CN115124551B - Preparation method of high-purity midostaurin - Google Patents
Preparation method of high-purity midostaurin Download PDFInfo
- Publication number
- CN115124551B CN115124551B CN202110314921.5A CN202110314921A CN115124551B CN 115124551 B CN115124551 B CN 115124551B CN 202110314921 A CN202110314921 A CN 202110314921A CN 115124551 B CN115124551 B CN 115124551B
- Authority
- CN
- China
- Prior art keywords
- midostaurin
- formula
- solvent
- water
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229950010895 midostaurin Drugs 0.000 title claims abstract description 69
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000012453 solvate Substances 0.000 claims description 28
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 21
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 18
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 9
- 235000011009 potassium phosphates Nutrition 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 235000019800 disodium phosphate Nutrition 0.000 claims description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 32
- -1 midostaurin compound Chemical class 0.000 abstract description 9
- 150000007529 inorganic bases Chemical class 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 239000000047 product Substances 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 description 4
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of high-purity midostaurin. Specifically, the method comprises the following steps: reacting a compound represented by formula N-1 with benzoyl chloride in the presence of a base (e.g., an inorganic base) in a pyrrolidone-type solvent, thereby forming midostaurin. The preparation method of the invention does not need toxic and dangerous reagent, the used reagent is cheap and easy to obtain, the production cost is reduced, the method is suitable for industrial mass production, the reaction byproducts are few, the chemical purity of the product midostaurin compound can reach 99.6 percent by one-time refining, and a plurality of impurities can be easily controlled below 0.10 percent.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of high-purity midostaurin.
Background
Midostaurin (Midostaurin) is an oral PKC inhibitor from the North China pharmaceutical industry. FDA approved it in combination with chemotherapy for newly diagnosed FLT3 positive Acute Myelogenous Leukemia (AML) at month 4 and 28 of 2017. The structural formula is as follows:
there are several documents reporting methods for preparing midostaurin, wherein the preparation method disclosed in EP0296110 is shown in the following route 1, a solvent (chloroform) is used in the route 1, and post-treatment is required to perform column chromatography purification operation, which causes great harm to environment and operators and high cost;
Route 1
The preparation method disclosed in WO2006048296 is shown in the following route 2, wherein benzoic anhydride is condensed at high temperature in a mixed solvent of ethanol and water, the yield is only about 82%, multiple purifications are possibly needed, and the condition of related impurities is unknown;
Route 2
Youji Huaxue,34 (8), 1603-1608;2014 is shown in the following scheme 3: yield: 94% in which no qualitative and quantitative study of impurities was performed;
Route 3
The preparation process disclosed in WO2018165071 is shown in scheme 4, which uses DMF as solvent and DIPEA as base, and requires a large amount of solvent (425 volumes in total) for the post-treatment according to the description, and is not suitable for industrial scale-up;
Route 4
The preparation process disclosed in WO2019215759 is shown in scheme 5 below, which uses the expensive and explosive condensing agent HBTU for the condensation reaction in a yield of only 70%.
Route 5
In addition, WO2020200945A1 teaches that there is a significant increase in oxidized impurities of midostaurin, after long-term stability testing in a pressurized air environment. This patent discloses that after purification of the crude midostaurin with a purity of 99.08% in a yield of 95%, the product midostaurin is finally obtained in a yield of 85% of 99.69%. It can be seen that slightly increasing the purity of midostaurin results in a substantial decrease in its yield.
In view of the foregoing, there is a great need in the art to develop a new method for preparing midostaurin that combines product yield and purity, simple post-treatment, and suitability for industrialization.
Disclosure of Invention
Aiming at the defects that the preparation method of the midostaurin in the prior art has great environmental hazard, more impurities, the yield and the purity cannot be considered, the industrial production is not facilitated, and the like, the invention provides the preparation method of the high-purity midostaurin. The preparation method of the invention does not need to adopt toxic and expensive reagents, has mild reaction conditions, and the obtained product has high yield and high purity, and is suitable for industrial production.
The invention adopts the following technical scheme to solve the technical problems:
In a first aspect of the present invention, there is provided a process for the preparation of high purity midostaurin comprising the steps of:
reacting a compound represented by formula N-1 with benzoyl chloride in a pyrrolidone type solvent in the presence of a base, thereby forming midostaurin;
in another preferred embodiment, the base is an inorganic base.
In another preferred embodiment, the base (e.g., inorganic base) is selected from the group consisting of: alkali metal carbonates, alkali metal phosphates, alkali metal bicarbonates, alkali metal hydrogen phosphates, or combinations thereof.
In another preferred embodiment, the alkali metals are each independently selected from the group consisting of: lithium, sodium, potassium or cesium.
In another preferred embodiment, the alkali metal carbonate is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof.
In another preferred embodiment, the alkali metal phosphate is potassium phosphate.
In another preferred embodiment, the alkali metal bicarbonate is selected from the group consisting of: sodium hydrogen phosphate, potassium hydrogen phosphate, or a combination thereof.
In another preferred embodiment, the base (e.g., inorganic base) is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, or combinations thereof.
In another preferred embodiment, the molar ratio of the base to the compound represented by the formula N-1 is (1.5-5): 1; preferably, (2-3): 1.
In another preferred embodiment, the pyrrolidone solvent is NMP (N-methylpyrrolidone).
In another preferred example, the pyrrolidone type solvent is used in an amount of 3 to 20mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, the molar ratio of benzoyl chloride to the compound represented by the formula N-1 is (1-3): 1.
In another preferred embodiment, the reaction temperature of the reaction is-10 to 10 ℃.
In another preferred embodiment, the reaction time of the reaction is 1 to 4 hours.
In another preferred embodiment, the method further comprises a post-treatment step for isolating and/or purifying midostaurin.
In another preferred embodiment, the preparation method comprises the following steps:
(S1) reacting a compound represented by formula N-1 with benzoyl chloride in a pyrrolidone type solvent in the presence of a base, thereby forming midostaurin; and
(S2) a post-treatment step for isolating and/or purifying midostaurin.
In another preferred embodiment, the post-processing step includes:
(1) Adding a mixed solvent of an alcohol solvent and water, collecting the solid (e.g., by filtration), and optionally drying the solid to obtain a solvate of midostaurin and pyrrolidone solvents; and
(2) Converting the solvate obtained in step (1) to form midostaurin.
In another preferred embodiment, in step (1), the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination thereof.
In another preferred embodiment, in the step (1), the alcohol solvent is used in an amount of 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, in the step (1), the volume ratio of water to the alcohol solvent is (8.0 to 12.0): 1.
In another preferred embodiment, in the step (1), a mixed solvent of an alcohol solvent and water is added at 0 to 10 ℃.
In another preferred embodiment, step (2) includes the steps of:
(2.1) mixing the solvate with DMF (N, N-dimethylformamide) to obtain a mixture of the solvate and DMF;
(2.2) mixing the mixture obtained in the step (2.1) with water, collecting the solid therein, and drying to obtain midostaurin.
In another preferred embodiment, in step (2.1), the mixture of solvate and DMF is a solution of the solvate in DMF.
In another preferred embodiment, in the step (2), DMF is used in an amount of 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, in the step (2), the amount of water is 8.0 to 12.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, the preparation method comprises the steps of:
(S1) reacting a compound represented by the formula N-1 with benzoyl chloride in a pyrrolidone type solvent in the presence of a base, thereby obtaining a reaction system containing midostaurin;
(S2.1) adding a mixed solvent consisting of an alcohol solvent and water into the reaction system obtained in the step (S1), collecting solids in the mixed solvent, and optionally drying the solids to obtain a solvate of midostaurin and pyrrolidone solvents; and
(S2.2) converting the solvate obtained in step (S2.1) to form midostaurin.
In another preferred embodiment, in step (S2.1), the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination thereof.
In another preferred embodiment, in the step (S2.1), the alcohol solvent is used in an amount of 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, in the step (S2.1), the volume ratio of water to the alcohol solvent is (8.0 to 12.0): 1.
In another preferred embodiment, in the step (S2.1), a mixed solvent of an alcohol solvent and water is added at 0 to 10 ℃.
In another preferred embodiment, step (S2.2) comprises the steps of:
(S2.2.1) mixing the solvate with DMF (N, N-dimethylformamide) to obtain a mixture of the solvate and DMF;
(S2.2.2) mixing the mixture obtained in step (S2.2.1) with water, collecting the solid therein, and drying to obtain midostaurin.
In another preferred embodiment, in the step (S2.2), DMF is used in an amount of 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, in the step (S2.2), the amount of water is 8.0 to 12.0mL/g relative to the mass of the compound represented by the formula N-1.
In a second aspect of the invention, there is provided a compound of formula c,
In a third aspect of the invention there is provided the use of a compound of formula c as described in the second aspect as an impurity control for midostaurin.
In another preferred embodiment, the impurity control is a control vial used in quality control of an midostaurin drug substance and/or a pharmaceutical composition comprising midostaurin.
In a fourth aspect of the invention there is provided a composition comprising midostaurin having an HPLC purity of 99.5% (preferably, HPLC purity of 99.6%).
In another preferred embodiment, the composition has any single impurity content of 0.15% or less, preferably 0.10% or less.
In another preferred embodiment, the midostaurin is midostaurin prepared by the preparation method as described in the first aspect.
In a fifth aspect of the invention, there is provided an NMP solvate of midostaurin.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies, and have unexpectedly found that a solvent having a pyrrolidone type solvent as a reaction system can not only provide a reaction system enabling a compound of formula N-1 and benzoyl chloride to react efficiently and that the solvent does not participate in the reaction to generate additional impurities, but also that the midostaurin formed in the reaction system can be obtained directly after a simple treatment in the form of a solvate having excellent impurity removing ability and being easily converted into midostaurin (i.e., a solvate with a pyrrolidone type solvent). In addition, the inventors have found that the reaction using an inorganic base such as potassium phosphate, potassium carbonate, etc. can also significantly reduce the amount of impurities generated by the reaction and improve the purity of the product. Based on this, the inventors completed the present invention.
Terminology
In this context, unless otherwise indicated, the abbreviations have the usual meaning well known to the person skilled in the art, for example DMF means N, N-dimethylformamide, NMP means N-methylpyrrolidone,
Preparation method
The invention aims to solve the technical problems that the preparation method of the midostaurin in the prior art has the defects of large environmental hazard, more impurities, incapacity of considering both yield and purity, and is unfavorable for industrial production, and the like, and provides the preparation method of the high-purity midostaurin. The preparation method of the invention does not need to adopt toxic and expensive reagents, has mild reaction conditions, and the obtained product has high yield and high purity, and is suitable for industrial production.
The invention adopts the following technical scheme to solve the technical problems:
The invention provides a preparation method of high-purity midostaurin, which comprises the following steps: in pyrrolidone solvent, under the action of alkali (such as inorganic alkali), reacting a compound shown as a formula N-1 with benzoyl chloride to obtain midostaurin;
preferably, the pyrrolidone type solvent is N-methyl pyrrolidone.
The pyrrolidone type solvent may be used in an amount conventional in the art for carrying out such reactions, preferably in a volume to mass ratio of 3 to 20mL/g, more preferably 3 to 10mL/g, for example, about 10mL/g, about 9, 8, 7, 6, 5mL/g or about 4mL/g, to the compound represented by formula N-1.
The inorganic base may be a conventional inorganic base in the art for carrying out such reactions, preferably one or more of alkali metal carbonates, alkali metal phosphates, alkali metal bicarbonates and alkali metal hydrogen phosphates. 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 () may be a conventional amount in the art for carrying out such a reaction, and preferably the molar ratio thereof to the compound represented by the formula N-1 is 1.5 to 5, more preferably 2 to 3, for example, 3.0 or 2.0.
The benzoyl chloride may be used in an amount conventional in the art for carrying out such a reaction, preferably in a molar ratio of 1 to 3, more preferably 1.1 to 2.0, most preferably 1.4 to 1.6, for example, 1.4 or 1.5, to the compound represented by the formula N-1.
The rate and/or mode of adding benzoyl chloride is not particularly limited as long as the reaction conditions can be maintained, and for example, the reaction system temperature may be maintained at a desired reaction temperature (e.g., maintained at-10 to 10 ℃). Preferably, benzoyl chloride is added dropwise.
The dripping speed is not particularly limited, and the temperature of the reaction system is only between-10 and 10 ℃.
The temperature of the reaction may be conventional in the art for carrying out such reactions, and is preferably-10 to 10 ℃, more preferably-5 to 5 ℃, for example, 0 to 5 ℃.
The monitoring method of the reaction may be a conventional monitoring method (e.g., TLC, HPLC or NMR) which may be used in the art to perform such a reaction, and preferably the content of the compound represented by formula N-1 is not changed any more to the end point of the reaction.
The reaction time of the reaction may be a conventional time in the art for carrying out such a reaction, preferably 1 to 4 hours, for example, 2 hours.
The post-treatment of the reaction may be a conventional post-treatment method in the art for carrying out such a reaction, preferably it comprises the steps of: (1) After the reaction is finished, optionally adding an alcohol solvent and water into a reaction system at 0-10 ℃, filtering and drying to obtain a solvate of midostaurin and pyrrolidone solvents; (2) The solvent is converted to midostaurin under suitable conditions, for example by mixing the solvate with water in a mixture of DMF, filtering and drying to give midostaurin.
Wherein,
In the step (1), the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.
The amount of the alcohol solvent may be a conventional amount for such post-treatment in the art, and preferably the volume to mass ratio thereof to the compound represented by the formula N-1 is 1.0 to 3.0mL/g, for example, 2.0mL/g. The water may be used in amounts conventional in the art for such post-treatments, preferably in a volume ratio of 8.0 to 12.0, for example, 10.0, to the methanol.
In step (2), the DMF may be used in an amount conventional in the art for such post-treatment, preferably in a volume to mass ratio of 1.0 to 3.0mL/g, e.g., 2.0mL/g, to the compound represented by formula N-1. The amount of water may be that which is conventional in the art for such post-treatment, and preferably the volume to mass ratio thereof to the compound represented by formula N-1 is 8.0 to 12.0mL/g, for example, 10.0mL/g.
The invention also provides a composition containing midostaurin, wherein the HPLC purity of the midostaurin is more than or equal to 99.5%; preferably, 99.6% or more.
In a preferred embodiment, the composition comprising midostaurin has any single impurity content of less than or equal to 0.15%, preferably less than or equal to 0.10%.
The invention also provides midostaurin impurity, which has the structure shown as follows:
The impurity reference substance can be used for quality control of midostaurin bulk drug and/or pharmaceutical composition containing midostaurin.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein. The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
In the present invention, DMF is N, N-dimethylformamide and NMP is N-methylpyrrolidone.
In the present invention, the content of impurities refers to HPLC purity unless otherwise specified.
In the present invention, the operation temperature, if not limited, is carried out at room temperature. The room temperature is 0-35 ℃, preferably 20-30 ℃.
The reagents and materials used in the invention are commercially available unless otherwise specified.
The invention has the positive progress effects that:
(1) No toxic and dangerous reagent is needed, the used reagent is cheap and easy to obtain, the production cost is reduced, and the method is suitable for industrial mass production.
(2) The reaction basically does not produce impurities which are difficult to remove, and the amount of solvent needed for post-treatment is small.
(3) The reaction product is easily separated from the reaction system.
(4) The chemical purity of the product midostaurin compound can reach 99.6% by one-time refining with few reaction byproducts, and a plurality of impurities can be easily controlled below 0.10%.
(5) The yield and purity can be simultaneously considered.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Raw materials and general methods:
1. The starting materials used in the examples were prepared by biological fermentation methods, supplied by the Yangzhou division of Orett pharmaceutical Co., ltd, with reference to EP296110B 1.
2. Nuclear magnetism 1 H-NMR measurement method
300MHz，Bruker AV III 300 spectrometer。
Example 1:
A compound of the formula N-1 (5.0 g,10.72 mmol) was added to 50mL of NMP and the temperature was lowered to 0-5 ℃. Potassium phosphate (6.8 g,32.15 mmol) was added, and benzoyl chloride (2.26 g,16.08 mmol) was added dropwise. After the dripping, the reaction is carried out for 2 hours with heat preservation. Dropwise adding 10mL of methanol and 100mL of water at the temperature of 0-10 ℃, filtering and drying to obtain NMP solvate (determined by nuclear magnetism) of midostaurin, wherein the HPLC purity is 99.50%. The solvate is dissolved in 10mL DMF at room temperature, added dropwise to 50mL water and stirred for 2 hours for filtration, and dried to give 5.81g of midostaurin amorphous solid with a yield of 95.0% and an HPLC purity of 99.56%. Solvent residue: NMP 73ppm, DMF 98ppm (much less than the required solvent residual limits (NMP limit: 530ppm; DMF limit: 880 ppm)); optical rotation value +176° (test conditions: detection wavelength 589nm; concentration 1g/100mL DMF; temperature 20 ℃).
1H-NMR(300MHz,CDCl3)δ:9.47(1H,d,J＝7.8Hz),7.87(1H,d,J＝7.7Hz),7.77(1H,d,J＝8.2Hz),7.67～7.29(9H,m),7.22(1H,d,J＝7.9Hz),6.90(1H,NH),6.81～6.42(1H,m),5.36～5.09(1H,m),4.97(2H,s),4.25(1H,s),2.83(3H,s),2.78～2.59(2H,m),2.53(3H,s),2.49(3H,s).
Example 2:
A compound of formula N-1 (5.0 g,10.72 mmol) was added to 20mL NMP and the temperature was reduced to 0-5 ℃. Potassium phosphate (4.6 g,21.44 mmol) was added thereto, and benzoyl chloride (2.10 g,15.01 mmol) was added dropwise thereto at a temperature of 0 to 5 ℃. After the dripping, the reaction is carried out for 2 hours with heat preservation. Dropwise adding 10mL of methanol and 100mL of water at the temperature of 0-10 ℃, filtering and drying to obtain NMP solvate of midostaurin, wherein the purity of the NMP solvate is 99.60 percent. The solvate is dissolved in 10mL DMF at room temperature, added dropwise to 50 mL water and stirred for 2 hours for filtration, and dried to give midostaurin amorphous solid with a yield of 5.91g and a purity of 99.60% by HPLC. Solvent residue: NMP 21ppm, DMF 45ppm; optical rotation value +175° (test conditions: detection wavelength 589nm; concentration 1g/100mL DMF; temperature 20 ℃).
Example 3:
A compound of formula N-1 (5.0 g,10.72 mmol) was added to 20mL NMP and the temperature was reduced to 0-5 ℃. Potassium carbonate (2.9 g,21.44 mmol) was added thereto, and benzoyl chloride (2.10 g,15.01 mmol) was added dropwise thereto at a temperature of 0 to 5 ℃. After the dripping, the reaction is carried out for 2 hours with heat preservation. Dropwise adding 10mL of methanol and 100mL of water at the temperature of 0-10 ℃, filtering and drying to obtain NMP solvate of midostaurin: 6.94g and HPLC purity of 99.68%. The solvate was dissolved in 10mL DMF at room temperature, added dropwise to 50mL water, stirred for 2 hours, filtered and dried to give midostaurin amorphous solid 5.83g in 95.42% yield.
Comparative example 1:
A compound of formula N-1 (5.0 g,10.72 mmol) was added to 20mL of DMF and the temperature was reduced to 0-5 ℃. Potassium phosphate (4.6 g,21.44 mmol) was added, and benzoyl chloride (2.10 g,15.01 mmol) was added dropwise. After the dripping, the reaction is carried out for 2 hours with heat preservation. Methanol 10mL and water 100mL are added dropwise at the temperature of 0-10 ℃, midostaurin 5.82g is obtained by filtration and drying, the yield is 95.20%, and the HPLC purity is 97.50% (impurity e 2.0%).
Comparative example 2:
A compound of formula N-1 (5.0 g,10.72 mmol) was added to 80mL DCM and cooled to 0-5 ℃. Triethylamine (2.16 g,21.44 mmol) was added and benzoyl chloride (2.10 g,15.01 mmol) was added dropwise. After the dripping, the reaction is carried out for 2 hours with heat preservation. 10mL of methanol and 100mL of water are added dropwise at the temperature of 0-10 ℃, 5.88g of midostaurin is obtained by separating and concentrating, the yield is 96.40%, and the HPLC purity is 91.23% (containing more unknown impurities).
Comparative example 3:
A compound (5.0 g,10.72 mmol) represented by formula N-1 was added to a mixed solvent of 80mL of ethanol/water at a volume ratio of 5/1, triethylamine (2.16 g,21.44 mmol) was added, the temperature was raised to 70℃and benzoic anhydride (2.10 g,15.01 mmol) was added dropwise. And (5) carrying out heat preservation reaction until the end. 100mL of water is added dropwise at the temperature of 0-10 ℃, stirring is carried out for 2 hours, and then midostaurin is obtained by filtering and drying, 5.85g is obtained, the yield is 95.90%, and the HPLC purity is 93.5% (impurity b 1.02%, impurity c 2.13%).
Example 4:
a compound of formula N-1 (5.0 g,10.72 mmol) was added to 20mL NMP and the temperature was reduced to 0-5 ℃. 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 ℃. After the dripping, the reaction is carried out for 2 hours with heat preservation. Dropwise adding 10mL of methanol and 100mL of water at the temperature of 0-10 ℃, filtering and drying to obtain NMP solvate of midostaurin: 6.96g, HPLC purity 95.62%. The solvate was dissolved in 10mL of DMF at room temperature, added dropwise to 50 mL of water, stirred for 2 hours, filtered and dried to give midostaurin amorphous solid 5.73g in 93.78% yield.
The structure and content of the impurities of the examples and comparative examples were identified as follows:
Impurity c nuclear magnetic data
1H-NMR(300MHz,CDCl3)δ:9.34(1H,d,J＝7.8Hz),9.19(1H,d,J＝7.9Hz),7.75(1H,s,NH),772(1H,s),7.57(1H,d,J＝7.2Hz),7.52(1H,d,J＝5.0Hz),7.44～7.38(5H,m),7.25(1H,d,J＝7.4Hz),6.70(1H,s),5.24(1H,s),4.18(1H,s),2.85(3H,s),2.70～2.63(2H,m),2.53(3H,s),2.36(3H,s).
| Examples | 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 |
| Comparative example 2 | 91.23 | 0.05 | 0.52 | 0.47 | 0.36 | N.D. |
| Comparative example 3 | 93.50 | 0.04 | 1.02 | 1.07 | 2.13 | N.D. |
| Example 4 | 95.62 | 0.01 | 1.25 | 1.28 | 0.16 | N.D. |
Note that N.D. indicates the reaction product in which the solvent participates when DMF is the solvent as impurity e. Impurity c has a weaker liquid phase response than the main peak and other impurities, and the impurity data are all content (RC) values.
Detection conditions:
Instrument: agilent 1260 series HPLC.
Chromatographic column: ACE Excel 3 CN-ES,4.6X250mm,3 μm (P/N.: EXL-1113-2546U)
Column temperature: 10 DEG C
Sample cell temperature: 5℃ \
Mobile phase A500. Mu.L of chromatographically pure phosphoric acid in 1000mL deionized water
Mobile phase B chromatographic pure acetonitrile
| Time (minutes) | % Mobile phase A | % Mobile phase B |
| 0 | 60 | 40 |
| 20 | 50 | 50 |
| 50 | 5 | 95 |
| 53 | 5 | 95 |
| 53.5 | 60 | 40 |
| 60 | 60 | 40 |
Flow rate: 1.0 ml/min
Measurement time: 60 minutes
Detection wavelength: 230 nm
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (7)
1. A method for preparing midostaurin, comprising the steps of:
(S1) reacting a compound represented by formula N-1 with benzoyl chloride in a pyrrolidone type solvent in the presence of a base, thereby forming midostaurin; and
(S2) a post-treatment step for isolating and/or purifying midostaurin;
And, the post-processing step includes:
(1) Adding a mixed solvent consisting of an alcohol solvent and water, collecting the solid therein, and optionally drying the obtained solid, thereby obtaining a solvate of midostaurin and pyrrolidone solvents; and
(2) Converting the solvate from step (1) to form midostaurin;
Wherein,
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 pyrrolidone solvent is NMP;
the alcohol solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination thereof;
In the mixed solvent composed of the alcohol solvent and water, the volume ratio of the water to the alcohol solvent is (8.0-12.0): 1.
2. The method of claim 1, wherein,
The base is selected from the group consisting of: sodium carbonate, potassium phosphate, or a combination thereof.
3. The method of manufacturing of claim 1, further comprising one or more features selected from the group consisting of:
a. the molar ratio of the alkali to the compound shown as the formula N-1 is (1.5-5): 1;
b. the molar ratio of the benzoyl chloride to the compound shown as the formula N-1 is (1-3): 1;
c. the reaction temperature of the reaction is-10 ℃;
d. the reaction time of the reaction is 1-4 hours;
e. The dosage of the pyrrolidone solvent is 3-20 mL/g relative to the mass of the compound shown in the formula N-1.
4. The process according to claim 3, wherein the molar ratio of the base to the compound represented by the formula N-1 is (2 to 3): 1.
5. The method of manufacturing of claim 1, further comprising one or more features selected from the group consisting of:
b. in the step (1), the alcohol solvent is used in an amount of 1.0-3.0 mL/g relative to the mass of the compound represented by the formula N-1;
d. in the step (1), a mixed solvent consisting of an alcohol solvent and water is added at 0-10 ℃.
6. The method of claim 1, wherein step (2) comprises the steps of:
(2.1) mixing the solvate with DMF to obtain a mixture of the solvate and DMF;
(2.2) mixing the mixture obtained in the step (2.1) with water, collecting the solid therein, and drying to obtain midostaurin.
7. The process according to claim 1, wherein in the step (2), DMF is used in an amount of 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1; and/or, in the step (2), the water is used in an amount of 8.0 to 12.0mL/g relative to the mass of the compound represented by the formula N-1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110314921.5A CN115124551B (en) | 2021-03-24 | 2021-03-24 | Preparation method of high-purity midostaurin |
| PCT/CN2022/082265 WO2022199576A1 (en) | 2021-03-24 | 2022-03-22 | Method for preparing high-purity midostaurin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110314921.5A CN115124551B (en) | 2021-03-24 | 2021-03-24 | Preparation method of high-purity midostaurin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115124551A CN115124551A (en) | 2022-09-30 |
| CN115124551B true CN115124551B (en) | 2024-04-30 |
Family
ID=83374021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110314921.5A Active CN115124551B (en) | 2021-03-24 | 2021-03-24 | Preparation method of high-purity midostaurin |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115124551B (en) |
| WO (1) | WO2022199576A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124551B (en) * | 2021-03-24 | 2024-04-30 | 奥锐特药业(天津)有限公司 | Preparation method of high-purity midostaurin |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101703509A (en) * | 2001-10-30 | 2010-05-12 | 诺瓦提斯公司 | Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity |
| CN102101866A (en) * | 2010-11-04 | 2011-06-22 | 中国海洋大学 | Halogenated derivatives of staurosporine, and preparation method thereof and use thereof |
| CN102627658A (en) * | 2004-11-05 | 2012-08-08 | 诺瓦提斯公司 | Organic compounds |
| CN104302638A (en) * | 2012-05-15 | 2015-01-21 | 诺华股份有限公司 | Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1 |
| CN106083830A (en) * | 2016-06-01 | 2016-11-09 | 中国海洋大学 | Bisindole maleimide derivant and its production and use |
| WO2019215759A1 (en) * | 2018-05-09 | 2019-11-14 | Alaparthi Lakshmi Prasad | An improved process for preparation of midostaurin |
| CN111393454A (en) * | 2020-05-07 | 2020-07-10 | 奥锐特药业(天津)有限公司 | Novel crystalline form of midostaurin and process for its preparation |
| WO2020261293A1 (en) * | 2019-06-24 | 2020-12-30 | Dr. Reddy's Laboratories Limited | Process for preparation of midostaurin |
| WO2022199576A1 (en) * | 2021-03-24 | 2022-09-29 | 扬州联澳生物医药有限公司 | Method for preparing high-purity midostaurin |
Family Cites Families (2)
| 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 |
| IT201900004729A1 (en) * | 2019-03-29 | 2020-09-29 | Procos Spa | Process for the preparation of high purity midostaurin |
-
2021
- 2021-03-24 CN CN202110314921.5A patent/CN115124551B/en active Active
-
2022
- 2022-03-22 WO PCT/CN2022/082265 patent/WO2022199576A1/en active Application Filing
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101703509A (en) * | 2001-10-30 | 2010-05-12 | 诺瓦提斯公司 | Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity |
| CN102627658A (en) * | 2004-11-05 | 2012-08-08 | 诺瓦提斯公司 | Organic compounds |
| CN102101866A (en) * | 2010-11-04 | 2011-06-22 | 中国海洋大学 | Halogenated derivatives of staurosporine, and preparation method thereof and use thereof |
| CN104302638A (en) * | 2012-05-15 | 2015-01-21 | 诺华股份有限公司 | Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1 |
| CN106083830A (en) * | 2016-06-01 | 2016-11-09 | 中国海洋大学 | Bisindole maleimide derivant and its production and use |
| WO2019215759A1 (en) * | 2018-05-09 | 2019-11-14 | Alaparthi Lakshmi Prasad | An improved process for preparation of midostaurin |
| WO2020261293A1 (en) * | 2019-06-24 | 2020-12-30 | Dr. Reddy's Laboratories Limited | Process for preparation of midostaurin |
| CN111393454A (en) * | 2020-05-07 | 2020-07-10 | 奥锐特药业(天津)有限公司 | Novel crystalline form of midostaurin and process for its preparation |
| WO2022199576A1 (en) * | 2021-03-24 | 2022-09-29 | 扬州联澳生物医药有限公司 | Method for preparing high-purity midostaurin |
Non-Patent Citations (1)
| Title |
|---|
| PKC-412卤代衍生物的合成及细胞毒性活性研究;王立平，等;《有机化学》;第34卷;第1603-1608页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115124551A (en) | 2022-09-30 |
| WO2022199576A1 (en) | 2022-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110642897B (en) | Preparation method of beta-nicotinamide riboside chloride | |
| EP3822259A1 (en) | Method for synthesizing valsartan | |
| CN115124551B (en) | Preparation method of high-purity midostaurin | |
| CN114591187B (en) | Preparation method of 1,3-bis (tris (hydroxymethyl) methylamino) propane | |
| CN106279207A (en) | A kind of synthetic method of cefdinir | |
| CN117924163A (en) | Impurity compound of isaconazole onium sulfate and preparation method thereof | |
| CN108250195A (en) | The novel synthesis of 9-hydroxy-risperidone | |
| CN111925317B (en) | Ropivacaine hydrochloride impurity and preparation method thereof | |
| CN111116477B (en) | Synthesis process of doramelamine | |
| CN113603813A (en) | Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof | |
| JP2018525376A (en) | Novel process for producing chromanol derivatives | |
| CN107286143B (en) | Canagliflozin medicine impurity and preparation method and application thereof | |
| CN115385907B (en) | Room-temperature stable crystal form of pyridoimidazole thiopropionic acid anti-gout compound and preparation method thereof | |
| CN114539285A (en) | Preparation method of mabarosavir | |
| CN112679438A (en) | Process for the preparation of semetinib | |
| CN112479970A (en) | Indole beta-site alkylation method without participation of transition metal | |
| CN103980293B (en) | 3-vinyl-7-(thiazole methoxyimino) preparation method of Cephalosporanic acid | |
| CN101747251B (en) | Crystal of doripenem intermediate and preparation method thereof | |
| US10207986B2 (en) | Method for preparing D-arginine | |
| CN111004236B (en) | Dynamic kinetic resolution method of WXFL10203614 intermediate | |
| CN108530381B (en) | Method for preparing diamine derivative from amide ester | |
| CN114031651B (en) | Preparation method of aroyl bromosugar with alpha configuration | |
| CN110922355A (en) | Preparation method of nicorandil | |
| WO2006009374A1 (en) | Process for preparing levofloxacin or its hydrate | |
| CN117362370B (en) | Nucleoside phosphoramidite monomer and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |