Preparation method of methyl 2-pyrimidinecarboxylate

Abstract

The invention discloses a preparation method of methyl 2-pyrimidinecarboxylate. The invention provides a preparation method of methyl 2-pyrimidinecarboxylate, which comprises the following steps: step (1), reacting 2-cyanopyrimidine with methanol in the presence of water and acid; and (2) adding a dehydrating agent into the reaction liquid in the step (1) to prepare the 2-pyrimidinecarboxylic acid methyl ester. The preparation method disclosed by the invention has one or more advantages of simplicity in operation, high yield, high purity, low cost and suitability for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical organic synthesis, and in particular to a method for preparing methyl 2-pyrimidinecarboxylate. Background Art

[0002] Pyrimidines, as an important class of organic compounds, have broad application prospects in medicine, pesticides, materials science, and other fields. Among them, methyl 2-pyrimidinecarboxylate, a pyrimidine derivative with a specific structure and rich chemical reactivity, has significant application potential in the preparation of pyrimidine bioactive molecules and organic synthesis.

[0003] Methyl 2-pyrimidinecarboxylate (also known as methyl pyrimidine-2-carboxylate) can be used as a biomaterial or organic compound in life science research. It is also an important synthetic intermediate used in the synthesis of other drugs or organic compounds, participating in the construction of drug molecule backbones or introducing specific functional groups, thereby imparting specific biological activity or pharmacological effects to drugs.

[0004] (1) Construction of pyrimidine skeleton

[0005] Methyl 2-pyrimidinecarboxylate contains a pyrimidine ring, a structural feature that makes it an ideal candidate for building the backbone of pyrimidine compounds. In drug development, pyrimidine backbones have attracted significant attention due to their unique biological activities and are often used to synthesize drugs with antibacterial, antiviral, and antitumor properties.

[0006] (2) As a precursor of a specific skeleton

[0007] 1. Synthesis of pyrimidine derivatives: Methyl 2-pyrimidinecarboxylate can be converted into various pyrimidine derivatives through a series of chemical reactions. These derivatives have a wide range of applications in pharmaceutical synthesis, such as as antibacterial and antiviral agents.

[0008] 2. Construction of complex molecular structures: When synthesizing complex organic molecules, 2-pyrimidinecarboxylic acid methyl ester can be used as a starting material or intermediate. By introducing other functional groups or performing structural modifications, molecular structures with specific biological activities can be constructed.

[0009] 3. Participate in the synthesis of heterocyclic compounds: The combination of pyrimidine rings with other heterocycles (such as pyridine and quinoline) can produce compounds with unique pharmacological effects. Methyl 2-pyrimidinecarboxylate plays an important role in the synthesis of this class of compounds.

[0010] In recent years, with the continuous deepening of research on pyrimidine compounds, people have made beneficial explorations into their synthesis methods and applications. As an important class of pyrimidine compounds, 2-pyrimidinecarboxylic acid methyl ester has also attracted considerable attention for its preparation method.

[0011] [New Journal of Chemistry, 2020, V44, #26, 11237-11247] reported the preparation of methyl 2-pyrimidinecarboxylate (Route 1) from 2-pyrimidinecarboxylic acid in a sulfuric acid-catalyzed, methanol-reflux reaction, yielding 68%. Based on previous reports, using 2-pyrimidinecarboxylic acid as a starting material is not an ideal preparation method in terms of yield. Furthermore, the carboxylic acid starting material used in this route is typically obtained by hydrolysis of 2-cyanopyrimidine or oxidation of 2-methylpyrimidine, which is relatively expensive and unsuitable for commercial production.

[0012]

[0013] Several publications have reported using 2-cyanopyrimidine as a starting material (Route 2) for direct hydrolysis in methanol-hydrogen chloride to yield methyl 2-pyrimidinecarboxylate. Compared to Route 1, this route offers readily available and inexpensive raw materials and avoids the need for formic acid. US2010 / 63066 reported an 81% isolated yield, the best reported result, but purity data were not provided. However, during scale-up, the yield stability of this step was found to be poor, often 30–50% lower than in the laboratory.

[0014] Summary of the Invention

[0015] The technical problem to be solved by the present invention is to provide a method for preparing methyl 2-pyrimidinecarboxylate in order to overcome the drawbacks of the prior art methods for preparing methyl 2-pyrimidinecarboxylate. The preparation method of the present invention has one or more advantages of being simple to operate, having a high yield and purity, being low in cost, and being suitable for industrial production.

[0016] The present invention provides a method for preparing methyl 2-pyrimidinecarboxylate, which comprises the following steps:

[0017] Step (1): 2-cyanopyrimidine reacts with methanol in the presence of water and acid;

[0018] Step (2): Add a dehydrating agent to the reaction solution of step (1) to prepare 2-pyrimidinecarboxylic acid methyl ester.

[0019] In one embodiment of the present invention, in step (1), the water is purified water.

[0020] In one embodiment of the present invention, in step (1), the acid is hydrogen chloride; for example, hydrogen chloride gas.

[0021] In one embodiment of the present invention, in step (1), the acid and the methanol are present in the form of an alcoholic acid solution; preferably a methanolic hydrogen chloride solution; for example, a 2-6 M methanolic hydrogen chloride solution; and for example, a 4 M methanolic hydrogen chloride solution.

[0022] In one embodiment of the present invention, in step (1), the molar ratio of the 2-cyanopyrimidine to the acid is 1:(3-5); preferably 1:4.2.

[0023] In one embodiment of the present invention, in step (1), the molar ratio of the 2-cyanopyrimidine to the water is 1:(1-1.2); preferably 1:1.

[0024] In one embodiment of the present invention, in step (1), the mass volume ratio of the 2-cyanopyrimidine to the methanol is 1 g: (8-12) mL; preferably 1 g: 9 mL or 1 g: 8 mL.

[0025] In one embodiment of the present invention, in step (1), the mass volume ratio of the 2-cyanopyrimidine to the hydrogen chloride methanol solution is 1 g: (8-12) mL; preferably 1 g: 10 mL or 1 g: 9.5 mL.

[0026] In one embodiment of the present invention, in step (1), the reaction temperature is 30-55°C; preferably 42-48°C.

[0027] In a certain embodiment of the present invention, in step (1), the reaction time is 12-16 h, preferably 14 h.

[0028] In one embodiment of the present invention, in step (1), the reaction is terminated when the residual 2-cyanopyrimidine is detected to be ≤3%; preferably ≤1%. The detection can be performed by HPLC.

[0029] In one embodiment of the present invention, the step (1) further comprises the following post-processing: temperature control and concentration; the temperature control may be controlled at 30-45 o C.

[0030] In one embodiment of the present invention, in step (2), the dehydrating agent is thionyl chloride or oxalyl chloride.

[0031] In one embodiment of the present invention, the molar ratio of 2-cyanopyrimidine in step (1) to the dehydrating agent in step (2) is 1:(1.5-2.5); preferably 1:2.

[0032] In one embodiment of the present invention, in step (2), the reaction temperature is 30-70°C; preferably 40-50°C or 50-60 o C.

[0033] In one embodiment of the present invention, in step (2), the reaction time is 1.5-5 h; preferably 3 h or 2 h.

[0034] In one embodiment of the present invention, in step (2), the reaction is terminated when the residual 2-pyrimidinecarboxylic acid in the reaction is detected to be ≤3%; preferably ≤1%. The detection can be performed by HPLC.

[0035] In the present invention, the HPLC detection is a conventional detection method in the art.

[0036] In one embodiment of the present invention, step (2) further includes the following post-processing:

[0037] ① Temperature control, concentration, cooling, and water addition; preferably,

[0038] The temperature control is to control the temperature between 15-35 o C;

[0039] The temperature is reduced to -10-20 o C; preferably 0-10 o C;

[0040] The adding of water is dropwise addition of purified water;

[0041] The mass volume ratio of the 2-cyanopyrimidine to the water is 1 g: (3-5) mL; preferably 1 g: 4 mL;

[0042] ② Temperature control, pH adjustment, extraction, and merging of organic phases; preferably,

[0043] The temperature control is to control the temperature between 0-10 o C;

[0044] The pH is adjusted to pH=7 by sodium carbonate;

[0045] The extraction is firstly extracted with dichloromethane, and then extracted with a mixed solvent of dichloromethane and methanol; the volume ratio of dichloromethane to methanol in the mixed solvent can be 10:1;

[0046] ③ Temperature control, crystallization, filtration and drying; preferably,

[0047] The temperature control is to control the temperature to 20-50 o C; preferably 35-40 o C;

[0048] The crystallization solvent is an alkane solvent; for example, n-heptane;

[0049] The crystallization temperature is 0-25 o C; preferably 10-15 o C.

[0050] In one embodiment of the present invention, the raw materials for the preparation method of methyl 2-pyrimidinecarboxylate are the water, the acid, the methanol, the 2-cyanopyrimidine and the dehydrating agent.

[0051] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0052] The reagents and raw materials used in the present invention are commercially available.

[0053] The positive progress of the present invention is that the present invention provides a method for preparing methyl 2-pyrimidinecarboxylate. The preparation method of the present invention has one or more advantages of simple operation, high yield, high purity, low cost, and suitability for industrial production. DETAILED DESCRIPTION

[0054] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0055] Example 1

[0056] Add 100g of 2-cyanopyrimidine to the reactor, add 1L of 4M hydrogen chloride methanol solution, add 17.1g of purified water (1.0eq), adjust the temperature to 20-30℃, stir until dissolved; then heat to 42-48℃ and stir for 14 hours; HPLC detection of raw material residue ≤1%; control at 45 o C below, and concentrated in vacuo to ~200 mL;

[0057] Cool down to 20~25 o C, add 226g thionyl chloride (2.0eq) dropwise to the concentrated solution; after completion, heat to 40~50 o C for 3 hours, and the HPLC test showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%. The temperature was controlled at 35 o C below, further concentrated to ~100 mL;

[0058] Adjust the temperature to 0~10 o C, add 400mL of purified water to the kettle and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate to the solution in batches until the pH is ~7; add 1L of dichloromethane and stir to extract the product; the aqueous phase is then extracted three times with a dichloromethane-isopropanol = 7:1 mixed solvent, 400mL each time;

[0059] Combine the organic phases and control the temperature at 35-40 o C under reduced pressure and concentrated until the flow stops; maintain the temperature at 25~35 oC, add 400mL of n-heptane to the reactor and further cool it to 10~15 o C. and stirred for 4 hours; filtered and dried in vacuo to obtain 125.9 g of an off-white solid with a purity of 99.6% and a molar yield of 95.8%. 1H NMR (DMSO-d6, 400 MHz): d=9.38 ppm(2H), 7.94 ppm(1H), 4.49 ppm(3H), MS=139.0(M+1).

[0060] Example 2

[0061] Add 0.9L methanol into the reactor and cool it down to 0~10 o C. Pass hydrogen chloride gas into the reactor until saturated; add 100 g of 2-cyanopyrimidine to the reactor, add 17.1 g of purified water (1.0 eq), adjust the temperature to 20-30°C, and stir until dissolved; then raise the temperature to 42-48°C and stir for 16 hours; HPLC analysis shows that the remaining raw material is ≤1%;

[0062] Controlled at 45 o Below ℃, vacuum concentrate to ~200mL, cool to 20~25 o C, add 226g thionyl chloride (2.0eq) dropwise to the concentrated solution; after completion, heat to 40~50 o C for 3 hours, and the HPLC test showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%. The temperature was controlled at 35 o C below, further concentrated to ~100 mL;

[0063] Adjust the temperature to 0~10 o C, add 400mL of purified water to the kettle and stir to dissolve; control the temperature at 10 o Below 37°C, sodium carbonate was added to the solution in batches until the pH reached 7; 1 L of dichloromethane was added and stirred to extract the product; the aqueous phase was then extracted three times with a 10:1 dichloromethane-methanol mixture, 400 mL each time;

[0064] Combine the organic phases and control the temperature at 35-40 o C under reduced pressure and concentrated until the flow stops; maintain the temperature at 25~35 o C, add 400mL of n-heptane to the reactor and further cool it to 10~15 o C and stirred for 4 hours; filtered and dried in vacuo to obtain 123.8 g of an off-white solid with a purity of 99.1% and a molar yield of 94.2%.

[0065] Example 3

[0066] Add 100 g of 2-cyanopyrimidine to a reactor, add 1 L of 4 M methanolic hydrogen chloride solution, add 17.1 g of purified water (1.0 eq), adjust the temperature to 20-30°C, and stir until dissolved. Then raise the temperature to 42-48°C and stir for 14 hours. HPLC detection shows that the remaining raw material is ≤1%.

[0067] Controlled at 45 o Below ℃, vacuum concentrate to ~200mL, cool to 20~25 o C, add 242g oxalyl chloride (2.0eq) dropwise to the concentrate; after completion, heat to 50~60 o C for 2 hours, and the HPLC test showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%. The temperature was controlled at 35 o C below, further concentrated to ~100 mL;

[0068] Adjust the temperature to 0~10 o C, add 400mL of purified water to the kettle and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate to the solution in batches until the pH is ~7; add 1L of dichloromethane and stir to extract the product; the aqueous phase is then extracted three times with a dichloromethane-isopropanol = 7:1 mixed solvent, 400mL each time;

[0069] Combine the organic phases and control the temperature at 35-40 o C under reduced pressure and concentrated until the flow stops; maintain the temperature at 25~35 o C, add 400mL of n-heptane to the reactor and further cool it to 10~15 o C and stirred for 4 hours; filtered and dried in vacuo to obtain 124.5 g of an off-white solid with a purity of 99.3% and a molar yield of 94.7%.

[0070] Example 4

[0071] Add 50 kg of 2-cyanopyrimidine to a reactor, add 395 kg of 4 M hydrogen chloride methanol solution, add 8.5 kg of purified water (1.0 eq), adjust the temperature to 20-30°C, and stir until dissolved. Then raise the temperature to 42-48°C and stir for 14 hours. HPLC test shows that the remaining raw material is ≤1%.

[0072] Controlled at 45 o Below ℃, vacuum concentrate to ~200L, cool to 20~25 o C, add 113.3kg thionyl chloride (2.0eq) dropwise to the concentrated solution; after completion, heat to 50~60 o C for 2 hours, and the HPLC test showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%. The temperature was controlled at 35 o C below, further concentrated to ~100L;

[0073] Adjust the temperature to 0~10 o C, add 200kg purified water into the kettle and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate to the solution in batches until the pH is ~7; add 660kg of dichloromethane and stir to extract the product; the aqueous phase is then extracted three times with a dichloromethane-isopropanol = 7:1 mixed solvent, each time 520kg;

[0074] Combine the organic phases and control the temperature at 35-40 o C under reduced pressure and concentrated until the flow stops; maintain the temperature at 25~35 o C, add 400mL of n-heptane to the reactor and further cool it to 10~15 o C and stirred for 4 hours; filtered and dried in vacuo to obtain 61.1 kg of an off-white solid with a purity of 99.1% and a molar yield of 93.0%.

[0075] Comparative Example 1

[0076] Add 50 kg of 2-cyanopyrimidine to a reactor, add 395 kg of 4 M hydrogen chloride methanol solution, add 8.5 kg of purified water (1.0 eq), adjust the temperature to 20-30°C, and stir until dissolved. Then raise the temperature to 42-48°C and stir for 14 hours. HPLC test shows that the remaining raw material is ≤1%.

[0077] Controlled at 45 o Below ℃, vacuum concentrate to ~100L, cool to 20~25 o C; adjust the temperature to 0~10 o C, add 200kg purified water into the kettle and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate to the solution in batches until the pH is ~7; add 660kg of dichloromethane and stir to extract the product; the aqueous phase is then extracted three times with a dichloromethane-isopropanol = 7:1 mixed solvent, each time 520kg;

[0078] Combine the organic phases and control the temperature at 35-40 o C under reduced pressure and concentrated until the flow stops; maintain the temperature at 25~35 o C, add 137kg of n-heptane to the reactor and further cool it to 10-15 o C and stirred for 4 hours; filtered and dried in vacuo to obtain 26.3 kg of off-white solid with a purity of 99.2% and a molar yield of 40.1%.

Claims

1. A method for preparing methyl 2-pyrimidinecarboxylate, characterized in that: It includes the following steps, Step (1): reacting 2-cyanopyrimidine with methanol in the presence of water and an acid; Step (2): Add a dehydrating agent to the reaction solution of step (1) to prepare 2-pyrimidinecarboxylic acid methyl ester.

2. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, characterized in that It satisfies one or more of the following conditions: (1) In step (1), the water is purified water; (2) In step (1), the acid is hydrogen chloride; (3) In step (1), the acid and the methanol are present in the form of an alcohol solution of the acid; (4) In step (1), the molar ratio of the 2-cyanopyrimidine to the acid is 1:(3-5); (5) In step (1), the molar ratio of the 2-cyanopyrimidine to the water is 1:(1-1.2); (6) In step (1), the mass volume ratio of the 2-cyanopyrimidine to the methanol is 1 g: (8-12) mL; (7) In step (1), the reaction temperature is 30-55°C; (8) In step (1), the reaction time is 12-16 h; (9) In step (1), when the remaining 2-cyanopyrimidine is detected to be ≤ 3%, the reaction is terminated; and (10) The step (1) further includes the following post-treatment: temperature control and concentration.

3. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 2, characterized in that: It satisfies one or more of the following conditions: (1) In step (1), the acid is hydrogen chloride gas; (2) In step (1), the alcoholic acid solution is a methanolic hydrogen chloride solution; (3) In step (1), the molar ratio of the 2-cyanopyrimidine to the acid is 1:4.2; (4) In step (1), the molar ratio of the 2-cyanopyrimidine to the water is 1:1; (5) In step (1), the mass volume ratio of the 2-cyanopyrimidine to the methanol is 1 g:9 mL or 1 g:8 mL; (6) In step (1), the reaction temperature is 42-48°C; (7) In step (1), the reaction time is 14 h; (8) In step (1), when the remaining 2-cyanopyrimidine is detected to be ≤ 1%, the reaction is terminated; and (9) In step (1), the temperature is controlled at 30-45 o C.

4. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 3, characterized in that: It satisfies one or more of the following conditions: (1) In step (1), the hydrogen chloride methanol solution is a 2-6M hydrogen chloride methanol solution; (2) In step (1), the mass volume ratio of the 2-cyanopyrimidine to the hydrogen chloride methanol solution is 1 g: (8-12) mL; and (3) In step (1), the detection is HPLC detection.

5. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 4, characterized in that: It satisfies one or both of the following conditions: (1) In step (1), the hydrogen chloride methanol solution is a 4M hydrogen chloride methanol solution; and (2) In step (1), the mass volume ratio of the 2-cyanopyrimidine to the hydrogen chloride methanol solution is 1 g:10 mL or 1 g:9.5 mL.

6. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, characterized in that: It satisfies one or more of the following conditions: (1) In step (2), the dehydrating agent is thionyl chloride or oxalyl chloride; (2) The molar ratio of 2-cyanopyrimidine in step (1) to the dehydrating agent in step (2) is 1:(1.5-2.5); (3) In step (2), the reaction temperature is 30-70°C; (4) In step (2), the reaction time is 1.5-5 h; (5) In step (2), when the remaining 2-pyrimidinecarboxylic acid in the detection reaction is ≤ 3%, the reaction is terminated; and (6) Step (2) further includes the following post-processing: ① Temperature control, concentration, cooling, and water addition; ② Temperature control, pH adjustment, extraction, and merging of organic phases; ③ Temperature control, crystallization, filtration and drying.

7. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 6, characterized in that: It satisfies one or more of the following conditions: (1) The molar ratio of 2-cyanopyrimidine in step (1) to the dehydrating agent in step (2) is 1:2; (2) In step (2), the reaction temperature is 40-50°C or 50-60°C. o C; (3) In step (2), the reaction time is 3 h or 2 h; (4) In step (2), when the remaining 2-pyrimidinecarboxylic acid in the detection reaction is ≤ 1%, the reaction is terminated; (5) In the above ①, the temperature control is to control the temperature between 15-35 o C; The temperature is reduced to -10-20 o C; The adding of water is dropwise addition of purified water; The mass volume ratio of the 2-cyanopyrimidine to the purified water is 1 g: (3-5) mL; (6) In the above ②, the temperature control is to control the temperature between 0-10 o C; The pH is adjusted to pH=7 by sodium carbonate; The extraction is firstly extracted with dichloromethane, and then extracted with a mixed solvent of dichloromethane and methanol; and (7) In the above ③, the temperature control is to control the temperature to 20-50 o C; The crystallization solvent is an alkane solvent; The crystallization temperature is 0-25 o C.

8. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 7, characterized in that: In the step (2), the detection is HPLC detection.

9. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 7, characterized in that: It satisfies one or more of the following conditions: (1) In the above ①, the temperature is reduced to 0-10 o C; In ①, the mass volume ratio of the 2-cyanopyrimidine to the purified water is 1 g: 4 mL; (2) In the above method ②, the volume ratio of dichloromethane to methanol in the mixed solvent is 10:1; and (3) In the above ③, the temperature control is to control the temperature to 35-40 o C; The crystallization solvent is n-heptane; The crystallization temperature is 10-15 o C.

10. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, characterized in that: The raw materials of the preparation method of methyl 2-pyrimidinecarboxylate are the water, the acid, the methanol, the 2-cyanopyrimidine and the dehydrating agent.

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