Preparation method of Tovorafenib

Abstract

The invention relates to a preparation method of Tovorafenib (Tovorafenib). According to the preparation method disclosed by the invention, HATU is adopted for amidation, so that the reaction time can be effectively shortened, and the yield can be improved; according to the invention, an amino-free compound is selected as an initial raw material, so that the interference of amino on the reaction during amidation is avoided, and the reaction yield is increased; according to the preparation method disclosed by the invention, a cyclic compound is constructed from an initial raw material and then is combined into a target product, the existing commercial compound is selected, key synthesis steps are focused, the operation method is simple and convenient, and the reaction steps are greatly shortened; the post-treatment of the multi-step reaction is simple, and the method is suitable for batch production.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a method for preparing Tovorafenib. Background Art

[0002] Tovorafenib is an oral, brain-penetrating pan-RAF kinase inhibitor developed by Day One Biopharmaceuticals that can inhibit wild-type and certain mutant forms of BRAF, CRAF, and ARAF protein kinases. On October 30, 2023, Day One announced that the FDA accepted the new drug application for Tovorafenib for the treatment of recurrent or progressive pediatric low-grade glioma (pLGG) and obtained priority review. On April 23, 2024, Day One Biopharmaceuticals' Tovorafenib tablets (specification 100MG) and Tovorafenib oral suspension (specification 25MG / ML) were approved for marketing by the US FDA.

[0003] Tovorafenib's NDA is based on the results of an open-label pivotal Phase 2 trial evaluating Tovorafenib as a once-weekly monotherapy for patients with recurrent or progressive pLGG aged 6 months to 25 years. In November 2023, the results of this Phase 2 (FIREFLY-1) trial of Tovorafenib were published in Nature Medicine. The results showed that Tovorafenib may be an effective treatment for recurrent / refractory pediatric low-grade gliomas carrying BRAF mutations, bringing new hope for the treatment of pediatric low-grade gliomas. The results showed that according to independent review assessment, in patients with high-grade gliomas in neuro-oncology (RANO-HGG), the overall response rate (ORR) was 67%, reaching the pre-set primary endpoint of Group 1, with a median duration of response (DOR) of 16.6 months, and a median time to response (TTR) of 3.0 months (secondary endpoint). In patients with pediatric neuro-oncology low-grade glioma (RAPNO), the ORR was 51%, the median DOR was 13.8 months, and the median TTR was 5.3 months.

[0004] The chemical structure of Tovorafenib is shown in Formula I:

[0005]

[0006] However, the current preparation method for Tovorafenib still needs to be improved. Summary of the invention

[0007] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, an object of the present invention is to propose a method for preparing a compound Tovorafenib shown in Formula I. Relative to the prior art, the preparation method of the present invention is to hydrolyze the ester group of the compound shown in Formula 1 as the initial raw material under an alkaline environment to obtain the corresponding carboxylic acid compound (the compound shown in Formula 2), condense the compound shown in Formula 2 with a chiral heterocyclic amine aniline compound (the compound shown in Formula 3) to obtain an amide compound (the compound shown in Formula 4), hydrolyze the ester group again to obtain the corresponding carboxylic acid compound (the compound shown in Formula 5), ​​condense again to obtain an amide compound (the compound shown in Formula 7), and finally convert the halogen into an amino group under an ammonia environment to obtain the target product Tovorafenib.

[0008] In one aspect of the present invention, the present invention provides a method for preparing Tovorafenib, a compound represented by Formula I. According to an embodiment of the present invention, the preparation method comprises:

[0009] (1) contacting the compound represented by Formula 1 with LiOH to obtain the compound represented by Formula 2;

[0010] (2) contacting the compound represented by Formula 2 with the compound represented by Formula 3, HATU, and DIPEA to obtain the compound represented by Formula 4;

[0011] (3) contacting the compound represented by Formula 4 with LiOH to obtain the compound represented by Formula 5;

[0012] (4) contacting the compound represented by Formula 5 with the compound represented by Formula 6, HATU, and DIPEA to obtain the compound represented by Formula 7;

[0013] (5) contacting the compound represented by Formula 7 with aqueous ammonia to obtain the compound represented by Formula I, Tovorafenib,

[0014]

[0015] The inventors found that, using the preparation method of the present invention, with the compound of Formula 1 and LiOH as starting materials, a total of 5 steps of reaction can be performed to successfully synthesize and prepare the target product Tovorafenib.

[0016] The term "contact" as used herein should be understood in a broad sense, and can be any manner that allows at least two reactants to undergo a chemical reaction, such as mixing the two reactants under appropriate conditions. If necessary, the reactants to be contacted can be mixed under stirring, and thus, the type of stirring is not particularly limited, and can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0018] According to an embodiment of the present invention, the method for preparing the compound shown in Formula 2, the compound shown in Formula 4, the compound shown in Formula 5, the compound shown in Formula 7, and the compound shown in Formula I may also have at least one of the following additional technical features:

[0019] According to an embodiment of the present invention, the chemical reaction described in the present invention can be carried out according to any method known in the art. The source of the raw materials of the compound shown in Formula 2, the compound shown in Formula 4, the compound shown in Formula 5, the compound shown in Formula 7, and the compound shown in Formula I is not particularly limited, and it can be prepared by any known method or commercially available. For example, the CAS of the compound shown in Formula 1 is: 1554322-22-3, and the CAS of the compound shown in Formula 3 is: 2272619-84-6.

[0020] According to an embodiment of the present invention, in step (1), the contacting method of the compound represented by Formula 1 and LiOH is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 1 and LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 2 by using this method can be further improved.

[0021] According to an embodiment of the present invention, in step (1), the following steps are included: in a reaction bottle, THF and H2O are mixed at a volume ratio of 1:1, and then the compound shown in Formula 1 is added, stirred and cooled to 0°C to 5°C, LiOH is added, and the reaction solution is naturally heated to room temperature, and stirred for 2 hours and 45 minutes to 3 hours and 30 minutes. TLC shows that the compound shown in Formula 1 is completely reacted, and the reaction solution is concentrated under reduced pressure, THF is removed, and the remaining liquid is added with ether to extract the water layer, the water layer is cooled to 0°C, and HCl solution is added to pH 3, and ethyl acetate is added to the acidified aqueous phase for extraction, and the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to dryness to obtain the compound shown in Formula 2. In this way, the efficiency of the contact reaction between the compound shown in Formula 1 and LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula 2 by using this method can be further improved.

[0022] According to an embodiment of the present invention, in step (1), the molar ratio of the compound represented by Formula 1 to LiOH is 1:(1.5-3), preferably the molar ratio of the compound represented by Formula 1 to LiOH is 1:2. Thus, the efficiency of preparing the compound represented by Formula 2 by this method can be further improved.

[0023] According to an embodiment of the present invention, in step (1), the stirring reaction time is preferably 3 hours.

[0024] According to a specific embodiment of the present invention, in step (1), the following steps are included: in a reaction bottle, THF (40 mL) and H2O (40 mL) are mixed, and then the compound represented by formula 1 (10 g, 48.31 mmol) is added, and the temperature is cooled to 0°C to 5°C with stirring, and LiOH (2.31 g, 96.61 mmol) is added. After the reaction solution is naturally warmed to room temperature, the reaction is stirred for 3 hours. TLC shows that the compound represented by formula 1 is completely reacted, and the reaction solution is concentrated under reduced pressure to remove THF. The remaining liquid is added with ether (2x40 mL) to extract the water layer, and the water layer is cooled to 0°C, and 3M HCl solution is added to pH 3. Ethyl acetate (2x40 mL) is added to the acidified aqueous phase for extraction. After the organic phases are combined, 40 mL of saturated brine is added for washing, and the filtrate is dried over anhydrous sodium sulfate. The filtrate is concentrated to dryness under reduced pressure to obtain the compound represented by formula 2, with an amount of 7.95 g and a yield of 85.3%.

[0025] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 2 with the compound represented by Formula 3, HATU, and DIPEA is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 2 and the compound represented by Formula 3, HATU, and DIPEA can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 4 using this method can be further improved.

[0026] According to an embodiment of the present invention, in step (2), the following steps are included: adding the compound of formula 2 and the compound of formula 3 to DMF at 0°C, stirring, then adding 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole [4,5-b] pyridine-3-oxide hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA), the reaction solution is naturally heated to room temperature and stirred for reaction for 5.5 to 7 hours, after the reaction is completed, water is added to the reaction solution for washing, and then ethyl acetate is added for extraction, the organic phases are combined and then washed with saturated brine, dried over anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain the compound of formula 4. Thus, the efficiency of the contact reaction between the compound of formula 2 and the compound of formula 3, HATU, and DIPEA can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 4 using this method can be further improved.

[0027] According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3, HATU, and DIPEA is 1:(1.0-1.2):(1.2-2.0):(1.5-3.0), and preferably the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3, HATU, and DIPEA is 1:1.02:1.5:2.0. Thus, the efficiency of preparing the compound represented by Formula 4 by this method can be further improved.

[0028] According to an embodiment of the present invention, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):1, and preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 4:1.

[0029] According to an embodiment of the present invention, in step (2), the reaction solution is preferably stirred and reacted for 6 hours after the reaction solution is naturally heated to room temperature.

[0030] According to a specific embodiment of the present invention, in step (2), the following steps are included: at 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (6.89 g, 37.00 mmol) are added to DMF (80 mL), stirred, and then HATU (20.69 g, 54.41 mmol) and DIPEA (9.38 g, 72.54 mmol) are added. The reaction solution is naturally warmed to room temperature and stirred for reaction for 6 hours. After the reaction is completed, 80 mL of water is added to the reaction solution for washing, and then ethyl acetate (2x80 mL) is added for extraction. After the organic phases are combined, 80 mL of saturated brine is added for washing, and the organic phases are dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain a compound represented by formula 4, with an amount of 10.36 g and a yield of 79.1%.

[0031] According to an embodiment of the present invention, in step (3), the contacting method of the compound represented by Formula 4 and LiOH is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 4 and LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 5 by using this method can be further improved.

[0032] According to an embodiment of the present invention, in step (3), the following steps are included: in a reaction container, THF and H2O are mixed in a volume ratio of 1:1, and then the compound shown in Formula 4 is added, the temperature is cooled to 0°C to 5°C with stirring, LiOH is added, and the reaction solution is naturally heated to room temperature, and the reaction is stirred for 2 hours and 45 minutes to 3 hours and 30 minutes. TLC shows that the compound shown in Formula 1 is completely reacted, and the reaction solution is concentrated under reduced pressure to remove THF. The remaining liquid is added with ether to extract the water layer, the water layer is cooled to 0°C, HCl solution is added to the pH of 3, ethyl acetate is added to the acidified aqueous phase for extraction, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound shown in Formula 5.

[0033] According to an embodiment of the present invention, in step (3), the molar ratio of the compound represented by formula 4 to LiOH is 1:(1.4-3), preferably the molar ratio of the compound represented by formula 4 to LiOH is 1:2. Thus, the efficiency of preparing the compound represented by formula 5 by this method can be further improved.

[0034] According to an embodiment of the present invention, in step (3), the stirring reaction time is preferably 3 hours.

[0035] According to a specific embodiment of the present invention, in step (3), the following steps are included: in a reaction container, THF (350 mL) and H2O (350 mL) are mixed, and then the compound shown in Formula 4 (80.0 g, 221.5 mmol) is added, and the temperature is cooled to 0°C to 5°C with stirring, and LiOH (10.6 g, 443.0 mmol) is added. After the reaction solution naturally rises to room temperature, the reaction is stirred for 3 hours. TLC shows that the compound shown in Formula 1 is completely reacted, and the reaction solution is concentrated under reduced pressure to remove THF. Ethyl ether (2x400 mL) is added to the residue to extract the water layer, and the water layer is cooled to 0°C, and 3M HCl solution is added to pH 3. Ethyl acetate (2x400 mL) is added to the acidified aqueous phase for extraction. After the organic phases are combined, 400 mL of saturated brine is added for washing, and the filtrate is dried over anhydrous sodium sulfate. The filtrate is concentrated to dryness under reduced pressure to obtain the compound shown in Formula 5, with an amount of 63.98 g and a yield of 83.2%.

[0036] According to an embodiment of the present invention, in step (4), the contacting method of the compound represented by Formula 5 with the compound represented by Formula 6, HATU, and DIPEA is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 5 and the compound represented by Formula 6, HATU, and DIPEA can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 7 by using this method can be further improved.

[0037] According to an embodiment of the present invention, in step (4), the following steps are included: adding the compound of formula 5 and the compound of formula 6 to DMF at 0°C, stirring, then adding HATU and DIPEA, stirring and reacting the reaction solution after the reaction solution naturally rises to room temperature for 5.5 to 7.5 hours, adding water to the reaction solution for washing, then adding ethyl acetate for extraction, adding saturated brine to the organic phase after merging, washing, drying over anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to evaporate the solvent, and purifying the concentrate by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent to obtain the compound of formula 7. Thus, the efficiency of the contact reaction between the compound of formula 5 and the compound of formula 6, HATU, and DIPEA can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 7 by using this method can be further improved.

[0038] According to an embodiment of the present invention, in step (4), the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6, HATU, and DIPEA is 1:(0.99-1.25):(1.3-2.5):(1.6-3.0), and preferably the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6, HATU, and DIPEA is 1:1.05:1.5:2.0. Thus, the efficiency of preparing the compound represented by Formula 7 by this method can be further improved.

[0039] According to an embodiment of the present invention, in step (4), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):1, and preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 4:1.

[0040] According to an embodiment of the present invention, in step (4), the reaction solution is preferably stirred and reacted for 6 hours after the reaction solution is naturally heated to room temperature.

[0041] According to a specific embodiment of the present invention, in step (4), the following steps are included: at 0°C, the compound represented by formula 5 (5.8 g, 16.71 mmol) and the compound represented by formula 6 (3.45 g, 17.55 mmol) are added to DMF (80 mL), stirred, and then HATU (9.53 g, 25.06 mmol) and DIPEA (4.32 g, 33.42 mmol) are added. The reaction solution is naturally warmed to room temperature and stirred for reaction for 6 hours. After the reaction is completed, 60 mL of water is added to the reaction solution for washing, and then ethyl acetate (2x60 mL) is added for extraction. After the organic phases are combined, 60 mL of saturated brine is added for washing, and the organic phases are dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 7, with an amount of 7.10 g and a yield of 80.8%.

[0042] According to an embodiment of the present invention, in step (5), the contacting method of the compound represented by Formula 7 and ammonia water is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 7 and ammonia water can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula I by using this method can be further improved.

[0043] According to an embodiment of the present invention, in step (5), the following steps are included: at 0°C, 30% ammonia water is added dropwise to a THF solution containing the compound of formula 7, the reaction solution is stirred at 0°C for 1 hour, and then the THF is removed by concentrating under reduced pressure, the residue is added with ether and HCl solution and shaken vigorously, the liquid is separated, a saturated sodium bicarbonate solution is added to the aqueous phase, and the pH is adjusted to 10, ethyl acetate is added to the aqueous phase for extraction, and the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the compound of formula I, Tovorafenib. Thus, the efficiency of the contact reaction between the compound of formula 7 and ammonia water can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula I, Tovorafenib, by using this method can be further improved.

[0044] According to an embodiment of the present invention, in step (5), the weight volume ratio (g / v) of the compound represented by Formula 7 to 30% ammonia water is 2: 1. Thus, the efficiency of preparing the compound represented by Formula I by this method can be further improved.

[0045] According to a specific embodiment of the present invention, in step (5), the following steps are included: at 0°C, 30% ammonia water (30 ml) is added dropwise to a THF (1000 ml) solution containing the compound of formula 7 (60.0 g, 114.1 mmol), the reaction solution is stirred at 0°C for 1 hour, and then concentrated under reduced pressure to remove THF, ether (300 ml) and 1M HCl solution (300 mL) are added to the residue and the mixture is shaken vigorously, and the liquid is separated, saturated sodium bicarbonate solution is added to the aqueous phase to adjust the pH to 10, ethyl acetate (2x400 mL) is added to the aqueous phase for extraction, the organic phases are combined, 400 mL of saturated brine is added, the mixture is washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo to obtain the compound of formula I, Tovorafenib, with an amount of 47.31 g and a yield of 81.9%. The purity is 99.6% (HPLC) and the optical purity is 98.8% (chiral HPLC).

[0046] According to a specific embodiment of the present invention, the synthesis route of the compound Tovorafenib represented by Formula I can be as follows:

[0047]

[0048] Compared with the prior art, the method for preparing Tovorafenib of the present invention has at least the following beneficial effects:

[0049] 1. Compared with the prior art, the preparation method of the present invention is to hydrolyze the ester group of the initial raw material compound represented by Formula 1 under an alkaline environment to obtain the corresponding carboxylic acid compound (the compound represented by Formula 2), condense the compound represented by Formula 2 with a chiral heterocyclic amine aniline compound (the compound represented by Formula 3) to obtain an amide compound (the compound represented by Formula 4), hydrolyze the ester group again to obtain the corresponding carboxylic acid compound (the compound represented by Formula 5), ​​condense again to obtain an amide compound (the compound represented by Formula 7), and finally convert the halogen into an amino group under an ammonia environment to obtain the target product Tovorafenib.

[0050] 2. Compared with the prior art methods, the present invention has the following significant advantages: (1) Compared with CN 101784545 B, which uses oxalyl chloride as an acylating agent during amidation, the preparation method of the present invention uses HATU for amidation, which can effectively reduce the reaction time and improve the yield. (2) The present invention selects a compound without an amine group as the initial raw material, avoids the interference of the amine group on the reaction during amidation, and improves the reaction yield. (3) Compared with the prior art (such as CN101784545 B), the preparation method of the present invention constructs a cyclic compound from the initial raw material and then combines it into a target product. The present invention selects existing commercial compounds, focuses on key synthesis steps, and has a simple operation method, which greatly shortens the reaction steps. (4) Thanks to the higher yield, the post-processing of the multi-step reaction of the present invention is simple and suitable for mass production. DETAILED DESCRIPTION

[0051] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0052] Example 1 Synthesis of the compound represented by formula 2

[0053] In a reaction flask, THF (40 mL) and H2O (40 mL) were mixed, and then the compound represented by Formula 1 (10 g, 48.31 mmol) was added, and the temperature was cooled to 0°C to 5°C with stirring, and LiOH (2.31 g, 96.61 mmol) was added. After the reaction solution naturally warmed to room temperature, the reaction was stirred for 3 hours. TLC showed that the compound represented by Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF, and ether (2x40 mL) was added to the remaining liquid to extract the water layer. The water layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x40 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 40 mL of saturated brine was added for washing, and the filtrate was dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness under reduced pressure to obtain the compound represented by Formula 2, with an amount of 7.95 g and a yield of 85.3%.

[0054] LC-MS (APCI): m / z = 193.0 (M+1) + .

[0055] Example 2 Synthesis of the compound represented by formula 2

[0056] In a reaction flask, THF (40 mL) and H2O (40 mL) were mixed, and the compound of Formula 1 (10 g, 48.31 mmol) was added. The mixture was stirred and cooled to 0°C to 5°C. LiOH (1.74 g, 72.47 mmol) was added. After the reaction solution naturally warmed to room temperature, the mixture was stirred and reacted for 2 hours and 45 minutes. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF. Ether (2x40 mL) was added to the remaining liquid to extract the water layer. The water layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x40 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 40 mL of saturated brine was added for washing, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the compound of Formula 2. The yield was 7.75 g, and the yield was 83.4%.

[0057] Example 3 Synthesis of the compound represented by formula 2

[0058] In a reaction flask, THF (40 mL) and H2O (40 mL) were mixed, and the compound of Formula 1 (10 g, 48.31 mmol) was added. The mixture was stirred and cooled to 0°C to 5°C. LiOH (3.47 g, 144.93 mmol) was added. After the reaction solution naturally warmed to room temperature, the mixture was stirred for reaction for 3 hours and 30 minutes. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF. Ether (2x40 mL) was added to the residue to extract the aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x40 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 40 mL of saturated brine was added for washing, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the compound of Formula 2. The yield was 7.90 g and the yield was 84.7%.

[0059] Example 4 Synthesis of the compound represented by formula 4

[0060] At 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (6.89 g, 37.00 mmol) were added to DMF (80 mL) and stirred. HATU (20.69 g, 54.41 mmol) and DIPEA (9.38 g, 72.54 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 6 hours. After the reaction was completed, 80 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x80 mL) was added for extraction. The organic phases were combined and washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 4, with an amount of 10.36 g and a yield of 79.1%.

[0061] LC-MS (APCI): m / z = 361.0 (M+1) + .

[0062] Example 5 Synthesis of the compound represented by formula 4

[0063] At 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (6.75 g, 36.27 mmol) were added to DMF (80 mL) and stirred. HATU (16.55 g, 43.52 mmol) and DIPEA (7.03 g, 54.41 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for reaction for 5.5 hours. After the reaction was completed, 80 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x80 mL) was added for extraction. The organic phases were combined and washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain the compound represented by formula 4, with an amount of 10.15 g and a yield of 77.5%.

[0064] Example 6 Synthesis of the compound represented by formula 4

[0065] At 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (8.10 g, 43.52 mmol) were added to DMF (80 mL) and stirred, and then HATU (27.58 g, 72.54 mmol) and DIPEA (14.06 g, 108.81 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 7 hours. After the reaction was completed, 80 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x80 mL) was added for extraction. The organic phases were combined and washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 6:1 to obtain the compound represented by formula 4, with an amount of 10.31 g and a yield of 78.7%.

[0066] Comparative Example 1 Synthesis of the Compound Represented by Formula 4

[0067] At 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (9.46 g, 50.78 mmol) were added to DMF (80 mL) and stirred, and HATU (34.48 g, 90.68 mmol) and DIPEA (16.41 g, 126.95 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 6 hours. After the reaction was completed, 80 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x80 mL) was added for extraction. The organic phases were combined and washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 4, with an amount of 10.07 g and a yield of 76.9%.

[0068] It can be seen that changing the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3, HATU, and DIPEA to 1:1.4:2.5:3.5 does not further improve the efficiency (yield) of preparing the compound represented by Formula 4.

[0069] Example 7 Synthesis of the compound represented by formula 5

[0070] In a reaction vessel, THF (350 mL) and H2O (350 mL) were mixed, and then the compound represented by Formula 4 (80.0 g, 221.5 mmol) was added, and the temperature was cooled to 0°C to 5°C with stirring, and LiOH (10.6 g, 443.0 mmol) was added. After the reaction solution naturally warmed to room temperature, the reaction was stirred for 3 hours. TLC showed that the compound represented by Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF, and ether (2x400 mL) was added to the residue to extract the water layer. The water layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x400 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 400 mL of saturated brine was added for washing, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the compound represented by Formula 5, with an amount of 63.98 g and a yield of 83.2%.

[0071] LC-MS (APCI): m / z = 347.0 (M+1) + .

[0072] Example 8 Synthesis of the compound represented by formula 5

[0073] In a reaction vessel, THF (350 mL) and H2O (350 mL) were mixed, and then the compound represented by Formula 4 (80.0 g, 221.5 mmol) was added, and the temperature was cooled to 0°C to 5°C with stirring, and LiOH (7.43 g, 310.2 mmol) was added. After the reaction solution naturally warmed to room temperature, the reaction was stirred for 2 hours and 45 minutes. TLC showed that the compound represented by Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF, and ether (2x400 mL) was added to the residue to extract the water layer. The water layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x400 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 400 mL of saturated brine was added for washing, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the compound represented by Formula 5, with an amount of 62.13 g and a yield of 80.8%.

[0074] Example 9 Synthesis of the compound represented by formula 5

[0075] In a reaction vessel, THF (350 mL) and H2O (350 mL) were mixed, and then the compound represented by Formula 4 (80.0 g, 221.5 mmol) was added, and the temperature was cooled to 0°C to 5°C with stirring, and LiOH (15.91 g, 664.5 mmol) was added. After the reaction solution naturally warmed to room temperature, the reaction was stirred for 3 hours and 30 minutes. TLC showed that the compound represented by Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure to remove THF, and ether (2x400 mL) was added to the residue to extract the water layer. The water layer was cooled to 0°C, and 3M HCl solution was added to pH 3. Ethyl acetate (2x400 mL) was added to the acidified aqueous phase for extraction. After the organic phases were combined, 400 mL of saturated brine was added for washing, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the compound represented by Formula 5, with an amount of 63.06 g and a yield of 82.0%.

[0076] Example 10 Synthesis of the compound represented by formula 7

[0077] At 0°C, the compound represented by Formula 5 (5.8 g, 16.71 mmol) and the compound represented by Formula 6 (3.45 g, 17.55 mmol) were added to DMF (80 mL) and stirred. HATU (9.53 g, 25.06 mmol) and DIPEA (4.32 g, 33.42 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 6 hours. After the reaction was completed, 60 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x60 mL) was added for extraction. The organic phases were combined and washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by Formula 7, with an amount of 7.10 g and a yield of 80.8%.

[0078] LC-MS (APCI): m / z = 525.0 (M+1) + .

[0079] Example 11 Synthesis of the compound represented by formula 7

[0080] At 0°C, the compound represented by Formula 5 (5.8 g, 16.71 mmol) and the compound represented by Formula 6 (3.25 g, 16.54 mmol) were added to DMF (80 mL) and stirred, and HATU (8.26 g, 21.72 mmol) and DIPEA (3.46 g, 26.77 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for reaction for 5.5 hours. After the reaction was completed, 60 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x60 mL) was added for extraction. The organic phases were combined and washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 3:1 to obtain the compound represented by Formula 7, with an amount of 6.91 g and a yield of 78.7%.

[0081] Example 12 Synthesis of the compound represented by formula 7

[0082] At 0°C, the compound represented by Formula 5 (5.8 g, 16.71 mmol) and the compound represented by Formula 6 (4.11 g, 20.89 mmol) were added to DMF (80 mL) and stirred. HATU (15.89 g, 41.78 mmol) and DIPEA (6.48 g, 50.13 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 7.5 hours. After the reaction was completed, 60 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x60 mL) was added for extraction. The organic phases were combined and washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 6:1 to obtain the compound represented by Formula 7, with an amount of 7.02 g and a yield of 79.9%.

[0083] Comparative Example 2 Synthesis of the Compound Represented by Formula 7

[0084] At 0°C, the compound represented by Formula 5 (5.8 g, 16.71 mmol) and the compound represented by Formula 6 (4.27 g, 21.72 mmol) were added to DMF (80 mL) and stirred. HATU (19.06 g, 50.13 mmol) and DIPEA (8.64 g, 66.84 mmol) were added. The reaction solution was naturally warmed to room temperature and stirred for 7 hours. After the reaction was completed, 60 mL of water was added to the reaction solution for washing, and then ethyl acetate (2x60 mL) was added for extraction. The organic phases were combined and washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to evaporate the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by Formula 7, with an amount of 6.87 g and a yield of 78.2%.

[0085] It can be seen that changing the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6, HATU, and DIPEA to 1:1.3:3:4 and stirring the reaction for 7 hours did not further improve the efficiency (yield) of preparing the compound represented by Formula 7.

[0086] Example 13 Preparation of the compound Tovorafenib represented by formula I

[0087] At 0°C, 30% ammonia water (30 ml) was added dropwise to a THF (1000 ml) solution containing the compound of formula 7 (60.0 g, 114.1 mmol). The reaction solution was stirred at 0°C for 1 hour, and then concentrated under reduced pressure to remove THF. The residue was added with ether (300 ml) and 1M HCl solution (300 mL) and shaken vigorously. The liquid was separated, and a saturated sodium bicarbonate solution was added to the aqueous phase to adjust the pH to 10. The aqueous phase was extracted with ethyl acetate (2x400 mL). The organic phases were combined, washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the compound of formula I, Tovorafenib, with an amount of 47.31 g and a yield of 81.9%. The purity was 99.6% (HPLC) and the optical purity was 98.8% (chiral HPLC).

[0088] LC-MS (APCI): m / z = 505.6 (M+1) + .

[0089] 1 H NMR(400MHz,DMSO-d6)d ppm 11.78(s,1H)9.53(d,J=7.82Hz,1H)8.79(s,1H)8.76(s,1H)8.58(s,1H)8.37(s,1H)7.86(br .s.,1H)7.46(br.s.,1H)5.35(tdd,J=7.27,7.27,7.21,7.09Hz,1H)1.59(d,J=6.85Hz,3H).

[0090] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0091] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing Tovorafenib, characterized in that: include: (1) contacting the compound represented by Formula 1 with LiOH to obtain the compound represented by Formula 2; (2) contacting the compound represented by Formula 2 with the compound represented by Formula 3, HATU, and DIPEA to obtain the compound represented by Formula 4; (3) contacting the compound represented by Formula 4 with LiOH to obtain the compound represented by Formula 5; (4) contacting the compound represented by Formula 5 with the compound represented by Formula 6, HATU, and DIPEA to obtain the compound represented by Formula 7; (5) contacting the compound represented by Formula 7 with aqueous ammonia to obtain the compound represented by Formula I, Tovorafenib, 2. The method according to claim 1, characterized in that: In step (1), the following steps are included: in a reaction bottle, THF and H2O are mixed in a volume ratio of 1:1, and then the compound shown in formula 1 is added, the temperature is cooled to 0°C to 5°C with stirring, LiOH is added, the reaction solution is naturally warmed to room temperature, and the reaction is stirred for 2 hours and 45 minutes to 3 hours and 30 minutes. TLC shows that the compound shown in formula 1 is completely reacted, the reaction solution is concentrated under reduced pressure, THF is removed, and the remaining liquid is added with ether to extract the water layer, the water layer is cooled to 0°C, HCl solution is added to the pH of 3, ethyl acetate is added to the acidified aqueous phase for extraction, the organic phases are combined, saturated brine is added for washing, anhydrous sodium sulfate is dried, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound shown in formula 2.

3. The method according to claim 2, characterized in that In step (1), the molar ratio of the compound represented by formula 1 to LiOH is 1:(1.5-3), preferably the molar ratio of the compound represented by formula 1 to LiOH is 1:2; Optionally, in step (1), the stirring reaction time is preferably 3 hours.

4. The method according to claim 1, characterized in that: In step (2), the following steps are included: adding the compound represented by formula 2 and the compound represented by formula 3 to DMF at 0°C, stirring, then adding HATU and DIPEA, and stirring the reaction solution after the reaction solution is naturally heated to room temperature for 5.5 to 7 hours. After the reaction is completed, water is added to the reaction solution for washing, and then ethyl acetate is added for extraction. After the organic phases are combined, saturated brine is added for washing, and the organic phases are dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain a compound represented by formula 4.

5. The method according to claim 4, characterized in that In step (2), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3, HATU, and DIPEA is 1:(1.0-1.2):(1.2-2.0):(1.5-3.0), preferably the molar ratio of the compound represented by formula 2 to the compound represented by formula 3, HATU, and DIPEA is 1:1.02:1.5:2.0; Optionally, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):1, preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 4:1; Optionally, in step (2), the reaction solution is preferably allowed to naturally warm to room temperature and then stirred for reaction for 6 hours.

6. The method according to claim 1, characterized in that In step (3), the following steps are included: in a reaction container, THF and H2O are mixed in a volume ratio of 1:1, and then the compound shown in formula 4 is added, the temperature is cooled to 0°C to 5°C by stirring, LiOH is added, the reaction solution is naturally warmed to room temperature, and the reaction is stirred for 2 hours and 45 minutes to 3 hours and 30 minutes. TLC shows that the compound shown in formula 1 is completely reacted, the reaction solution is concentrated under reduced pressure, THF is removed, and the remaining liquid is added with ether to extract the water layer, the water layer is cooled to 0°C, HCl solution is added to the pH of 3, ethyl acetate is added to the acidified aqueous phase for extraction, the organic phase is combined, saturated brine is added for washing, anhydrous sodium sulfate is dried, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound shown in formula 5; Optionally, in step (3), the molar ratio of the compound represented by formula 4 to LiOH is 1:(1.4-3), preferably the molar ratio of the compound represented by formula 4 to LiOH is 1:2; Optionally, in step (3), the stirring reaction time is preferably 3 hours.

7. The method according to claim 1, characterized in that In step (4), the following steps are included: adding the compound represented by formula 5 and the compound represented by formula 6 to DMF at 0°C, stirring, then adding HATU and DIPEA, and stirring the reaction solution after the reaction solution is naturally warmed to room temperature for 5.5 to 7.5 hours, adding water to the reaction solution for washing, and then adding ethyl acetate for extraction, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to evaporate the solvent, and purifying the concentrate by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain a compound represented by formula 7.

8. The method according to claim 7, characterized in that In step (4), the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6, HATU, and DIPEA is 1:(0.99-1.25):(1.3-2.5):(1.6-3.0), preferably the molar ratio of the compound represented by Formula 5 to the compound represented by Formula 6, HATU, and DIPEA is 1:1.05:1.5:2.0; Optionally, in step (4), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):1, preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 4:1; Optionally, in step (4), the reaction solution is preferably allowed to naturally warm to room temperature and then stirred for reaction for 6 hours.

9. The method according to claim 1, characterized in that: In step (5), the following steps are included: at 0°C, 30% ammonia water is added dropwise to a THF solution containing the compound of formula 7, the reaction solution is stirred at 0°C for 1 hour, and then the THF is removed by vacuum concentration, ether and HCl solution are added to the residue and the mixture is shaken vigorously, the liquid is separated, saturated sodium bicarbonate solution is added to the aqueous phase, the pH value is adjusted to 10, ethyl acetate is added to the aqueous phase for extraction, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo to obtain the compound of formula I, Tovorafenib; Optionally, in step (5), the weight volume ratio (g / v) of the compound represented by formula 7 and 30% ammonia water is 2:

1.

10. The method according to claim 1, characterized in that In step (1), the following steps are included: in a reaction flask, THF (40 mL) and H2O (40 mL) are mixed, and then the compound represented by formula 1 (10 g, 48.31 mmol) is added, the temperature is cooled to 0°C to 5°C with stirring, LiOH (2.31 g, 96.61 mmol) is added, the reaction solution is naturally warmed to room temperature, and the reaction is stirred for 3 hours. TLC shows that the compound represented by formula 1 is completely reacted, the reaction solution is concentrated under reduced pressure, THF is removed, and ether (2x40 mL) is added to the remaining liquid to extract the water layer, the water layer is cooled to 0°C, 3M HCl solution is added to pH 3, ethyl acetate (2x40 mL) is added to the acidified aqueous phase for extraction, the organic phases are combined, 40 mL of saturated brine is added for washing, dried over anhydrous sodium sulfate, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound represented by formula 2, with an amount of 7.95 g and a yield of 85.3%; In step (2), the following steps are included: at 0°C, the compound represented by formula 2 (7.0 g, 36.27 mmol) and the compound represented by formula 3 (6.89 g, 37.00 mmol) are added to DMF (80 mL), stirred, and then HATU (20.69 g, 54.41 mmol) and DIPEA (9.38 g, 72.54 mmol) are added. The reaction solution is naturally warmed to room temperature and stirred for reaction for 6 hours. After the reaction is completed, 80 mL of water is added to the reaction solution for washing, and then ethyl acetate (2x80 mL) is added for extraction. After the organic phases are combined, 80 mL of saturated brine is added for washing, and the organic phases are dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain a compound represented by formula 4, with an amount of 10.36 g and a yield of 79.1%; In step (3), the following steps are included: in a reaction container, THF (350 mL) and H2O (350 mL) are mixed, and then the compound shown in formula 4 (80.0 g, 221.5 mmol) is added, the temperature is cooled to 0°C to 5°C with stirring, LiOH (10.6 g, 443.0 mmol) is added, the reaction solution is naturally warmed to room temperature, and the reaction is stirred for 3 hours. TLC shows that the compound shown in formula 1 is completely reacted, the reaction solution is concentrated under reduced pressure, THF is removed, ether (2x400 mL) is added to the residue to extract the water layer, the water layer is cooled to 0°C, 3M HCl solution is added to pH 3, ethyl acetate (2x400 mL) is added to the acidified aqueous phase for extraction, the organic phases are combined, 400 mL of saturated brine is added for washing, dried over anhydrous sodium sulfate, and the filtrate is concentrated to dryness under reduced pressure to obtain the compound shown in formula 5, with an amount of 63.98 g and a yield of 83.2%; In step (4), the following steps are included: at 0°C, the compound represented by formula 5 (5.8 g, 16.71 mmol) and the compound represented by formula 6 (3.45 g, 17.55 mmol) are added to DMF (80 mL), stirred, and then HATU (9.53 g, 25.06 mmol) and DIPEA (4.32 g, 33.42 mmol) are added. The reaction solution is naturally warmed to room temperature and stirred for reaction for 6 hours. After the reaction is completed, 60 mL of water is added to the reaction solution for washing, and then ethyl acetate (2x60 mL) is added for extraction. After the organic phases are combined, 60 mL of saturated brine is added for washing, and the organic phases are dried over anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to evaporate the solvent, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound represented by formula 7, with an amount of 7.10 g and a yield of 80.8%; In step (5), the following steps are included: at 0°C, 30% ammonia water (30 ml) is added dropwise to a THF (1000 ml) solution containing the compound of formula 7 (60.0 g, 114.1 mmol), the reaction solution is stirred at 0°C for 1 hour, and then concentrated under reduced pressure to remove THF, ether (300 ml) and 1M HCl solution (300 mL) are added to the residue and the mixture is shaken vigorously, and the liquid is separated, saturated sodium bicarbonate solution is added to the aqueous phase to adjust the pH to 10, ethyl acetate (2 x 400 mL) is added to the aqueous phase for extraction, and the organic phases are combined, washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo to obtain the compound of formula I, Tovorafenib, with an yield of 47.31 g and a yield of 81.9%. The purity is 99.6% (HPLC) and the optical purity is 98.8% (chiral HPLC).

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