Doravirine intermediate, and use thereof and synthesis method therefor

Abstract

The present invention relates to a doravirine intermediate, and the use thereof and a synthesis method therefor, which belong to the technical field of pharmaceutical chemistry. The method for synthesizing the doravirine intermediate comprises the following steps: (1) mixing ethyl 2-fluoroacetate with 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with solvent I, and then dropwise adding sodium bis(trimethylsilyl)amide to form compound 1; (2) adding an ammonia source into the reaction liquid of compound 1 to obtain compound 2; (3) dissolving compound 2 in solvent II, adding a catalyst, and heating and ring-closing the mixture to obtain compound 3; and (4) dissolving compound 3 in toluene, adding thionyl chloride, and dropwise adding pyridine to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. The synthesis method of the present invention has a low raw material cost and a short process period, is environmentally friendly, and is suitable for process scaled-up production.

Description

Doravirine intermediate and its application and synthesis method Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a doravirine intermediate and an application and synthesis method thereof. 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 is disclosed in the document Org. Lett. 2015, 17, 1353-1356. The specific synthetic 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 doravirine intermediate, its application, and synthesis method. The present invention uses ethyl 2-fluoroacetate and 4-ethoxy-1,1,1-trifluoro-3-butene-2-one as raw materials, and performs addition, aminolysis, cyclization, and dehydroxylation steps to ultimately obtain the doravirine intermediate 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. This method has low raw material costs, a short process cycle, is environmentally friendly, and is suitable for scaled-up production.

[0012] In the first aspect, the present invention provides a doravirine intermediate having the structure .

[0013] In a second aspect, the present invention provides a method for synthesizing a doravirine intermediate, and the synthetic route is as follows:

[0014]

[0015] Compound 2 is dissolved in solvent 2, a catalyst is added, and the mixture is heated to undergo cyclization to obtain compound 3.

[0016] Furthermore, the second solvent is dioxane.

[0017] Furthermore, the catalyst is hydrochloric acid.

[0018] Furthermore, based on compound 2, the feeding amount of dioxane is 5-8 mL / g, the feeding molar ratio of hydrochloric acid is 0.025-0.050 mol / mol, and the concentration of hydrochloric acid is 2-3 mol / mL.

[0019] In a third aspect, the present invention provides an application of a doravirine intermediate in the preparation of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. 2-Hydroxy-3-fluoro-4-trifluoromethylpyridine is an important intermediate in the synthesis of doravirine and can be used to prepare doravirine.

[0020] In a fourth aspect, the present invention also provides a method for synthesizing a doravirine intermediate, and the synthetic route is as follows:

[0021]

[0022] The following steps are involved:

[0023] (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 dropwise to form compound 1;

[0024] (2) adding an ammonia source to the reaction solution of compound 1 to obtain compound 2;

[0025] (3) Compound 2 is dissolved in solvent 2, a catalyst is added, and the mixture is heated to close the ring to obtain compound 3;

[0026] (4) Compound 3 was dissolved in toluene, thionyl chloride was added, and pyridine was added dropwise to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

[0027] Furthermore, in step (1), the first solvent is an aprotic solvent, preferably at least one selected from tetrahydrofuran or toluene.

[0028] Furthermore, in step (1), the reaction temperature is -50~-25°C.

[0029] Furthermore, in step (1), based on ethyl 2-fluoroacetate, the amount of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one added is 1.0-1.3 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.

[0030] Furthermore, in step (2), the reaction temperature is 35-40°C.

[0031] Furthermore, in step (2), the ammonia source is selected from ammonia gas or ammonia methanol solution, and the concentration of the ammonia methanol solution is preferably 20% to 25%.

[0032] Furthermore, in step (2), the feeding amount of ammonia is 3.5-4.5 mol / mol based on ethyl 2-fluoroacetate.

[0033] Furthermore, after the reaction in step (2) is completed, the reaction solution is concentrated to remove the remaining ammonia and most of the methanol, and then ethyl acetate and purified water are added, stirred and separated to remove the salt generated in the reaction system. The organic phase is washed with acid water and then dried and concentrated to obtain a crude product of compound 2.

[0034] Furthermore, in step (2), the acid water is a citric acid aqueous solution.

[0035] Furthermore, isopropyl ether is added to the crude compound 2 obtained in step (2) for slurrying to obtain pure compound 2.

[0036] Furthermore, in step (2), based on ethyl 2-fluoroacetate, the feeding amount of ethyl acetate is 5-8 mL / g, the feeding amount of acid water is 5-8 mL / g, the acid water is 10% citric acid solution, and the feeding amount of isopropyl ether is 2-5 mL / g.

[0037] Furthermore, in step (3), the reaction temperature is 80-95°C.

[0038] Furthermore, in step (3), the second solvent is dioxane.

[0039] Furthermore, in step (3), the catalyst is hydrochloric acid.

[0040] Furthermore, in step (3), based on compound 2, the feeding amount of dioxane is 5-8 mL / g, the feeding molar ratio of hydrochloric acid is 0.025-0.050 mol / mol, and the concentration of hydrochloric acid is 2-3 mol / mL.

[0041] Furthermore, in step (4), the reaction temperature is 55-65°C.

[0042] Furthermore, in step (4), based on compound 2, the feeding amount of toluene is 5-10 mL / g, the feeding amount of thionyl chloride is 5-8 mol / mol, and the feeding amount of pyridine is 3-5 mol / mol.

[0043] Furthermore, in step (4), after the pyridine reaction is completed, the reaction solution is concentrated under reduced pressure, ethyl acetate and water are added to separate the mixture, the organic phase is washed with water, the aqueous phases are combined, extracted with ethyl acetate, the organic phases are combined and concentrated, and methyl tert-butyl ether is added to slurry to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

[0044] Furthermore, in step (4), the amount of methyl tert-butyl ether added is 2-5 mL / g based on compound 2.

[0045] Furthermore, step (4) further includes drying the 2-hydroxy-3-fluoro-4-trifluoromethylpyridine, and the drying method can be vacuum drying or forced air drying.

[0046] Furthermore, the drying method of step (4) is vacuum drying, the vacuum drying temperature is 40~50°C, the vacuum degree is -0.08~-0.10MPa, and the vacuum drying time is 8~20 hours. Beneficial effects

[0047] The beneficial effects of the present invention are:

[0048] The present invention provides a synthetic route for 2-hydroxy-3-fluoro-4-trifluoromethylpyridine, an intermediate of doravirine, with low raw material cost, short process cycle, green environmental protection, and suitable for process scale-up production. The reaction solution of compound 1 obtained by the synthetic method of the present invention can be directly subjected to the next reaction. The reaction solution of compound 2 and compound 3 is simply treated and concentrated to obtain a crude product, which can be directly subjected to the next reaction without special purification. Compound 1 exists in the form of a sodium salt in the reaction system and has no effect on the next conversion. In the synthesis process of compound 2, an excess of ammonia source is used, so the reaction solution of compound 2 is subjected to atmospheric distillation to remove the remaining ammonia and most of the methanol. Ethyl acetate and purified water are added, stirred and separated, and the generated salts in the reaction system are removed. After the organic phase is concentrated, isopropyl ether is added for pulping to obtain a pure compound 2. There is no difference between the reaction solution of compound 3 before and after purification after reaction with thionyl chloride and pyridine.

[0049] The present invention uses ethyl 2-fluoroacetate as a raw material, replacing ethyl bromofluoroacetate in the prior art, thereby improving atom utilization, reducing costs, and reducing halogen pollution. Furthermore, the present invention is simple to operate, has few side reactions, a short production cycle, alleviates environmental pressure, facilitates solvent recovery, significantly reduces production costs, eliminates excessive post-processing losses of intermediates, and obtains a high yield and high purity product, making it particularly suitable for industrial production and having significance for drug quality control and clinical efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] 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.

[0051] FIG1 is a HPLC chromatogram of compound 3 prepared in Example 4.

[0052] FIG2 is the HNMR spectrum of compound 3 prepared in Example 4.

[0053] FIG3 is the MS spectrum of compound 3 prepared in Example 4.

[0054] FIG4 is an HPLC chromatogram of compound 4 prepared in Example 4.

[0055] FIG5 is the HNMR spectrum of compound 4 prepared in Example 4. DETAILED DESCRIPTION

[0056] 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

[0057] A method for synthesizing a doravirine intermediate is as follows:

[0058] (1) In a 250 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 -35 °C with dry ice, and add 20.6 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (122.5 mmol, 1.3 eq). After the temperature in the reaction flask drops to -35 °C~-25 °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. The addition rate is controlled according to the temperature of the reaction solution. The addition time is about 1 h. After the addition is completed, keep warm and stir for 30 min. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is <1.0%, and the reaction is complete.

[0059] (2) The reaction solution was heated to 0-5°C and 28.8 g (424.2 mmol, 4.5 eq) of the prepared 25% ammonia methanol solution was slowly poured in. The color of the reaction solution darkened and the internal temperature remained essentially unchanged or decreased. After heating to 35-40°C, the reaction was stirred overnight. HPLC monitoring showed that the concentration of compound 1 was <1.0%, indicating the reaction was terminated. The remaining ammonia was removed by atmospheric distillation. The evaporated ammonia was absorbed and reused with methanol. 50 g of ethyl acetate and 50 g of purified water were added and stirred for 30 min. The mixture was allowed to stand for separation. The organic phase was washed once with 50 g of 10% citric acid solution. The organic phase was dried and concentrated to obtain a crude compound 2. 30 g of isopropyl ether was added and the mixture was beaten to obtain 15.5 g of pure compound 2 with a yield of 67.1%.

[0060] (3) In a 250 ml reaction flask, add 15.5 g (63.22 mmol, 1.0 eq) of compound 2 from the previous step, add 80 g of 1,4-dioxane, add 1.6 mL (3.2 mmol, 0.05 eq) of 2 mol / L hydrochloric acid, and stir at 90 °C overnight. Sample HPLC analysis showed that compound 2 was less than 1.0%, and the reaction was terminated. The reaction solvent and water were removed by vacuum distillation to obtain crude compound 3. (4) In a 250 ml reaction flask, add crude compound 3 from the previous step (63.22 mmol, 1.0 eq), add 77 g of toluene, and add 60.2 g (505.8 mmol, 8.0 eq) of thionyl chloride, and stir at room temperature. Add 25 g (316.1 mmol, 5.0 eq) of pyridine, the reaction was exothermic, and the temperature was controlled at 55-65 °C and stirred for 1 h. Sample HPLC analysis showed that compound 3 was less than 1.0%, and the reaction was terminated. The remaining thionyl chloride was evaporated under reduced pressure, water and ethyl acetate were added, and the mixture was allowed to stand for separation. The organic phase was washed twice with water, the combined aqueous phases were extracted twice with ethyl acetate, and the combined organic phases were dried and concentrated to obtain a crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. 24 mL of methyl tert-butyl ether was added to the mixture for pulping and then filtered. The mixture was vacuum dried at 50°C and -0.08 MPa for 16 h to obtain 7.1 g of an off-white solid, i.e., compound 4. The total yield of the four steps was 41.5%, and the purity of the product was 99.472% as determined by HPLC. The specific test results are shown in Table 1.

[0061] Table 1 HPLC test results of compound 4

[0062] Example 2

[0063] A method for synthesizing a doravirine intermediate is as follows:

[0064] (1) In a 1000ml reaction flask, add 100g of toluene and 50g of ethyl 2-fluoroacetate (471.3mmol, 1.0eq). After N2 replacement, cool to below -35℃ with dry ice, add 87.1g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (518.4mmol, 1.1eq). After the temperature in the reaction flask drops to -25℃~-35℃, measure 259.2ml of 2mol / L NaHMDS tetrahydrofuran solution (518.4mmol, 1.1eq) and add it dropwise to the reaction flask. The addition process is exothermic. The addition speed is controlled according to the temperature of the reaction solution. The addition time is about 1h. After the addition is completed, stir and keep warm for 30min. Samples are taken for HPLC detection. The raw material ethyl 2-fluoroacetate is <1.0%, and the reaction is complete.

[0065] (2) The reaction solution was heated to 0-5°C and 146 g (1.89 mol, 4.0 eq) of the prepared 22% ammonia methanol solution was slowly poured in. The color of the reaction solution darkened and the internal temperature remained essentially unchanged or decreased. After heating to 35-40°C, the reaction was stirred overnight. HPLC monitoring showed that the concentration of compound 1 was <1.0%, indicating the reaction was terminated. The remaining ammonia was removed by atmospheric distillation. The evaporated ammonia was absorbed and reused with methanol. 250 g of ethyl acetate and 250 g of purified water were added and stirred for 30 min. The mixture was allowed to stand for separation. The organic phase was washed once with 250 g of acid water (10% citric acid solution). The organic phase was dried and concentrated to obtain a crude compound 2. 150 g of isopropyl ether was added and the mixture was slurried to obtain 83 g of pure compound 2 with a yield of 71.8%.

[0066] (3) In a 1000 ml reaction flask, add 83 g (338.5 mmol, 1.0 eq) of compound 2 from the previous step, 400 g of 1,4-dioxane, and 6.8 mL (13.6 mmol, 0.04 eq) of 2 mol / L hydrochloric acid. Stir overnight at 90°C. HPLC analysis showed that the concentration of compound 2 was <1.0%, indicating the reaction was terminated. The reaction solvent and water were removed by distillation under reduced pressure to obtain crude compound 3.

[0067] (4) In a 1000 ml reaction flask, add the crude compound 3 (338.5 mmol, 1.0 eq), 400 g of toluene, and 241.6 g of thionyl chloride (2.03 mol, 6.0 eq) and stir at room temperature. Add 107.1 g of pyridine (1.35 mmol, 4.0 eq). The reaction is exothermic and the temperature is maintained at 55–65°C. Stir for 1 h. Samples are taken by HPLC. The concentration of compound 3 is <1.0%, indicating the reaction is terminated. The remaining thionyl chloride was evaporated under reduced pressure, water and ethyl acetate were added, and the mixture was allowed to stand for separation. The organic phase was washed twice with water, the combined aqueous phases were extracted twice with ethyl acetate, and the combined organic phases were dried and concentrated to obtain a crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. 120 mL of methyl tert-butyl ether was added, the mixture was slurried, and then filtered. The mixture was vacuum dried at 50° C. and −0.08 MPa for 16 h to obtain 37.7 g of an off-white solid. The total yield of the four steps was 44.2%. The purity of the product was 99.869% as determined by HPLC. The specific test results are shown in Table 2.

[0068] Table 2 HPLC test results of compound 4

[0069] Example 3

[0070] A method for synthesizing a doravirine intermediate is as follows:

[0071] (1) In a 5L reaction flask, add 400g of toluene and 200g of ethyl 2-fluoroacetate (1.89mol, 1.0eq). After N2 replacement, cool to below -35℃ with dry ice, add 316.9g of raw material 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (1.89mmol, 1.0eq). After the temperature in the reaction flask drops to -25℃~-35℃, measure 990ml of 2mol / L NaHMDS tetrahydrofuran solution (1.98mol, 1.05eq) and add it dropwise to the reaction flask. The addition process is exothermic. The addition speed is controlled according to the temperature of the reaction solution. The addition time is about 2h. 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.

[0072] (2) The reaction solution was heated to 0-5°C and 468.2 g (6.6 mol, 3.5 eq) of the prepared 24% ammonia methanol solution was slowly poured in. The color of the reaction solution darkened and the internal temperature remained essentially unchanged or decreased. After heating to 35-40°C, the reaction was stirred overnight. HPLC monitoring showed that the concentration of compound 1 was <1.0%, indicating the reaction was terminated. The remaining ammonia was removed by atmospheric distillation. The evaporated ammonia was absorbed and reused with methanol. 1000 g of ethyl acetate and 1000 g of purified water were added and stirred for 30 min. The mixture was allowed to stand for separation. The organic phase was washed once with 1000 g of acid water (10% citric acid solution). The organic phase was dried and concentrated to obtain a crude compound 2. 600 g of isopropyl ether was added to the mixture and the pure compound 2 was obtained by slurrying with 327 g of the pure compound 2, with a yield of 70.7%.

[0073] (3) In a 3 L reaction flask, add 327 g (1.33 mol, 1.0 eq) of compound 2 from the previous step, 1500 g of 1,4-dioxane, and 20 mL (40 mmol, 0.03 eq) of 2 mol / L hydrochloric acid. Stir overnight at 90°C. HPLC analysis showed that the concentration of compound 2 was <1.0%, indicating the reaction was terminated. The reaction solvent and water were removed by distillation under reduced pressure to obtain crude compound 3.

[0074] (4) In a 3L reaction flask, add the crude product of compound 3 (1.33 mol, 1.0 eq), 1500 g of toluene, and 791 g of thionyl chloride (5.34 mol, 5.0 eq) and stir at room temperature. Add 316.5 g of pyridine (4 mol, 3.0 eq), the reaction is exothermic, and the temperature is controlled at 55-65 °C and stirred for 1 h. Sample HPLC analysis shows that compound 3 is <1.0%, and the reaction is terminated. The remaining thionyl chloride is evaporated under reduced pressure, water and ethyl acetate are added, and the mixture is allowed to stand for separation. The organic phase is washed twice with water, the combined aqueous phases are extracted twice with ethyl acetate, and the combined organic phases are dried and concentrated to obtain crude 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. 480 mL of methyl tert-butyl ether is added to the mixture, and the mixture is slurried and filtered. The mixture is vacuum dried at 50 °C and -0.08 MPa for 16 h to obtain 149 g of an off-white solid. The total yield of the four steps is 43.7%. The purity of the product is 99.908% as determined by HPLC. The specific test results are shown in Table 3.

[0075] Table 3 HPLC test results of compound 4

[0076] Example 4

[0077] A method for synthesizing a doravirine intermediate is as follows:

[0078] (1) In a 20L reaction flask, add 1290g of toluene and 742g of ethyl 2-fluoroacetate (6.99mol, 1.0eq). After N2 replacement, cool to below -30℃ with dry ice, add 1290g of raw material 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (7.69mol, 1.1eq). After the temperature in the reaction flask drops to -35℃~-25℃, measure 3.68L of 2mol / L NaHMDS tetrahydrofuran solution (7.35mol, 1.05eq) and add it dropwise to the reaction flask. The addition process is exothermic. The addition rate is controlled according to the temperature of the reaction solution. The addition time is about 7h. 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.

[0079] (2) The reaction solution was heated to 0-5°C and 1670 g (24.5 mol, 3.5 eq) of the prepared 25% ammonia methanol solution was slowly poured in. The color of the reaction solution darkened and the internal temperature remained essentially unchanged or decreased. After heating to 35-40°C, the reaction was stirred overnight. HPLC monitoring showed that the concentration of compound 1 was <1.0%, indicating the reaction was terminated. The remaining ammonia was removed by atmospheric distillation. The evaporated ammonia was absorbed and reused with methanol. 3710 g of ethyl acetate and 3710 g of purified water were added and stirred for 30 min. The mixture was allowed to stand for separation. The organic phase was washed once with 3710 g of acid water (10% citric acid solution). The organic phase was dried and concentrated to obtain a crude compound 2. 2220 g of isopropyl ether was added for slurrying to obtain 1312 g of pure compound 2 with a yield of 76.5%.

[0080] (3) In a 10 L reaction flask, add 1312 g (5.35 mol, 1.0 eq) of compound 2 from the previous step, 6500 g of 1,4-dioxane, and 80 mL (160 mmol, 0.03 eq) of 2 mol / L hydrochloric acid solution, and stir at 90°C overnight. HPLC analysis showed that the concentration of compound 2 was <1.0%, indicating that the reaction was terminated. The reaction solvent and water were removed by distillation under reduced pressure to obtain crude compound 3. Compound 3 was tested. The HPLC test spectrum is shown in Figure 1. The results are shown in Table 4:

[0081] Table 4 HPLC test results of compound 3

[0082]

[0083] The HNMR and MS spectra are shown in Figures 2 and 3 .

[0084] (4) In a 10L reaction flask, add the crude product of compound 3 (5.35mol, 1.0eq), 5700g of toluene, and 3185g of thionyl chloride (26.9mol, 5.0eq) and stir at room temperature. Add 1270g of pyridine (16.1mol, 3.0eq), the reaction is exothermic, and the temperature is controlled at 55-65℃ and stirred for 1h. Sample HPLC analysis shows that compound 3 is less than 1.0%, and the reaction is terminated. The remaining thionyl chloride is evaporated under reduced pressure, water and ethyl acetate are added, and the mixture is allowed to stand for separation. The organic phase is washed twice with water, the combined aqueous phases are extracted twice with ethyl acetate, and the combined organic phases are dried and concentrated to obtain the crude product of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine. Add 2000mL of methyl tert-butyl ether, beat the mixture, filter, and vacuum dry at 50℃ and -0.08MPa for 16h to obtain 741g of off-white solid. The total yield of the four steps is 58.5%, and the purity of the product is 99.94% as determined by HPLC. The product was tested, and the HPLC test spectrum is shown in Figure 4, and the results are shown in Table 5:

[0085] Table 5 HPLC detection data of compound 4

[0086]

[0087] The HNMR spectrum is shown in Figure 5.

[0088] 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. Doravirine intermediates, 。 2. A method for synthesizing the doravirine intermediate according to claim 1, characterized in that: The synthetic route is as follows: ； Compound 2 is dissolved in solvent 2, a catalyst is added, and the mixture is heated to obtain compound 3 for cyclization.

3. Use of the doravirine intermediate as claimed in claim 1 in the preparation of 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

4. 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 dropwise to form compound 1; (2) adding an ammonia source to the reaction solution of compound 1 to obtain compound 2; (3) Compound 2 is dissolved in solvent 2, a catalyst is added, and the mixture is heated to obtain compound 3; (4) Compound 3 is dissolved in toluene, thionyl chloride is added, and pyridine is added dropwise to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

5. The method for synthesizing a doravirine intermediate according to claim 4, wherein: After the reaction in step (2) is completed, the reaction solution is concentrated, and then ethyl acetate and purified water are added to stir and separate the liquids. The organic phase is washed with acid water and then dried and concentrated to obtain a crude product of compound 2.

6. The method for synthesizing a doravirine intermediate according to claim 5, wherein: Isopropyl ether was added to the crude compound 2 obtained in step (2) for slurrying to obtain a pure compound 2.

7. The method for synthesizing a doravirine intermediate according to claim 6, wherein: In step (4), after the pyridine reaction is completed, the reaction solution is concentrated under reduced pressure, ethyl acetate and water are added to separate the organic phase, the organic phase is washed with water, the aqueous phases are combined, extracted with ethyl acetate, the organic phases are combined and concentrated, and methyl tert-butyl ether is added to slurry to obtain 2-hydroxy-3-fluoro-4-trifluoromethylpyridine.

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