Carmonitinib intermediate and preparation method thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthetic Carmonitinib intermediate and a preparation method thereof, and the preparation method comprises the following steps: # imgabs0, in which R is an amino protecting group; comprising the following steps: (1) carrying out protective reaction on a compound shown in a formula 6 and R-Cl or anhydride to obtain a compound shown in a formula 7; (2) carrying out substitution reaction on the compound shown in the formula 7 to obtain a compound shown in a formula SM-001; (3) carrying out Suzuki coupling reaction on the compound shown as the formula SM-001 and a compound shown as a formula 12 to obtain a compound shown as a formula 13; (4) performing Mukaiyama hydration reaction on the compound shown in the formula 13 to obtain a compound shown in a formula 14; and (5) carrying out a deprotection reaction on the compound shown in the formula 14 to obtain the carmonitinib. Most of the intermediates obtained in the reaction process do not need to be purified, the next-step reaction can be directly carried out, the operation is easy, the cost is low, the reaction yield is high, and the purity is good; a plurality of brand new intermediates are obtained in the synthesis process, and the intermediates are stable in property, simple and convenient to operate and easy to realize industrial mass production.

Description

Technical Field

[0001] The invention relates to a camencetinib intermediate and a preparation method thereof, and belongs to the technical field of medicine and chemistry. Background Art

[0002] Camositinib, CAS: 2417489-10-0, has a chemical structure as shown below:

[0003]

[0004] In August 2023, the U.S. FDA granted fast track designation for lunresertib combined with camencitinib for the treatment of endometrial cancer with CCNE1 amplification or FBXW7 or PPP2R1A mutations in patients previously treated with platinum-containing and immunosuppressive therapies.

[0005] Currently, only one preparation route of Camonsetinib is disclosed. WO2020087170A1 provides a preparation route of Camonsetinib, and the reaction route is as follows:

[0006]

[0007] The patent reports that 2,6-difluoro-4-iodopyridine is used as the starting material, and first undergoes a microwave reaction, which is not suitable for industrial scale-up; secondly, the intermediate I is synthesized, but the yield is extremely low and unstable, and the dangerous reagent n-butyl lithium is required, which faces operational risks. Finally, the yield of the protection reaction is low, only 25.43%.

[0008] Therefore, there is an urgent need to develop a new method for preparing Camonsetinib. Summary of the invention

[0009] In order to solve the technical problems existing in the above reports, the present invention provides a new method for synthesizing Camonsetinib, as well as a new Camonsetinib intermediate and a preparation method thereof.

[0010] In order to overcome the defects of the prior art and achieve the requirements of commercial scale-up production, the present invention adopts the following preferred technical solutions:

[0011] The first aspect of the present invention provides a method for preparing a compound of formula 14, and the reaction formula is as follows:

[0012]

[0013] The steps include:

[0014] (1) subjecting the compound of formula SM-001 to a Suzuki coupling reaction with compound 12 to obtain a compound of formula 13;

[0015] (2) subjecting the compound of formula 13 to a Mukaiyama hydration reaction to obtain a compound of formula 14;

[0016] R is an amino protecting group.

[0017] The term "amino protecting group" refers to a group that is easily removed and introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Tos), benzenesulfonyl, trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzoyl, benzyl (Bn), p-methoxybenzyl (PMB), [2-(trimethylsilyl)ethoxy]methyl (SEM), etc.

[0018] As a further improvement of the present invention, the Suzuki coupling reaction in step (1) is a reaction of the compound of formula SM-001 in water or an organic solvent or a mixed solvent of water and an organic solvent, in the presence of a palladium catalyst and a base, with a compound of formula 12, wherein the palladium catalyst is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 , XPhosPdG 2 ,RuPhosPdG 2 ,SPhosPdG 2 ,tBuBrettPhosPdG 2 , XPhosPdG 3 ,RuPhosPdG 3 ,SPhosPdG 3 ,tBuBrettPhosPdG 3 One or more of the following;

[0019] As a further improvement of the present invention, the molar ratio of the SM-001 compound of step (1) to the palladium catalyst is 1:

[0020] (0.05-0.2), preferably 1:(0.08-0.12);

[0021] As a further improvement of the present invention, the base in step (1) is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium fluoride, cesium carbonate, sodium hydroxide, barium hydroxide, lithium carbonate, etc.;

[0022] As a further improvement of the present invention, the molar ratio of the compound of formula SM-001 to the base in step (1) is 1:(2-5), preferably 1:(2.5-3.5);

[0023] As a further improvement of the present invention, the molar ratio of the compound of formula SM-001 in step (1) to the compound of formula 12 is 1:(0.8-1.5), preferably 1:(1.1-1.3);

[0024] As a further improvement of the present invention, the organic solvent in step (1) is selected from one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, water, toluene, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide;

[0025] As a further improvement of the present invention, the temperature of the Suzuki coupling reaction in step (1) is 60 to 120° C., preferably 70 to 110° C., more preferably 80 to 100° C.;

[0026] As a further improvement of the present invention, the mass amount of the organic solvent in step (1) is 5 to 20 times, preferably 10 to 13 times, the mass amount of the compound of formula SM-001 in mL;

[0027] As a further improvement of the present invention, the Mukaiyama hydration reaction in step (2) is a reaction of a compound of formula 13 with a metal catalyst and silane in an organic solvent under an oxygen atmosphere, wherein the metal catalyst is Co(acac) 2 or Mn(III);

[0028] As a further improvement of the present invention, the silane in step (2) is selected from PhSiH 3 or Et 3 SiH;

[0029] As a further improvement of the present invention, the molar ratio of the compound of formula 13 to the metal catalyst in step (2) is 1:(0.1-1), preferably 1:(0.4-0.6);

[0030] As a further improvement of the present invention, the molar ratio of the compound of formula 13 to silane in step (2) is 1:(1-6), preferably 1:(2-4);

[0031] As a further improvement of the present invention, the organic solvent in step (2) is selected from one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, isopropanol, toluene, acetonitrile, dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide;

[0032] As a further improvement of the present invention, the reaction temperature of the Mukaiyama hydration reaction in step (2) is -10 to 10°C, preferably -5 to 5°C;

[0033] As a further improvement of the present invention, the reaction time of the Mukaiyama hydration reaction in step (2) is 0.5 to 10 hours, preferably 1 to 3 hours;

[0034] The second aspect of the present invention provides a method for preparing a camencetinib compound, and the reaction formula is as follows:

[0035]

[0036] Wherein R is an amino protecting group, and preferably the substituents are defined as in the first aspect;

[0037] The steps include:

[0038] (1) subjecting the compound of formula SM-001 to a Suzuki coupling reaction with the compound of formula 12 to obtain a compound of formula 13;

[0039] (2) subjecting the compound of formula 13 to a Mukaiyama hydration reaction to obtain a compound of formula 14;

[0040] (3) subjecting the compound of formula 14 to a deprotection reaction to obtain Camositinib.

[0041] The following methods are included:

[0042] The preparation methods of steps (1) and (2) refer to all the technical solutions of the first aspect mentioned above.

[0043] As a further improvement of the present invention, in the deprotection reaction of step (3), the compound of formula 14 is reacted with an acid or an acid and Et 3 The reaction is carried out in the presence of SiH; the acid is selected from TFA, HCl, HBr, AcOH, H 3 PO 4 , HCl / 1,4-Dioxane, HCl / MeOH, etc.;

[0044] As a further improvement of the present invention, the molar ratio of the compound of formula 14 to the acid in step (3) is 1:(1-5), preferably 1:(2.5-3.5);

[0045] As a further improvement of the present invention, the compound of formula 14 in step (3) is reacted with Et 3 The molar ratio of SiH is 1:(1-5), preferably 1:(2.5-3.5);

[0046] As a further improvement of the present invention, the organic solvent in step (3) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, methanol, ethyl acetate, dioxane or acetonitrile;

[0047] As a further improvement of the present invention, the temperature of the deprotection reaction in step (3) is -20 to 20°C, preferably -10 to 10°C, more preferably -5 to 5°C;

[0048] As a further improvement of the present invention, the mass amount of the organic solvent in step (3) is 5 to 20 times, preferably 10 to 13 times, the mass amount of the compound of formula 14 in mL;

[0049] The third aspect of the present invention provides a method for preparing a compound of formula SM-001, and the reaction formula is as follows:

[0050]

[0051] Wherein R is an amino protecting group, and preferably the substituents are defined as in the first aspect;

[0052] The steps include:

[0053] (1) subjecting the compound of formula 6 to a protection reaction with R-Cl or anhydride to obtain a compound of formula 7;

[0054] (2) subjecting the compound of formula 7 to a substitution reaction to obtain a compound of formula SM-001;

[0055] As a further improvement of the present invention, the compound of formula 6 in step (1) is reacted with R-Cl or anhydride in an organic solvent in the presence of a base;

[0056] As a further improvement of the present invention, the molar ratio of the compound of formula 6 to R-Cl or anhydride in step (1) is 1:(1-5), preferably 1:(2.5-3.5);

[0057] As a further improvement of the present invention, the base in step (1) can be one or more of triethylamine, N,N-diisopropylethylamine, triisopropylamine and other tertiary amines, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases;

[0058] As a further improvement of the present invention, the molar ratio of the compound of formula 6 to the base in step (1) is 1:(1-10), preferably 1:(4-6);

[0059] As a further improvement of the present invention, the organic solvent in step (1) is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably N-methylpyrrolidone, and the volume amount mL of the organic solvent is 1 to 15 times the mass amount g of the compound of formula 6, preferably 8 to 12 times;

[0060] As a further improvement of the present invention, the reaction temperature of step (1) is 15 to 45° C.; the reaction time is 1 to 10 h, preferably 2 to 6 h.

[0061] As a further improvement of the present invention, the compound of formula 7 in step (2) is reacted in an organic solvent in the presence of a base; the base may be one or more of an organic base such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, diisopropylethylamine, triisopropylamine, etc.; the inorganic base may be one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.;

[0062] As a further improvement of the present invention, the molar ratio of the compound of formula 7 in step (2) to the base is 1:(1-6), preferably 1:(2-4);

[0063] As a further improvement of the present invention, the organic solvent in step (2) is selected from methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; the volume amount of the organic solvent mL is 1 to 10 times the mass amount of the compound of formula 7 g, preferably 1 to 5 times;

[0064] As a further improvement of the present invention, the reaction temperature of step (2) is 80-120° C.; the reaction time is 1-6 h, preferably 2-4 h.

[0065] The fourth aspect of the present invention provides a new key intermediate compound of formula 7 and a compound of formula 13, the structures of which are as follows:

[0066]

[0067] Wherein R is an amino protecting group, and preferably the substituents are defined as in the first aspect;

[0068] As a further improvement of the present invention, preferably the compound

[0069]

[0070] The fifth aspect of the present invention provides new intermediate compounds of formula SM-001 and formula 14, whose structures are shown below:

[0071]

[0072] Wherein R is independently selected from Tos and PMB.

[0073] The sixth aspect of the present invention provides the use of the compounds of formula 7 and formula 13 in the preparation of camencertinib or its intermediates.

[0074] The seventh aspect of the present invention provides a method for preparing Camonsetinib, the specific steps of which are as follows:

[0075]

[0076] Wherein R is an N-protecting group, as described in the first part above.

[0077] Compared with the prior art, the present invention has the following beneficial effects:

[0078] (1) Most of the intermediates obtained during the reaction do not need to be purified and can be directly used for the next reaction. They are easy to operate and purify, which reduces costs and is conducive to commercial applications.

[0079] (2) The yield of the prior art for preparing the intermediate compound 6 to SM-001 is only 20.7%, while the yield of the present invention can reach 37.8%, an increase of 17%;

[0080] (3) The applicant repeated the prior art method and found that the yield of the intermediate compound I was extremely low. After repeated attempts, the yield was only 4%, which showed poor reproducibility.

[0081] (4) A number of new intermediates are obtained during the synthesis process, which are of great significance to the synthesis of Camonsetinib. In addition, the intermediates have stable properties, are easy to operate, have good reproducibility, high yield, and good product purity, making it easy to achieve large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 The product obtained by Example 6 of the present invention 1 H-NMR spectrum

[0083] Figure 2 The product obtained by Example 7 of the present invention 1 H-NMR spectrum

[0084] Figure 3 The product obtained by Example 8 of the present invention 1 H-NMR spectrum

[0085] Figure 4 The product obtained in Example 10 of the present invention 1 H-NMR spectrum

[0086] Figure 5 HPLC purity spectrum of the product obtained in Example 10 of the present invention

[0087] Figure 6 LCMS purity spectrum of the product obtained in Example 10 of the present invention

[0088] Figure 7 LCMS purity spectrum of the crude product obtained in Comparative Example 11 of the present invention DETAILED DESCRIPTION

[0089] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0090] Example 1

[0091] Synthesis of 1-benzyl-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0092]

[0093] Compound 2' (10 g, 120.35 mmol, 1.0 eq) was added to HCl (72 mL, 6 N) and NaNO under ice water bath. 2 (8.7 g, 126.37 mmol, 1.05 eq in 36 mL H 2 O), reacted at 30°C for 1 hour, and then SnCl was added in an ice water bath 2 (45.6 g, 240.70 mmol, 2 eq in 46 mL HCl), react at 30° C. for 2 hours, and filter directly to obtain compound 4 (11.8 g, 100% yield).

[0094] Example 2

[0095] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0096]

[0097] Compound 4 (10.94 g, 111.57 mmol, 3.0 eq) was dissolved in EtOH (50 mL), 3 (10.0 g, 37.19 mmol, 1.0 eq) was added and stirred at 30 °C for 20 minutes. Compound 5 was detected by LCMS, and the reaction solution was filtered to obtain a solid product. The solid was eluted with EA and saturated NaHCO 3 Extraction, washing the organic phase with saturated NaCl, and concentrating the organic phase to obtain yellow solid compound 5 (10.5 g, yield 81.31%)

[0098] Example 3

[0099] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0100]

[0101] Compound 5 (80 g, 349.08 mmol, 1 eq) was dissolved in NMP (700 mL) and stirred at 135°C for 4 hours. Compound 6 was detected by LCMS, and the organic phase was concentrated, spin-dried, and methyl tert-butyl ether was added to slurry to precipitate solids, which were vacuum dried to obtain yellow solid compound 6 (75.41 g, yield 100%).

[0102] Example 4

[0103] Synthesis of N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0104]

[0105] Compound 6 (75.41 g, 229.17 mmol, 1 eq) was added to NMP (700 mL), and then DIEA (148.09 g, 1145.87 mmol, 5 eq) and SEMCl (114.62 g, 687.52 mmol, 3 eq) were added, and the reaction was kept at 30°C for 4 hours. Compound 7 was detected by LCMS, and the aqueous phase was extracted with EA (1000 mL x 2), and then the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 7 as a yellow liquid (105.26 g, 100% yield).

[0106] Example 5

[0107] Synthesis of N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide:

[0108]

[0109] Compound 7 (179.76 g, 391.35 mmol, 1 eq) was added to DMF (600 mL), and then DIEA (151.73 g, 1174.06 mmol, 3 eq) and compound 8 (118.76 g, 1174.06 mmol, 3 eq) were added, and the reaction was kept at 100°C for 3 hours. Compound 9 was detected by LCMS, and the aqueous phase was extracted with EA (1000 ml x 2), and then the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound SM-001 as a yellow liquid (80 g, 37.82% yield).

[0110] Example 6

[0111] Synthesis of 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-acetoxy-1H-benzo[d]imidazole-6-carboxamide:

[0112]

[0113] Compound 10 (35 g, 277.6 mmol) was dissolved in THF (1000 mL) and heated at -78 °C under N 2 LiHMDS (280 mL, 277.6 mmol) was added under N 2 9 (148 g, 416.1 mmol) was added under a 2% CO atmosphere and the resulting mixture was stirred at 28° C. for 2 h. The combined mixture was treated with H 2 O (500 mL) and extracted with EA (500 mL×3). The combined organic layer was washed with brine (600 mL), dried and filtered, concentrated under reduced pressure, and the crude product was purified to obtain yellow oily compound 11 (48 g, 66.6% yield).

[0114] Example 7

[0115] Synthesis of 1-(4-methylbenzenesulfonyl)-N,N,2-trimethyl-4-pivaloyloxy-1H-benzo[d]imidazole-6-carboxamide:

[0116]

[0117] Compound 11 (25 g, 96.9 mmol) was dissolved in dioxane (300 mL) and stirred at N 2 Under protection, KOAc (28 g, 291 mmol), B 2 Pin 2 (29.5 g, 116 mmol) and Pd(dppf)Cl 2 The resulting mixture was stirred at 90°C for 16 hours, filtered through celite and concentrated under reduced pressure to obtain a crude product, which was purified to obtain compound 12 (15 g, 65.8% yield) as a white solid.

[0118] Example 8

[0119] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0120]

[0121] Compound 12 (6.8 g, 28.8 mmol) was dissolved in dioxane / H 2 O (5 / 1, 150 mL), in N 2 Under protection, Na 2 CO 3 (7.6g, 72mmol), YS-001 (13g, 24mmol) and Pd(dppf)Cl 2 (1.7 g, 2.4 mmol). The resulting mixture was stirred at 90° C. for 4 hours, filtered through celite and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain compound 13 (10 g, 79.54% yield) as a yellow oil.

[0122] Example 9

[0123] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0124]

[0125] Compound 13 (3 g, 5.4 mmol) was dissolved in iPrOH / DCM (7 / 1, 30 mL) and stirred at 0.5 °C. 2 Mn(III) salt (1.7 g, 2.7 mmol), PhSiH 3 (1.86 g, 16.2 mmol). The resulting mixture was stirred at 0 °C for 2 h. The combined mixture was treated with H 2 O (30 mL) and extracted with EA (50 mL×2). The combined organic layer was washed with brine (50 mL), dried and filtered, concentrated under reduced pressure, and the crude product was purified to obtain yellow oily compound 14 (1.3 g, purity 82%, mixture) with a yield of 40%.

[0126] Example 10

[0127] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0128]

[0129] In N 2 Under protection, compound 14 (1.3 g, 2.4 mmol) was dissolved in DCM (15 mL), and TFA (822 mg, 7.2 mmol), Et 3 SiH (838 mg, 7.2 mmol). The resulting mixture was stirred at 0 °C for 2 h. The combined mixture was treated with H 2The reaction mixture was diluted with 4% paraformaldehyde (2% NaOH) and extracted with 1% paraformaldehyde (30 mL) and DCM (20 mL x 2). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give Camonsertib (550 mg, 56% yield) as a white solid.

[0130] Preparative HPLC: Instrument: Shimadzu, Pump: LC-20AP, Detector: SPD-20A, Wavelength: 214nm & 254nm, Column: Ultimate XB-C18, 50*250mm, 10um (PARP-05), Mobile phase: A: 10mMNH 4 HCO 3 B: Acetonitrile, injector volume / concentration: 2.4 ml per injection, dissolved in DMF, 20.7 mg / mL, run time: 30 minutes, flow rate: 70 mL / min.

[0131] Comparative Example 1

[0132] Synthesis of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazole-6-carboxamide:

[0133]

[0134] Compound G (500 mg, 0.926 mmol, 1.0 eq) was dissolved in 5 mL of tetrahydrofuran and cooled to -78 °C. Under nitrogen protection, n-butyl lithium (2.5 M, 0.48 ml, 1.3 eq) was slowly added. After the addition, the mixture was stirred at -78 °C for 40 min. Then, a 1.5 mL tetrahydrofuran solution of compound G (350 mg, 2.78 mmol, 3.0 eq) was slowly added to the solution. The flask was taken out of the dry ice bath and stirred at room temperature for 1 h. Then, saturated NH 4 The mixed solution was quenched with CI solution, and EtOAc was added, and then the organic phase was separated, the aqueous phase was extracted twice with EtOAc, and the organic phases were combined, washed with saturated saline solution, and then washed with Na 2 SO 4 The solution was dried, filtered and evaporated under reduced pressure, and preparative HPLC gave Compound I (20 mg, yield 4%).

Claims

1. A method for preparing a compound of formula 14, the reaction formula is as follows: The steps include: (1) subjecting the compound of formula SM-001 to a Suzuki coupling reaction to obtain a compound of formula 13; (2) subjecting the compound of formula 13 to a Mukaiyama hydration reaction to obtain a compound of formula 14; R is an amino protecting group; Preferably, the amino protecting group is selected from tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Tos), benzenesulfonyl, trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzoyl, benzyl (Bn), p-methoxybenzyl (PMB), [2-(trimethylsilyl)ethoxy]methyl (SEM).

2. A method for preparing Camonsetinib, the reaction formula is as follows: R is an amino protecting group, and preferably the substituents are defined as in claim 1; The steps include: (1) subjecting the compound of formula SM-001 to a Suzuki coupling reaction with the compound of formula 12 to obtain a compound of formula 13; (2) subjecting the compound of formula 13 to a Mukaiyama hydration reaction to obtain a compound of formula 14; (3) subjecting the compound of formula 14 to a deprotection reaction to obtain Camositinib.

3. The preparation method according to claim 1 or 2, characterized in that: The Suzuki coupling reaction of step (1) of claim 1 or step (1) of claim 2 comprises reacting a compound of formula SM-001 in water or an organic solvent or a mixed solvent of water and an organic solvent, in the presence of a palladium catalyst and a base, with a compound of formula 12; Step (1) also satisfies one or more of the following conditions: And / or, preferably, the palladium catalyst is selected from one or more of Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd2(dba)3, XPhosPdG2, RuPhosPdG2, SPhosPdG2, tBuBrettPhosPdG2, XPhosPdG3, RuPhosPdG3, SPhosPdG3, tBuBrettPhosPdG3, etc.; And / or, preferably, the molar ratio of the compound of formula SM-001 in step (1) to the palladium catalyst is 1:(0.05-0.2), preferably 1:(0.08-0.12); And / or, preferably, the base in step (1) is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium fluoride, cesium carbonate, sodium hydroxide, barium hydroxide, lithium carbonate, etc.; And / or, preferably, the molar ratio of the compound of formula SM-001 in step (1) to the base is 1:(2-5), preferably 1:(2.5-3.5); and / or, preferably, the molar ratio of the compound of formula SM-001 in step (1) to formula 12 is 1:(0.8-1.5), preferably 1:(1.1-1.3); And / or, preferably, the organic solvent in step (1) is selected from one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, water, toluene, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide; And / or, preferably, the temperature of the Suzuki coupling reaction in step (1) is 60 to 120° C., preferably 70 to 110° C., more preferably 80 to 100° C.; And / or, preferably, the mass amount (mL) of the organic solvent in step (1) is 5 to 20 times the mass amount (g) of the compound of formula SM-001, preferably 10 to 13 times.

4. The preparation method according to claim 1 or 2, characterized in that: The Mukaiyama hydration reaction of step (2) of claim 1 or step (2) of claim 2 comprises reacting a compound of formula 13 with a metal catalyst and silane in an organic solvent under an oxygen atmosphere, wherein the metal catalyst is Co(acac)2 or Mn(III); Step (2) also satisfies one or more of the following conditions: And / or, preferably, the silane in step (2) is selected from PhSiH3 or Et3SiH; And / or, preferably, the molar ratio of the compound of formula 13 in step (2) to the Co(acac)2 catalyst is 1:(0.1-1), preferably 1:(0.4-0.6); And / or, preferably, the molar ratio of the compound of formula 13 to silane in step (2) is 1:(1-6), preferably 1:(2-4); and / or, preferably, the organic solvent in step (2) is selected from one or more of 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, isopropanol, toluene, acetonitrile, dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide; And / or, preferably, the reaction temperature of the Mukaiyama hydration reaction in step (2) is -10 to 10°C, preferably -5 to 5°C; and / or, preferably, the reaction time of the Mukaiyama hydration reaction in step (2) is 0.5 to 10 hours, preferably 1 to 3 hours.

5. The preparation method according to claim 2, characterized in that: In the deprotection reaction of step (3), the compound of formula 14 is reacted in water or an organic solvent or a mixed solvent of water and an organic solvent in the presence of an acid or an acid and a silane; Step (3) satisfies one or more of the following conditions: And / or, preferably, the silane in step (3) is selected from PhSiH3 or Et3SiH; And / or, preferably, the acid in step (3) is selected from one or more of TFA, HCl, HBr, AcOH, H3PO4; And / or, preferably, the acid in step (3) is selected from HCl / 1,4-Dioxane or HCl / MeOH solution; And / or, preferably, the molar ratio of the compound of formula 14 to the acid in step (3) is 1:(1-5), preferably 1:(2.5-3.5); and / or, preferably, the molar ratio of the compound of formula 14 in step (3) to Et3SiH is 1:(1-5), preferably 1:(2.5-3.5); and / or, preferably, the organic solvent in step (3) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, One or more of dichloromethane, methanol, ethyl acetate, dioxane or acetonitrile; And / or, preferably, the temperature of the hydrolysis reaction in step (3) is -20 to 20°C, preferably -10 to 10°C, more preferably -5 to 5°C; and / or, preferably, the mass amount (mL) of the organic solvent in step (3) is 5 to 20 times the mass amount (g) of the compound of formula 14, preferably 10 to 13 times.

6. The preparation method according to claim 1 or 2, characterized in that: The preparation method of the compound of formula SM-001 is as follows: Wherein R is an amino protecting group; preferably, the substituents are defined as in claim 1; The steps include: (1) subjecting the compound of formula 6 to a protection reaction with R-Cl or anhydride to obtain a compound of formula 7; (2) Substitution reaction is performed on the compound of formula 7 to obtain the compound of formula SM-001.

7. The preparation method according to claim 6, characterized in that: The step (1) comprises reacting a compound of formula 6 with R-Cl or anhydride in an organic solvent in the presence of a base; Step (1) satisfies one or more of the following conditions: And / or, preferably, the molar ratio of the compound of formula 6 in step (1) to R-Cl or anhydride is 1:(1-5), preferably 1: (2.5～3.5)； And / or, preferably, the base in step (1) can be one or more of triethylamine, N,N-diisopropylethylamine, triisopropylamine and other tertiary amines, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases; And / or, preferably, the molar ratio of the compound of formula 6 in step (1) to the base is 1:(1-10), preferably 1:(4-6); And / or, preferably, the organic solvent in step (1) is selected from ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, methanol, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, preferably N-methylpyrrolidone, and the mass amount (mL) of the organic solvent is 1 to 15 times the mass amount (g) of the compound of formula 6, preferably 8 to 12 times; And / or, preferably, the reaction temperature of step (1) is 15 to 45° C.; the reaction time is 1 to 10 h, preferably 2 to 6 h.

8. The preparation method according to claim 6, characterized in that: The substitution reaction in step (2) comprises reacting a compound of formula 7 in an organic solvent in the presence of a base; Step (2) satisfies one or more of the following conditions: The base can be one or more of organic bases such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, diisopropylethylamine, triisopropylamine, etc.; the inorganic base can be one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; And / or, preferably, the molar ratio of the compound of formula 7 in step (2) to the base is 1:(1-6), preferably 1:(2-4); And / or, preferably, the organic solvent in step (2) is selected from methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; the mass amount (mL) of the organic solvent is 1 to 10 times the mass amount (g) of the compound of formula 7, preferably 1 to 5 times; And / or, preferably, the reaction temperature of step (2) is 80-120° C.; the reaction time is 1-6 h, preferably 2-4 h.

9. A compound of formula 7 and a compound of formula 13, the structures of which are as follows: Wherein R is selected from an amino protecting group; preferably, R is independently selected from tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Tos), benzenesulfonyl, trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), formyl, acetyl, benzoyl, benzyl (Bn), p-methoxybenzyl (PMB), [2-(trimethylsilyl)ethoxy]methyl (SEM); The following compounds are further preferred: And / or, a compound of formula SM-001 and a compound of formula 14 have the following structures: Wherein R is independently selected from p-toluenesulfonyl (Tos) or p-methoxybenzyl (PMB).

10. A method for preparing Camonsetinib, characterized in that: The synthetic route is as follows: The invention comprises the preparation method according to claim 1 or 2 or the use of the compound according to claim 9 in the preparation of Camonsetinib.

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