A method for synthesizing 2-chloro-5-ethylpyrimidine

Abstract

This invention discloses a method for synthesizing 2-chloro-5-ethylpyrimidine. The steps of the synthesis method of this invention are as follows: (1) 5-bromo-2-chloropyrimidine is dissolved in organic solvent I, and under the protection of an inert gas, a catalyst is added, the temperature is lowered to -5℃ to 5℃, ethyl magnesium bromide solution is added, and after the addition is complete, the temperature is raised to 15℃~40℃, and the reaction is stirred for 8~20h; (2) After the reaction is complete, the reaction solution is post-treated to obtain the target compound 2, namely 2-chloro-5-ethylpyrimidine. The synthesis method of this invention realizes the one-step conversion of compound 5-bromo-2-chloropyrimidine into compound 2-chloro-5-ethylpyrimidine, and the reaction conditions are relatively mild, the post-treatment and purification are simple, and the process can be scaled up; finally, compound 2-chloro-5-ethylpyrimidine is obtained with short steps, simple operation, low cost, relatively mild reaction, and high yield conditions.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 2-chloro-5-ethylpyrimidine. Background Technology

[0002] Pyrimidine compounds have wide applications in medicine, pesticides, cosmetics, chemicals, and photosensitizers. In medicine, they are primarily used to synthesize antitumor, antiviral, antituberculosis, and anticancer drugs. Pyrimidines are the core structural unit of many antitumor drugs, such as fluorouracil, cyclophosphamide, and methotrexate. These drugs can inhibit the proliferation and division of cancer cells, thus achieving therapeutic effects. Pyrimidine compounds can also be used to prepare antiviral drugs, such as zanavir and ribavirin. These drugs can inhibit viral DNA or RNA synthesis, thereby inhibiting viral replication. Pyrimidines are also the structural basis of many alkaloids, such as cinnamine and cinnamine. These alkaloids possess various biological activities, including antitumor, antiviral, analgesic, and anesthetic effects.

[0003] Compound 2-chloro-5-ethylpyrimidine is an important pyrazole compound and a crucial building block in molecular structures. It serves as a key intermediate and a building block for drug molecules. For example, in patent WO03099793, it is used in the synthesis of a 1,2-oxazole derivative with hypoglycemic and lipid-lowering activities; in patent WO2012 / 011707, it is used in the synthesis of a substituted pyridone derivative that can activate GPR119 and can be used to treat metabolic disorders, namely diabetes, diabetes-related diseases, diabetes-related microvascular complications, diabetes-related macrovascular complications, cardiovascular diseases, metabolic syndrome and its constituent diseases, obesity, and other diseases; in patent WO2020 / 247447, it is used in the synthesis of an orexin receptor antagonist that can be used to treat or prevent neurological and psychiatric diseases related to orexin receptors; and in patent WO2024 / 050061, it is used in the synthesis of pyrazole and imidazole derivatives that can act as dual regulators of orexin and κ-opioid receptors.

[0004] In the existing technology, the synthetic route for the compound 2-chloro-5-ethylpyrimidine has disadvantages such as easy generation of by-products and low yield. There is an urgent need to provide a new synthetic route to reduce by-products, improve production efficiency, and save costs. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 2-chloro-5-ethylpyrimidine. The synthesis method described in this invention has the advantages of low cost, short steps, ease of operation, mild reaction conditions, low safety risks, and high yield.

[0006] The technical solution of the present invention is as follows: A method for synthesizing 2-chloro-5-ethylpyrimidine, the method comprising the following steps: .

[0007] Specifically, the steps include the following: (1) Dissolve compound 1, namely 5-bromo-2-chloropyrimidine, in organic solvent I. Under the protection of an inert gas, add a catalyst, cool down to -5℃ to 5℃, add ethyl magnesium bromide solution, and after the addition is complete, heat up to 15℃~40℃ and stir the reaction for 8~20h.

[0008] (2) After the reaction is complete, the reaction solution is post-treated to obtain target compound 2, namely 2-chloro-5-ethylpyrimidine.

[0009] Further, in step (1), the molar ratio of compound 1 to ethyl magnesium bromide is 1.0:1.0~2.0.

[0010] Further, in step (1), the molar ratio of compound 1 to ferric acetylacetonate is 1.0:0.15~0.8.

[0011] Further, in step (1), the catalyst is selected from at least one of ferric acetylacetonate, ferric chloride, and ferrous bromide.

[0012] Further, in step (1), the ethyl magnesium bromide solution is at least one of the following: ethyl magnesium bromide tetrahydrofuran solution, ethyl magnesium bromide 2-methyltetrahydrofuran solution, ethyl magnesium bromide methyl tert-butyl ether solution, and ethyl magnesium bromide diethyl ether solution.

[0013] Further, in step (1), the organic solvent I is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, n-hexane, diethyl ether, ethylbenzene, and n-heptane.

[0014] Further, in step (1), the inert gas is nitrogen and / or argon.

[0015] Furthermore, in step (2), the specific process of post-processing is as follows: After the reaction was complete, the reaction solution was cooled to -5°C to 5°C, and a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with organic solvent II, and the organic phases were combined. The organic phases were washed, dried, and concentrated to obtain a crude product. The crude product was purified to obtain the target compound 2, namely 2-chloro-5-ethylpyrimidine.

[0016] Furthermore, the organic solvent II is selected from one or more of methyl tert-butyl ether and diethyl ether.

[0017] Furthermore, the purification method is selected from one or more of column chromatography, distillation, recrystallization, and pulping.

[0018] The beneficial technical effects of this invention are as follows: This invention proposes a method for synthesizing 2-chloro-5-ethylpyrimidine. Using 5-bromo-2-chloropyrimidine as a starting material, the method reacts with ethyl magnesium bromide in the presence of a catalyst to obtain the target compound 2-chloro-5-ethylpyrimidine. This method achieves a one-step conversion of 5-bromo-2-chloropyrimidine to 2-chloro-5-ethylpyrimidine under relatively mild reaction conditions, simple post-processing and purification, and allows for scale-up. Ultimately, this invention yields the target compound 2-chloro-5-ethylpyrimidine with a concise process, simple operation, low cost, relatively mild reaction conditions, and ideal yield. Attached Figure Description

[0019] Figure 1 The image shows the 1H NMR spectrum of 2-chloro-5-ethylpyrimidine prepared in Example 1 of this invention. Detailed Implementation

[0020] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0021] Example 1 A method for synthesizing 2-chloro-5-ethylpyrimidine includes the following steps: (1) Dissolve 5-bromo-2-chloropyrimidine (500.00 g, 2.58 mol, 1.00 eq) in tetrahydrofuran (5.0 L), and add ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) under the protection of inert nitrogen gas. Cool to 0℃, slowly add ethyl magnesium bromide solution (2.0 M solution in THF, 1.68kmL, 3.36mol, 1.30eq), and allow to rise naturally to room temperature. Stir and react at room temperature (approximately 25℃) for 12 hours.

[0022] (2) After the reaction is complete, the reaction solution is cooled to 0°C, and a saturated ammonium chloride solution (2.0 L) is added to quench the reaction. The solution is then extracted twice with methyl tert-butyl ether (2.0 L × 2). The organic phases are combined, and the organic phases are subjected to... The sample was washed twice with water (2.0L × 2), once with saturated brine (2.0L), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by distillation to obtain the target compound 2, namely 2-chloro-5-ethylpyrimidine (359.90g, 98% purity, 96% yield).

[0023] The 1H NMR spectrum of the obtained compound 2 (2-chloro-5-ethylpyrimidine) is as follows: Figure 1 As shown, the characterization data is as follows: 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.24(t, J = 7.7 Hz, 3H). Example 2

[0024] The reaction procedure was basically the same as in Example 1, except that the ethyl magnesium bromide solution (2.0 M solution in THF, 1.68 kmL, 3.36 mol, 1.30 eq) in Example 1 was replaced with ethyl magnesium bromide solution (2.0 M solution in THF, 1.29 kmL, 2.58 mol, 1.00 eq), and the yield of compound 2 was 92%.

[0025] Example 3

[0026] The reaction procedure was basically the same as in Example 1, except that the ethyl magnesium bromide solution (2.0 M solution in THF, 1.68 kmL, 3.36 mol, 1.30 eq) in Example 1 was replaced with ethyl magnesium bromide solution (2.0 M solution in THF, 1.94 kmL, 3.88 mol, 1.50 eq), and the yield of compound 2 was 96%.

[0027] Example 4

[0028] The reaction procedure was basically the same as in Example 1, except that the ethyl magnesium bromide solution (2.0 M solution in THF, 1.68 kmL, 3.36 mol, 1.30 eq) in Example 1 was replaced with ethyl magnesium bromide solution (2.0 M solution in THF, 2.58 kmL, 5.17 mol, 2.00 eq), and the yield of compound 2 was 94%.

[0029] Example 5

[0030] The reaction procedure was basically the same as in Example 1, except that ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) in Example 1 was replaced with ferric acetylacetonate (136.94 g, 387.74 mmol, 0.15 eq), and the yield of compound 2 was 91%.

[0031] Example 6

[0032] The reaction steps were basically the same as in Example 1, except that ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) in Example 1 was replaced with ferric acetylacetonate (456.46 g, 1.29 mol, 0.50 eq), and the yield of compound 2 was 96%.

[0033] Example 7

[0034] The reaction procedure was basically the same as in Example 1, except that ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) in Example 1 was replaced with ferric acetylacetonate (730.34 g, 2.07 mol, 0.80 eq), and the yield of compound 2 was 94%.

[0035] Example 8

[0036] The reaction steps were basically the same as in Example 1, except that ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) in Example 1 was replaced with ferric chloride (125.78 g, 775.48 mmol, 0.30 eq), and the yield of compound 2 was 90%.

[0037] Example 9

[0038] The reaction steps were basically the same as in Example 1, except that ferric acetylacetonate (273.88 g, 775.48 mmol, 0.30 eq) in Example 1 was replaced with ferrous bromide (167.24 g, 775.48 mmol, 0.30 eq), and the yield of compound 2 was 92%.

[0039] Example 10

[0040] The reaction procedure was basically the same as in Example 1, except that the ethyl magnesium bromide solution (2.0 M solution in THF, 1.68 kmL, 3.36 mol, 1.30 eq) in Example 1 was replaced with ethyl magnesium bromide solution (1.0 M solution in tert-butyl methyl ether, 3.36 kmL, 3.36 mol, 1.30 eq), and the yield of compound 2 was 94%.

[0041] Example 11

[0042] The reaction procedure was basically the same as in Example 1, except that the ethyl magnesium bromide solution (2.0 M solution in THF, 1.68 kmL, 3.36 mol, 1.30 eq) in Example 1 was replaced with ethyl magnesium bromide solution (3.0 M indiethyl ether, 1.12 kmL, 3.36 mol, 1.30 eq), and the yield of compound 2 was 95%.

[0043] Example 12

[0044] The reaction steps were basically the same as in Example 1, except that tetrahydrofuran (5.0 L) in Example 1 was replaced with 2-methyltetrahydrofuran (5.0 L), and the yield of compound 2 was 95%.

[0045] Example 13

[0046] The reaction steps were basically the same as in Example 1, except that tetrahydrofuran (5.0 L) in Example 1 was replaced with ethylene glycol dimethyl ether (5.0 L), and the yield of compound 2 was 93%.

[0047] As can be seen from Examples 1-4, when the molar ratio of compound 1 to ethyl magnesium bromide is 1.0:(1.0~2.0), the yield of compound 2 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 1 to ethyl magnesium bromide is 1.0:1.3 and 1.0:1.5.

[0048] As can be seen from Examples 1 and 5-7, when the molar ratio of compound 1 to ferric acetylacetonate is 1.0:(0.15~0.8), the yield of compound 2 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 1 to ferric acetylacetonate is 1.0:0.3 and 1.0:0.5.

[0049] As can be seen from Examples 1 and 8-9, the reaction proceeded smoothly when ferric acetylacetonate, ferric chloride, and ferrous bromide were used as catalysts, respectively, and the yield of compound 2 was high, not less than 90%. Among them, the reaction yield was the highest when ferric acetylacetonate was used as a catalyst.

[0050] As can be seen from Examples 1 and 10-11, the yields of compound 2 are all high, not less than 90%, when using tetrahydrofuran solution of ethyl magnesium bromide, tert-butyl methyl ether solution of ethyl magnesium bromide, and diethyl ether solution of ethyl magnesium bromide, respectively. Among them, the reaction yield is the highest when tetrahydrofuran solution of ethyl magnesium bromide is used for the reaction.

[0051] As can be seen from Examples 1 and 12-13, the reaction proceeded smoothly when tetrahydrofuran, 2-methyltetrahydrofuran, and ethylene glycol dimethyl ether were used as solvents, respectively. The yield of compound 2 was high in all cases, not less than 90%. Among them, the reaction yield was the highest when tetrahydrofuran was used as a catalyst.

[0052] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-chloro-5-ethylpyrimidine, characterized in that, The synthesis method is carried out according to the following procedure: 。 2. The synthesis method according to claim 1, characterized in that, Specifically, the steps include the following: (1) Dissolve compound 1, namely 5-bromo-2-chloropyrimidine, in organic solvent I, add catalyst under inert gas protection, cool to -5℃ to 5℃, add ethyl magnesium bromide solution, after addition, heat to 15℃~40℃, and stir the reaction for 8~20h. (2) After the reaction is complete, the reaction solution is post-treated to obtain target compound 2, namely 2-chloro-5-ethylpyrimidine.

3. The synthesis method according to claim 2, characterized in that, In step (1), The molar ratio of compound 1 to ethyl magnesium bromide is 1.0: 1.0~2.

0.

4. The synthesis method according to claim 2, characterized in that, In step (1), The molar ratio of compound 1 to the catalyst is 1.0: 0.15~0.

8.

5. The synthesis method according to claim 2, characterized in that, In step (1), The catalyst is selected from at least one of ferric acetylacetonate, ferric chloride, and ferrous bromide.

6. The synthesis method according to claim 2, characterized in that, In step (1), The ethyl magnesium bromide solution is at least one of the following: ethyl magnesium bromide tetrahydrofuran solution, ethyl magnesium bromide 2-methyltetrahydrofuran solution, ethyl magnesium bromide methyl tert-butyl ether solution, and ethyl magnesium bromide diethyl ether solution.

7. The synthesis method according to claim 2, characterized in that, In step (1), The organic solvent I is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, n-hexane, diethyl ether, ethylbenzene, and n-heptane.

8. The synthesis method according to claim 2, characterized in that, In step (2), After the reaction was complete, the reaction solution was cooled to -5°C to 5°C, and a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with organic solvent II, and the organic phases were combined. The organic phases were washed, dried, and concentrated to obtain a crude product. The crude product was purified to obtain the target compound 2, namely 2-chloro-5-ethylpyrimidine.

9. The synthesis method according to claim 8, characterized in that, In step (2), The organic solvent II is selected from one or more of methyl tert-butyl ether and diethyl ether; The purification method is selected from one or more of column chromatography, distillation, recrystallization, and pulping.

10. The synthesis method according to claim 2, characterized in that, The inert gas is nitrogen and / or argon.

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