CN111848490A - Preparation method of high-purity ethanesulfonic acid nintedanib - Google Patents
Preparation method of high-purity ethanesulfonic acid nintedanib Download PDFInfo
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- CN111848490A CN111848490A CN202010854183.9A CN202010854183A CN111848490A CN 111848490 A CN111848490 A CN 111848490A CN 202010854183 A CN202010854183 A CN 202010854183A CN 111848490 A CN111848490 A CN 111848490A
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
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- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
Abstract
The invention discloses a preparation method of high-purity ethanesulfonic acid nintedanib, which comprises the following steps: step 1, carrying out one-pot reaction on toluene, SM01, triethyl orthobenzoate, acetic anhydride and DMAP, and carrying out suction filtration to obtain a high-purity intermediate INT 02; step 2, carrying out reaction on INT02 and SM02 in a specific solvent system, and separating to obtain an intermediate INT 03; step 3, reacting INT03 with methanol and KOH to obtain INT 04; and 4, reacting INT04, methanol and ethanesulfonic acid, and adding methyl tertiary butyl ether and isopropyl ether to obtain the ethanesulfonic acid nintedanib.
Description
Technical Field
The invention relates to a preparation method of high-purity ethanesulfonic acid nintedanib, belonging to the field of drug synthesis.
Background
The Nintedanib ethanesulfonate is an oral small molecule kinase inhibitor developed by Varinger Invitrogen, Germany, and can simultaneously block the signal transduction pathways of Vascular Endothelial Growth Factor Receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and Fibroblast Growth Factor Receptor (FGFR). FDA and EMA of the united states approved nintedanib for the treatment of Idiopathic Pulmonary Fibrosis (IPF) in 2014, EMA of the european union approved nintedanib in combination with Docetaxel (Docetaxel) in 2014 for use in adult patients with locally advanced or metastatic or locally recurrent NSCLC who were histologically diagnosed as adenocarcinoma after first-line chemotherapy. The 2016 European Commission (EC) and the U.S. Food and Drug Administration (FDA) grant nintedanib orphan drug eligibility for the treatment of systemic sclerosis (SSc, also known as scleroderma) and its associated interstitial lung disease (SSc-ILD).
The synthesis routes and preparation methods of the ethanesulfonic acid nintedanib have many reports, and the published synthesis routes and preparation methods are checked, so that the ethanesulfonic acid nintedanib is prepared by protecting different functional groups of the following three intermediates SM01, SM02 and INT02 and deprotecting groups through different chemical reactions, different reaction sequences and different linking modes.
The technical scheme of synthesizing the nintedanib by taking SM01 (2-oxoindole-6-methyl formate) as a starting material is more, and CN104844499 takes SM01, methyl benzoate and SM02 as raw materials, and is condensed by taking DMF (dimethyl formamide) or methanol as a solvent under the action of inorganic base to obtain a crude product of the nintedanib, and the crude product is refined by dichloromethane/methanol to obtain a finished product. CN105461609 is condensed with benzaldehyde by SM01, then hydroxyl on the double bond is replaced by halogen, and then the halogen is connected with amino in SM02 to obtain the nintedanib. CN101883756 uses SM01 as starting material, after condensation reaction with chloroacetic anhydride and triethyl orthobenzoate, removes amino protecting group (chloroacetyl group), and then connects with amino group in SM02, to obtain Nintedanib, the route is basically the same as the synthesis route reported in journal synthesis chemistry 2015,23(8),763-766, the main difference is that chloroacetic anhydride replaces acetic anhydride, and toluene is removed as solvent and non-ethanesulfonate.
The patent WO2009/071523 describes that 4-chloro-3-nitrobenzoic acid is used as a starting material, methyl ester is formed first, then the methyl ester is condensed with dimethyl malonate, Pd/C is catalyzed and hydrogenated to prepare SM01, and then the SM01 is condensed with chloroacetic anhydride and triethyl orthobenzoate to react, then an amino protecting group (chloroacetyl group) is removed, and the obtained product is connected with an amino group in SM02 (N-methyl-4-nitroaniline is used as a raw material to prepare SM02) to obtain the ninhydrin. There is no big difference with CN 101883756.
Patent CN107935909 reports that 3-nitro-4-halogen methyl benzoate is used as raw material, condensed with methyl (ethyl) benzoylacetate, and subjected to hydrogenation and cyclization reactions to obtain 3-benzoyl substituted SM01, hydroxyl on double bond is substituted by halogen, and then connected with amino in SM02 to obtain nintedanib. This route differs from CN105461609 only in the way of introducing benzoyl at SM 01.
The above background analysis shows that the current patent related to the preparation of the ethanesulfonic acid nintedanib takes SM01 or INT02 which is the next intermediate thereof or other chemical raw materials (such as 3-nitro-4-halogen methyl benzoate) capable of preparing SM01 as starting materials, amino protecting groups are removed, and then the starting materials and SM02 are subjected to condensation reaction to form salt with ethanesulfonic acid to obtain the product. One of the methods is to prepare an intermediate in a one-pot way (such as CN104844499) to simplify the operation, but the intermediate cannot be separated due to complex reaction, so that the purity of the product is reduced.
The method comprises the steps of taking SM01 or an intermediate INT02 of the next step of the method or other chemical raw materials (such as 3-nitro-4-halogen methyl benzoate) capable of preparing SM01 as starting raw materials, removing an amino protecting group firstly, and then carrying out condensation reaction with SM02 to obtain the nintedanib, wherein the amino protecting group in the compound INT02 is removed firstly, so that an imino group is exposed, and the next step of condensation reaction with SM02 is easy to compete with an amino group in SM02, so that the generation of byproducts is increased, and the purity of the product is finally reduced.
In the salifying process of nintedanib and ethanesulfonic acid, the patent CN109988094 of the Chi pharmacy application in Shiyao group uses methanol as a reaction solvent, and the generation of genotoxic impurities can be reduced by adopting a method of dripping isopropanol for crystallization after the reaction is finished. In the scheme, methyl tert-butyl ether is adopted as a crystallization solvent, so that the generation of the gene impurities can be avoided. In the experiment of the salification process, specific impurities exist at the position of 0.9 time of retention time of the main peak of the nintedanib, the nintedanib is difficult to remove by adopting a methyl tertiary butyl ether crystallization or washing method, and although the specific impurities in front of the main peak of the nintedanib in a liquid phase diagram can be reduced by adjusting the ratio, the temperature, the time and the crystallization solvent of the nintedanib and the ethanesulfonic acid in the salification process: n on the piperazine ring is methylated (chemical name: 1H-indole-6-carboxylic acid, 2, 3-dihydro-3- [ [ [4- [ methyl [ (4-dimethyl-1-piperazinyl) acetyl ] amino ] phenyl ] amino ] phenylmethylene ] -2-oxo-, methyl ester; IMP01), but the impurities obtained by the conventional method are all 0.1% or more.
The inventor unexpectedly finds that in the last purification step of the ethanesulfonic acid nintedanib, isopropyl ether is dropwise added into a crystallization solution, and the content of the specific impurity IMP01 can be greatly reduced to be below 0.1% by adopting a staged crystallization method.
Disclosure of Invention
The invention discloses a preparation method of high-purity ethanesulfonic acid nintedanib, which comprises the following steps:
the operation steps are as follows:
s1: preparation of intermediate INT 02:
adding toluene, SM01, triethyl orthobenzoate, acetic anhydride and DMAP into a reaction kettle at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating out part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
s2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF into a reaction kettle at room temperature, stirring and heating to 60-65 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into the reaction kettle, and the temperature is raised to 50-55 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
s4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
Wherein in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 4-8: 5-10: 10-20: 0.01-0.05, the solvent is toluene, the reflux temperature of the reaction is 104-110 ℃, and the stirring time of the reaction is 6-10 h.
In step S1, the volume of the evaporated solvent is 2-5 times of the weight of the starting material SM 01;
in step S1, cooling the reaction solution to 55-60 ℃, keeping the temperature, stirring and growing the crystals for 1h, cooling to 20-25 ℃, keeping the temperature and growing the crystals for 1 h;
in step S1, the amount of toluene washed by the cake was 3 to 6 times the weight of SM 01.
In the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.7-1: 4-8: 2-8, DMF as solvent, 60-65 ℃ as reaction temperature and 8-12h as reaction time;
in step S2, cooling the reaction solution to 20-25 deg.C, maintaining the temperature, stirring, and growing crystal for 1h, cooling to 0-10 deg.C, maintaining the temperature, and growing crystal for 1 h;
in the step S3, the mass ratio of INT03 to methanol to potassium hydroxide is 1: 10-16: 0.01-0.05, the solvent is methanol, the reaction temperature is 50-55 ℃, and the reaction time is 2-4 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
In step S3, cooling the reaction solution to 0-10 ℃, preserving heat and growing crystal for 1h, and filtering;
in the step S4, the mass ratio of INT04 to the ethanesulfonic acid solution to the methanol to the methyl tertiary butyl ether to the isopropyl ether is 1: 0.3-0.4: 7-10: 5-10: 2-4, the solvent is methanol, the reaction temperature is 50-55 ℃, and the reaction time is 1-3 h;
in the step S4, the dripping temperature of the ethanesulfonic acid solution is 50-55 ℃, after the dripping is finished and the temperature is kept, stirring and cooling are carried out to 40-45 ℃, and methyl tertiary butyl ether is dripped;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-10 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
in step S4, the mass ratio of methyl tertiary butyl ether to isopropyl ether is 10: 5-10.
In the present invention, SM 01: 2-oxoindole-6-carboxylic acid methyl ester; SM 02: n- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide; INT 02: (E) -1-acetyl-3- [ ethoxyphenylmethylene ] -2-oxo-1H indole-6-carboxylic acid methyl ester, DMAP: 4-dimethylaminopyridine, all commercially available.
The core steps of the invention are:
s1: preparation of intermediate INT 02:
adding toluene, SM01, triethyl orthobenzoate, acetic anhydride and DMAP into a reaction kettle at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating out part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
s2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF into a reaction kettle at room temperature, stirring and heating to 60-65 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
s4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
The invention has the beneficial effects that:
1. firstly, preparing an intermediate INT02 by a one-pot method, taking toluene as a solvent, adding a catalyst 4-Dimethylaminopyridine (DMAP), improving the reaction efficiency and the product purity, shortening the original reaction time from 10-15h to 6-10h, and simultaneously realizing the recycling of the solvent toluene, so that the process is energy-saving and environment-friendly, the operation is simple and convenient, and the purity of the intermediate INT02 is more than 99.0%. (details are shown in Table 2, examples 1-7)
2. In the preparation of INT03, further deacetylation is avoided by controlling the solvent and the reaction temperature, and the reaction can be effectively controlled to stay in INT 03; meanwhile, high-purity INT03 is obtained by separation, so that the generation of ethyl ester exchange impurities is effectively controlled. One-step quality control is added, and the exceeding risk of other impurities is effectively reduced, so that the quality of the ethanesulfonic acid nintedanib is guaranteed.
3. And (3) carrying out alkaline hydrolysis on the high-purity INT03 in a methanol solvent to prepare an intermediate INT04, and salifying the intermediate INT04 and ethanesulfonic acid in the methanol solvent to prepare a finished product, so that the quality of the finished product of the ethanesulfonic acid nintedanib is easier to control. (in the prior art, the product is directly obtained by adopting a one-pot method without separating and purifying intermediates or the product is obtained by adopting a method that INT02 is firstly deaminated and then condensed and connected with SM02, and the byproducts are more)
4. In the step of preparing the ethanesulfonic acid nintedanib, the raw material proportion, the reaction temperature and the time are controlled, a staged crystallization process is adopted, methyl tert-butyl ether is used for crystallization, isopropyl ether is used for crystallization at a lower temperature, so that the crystals are completely separated out, specific impurities are removed, and finally the purity of the ethanesulfonic acid nintedanib product is not lower than 99.5%, and any single impurity is not higher than 0.1%. (isopropyl ether is not used in the prior art, has larger polarity than methyl tert-butyl ether, and has good removal effect on organic impurities with polarity larger than that of the product)
Table one: the beneficial effects of the invention are further illustrated by comparative experiments as follows:
note: the closest prior art is example 1 in CN109988094
Wherein, the content detection method of specific impurity IMP01, total impurities and any other single impurities comprises the following steps:
liquid chromatograph: thermo Fisher U3000 or performance equivalent instrument; a chromatographic column: welch Xtimate C184.6X 150mm 3 μm;
mobile phase 0.01mol/L diammonium phosphate solution (pH 6.6 ± 0.1): about 1.32g of diammonium hydrogen phosphate is weighed into 1L of purified water, and after complete dissolution, the pH is adjusted to 6.6 +/-0.1 by phosphoric acid and shaking is carried out uniformly. Test solution (0.6 mg/ml): weighing about 30mg of the product, accurately weighing, placing in a 50ml measuring flask, adding about 25ml of methanol-water (70: 30), performing ultrasonic treatment for about 2 minutes to dissolve, cooling, adding methanol-water (70: 30) to dilute to scale, and shaking to obtain sample solution. Measurement and calculation: precisely measuring blank solvent and sample solution 10 μ l each, injecting into liquid chromatograph, and recording chromatogram. Calculated as peak area by principal component control method.
In conclusion, the invention adjusts the proportion of reactants, optimizes the reaction time, the temperature and the post-treatment mode, selects the specific catalyst and the crystallization solvent, improves the reaction efficiency of the intermediate, shortens the reaction time, improves the purity of the intermediate, obtains the high-purity ethanesulfonic acid nintedanib by adopting different crystallization solvents and stage crystallization processes in the preparation of the ethanesulfonic acid nintedanib, reduces the production cost, has the advantages of high efficiency and clean production, and has strong operability, the purity of the obtained ethanesulfonic acid nintedanib product is not less than 99.5%, and any single impurity is not more than 0.1%.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
1730g of toluene, 200gSM01 g of triethyl orthobenzoate, 1170g of acetic anhydride and 4g of DMAP are added into a reactor at room temperature, mechanical stirring is carried out, the temperature is increased, reflux reaction is carried out, part of solvent is evaporated out in the reaction process, the temperature is reduced, and crystal growth is carried out by stirring and heat preservation. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 5.8: 5.4: 8.7: 0.02, the reflux temperature of the reaction is 104-110 ℃, and the stirring time of the reaction is 7 h.
In step S1, the volume of the evaporated solvent is 2 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 60-65 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.8: 6: 3, and the reaction time is 10 h;
s3: preparation of intermediate INT 04:
INT03 and methanol were added to the reactor, stirred and warmed to 50-55 ℃. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 10: 0.02, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.3: 7: 6: 3, and the reaction time is 1-3h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-10 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 2
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
adding 1000g of toluene, 100gSM01 g of triethyl orthobenzoate, 620g of acetic anhydride and 3g of DMAP into a reactor at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 6.2: 6.1: 10: 0.03, the reflux temperature of the reaction is 106-114 ℃, and the stirring time of the reaction is 6 h.
In step S1, the volume of the evaporated solvent is 3 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 60-65 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.9: 7: 4, and the reaction time is 11 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 45-50 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-5 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 12: 0.03, and the reaction time is 3 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.3: 8: 7: 4, and the reaction time is 2h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 25-30 ℃ firstly, and crystal growth is carried out for 1h under the condition of heat preservation; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 3
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
1200g of toluene, 100gSM01 g of triethyl orthobenzoate, 520g of triethyl orthobenzoate, 720g of acetic anhydride and 4g of DMAP are added into a reactor at room temperature, the mechanical stirring, the temperature rising and the reflux reaction are carried out, part of solvent is evaporated out in the reaction process, the temperature is reduced, the heat preservation and the stirring are carried out, and the crystal growth is carried out. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 5.2: 7.2: 12: 0.04, the reflux temperature of the reaction is 104-114 ℃, and the stirring time of the reaction is 8 h.
In step S1, the volume of the evaporated solvent is 4 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 4 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 50-55 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 30 ℃, then cooling to 0-5 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.8: 6: 4, and the reaction time is 12 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 40-45 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 5-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 14: 0.04, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 45 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-5 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with isopropyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.4: 10: 8: 4, and the reaction time is 2h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 15-20 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 4
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
1300g of toluene, 100gSM01 g of triethyl orthobenzoate, 550g of triethyl orthobenzoate, 750g of acetic anhydride and 5g of DMAP are added into a reactor at room temperature, the mechanical stirring, the temperature rising and the reflux reaction are carried out, part of solvent is evaporated out in the reaction process, the temperature is reduced, the heat preservation and the stirring are carried out, and the crystal growth is carried out. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 5.5: 7.5: 13: 0.05, the reflux temperature of the reaction is 105-110 ℃, and the stirring time of the reaction is 8 h.
In step S1, the volume of the evaporated solvent is 4 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 50-60 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.8: 8: 5, and the reaction time is 10 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 50-60 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 5-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 14: 0.03, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 55 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with chilled water to 45 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-5 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.4: 10: 8: 4, and the reaction time is 1h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 5
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
adding 500g of toluene, 50gSM01 g of triethyl orthobenzoate, 400g of acetic anhydride and 2.5g of DMAP into a reactor at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 8: 7: 10: 0.05, the reflux temperature of the reaction is 102-112 ℃, and the stirring time of the reaction is 10 hours.
In step S1, the volume of the evaporated solvent is 5 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 50-60 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.9: 8: 4, and the reaction time is 10 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 40-50 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 12: 0.04, and the reaction time is 1 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 40-50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with chilled water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-5 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether and isopropyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.3: 10: 9: 5, and the reaction time is 1h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 25-30 ℃ firstly, and crystal growth is carried out for 1h under the condition of heat preservation; then adding isopropyl ether dropwise, then reducing the temperature to 5-10 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 6
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
1100g of toluene, 100gSM01 g of triethyl orthobenzoate, 450g of acetic anhydride and 2g of DMAP are added into a reactor at room temperature, mechanical stirring is carried out, the temperature is raised, reflux reaction is carried out, part of solvent is evaporated out in the reaction process, the temperature is lowered, and heat preservation, stirring and crystal growth are carried out. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 4.5: 6: 11: 0.02, the reflux temperature of the reaction is 102-110 ℃, and the stirring time of the reaction is 9 h.
In step S1, the volume of the evaporated solvent is 3 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 50-60 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.7: 7: 4, and the reaction time is 9 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 50-60 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 13: 0.02, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50-55 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with chilled water to 40-45 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with isopropyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.4: 10: 6, and the reaction time is 1h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
example 7
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
adding 600g of toluene, 50gSM01 g of triethyl orthobenzoate, 200g of acetic anhydride and 2g of DMAP into a reactor at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 4: 6: 12: 0.04, the reflux temperature of the reaction is 105-115 ℃, and the stirring time of the reaction is 8 hours.
In step S1, the volume of the evaporated solvent is 3 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 50-60 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.9: 6: 4, and the reaction time is 12 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 50-60 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 10: 0.03, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 55 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with chilled water to 45 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-5 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether and isopropyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.4: 8: 6: 4, and the reaction time is 1h with methanol as a solvent;
in the step S4, after methyl tertiary butyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
comparative example 1
A preparation method of high-purity ethanesulfonic acid nintedanib comprises the following steps:
s1: preparation of intermediate INT 02:
1300g of toluene, 100gSM01 g of triethyl orthobenzoate, 550g of triethyl orthobenzoate, 750g of acetic anhydride and 5g of DMAP are added into a reactor at room temperature, the mechanical stirring, the temperature rising and the reflux reaction are carried out, part of solvent is evaporated out in the reaction process, the temperature is reduced, the heat preservation and the stirring are carried out, and the crystal growth is carried out. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
in the step S1, the mass ratio of SM01 to triethyl orthobenzoate to acetic anhydride to toluene to DMAP is 1: 5.5: 7.5: 13: 0.05, the reflux temperature of the reaction is 90-100 ℃, and the stirring time of the reaction is 8 h.
In step S1, the volume of the evaporated solvent is 3 times of the weight of the starting material SM 01;
in step S1, the amount of cake-washed toluene was 3 times the weight of SM 01.
S2: preparation of intermediate INT 03:
adding INT02, SM02 and DMF (dimethyl formamide) into a reactor at room temperature, stirring and heating to 40-50 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
in the step S2, the mass ratio of INT02, SM02, DMF and methyl tertiary butyl ether is 1: 0.8: 8: 5, and the reaction time is 10 h;
s3: preparation of intermediate INT 04:
INT03 and methanol are added into a reactor, and the temperature is raised to 40-50 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 5-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
in the step S3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 14: 0.03, and the reaction time is 2 h;
in step S3, the methanol is used as a reaction solvent, a complex base and a washing solution in a weight ratio of 8: 1: 2.
S4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 45 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 35 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
In the step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tertiary butyl ether and isopropyl ether is 1: 0.4: 10: 8: 4, and the reaction time is 0.5h when the solvent is methanol;
comparative example 2
The difference from example 1 is that:
s1: preparation of intermediate INT02 without addition of catalyst DMAP
The effects are all better than those of comparative example 1: the process parameters are different; comparative example 2: no catalyst is added in step S1; comparative example 3: step S1 is not to evaporate part of the solvent; comparative example 4: in step S1, no catalyst is added and no part of the solvent is distilled off; comparative example 5: directly crystallizing by one step by adopting methyl tert-butyl ether; comparative example 6: the solvents adopted by the stage crystallization are all isopropyl ether; comparative example 7: the intermediate INT02 is prepared by firstly removing amino protection, then condensing with SM02, and then salifying with ethanesulfonic acid solution.
Comparative example 3
The difference from example 2 is that:
s1: preparation of intermediate INT02 without distilling off a portion of the solvents toluene and ethyl acetate
Comparative example 4
The difference from example 3 is that:
s1: preparation of intermediate INT02 without addition of DMAP catalyst and without distillation of part of the solvents toluene and ethyl acetate
Comparative example 5
The difference from example 4 is that: direct one-step crystallization by adopting methyl tert-butyl ether
S4: preparation of the ethanesulfonic acid nintedanib:
in the step S4, after methyl tertiary butyl ether is dripped, the temperature of the reaction liquid is firstly reduced to 20-25 ℃, then reduced to 0-5 ℃, and the heat preservation and crystal growth are carried out for 1 hour for filtration;
comparative example 6
The difference from example 5 is that: the solvents adopted by stage crystallization are all isopropyl ether
S4: preparation of the ethanesulfonic acid nintedanib:
in the step S4, the mass ratio of INT04, the ethanesulfonic acid solution, the methanol and the isopropyl ether is 1: 0.4: 10, and the reaction time is 1h with the solvent of the methanol;
in the step S4, after the isopropyl ether is dripped, the reaction solution is cooled to 20-25 ℃, and the temperature is kept for 1 hour to grow the crystals; then adding isopropyl ether dropwise, then reducing the temperature to 0-5 ℃, preserving the temperature and growing the crystals for 1h, and filtering;
comparative example 7
Referring to CN101883756 example 4, the intermediate INT02 was prepared by first deaminating, then condensing with SM02 and then salifying with ethanesulfonic acid solution as follows.
In step S2, a solution of potassium hydroxide (0.41g, 0.006mol) in methanol (4ml) was added dropwise to a suspension of intermediate INT02(8.0g, 0.022mol) in methanol (32ml) at 50-55 ℃. The mixture was then stirred for 30 minutes, cooled to 0 ℃ and maintained under stirring for 2 hours. Filtration and washing of the solid with cold methanol (24ml) and drying in vacuo gave 5.8g of a pale yellow solid.
In step S3, a suspension of the solid methyl 3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (5.0g, 0.016mol) and N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (4.3g, 0.016mol) of the previous step in a mixture of methanol (36ml) and N, N-dimethylformamide (10ml) was heated to reflux. After refluxing for 7 hours, the suspension was cooled to 0 ℃ and maintained under stirring for a further 2 hours. The solid was filtered, washed with methanol (40ml) and dried in vacuo to yield 7.5g of INT04 as a yellow powder.
The present invention is not limited to the above-described embodiments, and various changes may be made by those skilled in the art, and any changes equivalent or similar to the present invention are intended to be included within the scope of the claims.
TABLE 2 Effect of the Ethanesulfonic acid nintedanib products prepared in the respective examples and comparative examples
From the data in the table, it can be seen that the intermediate INT02 and the nedanib ethanesulfonate products prepared in examples 1 to 7 within the process range of the present invention have high purity, the yield of the nedanib ethanesulfonate products is good, the content of any single impurity is low, and the effect is better than that of comparative example 1: the process parameters are different; comparative example 2: no catalyst is added in step S1; comparative example 3: step S1 is not to evaporate part of the solvent; comparative example 4: in step S1, no catalyst is added and no part of the solvent is distilled off; comparative example 5: directly crystallizing by one step by adopting methyl tert-butyl ether; comparative example 6: the solvents adopted by the stage crystallization are all isopropyl ether; comparative example 7: the intermediate INT02 is prepared by firstly removing amino protection, then condensing with SM02, and then salifying with ethanesulfonic acid solution. The effect of example 4 is particularly optimum. According to the preparation method of the high-purity ethanesulfonic acid nintedanib, DMAP is selected as a catalyst in the process of preparing the intermediate INT02, partial solvent is evaporated in the reaction process, the reaction time is shortened, the purity of the intermediate INT02 is improved, different crystallization solvents and stage crystallization processes are adopted after the crude product of the ethanesulfonic acid nintedanib is obtained, the purity of the obtained ethanesulfonic acid nintedanib product is not lower than 99.5%, and any single impurity is not more than 0.1%. Reduces the production cost and has the advantages of high efficiency and clean production.
Claims (8)
1. A preparation method of high-purity ethanesulfonic acid nintedanib is characterized by comprising the following steps: the synthetic route is as follows:
2. the production method according to claim 1, characterized in that: the method comprises the following steps:
step 1: preparation of intermediate INT 02:
adding toluene, SM01, triethyl orthobenzoate, acetic anhydride and DMAP into a reaction kettle at room temperature, mechanically stirring, heating, carrying out reflux reaction, evaporating out part of solvent in the reaction process, cooling, keeping the temperature, stirring and growing crystals. Filtering, washing a filter cake with toluene, crushing a wet product, and drying in vacuum to obtain a grayish soil solid product INT 02;
step 2: preparation of intermediate INT 03:
adding INT02, SM02 and a solvent into a reaction kettle at room temperature, stirring and heating to 60-70 ℃, carrying out heat preservation reaction, stirring and slowly cooling to 25 ℃, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, filtering, washing a filter cake with methyl tertiary butyl ether, and carrying out vacuum drying on the solid to obtain a yellow solid INT 03;
and step 3: preparation of intermediate INT 04:
INT03 and methanol are added into the reaction kettle, and the temperature is raised to 50-55 ℃ by stirring. Dripping KOH/methanol solution while stirring, keeping the temperature for reaction, and slowly cooling to 0-10 ℃. Preserving heat, growing crystals, filtering, washing a filter cake with cold methanol, and drying the solid in vacuum to obtain a yellow solid INT 04;
and 4, step 4: preparation of the ethanesulfonic acid nintedanib:
adding INT04 and methanol into a reaction kettle at room temperature, stirring and heating to 50 ℃, dripping 70% ethanesulfonic acid solution, carrying out heat preservation reaction, cooling with cold water to 40 ℃, dripping methyl tert-butyl ether, slowly cooling to room temperature, dripping isopropyl ether, then cooling to 0-10 ℃, carrying out heat preservation and crystal growth for 1h, carrying out suction filtration, washing a filter cake with methyl tert-butyl ether, and carrying out vacuum drying on a wet product to obtain yellow solid ethanesulfonic acid nintedanib.
3. The method of claim 2, wherein: wherein in the step 1, the mass ratio of SM01, triethyl orthobenzoate, acetic anhydride, toluene and DMAP is 1: 4-8: 5-10: 8-16: 0.01-0.05, the solvent is toluene, the reflux temperature of the reaction is 104-110 ℃, and the stirring time of the reaction is 6-10 h.
4. The method of claim 2, wherein: wherein, in the step 1, the volume of the evaporated solvent is 2 to 5 times of the weight of the starting material SM 01; in the step 1, the temperature of the reaction liquid is firstly reduced to 55-60 ℃, the reaction liquid is kept warm and stirred for growing crystal for 1h, the temperature is reduced to 20-25 ℃, and the temperature is kept warm and the crystal is grown for 1 h; in step 1, the amount of toluene washed by the filter cake was 3-6 times the weight of SM 01.
5. The method of claim 2, wherein: wherein, in the step 2, the solvent is selected from: one or more mixed systems of toluene, N-dimethylformamide, N-dimethylformamide and dimethyl sulfone; in the step 2, the reaction temperature is 55-100 ℃; in the step 2, the mass ratio of INT02 to SM02 to solvent to methyl tertiary butyl ether is 1: 0.7-1: 4-8: 2-8, the solvent is DMF, the reaction temperature is 60-65 ℃, and the reaction time is 8-12 h; in the step 2, the temperature of the reaction liquid is firstly reduced to 20-25 ℃, the heat preservation and the stirring are carried out for crystal growth for 1h, the temperature is reduced to 0-10 ℃, and the heat preservation and the crystal growth are carried out for 1 h.
6. The method of claim 2, wherein: in the step 3, the mass ratio of INT03, methanol and potassium hydroxide is 1: 10-16: 0.01-0.05, the solvent is methanol, the reaction temperature is 50-55 ℃, and the reaction time is 1-4 h; in step 3, the methanol is used as a reaction solvent, an alkali and washing, and the weight ratio is 8: 1: 2; in step 3, the temperature of the reaction liquid is reduced to 0-10 ℃, and the reaction liquid is filtered after heat preservation and crystal growth for 1 hour.
7. The method of claim 2, wherein: in the step 4, the mass ratio of INT04, the ethanesulfonic acid solution, the methanol, the methyl tertiary butyl ether and the isopropyl ether is 1: 0.3-0.4: 7-10: 5-10: 2-4, the solvent is the methanol, the reaction temperature is 50-55 ℃, and the reaction time is 1-3 hours; in the step 4, the dripping temperature of the ethanesulfonic acid solution is 50-55 ℃, after the dripping is finished and the temperature is kept, stirring and cooling are carried out to 40-45 ℃, and methyl tertiary butyl ether is dripped; in the step 4, after methyl tertiary butyl ether is dropwise added, the reaction solution is cooled to 20-25 ℃, and crystal growth is carried out for 1h under the condition of heat preservation; then isopropyl ether is added dropwise, then the temperature is reduced to 0-10 ℃, crystal growth is carried out for 1h under the condition of heat preservation, and filtration is carried out.
8. The method according to claim 7, wherein: the mass ratio of the methyl tertiary butyl ether to the isopropyl ether is 10: 5-10.
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| CN112592307B (en) * | 2021-02-26 | 2021-06-18 | 上海翰森生物医药科技有限公司 | Preparation method of nintedanib intermediate |
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