CN111072636B - Synthesis method of flumatinib - Google Patents
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Abstract
The invention discloses a synthesis method of flumatinib mesylate, and particularly provides a method for preparing flumatinib by using 4-methyl-3- (trifluoromethyl) benzonitrile as an initial raw material through three steps of reactions of bromination, substitution and coupling. The method has reasonable route and simple operation, avoids introducing genotoxic impurities, has high yield and purity, and is beneficial to the industrial production of the flumatinib and the improvement of the medicine quality.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of flumatinib mesylate.
Background
In recent years, imatinib has become a first-line drug for treating chronic myeloid leukemia, but is easily resistant after use. The flumatinib mesylate is a new generation of leukemia treatment drug developed on the basis of imatinib, is mainly used for treating chronic granulocytic leukemia, and can better solve the drug resistance problem.
The chemical name of the flumatinib mesylate is: 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 6-methyl-5- [ [4- (3-pyridinyl) -2-pyrimidinyl ] amino ] pyridin-3-yl ] -3- (trifluoromethyl) -benzamide methanesulfonate having the following specific structure:
flumatinib mesylate is a novel second-generation BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) which is independently developed in China. Clinical study results show that compared with imatinib, the flumatinib treats chronic myelogenous leukemia (CML-CP) in a chronic stage, cytogenetic and molecular treatment responses are faster and response rate is higher, and adverse events such as edema, limb pain, rash, neutropenia and the like are lower in incidence rate. On the aspect of hematologic toxicity, the incidence of neutropenia and anemia of the flumatinib group is obviously lower than that of imatinib. On non-hematologic toxicity, rash and eyelid edema occurred significantly lower in the flumatinib group than in imatinib. This study demonstrates that flumatinib, a first-line treatment for newly diagnosed CML-CP patients, has a faster and deeper molecular response than imatinib. The flumatinib treatment has good safety and tolerance.
WO2006069525 discloses a process for the preparation of aminopyrimidines and relates to a process for the preparation of products by condensation reactions, and also discloses some specific condensing agents. However, in general, the use of a condensing agent leads to complicated post-reaction treatment for ensuring the product quality, specifically, silica gel column chromatography is used to remove a large amount of by-products generated by the use of the condensing agent, which finally increases the production cost and affects the reaction yield, and thus, the method is not suitable for industrial production.
The Synthetic Communications,40: 2564-:
however, the intermediate 7 is needed in the reaction process, and the residue of the intermediate 7 can cause toxicity to genes and is not beneficial to drug production. CN102796079A discloses that in the preparation method of imatinib, an intermediate which can generate genotoxicity is required, which is not favorable for drug production and affects drug quality.
CN107663151A discloses a preparation method of flumatinib intermediate 4- [ (4-methyl-1-piperazinyl) methyl ] -3-trifluoromethylbenzoic acid, which comprises the following specific steps:
however, the method needs to firstly use a bromination reagent for substitution reaction, then carry out carboxyl protection, then react with N-methylpiperazine, and finally remove carboxyl protecting groups, so that the operation steps are more, and the yield is low.
CN105884746A discloses a method for synthesizing flumatinib, but the method uses a hydrogenation reduction step, is dangerous to operate, has high requirements on equipment and reaction conditions, and is not suitable for large-scale industrial production.
Therefore, a method for synthesizing flumatinib, which is simple in operation, reasonable in route, beneficial to industrial production and capable of avoiding introduction of genotoxic impurities and beneficial to industrial production, needs to be developed.
Disclosure of Invention
The invention aims to provide a simple method for synthesizing flumatinib, which has the advantages of reasonable reaction route, simple operation, convenient post-treatment, high yield and purity, avoidance of introducing genotoxic impurities and suitability for industrial production.
The invention discloses a preparation method of flumatinib shown in formula (I), which comprises the following specific steps:
preparation of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide:
the method specifically comprises the following process steps:
step a) reacting 4-methyl-3- (trifluoromethyl) benzonitrile serving as a raw material with a halogenating agent, an initiator and N-methylpiperazine in a solvent to prepare 4- ((4-methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) benzonitrile (intermediate 2);
and (b) reacting the intermediate 2 in the step b) under the conditions of a catalyst and an organic solvent to obtain the 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (intermediate 3).
Wherein the step a) halogenating agent is selected from brominating or chlorinating agents;
preferably, the brominating agent is selected from N-bromosuccinimide (NBS), phenyltrimethylammonium Tribromide (TBAB), bromine water, pyridine tribromide (PHBP) or dibromohydantoin, preferably N-bromosuccinimide (NBS), bromine water or dibromohydantoin, more preferably N-bromosuccinimide (NBS) or bromine water, further preferably N-bromosuccinimide.
Preferably, the chlorinating agent is selected from chlorine, hydrogen chloride, PCl 3 、PCl 5 、SO 2 Cl 2 Or COCl 2 Preferably PCl 3 、PCl 5 、SO 2 Cl 2 Or COCl 2 More preferably PCl 3 、PCl 5 Or SO 2 Cl 2 Further, PCl is preferable 5 。
The initiator is selected from azobisisobutyronitrile, cumyl peroxide, tert-butyl hydroperoxide, cumyl hydroperoxide or benzoyl peroxide.
The solvent is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, trichloromethane, 1, 2-dichloroethane, carbon tetrachloride, diethyl ether, petroleum ether, benzene or carbon disulfide, preferably one or more of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, carbon tetrachloride or diethyl ether, more preferably one or more of N, N-dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate or carbon tetrachloride, and further preferably tetrahydrofuran or acetonitrile.
The amount of the halogenating agent used is 1.5 to 2.5 times, preferably 1.5 to 2.0 times, and more preferably 1.8 times that of the compound of formula 1; the amount of the initiator is 0.02 to 0.15 times, preferably 0.03 to 0.10 times, more preferably 0.05 to 0.08 times, and still more preferably 0.06 times that of the halogenating agent; the amounts refer to the molar mass ratio.
The reaction temperature is selected from 60-110 ℃, preferably 70-100 ℃, more preferably 80-90 ℃, and further preferably 85 ℃.
The catalyst in the step b) is selected from metal catalysts, preferably palladium acetate, cuprous bromide, nickel chloride and V 2 O 5 One or more of zinc oxide and nickel oxide, preferably one or more of palladium acetate, cuprous bromide, nickel chloride and nickel oxide, more preferably palladium acetate, cuprous bromide or nickel chloride, and further preferably palladium acetate;
the organic solvent is selected from one or more of methanol, ethanol, isopropanol, benzene, diethyl ether, toluene, xylene, acetonitrile, DMF, THF or ethyl acetate, preferably one or more of ethanol, isopropanol, diethyl ether, xylene, acetonitrile or DMF, more preferably isopropanol, acetonitrile or DMF, and further preferably acetonitrile;
the dosage of the palladium acetate is 0.05 to 0.20 time, preferably 0.05 to 0.15 time, more preferably 0.05 to 0.10 time, and further preferably 0.06 time of that of the compound shown in the formula 1; the dosage ratio is a molar ratio.
The reaction temperature is between 120 ℃ and 160 ℃, preferably between 120 ℃ and 140 ℃, and more preferably between 135 ℃.
Preparation of N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine
The method specifically comprises the following process steps:
and step c) reacting N- (2-methyl-5-nitropyridine-3-yl) -4- (pyridine-3-yl) pyrimidine-2-amine serving as a raw material with a chlorinating agent in the presence of the chlorinating agent to obtain N- (5-chlorine-2-methylpyridine-3-yl) -4- (pyridine-3-yl) pyrimidine-2-amine (an intermediate 5).
In a preferred embodiment of the present invention, the chlorinating agent in step c) is selected from tris (4-chlorophenyl) phosphine, chlorine, phosphorus pentachloride or dichlorophenyl phosphine, preferably tris (4-chlorophenyl) phosphine, phosphorus pentachloride or dichlorophenyl phosphine, more preferably tris (4-chlorophenyl) phosphine or dichlorophenyl phosphine, and further preferably tris (4-chlorophenyl) phosphine;
the solvent used in step c) is selected from one or more of phenylphosphonic dichloride, ethyl acetate, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, ethanol or acetone, preferably one or more of phenylphosphonic dichloride, tetrahydrofuran, diethyl ether or acetone, more preferably one or more of phenylphosphonic dichloride, tetrahydrofuran or acetone, and further preferably phenylphosphonic dichloride;
the molar ratio of the chlorinating agent used in the step c) to the amount of N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine is 1.5-2.5:1, preferably 1.5-2.0:1, more preferably 1.8: 1;
the reaction temperature of the step c) is 160-220 ℃, preferably 180-220 ℃, and more preferably 200 ℃.
Preparation of N- (6-methyl-5- ((4- (pyridin-3-yl) pyrimidin-2-yl) methyl) pyridin-3-yl) -4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide
The method specifically comprises the following process steps:
step d) reacting 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (intermediate 3) with N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (intermediate 5) in the presence of a polar solvent, an antioxidant, a catalyst and an alkaline reagent to prepare flumatinib;
wherein, the polar solvent in step d) is selected from one or more of water, DMSO, DMF, methanol, ethanol, propanol, acetone, acetonitrile or formamide, preferably one or more of water, DMSO, DMF, methanol, ethanol, acetonitrile or formamide, more preferably one or more of water, DMSO, DMF, ethanol or formamide, and further preferably a mixed solvent of water and DMF;
polar solvent water: DMF is 1:200-600, preferably 1:200-400, more preferably 1:300 (volume ratio);
the antioxidant is selected from one or more of sodium ascorbate, tocopherol, Butyl Hydroxy Anisole (BHA), dibutyl hydroxy toluene (BHT), tert-butyl hydroquinone (TBHQ) or ascorbyl palmitate, preferably one or more of sodium ascorbate, tocopherol, dibutyl hydroxy toluene (BHT) or tert-butyl hydroquinone (TBHQ), more preferably tert-butyl hydroquinone;
the catalyst is selected from cuprous iodide, cuprous bromide, cuprous chloride or copper-zinc, preferably cuprous iodide or cuprous bromide, more preferably cuprous iodide;
the alkaline reagent is selected from one or more of potassium carbonate, ammonium carbonate, sodium carbonate, ethylenediamine, tetramethylethylenediamine, N ' -dimethylethylenediamine or tetraethylethylenediamine, preferably one or more of potassium carbonate, sodium carbonate, ethylenediamine, tetramethylethylenediamine or N, N ' -dimethylethylenediamine, more preferably one or more of potassium carbonate, ethylenediamine or N, N ' -dimethylethylenediamine, and further preferably a mixture of potassium carbonate or ethylenediamine;
the alkaline reagent potassium carbonate: ethylenediamine in a molar ratio of 5-20:1, preferably 10-20:1, more preferably 15: 1;
the molar ratio of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide to N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine is 1.5-2.5:1, preferably 1.5-2.0:1, more preferably 1.5: 1.
The reaction temperature is 90-150 ℃, preferably 100-140 ℃, more preferably 110-130 ℃, and further preferably 120 ℃.
The invention also aims to provide an intermediate of flumatinib, which has the following structure:
Detailed Description
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
Example 14 preparation of- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide
Weighing 4-methyl-3- (trifluoromethyl) benzonitrile (100.0mg) and placing the mixture into a reaction flask, adding tetrahydrofuran (250mL) into the reaction flask, stirring the solution until the tetrahydrofuran is dissolved, adding N-bromosuccinimide (173.0mg), azobisisobutyronitrile (5.3mg) and N-methylpiperazine (120mL) into the reaction solution, heating the reaction solution to 85 ℃, and reacting for 6 hours to obtain the reaction solution. Adding acetonitrile solvent (200mL) and palladium acetate (7.3mg) into the reaction solution, heating the reaction solution to 135 ℃, continuing to react for 2 hours, removing the organic solvent by rotary evaporation to obtain a concentrated solution, adding a sodium bicarbonate solution (200mL) and a mixed solution (200mL) of ethyl acetate/n-hexane in a volume ratio of 3:1 into the concentrated solution, stirring for 15 minutes, standing and layering to obtain an organic phase, repeating twice, combining the organic phases, concentrating under reduced pressure and drying with anhydrous magnesium sulfate to obtain an intermediate 3, namely 155.5mg of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide, wherein the yield is 95.6%.
MS m/z(ESI):302.3[M+H] + .
Example 24 preparation of- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide
Weighing 4-methyl-3- (trifluoromethyl) benzonitrile (100.0mg) into a reaction flask, adding acetonitrile (250mL) into the reaction flask, stirring the solution until the solution is dissolved, adding N-bromosuccinimide (173.0mg), azobisisobutyronitrile (5.3mg), and N-methylpiperazine (120mL) into the reaction solution, heating the reaction solution to 85 ℃, and reacting for 6 hours to obtain the reaction solution. Adding an isopropanol solvent (200mL) and palladium acetate (7.3mg) into the reaction solution, heating the reaction solution to 135 ℃, continuing to react for 2 hours, removing the organic solvent by rotary evaporation to obtain a concentrated solution, adding a sodium bicarbonate solution (200mL) and a mixed solution (200mL) of ethyl acetate and n-hexane in a volume ratio of 3:1 into the concentrated solution, stirring for 15 minutes, standing and layering to obtain an organic phase, repeating the operation twice, combining the organic phases, concentrating under reduced pressure and drying by anhydrous magnesium sulfate to obtain an intermediate 3, namely 152.6mg of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide, wherein the yield is 93.8%.
Example 34 preparation of- ((4-Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide
Weighing 4-methyl-3- (trifluoromethyl) benzonitrile (100.0mg) into a reaction flask, adding tetrahydrofuran (250mL) into the reaction flask, stirring the solution until the solution is dissolved, adding pyridine tribromide (310.9mg), azobisisobutyronitrile (5.3mg), and N-methylpiperazine (120mL) into the reaction solution, heating the reaction solution to 85 ℃, and reacting for 6 hours to obtain the reaction solution. Adding acetonitrile solvent (200mL) and nickel chloride (4.2mg) into the reaction solution, heating the reaction solution to 135 ℃, continuing to react for 2 hours, removing the organic solvent by rotary evaporation to obtain a concentrated solution, adding a sodium bicarbonate solution (200mL) and a mixed solution (200mL) of ethyl acetate/n-hexane in a volume ratio of 3:1 into the concentrated solution, stirring for 15 minutes, standing and layering to obtain an organic phase, repeating the operation twice, combining the organic phases, concentrating under reduced pressure and drying by anhydrous magnesium sulfate to obtain an intermediate 3, namely 153.3mg of 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide, wherein the yield is 94.2%.
EXAMPLE 4 preparation of N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine
Phenylphosphonic dichloride (200mL) and tris (4-chlorophenyl) phosphine (213.5mg) were added to a reaction flask, the solution was heated to 30 ℃ and stirred uniformly, and N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (100mg) was placed in the above solution, and the reaction solution was heated to 200 ℃ and reacted for 3 hours to obtain a reaction solution. The reaction was cooled to room temperature, and the reaction was neutralized by adding an ice-water mixture (200mL) and 50% anhydrous sodium hydroxide and extracted with ethyl acetate (200mL), the organic phase was retained, the operation was repeated twice, the organic phases were combined, and the organic phase was washed with saturated brine, concentrated under reduced pressure to give a residue, and dried over anhydrous magnesium sulfate to give intermediate 5, i.e., N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (92.1mg) with a yield of 96.7%.
MS m/z(ESI):298.8[M+H] + .
EXAMPLE 5 preparation of N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine
Phenylphosphonic dichloride (200mL) and dichlorophenyl phosphine (103.1mg) were added to a reaction flask, the solution was heated to 30 ℃ and stirred uniformly, and N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (100mg) was placed in the above solution, and the reaction solution was heated to 200 ℃ and reacted for 3 hours to obtain a reaction solution. The reaction was cooled to room temperature, and the reaction was neutralized by adding an ice-water mixture (200mL) and 50% anhydrous sodium hydroxide and extracted with ethyl acetate (200mL), the organic phase was retained, repeated twice, the organic phases were combined, and the organic phase was washed with saturated brine, concentrated under reduced pressure to give a residue, and dried over anhydrous magnesium sulfate to give intermediate 5, i.e., N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (91.7mg) in 96.2% yield.
MS m/z(ESI):298.8[M+H] + .
Example 6 preparation of N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine to a reaction flask was added phenylphosphonoyl dichloride (200mL) as a solvent, tris (4-chlorophenyl) phosphine (234.0mg), the solution was heated to 30 ℃ and stirred uniformly, and N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (100mg) was placed in the above solution, and the reaction solution was heated to 200 ℃ and reacted for 3 hours to obtain a reaction solution. The reaction was cooled to room temperature, and the reaction was neutralized by adding an ice-water mixture (200mL) and 50% anhydrous sodium hydroxide and extracted with ethyl acetate (200mL), the organic phase was retained, repeated twice, the organic phases were combined, and the organic phase was washed with saturated brine, concentrated under reduced pressure to give a residue, and dried over anhydrous magnesium sulfate to give intermediate 5, i.e., N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (91.3mg) in 95.8% yield.
MS m/z(ESI):298.8[M+H] + .
Example 7 preparation of flumatinib
N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (29.8mg), 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (45.2mg), cuprous iodide (3.8mg), potassium carbonate (20.7mg), ethylenediamine (0.6mg), tert-butylhydroquinone (1.7mg), water (1mL), DMF (300mL) were weighed into a reaction flask and stirred uniformly, the reaction solution was heated to 120 ℃, reacted for 6 hours, cooled to room temperature and filtered to obtain a solid substance, boiling water (200mL) and toluene (100mL) were added to wash the solid twice and dry the solid to obtain flumatinib 52.9mg, yield 94.3%, purity 99.9%.
MS m/z(ESI):562.6[M+H] + .
1 H NMR(500MHz,d 6 -DMSO，25℃)δ2.357(s,3H),2.426-2.449(m,3H),2.814(s,3H),2.907-2.931(m,2H),3.073(t,2H),3.405(br,1H),3.793(s,2H),7.525–7.551(m,2H),7.944(d,1H),8.291(d,1H),8.320(s,1H),8.516(d,1H),8.579(d,1H),8.625(s,1H),8.649-8.653(m,1H),8.699(d,1H),9.260(s,1H),9.301-9.304(br,1H),10.706(s,1H)ppm.
Example 8 preparation of flumatinib
N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (29.8mg), 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (45.2mg), cuprous iodide (3.8mg), potassium carbonate (20.7mg), ethylenediamine (0.6mg), tert-butylhydroquinone (1.7mg), water (1mL), DMSO (300mL) were weighed into a reaction flask and stirred uniformly, the reaction solution was heated to 120 ℃, reacted for 6 hours, cooled to room temperature and filtered to obtain a solid substance, boiling water (200mL) and toluene (100mL) were added to wash the solid twice, and the solid was dried to obtain flumatinib 51.6mg, yield 92.0%, and purity 99.9%.
It was confirmed that the mass spectrum and hydrogen spectrum thereof were consistent with those of example 7.
Example 9 preparation of Flumatinib
N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (29.8mg), 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (45.2mg), cuprous iodide (3.8mg), potassium carbonate (20.7mg), ethylenediamine (0.6mg), tert-butylhydroquinone (1.7mg), water (1mL), DMF (600mL) were weighed into a reaction flask and stirred uniformly, the reaction solution was heated to 120 ℃, reacted for 6 hours, cooled to room temperature and filtered to obtain a solid substance, boiling water (200mL) and toluene (100mL) were added to wash the solid twice, and the solid was dried to obtain flumatinib 52.4mg, yield 93.4%, and purity 99.9%.
It was confirmed that the mass spectrum and hydrogen spectrum thereof were consistent with those of example 7.
Example 10 preparation of Flumatinib
N- (5-chloro-2-methylpyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine (29.8mg), 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (45.2mg), cuprous iodide (3.8mg), potassium carbonate (20.7mg), ethylenediamine (0.6mg), dibutylhydroxytoluene (2.2mg), water (1mL), DMF (300mL) were weighed into a reaction flask and stirred uniformly, the reaction solution was heated to 120 ℃, reacted for 6 hours, cooled to room temperature and filtered to obtain a solid substance, boiling water (200mL) and toluene (100mL) were added to wash the solid twice, and the solid was dried to obtain flumatinib 52.3mg, yield 93.1%, purity 99.9%.
The mass spectrum and hydrogen spectrum were confirmed to be consistent with example 7.
Claims (15)
1. A preparation method of flumatinib specifically comprises the following steps:
reacting the intermediate 3 and the intermediate 5 in the step d) in the presence of a polar solvent, an antioxidant, a catalyst and an alkaline reagent to prepare the flumatinib;
wherein the content of the first and second substances,
the polar solvent is selected from a mixed solvent of water and DMF;
the antioxidant is selected from dibutyl hydroxy toluene or tert-butyl hydroquinone;
the catalyst is selected from cuprous iodide;
the alkaline agent is selected from a mixture of potassium carbonate and ethylenediamine.
2. The process of claim 1, wherein the molar ratio of intermediate 3 to intermediate 5 is 1.5-2.5: 1.
3. The process of claim 1, wherein the molar ratio of intermediate 3 to intermediate 5 is 1.5-2.0: 1.
4. The process of claim 1, wherein the molar ratio of intermediate 3 to intermediate 5 is 1.5: 1.
5. The method according to claim 1, wherein the ratio of polar solvent water: the volume ratio of DMF is 4-8: 1.
6. The method for preparing a compound according to claim 1, wherein the ratio of polar solvent water: the volume ratio of DMF is 4-6: 1.
7. The method for preparing a compound according to claim 1, wherein the ratio of polar solvent water: the volume ratio of DMF was 5: 1.
8. The process according to claim 1, wherein the ratio of the alkaline reagent potassium carbonate: the molar ratio of the ethylenediamine is 5-20: 1.
9. The process according to claim 1, wherein the ratio of the alkaline reagent potassium carbonate: the molar ratio of the ethylenediamine is 10-20: 1.
10. The process according to claim 1, wherein the ratio of the alkaline reagent potassium carbonate: the molar ratio of ethylenediamine was 15: 1.
11. The preparation method according to claim 1, wherein the preparation method of the intermediate 5 comprises the following steps:
step c), reacting N- (2-methyl-5-nitropyridine-3-yl) -4- (pyridine-3-yl) pyrimidine-2-amine serving as a raw material with a chlorinating agent in an organic solvent to prepare an intermediate 5;
wherein the chlorinating agent is selected from tris (4-chlorophenyl) phosphine or dichlorophenyl phosphine;
the organic solvent is selected from phenylphosphonic dichloride.
12. The method according to claim 11, wherein the molar ratio of the chlorinating agent used in step c) to the amount of N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine is 1.5-2.5: 1.
13. The method according to claim 11, wherein the molar ratio of the chlorinating agent used in step c) to the amount of N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine is 1.5 to 2.0: 1.
14. The process according to claim 11, wherein the molar ratio of chlorinating agent used in step c) to the amount of N- (2-methyl-5-nitropyridin-3-yl) -4- (pyridin-3-yl) pyrimidin-2-amine used is 1.8: 1.
15. The method according to claim 1, wherein the method for preparing the intermediate 3 comprises:
step a), 4-methyl-3- (trifluoromethyl) benzonitrile is used as a raw material and reacts with a halogenating agent, an initiator and N-methylpiperazine to prepare 4- ((4-methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) benzonitrile;
reacting the intermediate 2 in the step b) with a catalyst to obtain 4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide;
wherein the content of the first and second substances,
the halogenating agent in step a) is selected from N-bromosuccinimide or pyridine tribromide;
the initiator in step a) is selected from azobisisobutyronitrile;
the reaction solvent in the step a) is selected from tetrahydrofuran or acetonitrile;
the catalyst in the step b) is selected from palladium acetate or nickel chloride;
the reaction solvent in step b) is selected from isopropanol, acetonitrile or DMF.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201911294896.8A CN111072636B (en) | 2019-12-16 | 2019-12-16 | Synthesis method of flumatinib |
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| CN107098884A (en) * | 2016-02-19 | 2017-08-29 | 中国科学院上海药物研究所 | The aminopyridines and its preparation and use of one class substitution |
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