Preparation method of tovorafenib intermediate

Abstract

The invention discloses a preparation method of a tovorafenib intermediate, and belongs to the field of organic synthesis. The tovorafenib intermediate is (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl) pyridine-2-yl) thiazole-5-carboxamide, and the method mainly comprises the following steps: dissolving 2-acetyl-N-(5-chloro-4-(trifluoromethyl) pyridine-2-yl) thiazole-5-carboxamide in a solvent, adding p-toluenesulfonic acid, dropwise adding S (-)-alpha-phenylethylamine for reaction, and carrying out column chromatography separation to obtain the tovorafenib intermediate. Recovering the solvent from the product to obtain an oily intermediate; then dropwise adding S (-)-alpha-phenylethylamine, and adding DBU for reaction; and after the reaction is finished, carrying out reduced pressure distillation to recover the S (-)-alpha-phenylethylamine, so as to obtain an oily substance, adding water into the oily substance, and crystallizing, so as to obtain the tovorafenib intermediate. According to the method, S (-)-alpha-phenylethylamine is used as a reactant and a chiral inducer at the same time, p-toluenesulfonic acid is used as a condensation catalyst, and DBU is used for catalyzing epimerization; the theoretical 100% yield is achieved through high-temperature racemization.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a tovorafenib intermediate. Background Art

[0002] Tovorafenib, CAS registration number: 1096708-71-2; molecular formula:

[0003] C 17 H 12 Cl2F3N7O2S is used to treat recurrent or refractory low-grade glioma in children aged ≥0.5 years. It is suitable for patients with BRAF gene fusion, BRAF gene rearrangement or BRAF V600 gene mutation. Tovorafenib is a kinase inhibitor with two dosage forms: oral tablets (100 mg) and oral suspension (25 mg / mL), once a week, and the dose is related to body surface area. The most common (incidence ≥30%) side effects of Tovorafenib include rash, hair color changes, fatigue, viral infection, vomiting, bleeding, fever, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. Tovorafenib is developed by DayOne Biopharmaceuticals, Inc. and is the 14th innovative drug (Noveldrugs) approved by the FDA in 2024.

[0004] (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Formula 1), CAS registration number: 1095823-62-3, is a key intermediate in the production of tovorafenib.

[0005]

[0006] WO2018220533 reports the preparation of chiral N-(2-pyridyl)-2-(1-aminoethyl)-1,3-thiazole-5-carboxamide represented by Formula 1 by a resolution method.

[0007] WO2010078408 and WO2009006389 used racemic amine as substrate to obtain chiral N-(2-pyridyl)-2-(1-aminoethyl)-1,3-thiazole-5-carboxamide as shown in Formula 1:

[0008] The above-mentioned method cannot effectively separate the chiral amine during the resolution process, resulting in a low yield of the chiral amine, reaching a maximum yield of 50%. The selectivity of the resolution reaction is often affected by the reaction conditions. Low selectivity can cause the target chiral amine to be mixed with other byproducts, thereby reducing the purity.

[0009] WO2018220533 prepared chiral N-(2-pyridyl)-2-(1-aminoethyl)-1,3-thiazole-5-carboxamide of Formula 1 by asymmetric hydrogenation:

[0010]

[0011] However, this reaction has disadvantages such as high catalyst cost, harsh reaction conditions (high pressure, anhydrous and oxygen-free), difficulty in scale-up production (catalyst recovery, safety, and reproducibility), and insufficient selectivity for certain substrates. Summary of the Invention

[0012] The present invention aims to overcome the shortcomings of the prior art and provides a method for preparing a tovorafenib intermediate. The tovorafenib intermediate referred to herein is (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, CAS No. 1095823-62-3, and its structural formula is provided in the background art. The preparation method provided by the present invention addresses the problems of low chiral amine yield, high catalyst cost, and harsh reaction conditions in the prior art.

[0013] In order to achieve the above object, the present invention provides a method for preparing a tovorafenib intermediate, which comprises the following steps:

[0014] (a) dissolving 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide in a solvent, adding p-toluenesulfonic acid in an amount of 0.1-1% by weight of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, and cooling the mixture to 0-5°C;

[0015] (b) adding S(-)-α-phenylethylamine dropwise to the mixture of step (a) at 0-15° C., and subjecting the mixture to reflux reaction after the addition is complete, while removing the generated water through a water separator during the reaction;

[0016] (c) recovering toluene by rotary evaporation after the reaction to obtain an oily intermediate;

[0017] (d) adding the oily intermediate to a reactor, then dropwise adding S(-)-α-phenylethylamine, heating, and then adding 1,8-diazacyclo[5.4.0]undecene to react;

[0018] (e) After the reaction, S(-)-α-phenylethylamine was recovered by distillation under reduced pressure to obtain an oily substance. Water was added to the oily substance and crystallized to obtain (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide.

[0019] The preparation process of the present invention is expressed as follows in the form of a reaction formula:

[0020]

[0021] The solvent in step (a) is preferably a solvent that can dissolve the reaction raw materials to improve the reaction efficiency. The amount of solvent used is not limited based on the ability to dissolve the reaction raw materials. Taking into account the energy consumption of subsequent rotary evaporation, the amount of solvent used is preferably less. For example, the amount of solvent used that just dissolves the reaction raw materials is defined as the minimum amount. The recommended amount of solvent used can be selected as 1-10 times the minimum amount, preferably 1-5 times. Typically, but not limited to, the solvent can be selected as toluene.

[0022] During the entire reaction process of the present invention, S(-)-α-phenylethylamine is added in step (b) and step (d), respectively. The S(-)-α-phenylethylamine added in both steps can be the S(-)-α-phenylethylamine recovered in step (e). Preferably, the S(-)-α-phenylethylamine recovered in step (e) is purified and then reused in step (b) and / or step (d) directly or together with fresh S(-)-α-phenylethylamine, thereby greatly reducing reaction costs and raw material consumption. The S(-)-α-phenylethylamine serves as both a reactant and a chiral inducer, achieving dual-function chirality control.

[0023] According to an embodiment of the present invention, step (b) is the first addition of S(-)-α-phenylethylamine. The molar ratio of S(-)-α-phenylethylamine to 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide added in this step is 1.0:1 to 1.2:1. During the addition process, the system is preferably maintained at a low temperature, preferably 0–15°C. After the addition of S(-)-α-phenylethylamine, a reflux reaction is performed. Preferably, the reaction temperature is 85°C and the reflux reaction time is 5-15 hours.

[0024] Step (d) is a second addition of S(-)-α-phenylethylamine. Preferably, the mass ratio of the S(-)-α-phenylethylamine added dropwise in step (d) to the oily intermediate is 1:1.5 to 1:2.5.

[0025] Furthermore, in step (d), the reaction mass after the dropwise addition of S(-)-α-phenylethylamine is heated to 90-100° C. and then 1,8-diazacyclo[5.4.0]undecene (DBU) is added. Preferably, the amount of 1,8-diazacyclo[5.4.0]undecene added is 0.4-0.6% by weight of the oily intermediate.

[0026] Furthermore, in step (d), the reaction temperature is 95-115° C., and the reaction time is 6-12 hours.

[0027] According to an embodiment of the present invention, in step (e), the amount of water added is 1-2 times the weight of the oil; and the crystallization temperature is controlled at -5 to 5°C.

[0028] Compared with the prior art, the present invention has the following effects and advantages:

[0029] 1) Bifunctional chirality control: The present invention adds S(-)-α-phenylethylamine in both steps (b) and (d). The S(-)-α-phenylethylamine added in both steps can be the S(-)-α-phenylethylamine recovered in step (e), thereby significantly reducing reaction costs and raw material consumption. S(-)-α-phenylethylamine serves as both a reactant and a chiral inducer, avoiding the need for intermediate separation and purification steps when different reagents are used in the two steps, significantly reducing the number of process steps. Furthermore, the present invention utilizes S(-)-α-phenylethylamine to achieve bifunctional chirality control; combined with subsequent dynamic kinetic resolution (DKR), a theoretical 100% yield is achieved through high-temperature racemization.

[0030] 2) The process of the present invention constructs a synergistic catalytic system, using p-toluenesulfonic acid as a catalyst for the acid-catalyzed condensation in step (b), and using DBU as a catalyst for the base-catalyzed epimerization in step (d); the entire process has high catalytic efficiency and fast reaction speed.

[0031] 3) The product (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide obtained by the present invention has a high yield and an ee value of up to 99.5%.

[0032] 4) The raw materials of the present invention are simple and easy to obtain, the three wastes are small, the pollution is small, and it is suitable for industrial production.

[0033] Other features and advantages of the present invention will be described in detail in the following detailed description. DETAILED DESCRIPTION

[0034] The preferred embodiments of the present invention will be described in more detail below. Although the preferred embodiments of the present invention are described below, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. Instead, these embodiments are provided to make the present invention more thorough and complete and to fully convey the scope of the present invention to those skilled in the art.

[0035] The following examples provide those of ordinary skill in the art with an understanding of how to make and evaluate the present invention, and the examples are intended to be illustrative of the present disclosure and are not intended to limit the scope thereof. Although every effort has been made to ensure the accuracy of the values ​​(e.g., amounts, temperatures, etc.), some errors and deviations should be considered. Unless otherwise indicated, temperatures are in ° C. or at ambient temperature, and pressures are at or near atmospheric pressure.

[0036] Example 1

[0037] 3500 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide was added to 10 liters of toluene, followed by 3.5 g of p-toluenesulfonic acid. The mixture was cooled to 0°C, and 1210 g of S(-)-α-phenylethylamine was added dropwise, maintaining the temperature at 0°C. After the addition was complete, the mixture was refluxed at 85°C for 5 hours. The reaction water was separated by a water separator, and the toluene was recovered by rotary evaporation to yield 4500 g of an oil. 4500 g of the oil was added to a three-necked flask, and 6750 g of S(-)-α-phenylethylamine was added dropwise. The mixture was heated to 90°C, and 18 g of 1,8-diazacyclo[5.4.0]undecene was added dropwise. The temperature was raised to 95°C and the reaction was allowed to proceed for 6 hours. The S(-)-α-phenylethylamine was recovered to obtain an oil. 4500 g of water was added to the oil, and crystallization was carried out at -5°C to obtain 3100 g of (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide. The yield was 88.6%, and the ee value was 99.5%.

[0038] 1H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.71(s,1H),8.59(s,1H),4.22(q,J=6.7Hz,1H),1.40(d,J=6.7Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ

[0039] 185.78,158.85,150.19,148.31,144.27,131.90,121.61,120.02,118.89,110.42,48.21,22.97.

[0040] Example 2

[0041] 3500 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide was added to 10 liters of toluene, followed by 20 g of p-toluenesulfonic acid. The mixture was cooled to 3°C, and 1450 g of S(-)-α-phenylethylamine was added dropwise, maintaining the temperature at 10°C. After the addition was complete, the mixture was refluxed at 85°C for 10 hours. The reaction water was separated by a water separator, and the toluene was recovered by rotary evaporation to yield 4620 g of an oil. 4620 g of the oil was added to a three-necked flask, and 9240 g of S(-)-α-phenylethylamine was added dropwise. The mixture was heated to 95°C, and 23.1 g of 1,8-diazacyclo[5.4.0]undecene was added dropwise. The temperature was raised to 110°C and the reaction was allowed to proceed for 8 hours. The S(-)-α-phenylethylamine was recovered to obtain an oil. 6930 g of water was added to the oil, and crystallization was carried out at 0°C to obtain 3300 g of (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, with a yield of 94.3% and an ee value of 99.5%.

[0042] Example 3

[0043] 3500 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide was added to 10 liters of toluene, followed by 35 g of p-toluenesulfonic acid. The mixture was cooled to 5°C, and 1452 g of S(-)-α-phenylethylamine was added dropwise, maintaining the temperature at 15°C. After the addition was complete, the mixture was refluxed at 85°C for 15 hours. The reaction water was separated by a water separator, and the toluene was recovered by rotary evaporation to yield 4610 g of an oil. 4610 g of the oil was added to a three-necked flask, and 11525 g of S(-)-α-phenylethylamine was added dropwise. The mixture was heated to 100°C, and 27.66 g of 1,8-diazacyclo[5.4.0]undecene was added dropwise. The temperature was raised to 115°C and the reaction was allowed to proceed for 12 hours. The S(-)-α-phenylethylamine was recovered to obtain an oil. 9220 g of water was added to the oil, and crystallization was carried out at 5°C to obtain 3350 g of (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, with a yield of 95.7% and an ee value of 99.8%.

[0044] While various embodiments of the present invention have been described above, the above description is intended to be illustrative, not exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A method for preparing a tovorafenib intermediate, characterized in that: The following steps are involved: (a) dissolving 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide in a solvent, adding p-toluenesulfonic acid in an amount of 0.1-1% by weight of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, and cooling the mixture to 0-5°C; (b) adding S(-)-α-phenylethylamine dropwise to the mixture of step (a) at 0-15° C., and then refluxing the mixture to remove generated water through a water separator during the reaction; (c) recovering toluene by rotary evaporation after the reaction to obtain an oily intermediate; (d) adding the oily intermediate to a reactor, then dropwise adding S(-)-α-phenylethylamine, heating, and then adding 1,8-diazacyclo[5.4.0]undecene to react; (e) After the reaction, S(-)-α-phenylethylamine was recovered by distillation under reduced pressure to obtain an oily substance. Water was added to the oily substance and crystallized to obtain (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide.

2. The method according to claim 1, wherein: The solvent in step (a) is toluene.

3. The method according to claim 1, wherein: In step (b), the molar ratio of S(-)-α-phenylethylamine to 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide is 1.0:1 to 1.2:1; the reflux reaction temperature is 85° C., and the reflux reaction time is 5-15 hours.

4. The method according to claim 1, wherein: The mass ratio of S(-)-α-phenylethylamine added dropwise in step (d) to the oily intermediate is 1:1.5 to 1:2.

5.

5. The method according to claim 1, wherein: In step (d), the reaction mass after the dropwise addition of S(-)-α-phenylethylamine is heated to 90-100° C. and then 1,8-diazacyclo[5.4.0]undecene is added. The amount of 1,8-diazacyclo[5.4.0]undecene added is 0.4-0.6% by weight of the oily intermediate.

6. The method according to claim 1, wherein: In step (d), the reaction temperature is 95-115° C. and the reaction time is 6-12 hours.

7. The method according to claim 1, wherein: The S(-)-α-phenylethylamine recovered in step (e) is purified and recycled for use in step (b) or step (d).

8. The method according to claim 1, wherein: In step (e), the amount of water added is 1-2 times the weight of the oil; and the crystallization temperature is controlled at -5 to 5°C.

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