Method for synthesizing doravirine intermediate

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and to a method for synthesizing a doravirine intermediate. The synthesis method of the present invention comprises: (1) mixing ethyl 2-fluoroacetate with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one in a first solvent and adding sodium bis(trimethylsilyl)amide for a reaction to generate compound 1; (2) adding triethylamine and trifluoroacetic anhydride to a reaction solution of compound 1 for a reaction to generate compound 2; (3) adding an ammonia source to a reaction solution of compound 2 to obtain compound 3 and compound 4; and (4) adding a second solvent and heating the resulting mixture for cyclization to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. The present invention has low raw material cost and is a synthesis method, which has a short process cycle, is environmentally friendly, and is suitable for scale-up process production.

Description

A method for synthesizing a doravirine intermediate Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a method for synthesizing a doravirine intermediate. Background Art

[0002] Doravirine (Pifeltro), like efavirenz and rilpivirine, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretroviral drugs for adults with HIV-1 infection who have no prior antiretroviral treatment history. Doravirine has a low clearance rate, with an elimination half-life of 15 hours. Its effects on lipids and body weight are superior to similar drugs, and its tolerability is relatively low. When used in combination with methadone, no dose adjustment is required. This new option in the same class is available for those intolerant to efavirenz and nevirapine.

[0003] 2-Hydroxy-3-fluoro-4-trifluoromethylpyridine (CAS: 1227594-89-9) is an important intermediate in the synthesis of doravirine. Its structure is as follows:

[0004] .

[0005] After searching, the method for synthesizing this intermediate was disclosed in the document Org. Lett. 2015, 17, 1353-1356. The specific synthesis route is as follows:

[0006]

[0007] It uses ethyl bromofluoroacetate as the starting material, reacts with 4-ethoxy-1,1,1-trifluoro-3-butene-2-one via a zinc reagent to obtain compound 5, which is then reacted with ammonia methanol and treated with phosphoric acid to obtain compound 6, namely 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. Technical issues

[0008] The existing method for synthesizing 2-hydroxy-3-fluoro-4-trifluoromethylpyridine has the following defects:

[0009] 1. All existing processes use ethyl bromofluoroacetate as the starting material, but this raw material is expensive and not readily available;

[0010] 2. The existing process does not have a clear operating method and requires special equipment such as tubular reactors and special operations such as double-drop addition. We used normal laboratory equipment to verify the process and were unable to obtain the product. Without special equipment, we could not obtain the product through this process in the laboratory. Without special production equipment, we could not scale up production. Summary of the Invention

[0011] To address the problems of expensive raw materials and low overall yield in existing 2-hydroxy-3-fluoro-4-trifluoromethylpyridine synthesis methods, the present invention provides a method for synthesizing a doravirine intermediate. This method uses ethyl 2-fluoroacetate and 4-ethoxy-1,1,1-trifluoro-3-butene-2-one as raw materials, and undergoes addition, dehydroxylation, aminolysis, and cyclization to ultimately obtain the doravirine intermediate 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. This method offers low raw material costs, a short process cycle, and is environmentally friendly and suitable for scale-up production.

[0012] A method for synthesizing a doravirine intermediate, the synthetic route is as follows:

[0013]

[0014] The following steps are involved:

[0015] (1) Ethyl 2-fluoroacetate and 4-ethoxy-1,1,1-trifluoro-3-butene-2-one were mixed with solvent 1, and sodium bis(trimethylsilyl)amide was added to react to form compound 1;

[0016] (2) adding triethylamine and trifluoroacetic anhydride to the reaction solution of compound 1 to react and generate compound 2;

[0017] (3) adding an ammonia source to the reaction solution of compound 2 to obtain compound 3 and compound 4;

[0018] (4) Add solvent and heat the mixture to close the ring to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

[0019] Furthermore, in step (1), the first solvent is an aprotic solvent, preferably at least one selected from toluene or tetrahydrofuran.

[0020] Furthermore, in step (1), the reaction temperature is -50~-25°C.

[0021] Furthermore, in step (1), based on ethyl 2-fluoroacetate, the amount of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one added is 1.0-1.5 mol / mol, the amount of sodium bis(trimethylsilyl)amide added is 1.05-1.1 mol / mol, and the amount of toluene added is 2-5 mL / g.

[0022] Furthermore, in step (2), the reaction temperature of compound 1 with triethylamine and trifluoroacetic anhydride is -40°C to -30°C.

[0023] Furthermore, in step (2), the amount of triethylamine added is 3.0-4.0 mol / mol, and the amount of trifluoroacetic anhydride added is 2.0-3.0 mol / mol, calculated as ethyl 2-fluoroacetate. When the amount of triethylamine added is less than 3.0 mol / mol and the amount of trifluoroacetic anhydride added is less than 2.0 mol / mol, the reaction of compound 1 is incomplete.

[0024] Furthermore, in step (2), after the reaction is completed, ethyl acetate is added to the reaction system, and then washed with water, acid water and alkaline water in sequence; the organic phase is concentrated to obtain compound 2.

[0025] Furthermore, the acidic water is a citric acid solution, and the alkaline aqueous solution is a sodium bicarbonate solution.

[0026] Furthermore, in step (2), the feeding amount of ethyl acetate is 5-10 mL / g, calculated as ethyl 2-fluoroacetate.

[0027] Furthermore, in step (3), the amount of methanol added is 2-5 mL / g based on ethyl 2-fluoroacetate.

[0028] Furthermore, in step (3), the amount of ammonia fed is 3.5-4.5 mol / mol, calculated as ethyl 2-fluoroacetate, and the reaction temperature is 25-35°C. Compound 2 has cis-trans isomers. The cis configuration can react to obtain compound 4, and the trans configuration can react to obtain compound 3. The trans configuration of compound 2 basically does not react at low temperatures (when the temperature is below 10°C), which will affect the final product yield. Therefore, the reaction temperature is controlled at 25-35°C to ensure that compound 2 is smoothly converted into compound 3 and compound 4.

[0029] Furthermore, in step (3), the ammonia source is selected from ammonia gas or ammonia methanol solution.

[0030] Furthermore, in step (3), the concentration of the ammonia methanol solution is 20% to 25%.

[0031] Furthermore, in step (4), the second solvent is selected from dimethyl sulfoxide or N-methylpyrrolidone.

[0032] Furthermore, in step (4), the reaction temperature is 120-180°C.

[0033] Furthermore, in step (4), the amount of N-methylpyrrolidone added is 5-10 mL / g based on the amount of ethyl 2-fluoroacetate added.

[0034] Furthermore, step (4) further comprises: after the cyclization reaction is completed, evaporating the solvent, then adding water, and performing solid-liquid separation to obtain a crude product; the obtained crude product is slurried with ethyl acetate or methyl tert-butyl ether, and vacuum dried to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

[0035] Furthermore, the vacuum drying temperature is 40-50° C., the vacuum degree is -0.08-0.1 MPa, and the vacuum drying time is 8-20 hours. Advantageous Effects of the Invention

[0036] The beneficial effects of the present invention are:

[0037] The present invention uses a low-cost, short-cycle, environmentally friendly, and scale-up-friendly route to synthesize 2-hydroxy-3-fluoro-4-trifluoromethylpyridine, a doravirine intermediate. The reaction solution of compound 1 obtained by the synthesis method of the present invention can be directly subjected to the next reaction. The reaction solutions of compounds 2 and 3 are simply treated and concentrated to obtain a crude product that can be directly subjected to the next reaction without requiring special purification. Compound 1 exists in the reaction system as a sodium salt and does not affect the next conversion, so the reaction solution of compound 1 can be directly subjected to the next reaction. Excess triethylamine and trifluoroacetic anhydride are used in the reaction to produce compound 2, so the reaction solution of compound 2 is washed with purified water, acidic water, and alkaline water. The reaction solution of compound 3 reacts with NMP at 150°C in the absence of purification, both before and after purification.

[0038] The invention has the advantages of low raw material cost, simple operation, few side reactions, short production cycle, reduced environmental pressure, convenient solvent recovery, greatly saving production cost, no excessive post-processing loss of intermediates, high yield and high purity of the obtained product, being particularly suitable for industrial production, and having significance for drug quality control and clinical efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0040] FIG1 is an HPLC spectrum of the product prepared in Example 5.

[0041] FIG2 is the HNMR spectrum of the product prepared in Example 5.

[0042] FIG3 is the MS spectrum of the product prepared in Example 5. DETAILED DESCRIPTION

[0043] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments 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 creative efforts should fall within the scope of protection of the present invention. Example 1

[0044] A method for synthesizing a doravirine intermediate is as follows:

[0045] (1) In a 500 mL reaction flask, add 20 g of tetrahydrofuran and 10 g of ethyl 2-fluoroacetate (94.25 mmol, 1.0 eq). After N2 replacement, cool to below -50 °C with dry ice, add 23.77 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (141.38 mmol, 1.5 eq). After the temperature in the reaction flask drops to -45 °C~-55 °C, measure 51.8 ml of 2 mol / L NaHMDS tetrahydrofuran solution (103.6 mmol, 1.1 eq) and add it dropwise to the reaction flask. The addition process is exothermic, and the addition rate is adjusted according to the temperature change of the reaction system. The addition time is about 1 h. After the addition is completed, stir and keep warm for 30 min. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is less than 1.0%, and the reaction is complete.

[0046] (2) Weigh 38.15 g (377 mmol, 4 eq) of triethylamine and add it to the reaction flask. Weigh 59.40 g (282.75 mmol, 3 eq) of trifluoroacetic anhydride and add it dropwise to the reaction flask. Control the temperature at -45°C to -55°C. The addition rate should be adjusted according to the temperature change of the reaction system. The addition time should be about 1 hour. After the addition is complete, control the temperature and stir for 20 minutes. Remove the ice bath and naturally warm to room temperature (20°C). Weigh 16 g of methanol and add it dropwise to the reaction flask. Control the temperature at 0°C to 10°C. The initial addition process is exothermic. The addition rate should be adjusted according to the temperature change of the reaction system. The addition time should be about 15 minutes to quench the reaction. After the addition is complete, add 50 g of ethyl acetate and 50 g of purified water, stir for 20 minutes, and then stand for separation. The organic phase is washed with 50 g of 10% citric acid aqueous solution and 8% sodium bicarbonate aqueous solution respectively. The organic phase is concentrated to obtain the crude compound 2 for later use.

[0047] (3) In a 250 mL reaction flask, add the crude compound 2 from the previous step, 16 g of methanol, and 25.64 g (377 mmol, 4 eq) of a 25% ammonia solution in methanol. Stir overnight at 25-30°C. HPLC analysis of the sample indicates that the concentration of compound 2 is <1.0%, indicating the reaction is terminated. Remove the remaining ammonia by atmospheric distillation. The evaporated ammonia can be absorbed with methanol to obtain crude compounds 3 and 4.

[0048] (4) In a 100 mL reaction flask, the crude products of compounds 3 and 4 from the previous step were added, along with 30 g of NMP. The temperature was raised to 180°C and stirred for 12 h. Samples were taken by HPLC, and the concentration of compound 3 was <1.0%, indicating the reaction was terminated. Most of the NMP was removed by evaporation under reduced pressure, maintaining the fluidity of the reaction system. A large amount of water was added and stirred for 1 h. The crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine was obtained by filtration. The product was slurried with ethyl acetate and filtered. The product was vacuum dried at 45°C and -0.08 MPa for 16 h to obtain 7.4 g of an off-white solid. The total yield of the four steps was 43.3%. The purity of the product was 99.837% as determined by HPLC. The specific test results are shown in Table 1.

[0049] Table 1 HPLC test results of products

[0050] Example 2

[0051] A method for synthesizing a doravirine intermediate is as follows:

[0052] (1) In a 3000 ml reaction flask, add 120 g of toluene and 60 g of ethyl 2-fluoroacetate (562.5 mmol, 1.0 eq). After N2 replacement, cool to below -40 °C with dry ice, and add 123.6 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (735.2 mmol, 1.3 eq). After the temperature in the reaction flask drops to -35 °C~-40 °C, measure 311 ml of 2 mol / L NaHMDS tetrahydrofuran solution (622.1 mmol, 1.1 eq) and add it dropwise to the reaction flask. The addition process is exothermic, and the addition rate is subject to temperature changes. The addition time is about 2 h. After the addition is completed, stir and keep warm for 30 min. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is less than 1.0%, and the reaction is complete.

[0053] (2) Weigh 227.7 g (2.25 mol, 4.0 eq) of triethylamine and add it to the reaction flask. Weigh 354.4 g (1.68 mol, 3.0 eq) of trifluoroacetic anhydride and add it dropwise to the reaction flask. Control the temperature at -35°C to -40°C. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 2 h. After the addition is complete, control the temperature and stir for 20 min. Remove the ice bath and naturally warm to room temperature (20°C). Weigh 100 g of methanol and add it dropwise to the reaction flask. Control the temperature at 0-10°C. The initial addition process is exothermic. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 30 min to quench the reaction. After the addition is complete, add 300 g of ethyl acetate and 300 g of purified water. Stir for 20 min and then stand for separation. Wash the organic phase with 300 g of 10% citric acid aqueous solution and 8% sodium bicarbonate aqueous solution respectively. Concentrate the organic phase to obtain the crude compound 2 for later use.

[0054] (3) In a 1000 mL reaction flask, add the crude compound 2 from the previous step, 100 g of methanol, and 166.3 g (2.25 mol, 4.0 eq) of a 23% ammonia solution in methanol. Stir overnight at 30-35°C. HPLC analysis of the sample indicates that the concentration of compound 2 is <1.0%, indicating the reaction is terminated. Remove the remaining ammonia by atmospheric distillation. The evaporated ammonia can be absorbed in methanol to obtain crude compounds 3 and 4.

[0055] (4) In a 500 mL reaction flask, the crude products of compounds 3 and 4 from the previous step were added, along with 180 g of NMP. The temperature was raised to 160°C and stirred for 12 h. Samples were taken by HPLC, and the concentration of compound 3 was <1.0%, indicating the reaction was terminated. Most of the NMP was removed by evaporation under reduced pressure, maintaining the fluidity of the reaction system. A large amount of water was added and stirred for 1 h. The crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine was obtained by filtration. The product was slurried with ethyl acetate and filtered. The product was vacuum dried at 45°C and -0.08 MPa for 16 h to obtain 52.2 g of an off-white solid. The total yield of the four steps was 51.0%. The purity of the product was 99.170% as determined by HPLC. The specific test results are shown in Table 2.

[0056] Table 2 HPLC test results of products

[0057] Example 3

[0058] A method for synthesizing a doravirine intermediate is as follows:

[0059] (1) In a 10L reaction flask, add 400g of toluene and 200g of ethyl 2-fluoroacetate (1.89mol, 1.0eq). After N2 replacement, cool to below -30~-35℃ with dry ice. Add 316.9g (1.89mol, 1.0eq) of raw material 4-ethoxy-1,1,1-trifluoro-3-butene-2-one. After the temperature in the reaction flask drops to -30℃~-35℃, measure 1000ml (1.98mol, 1.05eq) of 2mol / L NaHMDS tetrahydrofuran solution and add it dropwise to the reaction flask. The addition process is exothermic and the addition rate is subject to temperature changes. The addition time is about 3h. After the addition is completed, keep warm and stir for 30min. Sample HPLC detection shows that the raw material ethyl 2-fluoroacetate is less than 1.0%, and the reaction is complete.

[0060] (2) Weigh 669.4 g (6.62 mol, 3.5 eq) of triethylamine and add it to the reaction flask. Weigh 992.4 g (4.73 mol, 2.5 eq) of trifluoroacetic anhydride and add it dropwise to the reaction flask. Control the temperature at -30°C to -35°C. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 2 h. After the addition is complete, control the temperature and stir for 20 min. Remove the ice bath and naturally warm to room temperature (20°C). Weigh 320 g of methanol and add it dropwise to the reaction flask. Control the temperature at 0-10°C. The initial addition process is exothermic. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 40 min to quench the reaction. After the addition is complete, add 1000 g of ethyl acetate and 1000 g of purified water. Stir for 30 min and then stand for separation. Wash the organic phase with 1000 g of 10% citric acid aqueous solution and 8% sodium bicarbonate aqueous solution respectively. Concentrate the organic phase to obtain the crude compound 2 for later use.

[0061] (3) In a 2000 ml reaction flask, add the crude compound 2 from the previous step, 320 g of methanol, and 514 g (7.56 mol, 4.0 eq) of a 25% ammonia methanol solution. Stir overnight at 25-30°C. HPLC analysis of the sample indicates that the concentration of compound 2 is <1.0%, indicating the reaction is terminated. Remove the remaining ammonia by atmospheric distillation. The evaporated ammonia can be absorbed in methanol to obtain crude compounds 3 and 4.

[0062] (4) In a 100 ml reaction flask, the crude products of compounds 3 and 4 from the previous step were added, along with 600 g of NMP. The temperature was raised to 150°C and stirred for 12 h. Samples were taken by HPLC, and the concentration of compound 3 was <1.0%, indicating the reaction was terminated. Most of the NMP was removed by evaporation under reduced pressure, maintaining the fluidity of the reaction system. A large amount of water was added and stirred for 1 h. The crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine was obtained by filtration. The product was slurried with ethyl acetate and filtered. The product was vacuum dried at 45°C and -0.008 MPa for 16 h to obtain 183 g of an off-white solid. The total yield of the four steps was 53.6%. The purity of the product was 99.910% as determined by HPLC. The specific test results are shown in Table 3.

[0063] Table 3 HPLC test results of products

[0064] Example 4

[0065] A method for synthesizing a doravirine intermediate is as follows:

[0066] (1) In a 20L reaction flask, add 1000g of toluene and 500g of ethyl 2-fluoroacetate (4.71mol, 1.0eq). After N2 replacement, cool to below -40℃ with dry ice, and add 871.5g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (5.18mol, 1.1eq). After the temperature in the reaction flask drops to -30℃~-25℃, measure 2475ml of 2mol / L NaHMDS tetrahydrofuran solution (4.95mol, 1.05eq) and add it dropwise to the reaction flask. The addition process is exothermic, and the addition rate is subject to temperature changes. The addition time is about 3h. After the addition is completed, keep warm and stir for 30min. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is <1.0%, and the reaction is complete.

[0067] (2) Weigh 1430 g (14.14 mol, 3.0 eq) of triethylamine and add it to the reaction flask. Weigh 1980 g (9.43 mol, 2.0 eq) of trifluoroacetic anhydride and add it dropwise to the reaction flask. Control the temperature between -30°C and -45°C. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 3 h. After the addition is complete, control the temperature and stir for 20 min. Remove the ice bath and naturally warm to room temperature (20°C). Weigh 800 g of methanol and add it dropwise to the reaction flask. Control the temperature between 0 and 10°C. The initial addition process is exothermic. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 15 min to quench the reaction. After the addition is complete, add 2500 g of ethyl acetate and 2500 g of purified water. Stir for 20 min and then stand for separation. Wash the organic phase with 2500 g of 10% citric acid aqueous solution and 8% sodium bicarbonate aqueous solution respectively. Concentrate the organic phase to obtain the crude compound 2 for later use.

[0068] (3) In a 5 L reaction flask, add the crude compound 2 from the previous step, 1000 g of methanol, and 1335 g (16.5 mol, 3.5 eq) of a 21% ammonia methanol solution. Stir overnight at 30-35°C. HPLC analysis of the sample indicates that the concentration of compound 2 is <1.0%, indicating the reaction is terminated. Remove the remaining ammonia by atmospheric distillation. The evaporated ammonia can be absorbed with methanol to obtain crude compounds 3 and 4.

[0069] (4) In a 5 L reaction flask, the crude products of compounds 3 and 4 from the previous step were added, along with 1500 g of NMP. The temperature was raised to 140°C and stirred for 14 h. Samples were taken by HPLC, and the concentration of compound 3 was <1.0%, indicating the reaction was terminated. Most of the NMP was removed by evaporation under reduced pressure, maintaining the fluidity of the reaction system. A large amount of water was added and stirred for 1 h. The crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine was obtained by filtration. The product was slurried with ethyl acetate and filtered. The product was vacuum dried at 45°C and -0.008 MPa for 16 h to obtain 420 g of an off-white solid. The total yield of the four steps was 49.2%. The purity of the product was 99.867% as determined by HPLC. The specific test results are shown in Table 4.

[0070] Table 4 HPLC test results of products

[0071] Example 5

[0072] A method for synthesizing a doravirine intermediate is as follows:

[0073] (1) In a 100L reactor, add 3680g of toluene and 2120g of ethyl 2-fluoroacetate (20mol, 1.0eq). After N2 replacement, cool to below -30℃ with dry ice, add 3357g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (20mol, 1.0eq). After the temperature in the reaction flask drops to -35℃~-25℃, measure 10.5L of 2mol / L NaHMDS tetrahydrofuran solution (21mol, 1.05eq) and add it dropwise to the reaction flask. The addition process is exothermic, and the addition rate is subject to temperature changes. The addition time is about 4h. After the addition is completed, keep warm and stir for 1h. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is less than 1.0%, and the reaction is complete.

[0074] (2) Weigh 6070 g (60 mol, 3.0 eq) of triethylamine and add it to the reaction flask. Weigh 8400 g (40 mol, 2.0 eq) of trifluoroacetic anhydride and add it dropwise to the reaction flask. Control the temperature at -40°C to -30°C. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 3 h. After the addition is completed, control the temperature and stir for 30 min. Remove the ice bath and naturally warm to room temperature (20°C). Weigh 3320 g of methanol and add it dropwise to the reaction flask. Control the temperature at 0°C to 10°C. The initial addition process is exothermic. Adjust the addition rate according to the temperature change of the reaction system. The addition time is about 1 h to quench the reaction. After the addition is completed, add 10.6 kg of ethyl acetate and 10.0 kg of purified water. Stir for 1 h and then stand for separation. Wash the organic phase with 10.0 kg of 10% citric acid aqueous solution and 8% sodium bicarbonate aqueous solution respectively. Concentrate the organic phase to obtain the crude compound 2 for later use.

[0075] (3) In a 20 L reaction flask, add the crude compound 2 from the previous step, 3320 g of methanol as solvent, and 4760 g (70 mol, 3.5 eq) of a 25% ammonia solution in methanol. Stir overnight at 35°C. HPLC analysis of the sample reveals a concentration of compound 2 <1.0%, indicating the reaction is terminated. Remove the remaining ammonia by atmospheric distillation. The evaporated ammonia can be absorbed with methanol to obtain crude compounds 3 and 4.

[0076] (4) In a 20 L reaction flask, the crude products of compounds 3 and 4 from the previous step were added, along with 6360 g of NMP. The temperature was raised to 150°C and stirred for 12 h. Samples were taken by HPLC, and the concentration of compound 3 was <1.0%, indicating the reaction was terminated. Most of the NMP was removed by evaporation under reduced pressure, maintaining the fluidity of the reaction system. A large amount of water was added and stirred for 1 h. The crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine was obtained by filtration. The crude product was slurried with ethyl acetate and filtered. The product was vacuum dried at 45°C and -0.008 MPa for 16 h to obtain 1991 g of an off-white solid. The total yield of the four steps was 55.0%, and the purity of the product was 99.923% as determined by HPLC. The HPLC spectrum of the product is shown in Figure 1, and the specific test results are shown in Table 5. The HNMR spectrum and MS spectrum are shown in Figures 2 and 3.

[0077] Table 5 Product HPLC test data

[0078]

[0079] Although the present invention has been described in detail with reference to the accompanying drawings and in conjunction with preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, persons of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any changes or substitutions that can be easily conceived by persons skilled in the art within the technical scope disclosed in the present invention shall be within the scope of protection of the present invention.

Claims

1. A method for synthesizing a doravirine intermediate, characterized in that: The synthetic route is as follows: ； The following steps are involved: (1) Ethyl 2-fluoroacetate and 4-ethoxy-1,1,1-trifluoro-3-butene-2-one are mixed with solvent 1, and sodium bis(trimethylsilyl)amide is added to react to generate compound 1; (2) adding triethylamine and trifluoroacetic anhydride to the reaction solution of compound 1 to react and generate compound 2; (3) adding an ammonia source to the reaction solution of compound 2 to obtain compounds 3 and 4; (4) Add a solvent and heat the mixture to carry out cyclization to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

2. The method for synthesizing a doravirine intermediate according to claim 1, wherein: In step (2), after the reaction is completed, ethyl acetate and water are added to the reaction system, and the organic phase is washed with acid water and alkaline water in sequence after standing for liquid separation, and the organic phase is concentrated to obtain compound 2.

3. The method for synthesizing a doravirine intermediate according to claim 1, wherein: Step (4) also includes evaporating the solvent after the cyclization reaction is completed, then adding water and performing solid-liquid separation to obtain a crude product.

4. The method for synthesizing a doravirine intermediate according to claim 3, wherein: The crude product obtained in step (4) is slurried with ethyl acetate or methyl tert-butyl ether and dried to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

Images