Preparation method of darafenib

Abstract

The invention provides a preparation method of darafenib, and belongs to the technical field of medicine synthesis. The preparation method provided by the invention comprises the following steps: by taking a compound 3 (namely 3-{[(2, 6-difluorophenyl) sulfonyl] amino}-2-fluorobenzoic acid methyl ester) as a starting raw material, adding an amino reagent, carrying out condensation reaction with a compound 15 (namely (4-methylpyrimidine-2-yl)-carbamic acid tert-butyl ester) to obtain an intermediate 16, carrying out substitution reaction with a halogenating reagent to obtain an intermediate 17, and carrying out condensation reaction on the intermediate 17 and a compound 16 to obtain a compound 16. Then, carrying out coupling-ring closing reaction on the intermediate 18 and trimethyl thioacetamide to obtain an intermediate 18; and finally, removing a protecting group under an acidic condition to obtain darafenib. The preparation method of Darrafenib provided by the invention overcomes the defects of harsh reaction conditions, difficult post-treatment and the like, has the advantages of easily available raw materials, simple process, mild reaction conditions, environmental protection, economy and the like, and is high in product yield and purity and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, and in particular to a method for preparing dabrafenib. Background Technology

[0002] Dabrafenib mesylate, chemically named N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazolyl-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide mesylate, is an anti-tumor drug that inhibits tumor growth by suppressing cell proliferation. Dabrafenib is a potent BRAF inhibitor that exerts its anti-tumor effect in various tumors with BRAF V600E or V600K mutations, particularly melanoma, non-small cell lung cancer, and undifferentiated thyroid carcinoma. Its formulations can be used to treat BRAF V600 mutation-positive unresectable or metastatic melanoma. In combination with trametinib, it is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma and as adjuvant therapy after stage III melanoma. Currently, dabrafenib formulations have been approved in multiple countries and regions, playing an important role in the treatment of various cancers and the health of patients.

[0003] Since dabrafenib is an important compound for cancer treatment, its cost-effective synthesis is a research focus for pharmaceutical scientists. Currently, the literature mainly reports five methods for preparing dabrafenib, as detailed below.

[0004] 1) Synthesis Method 1: 200980126781.6 (Publication No.: CN102083312A) discloses a method that uses compound 2 (methyl 3-amino-2-fluorobenzoate) as the starting material and reacts with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain sulfonamide intermediate 3. Under the action of LiHMDS, it undergoes a condensation reaction with 2-chloro-4-methylpyrimidine to produce intermediate 4. Intermediate 4 is brominated with NBS and then undergoes a coupling and cyclization reaction with trimethylthioacetamide to produce intermediate 5. Intermediate 5 reacts with ammonia water under high temperature and high pressure to generate dabrafenib. Finally, it forms a salt with methanesulfonic acid to obtain dabrafenib methanesulfonate. The route is shown in Formula 1 below.

[0005] Formula 1;

[0006] 2) Synthesis Method 2: 201310586872.6 (Publication No.: CN103588767A) The target compound can be obtained through steps such as sulfonamide, halogenation, thiazole cyclization, acylation, and pyrimidine cyclization. However, the last step, pyrimidine cyclization, has a high reaction temperature and is highly dangerous to use with the strong oxidant guanidine nitrate. The route is shown in Equation 2 below.

[0007] Formula 2;

[0008] 3) Synthesis Method 3: (Patent Publication No.: CN102083312A) discloses a method that uses compound 2 (methyl 3-amino-2-fluorobenzoate) as the starting material, acetylates it to obtain intermediate 7, then reacts it with 2-chloro-4-methylpyrimidine to obtain intermediate 8, brominates it, then couples it with trimethylthioacetamide and cyclizes it to obtain intermediate 9, then deacetylates it, and then reacts it with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain intermediate 5, and finally reacts it with ammonia under high temperature and high pressure to obtain dabrafenib. The route is shown in Formula 3 below.

[0009] Formula 3;

[0010] 4) Synthesis Method 4: 201711449350.6 (Publication No.: CN107987071A) reported the reaction of starting material 10 (2-tert-butyl-4-chlorothiazol) and N,N-dimethyl-2-acryloyl chloride under triethylamine conditions to generate intermediate 11. Intermediate 11 was cyclized with N-carbamoylimide propionamide under sodium hydroxide conditions to obtain intermediate 12. Intermediate 12 was coupled with 2-fluoroaniline under aluminum trichloride catalysis to generate intermediate 13. Intermediate 13 was reacted with compound 1 (2,6-difluorobenzenesulfonyl chloride) to obtain intermediate 14. The intermediate was hydrolyzed by reflux with hydrochloric acid to obtain dabrafenib. The route is shown in Formula 4 below.

[0011] Equation 4;

[0012] 5) Synthesis method five: WO2016 / 059548 reported that in the solvent of dimethyl sulfoxide, compound 1 reacts with formamide at high temperature under the action of base to obtain dabrafenib, and the route is shown in Formula 5 below.

[0013] Formula 5;

[0014] The above methods reveal that Synthesis Method 1 is cumbersome, produces a high level of impurities in the finished product, and involves a high-temperature, high-pressure ammoniation reaction, posing a high production hazard and requiring sophisticated equipment. Synthesis Method 2 involves a high pyrimidine cyclization temperature and the use of strong oxidizing reagents, making it unsuitable for industrial production. Synthesis Method 3 uses an amino protecting group, has a long production route, is cumbersome, and also involves a high-temperature, high-pressure ammoniation reaction, posing a high production hazard and requiring sophisticated equipment. Synthesis Method 4 has a long production route, requires sophisticated equipment, and has high production costs. Synthesis Method 5 requires silica gel column purification, making it unsuitable for industrial production. Therefore, providing a high-yield, high-purity, simple, economical, and environmentally friendly method for the preparation of dabrafenib is of great significance. Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing dabrafenib. The preparation method provided by this invention uses readily available raw materials, has a simple process, mild reaction conditions, is environmentally friendly and economical, and produces dabrafenib products with high yield and purity.

[0016] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0017] This invention provides a method for preparing dabrafenib, comprising the following steps:

[0018] (1) Compound 3, the first solvent, the amine reagent and compound 15 were mixed and subjected to a condensation reaction to obtain intermediate 16;

[0019] (2) The intermediate 16 obtained in step (1), the second solvent and the halogenated reagent are mixed and a substitution reaction is carried out to obtain intermediate 17;

[0020] (3) After mixing the intermediate 17 obtained in step (2), the third solvent and trimethylthioacetamide, a coupling-cyclization reaction is carried out to obtain intermediate 18;

[0021] (4) Mix the intermediate 18 from step (3), the third solvent, and the acid to remove the protecting group, thereby obtaining dabrafenib;

[0022]

[0023] Preferably, the amino reagent in step (1) is at least one of bis(trimethylsilyl)aminolithium (LiHMDS), bis(trimethyl)silyl)aminosodium (NaHMDS), and bis(trimethyl)silyl)aminopotassium (KHMDS).

[0024] Preferably, the molar ratio of compound 3 and compound 15 in step (1) is 1:(1~5).

[0025] Preferably, the temperature of the condensation reaction in step (1) is -10~50℃.

[0026] Preferably, the halogenating agent in step (2) is at least one of N-chlorosuccinimide, iodine, N-iodosuccinimide, bromine, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid TCCA, 1,3-dichloro-5,5-dimethylhydantoin DCDMH, (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid TBCA, dibromochloroacetic acid DBCA, and dibromohydantoin.

[0027] Preferably, the molar ratio of intermediate 16 and halogenated reagent in step (2) is 1:(0.5~2.5).

[0028] Preferably, the molar ratio of intermediate 17 and trimethylthioacetamide in step (3) is 1:(0.5~2.5).

[0029] Preferably, the temperature of the coupling-cyclization reaction in step (3) is -10~90℃.

[0030] Preferably, the acid in step (4) is at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid.

[0031] Preferably, the temperature of the deprotection reaction in step (4) is 20~80℃.

[0032] This invention provides a method for preparing dabrafenib, using compound 3 (i.e., methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate) as the starting material, adding an amine reagent, and reacting with compound 15 (i.e., (4-methylpyrimidin-2-yl)-tert-butyl carbamate) in a condensation reaction to obtain intermediate 16, then reacting with a halogenating reagent in a substitution reaction to obtain intermediate 17, then reacting with trimethylthioacetamide in a coupling-cyclization reaction to obtain intermediate 18, and finally removing the protecting group under acidic conditions to obtain dabrafenib. The dabrafenib preparation method provided by this invention replaces 2-chloro-4-methylpyrimidine in the synthesis method one with compound 15 (i.e., (4-methylpyrimidin-2-yl)-tert-butyl carbamate). This increases the polarity of subsequent intermediates, facilitating crystallization and avoiding cumbersome post-processing. Furthermore, compound 15 directly introduces the amino functional group into the dabrafenib compound, avoiding the harsh high-temperature and high-pressure reaction conditions required for introducing the amino functional group using reagents such as ammonia. The method provided by this invention has advantages such as readily available raw materials, simple process, mild reaction conditions, environmental friendliness, and economy. It also yields high-purity products, making it suitable for industrial production. Attached Figure Description

[0033] Figure 1 A flowchart illustrating the preparation method of dabrafenib provided by this invention;

[0034] Figure 2 The 1H NMR spectrum of intermediate 16 prepared in Example 1 of this invention;

[0035] Figure 3 The 1H NMR spectrum of intermediate 17 prepared in Example 1 of this invention;

[0036] Figure 4 The 1H NMR spectrum of intermediate 18 prepared in Example 1 of this invention;

[0037] Figure 5 The image shows the hydrogen NMR spectrum of dabrafenib prepared in Example 1 of this invention. Detailed Implementation

[0038] This invention provides a method for preparing dabrafenib, comprising the following steps:

[0039] (1) Compound 3, the first solvent, the amine reagent and compound 15 were mixed and subjected to a condensation reaction to obtain intermediate 16;

[0040] (2) The intermediate 16 obtained in step (1), the second solvent and the halogenated reagent are mixed and a substitution reaction is carried out to obtain intermediate 17;

[0041] (3) After mixing the intermediate 17 obtained in step (2), the third solvent and trimethylthioacetamide, a coupling-cyclization reaction is carried out to obtain intermediate 18;

[0042] (4) Mix the intermediate 18 from step (3), the third solvent, and the acid to remove the protecting group, thereby obtaining dabrafenib;

[0043]

[0044] Unless otherwise specified, all raw materials used in this invention are commercially available products in the art.

[0045] In this invention, compound 3, a first solvent, an amine reagent and compound 15 are mixed and subjected to a condensation reaction to obtain intermediate 16.

[0046] In this invention, the first solvent is preferably at least one selected from tetrahydrofuran, methyltetrahydrofuran, DMF, DMAc, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether, more preferably tetrahydrofuran or 1,4-dioxane. In this invention, the amine reagent is preferably at least one selected from bis(trimethylsilylamine)-lithium (LiHMDS), bis(trimethylsilylamine)-sodium (NaHMDS), and bis(trimethylsilylamine)-potassium (KHMDS). In this invention, the molar ratio of compound 3 to the amine reagent is preferably 1:(1~10), more preferably 1:(4~6). In this invention, the molar ratio of compound 3 to compound 15 is 1:(1~5). This invention controls the proportion of raw materials within the above range to promote the full reaction and obtain intermediate 16 with a high yield. In this invention, the temperature of the condensation reaction is preferably -10~50℃, more preferably 0~20℃. In this invention, the time of the condensation reaction is preferably 1~4 hours. The present invention promotes the full progress of the reaction by controlling the temperature of the condensation reaction within the above-mentioned range, thereby obtaining intermediate 16 with a high yield.

[0047] After the condensation reaction is completed, the present invention preferably adds 10% ammonium chloride aqueous solution to the product of the condensation reaction to quench the reaction, and then performs stirring, filtration, deionized water rinsing and first vacuum drying in sequence to obtain intermediate 16.

[0048] In this invention, the stirring time is preferably 1-2 hours. In this invention, the temperature of the first vacuum drying is preferably 45-55°C; the time of the first vacuum drying is preferably 8-12 hours.

[0049] After obtaining intermediate 16, the present invention mixes intermediate 16, a second solvent and a halogenating reagent to carry out a substitution reaction to obtain intermediate 17.

[0050] In this invention, the second reagent is preferably at least one of acetonitrile, DMF, DMAc, dichloromethane, ethyl acetate, and ethanol, more preferably acetonitrile or DMAc. In this invention, the halogenating reagent is preferably at least one of N-chlorosuccinimide, iodine, N-iodosuccinimide, bromine, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid (TCCA), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), (E)-3-(2,3,4,5-tetrabromophenyl)acrylate (TBCA), dibromochloroacetic acid (DBCA), and dibromohydantoin. In this invention, the molar ratio of intermediate 16 to the halogenating reagent is preferably 1:(0.5~2.5), more preferably 1:(0.9~1.5). In this invention, the temperature of the substitution reaction is preferably -10~80°C, more preferably 5~60°C. The present invention controls the amount of raw materials and the temperature of the substitution reaction within the above range to promote the reaction and obtain intermediate 17 with high yield.

[0051] After the substitution reaction is completed, the product of the substitution reaction is preferably post-processed to obtain intermediate 17.

[0052] In this invention, when the second reagent is preferably at least one of acetonitrile, dichloromethane, ethyl acetate, and ethanol, the post-processing preferably includes: sequentially cooling, stirring, filtering, rinsing with acetonitrile, and then vacuum drying the product of the substitution reaction to obtain intermediate 17; when the second reagent is preferably at least one of DMF and DMAc, the post-processing preferably includes: adding deionized water dropwise to the product of the substitution reaction to induce crystallization, and sequentially stirring, filtering, rinsing with deionized water, and then vacuum drying to obtain intermediate 17.

[0053] In this invention, the stirring time is preferably 1-2 hours. In this invention, the temperature of the second vacuum drying is preferably 45-65°C; the time of the second vacuum drying is preferably 3-17 hours.

[0054] After obtaining intermediate 17, the present invention mixes intermediate 17, a third solvent and trimethylthioacetamide and performs a coupling-cyclization reaction to obtain intermediate 18.

[0055] In this invention, the third solvent is preferably at least one selected from acetonitrile, DMF, DMAc, dioxane, acetone, ethyl acetate, ethanol, and methanol, more preferably DMF or DMAc. In this invention, the molar ratio of intermediate 17 to trimethylthioacetamide is preferably 1:(0.5~2.5), more preferably 1:(0.9~1.2). In this invention, the temperature of the coupling-cyclization reaction is preferably -10~90°C, more preferably 10~80°C, and even more preferably, the reaction is first carried out at room temperature and then at 60~80°C. In this invention, the time of the coupling-cyclization reaction is preferably 3~5 hours. This invention controls the amount of raw materials and the temperature of the coupling-cyclization reaction within the above ranges to promote the reaction and obtain intermediate 18 with a high yield.

[0056] After the coupling-cyclization reaction is completed, the product of the coupling-cyclization reaction is added dropwise to deionized water, and then stirred, filtered, washed with deionized water and dried under vacuum in sequence to obtain intermediate 18.

[0057] In this invention, the stirring time is preferably 1-2 hours. In this invention, the temperature of the third vacuum drying is preferably 45-55°C; the time of the third vacuum drying is preferably 8-12 hours.

[0058] After obtaining intermediate 18, the present invention mixes intermediate 18, a third solvent and an acid, and performs a deprotection reaction to obtain dabrafenib.

[0059] In this invention, the third solvent is preferably at least one selected from acetonitrile, tetrahydrofuran, dioxane, acetone, ethyl acetate, ethanol, methanol, and isopropanol, more preferably acetonitrile, ethanol, or acetone. In this invention, the acid is preferably at least one selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid. In this invention, the molar ratio of intermediate 18 to the acid is preferably 1:(1~10), more preferably 1:(3~8). In this invention, the temperature of the deprotection reaction is preferably 20~80°C, more preferably 20~60°C. In this invention, the time of the deprotection reaction is preferably 3~6 hours. This invention controls the amount of raw materials and the temperature of the deprotection reaction within the above ranges to promote the reaction and obtain a high yield of dabrafenib.

[0060] After the deprotection reaction is completed, the present invention preferably adds deionized water dropwise to the product of the deprotection reaction, and then performs pH adjustment, cooling, stirring, filtration, rinsing with ethanol aqueous solution and fourth vacuum drying in sequence to obtain dabrafenib.

[0061] In this invention, the pH adjustment is preferably performed using an aqueous sodium hydroxide solution to adjust the pH to 5-7. In this invention, the stirring time is preferably 1-2 hours. In this invention, the temperature of the fourth vacuum drying is preferably 45-55°C; the time of the fourth vacuum drying is preferably 4-10 hours.

[0062] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0063] Unless otherwise specified, all experiments were repeated three times, and the results are expressed as averages.

[0064] Figure 1 This is a flowchart illustrating the preparation process of dabrafenib in this invention.

[0065] Example 1

[0066] A method for preparing dabrafenib, comprising the following steps:

[0067] (1) Compound 3 (8g, 23.2mmol) was added to tetrahydrofuran (40mL), the temperature was lowered to 10℃, and LiHMDS tetrahydrofuran solution (1M) (58mL, 58mmol) was added dropwise. After the addition was completed, a solution of compound 15 (7.3g, 34.8mmol) dissolved in tetrahydrofuran (40mL) was added dropwise. After the addition was completed, LiHMDS tetrahydrofuran solution (1M) (58mL, 58mmol) was added dropwise. After the addition was completed, the condensation reaction was maintained at 10℃ for 1.5h. The condensation reaction of the raw materials was monitored by liquid phase. 10% ammonium chloride aqueous solution (300mL) was added dropwise to the product of the condensation reaction to quench the reaction. After stirring for 1h, the mixture was filtered. The solid obtained by filtration was washed with deionized water (48mL). The obtained solid was then placed in a vacuum drying oven at 50℃ for 10h to obtain 9.8g of intermediate 16 (yield 81%).

[0068] The molar ratio of compound 3 to the LiHMDS amine reagent is 1:5; the molar ratio of compound 3 to compound 15 is 1:1.5.

[0069] The characterization data of intermediate 16 obtained by detection are as follows: LCMS: m / z = 523.3 [M+H]+ ¹H NMR (500MHz, DMSO-d6) δppm 14.97 (s, ¹H), 10.87 (s, ¹H), 10.62 (s, ¹H), 8.26 (d, J=5.5Hz, ¹H), 7.72–7.75 (m, ¹H), 7.61–7.63 (m, ¹H), 7.37–7.40 (m, ¹H), 7.24–7.31 (m, ³H), 6.76 (d, J=5.5Hz, ¹H), 5.86 (s, ¹H), 1.50 (s, ⁹H). The ¹H NMR spectrum of intermediate 16 is shown below. Figure 2 As shown;

[0070] (2) The intermediate 16 (9g, 17.2mmol) obtained in step (1) was added to acetonitrile (135mL), cooled to 5°C, and N-chlorosuccinimide (2.3g, 17.2mmol) was slowly added. After the addition was complete, the temperature was raised to 50°C and the substitution reaction was stirred for 3h. The substitution reaction was monitored by liquid phase until the product of the substitution reaction was completed. The product of the substitution reaction was cooled to 10°C, stirred for 1h and filtered. The solid obtained by filtration was washed with acetonitrile (18mL) and then placed in a vacuum drying oven at 50°C for 5h to obtain 8.2g of intermediate 17 (yield 86%).

[0071] The preferred molar ratio of intermediate 16 to N-chlorosuccinimide halogenated reagent is 1:1;

[0072] The characterization data of intermediate 17 obtained by detection are as follows: LCMS: m / z = 557.2 [M+H] + ¹H NMR (500MHz, DMSO-d6) δppm 15.40 (s, ¹H), 11.02 (s, ¹H), 10.89 (s, ¹H), 8.42 (d, J=6Hz, ¹H), 7.70–7.73 (m, ¹H), 7.41–7.45 (m, ¹H), 7.25–7.33 (m, 4H), 6.92 (d, J=6Hz, ¹H), 1.49 (s, 9H). The ¹H NMR spectrum of intermediate 17 is shown below. Figure 3 As shown;

[0073] (3) The intermediate 17 (8g, 14.4mmol) obtained in step (2) was added to N,N-dimethylacetamide (72mL), cooled to 5°C, and trimethylthioacetamide (1.7g, 14.4mmol) was slowly added. After the addition was complete, the temperature was raised to room temperature and stirred for 1h. Then the temperature was raised to 75°C and stirred for 2h for coupling-cyclization reaction. The reaction of the raw materials was monitored by liquid phase. The product of the coupling-cyclization reaction was added dropwise to deionized water (144mL) to crystallize. After stirring for 1h, the mixture was filtered. The solid obtained by filtration was washed with deionized water (40mL) and then placed in a vacuum drying oven at 50°C for 9h to obtain 6.4g of intermediate 18 (yield 72%).

[0074] The preferred molar ratio of intermediate 17 to trimethylthioacetamide is 1:1;

[0075] The characterization data of intermediate 18 obtained by detection are as follows: LCMS: m / z = 620.3 [M+H]+. ¹H NMR (500MHz, DMSO-d6) δppm 10.89 (s, 1H), 10.06 (s, 1H), 8.33 (d, J = 5Hz, 1H), 7.66–7.69 (m, 1H), 7.42–7.47 (m, 2H), 7.31–7.34 (m, 1H), 7.22–7.25 (m, 2H), 6.34 (d, J = 5Hz, 1H), 1.49 (s, 9H), 1.42 (s, 9H). The ¹H NMR spectrum of intermediate 18 is shown below. Figure 4 As shown;

[0076] (4) The intermediate 18 (5g, 8.1mmol) obtained in step (3) and concentrated hydrochloric acid (2.7mL, 32.4mmol) were added to ethanol (25mL), heated to 65°C and stirred for 4h to remove the protecting group. After the removal of the protecting group of the raw material was completed by liquid phase monitoring, deionized water (50mL) was slowly added dropwise to the product of the removal of the protecting group. Then, the pH was adjusted to 6 with 10% sodium hydroxide aqueous solution, cooled to 15°C, stirred for 1h and filtered. The solid obtained by filtration was washed with 33% ethanol aqueous solution (30mL) and then placed in a vacuum drying oven at 50°C for 6h to obtain 3.9g of dabrafenib (yield 92%).

[0077] The molar ratio of intermediate 18 to acid is 1:4;

[0078] The characterization data of dabrafenib obtained by detection are as follows: LCMS: m / z = 520.2 [M+H]+. ¹H NMR (500MHz, DMSO-d6) δppm 10.88 (s, 1H), 7.98 (d, J = 5.5Hz, 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 = 5.5Hz, 1H), 1.41 (s, 9H). The ¹H NMR spectrum of dabrafenib is shown below. Figure 5 As shown.

[0079] Example 2

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

[0081] (1) Compound 3 (15 g, 43.4 mmol) was added to tetrahydrofuran (90 mL), the temperature was lowered to 5 °C, and NaHMDS tetrahydrofuran solution (1 M) (117 mL, 117 mmol) was added dropwise. After the addition was complete, a solution of compound 15 (10.9 g, 52 mmol) dissolved in tetrahydrofuran (45 mL) was added dropwise. After the addition was complete, NaHMDS tetrahydrofuran solution (1 M) (117 mL, 117 mmol) was added dropwise. After the addition was complete, the condensation reaction was maintained at 10 °C for 1.5 h. The reaction of the raw materials was monitored by liquid phase. The reaction was quenched by adding 10% ammonium chloride aqueous solution (600 mL) to the product of the condensation reaction. After stirring for 1 h, the mixture was filtered. The solid obtained by filtration was washed with deionized water (80 mL). The obtained solid was then placed in a vacuum drying oven and dried at 50 °C for 10 h to obtain 18.8 g of intermediate 16 (yield 83%).

[0082] The molar ratio of compound 3 to NaHMDS amine reagent is 1:5.4; the molar ratio of compound 3 to compound 15 is 1:1.2.

[0083] (2) The intermediate 16 (18g, 34.5mmol) obtained in step (1) was added to N,N-dimethylacetamide (108mL), cooled to 5°C, and N-chlorosuccinimide (5.1g, 37.9mmol) was slowly added. After the addition was complete, the mixture was kept warm and stirred for 2h to carry out the substitution reaction. The reaction of the raw materials was monitored by liquid phase. Deionized water (216mL) was added dropwise to the product of the substitution reaction to induce crystallization. After the addition was complete, the mixture was stirred for 1h and then filtered. The solid obtained by filtration was rinsed with deionized water (90mL) and then placed in a vacuum drying oven at 60°C for 15h to obtain 15.4g of intermediate 17 (yield 80%).

[0084] The preferred molar ratio of intermediate 16 to the N-chlorosuccinimide halogenating agent is 1:1.1;

[0085] (3) The intermediate 17 (12g, 21.5mmol) obtained in step (2) was added to N,N-dimethylacetamide (72mL), cooled to 5°C, and trimethylthioacetamide (2.8g, 23.7mmol) was slowly added. After the addition was completed, the temperature was raised to room temperature and stirred for 1h, and then raised to 75°C and stirred for 2h. The coupling-cyclization reaction of the raw materials was monitored by liquid phase until it was completed. The product of the coupling-cyclization reaction was added dropwise to deionized water (144mL) to crystallize. After stirring for 1h, the mixture was filtered. The solid obtained by filtration was washed with deionized water (60mL) and then placed in a vacuum drying oven at 50°C for 9h to obtain 10.5g of intermediate 18 (yield 79%).

[0086] The molar ratio of intermediate 17 to trimethylthioacetamide is preferably 1:1.1;

[0087] (4) The intermediate 18 (10g, 16.2mmol) obtained in step (3) and concentrated hydrochloric acid (5.4mL, 65mmol) were added to acetone (100mL), heated to 55°C and stirred for 6h to remove the protecting group. After the removal of the protecting group was completed by liquid phase monitoring, deionized water (200mL) was slowly added dropwise to the product of the removal of the protecting group. Then the pH was adjusted to 6 with 10% sodium hydroxide aqueous solution, cooled to 15°C, stirred for 2h and filtered. The solid obtained by filtration was washed with 33% ethanol aqueous solution (50mL) and then placed in a vacuum drying oven at 50°C for 10h to obtain 7.3g of dabrafenib (yield 87%).

[0088] The molar ratio of intermediate 18 to acid is 1:4.

[0089] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing dabrafenib, characterized in that, Includes the following steps: (1) Compound 3, the first solvent, the amine reagent and compound 15 were mixed and subjected to a condensation reaction to obtain intermediate 16; (2) The intermediate 16 obtained in step (1), the second solvent and the halogenated reagent are mixed and a substitution reaction is carried out to obtain intermediate 17; (3) After mixing the intermediate 17 obtained in step (2), the third solvent and trimethylthioacetamide, a coupling-cyclization reaction is carried out to obtain intermediate 18; (4) Mix the intermediate 18 from step (3), the third solvent, and the acid to remove the protecting group, thereby obtaining dabrafenib; ， ， ， ， ， 。 2. The preparation method according to claim 1, characterized in that, In step (1), the amino reagent is at least one of bis(trimethylsilyl)aminolithium (LiHMDS), bis(trimethyl)silyl)aminosodium (NaHMDS), and bis(trimethyl)silyl)aminopotassium (KHMDS).

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 3 to compound 15 is 1:(1~5).

4. The preparation method according to claim 2, characterized in that, The temperature of the condensation reaction in step (1) is -10~50℃.

5. The preparation method according to claim 1, characterized in that, In step (2), the halogenated reagent is at least one of N-chlorosuccinimide, iodine, N-iodosuccinimide, bromine, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid TCCA, 1,3-dichloro-5,5-dimethylhydantoin DCDMH, (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid TBCA, dibromochloroacetic acid DBCA, and dibromohydantoin.

6. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate 16 and halogenated reagent in step (2) is 1:(0.5~2.5).

7. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate 17 and trimethylthioacetamide in step (3) is 1:(0.5~2.5).

8. The preparation method according to claim 2, characterized in that, The temperature of the coupling-cyclization reaction in step (3) is -10~90℃.

9. The preparation method according to claim 1, characterized in that, The acid in step (4) is at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid.

10. The preparation method according to claim 1, characterized in that, The temperature for the deprotection reaction in step (4) is 20~80℃.

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