A preparation method of dabrafenib

Abstract

The present invention provides a method for preparing dabrafenib, belonging to the technical field of drug synthesis. The present invention uses N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide as a starting material, and then adds a silane-substituted amino reagent for substitution reaction, and then hydrolyzes in the presence of an acid to obtain dabrafenib, which has the advantages of easy availability of raw materials, simple process, mild reaction conditions, and environmental protection and economy. And the dabrafenib prepared by the present invention has high purity and high yield, and the dabrafenib mesylate generated after salification with methanesulfonic acid has high purity, small impurity A (not detected), high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing dabrafenib. Background Art

[0002] Dabrafenib mesylate, chemically named N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide mesylate, is an anti-tumor drug that inhibits tumor growth by inhibiting cell proliferation. Dabrafenib mesylate has a good development prospect in tumor trial production. Dabrafenib is an effective BRAF inhibitor that can play an anti-tumor role in a variety of tumors with BRAF V600E or V600K mutations, especially in melanoma, non-small cell lung cancer and anaplastic thyroid cancer. Dabrafenib has been approved in many countries and regions, providing a new option for the treatment of these refractory tumors. It is used in combination with trametinib for postoperative adjuvant treatment of BRAFV600 mutation-positive unresectable or metastatic melanoma and BRAFV600 mutation-positive melanoma. Dabrafenib is the first FDA-approved BRAF inhibitor for anaplastic thyroid cancer. Currently, some reports on the synthesis route of dabrafenib are described as follows.

[0003] 1) Synthesis route 1 (as shown below): Chinese patent 200980126781.6 discloses that compound 2 (3-amino-2-fluorobenzoic acid methyl ester) is used as a starting material, and reacts with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain sulfonamide intermediate 3, which undergoes affinity addition reaction with 2-chloro-4-methylpyrimidine under the action of LiHMDS to produce intermediate 4, and intermediate 4 undergoes condensation ring reaction with trimethylthioacetamide after NBS bromination to produce intermediate 5, and intermediate 5 reacts with ammonia water under high temperature and pressure to produce dabrafenib, and finally forms a salt with methanesulfonic acid to obtain dabrafenib mesylate. This route 1 is cumbersome to operate, has large impurities, and has a pressurized amination reaction, which is highly dangerous.

[0004]

[0005] Route 1

[0006] 2) Synthesis route 2 (as shown below), Chinese patent 201310586872.6 discloses that the target compound can be obtained through sulfonamidation, halogenation, thiazole cyclization, acylation, pyrimidine cyclization and other steps, but the last step of pyrimidine cyclization has a high reaction temperature and the use of a strong oxidant, guanidine nitrate, is highly dangerous. Therefore, route 2 is not suitable for industrial production.

[0007]

[0008] Route 2

[0009] 3) Synthesis route three (as shown below), Chinese patent with publication number CN102083312A discloses that compound 2 (3-amino-2-fluorobenzoic acid methyl ester) is used as the starting material, and intermediate 7 is obtained by acetylation, and then affinity addition reaction with 2-chloro-4-methylpyrimidine is performed to obtain intermediate 8, which is then brominated, condensed with trimethylthioacetamide, and ring-closed to obtain intermediate 8, which is then deacetylated, and then reacted with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain intermediate 5, and finally reacted with ammonia water under high temperature and high pressure to obtain dabrafenib. This route is similar to synthesis route one, but with more acetylation and deacetylation, and the operation steps are complicated.

[0010]

[0011] Route 3

[0012] 4) Synthesis route 4 (as shown below), Chinese patent 201711449350.6 reported that starting material 10 (2-tert-butyl-4-chlorothiazole) and N, N-dimethyl-2-acryloyl chloride react under triethylamine to generate intermediate 11, intermediate 11 and N-carbamide acyl propionamide are cyclized under sodium hydroxide to obtain intermediate 12, intermediate 12 and 2-fluoroaniline are coupled under the catalysis of aluminum chloride to generate intermediate 13, intermediate 13 reacts with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain intermediate 14, and hydrochloric acid reflux hydrolysis to obtain dabrafenib. Route 4 is relatively long, the operation is relatively cumbersome, and the final hydrochloric acid reflux conditions are relatively harsh, which is not conducive to scale-up industrial production.

[0013]

[0014] Route 4

[0015] At present, most industrial production adopts route 1, but the last step is to prepare dabrafenib by ammonolysis reaction of ammonia water under high temperature and high pressure conditions. The reaction conditions are harsh and dangerous. Moreover, the halogen fluorine on the benzene ring of the benzenesulfonamide group of dabrafenib further undergoes substitution reaction with ammonia water under the above high temperature and high pressure conditions to produce a diamine-containing impurity A with the following structure. The impurity A is similar to the structure of dabrafenib and is not easy to remove. It is difficult to remove by conventional crystallization methods. Therefore, it is necessary to develop an economical and environmentally friendly preparation method of dabrafenib with high yield, high product purity and mild reaction conditions;

[0016] Summary of the invention

[0017] The object of the present invention is to provide a method for preparing dabrafenib. The dabrafenib prepared by the method provided by the present invention has high purity and high yield. The dabrafenib mesylate generated after salification with methanesulfonic acid has high purity, little or almost no impurity A (undetectable), and high yield.

[0018] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0019] The present invention provides a method for preparing dabrafenib, characterized in that it comprises the following steps:

[0020] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide (hereinafter referred to as intermediate 5) and an organic solvent are mixed, and then a silane-substituted amine reagent is added to carry out a substitution reaction to obtain an intermediate 15 having the following structure;

[0021]

[0022] The intermediate 15 is mixed with an acid, subjected to a hydrolysis reaction, and then post-treated to obtain dabrafenib.

[0023] Preferably, the organic solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, DMF, DMSO, DMAC, dichloromethane, dichloroethane, dioxane, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether and chloroform.

[0024] Preferably, the silane-substituted amine reagent is at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and a reaction product of hexamethyldisilazane and metallic lithium / metallic sodium / metallic potassium / sodium hydride / lithium hydride / potassium hydride.

[0025] Preferably, the molar ratio of the N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide to the silane-substituted amine reagent is 1:(1-10).

[0026] Preferably, the substitution reaction is carried out in an inert atmosphere with stirring, and the temperature of the substitution reaction is -20 to 60°C.

[0027] Preferably, the acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid.

[0028] Preferably, the temperature of the hydrolysis reaction is -10 to 60°C, and the time of the hydrolysis reaction is 20 to 50 minutes.

[0029] Preferably, the post-treatment comprises: extracting, washing, concentrating, crystallizing, adjusting pH, filtering and drying the product of the hydrolysis reaction in sequence.

[0030] Preferably, the crystallization comprises: mixing the concentrated product and a polar organic solvent, heating the mixture to 30-50° C., and then adding water to precipitate crystals.

[0031] Preferably, the polar organic solvent is at least one of acetonitrile, propionitrile, methanol, ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone, DMF, DMAC, DMSO, NMP, tetrahydrofuran, and dioxane.

[0032] The present invention provides a method for preparing dabrafenib, and the synthesis route is shown below.

[0033]

[0034] The present invention uses N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide as the starting material, and has the advantages of easy raw material availability, simple process, mild reaction conditions, environmental protection and economy. In addition, the prior art uses intermediate 5 to react with ammonia water to generate dabrafenib, and then forms a salt with methanesulfonic acid to obtain dabrafenib mesylate with an impurity A content of 0.26%, which is not easy to remove and requires multiple refining to reduce it to less than 0.15%, resulting in a loss of yield and high cost. The dabrafenib prepared by the present invention has high purity and high yield. The dabrafenib mesylate generated after forming a salt with methanesulfonic acid has high purity, small or almost no impurity A (not detected), high yield, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the H NMR spectrum of dabrafenib prepared in Example 1 of the present invention;

[0036] Figure 2 This is the HPLC spectrum of dabrafenib mesylate prepared in Application Example 1 of the present invention;

[0037] Figure 3 This is the HPLC spectrum of dabrafenib mesylate prepared in Comparative Example 1 of the present invention;

[0038] Figure 4 The HPLC spectrum of the commercially available original drug dabrafenib mesylate capsules of the present invention. DETAILED DESCRIPTION

[0039] The present invention provides a method for preparing dabrafenib, characterized in that it comprises the following steps:

[0040] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and an organic solvent are mixed, and a silane-substituted amine reagent is added to carry out a substitution reaction to obtain an intermediate 15 having the following structure;

[0041] The intermediate 15 is mixed with an acid, subjected to a hydrolysis reaction, and then post-treated to obtain dabrafenib.

[0042] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the art.

[0043] In the present invention, the organic solvent is preferably at least one of tetrahydrofuran, methyltetrahydrofuran, DMF, DMSO, DMAC, dichloromethane, dichloroethane, dioxane, ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and chloroform, and more preferably one of tetrahydrofuran and dioxane.

[0044] In the present invention, the silane-substituted amine reagent is preferably at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and the reaction product of hexamethyldisilazane and metallic lithium / metallic sodium / metallic potassium / sodium hydride / lithium hydride / potassium hydride. In the present invention, the silane-substituted amine reagent is preferably added in the form of a solution; the solvent of the silane-substituted amine reagent solution is preferably at least one of methyl tert-butyl ether, toluene, hexane, 2-methyltetrahydrofuran, and tetrahydrofuran.

[0045] In the present invention, the mass ratio of the N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide to the volume ratio of the organic solvent is preferably 1 g:(1-20) mL, more preferably 1 g:(4-15) mL.

[0046] In the present invention, the molar ratio of the N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and the silane-substituted amine reagent is preferably 1:(1-10), more preferably 1:(3-6).

[0047] In the present invention, the substitution reaction is preferably carried out in an inert atmosphere, more preferably a nitrogen atmosphere; the temperature of the substitution reaction is preferably -20 to 60°C, more preferably 5 to 45°C.

[0048] In the present invention, the acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid. In the present invention, the temperature of the hydrolysis reaction is preferably -10 to 60°C, more preferably 10 to 45°C. In the present invention, the ratio of the mass of the intermediate 5 to the volume of the acid is preferably 1 g: (5 to 10) mL or the pH of the system is adjusted to ≤ 2 with an acid.

[0049] In the present invention, the post-treatment includes: extracting, washing, concentrating, crystallizing, adjusting pH, filtering and drying the product of the hydrolysis reaction in sequence.

[0050] In the present invention, the extraction solvent is at least one of ethyl formate, methyl formate, (n- / iso)propyl formate, (n- / iso / tert-)butyl formate, isopentyl formate, methyl acetate, amyl acetate, ethyl acetate, ethyl propionate, n-propyl acetate, isopropyl acetate, (n- / iso / sec-)butyl acetate, dichloromethane, ether, methyl propionate, ethyl propionate, propyl propionate, and (n- / iso / sec-)butyl propionate, more preferably one of ethyl acetate and propyl acetate.

[0051] In the present invention, the washing preferably includes washing with a 10% sodium carbonate aqueous solution and washing with a saturated sodium chloride aqueous solution in sequence. The present invention has no particular limitation on the concentration method, and the solvent can be removed by using a technical solution well known in the art.

[0052] In the present invention, the crystallization preferably comprises: mixing the concentrated product and a polar organic solvent, heating the mixture to 30-50° C., and then adding water to precipitate crystals;

[0053] In the present invention, the polar organic solvent is preferably at least one of acetonitrile, propionitrile, methanol, ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone, DMF, DMAC, DMSO, NMP, tetrahydrofuran, and dioxane, and more preferably at least one of acetonitrile, ethanol, and methanol. In the present invention, the heating temperature is more preferably 40 to 50° C., and more preferably 45° C.

[0054] In the present invention, the mass ratio of the intermediate 5, the polar organic solvent and water is preferably 1:(2-15):(6-30), and more preferably 1:(4-6):(8-15).

[0055] In the present invention, the pH is preferably adjusted by using an acid to adjust the pH value of the system to 4 to 14, more preferably 5 to 8; the acid is preferably at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid, more preferably one of hydrochloric acid and sulfuric acid.

[0056] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0057] Example 1

[0058] A method for preparing dabrafenib, comprising the following steps:

[0059] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (10 g, 18.6 mmol), was added to 1,4-dioxane (100 mL) under nitrogen protection. A tetrahydrofuran solution of LiHMDS (1 M) (93 mL, 93 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h. The mixture was heated to 45 °C and stirred for 1 h. The liquid phase was monitored to complete the substitution reaction of the raw materials to obtain intermediate 15. 4 M hydrochloric acid (60 mL) was continued to be added dropwise to the system to quench the reaction. The mixture was heated to room temperature for 3 h. , stirring for hydrolysis reaction for 0.5h, then adding ethyl acetate (150mL) for extraction and stratification, the organic layer was washed with 10% aqueous sodium carbonate solution (50mL) and saturated aqueous sodium chloride solution (50mL) in turn, separated and concentrated, and then acetonitrile (50mL) was added and the temperature was raised to 45°C, and then water (100mL) was added for crystallization, and then the pH was adjusted to 6 with 4M hydrochloric acid, cooled to 15°C, and filtered after stirring for 1h. The solid obtained by filtration was rinsed with 33% aqueous acetonitrile solution (60mL), and then placed in a vacuum drying oven at 50°C for 6h to obtain 8.9g of dabrafenib (yield 92%);

[0060] The mass ratio of the intermediate 5 to the volume of 1,4-dioxane is 1 g:10 mL;

[0061] The molar ratio of the intermediate 5 to the silane-substituted amine reagent LiHMDS is 1:5;

[0062] The mass ratio of the intermediate 5, the polar organic solvent acetonitrile and water is 1 g:5 mL:10 mL.

[0063] Detection of dabrafenib prepared in Example 1 LCMS: m / z=520.2[M+H] + , Figure 1This is the hydrogen nuclear magnetic spectrum of dabrafenib prepared in Example 1, wherein, 1HNMR (500 MHz, DMSO-d6) δppm 10.88 (s, 1H), 7.98 (d, J=5.5 Hz, 1H), 7.67-7.70 (m, 1H), 7.43-7.46 (m, 1H), 7.37-7.38 (m, 1H), 7.29-7.35 (m, 1H), 7.22-7.28 (m, 2H), 6.76 (s, 2H), 5.85 (d, J=5.5 Hz, 1H), 1.41 (s, 9H).

[0064] Application Example 1

[0065] Dabrafenib mesylate was prepared by using the dabrafenib prepared in Example 1 as a raw material, and the steps were as follows:

[0066] Take dabrafenib (5 g, 9.6 mmol) prepared in Example 1, add it to acetonitrile (27 mL), cool it to 20 ° C, add a mixture of methanesulfonic acid (1 g, 10.6 mmol) dissolved in purified water (3.8 mL) dropwise, and after the addition is complete, heat it to 55 ° C and stir to react for 2 h, then cool it to 5 ° C, continue stirring for 2 h and filter it. The solid obtained by filtration is rinsed with acetonitrile (60 mL), and then placed in a vacuum drying oven at 50 ° C and dried for 6 h to obtain 5.2 g of dabrafenib mesylate, with a yield of 88%. Impurity A was not detected. The HPLC spectrum of dabrafenib mesylate prepared in Application Example 1 is as follows Figure 2 As shown, it can be seen from the HPLC test data that the purity of dabrafenib mesylate prepared in Application Example 1 is 99.83%.

[0067] Example 2

[0068] A method for preparing dabrafenib, comprising the following steps:

[0069] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (80 g, 148 mmol), was added to 1,4-dioxane (1000 mL) under nitrogen protection, and a methyl tert-butyl ether solution of LiHMDS (1 M) (740 mL, 740 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 3 h, and then the temperature was raised to 45°C and stirred for 1 h. The liquid phase was monitored to see if the raw material substitution reaction was complete to obtain intermediate 15, and then The system was cooled to 10°C, 4M hydrochloric acid was added dropwise to quench the reaction until the pH of the system was ≤2, and 400 mL of ethyl acetate was added after stirring for hydrolysis reaction for 0.5 h to separate the layers, and the organic layer was washed with water (400 mL), separated and concentrated, acetonitrile (400 mL) was added, the temperature was raised to 45°C, and water (800 mL) was added for crystallization, cooled to 15°C, and the mixture was stirred for 1 h before filtering. The filtered solid was rinsed with 33% acetonitrile aqueous solution (480 mL), and then placed in a vacuum drying oven at 50°C for 6 h to obtain 69 g of dabrafenib with a yield of 89%;

[0070] The mass ratio of the intermediate 5 to the volume of 1,4-dioxane is 1 g:12.5 mL;

[0071] The molar ratio of the intermediate 5 to the silane-substituted amine reagent LiHMDS is 1:5;

[0072] The mass ratio of the intermediate 5, the polar organic solvent acetonitrile and water is 1 g:5 mL:10 mL.

[0073] Example 3

[0074] A method for preparing dabrafenib, comprising the following steps:

[0075] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (50 g, 93 mmol), was added to 1,4-dioxane (500 mL) under nitrogen protection. A 2-methyltetrahydrofuran solution (1 M) (470 mL, 470 mmol) of LIHMDS was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and then heated to 45 °C and stirred for 1 h. The liquid phase was monitored to complete the raw material substitution reaction to obtain intermediate 15, and the system was cooled and stirred. The mixture was cooled to 10°C, 4M hydrochloric acid was added dropwise to quench the reaction until the pH of the system was ≤2, and the mixture was stirred for hydrolysis reaction for 0.5h, and then 250mL of ethyl acetate was added for extraction and stratification. The organic layers were washed with water (250mL) respectively, and the layers were separated. The organic layers were concentrated, acetonitrile (250mL) was added and the temperature was raised to 45°C, and then water (500mL) was added for crystallization. The mixture was cooled to 15°C, and the mixture was stirred for 1h before filtering. The filtered solid was rinsed with 33% acetonitrile aqueous solution (300mL), and then dried in a vacuum drying oven at 50°C for 6h to obtain 42g of dabrafenib with a yield of 87%;

[0076] The mass ratio of the intermediate 5 to the volume of 1,4-dioxane is 1 g:10 mL;

[0077] The molar ratio of the intermediate 5 to the silane-substituted amine reagent LiHMDS is 1:5;

[0078] The mass ratio of the intermediate 5, the polar organic solvent acetonitrile and water is 1 g:5 mL:10 mL.

[0079] Embodiment 4:

[0080] A method for preparing dabrafenib, comprising the following steps:

[0081] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (80 g, 148 mmol), was added to 1,4-dioxane (800 mL) under nitrogen protection, and a tetrahydrofuran solution (1 M) (740 mL, 740 mmol) of sodium bis(trimethylsilyl)amide was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and then heated to 45°C and stirred for 1 h. The liquid phase was monitored to complete the substitution reaction of the raw materials to obtain intermediate 15. The system was then cooled to 10°C and 4 M sulfuric acid (240 mL L) quench the reaction, stir and hydrolyze for 0.5h, add ethyl acetate (1200mL) to separate the layers, wash the organic layer with 10% aqueous sodium carbonate solution (400mL) and saturated aqueous sodium chloride solution (400mL), separate the layers, concentrate the organic layer, add acetonitrile (400mL) and heat to 45°C, add water (800mL) to crystallize, adjust the pH to 5 with 4M hydrochloric acid, cool to 15°C, continue stirring for 1h and filter, wash the filtered solid with 33% aqueous acetonitrile solution (480mL), and dry it in a vacuum drying oven at 50°C for 6h to obtain 70g of dabrafenib with a yield of 91%;

[0082] The mass ratio of the intermediate 5 to the volume of 1,4-dioxane is 1 g:10 mL;

[0083] The molar ratio of the intermediate 5 to sodium bis(trimethylsilyl)amide is 1:5;

[0084] The mass ratio of the intermediate 5, the polar organic solvent acetonitrile and water is 1 g:5 mL:10 mL.

[0085] Embodiment 5:

[0086] A method for preparing dabrafenib, comprising the following steps:

[0087] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (60 g, 111 mmol), was added to 1,4-dioxane (600 mL) under nitrogen protection, and a tetrahydrofuran solution (1 M) (560 mL, 560 mmol) of potassium bis(trimethylsilyl)amide was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and then heated to 45°C and stirred for 1 h. The liquid phase was monitored to complete the substitution reaction of the raw materials to obtain intermediate 15. The system was then cooled to 10°C and 4M nitric acid (480 mL) was added dropwise. L) quench the reaction, stir and hydrolyze for 0.5h, add ethyl acetate (900mL) to separate the layers, wash the organic layer with 10% aqueous sodium carbonate solution (300mL) and saturated aqueous sodium chloride solution (300mL), separate the layers, concentrate the organic layer, add acetonitrile (300mL) and heat to 45°C, add water (600mL) to crystallize, then adjust the pH of the system to 5 with 4M hydrochloric acid, cool to 15°C, continue stirring for 1h and filter, wash the filtered solid with 33% aqueous acetonitrile solution (360mL), and dry it in a vacuum drying oven at 50°C for 6h to obtain 48g of dabrafenib with a yield of 83%;

[0088] The mass ratio of the intermediate 5 to the volume of 1,4-dioxane is 1 g:10 mL;

[0089] The molar ratio of the intermediate 5 to sodium bis(trimethylsilyl)amide is 1:5;

[0090] The mass ratio of the intermediate 5, the polar organic solvent acetonitrile and water is 1 g:5 mL:10 mL.

[0091] Embodiment 6:

[0092] A method for preparing dabrafenib, comprising the following steps:

[0093] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (100 g, 186 mmol), was added to tetrahydrofuran (1500 mL) under nitrogen protection, and a tetrahydrofuran solution of LiHMDS (1 M) (930 mL, 930 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 3 h. The liquid phase was monitored to complete the substitution reaction of the raw materials to obtain intermediate 15, and then the system was stirred at room temperature for 3 h. The mixture was cooled to 10°C, 4M hydrochloric acid (600 mL) was added dropwise to quench the reaction, and 900 mL of ethyl acetate was added for extraction and stratification. The organic layer was concentrated, tetrahydrofuran (500 mL) was added, and the temperature was raised to 45°C. Water (1000 mL) was added for crystallization, and then the pH was adjusted to 6 with a 10% aqueous sodium hydroxide solution. The mixture was cooled to 15°C, and the mixture was stirred for 1 h before being filtered. The solid obtained by filtration was rinsed with water (400 mL), and then dried in a vacuum drying oven at 50°C for 10 h to obtain 92 g of dabrafenib with a yield of 95%.

[0094] The mass ratio of the intermediate 5 to the volume of tetrahydrofuran is 1 g:15 mL;

[0095] The molar ratio of the intermediate 5 to sodium bis(trimethylsilyl)amide is 1:5;

[0096] The mass ratio of the intermediate 5, the polar organic solvent tetrahydrofuran and water is 1 g:5 mL:10 mL.

[0097] Embodiment 7:

[0098] A method for preparing dabrafenib, comprising the following steps:

[0099] N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, intermediate 5 (50 g, 93 mmol), was added to ethylene glycol dimethyl ether (400 mL) under nitrogen protection, and a tetrahydrofuran solution of LiHMDS (1 M) (470 mL, 470 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and then the temperature was raised to 45°C and stirred for 1 h. The liquid phase was monitored to complete the raw material substitution reaction to obtain intermediate 15. The system was then cooled to 10°C, and 4M hydrochloric acid (300 mL) was added dropwise to quench the reaction. The mixture was stirred for another 0.5 h for hydrolysis reaction, and then 500 mL of ethyl acetate was added for extraction and stratification. The organic layer was concentrated, and the organic layer was washed with 10% aqueous sodium carbonate solution (250 mL) and saturated aqueous sodium chloride solution (250 mL), respectively. The organic layer was separated and concentrated, and acetonitrile (250 mL) was added and the temperature was raised to 45° C., and then water (500 mL) was added for crystallization. The pH was then adjusted to 5 with 4 M hydrochloric acid, cooled to 15° C., and filtered after continued stirring for 1 h. The solid obtained by filtration was rinsed with 33% aqueous acetonitrile solution (300 mL), and then dried in a vacuum drying oven at 50° C. for 6 h to obtain 44 g of dabrafenib with a yield of 91%.

[0100] The mass ratio of the intermediate 5 to the volume ratio of ethylene glycol dimethyl ether is 1 g:8 mL;

[0101] The molar ratio of the intermediate 5 to sodium bis(trimethylsilyl)amide is 1:5;

[0102] The mass ratio of the intermediate 5, the polar organic solvent tetrahydrofuran and water is 1 g:5 mL:10 mL.

[0103] Comparative Example 1:

[0104] A) Reference patent 200980126781.6 (publication number: CN102083312A), Example 58c, the method in step D for preparing dabrafenib, the steps are: adding intermediate 5 (20 g, 37.2 mmol) to aqueous ammonia (28-30%, 400 mL), then putting it into a high-pressure reactor, heating it to 100°C and stirring it for 2 hours, cooling it to 20°C, continuing to stir it for 2 hours and then filtering it, and the filtered solid was rinsed with water (100 mL); adding the obtained solid wet product to ethyl acetate (300 mL) and water (40 mL), heating it to 100°C and stirring it for 2 hours; After stirring to 65°C and dissolving, the mixture was allowed to stand and the aqueous layer was separated. Water (20 mL) was added to the organic layer and stirred, and the pH was adjusted to 5.5 with dilute hydrochloric acid. Water (20 mL) was added and the aqueous layer was separated. Water (40 mL) was added to the organic layer and stirred. The aqueous layer was separated and the organic phase was concentrated in vacuo to about 60 mL. n-heptane (180 mL) was added dropwise for crystallization, and then cooled to 5°C. After stirring for 1 hour, the mixture was filtered. The solid obtained by filtration was rinsed with a mixture of ethyl acetate / n-heptane (1v / 3v, 80 mL), and then dried in a vacuum drying oven at 50°C for 4 hours to obtain 16.4 g of dabrafenib with a yield of 85%.

[0105] B) Referring to Patent 200980126781.6 (Publication No.: CN102083312A), the method in Example 58e was used to prepare dabrafenib mesylate: dabrafenib (15 g, 28.8 mmol) prepared in step A) of the above comparative example 1 was added to acetonitrile (79 mL), cooled to 20°C, and a mixture of methanesulfonic acid (3 g, 31.8 mmol) dissolved in purified water (11 mL) was added dropwise. After the addition was complete, the mixture was heated to 55°C. The reaction was stirred for 2 h, then cooled to 5 ° C., and filtered after stirring for another 2 h. The filtered solid was rinsed with acetonitrile (180 mL), and then placed in a vacuum drying oven at 50 ° C. and dried for 6 h to obtain 15.3 g of dabrafenib mesylate with a yield of 86%. The content of impurity A was 0.26 wt%. The purity of dabrafenib mesylate prepared in Comparative Example 1 was detected by the same HPLC method as in Application Example 1. The HPLC spectrum of dabrafenib mesylate prepared in Comparative Example 1 is as follows: Figure 3 As shown, it can be seen from the HPLC test data that the purity of dabrafenib mesylate prepared in Comparative Example 1 is 99.55%.

[0106] Figure 4 The HPLC spectrum of the original drug dabrafenib mesylate capsules purchased from a certain company is obtained by using the same HPLC method as in Application Example 1. Figure 4As shown in the table, the HPLC test data shows that the purity of the commercially available original drug dabrafenib mesylate capsules is 99.15%, and the impurity A content is 0.16wt%. The purity and impurity A content of application example 1 of the present invention, comparative example 1 and the commercially available original drug dabrafenib mesylate are shown in table 1.

[0107] Table 1 Statistics of purity and impurity A content of Application Example 1, Comparative Example 1 and the commercially available original drug dabrafenib mesylate

[0108]

[0109] In summary, the present invention provides a method for preparing dabrafenib, using N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide as a starting material, adding a silane-substituted amine reagent for a substitution reaction, and then hydrolyzing in the presence of an acid to obtain dabrafenib, which has the advantages of easy availability of raw materials, simple process, mild reaction conditions, environmental protection and economy. The dabrafenib prepared by the method provided by the present invention has high purity, high yield and few impurities, and the dabrafenib mesylate prepared by using it as a raw material has high purity, high yield and does not contain impurity A.

[0110] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing dabrafenib, characterized in that: The following steps are involved: N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and an organic solvent are mixed, and a silane-substituted amine reagent is added to carry out a substitution reaction to obtain an intermediate 15 having the following structure; Intermediate 15; mixing the intermediate 15 with an acid, performing a hydrolysis reaction, and performing post-treatment to obtain dabrafenib; The substitution reaction is carried out in a stirring, inert atmosphere, and the temperature of the substitution reaction is 5-45°C; The temperature of the hydrolysis reaction is 10-45°C, and the time of the hydrolysis reaction is 20-50min; The post-treatment comprises: extracting, washing, concentrating, crystallizing, adjusting pH, filtering and drying the product of the hydrolysis reaction in sequence; The silane-substituted amine reagent is at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and a reaction product of hexamethyldisilazane and metallic lithium / metallic sodium / metallic potassium / sodium hydride / lithium hydride / potassium hydride; The molar ratio of the N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and the silane-substituted amine reagent is 1:(1-10).

2. The preparation method according to claim 1, characterized in that: The organic solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, DMF, DMSO, DMAC, dichloromethane, dichloroethane, dioxane, ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether and chloroform.

3. The preparation method according to claim 1, characterized in that: The acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid.

4. The preparation method according to claim 1, characterized in that: The crystallization comprises: mixing the concentrated product and a polar organic solvent, heating the mixture to 30-50° C., and then adding water to precipitate crystals.

5. The preparation method according to claim 4, characterized in that: The polar organic solvent is at least one of acetonitrile, propionitrile, methanol, ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone, DMF, DMAC, DMSO, NMP, tetrahydrofuran, and dioxane.

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