CN113896732B - Preparation method and application of anticancer drug carbamatinib - Google Patents
Preparation method and application of anticancer drug carbamatinib Download PDFInfo
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- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a preparation method and application of an anticancer drug of carbamatinib. The invention obtains a target compound through eight steps of reactions, and relates to bromination, boc protection, suzuki coupling reaction, deprotection, nucleophilic substitution and cyclization, format reagent preparation and other important reactions. The raw materials used in the whole process are cheap and easy to obtain, a large amount of toxic raw materials such as palladium catalyst and sodium cyanide are avoided, the process steps are shortened, the process operation is simple and easy to control, the purification is convenient, and the method can be used for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an anticancer drug, namely carbamazepine. The method mainly uses cheap and easily-obtained starting materials, reduces the use of expensive catalysts, shortens the process steps, has mild reaction conditions, does not use extremely toxic substances such as sodium cyanide and the like, basically has no environmental protection pressure, and is suitable for industrial production.
Background
Carbamatinib (Capmatinib) is a potent, oral, selective, ATP-competitive c-Met kinase inhibitor. Capmatinib is effective in inhibiting proliferation and migration of c-met dependent tumor cells and in inducing apoptosis. Has antitumor activity. Capmatinib is an oral proto-oncogene c-Met inhibitor (also known as Hepatocyte Growth Factor Receptor (HGFR)) with potential anti-tumor activity. Capmatinib is widely used in clinical trials to study melanoma, gliosarcoma, solid tumors, colorectal cancer, and liver injury. The indication is primarily for the treatment of non-metastatic adult patients-small cell lung cancer (NSCLC) whose tumors have MET exon 14 skipping (MET ex 14) leading to mutations (as detected by FDA approved assays).
In 2007, US7767675 reports a synthetic route of capmatiib, 6-bromoquinoline, 4-bromo-3-fluorobenzoic acid and 1-amino urea nitrogen are used as starting materials, the capmatiib is obtained through thirteen steps of reactions, the total yield is less than 5%, and a large amount of expensive palladium catalysts, extremely toxic hazardous materials such as hydroxylamine hydrochloride and sodium cyanide are used in the process, so that the industrial production of the existing environment is not facilitated.
Disclosure of Invention
The invention aims to overcome the defects of the existing Capmatinib synthesis route and provide an effective method for preparing Capmatinib, and the method for preparing Capmatinib is shorter in route, milder in reaction condition, simpler in post-treatment, lower in cost and more reasonable in method by using cheap N-methyl-4-bromo-2-fluorobenzamide, 3-amino-1, 2, 4-triazin-6-one and 6-bromoquinoline as starting materials.
The technical scheme adopted by the invention is as follows: the preparation method of the anticancer drug carbamazepine comprises the following steps:
1) Brominating 3-amino-1, 2, 4-triazine-6-ketone (compound 1) with a brominating agent to obtain a compound 2;
2) The compound 2 is protected by a Boc protecting group to obtain a compound 3;
3) The compound 3 and the bis (pinacolato) diboron (compound 4) are subjected to suzuki coupling reaction to obtain a compound 5;
4) The compound 5 and N-methyl-4-bromo-2-fluorobenzamide (compound 6) are subjected to bimolecular coupling to generate a compound 7;
5) Deprotection of compound 7 under acidic conditions affords compound 8;
6) Nucleophilic substitution and cyclization of compound 8 and 1, 3-dichloro isopropanol (compound 9) under the action of base to compound 10;
7) Magnesium metal in a polar aprotic solvent with compound 10 to form grignard compound 11;
8) 6-bromoquinoline (compound 12) and compound 11 undergo nucleophilic substitution reaction under the action of a catalyst to obtain a target compound 13, namely carbamazepine.
The synthetic route of the invention is as follows:
further, step 1) includes the steps of: adding a brominating agent into a solvent, cooling to 5 ℃, stirring for 30min, adding 3-amino-1, 2, 4-triazin-6-one, heating to 60-90 ℃, carrying out heat preservation reaction for 6h, cooling to room temperature after the reaction is finished, slowly adding the reaction solution into ice water, fully stirring, extracting with ethyl acetate, taking organic phase, washing with water and sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness under reduced pressure, stirring the obtained product with n-hexane at 30 ℃ for 3h, filtering, and washing a filter cake with n-hexane to obtain a compound 2.
Preferably, the brominating agent is selected from the group consisting of bromine, phosphorus oxybromide, phosphorus tribromide, phosphorus pentabromide; the solvent is selected from N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, isopropyl acetate or toluene.
Further, step 2) comprises the steps of: adding the compound 2 and di-tert-butyl dicarbonate into a solvent, stirring for 4-8 hours at the temperature of 10-40 ℃, monitoring the end of the reaction by TLC, washing the obtained reaction liquid with purified water and aqueous solution of sodium chloride, concentrating an organic phase to dryness, adding methyl tert-butyl ether into the residue, pulping for 2 hours at room temperature, filtering, and washing a filter cake with the methyl tert-butyl ether to obtain the compound 3.
Preferably, the compound 2 is di-tert-butyl dicarbonate=1:1-1.5 according to the mole ratio; the solvent is selected from water, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile.
Further, step 3) includes the steps of: adding compound 3, alkali and bis (pinacolato) diboron (compound 4) into a solvent, stirring and dissolving, degassing for 20 minutes by using nitrogen, then adding a solvent solution of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating the reaction at 80-110 ℃ for 16-32 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding a 2N hydrochloric acid solution and ethyl acetate into the reaction liquid, stirring for 30 minutes, standing and layering, washing a water taking layer by using ethyl acetate, discarding organic matters, regulating pH=8 by using a 2N sodium hydroxide solution, extracting by using ethyl acetate, drying an organic phase by using anhydrous magnesium sulfate, filtering and concentrating to dryness, adding the obtained product into cyclohexane, heating to 60 ℃, keeping the temperature and stirring for 1 hour, naturally cooling to 30 ℃, stirring for 2 hours, filtering, washing a filter cake by using cyclohexane, and obtaining the compound 5.
Preferably, the base is selected from sodium methoxide, sodium ethoxide, sodium acetate, potassium acetate, sodium hydride, sodium amide, potassium carbonate or sodium hydroxide; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, dichloromethane, chloroform, toluene, 2-methyltetrahydrofuran or N-methylpyrrolidone.
Further, step 4) includes the steps of: adding a compound 5, N-methyl-4-bromo-2-fluorobenzamide (compound 6) and alkali into a solvent, stirring and dissolving at room temperature, introducing nitrogen into the solvent for degassing for 20min, then adding a catalyst, heating a reaction system to 90-110 ℃, protecting the nitrogen, stirring at a constant temperature for 16h, cooling a reaction liquid to room temperature after the reaction is finished, filtering, washing a filter cake with the solvent, concentrating the filtrate to dryness, adding residues into a 2N hydrochloric acid solution for full dissolution, washing with the solvent, discarding organic impurities, taking an aqueous phase, adjusting pH=8 with the 2N sodium hydroxide solution, gradually precipitating solids, stirring for 1h, filtering, washing the filter cake with purified water, pulping once with the purified water at room temperature, filtering, washing the filter cake with the purified water to obtain the compound 7.
The base is selected from potassium carbonate, sodium methoxide or sodium acetate; the catalyst is selected from cuprous chloride, cupric oxide, acetylcyclohexane or tetra (triphenylphosphine) palladium; the solvent is selected from N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, isopropyl acetate or toluene.
Further, step 5) comprises the steps of: adding the compound 7 into a mixed solvent of a solvent and an acid, stirring overnight at 10-30 ℃, removing the solvent under reduced pressure, stirring the obtained residue in sodium bicarbonate and dichloromethane for 30min, standing for layering, washing a water phase with dichloromethane, taking an organic phase, washing the organic phase with purified water and a sodium chloride aqueous solution, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the residue with isopropanol to obtain the compound 8.
Preferably, the solvent is selected from dichloromethane, chloroform, methanol, ethanol or acetonitrile; the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or glacial acetic acid.
Further, step 6) includes the steps of: adding 1, 3-dichloro isopropanol (compound 9), a solvent, purified water, alkali and a compound 8 into a reaction vessel at room temperature, heating the reaction system to 60-90 ℃ and continuously stirring for 14h, cooling the reaction liquid to room temperature after the reaction is finished, filtering, washing a filter cake by using a mixed solvent of ethanol and purified water, concentrating the collected filtrate, extracting by using ethyl acetate, collecting an organic phase, drying by using anhydrous sodium sulfate, dissolving the obtained product in ethanol, adding a 0.2N hydrochloric acid aqueous solution, stirring to obtain a slurry, heating the obtained slurry to 50 ℃ and stirring for 6h, naturally cooling to room temperature, slowly adding a saturated sodium bicarbonate aqueous solution, controlling the temperature to be not more than 25 ℃, extracting the obtained mixed solution by using ethyl acetate, taking the organic phase and concentrating to be dry under reduced pressure, adding methyl tert-butyl ether into the obtained product, stirring for 1h at 60 ℃, naturally cooling to room temperature, continuously stirring for 2h, filtering, washing the filter cake by using methyl tert-butyl ether, and obtaining a solid compound 10.
Preferably, the solvent is selected from ethanol, methanol or isopropanol; the base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
Further, step 7) includes the steps of: under the protection of nitrogen, adding magnesium metal into a solvent, stirring for 1h at room temperature, adding the compound 10 into the solvent, dropwise adding the mixture into a magnesium metal solution, controlling the temperature to be not more than 20-40 ℃, keeping the temperature at 35 ℃ and stirring for 4h after the dropwise addition is finished, filtering a reaction solution after the reaction is finished, washing a filter cake with the solvent, collecting the filtrate, concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a crude product, adding the crude product into a mixed solution of the solvent and methyl tertiary butyl ether, pulping for 1h at room temperature, filtering, washing the filter cake with the methyl tertiary butyl ether, and obtaining the compound 11.
Preferably, the solvent is selected from pyridine, tetrahydrofuran, 2-methyltetrahydrofuran or N-methylpyrrolidone.
Further, step 8) includes the steps of: adding 6-bromoquinoline (compound 12) and a catalyst into a solvent, stirring for 30min under the protection of nitrogen, dropwise adding a solvent solution of the compound 11 at a temperature of not more than 30 ℃, heating to 70 ℃ after the dropwise addition, preserving heat for 8h, cooling to room temperature after the reaction is finished, filtering, washing a filter cake with the solvent, concentrating the collected filtrate to dryness, dissolving the obtained residue in dichloromethane, heating to 40 ℃, adding activated carbon and diatomite, stirring for 30min, filtering, concentrating the filtrate to dryness, and finally recrystallizing with a mixed solvent of cyclohexane and ethyl acetate to obtain the target product compound 13.
Preferably, the catalyst is selected from the group consisting of bis (dibenzylidene acetone) palladium, tris (dibenzylidene acetone) palladium, tetrakis (triphenylphosphine) palladium; the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or toluene.
The beneficial effects of the invention are as follows: the reaction route provided by the invention is a brand new route, and has the advantages of low cost, no use of a large amount of expensive palladium-carbon catalyst, and no use of toxic reagents such as sodium cyanide, hydroxylamine hydrochloride and the like. The raw materials are easy to obtain, the impurity spectrum is clear, the reactions in each step do not involve special reactions, the method is suitable for industrial production, and the obtained final product has high chemical purity and optical purity and meets the requirements of raw materials.
Drawings
Fig. 1 is an HPLC diagram of compound 13 carbamazepine prepared in example 1.
Fig. 2 is a table of peak values of fig. 1.
Detailed Description
The foregoing of the invention is further elaborated upon by the following description of specific embodiments. It will be understood by those skilled in the art that the scope of the above subject matter of the present invention is not limited to the following method description; all techniques implemented based on the above description of the invention are within the scope of the invention.
Example 1 preparation method of anti-cancer drug Carmattinib
The synthetic route is as follows:
the preparation method comprises the following steps:
step 1: preparation of Compound 2
Phosphorus oxybromide (314.2 g,1.16 mol) was added to N, N-dimethylacetamide (1.4L), cooled to 5℃and stirred for 30 min; 3-amino-1, 2, 4-triazin-6-one (Compound 1) (112.1 g,1.0 mol) was added, heated to 75℃and reacted at a constant temperature for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, the reaction solution was slowly added to ice water (2.0L), after stirring sufficiently, extracted three times with ethyl acetate (1.0L. Times.3), the organic phases were combined, the organic phases were successively washed three times with water (500 mL. Times.2) and sodium chloride solution (500 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a pale yellow viscous material. The pale yellow dope was stirred with n-hexane (1L) at 30℃for 3 hours, filtered, and the cake was washed with n-hexane (100 mL) to give a pale yellow solid, namely compound 2, 165.3g, in a yield of 95.2%.
Step 2: preparation of Compound 3
Compound 2 (160 g,0.91 mol) and di-tert-butyl dicarbonate (218.3 g,1.0 mol) were added to tetrahydrofuran THF (700 mL), stirred at room temperature for 6h, and tlc monitored the end of the reaction. The resulting reaction solution was washed three times with purified water (500 mL. Times.2) and an aqueous sodium chloride solution (500 mL), and the organic phase was collected and concentrated to dryness. To the residue was added methyl tert-butyl ether (200 mL), slurried at room temperature for 2h, filtered, and the filter cake was washed with methyl tert-butyl ether (20 mL) to give compound 3, 232.8g as a yellow solid in 93.9% yield.
Step 3: preparation of Compound 5
Compound 3 (232 g,0.84 mol), potassium acetate (98.1 g,1.0 mol) and bis (pinacolato) diboron (compound 4) (253.9 g,1.0 mol) were added to 1, 4-dioxane (600 mL) and dissolved with stirring. Deaeration with nitrogen for 20 minutes. A solution of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (500 mg,0.6 mmol) in methylene chloride was then added and the reaction was heated at 90℃for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, 500mL of a 2N hydrochloric acid solution and 500mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 30 minutes and allowed to stand for delamination. After the aqueous layer was further washed with 200mL of ethyl acetate and the organics were discarded, the pH of the aqueous layer was adjusted to be basic (pH 8) with 2N sodium hydroxide solution, and then extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was added to 200mL cyclohexane, heated to 60 ℃, stirred at an elevated temperature for 1h, cooled naturally to 30 ℃, stirred for 2h, filtered, and the filter cake was washed with cyclohexane to give a pale yellow solid, compound 5, 232.7g, 86.1% yield.
Step 4: preparation of Compound 7
Compound 5 (230 g,0.71 mol), N-methyl-4-bromo-2-fluorobenzamide (compound 6) (197.7 g,0.85 mol) and dried potassium carbonate (158.1 g,1.56 mol) were added to N, N-dimethylacetamide (1.2L), dissolved by stirring at room temperature, and degassed by introducing nitrogen thereto for 20 minutes. Cuprous chloride (8.4 g,0.085 mol) was then added and the reaction was heated to 100deg.C under nitrogen and stirred at constant temperature for 16h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the cake was washed with N, N-dimethylacetamide (100 mL). The filter cake was concentrated to dryness, the residue was added to a 2N hydrochloric acid solution to be sufficiently dissolved, and washed three times with isopropyl acetate (400 ml×3), and the organic impurities were discarded. The aqueous phase was taken and adjusted to pH to alkaline (pH 8) with 2N sodium hydroxide solution, gradually solid precipitated, stirred for 1h, filtered, the filter cake was washed with 20ml of purified water and slurried once with 1000ml of purified water at room temperature, filtered, the filter cake was washed with 50ml of purified water and dried to give pale yellow solid, namely compound 7, 217.0g, yield 88.3%.
Step 5: preparation of Compound 8
Compound 7 (210 g,0.60 mol) was added to a mixed solvent (volume ratio, 1:2,1 l) of dichloromethane and 2N hydrochloric acid, the solution was stirred at room temperature overnight, the solvent was removed under reduced pressure, the resulting residue was stirred in 800mL of sodium hydrogencarbonate and dichloromethane (800 mL) for 30min, standing for delamination, the aqueous phase was washed once with 200mL of dichloromethane, the organic phases were combined, and the organic phases were washed with purified water (300 mL) and aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from isopropanol to give compound 8, 139.4g in 94% yield.
Step 6: preparation of Compound 10
1, 3-dichloroisopropyl alcohol (compound 9) (75.2 g,0.58 mol), ethanol (500 mL), purified water (70 mL), potassium hydroxide (33.6 g,0.6 mol) and compound 8 (130 g,0.53 mol) were added to the reaction vessel at room temperature, and then the reaction system was heated to 75℃for 14 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the cake was washed with a mixed solvent of ethanol and purified water (9:1). The collected filtrate was concentrated to 200mL, extracted with ethyl acetate (300 ml×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to give a dark brown solid. The dark brown solid was dissolved in ethanol (100 mL) and the solution was treated with 0.2N aqueous hydrochloric acid (400 mL) to give a slurry, the resulting slurry was heated to 50 ℃ and stirred for 6h with constant temperature, naturally cooled to room temperature, and then saturated aqueous sodium bicarbonate solution was slowly added, with the temperature controlled to not exceed 25 ℃. The resulting mixed solution was extracted three times with ethyl acetate (200 ml×3), the organic phases were combined, and the organic phases were concentrated to dryness under reduced pressure to give a pale yellow solid. Finally, 200mL of methyl tertiary butyl ether is used for pulping the pale yellow solid, the temperature is kept at 60 ℃ and stirring is carried out for 1h, the temperature is naturally reduced to room temperature, stirring is continued for 2h, filtering is carried out, and the methyl tertiary butyl ether is used for washing a filter cake, so that the pale yellow solid, namely the compound 10, 127.1g and the yield of 73.6 percent, is obtained.
Step 7: preparation of Compound 11
Magnesium metal (36 g,1.5 mol) was added to tetrahydrofuran (100 mL) under nitrogen and stirred at room temperature for 1h. Compound 10 (120 g,0.38 mol) was added to tetrahydrofuran (500 mL) and added dropwise to a solution of magnesium metal in tetrahydrofuran at a temperature not exceeding 30 ℃. After the completion of the dripping, the mixture is stirred for 4 hours at 35 ℃. After the reaction, the reaction solution was filtered, the cake was washed with 50mL of tetrahydrofuran, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude light gray solid. The crude product obtained was added to a mixed solution of tetrahydrofuran and methyl tert-butyl ether (1:1, 100 mL), slurried at room temperature for 1h, filtered, and the filter cake was washed with 10mL of methyl tert-butyl ether to give an off-white solid powder, compound 11, 128.1g, yield 98.1%.
Step 8: preparation of Compound 13 of interest
6-bromoquinoline (Compound 12) (79.8 g,0.38 mol) and bis (dibenzylideneacetone) palladium (3.9 g, 0.0070 mol) were added to toluene (200 mL), and after stirring for 30min under nitrogen protection, a solution of freshly prepared Compound 11 (120 g,0.34 mol) in tetrahydrofuran (500 mL) was added dropwise under controlled temperature not exceeding 30℃and the reaction was continued at 70℃for 8 hours. After the reaction, cooling to room temperature, filtering, washing a filter cake with tetrahydrofuran, concentrating the filtrate to dryness, dissolving the residue in dichloromethane, heating to 40 ℃, adding 1g of active carbon and diatomite respectively, stirring for 30min, filtering, and concentrating the filtrate to dryness. Finally, the mixture of cyclohexane and ethyl acetate is used for recrystallization, thus obtaining the target product 13, namely, the carbamazepine, 116.5g, the yield is 83.2 percent and the purity is 99.66 percent.
1 H NMR(400MHz，DMSO-d6)δppm 9.52(s，1H)，9.30(dd，1H，J＝5.5Hz，1.3Hz)，9.20(d，1H，J＝8.0Hz)，8.49(m，1H)，8.51(d，1H，J＝0.8Hz)，8.39(d，1H，J＝1.2Hz)，8.25(s，1H)，8.22(dd，1H，J＝9.0Hz，1.8Hz)，8.10-8.01(m，3H)，7.72(dd，1H，J＝7.1Hz，8.4Hz)，4.76(s，2H)，2.72(s，3H，J＝4.4Hz)； 13 C NMR(100MHz，DMSO-d6)δppm 164.1，160.4(d，J＝248.1Hz)，146.1，146.0，145.2，144.8，141.4，139.8，137.8，136.7，136.0(J＝8.6Hz)，131.9(J＝3.1Hz)，130.5，129.8，128.6，126.4(J＝14.9Hz)，126.2，122.7(J＝3Hz)，122.2，121.0，114.8(J＝5.6Hz)，28.9，26.6；MS：m/z＝413.09(M+H + )。
HPCL and peaks are shown in FIGS. 1 and 2. As can be seen from fig. 1 and fig. 2, the purity of the obtained carbamazepine is 99.66%, the maximum single impurity is 0.11%, the impurity content accords with the ICH guiding principle and the rule that the impurity content in pharmacopoeia is less than 0.15%, and the condition of serving as a raw material medicine is completely met.
Claims (17)
1. The preparation method of the anticancer drug carbamazepine is characterized by comprising the following steps:
1) Brominating 3-amino-1, 2, 4-triazine-6-ketone with a brominating agent to obtain a compound 2;
2) The compound 2 is protected by a Boc protecting group to obtain a compound 3;
3) The compound 3 and the bis (pinacolato) diboron are subjected to a suzuki coupling reaction to obtain a compound 5;
4) The compound 5 and N-methyl-4-bromo-2-fluorobenzamide are coupled by double molecules to generate a compound 7;
5) Deprotection of compound 7 under acidic conditions affords compound 8;
6) Nucleophilic substitution and cyclization of compound 8 and 1, 3-dichloro isopropanol under the action of base to synthesize compound 10;
7) Magnesium metal in a polar aprotic solvent with compound 10 to form grignard reagent compound 11;
8) 6-bromoquinoline and a compound 11 undergo nucleophilic substitution reaction under the action of a catalyst to obtain a target compound carbamazepine; the synthesis route is as follows:
。
2. the method of claim 1, wherein step 1) comprises the steps of: adding a brominating agent into a solvent, cooling to 5 ℃, stirring for 30min, adding 3-amino-1, 2, 4-triazin-6-one, heating to 60-90 ℃, carrying out heat preservation reaction for 6h, cooling to room temperature after the reaction is finished, slowly adding the reaction solution into ice water, fully stirring, extracting with ethyl acetate, taking organic phase, washing with water and sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness under reduced pressure, stirring the obtained product with n-hexane at 30 ℃ for 3h, filtering, and washing a filter cake with n-hexane to obtain a compound 2.
3. The preparation method according to claim 2, wherein the solvent is selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, isopropyl acetate and toluene.
4. The method of claim 1, wherein step 2) comprises the steps of: adding the compound 2 and di-tert-butyl dicarbonate into a solvent, stirring for 4-8 hours at the temperature of 10-40 ℃, monitoring the end of the reaction by TLC, washing the obtained reaction liquid with purified water and aqueous solution of sodium chloride, concentrating an organic phase to dryness, adding methyl tert-butyl ether into the residue, pulping for 2 hours at room temperature, filtering, and washing a filter cake with the methyl tert-butyl ether to obtain the compound 3.
5. The preparation method according to claim 4, wherein the molar ratio of the compound 2, di-tert-butyl dicarbonate=1:1-1.5; the solvent is selected from water, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile.
6. The method of claim 1, wherein step 3) comprises the steps of: adding the compound 3, alkali and bis (pinacolato) diboron into a solvent, stirring and dissolving, degassing for 20 minutes by using nitrogen, then adding a solvent solution of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating a reaction system at 80-110 ℃ for 16-32 hours, cooling the reaction solution to room temperature after the reaction is finished, adding a 2N hydrochloric acid solution and ethyl acetate into the reaction solution, stirring for 30 minutes, standing and layering, washing a water taking layer by using ethyl acetate and discarding organic matters, regulating pH=8 by using a 2N sodium hydroxide solution, extracting by using ethyl acetate, drying an organic phase by using anhydrous magnesium sulfate, filtering and concentrating to dryness, adding the obtained product into cyclohexane, heating to 60 ℃, keeping the temperature and stirring for 1 hour, naturally cooling to 30 ℃, stirring for 2 hours, filtering, washing a filter cake by using cyclohexane, and obtaining the compound 5.
7. The method according to claim 6, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium amide, potassium carbonate or sodium hydroxide; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, dichloromethane, chloroform, toluene, 2-methyltetrahydrofuran or N-methylpyrrolidone.
8. The method of claim 1, wherein step 4) comprises the steps of: adding the compound 5, N-methyl-4-bromo-2-fluorobenzamide and alkali into a solvent, stirring and dissolving at room temperature, introducing nitrogen into the solvent for degassing for 20min, then adding a catalyst, heating a reaction system to 90-110 ℃, protecting by nitrogen, keeping the temperature and stirring for 16h, cooling a reaction liquid to room temperature after the reaction is finished, filtering, washing a filter cake by the solvent, concentrating the filtrate to dryness, adding the residue into a 2N hydrochloric acid solution for fully dissolving, washing by the solvent, discarding organic impurities, taking an aqueous phase, adjusting pH=8 by a 2N sodium hydroxide solution, gradually precipitating solids, stirring for 1h, filtering, washing the filter cake by purified water, pulping once at room temperature, filtering, and washing the filter cake by the purified water to obtain the compound 7.
9. The method of claim 8, wherein the base is selected from the group consisting of potassium carbonate, sodium methoxide; the catalyst is selected from cuprous chloride or tetra (triphenylphosphine) palladium; the solvent is selected from N, N-dimethylacetamide, N-dimethylformamide, dimethyl sulfoxide, isopropyl acetate or toluene.
10. The method of claim 1, wherein step 5) comprises the steps of: adding the compound 7 into a mixed solvent of a solvent and an acid, stirring overnight at 10-30 ℃, removing the solvent under reduced pressure, stirring the obtained residue in sodium bicarbonate and dichloromethane for 30min, standing for layering, washing a water phase with dichloromethane, taking an organic phase, washing the organic phase with purified water and a sodium chloride aqueous solution, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the residue with isopropanol to obtain the compound 8.
11. The method of claim 10, wherein the solvent is selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, and acetonitrile.
12. The method of claim 1, wherein step 6) comprises the steps of: adding 1, 3-dichloro isopropanol, a solvent, purified water, alkali and a compound 8 into a reaction vessel at room temperature, heating a reaction system to 60-90 ℃ and continuously stirring for 14h, cooling a reaction liquid to room temperature after the reaction is finished, filtering, washing a filter cake by using a mixed solvent of ethanol and purified water, concentrating the collected filtrate, extracting by using ethyl acetate, collecting an organic phase, drying by using anhydrous sodium sulfate, concentrating to dryness, dissolving the obtained product in ethanol, adding a 0.2N hydrochloric acid aqueous solution, stirring to obtain a slurry, heating the obtained slurry to 50 ℃ and stirring for 6h, naturally cooling to room temperature, slowly adding a saturated sodium bicarbonate aqueous solution, controlling the temperature to be no more than 25 ℃, extracting the obtained mixed solution by using ethyl acetate, taking an organic phase and concentrating to dryness under reduced pressure, adding methyl tert-butyl ether into the obtained product, keeping the temperature and stirring for 1h at 60 ℃, naturally cooling to room temperature, continuously stirring for 2h, filtering, washing the filter cake by using methyl tert-butyl ether, and obtaining the compound 10.
13. The method of preparation according to claim 12, wherein the solvent is selected from ethanol, methanol or isopropanol; the base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
14. The method of claim 1, wherein step 7) comprises the steps of: under the protection of nitrogen, adding magnesium metal into a solvent, stirring for 1h at room temperature, adding the compound 10 into the solvent, dropwise adding the mixture into a magnesium metal solution, controlling the temperature to be not more than 20-40 ℃, keeping the temperature at 35 ℃ and stirring for 4h after the dropwise addition is finished, filtering a reaction solution after the reaction is finished, washing a filter cake with the solvent, collecting the filtrate, concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a crude product, adding the crude product into a mixed solution of the solvent and methyl tertiary butyl ether, pulping for 1h at room temperature, filtering, washing the filter cake with the methyl tertiary butyl ether, and obtaining the compound 11.
15. The method of preparation according to claim 14, wherein the solvent is selected from pyridine, tetrahydrofuran, 2-methyltetrahydrofuran or N-methylpyrrolidone.
16. The method of claim 1, wherein step 8) comprises the steps of: adding 6-bromoquinoline and a catalyst into a solvent, protecting with nitrogen, stirring for 30min, controlling the temperature to be no more than 30 ℃, dropwise adding a solvent solution of the compound 11, heating to 70 ℃ after the dropwise addition, preserving heat for 8h, cooling to room temperature after the reaction is finished, filtering, washing a filter cake with the solvent, concentrating the collected filtrate to dryness, dissolving the obtained residue in dichloromethane, heating to 40 ℃, adding activated carbon and diatomite, stirring for 30min, filtering, concentrating the filtrate to dryness, and finally recrystallizing with a mixed solvent of cyclohexane and ethyl acetate to obtain the target product compound 13.
17. The process of claim 16, wherein the catalyst is selected from the group consisting of bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium; the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or toluene.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641093A (en) * | 2006-11-22 | 2010-02-03 | 因塞特公司 | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| CN102083814A (en) * | 2008-05-21 | 2011-06-01 | 因西特公司 | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| CN110526916A (en) * | 2018-05-23 | 2019-12-03 | 成都海创药业有限公司 | Deuterated Capmatinib compound and application thereof |
| CN111825678A (en) * | 2020-06-05 | 2020-10-27 | 连庆泉 | Preparation method of carbamatinib |
| WO2021165818A1 (en) * | 2020-02-17 | 2021-08-26 | Novartis Ag | Process and intermediates for the preparation of 2-fluoro-n-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2yl]benzamide |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641093A (en) * | 2006-11-22 | 2010-02-03 | 因塞特公司 | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
| CN102083814A (en) * | 2008-05-21 | 2011-06-01 | 因西特公司 | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| CN110526916A (en) * | 2018-05-23 | 2019-12-03 | 成都海创药业有限公司 | Deuterated Capmatinib compound and application thereof |
| WO2021165818A1 (en) * | 2020-02-17 | 2021-08-26 | Novartis Ag | Process and intermediates for the preparation of 2-fluoro-n-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2yl]benzamide |
| CN111825678A (en) * | 2020-06-05 | 2020-10-27 | 连庆泉 | Preparation method of carbamatinib |
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