CN115124551A - Preparation method of high-purity midostaurin - Google Patents
Preparation method of high-purity midostaurin Download PDFInfo
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- CN115124551A CN115124551A CN202110314921.5A CN202110314921A CN115124551A CN 115124551 A CN115124551 A CN 115124551A CN 202110314921 A CN202110314921 A CN 202110314921A CN 115124551 A CN115124551 A CN 115124551A
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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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention provides a preparation method of high-purity midostaurin. Specifically, the method comprises the following steps: the compound of formula N-1 is reacted with benzoyl chloride in the presence of a base, such as an inorganic base, in a pyrrolidone-based solvent to form midostaurin. The preparation method of the invention does not need toxic and dangerous reagents, the used reagents are cheap and easy to obtain, the production cost is reduced, the preparation method is suitable for industrial mass production, reaction byproducts are few, the chemical purity of the product of the midostaurin compound can reach 99.6% by one-time refining, and a plurality of impurities are easy to control below 0.10%.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of high-purity midostaurin.
Background
Midostaurin (Midostaurin) is an oral PKC inhibitor, derived from the norwalk pharmaceutical industry. FDA approved it for newly diagnosed FLT 3-positive Acute Myeloid Leukemia (AML) in combination with chemotherapy on 28/4/2017. The structural formula is as follows:
a number of prior art reports on the preparation of midostaurin, of which EP0296110 discloses a process as shown in scheme 1, in which scheme 1 a solvent (chloroform) is used and the work-up requires column chromatography purification, which results in high environmental and operator hazards and high costs;
route 1
The preparation method disclosed in WO2006048296 is shown in scheme 2 below, which uses benzoic anhydride to condense at high temperature in a mixed solvent of ethanol and water, the yield is only about 82%, and multiple purifications may be required, and the related impurity conditions are unknown;
route 2
Youji Huaxue,34(8), 1603-; the preparation method disclosed in 2014 is shown in scheme 3 below: yield: 94%, wherein the impurities were not studied qualitatively and quantitatively;
route 3
The preparation process disclosed in WO2018165071 is shown in scheme 4, which scheme 4 uses DMF as solvent and DIPEA as base, and which process is documented to require large amounts of solvent (425 volumes total) for work-up and is not suitable for industrial scale-up;
route 4
The preparation process disclosed in WO2019215759 is shown in scheme 5 below, where the condensation reaction of scheme 5 uses HBTU, an expensive and explosive condensation agent, and the yield is only 70%.
Route 5
In addition, WO2020200945a1 indicates a significant increase in the oxidized impurities of midostaurin, as tested by the long-term stability of a pressurized air environment. This patent discloses that after purification of crude midostaurin, obtained in 95% yield and with a purity of 99.08%, finally the product midostaurin, 99.69%, is obtained in 85% yield. It can be seen that a slight increase in the purity of midostaurin results in a considerable decrease in the yield.
In view of the above, there is an urgent need in the art to develop a process for the preparation of midostaurin which combines product yield and purity, is simple in work-up, and is suitable for industrialization.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of high-purity midostaurin aiming at the defects of large environmental hazard, more impurities, incapability of considering yield and purity, inconvenience for industrial production and the like of the preparation method of the midostaurin in the prior art. The preparation method of the invention does not need to adopt toxic and expensive reagents, has mild reaction conditions, high yield and high purity of the obtained product, 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 of formula N-1 with benzoyl chloride in the presence of a base in a pyrrolidone-type solvent to form 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: an alkali metal carbonate, an alkali metal phosphate, an alkali metal bicarbonate, an alkali metal hydrogen phosphate, or a combination 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 carbonate of an alkali metal is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, or combinations 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 combinations 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 preferable example, the molar ratio of the alkali to the compound shown as the formula N-1 is (1.5-5): 1; preferably, (2-3): 1.
In another preferred example, the pyrrolidone-based solvent is NMP (N-methylpyrrolidone).
In another preferable example, the dosage of the pyrrolidone solvent is 3-20 mL/g relative to the mass of the compound shown in the formula N-1.
In another preferred example, the molar ratio of the benzoyl chloride to the compound shown as 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 the formula N-1 with benzoyl chloride in a pyrrolidone solvent in the presence of a base to form midostaurin; and
(S2) a post-treatment step for the isolation and/or purification of midostaurin.
In another preferred example, the post-processing step includes:
(1) adding a mixture of an alcoholic solvent and water, collecting the solid therein (e.g. by filtration), optionally drying the resulting solid, thereby obtaining a solvate of midostaurin and a pyrrolidone-type solvent; 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 preferable example, in the step (1), the amount of the alcohol solvent is 1.0-3.0 mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred example, in the step (1), the volume ratio of water to the alcohol solvent is (8.0-12.0): 1.
In another preferred example, in the step (1), a mixed solvent of an alcohol solvent and water is added at 0 to 10 ℃.
In another preferred example, the 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 step (2.1) with water, collecting the solid, and drying to obtain midostaurin.
In another preferred example, in step (2.1), the mixture of the solvate and DMF is a solution of the solvate in DMF.
In another preferred example, in the step (2), the amount of DMF is 1.0-3.0 mL/g relative to the mass of the compound shown in the formula N-1.
In another preferable example, in the step (2), the amount of water is 8.0-12.0 mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred embodiment, the preparation method comprises the following steps:
(S1) in a pyrrolidone solvent, in the presence of alkali, reacting a compound shown as a formula N-1 with benzoyl chloride to obtain a reaction system containing midostaurin;
(S2.1) adding a mixed solvent of an alcohol solvent and water to the reaction system obtained in the step (S1), collecting the solid therein, and optionally drying to obtain a solvate of midostaurin and a pyrrolidone-type solvent; and
(S2.2) converting the solvate obtained in step (S2.1) to form midostaurin.
In another preferred example, in step (S2.1), the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination thereof.
In another preferable example, in the step (S2.1), the amount of the alcohol solvent is 1.0 to 3.0mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred example, in the step (S2.1), the volume ratio of water to the alcohol solvent is (8.0-12.0): 1.
In another preferred example, in the step (S2.1), a mixed solvent of an alcohol solvent and water is added at 0 to 10 ℃.
In another preferred example, the step (S2.2) includes 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, and drying to obtain midostaurin.
In another preferred example, in the step (S2.2), the amount of DMF is 1.0-3.0 mL/g relative to the mass of the compound represented by the formula N-1.
In another preferred example, in the step (S2.2), the amount of water is 8.0-12.0 mL/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 bottle used in quality control of midostaurin drug substance and/or pharmaceutical compositions comprising midostaurin.
In a fourth aspect of the invention there is provided a composition comprising midostaurin with an HPLC purity of 99.5% or more, preferably 99.6% or more.
In another preferred embodiment, the composition contains less than or equal to 0.15, preferably less than or equal to 0.10% of any single impurity.
In another preferred embodiment, the midostaurin is midostaurin prepared by the preparation process according to the first aspect.
In a fifth aspect of the present invention, there is provided a NMP solvate of midostaurin.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have made extensive and intensive studies and have unexpectedly found that not only can a pyrrolidone-based solvent be used as a solvent for a reaction system to provide a reaction system which enables a compound of formula N-1 and benzoyl chloride to react efficiently without the solvent participating in the reaction to produce additional impurities, but also that midostaurin formation in the reaction system can be obtained directly after simple work-up in the form of a solvate (i.e., a solvate with a pyrrolidone-based solvent) which has excellent impurity removing ability and is easily converted to midostaurin. In addition, the inventors have also found that conducting the reaction using an inorganic base such as potassium phosphate, potassium carbonate, etc. can also significantly reduce the amount of impurities produced by the reaction and improve the purity of the product. Based on this, the inventors have completed the present invention.
Term(s) for
In this context, the abbreviations have the conventional meaning well known to the person skilled in the art, unless otherwise indicated, for example DMF means N, N-dimethylformamide, NMP means N-methylpyrrolidone,
preparation method
The invention aims to solve the technical problem that the preparation method of the midostaurin in the prior art has the defects of large environmental hazard, more impurities, incapability of considering yield and purity, inconvenience 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, high yield and high purity of the obtained product, 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 a pyrrolidone solvent, under the action of alkali (such as inorganic alkali), a compound shown as a formula N-1 and benzoyl chloride are reacted as follows to obtain midostaurin;
preferably, the pyrrolidone-type solvent is N-methylpyrrolidone.
The amount of the pyrrolidone solvent can be the conventional volume for carrying out such reaction in the field, and the volume-to-mass ratio of the pyrrolidone solvent to the compound shown as the formula N-1 is preferably 3-20 mL/g, more preferably 3-10 mL/g, for example, about 10mL/g, about 9, 8, 7, 6, 5mL/g or about 4 mL/g.
The inorganic base may be any conventional inorganic base known in the art for carrying out such reactions, and is preferably one or more of an alkali metal carbonate, an alkali metal phosphate, an alkali metal bicarbonate and an alkali metal hydrogen phosphate. The alkali metal is preferably lithium, sodium, potassium or cesium. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The alkali metal phosphate is preferably potassium phosphate. The bicarbonate of an alkali metal 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 amount conventionally used in the art for carrying out such a reaction, and preferably the molar ratio of the inorganic base 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 dosage of the benzoyl chloride can be the conventional dosage for carrying out the reaction in the field, and the molar ratio of the benzoyl chloride to the compound shown as the formula N-1 is preferably 1 to 3, more preferably 1.1 to 2.0, most preferably 1.4 to 1.6, for example, 1.4 or 1.5.
The addition rate and/or mode of the benzoyl chloride is not particularly limited as long as the reaction conditions can be maintained, and for example, the temperature of the reaction system can be maintained at a desired reaction temperature (for example, at-10 to 10 ℃). Preferably, the benzoyl chloride is added dropwise.
The dropping speed is not particularly limited, as long as the temperature of the reaction system is-10 to 10 ℃.
The reaction temperature can be the conventional temperature for carrying out the reaction in the field, 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) in the art for performing such a reaction, and it is preferable that the content of the compound represented by the formula N-1 is not changed any more to the end point of the reaction.
The reaction time of the reaction may be a time conventional in the art for carrying out such a reaction, and is preferably 1 to 4 hours, for example, 2 hours.
The work-up of the reaction may be a conventional work-up procedure in the art for carrying out such reactions, 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 a pyrrolidone solvent; (2) the solvent is converted to midostaurin under suitable conditions, for example by mixing the solvate with DMF in a mixture with water, filtering and drying to give midostaurin.
Wherein, the first and the second end of the pipe are connected with each other,
in the step (1), the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.
The dosage of the alcohol solvent can be the conventional dosage for carrying out the post-treatment in the field, and the volume mass ratio of the alcohol solvent to the compound shown as the formula N-1 is preferably 1.0-3.0 mL/g, for example, 2.0 mL/g. The amount of water may be that conventionally used in the art for such post-treatment, and preferably is in a volume ratio of 8.0 to 12.0, for example, 10.0, to the methanol.
In the step (2), the amount of DMF may be the amount conventionally used in the field for such post-treatment, and preferably the volume-to-mass ratio of DMF to the compound shown as the formula N-1 is 1.0-3.0 mL/g, for example, 2.0 mL/g. The amount of the water can be the conventional amount for carrying out the post-treatment in the field, and the volume mass ratio of the water to the compound shown as the formula N-1 is preferably 8.0-12.0 mL/g, for example, 10.0 mL/g.
The invention also provides a composition containing midostaurin, wherein the HPLC purity of the midostaurin is more than or equal to 99.5 percent; preferably, the content is more than or equal to 99.6 percent.
In a preferred embodiment, the composition comprising midostaurin has a content of any single impurity of less than or equal to 0.15%, preferably less than or equal to 0.10%.
The invention also provides a midostaurin impurity, the structure of which is as follows:
the impurity control may be used in quality control of midostaurin drug substance and/or pharmaceutical compositions comprising midostaurin.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space. The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the 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 is carried out at room temperature unless otherwise specified. The room temperature is 0-35 ℃, preferably 20-30 ℃.
Unless otherwise specified, reagents and starting materials for use in the invention are commercially available.
The positive progress effects of the invention are as follows:
(1) toxic and dangerous reagents are not needed, the used reagents are 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 difficult to remove, and the solvent amount required by post-treatment is small.
(3) The reaction product is easy to separate from the reaction system.
(4) The reaction by-products are few, the chemical purity of the product of the midostaurin compound can reach 99.6% by one-time refining, and a plurality of impurities are easily controlled below 0.10%.
(5) Can simultaneously take account of yield and purity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Raw materials and general procedure:
1. the raw materials used in the examples were prepared by biological fermentation from the Yangzhou division of Orett pharmaceutical Co., Ltd, see EP296110B 1.
2. Nuclear magnetism 1 H-NMR measurement method
300MHz，Bruker AV III 300 spectrometer。
Example 1:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 50mL of NMP, and cooling to 0-5 ℃. Potassium phosphate (6.8g,32.15mmol) was added and benzoyl chloride (2.26g,16.08mmol) was added dropwise. After the dropwise addition, the reaction was incubated for 2 hours. And (3) controlling the temperature to be 0-10 ℃, dropwise adding 10mL of methanol and 100mL of water, filtering and drying to obtain the NMP solvate of the midostaurin (determined by nuclear magnetism), wherein the HPLC purity is 99.50%. The solvate was dissolved in 10mL of DMF at room temperature, added dropwise to 50mL of water, stirred for 2 hours, filtered and dried to give 5.81g of midostaurin amorphous solid, 95.0% yield and 99.56% HPLC purity. Solvent residue: NMP 73ppm, DMF 98ppm (much less than the required solvent residue limit (NMP limit: 530 ppm; DMF limit: 880 ppm)); optical rotation value +176 ° (test conditions: detection wavelength 589 nm; concentration 1g/100mL DMF; temperature 20 ℃).
1 H-NMR(300MHz,CDCl 3 )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:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 20mL of NMP, and cooling to 0-5 ℃. Potassium phosphate (4.6g,21.44mmol) was added thereto, and benzoyl chloride (2.10g,15.01mmol) was added dropwise thereto while controlling the temperature at 0 to 5 ℃. After the dropwise addition, the reaction was incubated for 2 hours. And (3) dropwise adding 10mL of methanol and 100mL of water at the temperature of 0-10 ℃, filtering and drying to obtain an NMP solvate of midostaurin, wherein the HPLC purity is 99.60%. The solvate was dissolved in 10mL DMF at room temperature, added dropwise to 50mL water, stirred for 2 hours, filtered and dried to give 5.91g of midostaurin amorphous solid with 96.7% yield and 99.60% HPLC purity. Solvent residue: NMP 21ppm, DMF 45 ppm; optical rotation value +175 ° (test conditions: detection wavelength 589 nm; concentration 1g/100mL DMF; temperature 20 ℃).
Example 3:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 20mL of NMP, and cooling to 0-5 ℃. Potassium carbonate (2.9g, 21.44mmol) was added thereto, and benzoyl chloride (2.10g,15.01mmol) was added dropwise thereto while controlling the temperature at 0 to 5 ℃. After the dropwise addition, the reaction was incubated for 2 hours. And (3) controlling the temperature to be 0-10 ℃, dropwise adding 10mL of methanol and 100mL of water, and filtering and drying to obtain an NMP solvate of midostaurin: 6.94g, HPLC purity 99.68%. The solvate was dissolved in 10mL of DMF at room temperature, added dropwise to 50mL of water, stirred for 2 hours, filtered and dried to give 5.83g of midostaurin amorphous solid, yield 95.42%.
Comparative example 1:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 20mL of DMF, and cooling to 0-5 ℃. Potassium phosphate (4.6g,21.44mmol) was added and benzoyl chloride (2.10g,15.01mmol) was added dropwise. After the dropwise addition, the reaction was carried out for 2 hours under heat preservation. And (3) controlling the temperature to be 0-10 ℃, dropwise adding 10mL of methanol and 100mL of water, filtering and drying to obtain 5.82g of midostaurin, wherein the yield is 95.20%, and the HPLC purity is 97.50% (impurity e 2.0%).
Comparative example 2:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 80mL of DCM, and cooling to 0-5 ℃. Triethylamine (2.16g, 21.44mmol) was added and benzoyl chloride (2.10g,15.01mmol) was added dropwise. After the dropwise addition, the reaction was incubated for 2 hours. And (3) controlling the temperature to be 0-10 ℃, dropwise adding 10mL of methanol and 100mL of water, separating and concentrating to obtain 5.88g of midostaurin, wherein the yield is 96.40%, and the HPLC purity is 91.23% (containing more unknown impurities).
Comparative example 3:
adding a compound shown as a formula N-1 (5.0g,10.72mmol) into 80mL of mixed solvent with the volume ratio of ethanol to water being 5/1, adding triethylamine (2.16g, 21.44mmol), heating to 70 ℃, and dropwise adding benzoic anhydride (2.10g,15.01 mmol). And keeping the temperature to react till the end. And (3) dropping 100mL of water at 0-10 ℃, stirring for 2 hours, filtering and drying to obtain 5.85g of midostaurin, the yield is 95.90%, and the HPLC purity is 93.5% (impurity b 11.02%, impurity c 2.13%).
Example 4:
adding a compound (5.0g,10.72mmol) shown as a formula N-1 into 20mL of NMP, and cooling to 0-5 ℃. Triethylamine (2.16g, 21.44mmol) was added and benzoyl chloride (2.10g,15.01mmol) was added dropwise at controlled temperature of 0-5 ℃. After the dropwise addition, the reaction was incubated for 2 hours. And (3) controlling the temperature to be 0-10 ℃, dropwise adding 10mL of methanol and 100mL of water, and filtering and drying to obtain an NMP solvate of midostaurin: 6.96g, HPLC purity 95.62%. The solvate was dissolved in 10mL of DMF at room temperature, added dropwise to 50mL of water, stirred for 2 hours, filtered and dried to give 5.73g of midostaurin amorphous solid, yield 93.78%.
The structures and contents of the impurities of the examples and comparative examples were identified as follows:
nuclear magnetic data of impurity c
1 H-NMR(300MHz,CDCl 3 )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 that no impurity e was detected, and that the solvent participated in the reaction when DMF was used as 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 table are all content (RC) values.
Detection conditions are as follows:
the instrument comprises the following steps: agilent 1260 series HPLC.
A chromatographic column: ACE Excel 3 CN-ES,4.6X250mm,3 μm (P/N.: EXL-1113-
Column temperature: 10 deg.C
Temperature of the sample chamber: at 5 deg.C
Mobile phase A is a solution of 500. mu.L of chromatographically pure phosphoric acid dissolved in 1000mL of deionized water
Mobile phase B of 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
Measuring time: 60 minutes
Detection wavelength: 230 nm
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Claims (10)
1. A process for the preparation of high purity midostaurin, characterized in that it comprises the steps of:
reacting a compound of formula N-1 with benzoyl chloride in a pyrrolidone-based solvent in the presence of a base to form midostaurin;
2. the method according to claim 1,
the alkali is inorganic alkali; preferably, the base is selected from the group consisting of: an alkali metal carbonate, an alkali metal phosphate, an alkali metal bicarbonate, an alkali metal hydrogen phosphate, or a combination thereof; more preferably, the 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; and/or
The pyrrolidone solvent is NMP.
3. The method of claim 1, further comprising one or more characteristics 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; preferably, (2-3): 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 to 10 ℃;
d. the reaction time is 1-4 hours;
e. the dosage of the pyrrolidone solvent is 3-20 mL/g relative to the mass of the compound shown as the formula N-1.
4. A process according to claim 1, characterized in that it further comprises a post-treatment step for the isolation and/or purification of midostaurin;
and, the post-processing step includes:
(1) adding a mixed solvent of an alcohol solvent and water, collecting the solid therein, and optionally drying the obtained solid, thereby obtaining a solvate of midostaurin and a pyrrolidone solvent; and
(2) converting the solvate obtained in step (1) to form midostaurin.
5. The method of claim 4, further comprising one or more characteristics selected from the group consisting of:
a. in the step (1), the alcohol solvent is selected from the following group: methanol, ethanol, isopropanol, or a combination thereof;
b. in the step (1), the amount of the alcohol solvent is 1.0-3.0 mL/g relative to the mass of the compound shown as the formula N-1;
c. in the step (1), the volume ratio of water to the alcohol solvent is (8.0-12.0): 1;
d. in the step (1), a mixed solvent composed of an alcohol solvent and water is added at 0-10 ℃.
6. The method of claim 4, wherein the 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 step (2.1) with water, collecting the solid, and drying to obtain midostaurin.
7. A compound of the formula (c) wherein,
8. use of a compound of formula c according to claim 7 as an impurity control for midostaurin.
9. A composition comprising midostaurin in HPLC purity no less than 99.5%, preferably no less than 99.6%.
10. The composition of claim 9, wherein the composition contains no more than 0.15, preferably no more than 0.10% of any single impurity.
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| CN202110314921.5A CN115124551A (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 |
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| IT201900004729A1 (en) * | 2019-03-29 | 2020-09-29 | Procos Spa | Process for the preparation of high purity midostaurin |
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