Preparation method of 4-bromine-2-trifluorotert-butylpyridine

Abstract

The invention discloses a preparation method of 4-bromine-2-trifluorotert-butylpyridine, which comprises the following steps: continuously stirring potassium (4-bromine-2-pyridine) dimethyl propyl acetate and a decarboxylation inhibitor in the presence of a reaction solvent and a fluorination reagent, reacting at 30-120 DEG C, and performing post-treatment to obtain the 4-bromine-2-trifluorotert-butylpyridine. The method is simple in process, easy to operate, high in yield, high in product purity and easy for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and relates to a method for preparing a fluorine-containing drug intermediate. Background Art

[0002] Breast cancer is a phenomenon in which breast epithelial cells proliferate uncontrollably under the action of multiple carcinogens. In the early stages of the disease, symptoms such as breast lumps, nipple discharge, and axillary lymph node enlargement often occur. In the late stages, cancer cells may metastasize to distant sites, resulting in multi-organ lesions, which directly threaten the patient's life. With the advancement of medical technology, targeted drugs for different gene mutations have emerged in an endless stream, greatly improving the prognosis of patients. Among them, alpelisib, as a targeted drug for PIK3CA gene mutations, has brought new hope to many breast cancer patients. Alpelisib is an oral PI3K inhibitor developed by Novartis in Switzerland, specifically for patients with PIK3CA gene mutation breast cancer. It is the world's first targeted therapy approved by the U.S. Food and Drug Administration (FDA) for PIK3CA mutation HR+ / HER2- advanced or metastatic breast cancer.

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

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

[0005]

[0006] In route 1, dimethyl trifluoropropionic acid is used as the starting material, and the product is prepared through five steps of acyl chlorination, 4-methoxybutenone condensation, trifluoroacetic acid cyclization, ammonia hydration, and tribromophosphorus oxybromide bromination. The advantage of route 1 is that it uses trifluorodimethylpropionic acid, which has been industrialized, as the raw material. The raw material is easily available in the market and there are many suppliers. It is a route with a stable supply of raw materials. Its disadvantage is that the route is long and the cost is high.

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

[0008]

[0009] In route 2, 4-bromo-2-isopropylpyridine is used as a raw material to prepare 4-bromo-2-trifluoro-tert-butylpyridine through a one-step reaction of an electrophilic trifluoromethyl reagent Umemoto reagent. The advantage of route 2 is that the steps are short, but the disadvantage is that the Umemoto reagent is expensive and there is no commodity supply, making it difficult to industrialize.

[0010] In order to solve the shortcomings of the two routes and continuously reduce the manufacturing cost of Apellis, it is of great practical significance to study and invent a new route for preparing 4-bromo-2-trifluoro-tert-butylpyridine so that it has the potential to be suitable for large-scale industrial production. Summary of the invention

[0011] In view of this, the object of the present invention is to provide a method for preparing 4-bromo-2-trifluoro-tert-butylpyridine. A decarboxylation inhibitor is added to the fluorination reaction of (4-bromo-2-pyridyl)dimethylpropionic acid potassium to successfully prepare 4-bromo-2-trifluoro-tert-butylpyridine. The method has simple process, high yield and high purity of the obtained product, and is expected to be industrialized for production.

[0012] To this end, the present invention has adopted the following technical solutions:

[0013] A method for preparing 4-bromo-2-trifluoro-tert-butylpyridine comprises: continuously stirring (4-bromo-2-pyridyl)dimethyl propanoic acid potassium (as shown in formula I) and a decarboxylation inhibitor in the presence of a reaction solvent and a fluorination agent, reacting at 30° C. to 120° C. for 3 to 120 hours, and then post-treating to obtain 4-bromo-2-trifluoro-tert-butylpyridine (as shown in formula II).

[0014] The reaction circuit is as follows:

[0015]

[0016] Preferably, the decarboxylation inhibitor is selected from at least one of antimony trifluoride, antimony pentafluoride and bismuth trifluoride.

[0017] Preferably, the molar ratio of the decarboxylation inhibitor to potassium (4-bromo-2-pyridyl)dimethylpropanoate is (0.1-3):1.

[0018] Preferably, the reaction solvent is a reagent that provides anhydrous hydrogen fluoride.

[0019] Preferably, the reaction solvent is selected from at least one of anhydrous hydrogen fluoride, triethylamine trihydrogen fluoride, and pyridine trihydrogen fluoride.

[0020] Preferably, the fluorination agent is sulfur tetrafluoride.

[0021] Preferably, the molar ratio of sulfur tetrafluoride to (4-bromo-2-pyridyl)dimethylpropionic acid potassium is (2-20):1.

[0022] Preferably, the reaction is carried out at 60° C. for 12 hours.

[0023] Preferably, the post-treatment refers to: after the reaction is completed, pouring the reaction solution into ice water, adjusting the pH value to 4-12 with potassium hydroxide solution, extracting the aqueous phase with dichloromethane, repeating several times, combining the organic phases and drying with anhydrous sodium sulfate, concentrating, and distilling the concentrate under reduced pressure to obtain the product.

[0024] Preferably, the mass percentage concentration of the potassium hydroxide solution is 30%.

[0025] Preferably, the pH value is adjusted to 9-10.

[0026] Compared with the prior art, the present invention has the following beneficial technical effects:

[0027] The invention adds a decarboxylation inhibitor into the fluorination reaction of (4-bromo-2-pyridyl)dimethyl propanoic acid potassium to successfully prepare 4-bromo-2-trifluoro tert-butyl pyridine. The method has simple process, high yield and high purity of the obtained product. Moreover, the reaction conditions of the invention are simple and easy to operate, and the invention is more suitable for popularization and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The H NMR spectrum of the final product obtained in Example 1 is 1 H-NMR.

[0029] Figure 2 The NMR fluorine spectrum of the final product obtained in Example 1 is 19 F-NMR.

[0030] Figure 3 This is the GC spectrum of the final product obtained in Example 1.

[0031] Figure 4 This is the GC-MS spectrum of the final product obtained in Comparative Example 1. DETAILED DESCRIPTION

[0032] In order to better illustrate the present invention and facilitate understanding of the technical solution of the present invention, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the following embodiments are only used to illustrate the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0033] The reagents or instruments used in the following examples without indicating the manufacturer are all conventional products that can be purchased from the market. In the present invention, except for those otherwise specified, the raw materials used are all commercially available products. Among them, the reaction substrate (4-bromo-2-pyridyl) dimethyl propionic acid potassium is homemade, and can also be prepared by various methods disclosed in the literature.

[0034] Preparation of potassium (4-bromo-2-pyridyl) dimethyl propanoate

[0035] Add 4.3L of 2-methyltetrahydrofuran, 860g of 4-bromo-2-methylpyridine and 1180g of diethyl carbonate to the reaction bottle, start stirring, cool to below -40℃ in a dry ice ethanol bath, and drop 2.2L of n-butyl lithium hexane solution (the concentration of n-butyl lithium is 2.5mol / L). After the addition is complete, slowly raise the temperature to 20-25℃, keep warm and stir to react for 12 hours. Then, cool down to below -40℃ again, and add 475g of methyl bromide to the reaction bottle. Control the temperature below -40℃ and slowly drop 4L of n-butyl lithium hexane solution (the concentration of n-butyl lithium is 2.5mol / L). After the addition is complete, raise the temperature to 20-25℃ and react for 24 hours. Cool down to 0-5℃, drop a hydrochloric acid solution with a concentration of 1mol / L, and adjust the pH to 9. After stirring for 15 minutes, the phases were separated, and the organic phase was washed with water, dried, and concentrated to give 540 g of ethyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate.

[0036] 1000 g of ethyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate (3.68 mol) and 10 L of ethanol were added to a 20 L reactor, and the temperature in the reactor was lowered to 20°C by ice-water bath. Potassium hydroxide solution (formed by dissolving 227 g of potassium hydroxide in 530 g of water) was added dropwise to the reactor at a temperature below 25°C. After the addition was completed, the temperature was raised to 78°C and reacted for 10 hours. After the reaction was completed, the mixture was concentrated to dryness, and tertiary methyl ether was added to pulp to obtain 950 g of (4-bromo-2-pyridinyl) dimethyl propanoic acid potassium (as shown in Formula I).

[0037] Example 1 Preparation of 4-bromo-2-trifluoro-tert-butylpyridine

[0038] Add 90 g (4-bromo-2-pyridyl) dimethyl propanoic acid potassium (0.319 mol) and 57 g antimony trifluoride (0.319 mol) to a 2L monel autoclave, and seal the autoclave. Add 520 g anhydrous hydrogen fluoride and 413 g sulfur tetrafluoride (3.82 mol) into the autoclave. Seal the autoclave. Start stirring, slowly raise the temperature to 60°C and react for 12 hours.

[0039] After the reaction, post-treatment was performed: the reaction solution was poured into ice water and the pH value was adjusted to 9-10 with 30% by mass potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and repeated 3 times. The organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the product, which weighed 68 g.

[0040] The 1HNMR spectrum of the obtained product is as follows Figure 1 As shown, the nuclear magnetic fluorine spectrum (19FNMR) of the obtained product is as follows Figure 2 As shown, the gas chromatography (GC) of the obtained product is as follows Figure 3 shown.

[0041] right Figure 1 and Figure 2 The analysis results of the NMR spectrum shown are as follows:

[0042] 1H-NMR (400MHz, CDCl3): δ8.48~8.50 (d, 1H), δ7.87 (s, 1H), δ7.66~7.68 (d, 1H), δ1.56 (s, 6H).

[0043] 19F-NMR (376MHz, CDCl3): δ-74.15 (CF3).

[0044] The analysis results of the above nuclear magnetic resonance spectrum show that the obtained product is 4-bromo-2-trifluoro-tert-butylpyridine.

[0045] The gas chromatogram was normalized by Figure 3 Calculation and analysis were performed, and the results are shown in Table 1. According to Table 1, the purity of the obtained product was 99.63%, and the reaction yield of the substrate was calculated to be 79%.

[0046] Table 1: GC analysis results

[0047]

[0048] Example 2 Preparation of 4-bromo-2-trifluoro-tert-butylpyridine

[0049] Add 90 g (4-bromo-2-pyridyl) dimethyl propionic acid potassium (0.319 mol) and 84.8 g bismuth trifluoride (0.474 mol) to a 2L monel autoclave, and seal the autoclave. Add 520 g anhydrous hydrogen fluoride and 230 g sulfur tetrafluoride (2.13 mol) into the autoclave. Seal the autoclave. Start stirring, slowly raise the temperature to 60°C and react for 12 hours.

[0050] After the reaction, post-treatment was performed: the reaction solution was poured into ice water and the pH value was adjusted to 9-10 with 30% by mass potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and repeated 3 times. The organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain a product weighing 70 g.

[0051] The test results showed that the obtained product was 4-bromo-2-trifluoro-tert-butylpyridine with a purity of 99.2% and a reaction yield of 82%.

[0052] Example 3 Preparation of 4-bromo-2-trifluoro-tert-butylpyridine

[0053] Add 90 g (4-bromo-2-pyridyl) dimethyl propionic acid potassium (0.319 mol) and 57 g antimony trifluoride (0.319 mol) to a 2L monel autoclave, and seal the autoclave. Pass 910 g pyridine hydrogen fluoride solution and 413 g sulfur tetrafluoride into the autoclave. Seal the autoclave. Start stirring, slowly raise the temperature to 60°C and react for 12 hours.

[0054] After the reaction, post-treatment was performed: the reaction solution was poured into ice water and the pH value was adjusted to 9-10 with 30% by mass potassium hydroxide. The aqueous phase was extracted with 500 g of DCM (dichloromethane) each time, and repeated 3 times. The organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the product, which weighed 51 g.

[0055] The test results showed that the obtained product was 4-bromo-2-trifluoro-tert-butylpyridine with a purity of 99.5%. The reaction yield of the substrate was 60%.

[0056] Comparative Example 1

[0057] Add 90 g (4-bromo-2-pyridyl) dimethyl propanoic acid potassium (0.319 mol) to a 2L monel autoclave and seal the autoclave. Add 520 g anhydrous hydrogen fluoride and 413 g sulfur tetrafluoride. Seal the autoclave. Start stirring and slowly raise the temperature to 70°C for 12 hours.

[0058] After the reaction is completed, post-treatment is performed: the reaction solution is poured into ice water, and the pH value is adjusted to 9-10 with 30% by mass potassium hydroxide. The aqueous phase is extracted with 500 g of DCM (dichloromethane) each time, and repeated 3 times. The organic phases are combined and dried with anhydrous sodium sulfate, concentrated, and dichloromethane is removed under reduced pressure to obtain a product weighing 4 g.

[0059] The gas chromatography mass spectrum of the obtained product is as follows Figure 4 As shown, the results show: GCMS: [M] + =199, [MH] + =198, which is the molecular weight of the decarboxylate. The purity of the product is 95.2%. Further analysis revealed that its molecular formula is 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:

[0060]

[0061] It can be seen that the product prepared in Comparative Example 1 is a decarboxylation product, that is, no trifluoromethylation reaction occurs in Comparative Example 1, but a decarboxylation reaction occurs.

[0062] It should be noted that the embodiments described above are only used to explain the present invention and do not constitute any limitation to the present invention. The present invention is described by reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present invention may be modified as specified within the scope of the claims of the present invention, and the present invention may be revised without departing from the scope and spirit of the present invention. Although the present invention described therein relates to specific methods, materials and embodiments, it does not mean that the present invention is limited to the specific examples disclosed therein. On the contrary, the present invention can be extended to all other methods and applications with the same functions.

Claims

1. A method for preparing 4-bromo-2-trifluoro-tert-butylpyridine, comprising: Potassium (4-bromo-2-pyridyl)dimethylpropanoate and a decarboxylation inhibitor are continuously stirred in the presence of a reaction solvent and a fluorination agent, reacted at 30° C. to 120° C. for 3 to 120 hours, and then post-treated to obtain 4-bromo-2-trifluoro-tert-butylpyridine.

2. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The decarboxylation inhibitor is selected from at least one of antimony trifluoride, antimony pentafluoride and bismuth trifluoride.

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

1.

4. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The reaction solvent is a reagent that provides anhydrous hydrogen fluoride.

5. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The reaction solvent is selected from at least one of anhydrous hydrogen fluoride, triethylamine trihydrogen fluoride, and pyridine trihydrogen fluoride.

6. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The fluorination agent is sulfur tetrafluoride.

7. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The molar ratio of the sulfur tetrafluoride to (4-bromo-2-pyridyl)dimethylpropionic acid potassium is (2-20):

1.

8. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 1, characterized in that: The post-treatment means that after the reaction is completed, 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 extraction 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.

9. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 8, characterized in that: In the post-treatment, the mass percentage concentration of the potassium hydroxide solution is 30%.

10. The method for preparing 4-bromo-2-trifluoro-tert-butylpyridine according to claim 8, characterized in that: In the post-treatment, the pH value is adjusted to 9-10.

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