Preparation method of oxitinib mesylate
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of oxitinib mesylate.
Background
Lung cancer patients are classified into "small cell lung cancer" and "non-small cell lung cancer" according to cancer cell morphology. About 85% of lung cancer patients are "non-small cell lung cancer". The Epidermal Growth Factor Receptor (EGFR) mutation is the most common gene variation of east Asia patients including Chinese non-small cell lung cancer patients, accounting for about 50-60%, and most EGFR-mutated non-small cell lung cancer patients can obtain better treatment effect by using an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Currently, EGFR-TKI targeted drugs on the market can be roughly divided into three generations of first generation EGFR-TKI targeted drugs represented by gefitinib and erlotinib, the treatment effect is good, the effective rate of patients is about 50% -70%, but about 60% of patients have EGFR T790M action site drug resistance mutation after about 10 months of use. In the clinical practical application process of second-generation EGFR-TKI targeting drugs represented by afatinib and dacatinib, the curative effect of the second-generation EGFR-TKI targeting drugs represented by afatinib and dacatinib is not better than that of the first-generation targeting drugs, and the side effects of the second-generation targeting drugs are relatively larger. More importantly, after the first generation of targeted drugs have drug resistance, the second generation of targeted drugs cannot overcome the drug resistance, so that the clinical application of the current second generation of targeted drugs is not wide. Patients who develop T790M resistance mutations after treatment with existing EGFR-TKI targeted drugs have very limited options for subsequent drug treatment. The third generation EGFR-TKI new drug oxitinib can be used for treating metastatic non-small cell lung cancer patients with T790M drug resistance mutation and ineffective second generation EGFR-TKI drug treatment. Oxitinib is the only drug which can effectively treat EGFR T790M mutation positive metastatic non-small cell lung cancer at present, and can prolong the survival time of nearly 30 percent of EGFR mutation patients.
Oxitinib mesylate (Osimertinib Mesilate, AZD9291), with a well-established name: n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide methanesulfonate, developed by astrazen, england and approved in advance by the american Food and Drug Administration (FDA) for accelerated approval on the market in 11.13.2015 under the trade name: tiresar (TAGRISSO).
The preparation method of the oxitinib mesylate reported in the literature mainly comprises the following steps:
the method comprises the following steps: in patent CN103702990B of Aslikang, 2-methoxy-4-fluoroaniline, 1-methylindole and 2, 4-dichloropyrimidine are used as raw materials, and the product of oxitinib is finally obtained through 6 steps of reaction, wherein the synthetic route is as follows:
in the route, 4-fluoro-2-methoxyaniline (formula (9)) is nitrified by mixed acid, amino is easily oxidized by sulfuric acid, so that the yield is low, and 4-fluoro-2-methoxy-5-nitroaniline (formula (2)) and sulfuric acid are salified and need to be neutralized by a large amount of alkali in post-treatment, so that inorganic salt far larger than the weight of 4-fluoro-2-methoxy-5-nitroaniline is generated, and three wastes are difficult to treat. In the literature, the compound of formula (4) is prepared by using p-toluenesulfonic acid as a catalyst, and the p-toluenesulfonic acid contains water, so that 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole (the compound of formula (3)) is easily reacted with water in the reaction process to generate 2-hydroxyl impurities, the purity of the compound of formula (4) is difficult to improve, a large amount of p-toluenesulfonic acid is difficult to remove, and residual p-toluenesulfonic acid is easily generated in the subsequent step of using an alcohol solvent, and impurities with potential genotoxicity, such as ethyl p-toluenesulfonic acid and the like, are easily generated, so that the finished product has potential carcinogenic risk.
The N, N, N '-trimethylethylenediamine adopted for preparing the compound of the formula (6) has the purity of about 98% in the market, and the main impurities are N, N, N', N '-tetramethylethylenediamine and N, N' -dimethylethylenediamine, wherein the N, N '-dimethylethylenediamine participates in the reaction and generates a plurality of byproducts, so that the purity of the compound of the formula (6) is difficult to improve, the purity and the quality of the finished product of oxitinib mesylate are further influenced, and the high market price of the N, N, N' -trimethylethylenediamine is unfavorable for market popularization and use of the oxitinib product. And the purification of formula (6) requires column chromatography, which is not conducive to industrial production.
The second method comprises the following steps: jimin, Liyuan et al reported in patent CN104817541B that 4-fluoro-2-methoxy-5-nitroaniline was first reacted with N, N, N' -trimethylethylenediamine and acryloyl chloride by amino protection, and then reacted with 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole to prepare Oxititinib, the synthetic route was as follows:
in addition, in the step of preparing the oxitinib, p-toluenesulfonic acid is adopted as a catalyst, isobutanol is adopted as a solvent, and the impurity of the p-toluenesulfonic acid with genetic toxicity is easily generated in an acidic environment, so that the product has great safety risk.
Based on this, the development of a low-cost, high-yield and environment-friendly synthetic method of oxitinib mesylate is a problem to be solved currently.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method of oxitinib mesylate. The invention uses 4-fluoro-2-methoxy-5-nitroaniline and 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole to carry out condensation reaction, then carries out nucleophilic substitution reaction with N, N-dimethylethylenediamine, obtains a high-purity compound shown in formula (6) by Eschweiler-Clarke amine reduction alkylation, then uses water as a solvent, acetic acid and the like as cosolvent, carries out catalytic hydrogenation, carries out amidation reaction with acryloyl chloride to obtain high-purity oxitinib, and forms salt with methanesulfonic acid to obtain the oxitinib mesylate.
The technical scheme of the invention is as follows: the preparation method of oxitinib mesylate is characterized by comprising the following steps:
s1: the 4-fluoro-2-methoxy-5-nitroaniline (the compound shown in the formula (2)) and 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole (the compound shown in the formula (3)) are subjected to condensation reaction to obtain N- (4-fluoro-2-methoxy-t-nitrophenyl) -4- (1H-3-indolyl) pyrimidine-2-amine (the compound shown in the formula (4))
S2: replacing fluorine in the compound of formula (4) with 2- (dimethylamino) ethyl) (methyl) amino to obtain a compound of formula (6);
s3: reduction of the nitro group of the compound of formula (6) to an amino group;
s4: then replacing hydrogen on the amino group by acryloyl to obtain oxitinib, and finally salifying with methanesulfonic acid to obtain oxitinib mesylate;
it is characterized in that the utility model is characterized in that,
in the step S1, the solvent is organic solvent, and anhydrous liquid acid (such as methanesulfonic acid) is used as a catalyst;
the step S2 specifically includes: reacting a compound shown in a formula (4) with N, N-dimethylethylenediamine in an alcohol solvent in the presence of alkali to generate a compound shown in a formula (5), carrying out an Eshweiler-Clarke amine alkylation reaction, and reacting formic acid with formaldehyde and formic acid to obtain a compound shown in a formula (6) by taking formic acid as a solvent;
the step S3 specifically includes: adjusting the pH value of the compound of the formula (6) in water with acid until the compound is dissolved in solid, and carrying out catalytic hydrogenation through a catalyst to obtain a compound of a formula (7);
in the step S4, the compound of formula (7) reacts with acryloyl chloride to obtain oxitinib.
The synthetic route is as follows:
wherein the content of the first and second substances,
the anhydrous liquid acid of the step S1 is one of methanesulfonic acid, trifluoroacetic acid and trichloroacetic acid, and preferably methanesulfonic acid. The 2-position chlorine of the 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole can generate substitution reaction with water (water in a solvent and water introduced by a catalyst acid) in an acid environment to generate 2 which is hydroxyl substituted impurity, thereby influencing the purity of the compound of the formula (4), wherein the reaction formula is as follows. Therefore, the anhydrous acid and the non-aqueous solvent are adopted, the side reaction can be effectively avoided, and the product purity and yield are improved.
The organic solvent of the step S1 is one or a mixture of two of n-butanol, dioxane, n-pentanol, 2-pentanol and n-propanol, and dioxane is preferred.
The alcohol solvent in step S2 is one or a mixture of two of ethanol, isopropanol, n-propanol, n-butanol, n-pentanol and isoamyl alcohol, preferably n-butanol. The reactivity of other solvents is similar to that of the n-butanol in terms of easy recovery, low price and simplicity of post-treatment of the n-butanol.
The base in step S2 is diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc., preferably diisopropylethylamine.
The acid in the step S3 is one of acetic acid, formic acid, phosphoric acid, trifluoroacetic acid and trichloroacetic acid, and preferably acetic acid.
The catalyst in step S3 is one of palladium carbon, platinum carbon, and raney nickel, preferably platinum carbon.
The organic solvent in the step S4 is one or a mixture of two of dichloromethane, chloroform, tetrahydrofuran and dioxane, preferably dichloromethane. The salifying solvent is isopropyl acetate.
The reaction temperature of the step S1 is 70-90 ℃, the reaction temperature of the step S2 for preparing the compound of the formula (5) is 100-120 ℃, and the reaction temperature of the step S2 for preparing the compound of the formula (6) is 80-100 ℃; the reaction temperature for preparing the oxitinib in the step S4 is-5-10 ℃.
Preferably, the method specifically comprises the following steps:
s1: adding 4-fluoro-2-methoxy-5-nitroaniline and 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole into a solvent 1, 4-dioxane, adding methanesulfonic acid, reacting at 70-90 ℃ for 3-8H, cooling, crystallizing, pulping, and drying to obtain a compound shown in the formula (4);
s2: reacting a compound shown in the formula (4), an alcohol solvent, alkali and N, N-dimethylethylenediamine at 100-120 ℃ for 18-22 h under heat preservation, filtering, washing and drying after the reaction is finished, thus obtaining a compound shown in the formula (5); preserving the heat of the compound of the formula (5), formic acid and formaldehyde aqueous solution at 70-90 ℃ for 1.5-3.5 h, removing the solvent by reduced pressure evaporation, and performing post-treatment to obtain a compound of the formula (6);
s3: adding the compound shown in the formula (6) into water, adjusting the pH value to be solid and dissolving the compound by using acetic acid, and performing hydrogen reduction reaction by using platinum carbon as a catalyst; obtaining the compound shown in the formula (7) through post treatment;
s4: dissolving the compound shown in the formula (7) in an organic solvent, dropwise adding acryloyl chloride into the mixed solution in ice bath, stirring and reacting at 0-5 ℃, adding water after the reaction is finished, adjusting the pH value to be more than 10 by using alkali, standing and layering, evaporating an organic layer under reduced pressure, adding isopropyl acetate into residues, heating to reflux, and adding methanesulfonic acid to form salt to obtain the oseltamivir mesylate.
Wherein, the post-processing of step S2 is: and (3) adding water and activated carbon into residues obtained after the solvent is removed through reduced pressure evaporation for decolorization, adjusting the pH value to 10 by using a sodium hydroxide solution, then adding isopropyl acetate, stirring overnight, precipitating an off-white solid, filtering, washing with water, and washing with isopropyl acetate to obtain the compound shown in the formula (6).
Wherein, the post-processing of step S3 is: filtering out platinum carbon, washing with water, using the platinum carbon for use, adjusting the pH value of the filtrate to 10 by using a sodium hydroxide solution, precipitating a solid, filtering, washing with water, and drying to obtain the compound shown in the formula (7).
The molar ratio of the anhydrous liquid acid to the 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole in the step S1 is 0.2: 1-2: 1, preferably 0.3: 1-1: 1, and more preferably 0.5: 1.
The molar ratio of the compound of formula (4) to N, N-dimethylethylenediamine in step S2 is 1: 1.2-1: 2.0, preferably 1: 1.5; the molar ratio of the compound of formula (5) to formaldehyde is 1:1.5 to 1:3, preferably 1:1.5 to 1:2.
The molar ratio of the compound of formula (7) to acryloyl chloride in step S4 is 1: 1.0-1.2, and the molar ratio of the compound of formula (7) to methanesulfonic acid is 1: 1.0-1.2.
The invention has the beneficial effects that:
1. in the preparation process of the compound of formula (4), solvents such as dioxane and the like are used as solvents, anhydrous acids such as methanesulfonic acid and the like are used as catalysts, the reaction condition is mild, 3- (2-hydroxy-4-pyrimidinyl) -1-methyl-1H-indole which is difficult to remove is avoided, the reaction yield is improved to more than 92% from 55%, and the purity is improved to more than 99.5%.
2. The compound of the formula (6) is prepared by reacting an alcohol solvent with N, N-dimethylethylenediamine and then carrying out Eschweiler-Clarke amine reduction alkylation reaction, so that although the reaction steps are prolonged, impurities which are difficult to remove are avoided, and meanwhile, a column chromatography purification step is not required in the process, so that the method is more favorable for industrialization.
3. The invention creatively takes water as a solvent, the compound shown in the formula (6) is subjected to catalytic hydrogenation reduction by a mode of adjusting pH by acetic acid and the like, palladium carbon, platinum carbon, raney nickel and the like are green processes recommended by the environmental protection department, the three wastes are less, and the solvent can be recycled.
4. The invention directly adopts acryloyl chloride to prepare the oxitinib, simplifies the process and improves the reaction yield. And then the isopropyl acetate is salified with methanesulfonic acid, so that the generation of genotoxic impurities of ethyl methanesulfonate and isopropyl methanesulfonate is avoided due to the difficult degradability of the isopropyl acetate, the safety of the product of oxitinib methanesulfonate is improved, and the potential gene mutation of a patient caused by potential toxic impurities is avoided.
Compared with the Chinese patent CN103702990B, the method has the advantages of simple operation, little environmental pollution, high yield (about 70 percent of total yield), low cost and good product quality, and is more suitable for industrial production.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1: preparation of N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (compound of formula (4))
Adding 61.4g (0.33mol) of 4-fluoro-2-methoxy-5-nitroaniline and 73.1g (0.3mol) of 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole into a 2000ml reaction bottle filled with 1200ml of 1, 4-dioxane, adding 14.4g (0.15mol) of methanesulfonic acid, heating to 80 ℃, keeping the temperature for 5H at 80 ℃, cooling to 0-10 ℃ for crystallization, filtering, pulping with 70% of ethanol water, washing, drying to obtain 113.2g of yellow solid, wherein the yield is 96.0%, and the HPLC purity is 99.5%.
Example 2: preparation of N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-amine (compound of formula (4))
Adding 61.4g (0.33mol) of 4-fluoro-2-methoxy-5-nitroaniline and 73.1g (0.3mol) of 3- (2-chloro-4-pyrimidinyl) -1-methyl-1H-indole into a 2000ml reaction bottle filled with 1200ml of 1, 4-dioxane, adding 17.1g (0.15mol) of trifluoroacetic acid, heating to 80 ℃, keeping the temperature for 5H at 80 ℃, cooling to 0-10 ℃ for crystallization, filtering, pulping with 70% of ethanol water, washing, drying to obtain 111.4g of yellow solid, wherein the yield is 94.5%, and the HPLC purity is 99.7%.
Example 3: preparation of N '- (2- (dimethylamino) ethyl) -5-methoxy-N' - (4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) nitrobenzene-1, 4-diamine (compound of formula (5))
Heating 78.6g (0.2mol) of the compound of the formula (4), 800ml of N-butanol, 38.7g (0.3mol) of diisopropylethylamine and 26g (0.3mol) of N, N-dimethylethylenediamine to 110 ℃, keeping the temperature at 110 ℃ for reaction for 20h, cooling to room temperature after the reaction is finished, separating out yellow solid, filtering, washing with N-butanol, and drying to obtain 84.8g of yellow solid, wherein the yield is 92.0% and the HPLC purity is 99.7%.
Example 4: preparation of N '- (2- (dimethylamino) ethyl) -5-methoxy-N' - (4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) nitrobenzene-1, 4-diamine (compound of formula (5))
78.6g (0.2mol) of the compound of the formula (4), 800ml of N-butanol, 28.8g (0.3mol) of sodium tert-butoxide and 26g (0.3mol) of N, N-dimethylethylenediamine are heated to 110 ℃, kept at 110 ℃ for reaction for 20 hours, cooled to room temperature after the reaction is finished, yellow solid is separated out, 200ml of water is slowly added, filtered, washed by the N-butanol, washed by water and dried to obtain 83.9g of yellow solid, the yield is 91.0 percent, and the HPLC purity is 99.8 percent.
Example 5: preparation of N '- (2- (dimethylamino) ethyl) -5-methoxy-N' - (4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) nitrobenzene-1, 4-diamine (compound of formula (5))
78.6g (0.2mol) of the compound of the formula (4), 800ml of N-butanol, 33.6g (0.3mol) of potassium tert-butoxide and 26g (0.3mol) of N, N-dimethylethylenediamine are heated to 110 ℃, kept at 110 ℃ for reaction for 20h, cooled to room temperature after the reaction is finished, yellow solid is separated out, 200ml of water is slowly added, the filtration is carried out, the N-butanol is washed, and 82.7g of dried yellow solid is washed, the yield is 89.7 percent, and the HPLC purity is 99.9 percent.
Example 6: preparation of N ' - (2- (dimethylamino) ethyl) -5-methoxy-N ' -methyl-N ' - (4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) nitrobenzene-1, 4-diamine (compound of formula (6))
Adding 75g (0.162mol) of the compound shown in the formula (5), 250ml of formic acid and 19.5g (37%, 0.24mol) of formaldehyde aqueous solution into a 2000ml reaction flask, slowly heating to 90 ℃, keeping the temperature for 2h, evaporating the solvent under reduced pressure, adding 1000ml of water into the residue, adding 5g of activated carbon, continuing stirring for 1h, filtering to remove insoluble substances, adjusting the pH value to 10 by using sodium hydroxide solution, adding 500ml of isopropyl acetate, stirring overnight, precipitating off-white solid, filtering, washing with water, washing with isopropyl acetate to obtain 71.44g, the yield is 92.8%, and the HPLC purity is 99.7%.
Example 7: preparation of N ' - (2- (dimethylamino) ethyl) -5-methoxy-N ' -methyl-N ' - (4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) phenyl-1, 4-diamine (compound of formula (7))
70g (0.147mol) of the compound of the formula (6) and 1000ml of water were put into a 2000ml reaction flask, the pH value was adjusted with acetic acid until the solid was dissolved, the mixture was transferred into a 2000ml autoclave, 3.5g of platinum carbon (5% content on a dry basis) was added under nitrogen protection, nitrogen substitution was carried out 3 times, and hydrogen gas was introduced to the autoclave to carry out a reaction for 3 hours. Filtering platinum carbon, washing with water, using platinum carbon, adjusting pH value of filtrate to 10 with sodium hydroxide solution, precipitating solid, filtering, washing with water, and drying to obtain off-white solid 63g, with yield 96.3% and HPLC purity 99.8%.
Example 8: preparation of oseltamiib mesylate
Dissolving 63g (0.14mol) of the compound shown in the formula (7) in 800ml of dichloromethane, slowly dripping 15.2g (0.168mol) of acryloyl chloride into the mixed solution under ice bath, stirring the mixture at 0-5 ℃ for reacting for 2h, adding 500ml of water after the reaction is finished, adjusting the pH value to be more than 10 by using sodium hydroxide solution, discarding a water layer, washing an organic layer once by using 500ml of water, decompressing and evaporating the organic layer, adding 800ml of isopropyl acetate into residues, heating to reflux, slowly adding 14.8g (0.154mol) of methanesulfonic acid to obtain clear liquid, filtering through a 0.45 mu m filter membrane, cooling the filtrate to 0-5 ℃, separating out a white solid, filtering, washing cold isopropyl acetate to obtain 75g, and obtaining the yield of 90.0%.