A process for the preparation of 5-trifluoromethyluracil

Abstract

This invention provides a method for preparing 5-trifluoromethyluracil, relating to the field of pharmaceutical intermediate synthesis technology. Using triethyl orthoformate, urea, and dimethyl malonate as raw materials, the method yields the target product 5-trifluoromethyluracil through condensation, saponification, cyclization, and fluorination, exhibiting high atom economy. By promptly removing ethanol during the condensation reaction, this invention significantly reduces the amount of the impurity 2-aminomethylene-propionate dimethyl ester, thereby improving the yield of the target product. By controlling the saponification reaction temperature below 40°C, this invention avoids the generation of decarboxylation impurities (uracil) at reflux temperatures, further improving the yield of the target product. The preparation method provided by this invention offers high product yield, high purity, readily available raw materials, low cost, and a simple process, making it suitable for industrial production. Furthermore, the preparation method provided by this invention does not generate large amounts of HCl and hydrofluoric acid aqueous solutions, does not corrode equipment, and produces minimal waste, making it environmentally friendly.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing 5-trifluoromethyluracil. Background Technology

[0002] Trifluthyridine is a broad-spectrum antiviral drug that inhibits herpes simplex virus, herpes zoster virus, and other viruses, as well as HSV-I, HSV-II, CMV, varicella-zoster virus, and certain adenoviruses. 5-Trifluoromethyluracil (TFU) is a key intermediate in the synthesis of the anticancer drug trifluthyridine.

[0003] Chinese patent CN106892873A discloses a method for preparing 5-trifluoromethyluracil. Using 5-methyluracil as raw material, the product is obtained by sequentially undergoing chlorination, photochlorination, fluorination hydrolysis, and recrystallization. In the example, the amount of 5-methyluracil raw material used is 75 kg, and the amount of 5-trifluoromethyluracil obtained is 16.2-29.3 kg, with a total yield of only 14.8-26.8%. The total yield of 5-trifluoromethyluracil is low. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a method for preparing 5-trifluoromethyluracil. The preparation method provided by the present invention has a high overall yield of 5-trifluoromethyluracil.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for preparing 5-trifluoromethyluracil, comprising the following steps:

[0007] Triethyl orthoformate, urea, and dimethyl malonate were mixed and subjected to a condensation reaction to obtain a mixed product, which was a mixture of compound 4 and compound 5; ethanol was removed during the condensation reaction.

[0008] The mixture, strong alkali, and water are mixed and subjected to a saponification reaction, followed by a cyclization reaction under acidic conditions to obtain compound 8; the temperature of the saponification reaction is ≤40℃.

[0009] The compound 8, anhydrous hydrogen fluoride and sulfur tetrafluoride were mixed and subjected to a fluorination reaction to obtain 5-trifluoromethyluracil.

[0010]

[0011] Preferably, the molar ratio of dimethyl malonate to urea is 1:1 to 10.

[0012] Preferably, the molar ratio of dimethyl malonate to triethyl orthoformate is 1:1 to 20.

[0013] Preferably, the temperature of the condensation reaction is 95–125°C.

[0014] Preferably, the strong base includes alkali metal hydroxides and / or alkali metal alkoxides;

[0015] The mass ratio of the mixed product to the strong base is 1:0.8 to 10.

[0016] Preferably, the saponification reaction is carried out at a temperature of 35–40°C for 1–24 hours.

[0017] Preferably, the cyclization reaction occurs at a pH of 3 to 4 and a temperature of 20 to 25°C.

[0018] Preferably, the molar ratio of compound 8 to anhydrous hydrogen fluoride is 1:1 to 50; and the temperature of the system is ≤-20℃ when the anhydrous hydrogen fluoride is added.

[0019] Preferably, the molar ratio of compound 8 to sulfur tetrafluoride is 1:1 to 10;

[0020] The temperature of the system is ≤-40℃ when sulfur tetrafluoride is added.

[0021] Preferably, the fluorination reaction is carried out at a temperature of 25–120°C for 4–48 hours and at a pressure of 1–4 MPa.

[0022] This invention uses triethyl orthoformate, urea, and dimethyl malonate as raw materials, and obtains the target product 5-trifluoromethyluracil through condensation, saponification, cyclization, and fluorination, achieving high atom economy. In this invention, timely removal of ethanol during the condensation reaction significantly reduces the amount of the impurity 2-aminomethylene-propionate dimethyl ester, thereby improving the yield of the target product. By controlling the saponification reaction temperature below 40°C, this invention avoids the generation of decarboxylation impurities (uracil) at reflux temperatures, further improving the yield of the target product. As shown in the test results of the examples, the overall yield of 5-trifluoromethyluracil provided by this invention is as high as 54.4%. The preparation method provided by this invention has high product yield, high purity, readily available raw materials, low cost, and simple process, making it suitable for industrial production. Moreover, the preparation method provided by this invention does not generate large amounts of HCl and hydrofluoric acid aqueous solutions, does not corrode equipment, and produces less waste, making it environmentally friendly. Attached Figure Description

[0023] Figure 1 This is a flowchart illustrating the preparation route of 5-trifluoromethyluracil;

[0024] Figure 2 The hydrogen spectrum of a mixture of compounds 4 and 5;

[0025] Figure 3 The hydrogen spectrum of compound 8;

[0026] Figure 4 This is the proton NMR spectrum of 5-trifluoromethyluracil. Detailed Implementation

[0027] This invention provides a method for preparing 5-trifluoromethyluracil, comprising the following steps:

[0028] Triethyl orthoformate, urea, and dimethyl malonate were mixed and subjected to a condensation reaction to obtain a mixed product, which was a mixture of compound 4 and compound 5; ethanol was removed during the condensation reaction.

[0029] The mixture, strong alkali, and water are mixed and subjected to a saponification reaction, followed by a cyclization reaction under acidic conditions to obtain compound 8; the temperature of the saponification reaction is ≤40℃.

[0030] The compound 8, anhydrous hydrogen fluoride and sulfur tetrafluoride were mixed and subjected to a fluorination reaction to obtain 5-trifluoromethyluracil.

[0031]

[0032] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0033] In this invention, the preparation route of 5-trifluoromethyluracil (using KOH as an example of a strong base) is as follows: Figure 1 As shown.

[0034] In this invention, triethyl orthoformate, urea, and dimethyl malonate are mixed and subjected to a condensation reaction to obtain a mixed product, wherein the mixed product is a mixture of compound 4 and compound 5; ethanol is removed during the condensation reaction.

[0035] In this invention, the molar ratio of dimethyl malonate to urea is preferably 1:1 to 10, more preferably 1:1.1 to 1.5.

[0036] In this invention, the molar ratio of dimethyl malonate to triethyl orthoformate is preferably 1:1 to 20, more preferably 1:1 to 5, and even more preferably 1:1.1 to 1.5.

[0037] In this invention, the mixing is preferably agitated, and the mixing temperature is preferably room temperature. This invention does not have any special limitations on the stirring speed and time, as long as the raw materials are mixed evenly.

[0038] In this invention, the temperature of the condensation reaction is preferably 95–125°C, more preferably 115–125°C, and even more preferably 120°C. This invention does not specifically limit the time of the condensation reaction, provided that the remaining amount of dimethyl malonate is <1 wt%. The remaining amount of dimethyl malonate is preferably determined by HPLC detection. This invention does not specifically limit the conditions for HPLC detection; any method well-known to those skilled in the art for detecting dimethyl malonate content can be used. In this invention, the removal of ethanol preferably includes distillation.

[0039] After the condensation reaction is completed, the present invention preferably further includes cooling the obtained condensation reaction solution to 80-90°C (more preferably 85°C), adding water for slurrying, cooling to 0-5°C for crystallization, separating the solid and liquid, washing the obtained solid product with water, and drying to obtain a mixed product. In the present invention, the solid-liquid ratio of dimethyl malonate to slurrying water is preferably 1g:1-50mL, more preferably 1g:1-10mL, and even more preferably 1g:1-5mL; the slurrying is preferably carried out under stirring conditions, and the slurrying time is preferably 1-24h, more preferably 1-2h; the present invention controls the temperature of the system at 80-90°C when water is added, so that a slurry-like substance is formed after water is added, avoiding solid agglomeration, which increases the difficulty of post-processing and reduces the yield of the target product. In the present invention, the crystallization time is preferably 1-10h, more preferably 1-2h; the crystallization is preferably carried out under stirring conditions. This invention does not specifically limit the solid-liquid separation; any solid-liquid separation method well-known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In this invention, the water washing is preferably water rinsing. In this invention, the drying temperature is preferably 90±5℃, more preferably 90℃. This invention does not specifically limit the drying time; drying to constant weight is sufficient. The drying preferably includes forced-air drying.

[0040] After obtaining the mixed product, the present invention mixes the mixed product, a strong alkali and water, performs a saponification reaction, and then performs a cyclization reaction under acidic conditions to obtain compound 8; the temperature of the saponification reaction is ≤40℃.

[0041] In this invention, the strong base preferably comprises an alkali metal hydroxide and / or an alkali metal alkoxide; the alkali metal hydroxide preferably comprises potassium hydroxide and / or sodium hydroxide; the alkali metal alkoxide preferably comprises potassium alkoxide and / or sodium alkoxide; and the alcohol in the alkali metal alkoxide preferably comprises methanol or ethanol. In this invention, the mass ratio of the mixed product to the strong base is preferably 1:0.8 to 10, more preferably 1:1 to 1.5.

[0042] In this invention, the solid-liquid ratio of the mixed product to water is preferably 1g:5-300mL, more preferably 1g:10-15mL.

[0043] In this invention, the mixing is preferably agitated, and the mixing temperature is preferably room temperature. This invention does not have any special limitations on the stirring speed and time, as long as the raw materials are mixed evenly.

[0044] In this invention, the temperature of the saponification reaction is preferably 35–40°C, more preferably 36–39°C, and even more preferably 37–38°C; the time of the saponification reaction is preferably 1–24 h, more preferably 5–24 h, and even more preferably 15–24 h. In this invention, taking potassium hydroxide as the strong alkali as an example, the saponification reaction yields a mixture of compound 6 and compound 7.

[0045] In this invention, the pH value (acidic condition) of the cyclization reaction is preferably 3-4, more preferably 3-3.5; the acid used in the acidic condition preferably includes one or more of hydrochloric acid, acetic acid, sulfuric acid, and formic acid, and the acid is preferably used in the form of an aqueous acid solution. This invention does not have a particular limitation on the concentration of the aqueous acid solution, as long as it can adjust the pH value to 3-4; specifically, 25-30 wt%, more preferably 25-28 wt%; the temperature of the cyclization reaction is preferably 20-25°C, more preferably 23-25°C. In this invention, the cyclization reaction is preferably carried out by cooling the saponification reaction solution obtained from the saponification reaction to 20-25°C, adding acid dropwise until the pH value is 3-4, and then stopping the addition of acid. In this invention, the cooling is preferably carried out under ice-water bath conditions. This invention does not have a particular limitation on the dropping rate of the acid, as long as it is added dropwise at a uniform rate.

[0046] After the cyclization reaction is completed, the present invention preferably further includes solid-liquid separation of the obtained cyclization reaction solution, washing the obtained solid product with water and drying it to obtain compound 8. The present invention does not have a particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In the present invention, the water washing is preferably water rinsing, and the water washing is preferably performed until the pH value of the resulting washing solution is 4-5, more preferably 4.5. In the present invention, the drying temperature is preferably ≤85℃, more preferably 70-85℃; the drying pressure is preferably -0.05 to -0.1 MPa, more preferably -0.09 MPa; the present invention does not have a particular limitation on the drying time, drying to constant weight is sufficient; the drying preferably includes forced-air drying.

[0047] After obtaining compound 8, the present invention mixes compound 8, anhydrous hydrogen fluoride and sulfur tetrafluoride, and carries out a fluorination reaction to obtain 5-trifluoromethyluracil.

[0048] In this invention, the molar ratio of compound 8 to anhydrous hydrogen fluoride is preferably 1:1 to 50, more preferably 1:5 to 50, and even more preferably 1:10 to 25.

[0049] In this invention, the molar ratio of compound 8 to sulfur tetrafluoride is preferably 1:1 to 10, more preferably 1:1.5 to 5, and even more preferably 1:2 to 3.

[0050] In this invention, the mixing is preferably performed by adding compound 8, cooling to ≤-20°C, adding anhydrous hydrogen fluoride, and then cooling to ≤-40°C before introducing sulfur tetrafluoride. In this invention, the system temperature during the introduction of sulfur tetrafluoride is more preferably -80 to -40°C, and even more preferably -80 to -45°C. In this invention, the system temperature during the addition of anhydrous hydrogen fluoride is more preferably -40 to -20°C.

[0051] In this invention, the temperature of the fluorination reaction is preferably 25–120°C, more preferably 50–100°C, and even more preferably 70–85°C; the time of the fluorination reaction is preferably 4–48 h, more preferably 4–48 h, even more preferably 5–30 h, and even more preferably 10–15 h; the pressure of the fluorination reaction is preferably 1–4 MPa, more preferably 2–2.5 MPa. The reactions occurring during the fluorination reaction in this invention are as follows:

[0052]

[0053] After the fluorination reaction is completed, the present invention preferably further includes cooling the obtained fluorination reaction solution to room temperature, releasing the pressure to normal pressure when the pressure of the fluorination reaction is greater than atmospheric pressure, purging with nitrogen, and then adding it to cold water to precipitate the solid. Solid-liquid separation is performed, and the obtained solid product is dried and recrystallized to obtain 5-trifluoromethyluracil (compound 9). In the present invention, the temperature of the cold water is preferably 0–15°C, more preferably 0–5°C. In a specific embodiment of the present invention, the cold water is preferably ice water. The function of the cold water is to dilute the hydrogen fluoride and precipitate the product. The present invention does not have a special limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as pressure filtration, vacuum filtration, or centrifugation. In the present invention, the drying temperature is preferably ≤85°C, more preferably 70–85°C; the present invention does not have a special limitation on the drying time; drying to constant weight is sufficient. In the present invention, the solvent for recrystallization is preferably an aqueous alcohol solution, and the volume fraction of alcohol in the aqueous alcohol solution is preferably 80–100%, more preferably 95%, and the alcohol preferably includes ethanol and / or methanol.

[0054] This invention uses triethyl orthoformate, urea, and dimethyl malonate as raw materials, and obtains the target product 5-trifluoromethyluracil through condensation, saponification, cyclization, and fluorination, achieving high atom economy. In this invention, timely removal of ethanol during the condensation reaction significantly reduces the amount of the impurity 2-aminomethylene-propionate dimethyl ester, thereby improving the yield of the target product. By controlling the saponification reaction temperature below 40°C, this invention avoids the generation of decarboxylation impurities (uracil) at reflux temperatures, further improving the yield of the target product. As shown in the test results of the examples, the overall yield of 5-trifluoromethyluracil provided by this invention is as high as 54.4%. The preparation method provided by this invention has high product yield, high purity, readily available raw materials, low cost, and simple process, making it suitable for industrial production. Moreover, the preparation method provided by this invention does not generate large amounts of HCl and hydrofluoric acid aqueous solutions, does not corrode equipment, and produces less waste, making it environmentally friendly.

[0055] Dimethyl 2-aminomethylene-propionic acid ester.

[0056] To further illustrate the present invention, the preparation method of 5-trifluoromethyluracil is described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0057] Example 1

[0058] (1) At room temperature, dimethyl malonate, triethyl orthoformate, and urea were added sequentially and stirred until homogeneous. The temperature was raised to 115°C, and the condensation reaction was carried out under stirring. Ethanol was collected by distillation. After no more ethanol flowed out, a sample was taken. HPLC analysis showed that the remaining amount of dimethyl malonate was <1 wt%. The temperature was lowered to 80°C, water was added, and the temperature was lowered to 0°C. The mixture was stirred for 1 h, filtered, and the resulting filter cake was washed with 300 mL of water and dried at 95°C for 24 h to obtain a mixture of compound 4 and compound 5 (when the amount of dimethyl malonate was 300 g, 348 g of mixed product was obtained, and the yield of compound 4 was approximately 76%). The mass ratio of dimethyl malonate, triethyl orthoformate, and urea was 300:403.8:166.7, the solid-liquid ratio of dimethyl malonate to water for stirring was 1 g:3 mL, and the solid-liquid ratio of dimethyl malonate to water for washing was 1 g:1 mL.

[0059] Figure 2 The hydrogen spectrum is for a mixture of compounds 4 and 5.

[0060] (2) At 25°C, a mixture of water, sodium hydroxide, and compounds 4 and 5 was added to the reactor and stirred for 1 hour. The temperature was then raised to 35–40°C and maintained for saponification for 24 hours. HPLC analysis showed that the remaining amount of compound 4 was <1 wt%. When the temperature was lowered to 25°C, concentrated hydrochloric acid (30 wt%) was added dropwise to adjust the pH to 4. The temperature was then lowered to 0°C, filtered, and the resulting filter cake was washed with water until the pH of the washing solution was 4. The resulting solid was dried at 85°C to obtain compound 8 (yield 93%, HPLC purity >99%). The mass ratio of the mixture of compounds 4 and 5, sodium hydroxide, and water used in the saponification reaction was 252.5:249.7:2626.

[0061] Figure 3 This is the hydrogen spectrum of compound 8.

[0062] (3) In a stainless steel autoclave, compound 8 was added, the temperature was lowered to 10°C, hydrogen fluoride was added, then the temperature was lowered to -40°C, sulfur tetrafluoride was added, the temperature was raised to 85°C, and the fluorination reaction was maintained at 2.0 MPa for 12 h. The temperature was then lowered to 25°C, and the pressure was released to atmospheric pressure. The material in the autoclave was pressed into ice water to precipitate the solid, filtered, and the obtained solid product was dried at 85°C to constant weight to obtain crude 5-trifluoromethyluracil. It was recrystallized with 95 v / v% ethanol aqueous solution, filtered, and the obtained solid product was dried at 85°C to constant weight to obtain 5-trifluoromethyluracil (yield 77%, HPLC purity > 99%). The molar ratio of compound 8, hydrogen fluoride, and sulfur tetrafluoride was 1:25:2. The molar ratio of compound 8 to ice water volume was 1 mol: 100 mL, and the molar ratio of compound 8 to ethanol aqueous solution volume was 1 mol: 20 mL.

[0063] Figure 4 This is the proton NMR spectrum of 5-trifluoromethyluracil.

[0064] Example 2

[0065] A mixture of compounds 4 and 5 was prepared according to the method of Example 1, the only difference being that in step (1), the condensation reaction temperature was 95°C and the total yield of compounds 4 and 5 was 65%.

[0066] Comparative Example 1

[0067] Compound 4 was prepared according to the method of Example 2, the only difference from Example 1 being that: after water rinsing, methanol rinsing was also performed (compound 5 was removed during methanol rinsing), to obtain compound 4 with a yield of 55%. The solid-liquid ratio of dimethyl malonate to methanol was 1 g:1 mL.

[0068] By comparing Example 2 and Comparative Example 1, it can be seen that the post-processing of the preparation method provided by the present invention after the condensation reaction does not require methanol washing. This is because the compound 5 generated in the condensation reaction stage can still be converted into an intermediate of the target product during the saponification process. Methanol has good solubility for compound 5. Therefore, removing methanol by washing with methanol will lead to a decrease in the total yield of 5-trifluoromethyluracil.

[0069] Comparative Example 2

[0070] 5-Trifluoromethyluracil was prepared according to the method of Example 1. The only difference from Example 1 is that in step (2), the saponification reaction temperature was 80°C, and the dried product was found to contain a large amount of uracil by HPLC, with only 1.2 wt% of compound 8.

[0071] Example 3

[0072] 5-Trifluoromethyluracil was prepared according to the method of Example 1, the only difference from Example 1 being that in step (2), the strong base was potassium hydroxide, yielding compound 8 (yield 92%, HPLC purity > 99%). The mass ratio of the mixture of compound 4 and compound 5, potassium hydroxide, and water used in the saponification reaction was 252.5:350.2:2626.

[0073] Example 4

[0074] 5-Trifluoromethyluracil was prepared according to the method of Example 1, the only difference from Example 1 being that in step (3), the molar ratio of compound 8, hydrogen fluoride and sulfur tetrafluoride was 1:12.25:1.5, and 5-trifluoromethyluracil was obtained (yield 68%, HPLC purity >99%).

[0075] Example 5

[0076] 5-Trifluoromethyluracil was prepared according to the method of Example 3, the only difference from Example 1 being that in step (3), the molar ratio of compound 8, hydrogen fluoride and sulfur tetrafluoride was 1:25:1.5, and 5-trifluoromethyluracil was obtained (yield 68%, HPLC purity > 99%).

[0077] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 5-trifluoromethyluracil, characterized in that, Includes the following steps: Triethyl orthoformate, urea and dimethyl malonate were mixed and subjected to a condensation reaction. The resulting condensation reaction solution was cooled to 80-90°C, water was added and the mixture was stirred. After cooling to 0-5°C, crystals were precipitated. The solid and liquid were separated, and the resulting solid product was washed with water and dried to obtain the mixed product. Ethanol is removed during the condensation reaction; The mixture, strong alkali, and water are mixed and subjected to a saponification reaction, followed by a cyclization reaction under acidic conditions to obtain compound 8; the temperature of the saponification reaction is ≤40℃. The compound 8, anhydrous hydrogen fluoride and sulfur tetrafluoride were mixed and subjected to a fluorination reaction to obtain 5-trifluoromethyluracil. 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of dimethyl malonate to urea is 1:1 to 10.

3. The preparation method according to claim 1, characterized in that, The molar ratio of dimethyl malonate to triethyl orthoformate is 1:1 to 20.

4. The preparation method according to claim 1, 2 or 3, characterized in that, The condensation reaction is carried out at a temperature of 95~125℃.

5. The preparation method according to claim 1, characterized in that, The strong base is an alkali metal hydroxide and / or an alkali metal alkoxide; The mass ratio of the mixed product to the strong base is 1:0.8~10.

6. The preparation method according to claim 1 or 5, characterized in that, The saponification reaction is carried out at a temperature of 35-40°C for 1-24 hours.

7. The preparation method according to claim 1, characterized in that, The cyclization reaction is carried out at a pH of 3-4 and a temperature of 20-25°C.

8. The preparation method according to claim 1, characterized in that, The molar ratio of compound 8 to anhydrous hydrogen fluoride is 1:1 to 50; the temperature of the system is ≤-20℃ when the anhydrous hydrogen fluoride is added.

9. The preparation method according to claim 1, characterized in that, The molar ratio of compound 8 to sulfur tetrafluoride is 1:1~10; The temperature of the system is ≤-40℃ when sulfur tetrafluoride is added.

10. The preparation method according to claim 1, 8, or 9, characterized in that, The fluorination reaction is carried out at a temperature of 25~120℃, for a time of 4~48h, and at a pressure of 1~4MPa.

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