Synthesis method of 7-bromo-8-fluoro-6-(trifluoromethyl) quinazoline-2, 4 (1H, 3H)-diketone
By optimizing the synthesis route of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione, using 2-fluoro-4-trifluoromethylbenzoic acid as raw material, and using multi-step reaction and purification methods, the problems of long synthesis routes and low yields in the prior art were solved, and industrial production with high purity and high yields were achieved.
Patent Information
- Application Number
- CN202510756024.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-07
- Publication Date
- 2025-09-02
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
In the prior art, the synthesis route of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione has a long synthesis route, low yield, and low product purity, making it difficult to meet the needs of industrial production.
2-fluoro-4-trifluoromethylbenzoic acid was used as raw material, and the reaction conditions and purification methods were optimized through reaction steps such as lithium reagent, Br2, tert-butanol, triethylamine, diphenyl azide phosphate, N-iodosuccinimide, CuCN and urea, and the reaction conditions and purification methods were optimized to synthesize 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.
Shorten the synthesis route, reduce wastewater and waste gas generation, improve the stability and purity of the product, enhance the product purity of each step of the reaction, and improve the total yield.
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Figure CN120574181A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. Background Art
[0002] RAS proteins are a class of small GTPases that play a key role in cellular signal transduction pathways. Under normal circumstances, RAS proteins cycle between activated and inactivated states, precisely regulating processes such as cell growth, differentiation, and apoptosis. However, when the RAS gene mutates, the RAS protein remains in an activated state, continuously transmitting proliferation signals to cells, leading to abnormal cell proliferation and blocked differentiation, thereby promoting the formation and development of tumors. RAS gene mutations have a high incidence in many cancers, such as pancreatic cancer, colorectal cancer, and lung cancer, making RAS proteins an extremely attractive target for anticancer drugs.
[0003] 7-Bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione is used as an anti-cancer target RAS inhibitor. By binding to the RAS protein, it can block the RAS protein from transmitting signals downstream, thereby preventing abnormal cell proliferation and survival signal transduction, inducing cancer cells to undergo apoptosis or cell cycle arrest. The traditional synthesis method of this compound is to use 2-fluoro-3-bromoaniline as the raw material and obtain the final product through 10 steps. This method has a long process, low overall yield, low product purity, and is difficult to purify. Therefore, it is of great significance to develop a high-yield synthesis method for 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione to meet industrial production requirements. Summary of the Invention
[0004] The present invention provides a method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione, which solves the problems of long synthesis route and low yield of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione in the related art.
[0005] The technical solutions of the present invention are as follows: The present invention provides a method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione, comprising the following steps: S1. Using 2-fluoro-4-trifluoromethylbenzoic acid as a raw material, Br2 is added in the presence of a lithium reagent and diisopropylamine to obtain compound A after reaction; S2. Add tert-butyl alcohol, triethylamine, and diphenylphosphoryl azide to the compound A, and heat the mixture to obtain compound B; S3, adding compound B to acetonitrile, and then adding N-iodosuccinimide to react to obtain compound C; S4. Compound C is added to dimethylformamide, and CuCN is added, and the mixture is heated under nitrogen to obtain compound D; S5. Compound D is reacted with urea to obtain 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.
[0006] As a further technical solution, in step S1, the molar ratio of 2-fluoro-4-trifluoromethylbenzoic acid, diisopropylamine, Br2, and lithium reagent is 1:2.4~2.8:2.5~2.9:2.2~2.7, preferably 1:2.6:2.7:2.2~2.7; and / or, The reaction temperature is -75 to -80°C, preferably -75°C; and the reaction time is 2 hours.
[0007] As a further technical solution, the lithium reagent is butyllithium.
[0008] As a further technical solution, in step S2, the mass volume ratio of compound A, triethylamine, DPPA, and tert-butanol is 70g:30-34g:80-81g:400-600mL, preferably 70g:32g:80.5g:500mL; and / or, The reaction temperature is 80-85° C., preferably 80° C., and the reaction time is 4-5 h, preferably 4 h.
[0009] As a further technical solution, in step S3, the mass volume ratio of the compound B, NIS, and acetonitrile is 87g:75-80g:550-650mL, preferably 87g:77g:600mL; and / or, The reaction temperature is 75-85° C., preferably 75° C., and the reaction time is 1-2 hours, preferably 1 hour.
[0010] As a further technical solution, in step S4, the mass volume ratio of the compound C, CuCN, and dimethylformamide is 110g:22-21g:200-250mL, preferably 110g:22.12g:220mL; and / or, The reaction temperature is 100-110° C., preferably 100° C., and the reaction time is 10-12 h, preferably 12 h.
[0011] As a further technical solution, in step S5, the mass ratio of compound D to urea is 7:9-11, preferably 7:10; and / or, The reaction temperature is 200-210° C., and the reaction time is 1.5-2 h.
[0012] As a further technical solution, the reaction condition is nitrogen.
[0013] As a further technical solution, in step S1, after the reaction, the reaction is quenched, the pH is adjusted to 2-3, extracted, filtered, and concentrated to obtain compound A.
[0014] As a further technical solution, in step S1, the quenching solvent is a saturated ammonium chloride aqueous solution.
[0015] As a further technical solution, in step S1, the pH adjusting reagent is a 36 wt% HCl aqueous solution.
[0016] As a further technical solution, in step S1, after the reaction, the reaction is quenched, the pH is adjusted to 2-3, extracted, and separated, and the organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound A.
[0017] As a further technical solution, the reagent used for the extraction is ethyl acetate.
[0018] As a further technical solution, in step S2, after the reaction, the reaction system is poured into ice water with stirring, filtered, and washed to obtain compound B.
[0019] As a further technical solution, the washing solvent is dichloromethane, and the washing is performed twice.
[0020] As a further technical solution, in step S3, after the reaction, compound C is obtained by quenching, extraction and concentration.
[0021] As a further technical solution, the quenching solvent is a saturated sodium bisulfite aqueous solution.
[0022] As a further technical solution, the extraction solvent is ethyl acetate.
[0023] As a further technical solution, in step S4, after the reaction, the reaction system is added into ice water for mixing, and the mixture is filtered, pulped, washed, and concentrated to obtain compound D.
[0024] As a further technical solution, the solvent for the pulping is ethyl acetate; and the number of times of the pulping is 3 times.
[0025] As a further technical solution, the washing is first washing with ammonia water and then washing with saturated sodium chloride.
[0026] As a further technical solution, in step S4, after the reaction, the reaction system is added into ice water and mixed, and the mixture is filtered, pulped, washed, concentrated, and rinsed to obtain compound D.
[0027] As a further technical solution, the eluting solvent is petroleum ether; and the eluting is performed twice.
[0028] As a further technical solution, in step S5, after the reaction, the reaction system is added into ice water and mixed, and 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione is obtained by filtration and washing.
[0029] As a further technical solution, the washing is first performed with water and then with methanol.
[0030] As a further technical solution, the temperature of water in the water washing is 0~5°C.
[0031] As a further technical solution, the water washing is performed twice, and the methanol washing is performed once.
[0032] The working principle and beneficial effects of the present invention are: In the present invention, 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione is synthesized using 2-fluoro-4-trifluoromethylbenzoic acid, a relatively common and readily available organic compound, as the starting material. This synthesis method has a short route and significantly reduces the generation of wastewater and exhaust gas. The intermediate products generated during the synthesis process have good stability, making them easy to separate and purify. The products of each reaction step can be fed into the next reaction at a high purity, avoiding the impact of impurities on subsequent reactions and further improving the purity and yield of the final product. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.
[0034] Figure 1 This is the reaction scheme for step 1 in Example 1; Figure 2 This is the reaction scheme for step 2 in Example 2; Figure 3 This is the reaction scheme for step 3 in Example 3; Figure 4 This is the reaction scheme for step 4 in Example 4; Figure 5 This is the reaction scheme for step 5 in Example 5; Figure 6 This is the structural NMR spectrum of the product in Example 5. DETAILED DESCRIPTION
[0035] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.
[0036] The abbreviations of the following reaction reagents are as follows: THF: tetrahydrofuran; DPPA: diphenylphosphoryl azide; NIS: N-iodosuccinimide; DMF: dimethylformamide; Urea: urea.
[0037] Example 1 A method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione comprises the following steps: S1. Under nitrogen protection, 400 mL of THF and 63.1 g of diisopropylamine were added to the reaction flask, and the temperature was cooled to -50 ° C with stirring. 240 mL of 2.5 M butyl lithium was added dropwise (the addition rate was 20 mL / min), and the temperature was continued to cool to -75 ° C. Then, a mixed solution of 50 g of 2-fluoro-4-trifluoromethylbenzoic acid and 150 mL of THF was added dropwise (the addition rate was 10 mL / min) to the reaction flask, and the mixture was stirred at -75 ° C for 2 h. Then, 105 g of Br2 was added dropwise (the addition rate was 10 mL / min). After stirring at -75 ° C for 2 h, 100 mL of saturated ammonium chloride aqueous solution was added to the reaction system for quenching. After returning to 0 ° C, the pH was adjusted to 2 with 36 wt% HCl aqueous solution, and ethyl acetate was added for extraction. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 68 g of compound A with a yield of 98%.
[0038] Comparative Examples 1 to 4 Based on Example 1, the only difference is that butyl lithium is replaced by HMDSLi or TMPMgCl·LiCl complex and the reaction temperature is adjusted. The yield of compound A, the results and the differences from Example 1 are shown in Table 1.
[0039] Table 1 Reaction results of comparative examples 1 to 4
[0040] Example 2 S2. Add 68 g of compound A prepared in Example 1 to 500 mL of tert-butanol, add 32 g of triethylamine and 80.5 g of DPPA, heat to 80°C, keep the temperature for reaction for 4 hours, then cool to room temperature. Pour the reaction system into 1 L of ice water and stir for 1 hour. Filter with suction, and rinse the solid with dichloromethane twice × 100 mL to obtain 87 g of compound B.
[0041] Example 3 S3. 87 g of compound B prepared in Example 2 was dissolved in 600 mL of acetonitrile, 77 g of NIS was added, and the temperature was raised to 75°C. After the reaction was kept at this temperature for 1 h, the heat was turned off and the temperature was lowered to room temperature. The reaction system was poured into 400 mL of cold water, and a saturated aqueous sodium bisulfite solution was added until the color faded. The aqueous phase was extracted with ethyl acetate 3 times × 200 mL. The liquids were separated, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and the solid was concentrated to obtain 110 g of compound C with a yield of 93.5%.
[0042] Comparative Examples 5-10 Based on Example 3, the only difference is that acetonitrile is replaced with dichloromethane or DMF, and the reaction temperature and time are adjusted to obtain the yield of compound C. The results and the differences from Example 3 are shown in Table 2.
[0043] Table 2 Reaction results of comparative examples 5 to 8
[0044] Example 4 S4. Under nitrogen protection, 110 g of compound C prepared in Example 3 was added to 220 mL of DMF, and 22.12 g of CuCN was added. After replacing with nitrogen three times, the mixture was heated to 100 ° C., reacted for 12 h, and then cooled to room temperature. The reaction system was slowly poured into 400 mL of ice water, stirred for 1 h, and filtered. The crude solid was slurried with ethyl acetate 3 times × 100 mL. The combined organic phases were washed with ammonia water once × 50 mL, washed with saturated sodium chloride once × 50 mL, and dried over anhydrous magnesium sulfate. The solid was concentrated and rinsed with petroleum ether twice × 10 mL to obtain 63 g of compound D with a yield of 72%.
[0045] Comparative Examples 11-15 Based on Example 4, the only difference is that the reaction temperature, reaction time or solvent are adjusted to obtain Compound D. The reaction results and the differences from Example 4 are shown in Table 3.
[0046] Table 3 Reaction results of Comparative Examples 9 to 12
[0047] Example 5 S5. Add 63g of compound D and 90g of Urea to the reactor, stir and heat to 200℃, react for 1.5h, then cool to room temperature. Slowly pour the reaction system into 300mL of ice water, stir for 1h, and filter. Rinse the solid with 0℃ water twice × 20mL and methanol once × 20mL to obtain 40.8g of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The product purity was 99.5% by HPLC, and the total yield was 51.92%. The structural NMR spectrum of the product is shown as follows: Figure 6 shown.
[0048] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. A method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione, characterized in that: The following steps are involved: S1. Using 2-fluoro-4-trifluoromethylbenzoic acid as a raw material, Br2 is added in the presence of a lithium reagent and diisopropylamine to obtain compound A after reaction; S2. Add tert-butyl alcohol, triethylamine, and diphenylphosphoryl azide to the compound A to obtain compound B after reaction; S3, adding compound B to acetonitrile, and then adding N-iodosuccinimide to react to obtain compound C; S4. Compound C is added to dimethylformamide, and CuCN is added, and the reaction is carried out under nitrogen to obtain compound D; S5. reacting compound D with urea to obtain 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione; The structural formula of the compound A is as follows: ； The structural formula of the compound B is as follows: ； The structural formula of the compound C is as follows: ； The structural formula of the compound D is as follows: 。 2. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S1, the molar ratio of 2-fluoro-4-trifluoromethylbenzoic acid, diisopropylamine, Br2, and lithium reagent is 1:2.4-2.8:2.5-2.9:2.2-2.7; and / or, The reaction temperature is -75~-80°C, and the reaction time is 2h.
3. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S2, the mass volume ratio of compound A, triethylamine, DPPA, and tert-butanol is 70g:30-34g:80-81g:400-600mL; and / or, The temperature of the heating reaction is 80-85° C., and the heating reaction time is 4-5 hours.
4. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S3, the mass volume ratio of the compound B, N-iodosuccinimide, and acetonitrile is 87 g:75-80 g:550-650 mL; and / or, The temperature of the heating reaction is 75-85° C., and the heating reaction time is 1-2 hours.
5. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S4, the mass volume ratio of compound C, CuCN, and dimethylformamide is 110 g:22-21 g:200-250 mL; and / or, The temperature of the heating reaction is 100-110° C., and the time of the heating reaction is 10-12 hours.
6. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S5, the mass ratio of compound D to urea is 7:9-11; and / or, The reaction temperature is 200-210° C., and the reaction time is 1.5-2 h.
7. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S1, after the reaction, the reaction is quenched, the pH is adjusted to 2-3, extracted, filtered, and concentrated to obtain compound A.
8. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S3, after the reaction, the product is quenched, extracted, and concentrated to obtain compound C.
9. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, wherein: In step S4, after the reaction, the reaction system is added into ice water and mixed, and the mixture is filtered, pulped, washed, and concentrated to obtain compound D.
10. The method for synthesizing 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione according to claim 1, characterized in that: In step S5, after the reaction, the reaction system is added into ice water and mixed, and filtered and washed to obtain 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.