Process for the preparation of 4-bromo-2-trifluoro-t-butylpyridine

Abstract

The application discloses a preparation method of 4-bromo-2-trifluoro-t-butylpyridine, which comprises the following steps: continuously stirring (4-bromo-2-pyridyl) dimethyl potassium and a decarboxylation inhibitor in a reaction solvent and a fluorination reagent, reacting at 30-120 DEG C, and then performing post-treatment to obtain 4-bromo-2-trifluoro-t-butylpyridine. The method is simple in process, easy to operate, high in yield and product purity, and easy to realize industrial production.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals and relates to a method for preparing a fluorine-containing pharmaceutical intermediate. Background Technology

[0002] Breast cancer is a condition in which breast epithelial cells proliferate uncontrollably under the influence of various carcinogenic factors. Early symptoms often include breast lumps, nipple discharge, and enlarged axillary lymph nodes. In later stages, distant metastasis of cancer cells can lead to multi-organ complications, directly threatening the patient's life. With advancements in medical technology, numerous targeted drugs targeting different gene mutations have emerged, significantly improving patient prognosis. Among them, apelisib, a targeted drug against PIK3CA gene mutations, has brought new hope to many breast cancer patients. Developed by Novartis in Switzerland, apelisib is an oral PI3K inhibitor specifically for patients with PIK3CA gene-mutant breast cancer. It was the first targeted therapy drug globally approved by the U.S. Food and Drug Administration (FDA) for PIK3CA-mutant HR+ / HER2- advanced or metastatic breast cancer.

[0003] 4-Bromo-2-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine, abbreviated as 4-bromo-2-trifluorotert-butylpyridine, CAS No.: 1357476-67-5, is a key intermediate in the synthesis of apegliflozin. Two synthetic routes for preparing this substance have been reported in the literature.

[0004] Route 1 is the synthesis process reported in WO2020 / 072892, as shown in the following formula.

[0005]

[0006] Route 1 uses dimethyltrifluoropropionic acid as the starting material and prepares the product through a five-step reaction process: acyl chloride, 4-methoxybutenone condensation, trifluoroacetic acid cyclization, ammonia nitrogen hybridization, and phosphorus tribromooxyphosphine bromination. The advantage of Route 1 is that it uses industrially available trifluorodimethylpropionic acid as a raw material, which is readily available in the market with numerous suppliers, ensuring a stable supply. Its disadvantages are the longer route and higher cost.

[0007] Route 2 is the route reported by CN112010803.

[0008]

[0009] In Route 2, 4-bromo-2-isopropylpyridine is prepared in a one-step reaction using the electrophilic trifluoromethyl reagent Umemoto's reagent. The advantage of Route 2 is its shorter procedure, but its disadvantages include the high cost and lack of readily available commercial supply of Umemoto's reagent, making industrialization difficult.

[0010] To address the shortcomings of the two existing routes and continuously reduce the manufacturing cost of apelis, researching and inventing new routes for the preparation of 4-bromo-2-trifluorotert-butylpyridine, making it potentially suitable for large-scale industrial production, is of significant practical importance. Summary of the Invention

[0011] In view of this, the purpose of this invention is to provide a method for preparing 4-bromo-2-trifluorotert-butylpyridine. By adding a decarboxylation inhibitor to the fluorination reaction of potassium (4-bromo-2-pyridinyl)dimethylacetate, 4-bromo-2-trifluorotert-butylpyridine was successfully prepared. This method is simple, has a high yield, and produces a product with high purity, thus it is expected to be industrialized.

[0012] Therefore, the present invention adopts the following technical solution:

[0013] A method for preparing 4-bromo-2-trifluorotert-butylpyridine includes: continuously stirring (4-bromo-2-pyridinyl)dimethylacetate potassium (as shown in Formula I) and a decarboxylation inhibitor in the presence of a reaction solvent and a fluorinating agent, reacting at 30°C to 120°C for 3 to 120 hours, and then performing post-treatment to obtain 4-bromo-2-trifluorotert-butylpyridine (as shown in Formula II).

[0014] The reaction pathway is as follows:

[0015]

[0016] (Ⅰ) (Ⅱ)

[0017] Preferably, the decarboxylation inhibitor is selected from at least one of antimony trifluoride, antimony pentafluoride, and bismuth trifluoride.

[0018] Preferably, the molar ratio of the decarboxylation inhibitor to potassium (4-bromo-2-pyridyl)dimethylacetate is (0.1-3):1.

[0019] Preferably, the reaction solvent is a reagent that provides anhydrous hydrogen fluoride.

[0020] Preferably, the reaction solvent is selected from at least one of anhydrous hydrogen fluoride, triethylamine trifluoride, and pyridine hydrogen fluoride.

[0021] Preferably, the fluorinating agent is sulfur tetrafluoride.

[0022] Preferably, the molar ratio of sulfur tetrafluoride to potassium (4-bromo-2-pyridyl)dimethylacetate is (2-20):1.

[0023] Preferably, the reaction is carried out at 60°C for 12 hours.

[0024] Preferably, the post-treatment refers to: after the reaction is complete, the reaction solution is poured into ice water, the pH value is adjusted to 4-12 with potassium hydroxide solution, the aqueous phase is extracted with dichloromethane, the process is repeated several times, the organic phases are combined and dried with anhydrous sodium sulfate, concentrated, and the concentrate is distilled under reduced pressure to obtain the product.

[0025] Preferably, the potassium hydroxide solution has a mass percentage concentration of 30%.

[0026] Preferably, the pH value is adjusted to 9-10.

[0027] Compared with the prior art, the present invention has the following beneficial technical effects:

[0028] This invention successfully prepared 4-bromo-2-trifluorotert-butylpyridine by adding a decarboxylation inhibitor to the fluorination reaction of potassium (4-bromo-2-pyridinyl)dimethylacetate. The method is simple, has a high yield, and produces a high-purity product. Furthermore, the reaction conditions of this invention are simple and easy to operate, making it more suitable for widespread application. Attached Figure Description

[0029] Figure 1 The 1H NMR spectrum of the final product obtained in Example 1 1 H-NMR.

[0030] Figure 2 The NMR fluorine spectrum of the final product obtained in Example 1 19 F-NMR.

[0031] Figure 3 This is the GC spectrum of the final product obtained in Example 1.

[0032] Figure 4 This is the GC-MS spectrum of the final product obtained in Comparative Example 1. Detailed Implementation

[0033] To better illustrate the present invention and facilitate understanding of its technical solutions, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the following embodiments are for illustrative purposes only and do not represent or limit the scope of protection of the present invention; the scope of protection of the present invention is defined by the claims.

[0034] Unless otherwise specified, all reagents and instruments used in the following examples are commercially available products. In this invention, unless otherwise specified, all raw materials used are commercially available products. The reaction substrate, potassium (4-bromo-2-pyridyl)dimethylacetate, was prepared in-house, but can also be prepared using various methods disclosed in the literature.

[0035] Preparation of potassium (4-bromo-2-pyridinyl)dimethylacetate

[0036] Add 4.3 L of 2-methyltetrahydrofuran, 860 g of 4-bromo-2-methylpyridine, and 1180 g of diethyl carbonate to the reaction flask. Start stirring and cool the flask to below -40°C in a dry ice-ethanol bath. Add 2.2 L of a 2.5 mol / L butyllithium hexane solution. After the addition is complete, slowly raise the temperature to 20–25°C and maintain the temperature with stirring for 12 hours. Then, cool the flask again to below -40°C and add 475 g of bromomethane. Slowly add 4 L of a 2.5 mol / L butyllithium hexane solution while maintaining the temperature below -40°C. After the addition is complete, raise the temperature to 20–25°C and react for 24 hours. Cool the flask to 0–5°C and add a 1 mol / L hydrochloric acid solution to adjust the pH to 9. After stirring for 15 minutes, the phases were separated, the organic phase was washed with water, dried, and concentrated to obtain 540 g of ethyl 2-(4-bromopyridin-2-yl)-2-methylpropionate.

[0037] 1000 g of ethyl 2-(4-bromopyridin-2-yl)-2-methylpropionate (3.68 mol) and 10 L of ethanol were added to a 20 L reactor, and the reactor temperature was lowered to 20 °C using an ice-water bath. A potassium hydroxide solution (formed by dissolving 227 g of potassium hydroxide in 530 g of water) was added dropwise to the reactor while maintaining the temperature below 25 °C. After the addition was complete, the temperature was raised to 78 °C and the reaction was carried out for 10 hours. After the reaction was complete, the solution was concentrated to dryness, and tertiary methyl ether was added and stirred to obtain 950 g of potassium (4-bromo-2-pyridin)dimethylacetate (as shown in Formula I).

[0038] Example 1: Preparation of 4-bromo-2-trifluorotert-butylpyridine

[0039] Add 90 g of potassium (4-bromo-2-pyridyl)dimethylacetate (0.319 mol) and 57 g of antimony trifluoride (0.319 mol) sequentially to a 2 L Monel autoclave, and seal the reactor. Then, introduce 520 g of anhydrous hydrogen fluoride and 413 g of sulfur tetrafluoride (3.82 mol) into the reactor. Seal the reactor again. Start stirring and slowly raise the temperature to 60 °C and react for 12 hours.

[0040] After the reaction was complete, post-treatment was performed: the reaction solution was poured into ice water, and the pH was adjusted to 9-10 with 30% potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and the process was repeated 3 times. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the product, which weighed 68 g.

[0041] The 1H NMR spectrum of the obtained product is as follows: Figure 1 As shown, the fluorine NMR spectrum (19F NMR) of the obtained product is as follows. Figure 2 As shown, the gas chromatography (GC) of the obtained product is as follows: Figure 3 As shown.

[0042] right Figure 1 and Figure 2 The analytical results of the nuclear magnetic resonance spectra shown are as follows:

[0043] 1H-NMR (400MHz, CDCl3): δ 8.48~8.50 (d, 1H), δ 7.87 (s, 1H), δ 7.66~7.68 (d, 1H), δ 1.56 (s, 6H).

[0044] 19F-NMR (376MHz, CDCl3): δ -74.15 (CF3).

[0045] The analysis results of the above nuclear magnetic resonance spectrum show that the obtained product is 4-bromo-2-trifluorotert-butylpyridine.

[0046] Gas chromatograms were analyzed using the normalization method. Figure 3 Calculations and analyses were performed, and the results are shown in Table 1 below. According to Table 1, the purity of the obtained product was 99.63%, and the calculated reaction yield of the substrate was 79%.

[0047] Table 1: GC Analysis Results

[0048]

[0049] Example 2 Preparation of 4-bromo-2-trifluorotert-butylpyridine

[0050] Add 90 g of potassium (4-bromo-2-pyridyl)dimethylacetate (0.319 mol) and 84.8 g of bismuth trifluoride (0.474 mol) sequentially to a 2 L Monel autoclave, and seal the reactor. Then introduce 520 g of anhydrous hydrogen fluoride and 230 g of sulfur tetrafluoride (2.13 mol) into the reactor. Seal the reactor again. Start stirring and slowly raise the temperature to 60 °C and react for 12 hours.

[0051] After the reaction was complete, post-treatment was performed: the reaction solution was poured into ice water, and the pH was adjusted to 9-10 with 30% potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and the process was repeated 3 times. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the product, which weighed 70 g.

[0052] The test results showed that the obtained product was 4-bromo-2-trifluorotert-butylpyridine with a purity of 99.2%. The substrate yield was 82%.

[0053] Example 3 Preparation of 4-bromo-2-trifluorotert-butylpyridine

[0054] Add 90 g of (4-bromo-2-pyridyl)dimethylacetic acid potassium (0.319 mol) and 57 g of antimony trifluoride (0.319 mol) sequentially to a 2 L Monel autoclave, and seal the reactor. Then, introduce 910 g of pyridine hydrogen fluoride solution and 413 g of sulfur tetrafluoride into the reactor. Seal the reactor again. Start stirring and slowly raise the temperature to 60 °C and react for 12 hours.

[0055] After the reaction was complete, post-treatment was performed: the reaction solution was poured into ice water, and the pH was adjusted to 9-10 with 30% potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and the process was repeated 3 times. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the product, which weighed 51 g.

[0056] The test results showed that the obtained product was 4-bromo-2-trifluorotert-butylpyridine with a purity of 99.5%. The substrate reaction yield was 60%.

[0057] Comparative Example 1

[0058] Add 90 g (0.319 mol) of potassium (4-bromo-2-pyridyl)dimethylacetate to a 2L Monel autoclave and seal the reactor. Introduce 520 g of anhydrous hydrogen fluoride and 413 g of sulfur tetrafluoride into the reactor. Seal the reactor again. Start stirring and slowly raise the temperature to 70°C for 12 hours.

[0059] After the reaction was complete, post-treatment was performed: the reaction solution was poured into ice water, and the pH was adjusted to 9-10 with 30% potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and the process was repeated 3 times. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and the dichloromethane was removed under reduced pressure to obtain the product, which weighed 4 g.

[0060] The gas chromatography-mass spectra of the obtained products are as follows: Figure 4 As shown, the results indicate: GCMS: [M] + =199, [MH] +=198, which is the molecular weight of the decarboxylate. The product purity is 95.2%. Further analysis revealed its molecular formula to be C8H. 10 BrN, Exact Mass: 199.00, m / z: 199.00 (100%); 201.00 (97.3%); 200.00 (8.7%); 202.00 (8.4%). The structural formula is as follows:

[0061]

[0062] It is evident that the product obtained in Comparative Example 1 is a decarboxylation product, meaning that no trifluoromethylation reaction occurred in Comparative Example 1, but rather a decarboxylation reaction did.

[0063] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein. On the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine comprising: Potassium (4-bromo-2-pyridyl) dimethylacetate and decarboxylation inhibitor are continuously stirred in the presence of reaction solvent and fluorination reagent, and reacted at 30-120 ℃ for 3-120 hours, and then after-treatment is performed to obtain 4-bromo-2-trifluoro-t-butylpyridine, wherein the decarboxylation inhibitor is at least one selected from antimony trifluoride, antimony pentafluoride and bismuth trifluoride, the reaction solvent is a reagent providing anhydrous hydrogen fluoride, and the fluorination reagent is sulfur tetrafluoride.

2. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that, The molar ratio of the decarboxylation inhibitor to potassium (4-bromo-2-pyridyl) dimethylacetate is (0.1-3):

1.

3. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that, The reaction solvent is at least one selected from anhydrous hydrogen fluoride, triethylamine trifluoride and pyridine hydrogen fluoride.

4. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that, The molar ratio of the sulfur tetrafluoride to potassium (4-bromo-2-pyridyl) dimethylacetate is (2-20):

1.

5. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that, The after-treatment refers to that after the reaction is completed, the reaction liquid is poured into ice water, a potassium hydroxide solution is used to adjust the pH value to 4-12, the water phase is extracted with dichloromethane for several times, the organic phases are combined and dried with anhydrous sodium sulfate, concentrated, and the concentrate is distilled under reduced pressure to obtain the product.

6. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 5, characterized in that, In the after-treatment, the mass percentage concentration of the potassium hydroxide solution is 30%.

7. The process for the preparation of 4-bromo-2-trifluoro-tert-butylpyridine according to claim 5, characterized in that, In the after-treatment, the pH value is adjusted to 9-10.

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