WO2019215759A1 - An improved process for preparation of midostaurin - Google Patents
An improved process for preparation of midostaurin Download PDFInfo
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- WO2019215759A1 WO2019215759A1 PCT/IN2019/050369 IN2019050369W WO2019215759A1 WO 2019215759 A1 WO2019215759 A1 WO 2019215759A1 IN 2019050369 W IN2019050369 W IN 2019050369W WO 2019215759 A1 WO2019215759 A1 WO 2019215759A1
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- midostaurin
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- staurosporine
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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
Definitions
- the present invention relates to a novel process for preparation of Midostaurin of formula I.
- Midostaurin is N-[(9S,l0R,l lR,l3R)-2,3,l0,l l,l2,l3-hexahydro-l0-methoxy-9- methyl-l-oxo-9,l3-epoxy-lH,9H-diindolo[l,2,3-gh:3',2',l '-lm]pyrrolo[3,4-j][l,7] benzodiazonin-l l-yl] -N-methylbenzamide of the following formula:
- the drug Midostaurin is used as an anti-tumour agent.
- the preparation of Midostaurin is disclosed in U.S. Patent No. 5,093,330.
- efficient, and industrially viable process of preparation the Midostaurin is certain important. Therefore, there is a continuing need for new process of preparation of Midostaurin.
- Staurosporine the basic element of the derivatives according to the present invention was isolated already in the year 1977 from cultures of Streptomyces staurosporeus AWAYA, TAKAHASHI and OMURA, sp. nov. AM 2282, cf. S. Omura et al., J. Antibiot. 30, 275-281 (1977). Hitherto, only the relative, but not the absolute configuration of staurosporin was known. The absolute configuration was published only recently by N. Funato et al., Tetrahedron Letters 35:8, 1251-1254 (1994) and corresponds to the mirror image of the structure, used up to now in the literature to denote the relative configuration of staurosporine.
- U.S. Patent No. 5,093,330 discloses N-benzoyl-staurosporine.
- the invention relates especially to a particular N-benzoyl-staurosporine derivative of the compound.
- the U.S. Patent No. 5,093,330 discloses in Example 18 process for the preparation of N- benzoyl-staurosporine derivative (Midostaurin) by reacting staurosporine with benzoyl chloride at room temperature in presences of N,N-diisopropylethylamine and chloroform. This process requires anhydrous conditions as benzoyl chloride gets converted to benzoic acid and the reaction doesn’t proceed to completion. Moreover it is observed that more impurities are formed in this reaction.
- EP2272850B1 discloses process for the preparation of crystalline form II of N-benzoyl-staurosporine.
- the invention relates especially to a particular crystalline form II of N-benzoyl-staurosporine of the compound.
- the European Patent No. EP2272850B1 discloses process for the preparation of N- benzoyl-staurosporine by reacting purified staurosporine in an alcohol solvent with benzoic anhydride. This process requires longer reaction times to proceed for reaction completion.
- the present invention is directed to provide novel process for the preparation of Midostaurin of formula I which is efficient, industrially viable wherein reaction conditions are mild and simple for operation, less expensive cost effective process.
- of the present invention is to provide an improved process for the preparation of N-[(9S,l0R,l lR,l3R)-2,3,l0,l l,l2,l3-hexahydro-l0- methoxy-9 -methyl- 1 -oxo-9, l3-epoxy- lH,9H-diindolo[ 1 ,2,3-gh:3 ',2', 1 '- lm]pyrrolo[3,4-j][l,7] benzodiazonin-l l-yl] -N-methylbenzamide (Midostaurin) of formula I and pharmaceutically acceptable salts thereof.
- of the present invention is to provide improved process for the preparation of Midostaurin by reacting staurosporine with benzoic acid.
- of the present invention is to provide improved process for the purifying of Midostaurin by treating with solvent and anti- solvent precipitation process.
- the term“pharmaceutically acceptable salt” refers to those salts which are suitable for pharmaceutical use, preferably for use in the tissues of humans and lower animals without undue irritation, allergic response and the like.
- Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
- the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid.
- suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts.
- suitable pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succ
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by direct reaction with the drug carboxylic acid or by using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
- purified refers to a compound that has been processed to remove impurities. Impurities can include solvents, reagents used to prepare the compound, starting materials, and byproducts of a reaction giving rise to the compound. In some embodiments, a purified compound is substantially free of other species.
- crude compound refers to a mixture containing a desired compound (such as a compound of Formula I as described herein) and at least one other species selected from a solvent, a reagent such as a base, a starting material, and a byproduct of a reaction giving rise to the desired compound.
- a desired compound such as a compound of Formula I as described herein
- a reagent such as a base, a starting material, and a byproduct of a reaction giving rise to the desired compound.
- Anti-solvent is a solvent which when added to an existing solution of a substance reduced the solubility of the substance.
- the terms “treating”, “contacting” and “reacting” are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be appreciated that the reaction which produces the indicated and/or desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or desired product.
- the present invention provides process for preparation of Midostaurin compound of formula I which comprising: (i) reacting the staurosporine with benzoic acid in presence of condensing agent and solvent;
- said condensing agent is selected from the group consisting of 2-( 1 H-benzotriazol- 1 -y 1) - 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate (HBTU) /N-Hydroxybenzotriazole (HOBt) / Diisopropylethylamine(DIPEA)
- product Midostaurin may be further purified or washed with the solvent multiple times to produce Midostaurin essentially free of impurites.
- the solvent is selected from but not limited to polar aprotic solvents are N-Methyl-2-pyrrolidone (NMP), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate (EtOAc), Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Dimethylacetamide; N,N-Diisopropyl ethylamine, dioxane, tetrahydrofuran, acetone, hexane, benzene, toluene, l,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, sulf
- the solvent can be any liquid in which the Midostaurin crude dissolves wherein the solvent can be a mixture of co-solvents the important point being that the solution of Midostaurin crude to be treated with another solvent or a mixture of co-solvents as anti-solvent.
- Solvents useful in the invention include materials that are liquid at room temperature, dissolve the material.
- the crude Midostaurin is dissolved in an amount of first solvent sufficient to dissolve the Midostaurin.
- the resulting Midostaurin solution is heated to about the boiling point of the first solvent.
- the addition of the second solvent, or anti-solvent takes place, with the addition of the second solvent or anti-solvent being added in an amount sufficient to precipitating Midostaurin from the solvents.
- the precipitation step comprises cooling the Midostaurin solution to room temperature sufficient to bring about Midostaurin. Most preferably the temperature sufficient for precipitation of Midostaurin is about 25°C.
- first solvent: second solvent or anti-solvent system combination is IPA : water.
- Example-2 Process for preparation of Midostaurin Prepared a solution of benzoic acid (50 mg; 0.4 mmol) and HBTU (170 mg; 0.45 mmol) in DMF. Added N,N-Diisopropyl ethyalmine (220 mL; 1.3 mmol). Stirred the mixture for 90 minutes at 25°C, charged staurosporine (600 mg; 1.3 mmol) to the reaction mixture. Stirred the reaction mixture for 4 hours. The reaction mass is diluted with water followed by extraction with ethyl acetate. The organic layer is dried over sodium sulphate and distilled under vacuum to get residue. Triturated the residue with ether. The solid obtained is filtered and dried to get Midostaurin. (Yield: 70%; purity by HPLC: 88%). The obtained solid is eluted with ethyl acetate and dichloromethane system to get Midostaurin with purity >97% by HPLC.
Abstract
The invention relates to a process for preparation of Midostaurin. More preferably the invention relates to process for the preparation of Midostaurin comprising reacting the staurosporine with benzoic acid in presences of condensing agent. In one aspect of the invention, to a new process for purifying Midostaurin.
Description
TITLE: AN IMPROVED PROCESS FOR PREPARATION OF
MIDOSTAURIN
FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of Midostaurin of formula I.
Midostaurin is N-[(9S,l0R,l lR,l3R)-2,3,l0,l l,l2,l3-hexahydro-l0-methoxy-9- methyl-l-oxo-9,l3-epoxy-lH,9H-diindolo[l,2,3-gh:3',2',l '-lm]pyrrolo[3,4-j][l,7] benzodiazonin-l l-yl] -N-methylbenzamide of the following formula:
Staurosporine, the basic element of the derivatives according to the present invention was isolated already in the year 1977 from cultures of Streptomyces staurosporeus AWAYA, TAKAHASHI and OMURA, sp. nov. AM 2282, cf. S. Omura et al., J. Antibiot. 30, 275-281 (1977). Hitherto, only the relative, but not the absolute configuration of staurosporin was known. The absolute configuration was published only recently by N. Funato et al., Tetrahedron Letters 35:8, 1251-1254 (1994) and corresponds to the mirror image of the structure, used up to now in the literature to denote the relative configuration of staurosporine. Accordingly, in the Tetrahedron Letters publication it is literally recommended "that the stereochemical notation for staurosporine which has been in common use hitherto should be revised". Although the absolute configuration was not known hitherto, it was unequivocally fixed (defined) by the designation as "staurosporine derivatives". Therefore, in order to avoid errors upon comparison with the priority applications, the original formulae are still used in the present application.
U.S. Patent No. 5,093,330 discloses N-benzoyl-staurosporine. The invention relates especially to a particular N-benzoyl-staurosporine derivative of the compound. The U.S. Patent No. 5,093,330 discloses in Example 18 process for the preparation of N- benzoyl-staurosporine derivative (Midostaurin) by reacting staurosporine with benzoyl chloride at room temperature in presences of N,N-diisopropylethylamine and chloroform. This process requires anhydrous conditions as benzoyl chloride gets converted to benzoic acid and the reaction doesn’t proceed to completion. Moreover it is observed that more impurities are formed in this reaction.
European Patent No. EP2272850B1 discloses process for the preparation of crystalline form II of N-benzoyl-staurosporine. The invention relates especially to a particular crystalline form II of N-benzoyl-staurosporine of the compound. The European Patent No. EP2272850B1 discloses process for the preparation of N- benzoyl-staurosporine by reacting purified staurosporine in an alcohol solvent with benzoic anhydride. This process requires longer reaction times to proceed for reaction completion. The present invention is directed to provide novel process for the preparation of Midostaurin of formula I which is efficient, industrially viable wherein reaction conditions are mild and simple for operation, less expensive cost effective process.
SUMMARY OF THE INVENTION
In accordance with one aspect, of the present invention is to provide an improved process for the preparation of N-[(9S,l0R,l lR,l3R)-2,3,l0,l l,l2,l3-hexahydro-l0- methoxy-9 -methyl- 1 -oxo-9, l3-epoxy- lH,9H-diindolo[ 1 ,2,3-gh:3 ',2', 1 '- lm]pyrrolo[3,4-j][l,7] benzodiazonin-l l-yl] -N-methylbenzamide (Midostaurin) of formula I and pharmaceutically acceptable salts thereof.
In accordance with yet another aspect, of the present invention is to provide improved process for the preparation of Midostaurin by reacting staurosporine with benzoic acid.
In accordance with yet another aspect, of the present invention is to provide improved process for the purifying of Midostaurin by treating with solvent and anti- solvent precipitation process. DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
For the purposes of the present invention, the following terms are defined below. The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.
The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are suitable for pharmaceutical use, preferably for use in the tissues of humans and lower animals without undue irritation, allergic response and the like.
Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by direct reaction with the drug carboxylic acid or by using
counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
The term "purified" refers to a compound that has been processed to remove impurities. Impurities can include solvents, reagents used to prepare the compound, starting materials, and byproducts of a reaction giving rise to the compound. In some embodiments, a purified compound is substantially free of other species.
The term "crude compound" refers to a mixture containing a desired compound (such as a compound of Formula I as described herein) and at least one other species selected from a solvent, a reagent such as a base, a starting material, and a byproduct of a reaction giving rise to the desired compound.
"Anti-solvent" is a solvent which when added to an existing solution of a substance reduced the solubility of the substance.
When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be appreciated that the reaction which produces the indicated and/or desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or desired product.
In the first embodiment the present invention provides process for preparation of Midostaurin compound of formula I which comprising:
(i) reacting the staurosporine with benzoic acid in presence of condensing agent and solvent;
(ii) isolating the product which is Midostaurin.
The above process is represented stepwise as shown below:
Scheme I
In certain embodiments, said condensing agent is selected from the group consisting of 2-( 1 H-benzotriazol- 1 -y 1) - 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate (HBTU) /N-Hydroxybenzotriazole (HOBt) / Diisopropylethylamine(DIPEA)
In certain embodiments, product Midostaurin may be further purified or washed with the solvent multiple times to produce Midostaurin essentially free of impurites.
In various embodiments, the solvent is selected from but not limited to polar aprotic solvents are N-Methyl-2-pyrrolidone (NMP), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate (EtOAc), Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Dimethylacetamide; N,N-Diisopropyl ethylamine, dioxane, tetrahydrofuran, acetone, hexane, benzene, toluene, l,4-dioxane, chloroform, diethyl ether, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides,
ethers, hydrocarbons, sulfolane methanol, ethanol, propanol, butanol, methylene chloride, monochlorobenzene, and EDC and ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane, and combinations thereof. In certain embodiments, product Midostaurin may be further purified or washed comprising:
i. treating Midostaurin crude with first solvent;
ii. adding a second solvent to the crude Midostaurin -first solvent mixture, wherein the second solvent is an anti-solvent;;
iii. precipitating Midostaurin from the solvents;
iv. collecting the crystals of Midostaurin; and
v. optionally washing and drying Midostaurin.
wherein the Midostaurin obtain is essentially free of impurities. The solvent, as mentioned, can be any liquid in which the Midostaurin crude dissolves wherein the solvent can be a mixture of co-solvents the important point being that the solution of Midostaurin crude to be treated with another solvent or a mixture of co-solvents as anti-solvent. Solvents useful in the invention include materials that are liquid at room temperature, dissolve the material.
Preferably, in this embodiment, the crude Midostaurin is dissolved in an amount of first solvent sufficient to dissolve the Midostaurin. Optionally the resulting Midostaurin solution is heated to about the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent, or anti-solvent, takes place, with the addition of the second solvent or anti-solvent being added in an amount sufficient to precipitating Midostaurin from the solvents.
Preferably the precipitation step comprises cooling the Midostaurin solution to room temperature sufficient to bring about Midostaurin. Most preferably the temperature sufficient for precipitation of Midostaurin is about 25°C.
Preferably, in this embodiment, first solvent: second solvent or anti-solvent system combination is IPA : water.
EXAMPLES Example- 1: Process for preparation of Midostaurin
Prepared a solution of benzoic acid (315 mg; 2.6 mmol) and HBTU (1076 mg; 2.8 mmol) in DMF cool the solution at lO°C and add N,N-Diisopropyl ethyalmine (1.37 mL; 7.7 mmol). Stirred the reaction mixture for 90 minutes at 25°C. To the reaction mixture charged staurosporine (600 mg; 1.3 mmol). Stirred the reaction mixture for 4 hours. The reaction mass is diluted with water followed by extraction with ethyl acetate. The organic layer is dried over sodium sulphate and distilled under vacuum to get residue. Triturated the residue with ether. The solid obtained is filtered and dried to get Midostaurin. (Yield: 61%; purity by HPLC: 88%). Midostaurin as obtained is purified by solvent - anti-solvent precipitation procedure using IPA and water. (Purity by HPLC: 97%)
Example-2: Process for preparation of Midostaurin Prepared a solution of benzoic acid (50 mg; 0.4 mmol) and HBTU (170 mg; 0.45 mmol) in DMF. Added N,N-Diisopropyl ethyalmine (220 mL; 1.3 mmol). Stirred the mixture for 90 minutes at 25°C, charged staurosporine (600 mg; 1.3 mmol) to the reaction mixture. Stirred the reaction mixture for 4 hours. The reaction mass is
diluted with water followed by extraction with ethyl acetate. The organic layer is dried over sodium sulphate and distilled under vacuum to get residue. Triturated the residue with ether. The solid obtained is filtered and dried to get Midostaurin. (Yield: 70%; purity by HPLC: 88%). The obtained solid is eluted with ethyl acetate and dichloromethane system to get Midostaurin with purity >97% by HPLC.
Claims
We Claim, [CLAIM 1], A process for the preparation of Midostaurin compound of formula
I which comprising:
(i) reacting the staurosporine with benzoic acid in presences of condensing agent and solvent;
(ii) purifying Midostaurin;
(iii) isolating Midostaurin.
[CLAIM 2\. The process according to claim 1, wherein condensing agent selected from the group consisting of 2-(lH-benzotriazol-l-yl) - 1,1, 3, 3- tetramethyluronium hexafluorophosphate (HBTU), N- Hydroxybenzotriazole (HOBt), Diisopropylethylamine(DIPEA).
[CLAIM 3]. The process according to claim 1, wherein solvent selected from the group consisting polar aprotic solvents.
[CLAIM 4]. The process according to claim 1, wherein polar aprotic solvents are N-Methyl-2-pyrrolidone (NMP), Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate (EtOAc), Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Dimethylacetamide and combinations thereof .
[CLAIM 5]. The process according to claim 1, wherein purification of
Midostaurin comprises,
(i) treating Midostaurin crude with first solvent;
(ii) adding a second solvent to the crude Midostaurin -first solvent mixture, wherein the second solvent is an anti- solvent;
(iii) precipitating Midostaurin from the solvents;
(iv) collecting the crystals of Midostaurin; and
(v) optionally washing and drying Midostaurin.
[CLAIM 6]. The process according to claim 5, wherein solvent is IPA.
[CLAIM 7]. The process according to claim 5, wherein anti solvent is water.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112812129A (en) * | 2020-12-31 | 2021-05-18 | 浙江海正药业股份有限公司 | Novel crystalline form of midostaurin, process for its preparation and its use |
| 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 |
| WO2022243679A2 (en) | 2021-05-18 | 2022-11-24 | Kinomica Limited | Methods and kits for predicting the efficacy of midostaurin for the treatment of cancer |
| 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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296110A2 (en) * | 1987-06-15 | 1988-12-21 | Ciba-Geigy Ag | Staurosporine derivatives substituted for the nitrogen atom of the methylamino group |
| US5093330A (en) * | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
| WO1993007153A1 (en) * | 1991-10-10 | 1993-04-15 | Schering Corporation | 4'-(n-substituted-n-oxide)staurosporine derivatives |
| US8198435B2 (en) * | 2004-11-05 | 2012-06-12 | Novartis Ag | Crystal form of N-benzoyl-staurosporine |
-
2019
- 2019-05-09 WO PCT/IN2019/050369 patent/WO2019215759A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296110A2 (en) * | 1987-06-15 | 1988-12-21 | Ciba-Geigy Ag | Staurosporine derivatives substituted for the nitrogen atom of the methylamino group |
| US5093330A (en) * | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
| WO1993007153A1 (en) * | 1991-10-10 | 1993-04-15 | Schering Corporation | 4'-(n-substituted-n-oxide)staurosporine derivatives |
| US8198435B2 (en) * | 2004-11-05 | 2012-06-12 | Novartis Ag | Crystal form of N-benzoyl-staurosporine |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112812129A (en) * | 2020-12-31 | 2021-05-18 | 浙江海正药业股份有限公司 | Novel crystalline form of midostaurin, process for its preparation and its use |
| WO2022142914A1 (en) * | 2020-12-31 | 2022-07-07 | 浙江海正药业股份有限公司 | Novel crystal form of midostaurin, preparation method therefor and use thereof |
| 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 |
| CN115124551A (en) * | 2021-03-24 | 2022-09-30 | 奥锐特药业(天津)有限公司 | Preparation method of high-purity midostaurin |
| 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 |
| WO2022243679A2 (en) | 2021-05-18 | 2022-11-24 | Kinomica Limited | Methods and kits for predicting the efficacy of midostaurin for the treatment of cancer |
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