Preparation method of tovorafenib chiral amine intermediate

Abstract

The invention discloses a preparation method of a tovorafenib chiral amine intermediate, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: by taking D-alanine as a raw material, carrying out Boc protection and amidation to obtain N-Boc-D-alaninamide, then carrying out thiocyclization to obtain a chiral aminothiazole ring, and finally, sequentially carrying out hydrolysis, amidation and deprotection to obtain the tovorafenib chiral amine intermediate. The process is green and environment-friendly, D-alanine is adopted as a chiral raw material, a chiral amine group is directly introduced, an expensive metal catalyst and a chiral ligand do not need to be adopted, the chiral amine protecting group is easy to remove, and the core competitiveness of the product is enhanced.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of a chiral amine intermediate of tovorafenib, and belongs to the technical field of synthesis of medical intermediates. BACKGROUND

[0002] The chiral amine intermediate is a frequently used molecular building block in biological and pharmaceutical molecules, such as tovorafenib, which is a type II RAF inhibitor approved by Day One Biopharmaceuticals for the treatment of recurrent / refractory low-grade glioma in children carrying BRAF fusion or V600 mutation, and was acceleratedly approved by FDA in April 2024. The trade name is Ojemda, and the generic name is tovorafenib. Among them, the chiral amine fragment with a thiazole ring is a key intermediate for synthesizing tovorafenib.

[0003] Patent US2009005359A1 adopts racemic N-Cbz-alanine amide as raw material, and obtains the key intermediate of tovorafenib through thio, ring closure, hydrolysis, acyl chloride, substitution and deprotection, and then chiral column separation. The reaction equation is as follows:

[0004]

[0005] The method first obtains a racemic amine, and finally adopts chiral column preparation and separation, so that at least more than 50% of the material is lost, and the Cbz protecting group needs to be removed by precious metal catalytic hydrogenation, so that the process economy and safety are not high.

[0006] Patent US2020317659A1 takes substituted 5-acetylthiazole-2-carboxylic acid as raw material, obtains intermediate 1 through amidation, then reacts with diphenylmethylamine to obtain imine intermediate 2, then adopts chiral induction catalysis to obtain chiral intermediate 3, and finally deprotects to obtain chiral amine key intermediate 4. The reaction equation is as follows:

[0007]

[0008] The chiral catalytic reduction of the imine in the route is a key point, and the use of a precious metal catalyst and a complex chiral ligand increases the process cost. The reaction has good chiral selectivity, but still needs chiral acid further crystallization and separation to improve the chiral purity. The initial raw material is an unconventional chemical product, which is expensive, and the deprotection of intermediate 3 by NBS reagent will produce a large amount of waste. SUMMARY

[0009] In order to overcome the above technical defects, the present application provides an economic and efficient preparation method of a tovorafenib chiral amine intermediate. The technical features of the method include: 1. An economic chiral amino acid is used as a chiral source, and there is no need to construct a chiral center again. 2. The protecting group of the chiral amine group is selected from a type that is easier to remove, thereby reducing the use of noble metal catalysts or the generation of a large amount of waste during removal.

[0010] The preparation method of the tovorafenib chiral amine intermediate provided by the present application comprises the following steps:

[0011]

[0012] P = Boc, Bn, Cbz;

[0013] In the first step, the D-alanine is used as a raw material, and a protecting group reagent is used to obtain compound 2;

[0014] In the second step, compound 2 is reacted with ammonia water in the presence of a condensing agent to obtain compound 3;

[0015] In the third step, compound 3 is reacted with a thio reagent to obtain compound 4;

[0016] In the fourth step, compound 4 is subjected to a cyclization reaction with methyl malonyl chloride to obtain compound 5;

[0017] In the fifth step, compound 5 is hydrolyzed under alkaline conditions to obtain compound 6;

[0018] In the sixth step, compound 6 is reacted with 2-amino-4-trifluoromethyl-5-chloropyridine in the presence of a condensing agent to obtain compound 7;

[0019] In the seventh step, compound 7 is subjected to deprotection under acidic or catalytic hydrogenation conditions to obtain the tovorafenib chiral amine intermediate.

[0020] Further, in the above technical solution, the protecting group reagent in the first step is selected from di-tert-butyl dicarbonate, benzyl chloroformate or benzyl bromide.

[0021] Further, in the above technical solution, the molar ratio of the D-alanine to the protecting group reagent in the first step is 1:1.0-1.5.

[0022] Further, in the above technical solution, the condensing agent in the second step is selected from 1-propyl phosphonic anhydride ethyl acetate solution or 1-hydroxybenzotriazole (HOBT), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride.

[0023] Further, in the above technical solution, the molar ratio of the compound 2 to ammonia and the condensing agent in the second step is 1:3.5-4.5.

[0024] Further, in the above technical solution, the thio reagent in the third step is selected from Lawesson's reagent.

[0025] Further, in the above technical solution, the molar ratio of the compound 3 to the thio reagent in the third step is 1:0.5-2.0.

[0026] Further, in the above technical solution, the molar ratio of the compound 4 to methyl malonyl chloride in the fourth step is 1:3.0-6.0.

[0027] Further, in the above technical solution, the base in the fifth step is selected from sodium hydroxide or potassium hydroxide.

[0028] Further, in the above technical solution, the molar ratio of the compound 6 to 2-amino-4-trifluoromethyl-5-chloropyridine in the sixth step is 1:1.0-2.0.

[0029] Further, in the above technical solution, the condensing agent in the sixth step is selected from 1-hydroxybenzotriazole (HOBT), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0030] Further, in the above technical solution, the acid condition in the seventh step is in hydrogen chloride, hydrochloric acid or trifluoroacetic acid, and the catalytic hydrogenation condition is to use a palladium-carbon catalyst and the hydrogen pressure is not more than 10 kg.

[0031] Advantages of the Invention

[0032] The preparation method uses D-alanine as a raw material, directly introduces the chiral amine required by the product, does not need to use catalysts, auxiliary ligands and other expensive reagents, uses a chiral amine protecting group to make it easier to remove, and reduces the generation of a large amount of waste. DETAILED DESCRIPTION

[0033]

[0034] Example 1:

[0035] D-alanine (20 g, 224.5 mmol) was dissolved in 100 mL of a mixture of tetrahydrofuran and water (1 / 1), and sodium hydroxide (9.8 g, 247.0 mmol) was added after being cooled in an ice bath. Then, the solution was cooled to 0°C, and Boc2O (53.9 g, 247.0 mmol) was added. After the reaction was completed, the organic phase of the reaction solution was dried by rotary evaporation, poured into 20 mL of ice water, and adjusted to pH = 4-5 with 1N dilute hydrochloric acid. The aqueous phase was extracted with 100 mL of ethyl acetate, and the combined organic phase was dried under reduced pressure to obtain 40 g of intermediate 2 at a yield of 94%.

[0036] Example 2:

[0037] Lawesson's reagent (8 g, 13.9 mmol) was added to a solution of intermediate 3 (5 g, 26.6 mmol) in tetrahydrofuran (200 mL) at 0°C. Then, the solution was warmed to room temperature and stirred for 5 hours. The reaction was completed by TLC, and the reaction solution was filtered. Saturated sodium bicarbonate (30 mL) was added to the mother liquor, and extraction was performed with methyl tert-butyl ether (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain 5 g of intermediate 4 as a yellow solid at a yield of 92%.

[0038] Example 3:

[0039] Lawesson's reagent (8 g, 13.9 mmol) was added to a solution of intermediate 3 (5 g, 26.6 mmol) in tetrahydrofuran (200 mL) at 0°C. Then, the solution was warmed to room temperature and stirred for 5 hours. The reaction was completed by TLC, and the reaction solution was filtered. Saturated sodium bicarbonate (30 mL) was added to the mother liquor, and extraction was performed with methyl tert-butyl ether (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain 5 g of intermediate 4 as a yellow solid at a yield of 92%.

[0040] Example 4

[0041] To a solution of intermediate 4 (5 g, 24.5 mmol) / DMF (50 mL), methylmalonyl chloride (16.7 g, 122.5 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 48 hours. The reaction was monitored by TLC until completion. The reaction solution was diluted with methyl tert-butyl ether (200 mL) and washed with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Purification was performed by column chromatography (ethyl acetate / n-heptane = 1 / 10–1 / 1) to give 5 g of intermediate 5, in 74% yield. LC-MS: 287 [M+1], 232 [M+1-56], 187 [M+1-100].

[0042] Example 5

[0043] Lithium hydroxide hydrate (25 mmol) was added to a solution of intermediate 5 (5 g, 17.5 mmol) in methanol and water (30 mL / 10 mL), and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Methanol was removed under reduced pressure, and the residue was adjusted to pH 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 4.2 g of intermediate 6, with a yield of 88%. LC-MS: 173 [M+1-100], 217 [M+1-56].

[0044] Example 6

[0045] Intermediate 6 (2 g, 7.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 11.1 mmol), 1-hydroxybenzotriazole (1.5 g, 11.1 mmol), and DIPE A (1.9 g, 14.8 mmol) were added to dichloromethane and stirred for 30 minutes. After adding 2-amino-4-trifluoromethyl-5-chloropyridine (1.5 g, 7.4 mmol), the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until completion. The reaction mixture was added to water, separated, and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Purification by column chromatography (petroleum ether / ethyl acetate = 5 / 1–1 / 2) yielded 2.6 g of intermediate 7, with a yield of 94%.

[0046] Example 7

[0047] Intermediate 7 (2 g, 4.4 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and trifluoroacetic acid (10 mL) was added. The mixture was then heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction solution was evaporated to dryness, and an aqueous sodium bicarbonate solution (20 mL) was added. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1–1 / 3) to give 1.5 g of tovorafenib chiral amine intermediate 8, with a yield of 97%.

[0048] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a chiral amine intermediate of tovorafenib, characterized in that, Includes the following steps: Where: P = Boc, Bn, Cbz; Step 1, Protection: Using D-alanine as a raw material, it is reacted with a protecting group reagent to obtain compound 2; The second step, amidation: Compound 2 reacts with ammonia in the presence of a condensing agent to give compound 3; The third step, thioreaction: Compound 3 reacts with a thioreagent to give compound 4; Step 4, cyclization reaction: Compound 4 undergoes a cyclization reaction with methylmalonyl chloride to give compound 5; Step 5, hydrolysis reaction: Compound 5 is hydrolyzed under alkaline conditions to give compound 6; Step 6, condensation reaction: Compound 6 reacts with 2-amino-4-trifluoromethyl-5-chloropyridine in the presence of a condensing agent to give compound 7; Step 7, Deprotection: Compound 7 is deprotected under acidic or catalytic hydrogenation conditions to obtain the key chiral amine intermediate of tovorafenib.

2. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: The first step involves selecting the protecting group reagent from di-tert-butyl dicarbonate, benzyl chloroformate, or benzyl bromide; the molar ratio of D-alanine to the protecting group reagent is 1:1.0 to 1.

5.

3. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: In the second step, the condensing agent is selected from ethyl acetate solution of 1-propylphosphonic anhydride or 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

4. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: In the second step, the molar ratio of compound 2, ammonia, and condensing agent is 1:3.5 to 4.

5.

5. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: Thirdly, the thioreagent is selected from Lawson's reagent; the molar ratio of compound 3 to the thioreagent is 1:0.5 to 2.

0.

6. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: In the fourth step, the molar ratio of compound 4 to methylmalonyl chloride is 1:3.0 to 6.

0.

7. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: Fifth step, the alkali is selected from sodium hydroxide or potassium hydroxide.

8. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: Step 6, the molar ratio of compound 6 to 2-amino-4-trifluoromethyl-5-chloropyridine is 1:1.0 to 2.

0.

9. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: The condensing agent in step six is ​​selected from 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate.

10. The method for preparing the chiral amine intermediate of tovorafenib according to claim 1, characterized in that: Step 7, the acidic conditions are hydrogen chloride, hydrochloric acid, or trifluoroacetic acid; The catalytic hydrogenation conditions are as follows: using a palladium-on-carbon catalyst, the reaction is carried out under a hydrogen pressure not exceeding 10 kg.

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