A process for the preparation of tovorafenib

Abstract

The application relates to a preparation method of Tovorafenib. In the preparation method, HATU is used for amidation, reaction time can be effectively reduced, and yield can be improved; in the application, an amine-free compound is selected as an initial raw material, and the interference of an amine group on the reaction is avoided during amidation, so that the reaction yield is improved; in the preparation method, a cyclic compound is constructed from an initial raw material, and then combined into a target product; the existing commercial compound is selected, the key synthesis step is focused on, the operation method is simple, and the reaction steps are greatly shortened; the post-treatment of the multi-step reaction is simple, and the batch production is suitable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular, it relates to a preparation method of Tovorafenib. BACKGROUND

[0002] Tovorafenib is an oral, brain-penetrating pan-RAF kinase inhibitor developed by Day One Biopharmaceuticals, which can inhibit wild-type and some 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 granted priority review. On April 23, 2024, Tovorafenib tablets (100MG) and Tovorafenib oral suspension (25MG / ML) developed by Day One Biopharmaceuticals were approved for marketing in the United States.

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

[0004] The chemical structural formula of Tovorafenib is shown as formula I:

[0005]

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

[0007] The present application aims to at least partially solve one of the technical problems in the related art. To this end, one object of the present application is to provide a preparation method of a compound Tovorafenib shown in Formula I. Compared with the prior art, the preparation method of the present application hydrolyzes the ester group of the compound shown in Formula 1 under an alkaline environment to obtain the corresponding carboxylic acid compound (the compound shown in Formula 2), condenses 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), hydrolyzes the ester group again to obtain the corresponding carboxylic acid compound (the compound shown in Formula 5), condenses again to obtain an amide compound (the compound shown in Formula 7), and finally converts the halogen into an amino group under an ammonia environment to obtain the target product Tovorafenib.

[0008] In one aspect of the present application, the present application provides a preparation method of a compound Tovorafenib shown in Formula I. According to an embodiment of the present application, the preparation method comprises:

[0009] (1) contacting a compound shown in Formula 1 with LiOH to obtain a compound shown in Formula 2;

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

[0011] (3) contacting the compound shown in Formula 4 with LiOH to obtain a compound shown in Formula 5;

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

[0013] (5) contacting the compound shown in Formula 7 with ammonia water to obtain the compound Tovorafenib shown in Formula I,

[0014]

[0015] The inventors have found that, by using the preparation method of the present application, the starting materials are the compound shown in Formula 1 and LiOH, and the target product Tovorafenib can be successfully synthesized by a total of 5 reaction steps.

[0016] The term "contacting" used herein should be interpreted broadly, which can be any way that can enable at least two reactants to chemically react, for example, the two reactants can be mixed 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, for example, it can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In the present text, the terms "first", "second", etc. are used only for descriptive purposes, and cannot be construed as indicating or implying relative importance or an indicated number of technical features. Thus, a feature defined with "first", "second", etc. can explicitly or implicitly comprise one or more of such features. In the description of the present application, the meaning of "a plurality" is two or more, unless explicitly specified otherwise.

[0018] According to embodiments of the present application, the above-mentioned method for preparing the compound of formula 2, the compound of formula 4, the compound of formula 5, the compound of formula 7, the compound of formula I can further have at least one of the following additional technical features:

[0019] According to embodiments of the present application, the chemical reactions described in the present application can be carried out according to any method known in the art. The source of the raw materials of the compound of formula 2, the compound of formula 4, the compound of formula 5, the compound of formula 7, the compound of formula I is not particularly limited, which can be prepared by any known method, or obtained commercially. For example, the cas of the compound of formula 1 is: 1554322-22-3, and the cas of the compound of formula 3 is: 2272619-84-6.

[0020] According to embodiments of the present application, in step (1), the contacting method of the compound of formula 1 with LiOH is not particularly limited. Thus, the efficiency of the contacting reaction of the compound of formula 1 with LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 2 by the method can be further improved.

[0021] According to embodiments of the present application, in step (1), the following steps are included: in a reaction bottle, THF and H2O are mixed in a volume ratio of 1:1, then the compound of formula 1 is added, stirring and cooling to 0-5℃, then LiOH is added, the reaction solution is naturally raised to room temperature, then stirring and reacting for 2 hours and 45 minutes to 3 hours and 30 minutes, TLC shows that the compound of formula 1 is completely reacted, the reaction solution is concentrated under reduced pressure, THF is removed, the remaining liquid is extracted with diethyl ether, the water layer is cooled to 0℃, HCl solution is added to pH 3, ethyl acetate is added to the acidified water phase for extraction, the combined organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to dryness, and the compound of formula 2 is obtained. Thus, the efficiency of the contacting reaction of the compound of formula 1 with LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 2 by the method can be further improved.

[0022] According to embodiments of the present application, in step (1), the molar ratio of the compound of formula 1 to LiOH is 1:(1.5-3), preferably the molar ratio of the compound of formula 1 to LiOH is 1:2. Thus, the efficiency of preparing the compound of formula 2 by the method can be further improved.

[0023] According to an embodiment of the present application, in step (1), the reaction is preferably stirred for 3 hours.

[0024] According to an embodiment of the present application, in step (1), the reaction is preferably stirred for 3 hours.

[0025] According to an embodiment of the present application, in step (2), the contacting manner of the compound of formula 2 and the compound of formula 3, HATU and DIPEA is not particularly limited. Thus, the contacting reaction efficiency of 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 by using the method can be further improved.

[0026] According to an embodiment of the present application, in step (2), the contacting manner of the compound of formula 2 and the compound of formula 3, HATU and DIPEA is not particularly limited. Thus, the contacting reaction efficiency of 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 by using the method can be further improved.

[0027] According to an embodiment of the present application, in step (2), the molar ratio of the compound of formula 2 to the compound of 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 of formula 2 to the compound of formula 3, HATU, and DIPEA is 1 : 1.02 : 1.5 : 2.0. In this way, the efficiency of preparing the compound of formula 4 using the method can be further improved.

[0028] According to an embodiment of the present application, 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 the petroleum ether / ethyl acetate mixed solvent is 4 : 1.

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

[0030] According to an embodiment of the present application, in step (2), the following steps are included: at 0°C, the compound of formula 2 (7.0 g, 36.27 mmol) and the compound of formula 3 (6.89 g, 37.00 mmol) are added to DMF (80 mL) and stirred, then HATU (20.69 g, 54.41 mmol) and DIPEA (9.38 g, 72.54 mmol) are added, the reaction solution is naturally raised to room temperature and stirred for 6 hours, after the reaction is completed, 80 mL of water is added to the reaction solution and washed, then ethyl acetate (2 x 80 mL) is added to extract, 80 mL of saturated brine is added to the combined organic phase and washed, anhydrous sodium sulfate is added for drying, 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 of formula 4, with a yield of 10.36 g and a yield of 79.1%.

[0031] According to an embodiment of the present application, in step (3), the contacting method of the compound of formula 4 and LiOH is not particularly limited. In this way, the efficiency of the contacting reaction of the compound of formula 4 and LiOH can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 5 using the method can be further improved.

[0032] According to an embodiment of the present application, in step (3), the following steps are included: mixing THF and H2O in a volume ratio of 1:1 in a reaction vessel, adding the compound shown as formula 4, stirring and cooling to 0-5°C, adding LiOH, allowing the reaction solution to naturally rise to room temperature, stirring and reacting for 2 hours and 45 minutes to 3 hours and 30 minutes, showing complete reaction of the compound shown as formula 1 by TLC, concentrating the reaction solution under reduced pressure, removing THF, adding diethyl ether to extract the aqueous layer, cooling the aqueous layer to 0°C, adding a HC1 solution to a pH of 3, adding ethyl acetate to extract the aqueous phase after acidification, washing the combined organic phase with saturated brine, drying with anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to dryness, and obtaining the compound shown as formula 5.

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

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

[0035] According to an embodiment of the present application, in step (3), the following steps are included: mixing THF (350 mL) and H2O (350 mL) in a reaction vessel, adding the compound shown as formula 4 (80.0 g, 221.5 mmol), stirring and cooling to 0-5°C, adding LiOH (10.6 g, 443.0 mmol), allowing the reaction solution to naturally rise to room temperature, stirring and reacting for 3 hours, showing complete reaction of the compound shown as formula 1 by TLC, concentrating the reaction solution under reduced pressure, removing THF, adding diethyl ether (2 x 400 mL) to extract the aqueous layer, cooling the aqueous layer to 0°C, adding a 3M HC1 solution to a pH of 3, adding ethyl acetate (2 x 400 mL) to extract the aqueous phase after acidification, washing the combined organic phase with 400 mL of saturated brine, drying with anhydrous sodium sulfate, concentrating the filtrate under reduced pressure to dryness, and obtaining the compound shown as formula 5, with a yield of 63.98 g and a yield rate of 83.2%.

[0036] According to an embodiment of the present application, in step (4), the contacting mode of the compound shown as formula 5, the compound shown as formula 6, HATU and DIPEA is not particularly limited. Thus, the efficiency of the contacting reaction of the compound shown as formula 5, the compound shown as formula 6, HATU and DIPEA can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown as formula 7 using the method can be further improved.

[0037] According to an embodiment of the present application, in step (4), the following steps are included: the compound of formula 5 and the compound of formula 6 are added into DMF at 0°C, stirred, then HATU and DIPEA are added, the reaction solution is naturally raised to room temperature, then stirred for 5.5-7.5 hours, water is added to the reaction solution for washing, then ethyl acetate is added for extraction, the combined organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to distill off the solvent, the concentrate is purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate to obtain the compound of formula 7. In this way, the efficiency of the contact reaction of the compound of formula 5 with 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 the method can be further improved.

[0038] According to an embodiment of the present application, in step (4), the molar ratio of the compound of formula 5 to the compound of 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 of formula 5 to the compound of formula 6, HATU and DIPEA is 1:1.05:1.5:2.0. In this way, the efficiency of preparing the compound of formula 7 by using the method can be further improved.

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

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

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

[0042] According to an embodiment of the present application, in step (5), the contacting manner of the compound of formula 7 with ammonia water is not particularly limited. Thus, the efficiency of the contacting reaction of the compound of formula 7 with ammonia water can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula I using the method can be further improved.

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

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

[0045] According to a specific embodiment of the present application, in step (5), the following steps are included: 30% ammonia water (30ml) is added dropwise to a THF (1000ml) solution containing the compound of formula 7 (60.0g, 114.1mmol) at 0°C, the reaction solution is stirred at 0°C for 1 hour, then THF is removed by concentration under reduced pressure, the residue is added with ether (300ml) and a 1M HCl solution (300ml) and shaken vigorously, the liquid is separated, saturated sodium bicarbonate solution is added to the water phase, the pH is adjusted to 10, the water phase is extracted with ethyl acetate (2x400ml), the combined organic phase is washed with 400ml of saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried to obtain the compound of formula I, Tovorafenib, in an amount of 47.31g, with a yield of 81.9%, a purity of 99.6% (HPLC) and an optical purity of 98.8% (chiral HPLC).

[0046] According to a specific embodiment of the present application, the synthesis route of the compound of formula I, Tovorafenib, can be as shown below:

[0047]

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

[0049] 1. Compared with the prior art, the preparation method of the application hydrolyzes the ester group of the compound shown in formula 1 in an alkaline environment to obtain the corresponding carboxylic acid compound (the compound shown in formula 2), condenses 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), hydrolyzes the ester group again to obtain the corresponding carboxylic acid compound (the compound shown in formula 5), condenses again to obtain an amide compound (the compound shown in formula 7), and finally converts the halogen into an amino group in an ammonia environment to obtain the target product Tovorafenib.

[0050] 2. Compared with the prior art method, the application has the following advantages: (1) Compared with CN 101784545 B, oxalyl chloride is used as an acylating agent during amide formation, and in the preparation method of the application, HATU is used for amide formation, which can effectively reduce the reaction time and improve the yield. (2) The application selects a compound without an amine group as the initial raw material, which avoids the interference of the amine group during amide formation and improves the reaction yield. (3) Compared with the prior art (such as CN 101784545 B), the preparation method of the application constructs a cyclic compound from the initial raw material and then combines it into the target product. The application selects an existing commercial compound and focuses on the key synthesis steps, which is simple to operate and greatly shortens the reaction steps. (4) Due to the high yield, the post-treatment of the multi-step reaction of the application is simple and suitable for batch production. DETAILED DESCRIPTION

[0051] The embodiments of the application are described in detail below. The embodiments described below are exemplary and are used to explain the application, and cannot be understood as a limitation of the application. If the specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in the art or according to the product instructions are used. If the reagents or instruments are not specified by the manufacturer, they are all conventional products that can be obtained by purchase.

[0052] Example 1 Synthesis of the compound shown in formula 2

[0053] In a reaction flask, THF (40 mL) and H2O (40 mL) were mixed, then the compound of Formula 1 (10 g, 48.31 mmol) was added, and the mixture was stirred and cooled to 0-5°C. LiOH (2.31 g, 96.61 mmol) was added, and the reaction solution was allowed to warm to room temperature. The reaction was stirred for 3 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure, and THF was removed. The remaining liquid was extracted with diethyl ether (2 x 40 mL) to obtain an aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to adjust the pH to 3. The acidified aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of Formula 2. The yield was 7.95 g, and the yield rate was 85.3%.

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

[0055] Synthesis of the compound of Formula 2 according to Example 2

[0056] In a reaction flask, THF (40 mL) and H2O (40 mL) were mixed, then the compound of Formula 1 (10 g, 48.31 mmol) was added, and the mixture was stirred and cooled to 0-5°C. LiOH (2.31 g, 96.61 mmol) was added, and the reaction solution was allowed to warm to room temperature. The reaction was stirred for 3 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure, and THF was removed. The remaining liquid was extracted with diethyl ether (2 x 40 mL) to obtain an aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to adjust the pH to 3. The acidified aqueous phase was extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of Formula 2. The yield was 7.95 g, and the yield rate was 85.3%.

[0057] Synthesis of the compound of Formula 2 according to Example 3

[0058] In a reaction flask, THF (40 mL) and H20 (40 mL) were mixed, then the compound of Formula 1 (10 g, 48.31 mmol) was added, and the reaction solution was stirred to cool to 0-5°C, then LiOH (3.47 g, 144.93 mmol) was added, and the reaction solution was allowed to naturally warm to room temperature, and stirred 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, THF was removed, and the residue was extracted with diethyl ether (2 x 40 mL) to obtain the aqueous layer, which was cooled to 0°C, then 3M HCl solution was added to pH 3, and the acidified aqueous phase was extracted with ethyl acetate (2 x 40 mL), the combined organic phase was washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to dryness to obtain the compound of Formula 2, the yield was 7.90 g, the yield was 84.7%.

[0059] Example 4 Synthesis of the compound of Formula 4

[0060] The compound of Formula 2 (7.0 g, 36.27 mmol) and the compound of Formula 3 (6.89 g, 37.00 mmol) were added to DMF (80 mL) at 0°C, stirred, then HATU (20.69 g, 54.41 mmol) and DIPEA (9.38 g, 72.54 mmol) were added, the reaction solution was allowed to naturally warm to room temperature, and stirred for 6 hours, after the reaction was completed, 80 mL of water was added to the reaction solution, then ethyl acetate (2 x 80 mL) was added to extract, the combined organic phase was washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent, the concentrate was purified by silica gel column chromatography using a mixture of petroleum ether / ethyl acetate (4:1, by volume) to obtain the compound of Formula 4, the yield was 10.36 g, the yield was 79.1%.

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

[0062] Example 5 Synthesis of the compound of Formula 4

[0063] To a stirred solution of compound of formula 2 (7.0 g, 36.27 mmol) and compound of formula 3 (6.75 g, 36.27 mmol) in DMF (80 mL) was added HATU (16.55 g, 43.52 mmol) and DIPEA (7.03 g, 54.41 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5.5 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 3:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 4 (10.15 g, 77.5% yield).

[0064] Example 6: Synthesis of compound of formula 4

[0065] To a stirred solution of compound of formula 2 (7.0 g, 36.27 mmol) and compound of formula 3 (8.10 g, 43.52 mmol) in DMF (80 mL) was added HATU (27.58 g, 72.54 mmol) and DIPEA (14.06 g, 108.81 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 6:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 4 (10.31 g, 78.7% yield).

[0066] Comparative Example 1: Synthesis of compound of formula 4

[0067] To a stirred solution of compound of formula 2 (7.0 g, 36.27 mmol) and compound of formula 3 (9.46 g, 50.78 mmol) in DMF (80 mL) was added HATU (34.48 g, 90.68 mmol) and DIPEA (16.41 g, 126.95 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 4:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 4 (10.07 g, 76.9% yield).

[0068] As can be seen, changing the molar ratio of the compound of formula 2 to the compound of formula 3, HATU, and DIPEA to 1:1.4:2.5:3.5 did not further improve the efficiency (yield) of preparing the compound of formula 4.

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

[0070] In a reaction vessel, THF (350 mL) and H2O (350 mL) were mixed, then the compound of formula 4 (80.0 g, 221.5 mmol) was added, and the mixture was stirred and cooled to 0-5°C, LiOH (10.6 g, 443.0 mmol) was added, the reaction solution was allowed to naturally warm to room temperature, and the mixture was stirred for 3 hours. TLC showed that the compound of formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure, THF was removed, and the residue was extracted with diethyl ether (2 x 400 mL) to obtain the aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to adjust the pH to 3. Ethyl acetate (2 x 400 mL) was added to the acidified aqueous phase to extract the organic phase. The combined organic phase was washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of formula 5. The yield was 63.98 g, and the yield was 83.2%.

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

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

[0073] In a reaction vessel, THF (350 mL) and H2O (350 mL) were mixed, then the compound of formula 4 (80.0 g, 221.5 mmol) was added, and the mixture was stirred and cooled to 0-5°C, LiOH (10.6 g, 443.0 mmol) was added, the reaction solution was allowed to naturally warm to room temperature, and the mixture was stirred for 3 hours. TLC showed that the compound of formula 1 was completely reacted. The reaction solution was concentrated under reduced pressure, THF was removed, and the residue was extracted with diethyl ether (2 x 400 mL) to obtain the aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to adjust the pH to 3. Ethyl acetate (2 x 400 mL) was added to the acidified aqueous phase to extract the organic phase. The combined organic phase was washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of formula 5. The yield was 63.98 g, and the yield was 83.2%.

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

[0075] In a reaction vessel, THF (350 mL) and H20 (350 mL) were mixed, then the compound of Formula 4 (80.0 g, 221.5 mmol) was added, and the mixture was stirred and cooled to 0-5°C, and LiOH (15.91 g, 664.5 mmol) was added. The reaction solution was allowed to warm to room temperature, and stirred 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, and THF was removed. The residue was extracted with diethyl ether (2 x 400 mL) to obtain an aqueous layer. The aqueous layer was cooled to 0°C, and 3M HCl solution was added to adjust the pH to 3. The acidified aqueous phase was extracted with ethyl acetate (2 x 400 mL). The combined organic phase was washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of Formula 5. The yield was 63.06 g, and the yield rate was 82.0%.

[0076] Example 10 Synthesis of the compound of Formula 7

[0077] The compound of Formula 5 (5.8 g, 16.71 mmol) and the compound of Formula 6 (3.45 g, 17.55 mmol) were added to DMF (80 mL) at 0°C, and stirred, and then HATU (9.53 g, 25.06 mmol) and DIPEA (4.32 g, 33.42 mmol) were added. The reaction solution was allowed to warm to room temperature, and stirred for 6 hours. After the reaction, 60 mL of water was added to the reaction solution, and then ethyl acetate (2 x 60 mL) was added to extract. The combined organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography using a mixture of petroleum ether / ethyl acetate (4:1 by volume) to obtain the compound of Formula 7. The yield was 7.10 g, and the yield rate was 80.8%.

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

[0079] Example 11 Synthesis of the compound of Formula 7

[0080] To a stirred solution of compound of formula 5 (5.8 g, 16.71 mmol) and compound of formula 6 (3.25 g, 16.54 mmol) in DMF (80 mL) was added HATU (8.26 g, 21.72 mmol) and DIPEA (3.46 g, 26.77 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5.5 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 60 mL). The organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 3:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 7 (6.91 g, 78.7% yield).

[0081] Example 12: Synthesis of compound of formula 7

[0082] To a stirred solution of compound of formula 5 (5.8 g, 16.71 mmol) and compound of formula 6 (4.11 g, 20.89 mmol) in DMF (80 mL) was added HATU (15.89 g, 41.78 mmol) and DIPEA (6.48 g, 50.13 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 7.5 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 60 mL). The organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 6:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 7 (7.02 g, 79.9% yield).

[0083] Example 12: Synthesis of compound of formula 7

[0084] To a stirred solution of compound of formula 5 (5.8 g, 16.71 mmol) and compound of formula 6 (4.27 g, 21.72 mmol) in DMF (80 mL) was added HATU (19.06 g, 50.13 mmol) and DIPEA (8.64 g, 66.84 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 60 mL). The organic layers were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 4:1 petroleum ether / ethyl acetate as the eluent to afford compound of formula 7 (6.87 g, 78.2% yield).

[0085] As can be seen, changing the molar ratio of the compound of formula 5 to the compound of 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 of formula 7.

[0086] Preparation of the compound of formula I, Tovorafenib

[0087] Ammonia solution (30 ml) was added dropwise to a solution of the compound of formula 7 (60.0 g, 114.1 mmol) in THF (1000 ml) at 0°C, and the reaction solution was stirred at 0°C for 1 hour. THF was removed by concentration under reduced pressure, and the residue was vigorously shaken with diethyl ether (300 ml) and 1M HC1 solution (300 mL), and then separated. Saturated sodium bicarbonate solution was added to the aqueous phase, and the pH was adjusted to 10. The aqueous phase was extracted with ethyl acetate (2 x 400 mL), and the combined organic phase was washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuum to obtain the compound of formula I, Tovorafenib, in an amount of 47.31 g, with a yield of 81.9%, and a purity of 99.6% (HPLC) and an optical purity of 98.8% (chiral HPLC) determined.

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

[0089] 1 H NMR (400 MHz, DMSO-d6) d ppm 11.78 (s, 1H) 9.53 (d, J = 7.82 Hz, 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, 7.09 Hz, 1H) 1.59 (d, J = 6.85 Hz, 3H).

[0090] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in the present specification and the features of the different embodiments or examples can be combined and combined by those skilled in the art without contradiction.

[0091] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and that variations, modifications, substitutions and changes can be made by those skilled in the art without departing from the scope of the present application.

Claims

1. A process for the preparation of Tovorafenib, characterized in that, include: (1) Contact the compound shown in Formula 1 with LiOH to obtain the compound shown in Formula 2; (2) Contact the compound shown in Formula 2 with the compound shown in Formula 3, HATU, and DIPEA to obtain the compound shown in Formula 4; (3) Contact the compound shown in Formula 4 with LiOH to obtain the compound shown in Formula 5; (4) Contact the compound shown in Formula 5 with the compound shown in Formula 6, HATU, and DIPEA to obtain the compound shown in Formula 7; (5) Contact the compound shown in Formula 7 with ammonia water to obtain the compound Tovorafenib shown in Formula I. ， In step (1), the following steps are included: In a reaction flask, THF and H2O are mixed in a volume ratio of 1:1, and then the compound shown in Formula 1 is added. The mixture is stirred and cooled to 0°C~5°C. LiOH is added. After the reaction solution is naturally heated to room temperature, the mixture is stirred and reacted for 2 hours 45 minutes to 3 hours 30 minutes. TLC shows that the compound shown in Formula 1 has completely reacted. The reaction solution is concentrated under reduced pressure to remove THF. The remaining liquid is added to diethyl ether to extract the aqueous layer. The aqueous layer is cooled to 0°C. HCl solution is added to the aqueous phase until the pH is 3. Ethyl acetate is added to the acidified aqueous phase for extraction. The organic phases are combined and washed with saturated brine. The mixture is dried with anhydrous sodium sulfate and the filtrate is concentrated under reduced pressure to dryness to obtain the compound shown in Formula 2. In step (1), the molar ratio of the compound shown in Formula 1 to LiOH is 1:(1.5~3). In step (2), the following steps are included: At 0°C, the compounds shown in Formula 2 and Formula 3 are added to DMF and stirred. Then HATU and DIPEA are added. After the reaction solution is naturally brought to room temperature, the reaction solution is stirred for 5.5 to 7 hours. After the reaction is completed, water is added to the reaction solution for washing, followed by extraction with ethyl acetate. After the organic phases are combined, saturated brine is added for washing, and the solution is dried with anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to remove the solvent. The concentrate is purified by silica gel column chromatography with a mixture of petroleum ether and ethyl acetate to obtain the compound shown in Formula 4. In step (2), the molar ratio of the compound shown in Formula 2 to the compound shown in Formula 3, HATU, and DIPEA is 1:(1.0~1.2):(1.2~2.0):(1.5~3.0). In step (3), the following steps are included: In the reaction vessel, THF and H2O are mixed in a volume ratio of 1:1, and then the compound shown in Formula 4 is added. The mixture is stirred and cooled to 0°C~5°C. LiOH is added. After the reaction solution is naturally heated to room temperature, the mixture is stirred and reacted for 2 hours 45 minutes to 3 hours 30 minutes. TLC shows that the compound shown in Formula 1 has completely reacted. The reaction solution is concentrated under reduced pressure to remove THF. The remaining liquid is added to diethyl ether to extract the aqueous layer. The aqueous layer is cooled to 0°C. HCl solution is added to the aqueous phase until the pH is 3. Ethyl acetate is added to the acidified aqueous phase for extraction. The organic phases are combined and washed with saturated brine. The solution is dried with anhydrous sodium sulfate and the filtrate is concentrated under reduced pressure to dryness to obtain the compound shown in Formula 5. In step (3), the molar ratio of the compound shown in Formula 4 to LiOH is 1:(1.4~3). In step (4), the following steps are included: the compound shown as formula 5 and the compound shown as formula 6 are added into DMF at 0°C, stirring, then HATU and DIPEA are added, the reaction solution is naturally raised to room temperature, and stirring reaction is performed for 5.5-7.5 hours, water is added to the reaction solution for washing, then ethyl acetate is added for extraction, the combined organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to remove the solvent, the concentrate is purified by silica gel column chromatography with petroleum ether / ethyl acetate mixed solvent to obtain the compound shown as formula 7; In step (4), the molar ratio of the compound shown as formula 5 to the compound shown as formula 6, HATU and DIPEA is 1:(0.99-1.25):(1.3-2.5):(1.6-3.0); In step (5), the following steps are included: 30% ammonia water is added dropwise into a THF solution containing the compound shown as formula 7 at 0°C, the reaction solution is stirred at 0°C for 1 hour, then THF is removed under reduced pressure, the residue is vigorously shaken with ether and HCl solution, the liquid is separated, saturated sodium bicarbonate solution is added to the aqueous phase, and the pH is adjusted to 10, then ethyl acetate is added to the aqueous phase for extraction, the combined organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried to obtain the compound shown as formula I, Tovorafenib; In step (5), the weight / volume ratio of the compound shown as formula 7 to 30% ammonia water is 2:

1.

2. The method of claim 1, wherein, In step (1), the molar ratio of the compound shown as formula 1 to LiOH is 1:

2.

3. The method of claim 1, wherein, In step (1), the stirring reaction time is 3 hours.

4. The method of claim 1, wherein, In step (2), the molar ratio of the compound shown as formula 2 to the compound shown as formula 3, HATU and DIPEA is 1:1.02:1.5:2.

0.

5. The method of claim 1, wherein, In step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):

1.

6. The method of claim 5, wherein, In step (2), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 4:

1.

7. The method of claim 1, wherein, In step (2), the reaction solution is naturally raised to room temperature, and stirring reaction is performed for 6 hours.

8. The method of claim 1, wherein, In step (3), the molar ratio of the compound shown as formula 4 to LiOH is 1:

2.

9. The method of claim 1, wherein, In step (3), the stirring reaction time is 3 hours.

10. The method of claim 1, wherein, In step (4), the molar ratio of the compound shown as formula 5 to the compound shown as formula 6, HATU and DIPEA is 1:1.05:1.5:2.

0.

11. The method of claim 1, wherein, In step (4), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (3-6):

1.

12. The method of claim 11, wherein, In step (4), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 4:

1.

13. The method of claim 1, wherein, In step (4), the reaction solution is naturally raised to room temperature, and stirring reaction is performed for 6 hours.

14. The method of claim 1, wherein, In step (1), the following steps are included: in a reaction bottle, 40 mL THF and 40 mL H2O are mixed, then 10 g of the compound shown in formula 1 is added, and stirring is performed to reduce the temperature to 0-5°C, then 2.31 g of LiOH is added, the reaction solution is naturally increased to room temperature, then stirring is performed 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, the remaining liquid is extracted with 2*40 mL of ether, the water layer is cooled to 0°C, 3M HCl solution is added to the pH of 3, then 2*40 mL of ethyl acetate is added to the acidified water phase for extraction, the combined organic phase is washed with 40 mL of saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to dryness, and the compound shown in formula 2 is obtained, with a yield of 7.95 g and a yield of 85.3%; In step (2), the following steps are included: 7.0 g of the compound shown in formula 2 and 6.89 g of the compound shown in formula 3 are added to 80 mL of DMF at 0°C, stirring is performed, then 20.69 g of HATU and 9.38 g of DIPEA are added, the reaction solution is naturally increased to room temperature, then stirring is performed for 6 hours, after the reaction is completed, 80 mL of water is added to the reaction solution for washing, then 2*80 mL of ethyl acetate is added for extraction, the combined organic phase is washed with 80 mL of saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to remove the solvent, the concentrate is purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1, and the compound shown in formula 4 is obtained, with a yield of 10.36 g and a yield of 79.1%; In step (3), the following steps are included: in a reaction container, 350 mL THF and 350 mL H2O are mixed, then 80.0 g of the compound shown in formula 4 is added, stirring is performed to reduce the temperature to 0-5°C, then 10.6 g of LiOH is added, the reaction solution is naturally increased to room temperature, then stirring is performed 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, 2*400 mL of ether is added to the residual liquid for extraction of the water layer, the water layer is cooled to 0°C, 3M HCl solution is added to the pH of 3, then 2*400 mL of ethyl acetate is added to the acidified water phase for extraction, the combined organic phase is washed with 400 mL of saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure to dryness, and the compound shown in formula 5 is obtained, with a yield of 63.98 g and a yield of 83.2%; In step (4), the following steps are included: 5.8 g of the compound shown in formula 5 and 3.45 g of the compound shown in formula 6 are added to 80 mL of DMF at 0°C, stirred, and then 9.53 g of HATU and 4.32 g of DIPEA are added. After the reaction solution is naturally raised to room temperature and stirred for 6 hours, the reaction is completed. Then 60 mL of water is added to the reaction solution for washing, and then 2×60 mL of ethyl acetate is added for extraction. After the organic phases are combined, 60 mL of saturated brine is added for washing, and then anhydrous sodium sulfate is added for drying. The filtrate is concentrated under reduced pressure to remove the solvent, and then 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 shown in formula 7, with a yield of 7.10 g and a recovery rate of 80.8%; In step (5), the following steps are included: 30 mL of 30% ammonia water is added dropwise to a solution of 60.0 g of the compound shown in formula 7 in 1000 mL of THF at 0°C, and the reaction solution is stirred at 0°C for 1 hour. Then THF is removed by concentration under reduced pressure, and then 300 mL of diethyl ether and 1M HCl solution are added to the residue and vigorously shaken. After the liquid is separated, saturated sodium bicarbonate solution is added to the water phase to adjust the pH to 10. Then 2×400 mL of ethyl acetate is added to the water phase for extraction, and then 400 mL of saturated brine is added to the combined organic phase for washing, anhydrous sodium sulfate is added for drying, and then the solution is concentrated under reduced pressure and dried in vacuum to obtain the compound shown in formula I, Tovorafenib, with a yield of 47.31 g and a recovery rate of 81.9%. The purity is 99.6% as determined by HPLC, and the optical purity is 98.8% as determined by chiral HPLC.

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