropwise at a temperature of 0-5 °C. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0-10° C., and the NMP solvate of midostaurin was filtered and dried to obtain the NMP solvate of midostaurin with a purity of 99.60% by HPLC.
  • solvate was dissolved in 10 mL of DMF at room temperature, added dropwise to 50 mL of water, stirred for 2 hours, filtered, and dried to obtain 5.91 g of midostaurin amorphous solid with a yield of 96.7% and a HPLC purity of 99.60%.
  • Solvent residue NMP 21ppm, DMF 45ppm; optical rotation value +175° (test conditions: detection wavelength 589nm; concentration 1g/100mL DMF; temperature 20 degrees).
  • the compound represented by formula N-1 (5.0 g, 10.72 mmol) was added to 20 mL of NMP, and the temperature was lowered to 0-5 °C. Potassium carbonate (2.9 g, 21.44 mmol) was added, and benzoyl chloride (2.10 g, 15.01 mmol) was added dropwise at a temperature of 0-5 °C. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0 to 10° C., and the NMP solvate of midostaurin was filtered and dried: 6.94 g, with HPLC purity of 99.68%.
  • the solvate was dissolved in 10 mL of DMF at room temperature, added dropwise to 50 mL of water, stirred for 2 hours, filtered, and dried to obtain midostaurin amorphous solid 5.83 g with a yield of 95.42%.
  • the compound represented by formula N-1 (5.0 g, 10.72 mmol) was added to 20 mL of DMF, and the temperature was lowered to 0-5 °C. Potassium phosphate (4.6 g, 21.44 mmol) was added and benzoyl chloride (2.10 g, 15.01 mmol) was added dropwise. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0 to 10 °C, and 5.82 g of midostaurin was obtained by filtration and drying, the yield was 95.20%, and the HPLC purity was 97.50% (impurity e 2.0%).
  • the compound represented by the formula N-1 (5.0 g, 10.72 mmol) was added to 80 mL of DCM, and the temperature was lowered to 0-5 °C. Triethylamine (2.16 g, 21.44 mmol) was added, and benzoyl chloride (2.10 g, 15.01 mmol) was added dropwise. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0 to 10° C., and the mixture was separated and concentrated to obtain midostaurin 5.88 g with a yield of 96.40% and HPLC purity of 91.23% (containing many unknown impurities).
  • the compound of formula N-1 (5.0g, 10.72mmol) was added to 80mL of a mixed solvent with a volume ratio of ethanol/water of 5/1, triethylamine (2.16g, 21.44mmol) was added, and the temperature was raised to 70°C , and benzoic anhydride (2.10 g, 15.01 mmol) was added dropwise. Incubate the reaction to the end. The temperature was lowered to 0-10°C, and 100 mL of water was added dropwise, stirred for 2 hours, filtered and dried to obtain midostaurin, 5.85 g, yield 95.90%, HPLC purity 93.5% (impurity b 1 1.02%, impurity c 2.13%).
  • the compound represented by formula N-1 (5.0 g, 10.72 mmol) was added to 20 mL of NMP, and the temperature was lowered to 0-5 °C. Triethylamine (2.16 g, 21.44 mmol) was added, and benzoyl chloride (2.10 g, 15.01 mmol) was added dropwise at a temperature of 0-5 °C. After the dropwise addition, the reaction was incubated for 2 hours. 10 mL of methanol and 100 mL of water were added dropwise under temperature control at 0-10° C., and the NMP solvate of midostaurin was filtered and dried: 6.96 g, with HPLC purity of 95.62%.
  • the solvate was dissolved in 10 mL of DMF at room temperature, added dropwise to 50 mL of water, stirred for 2 hours, filtered, and dried to obtain midostaurin amorphous solid 5.73 g with a yield of 93.78%.
  • Example midostaurin N-1 Impurity b1 Impurity b2 Impurity c Impurity e Example 1 99.56 0.02 0.06 0.06 0.06 N.D.
  • Example 2 99.60 0.03 0.07 0.07 0.06 N.D.
  • Example 3 99.68 0.01 0.05 0.06 0.08 N.D. Comparative Example 1 97.50 0.02 0.08 0.07 0.15 2.00
  • N.D. means not detected, impurity e is the product of the solvent participating in the reaction when DMF is the solvent.
  • the liquid phase response of impurity c is weaker than that of the main peak and other impurities, and the impurity data in the above table are all content (RC) values.
  • Mobile phase A a solution obtained by dissolving 500 ⁇ L of chromatographically pure phosphoric acid in 1000 mL of deionized water

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Abstract

L'invention concerne un procédé de préparation de midostaurine, le procédé comprenant l'étape suivante, consistant à : faire réagir un composé tel que représenté par la formule N-1 avec du chlorure de benzoyle dans un solvant de pyrrolidone en présence d'une base (telle qu'une base inorganique), formant ainsi de la midostaurine. Selon le procédé de préparation, des réactifs toxiques et dangereux ne sont pas nécessaires, les réactifs utilisés sont bon marché et facilement disponibles, le coût de production est réduit, le procédé de préparation est approprié pour une production industrielle en masse et il y a peu de sous-produits de réaction; et la pureté chimique d'un composé de midostaurine en tant que produit peut atteindre 99,6 % au moyen d'un raffinage primaire et la pluralité d'impuretés peut être facilement régulée à 0,10 % ou moins.
PCT/CN2022/082265 2021-03-24 2022-03-22 Procédé de préparation de midostaurine de haute pureté WO2022199576A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115124551A (zh) * 2021-03-24 2022-09-30 奥锐特药业(天津)有限公司 一种高纯度米哚妥林的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019215759A1 (fr) * 2018-05-09 2019-11-14 Alaparthi Lakshmi Prasad Procédé amélioré de préparation de midostaurine
US20200010481A1 (en) * 2017-03-06 2020-01-09 Teva Pharmaceutical Works Ltd. Solid state forms of midostaurin
CN111393454A (zh) * 2020-05-07 2020-07-10 奥锐特药业(天津)有限公司 米哚妥林的新晶型及其制备方法
WO2020200945A1 (fr) * 2019-03-29 2020-10-08 Procos S.P.A. Procédé de préparation de midostaurine à pureté élevée

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1582150B (zh) * 2001-10-30 2011-09-07 诺瓦提斯公司 作为flt3受体酪氨酸激酶活性抑制剂的星形孢菌素衍生物
JO2897B1 (en) * 2004-11-05 2015-09-15 نوفارتيس ايه جي Organic compounds
CN102101866A (zh) * 2010-11-04 2011-06-22 中国海洋大学 十字孢碱卤代衍生物及其制备方法和应用
PE20210667A1 (es) * 2012-05-15 2021-04-05 Novartis Ag Derivados de benzamida para la inhibicion de la actividad abl1, abl2 y bcr-abl1
CN110218206B (zh) * 2016-06-01 2022-03-04 中国海洋大学 双吲哚马来酰亚胺衍生物及其制备方法和用途
WO2020261293A1 (fr) * 2019-06-24 2020-12-30 Dr. Reddy's Laboratories Limited Procédé de préparation de midostaurine
CN115124551B (zh) * 2021-03-24 2024-04-30 奥锐特药业(天津)有限公司 一种高纯度米哚妥林的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200010481A1 (en) * 2017-03-06 2020-01-09 Teva Pharmaceutical Works Ltd. Solid state forms of midostaurin
WO2019215759A1 (fr) * 2018-05-09 2019-11-14 Alaparthi Lakshmi Prasad Procédé amélioré de préparation de midostaurine
WO2020200945A1 (fr) * 2019-03-29 2020-10-08 Procos S.P.A. Procédé de préparation de midostaurine à pureté élevée
CN111393454A (zh) * 2020-05-07 2020-07-10 奥锐特药业(天津)有限公司 米哚妥林的新晶型及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
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CN115124551A (zh) * 2021-03-24 2022-09-30 奥锐特药业(天津)有限公司 一种高纯度米哚妥林的制备方法
CN115124551B (zh) * 2021-03-24 2024-04-30 奥锐特药业(天津)有限公司 一种高纯度米哚妥林的制备方法

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