Synthesis method of compound 4-hydroxy-2-trifluoromethylpyrimidine

Abstract

The invention relates to a synthetic method of a compound 4-hydroxy-2-trifluoromethylpyrimidine, which comprises the following steps: by taking a compound ethyl trifluoroacetate and a compound 3-aminopropanamide as raw materials, firstly converting the raw materials into a compound 3-(2, 2, 2-trifluoroacetamido) propanamide, and then carrying out ring closing reaction to obtain the target compound 4-hydroxy-2-trifluoromethylpyrimidine. The synthetic route has the advantages of short steps, simple operation, low cost, mild reaction conditions, simple post-treatment and ideal yield, and is suitable for process amplification.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a compound 4-hydroxy-2-trifluoromethylpyrimidine. Background Art

[0002] Pyrimidine compounds are widely used in the fields of medicine, pesticides, cosmetics, chemicals, photosensitive materials, etc. Among them, in the field of medicine, pyrimidine compounds are mainly used to synthesize anti-tumor, anti-viral, anti-tuberculosis, anti-cancer and other drugs. Pyrimidine is the core structural unit of many anti-tumor drugs, such as fluorouracil, cyclophosphamide and methotrexate, etc. These drugs can inhibit the proliferation and division of cancer cells, thereby achieving the effect of treating tumors. Pyrimidine compounds can also be used to prepare antiviral drugs, such as zanavir and ribavirin, etc. These drugs can inhibit the synthesis of viral DNA or RNA, thereby achieving the effect of inhibiting viral replication. Pyrimidine is also the structural basis of many alkaloids, such as scutellarin, osmanthine, etc. These alkaloids have multiple biological activities, such as anti-tumor, anti-viral, analgesic, anesthesia, etc.

[0003] The compound 4-hydroxy-2-trifluoromethylpyrimidine is an important pyrazole compound and also an important molecular building block. As a key intermediate, 4-hydroxy-2-trifluoromethylpyrimidine is used in the synthesis of pyrimidine derivatives in patent WO2006 / 099231, which can be used to treat proliferative diseases; in patent CN116621778A, it is used in the synthesis of ubiquitin-specific proteasome system (USP) inhibitors; in patent CN117510503A, it is used in the synthesis of tyrosine and threonine kinase (PKMYT1) inhibitors; in patents WO2023 / 245166 and WO2022 / 261473, it is used in the synthesis of compounds that can treat coronavirus infection; in patent WO2008 / 076243, it is used in the synthesis of acyl bipiperidinyl compounds that can treat or prevent type 2 diabetes and similar diseases.

[0004] In the prior art, the synthesis of 4-hydroxy-2-trifluoromethylpyrimidine mainly uses 2-trifluoromethyl-4,6-dihydroxypyrimidine as a raw material, and requires four steps of chlorination, substitution, hydrogenation, and demethoxylation. This synthetic route has high cost of raw materials, long steps, certain risks in reaction conditions, low yield, and is not suitable for process scale-up. Summary of the invention

[0005] In view of the shortcomings of the prior art synthesis method of 4-hydroxy-2-trifluoromethylpyrimidine, the present invention provides a synthesis method of the compound 4-hydroxy-2-trifluoromethylpyrimidine. The entire synthesis process has the advantages of low cost, relatively mild reaction conditions, low safety hazards, ideal yield and suitability for process scale-up.

[0006] To achieve the above object, the present invention adopts the following technical solution:

[0007] A method for synthesizing a compound 4-hydroxy-2-trifluoromethylpyrimidine, using compound 1 (ethyl trifluoroacetate) and compound 2 (3-aminopropionamide) as raw materials, first converting them into compound 3 (3-(2,2,2-trifluoroacetamido)propionamide), and then undergoing a ring-closing reaction to obtain a target compound 4 (4-hydroxy-2-trifluoromethylpyrimidine), and the synthesis route thereof is as follows:

[0008]

[0009] Further, the synthesis method of 4-hydroxy-2-trifluoromethylpyrimidine comprises the following steps:

[0010] (1) adding raw material 1, namely ethyl trifluoroacetate, and raw material 2, namely 3-aminopropionamide, to an organic solvent I, heating the mixed solution to 60-200° C. for reaction for 10-40 hours, and after the reaction is completed, post-treating the reaction solution to obtain compound 3, namely 3-(2,2,2-trifluoroacetamido)propionamide;

[0011] (2) Compound 3 is added to an organic solvent II, and then an alkali solution is added dropwise, and the mixture is heated to 60-200° C. and reacted for 10-40 hours. After the reaction is completed, the reaction solution is post-treated to obtain the target compound 4, namely 4-hydroxy-2-trifluoromethylpyrimidine.

[0012] Furthermore, in step (1), the organic solvent I is selected from one or more of methanol, ethanol and acetonitrile.

[0013] Furthermore, in step (1), the mass volume ratio of the raw material 1 to the organic solvent I is 1:(4-40) in g / mL.

[0014] Furthermore, in step (1), the molar ratio of raw material 1 to raw material 2 is 1:(1.00-1.50).

[0015] Furthermore, in step (1), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature and concentrated under reduced pressure to obtain a crude product of compound 3, i.e., 3-(2,2,2-trifluoroacetamido)propionamide. The crude product does not need further purification and can be directly used in the next step.

[0016] Furthermore, in step (2), the base is selected from one or more of potassium tert-butoxide or sodium tert-butoxide.

[0017] Furthermore, in step (2), the organic solvent II is selected from one or more of toluene, 1,4-dioxane, and tetrahydrofuran.

[0018] Furthermore, in step (2), the mass volume ratio of the compound 3 to the organic solvent II is 1:(4-40) in g / mL.

[0019] Furthermore, in step (2), the molar ratio of compound 3 to potassium tert-butoxide is 1:(2.00-6.00).

[0020] Furthermore, in step (2), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is spin-dried, and then an organic solvent III is added to dissolve it. The resulting solution is washed, dried, and spin-dried to obtain a crude product, which is purified to obtain the target compound 4, namely 4-hydroxy-2-trifluoromethylpyrimidine.

[0021] Furthermore, in step (2), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0022] Furthermore, in step (2), the purification method is one or more selected from beating, column chromatography, recrystallization, or distillation.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The invention provides a method for preparing 4-hydroxy-2-trifluoromethylpyrimidine, wherein ethyl trifluoroacetate and 3-aminopropionamide are used as raw materials, first converted into 3-(2,2,2-trifluoroacetamido)propionamide, and then subjected to a ring-closing reaction to obtain a target compound 4-hydroxy-2-trifluoromethylpyrimidine. The synthetic route has short steps, simple operation, low cost, mild reaction conditions, simple post-treatment, ideal yield, and is suitable for process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the H NMR spectrum of compound 4 (4-hydroxy-2-trifluoromethylpyrimidine) in Example 1. DETAILED DESCRIPTION

[0026] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be described clearly and completely in conjunction with the drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of them. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs.

[0027] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0028] The following example synthesizes 4-hydroxy-2-trifluoromethylpyrimidine. Compound 1 (ethyl trifluoroacetate) and compound 2 (3-aminopropionamide) are used as raw materials, first converted into compound 3 (3-(2,2,2-trifluoroacetamido)propionamide), and then subjected to a ring-closure reaction to obtain the target compound 4 (4-hydroxy-2-trifluoromethylpyrimidine). The synthesis route is as follows:

[0029]

[0030] The technical solution of the present invention is further explained below by way of embodiments.

[0031] Example 1

[0032] In this example, the compound 4-hydroxy-2-trifluoromethylpyrimidine was synthesized by the following steps:

[0033] (1) Raw material 1, ethyl trifluoroacetate (200.00 g, 1.41 mol, 1.00 eq) and raw material 2, 3-aminopropionamide (124.03 g, 1.41 mol, 1.00 eq) were added to methanol (2.0 L), and the mixture was heated to 70° C. for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product of compound 3, 3-(2,2,2-trifluoroacetamido)propionamide (weight 251.20 g, purity 97%, yield 94%), which was used directly in the next step without further purification.

[0034] (2) Compound 3 (200.00 g, 1.09 mol, 1.00 eq) was added to toluene (2.0 L), and potassium tert-butoxide solution (1 M in THF, 4.35 kmL, 4.35 mol, 4.00 eq) was added dropwise, and the mixture was heated to 70 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was spin-dried. Ethyl acetate (1.0 L) was added to dissolve, washed once with saturated brine (1.0 L), dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was purified by beating with petroleum ether (2.0 L) to obtain the target compound 4, i.e., 4-hydroxy-2-trifluoromethylpyrimidine (light yellow powder, weight 175.30 g, purity 98%, yield 96%).

[0035] The H NMR spectrum of the obtained compound 4 (4-hydroxy-2-trifluoromethylpyrimidine) is as follows Figure 1 The obtained characterization data are as follows:

[0036] 1 H NMR (400MHz, dmso) δ13.23 (s, 1H), 8.60 (d, J = 5.8Hz, 1H), 6.97 (d, J = 5.8Hz, 1H).

[0037] Embodiments 2 to 8

[0038] Examples 2 to 8 are the same as Example 1, except that compound 1 (ethyl trifluoroacetate), compound 2 (3-aminopropionamide), organic solvent I in reaction step (1), and compound 3 (3-(2,2,2-trifluoroacetamido)propionamide), base, organic solvent II in reaction step (2) are adjusted, as shown in Table 1.

[0039] Through Examples 1 to 8, the effects of various reaction conditions on the reaction yield during the synthesis of the intermediate compound 3-(2,2,2-trifluoroacetamido)propionamide and the target compound 4-hydroxy-2-trifluoromethylpyrimidine were investigated. The results are shown in Table 1.

[0040] Table 1

[0041]

[0042]

[0043] Comparing Example 1-2, when the molar ratio of Compound 1: Compound 2 is 1.00:1.00, the reaction effect is already very good.

[0044] Comparing Examples 1 and 3-4, when the molar ratio of compound 3:base is 1.00:4.00, the reaction effect is already very good.

[0045] Comparing Examples 1 and 5, the reaction can obtain the product with a high yield using potassium tert-butoxide or sodium tert-butoxide as the base, among which potassium tert-butoxide has a better effect as the base.

[0046] Comparing Examples 1 and 6, the product can be obtained in high yield in both methanol and acetonitrile solvents, and methanol is more effective as a solvent.

[0047] Comparing Examples 1, 7-8, the product can be obtained in high yield in the solvents of tetrahydrofuran, toluene and 1,4-dioxane, among which toluene is more effective as a solvent.

[0048] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for synthesizing a compound 4-hydroxy-2-trifluoromethylpyrimidine, characterized in that: Using ethyl trifluoroacetate and 3-aminopropionamide as raw materials, they are first converted into 3-(2,2,2-trifluoroacetamido)propionamide, and then subjected to a ring-closure reaction to obtain the target compound 4-hydroxy-2-trifluoromethylpyrimidine. The synthetic route is as follows:

2. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 1, characterized in that: The synthesis method comprises the following steps: (1) adding the raw material (1), i.e., ethyl trifluoroacetate, and the raw material (2), i.e., 3-aminopropionamide, to an organic solvent (I), heating the mixed solution to 60-200° C. for reaction for 10-40 hours, and after the reaction is completed, post-treating the reaction solution to obtain compound (3), i.e., 3-(2,2,2-trifluoroacetamido)propionamide; (2) Compound (3) is added to an organic solvent (II), and then an alkaline solution is added dropwise. The mixture is heated to 60-200°C and reacted for 10-40 hours. After the reaction is completed, the reaction solution is post-treated to obtain the target compound (4), namely 4-hydroxy-2-trifluoromethylpyrimidine.

3. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (1), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature and concentrated under reduced pressure to obtain a crude product of compound (3), namely 3-(2,2,2-trifluoroacetamido)propionamide. The crude product is directly used in the next step without further purification.

4. The method for synthesizing 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (1), the organic solvent (I) is one or more of methanol, ethanol or acetonitrile.

5. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (1), the mass volume ratio of the raw material (1) to the organic solvent (I) is 1:(4-40) g / mL; In step (1), the molar ratio of the raw material (1) to the raw material (2) is 1:(1.00-1.50).

6. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (2), the base is selected from one or more of potassium tert-butoxide or sodium tert-butoxide. In step (2), the organic solvent (II) is one or more of toluene, 1,4-dioxane or tetrahydrofuran.

7. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (2), the mass volume ratio of the compound (3) to the organic solvent II is 1:(4-40) g / mL; In step (2), the molar ratio of the compound (3) to potassium tert-butoxide is 1:(2.00-6.00).

8. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (2), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is spin-dried, and then an organic solvent (III) is added to dissolve it. The resulting solution is washed, dried, and spin-dried to obtain a crude product, which is purified to obtain the target compound 4, namely 4-hydroxy-2-trifluoromethylpyrimidine.

9. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 8, characterized in that: In step (2), the organic solvent (III) is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

10. The method for synthesizing the compound 4-hydroxy-2-trifluoromethylpyrimidine according to claim 2, characterized in that: In step (2), the purification method is one or more selected from beating, column chromatography, recrystallization or distillation.

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