A process for the preparation of methyl 2-pyrimidinecarboxylate

Abstract

The application discloses a preparation method of 2-pyrimidine methyl formate. The application provides a preparation method of 2-pyrimidine methyl formate, which comprises the following steps: step (1), 2-cyanopyrimidine and methanol are reacted in the presence of water and acid; and step (2), a dehydrating agent is added into the reaction solution in step (1) to prepare 2-pyrimidine methyl formate. The preparation method has one or more advantages of simple operation, high yield, high purity, low cost and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical organic synthesis, in particular, to a preparation method of methyl 2-pyrimidinecarboxylate. BACKGROUND

[0002] Pyrimidine compounds are an important class of organic compounds with wide application prospects in the fields of medicine, pesticides, material science, etc. Among them, methyl 2-pyrimidinecarboxylate, as a pyrimidine derivative with specific structure and rich chemical reaction activity, has important application potential in the fields of preparing pyrimidine bioactive molecules and organic synthesis.

[0003] Methyl 2-pyrimidinecarboxylate (also known as pyrimidine-2-carboxylic acid methyl ester) can be used as a biomaterial or organic compound for life science related research. This compound is also an important synthetic intermediate, which can be used to synthesize other drugs or organic compounds, participate in the construction of the backbone of drug molecules or introduce specific functional groups, thereby endowing the drug with specific biological activity or pharmacological effect.

[0004] (1) Construction of pyrimidine skeleton

[0005] Methyl 2-pyrimidinecarboxylate itself contains a pyrimidine ring, which makes it an ideal choice for constructing the skeleton of pyrimidine compounds. In drug research and development, pyrimidine skeleton is of great concern due to its unique biological activity, and is often used to synthesize drugs with antibacterial, antiviral, antitumor and other pharmacological effects.

[0006] (2) Precursor of 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 wide application in drug synthesis, such as as antibacterial agents, antiviral drugs, etc.

[0008] 2. Construction of complex molecular structure: In the synthesis of complex organic molecules, methyl 2-pyrimidinecarboxylate can be used as a starting material or intermediate, by introducing other functional groups or modifying the structure, to construct a molecule structure with specific biological activity.

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

[0010] In recent years, with the continuous deepening of the research on pyrimidine compounds, people have made beneficial exploration on their synthesis methods and applications. Methyl 2-pyrimidinecarboxylate, as an important pyrimidine compound, its preparation method has also attracted much attention.

[0011] [New Journal of Chemistry, 2020, V44, #26, 11237-11247] reported that 2-pyrimidinecarboxylic acid was used as raw material to prepare methyl 2-pyrimidinecarboxylate (route 1) under the catalysis of sulfuric acid and refluxing with methanol, with a yield of 68%. According to the existing reports, using 2-pyrimidinecarboxylic acid as raw material is not an ideal preparation scheme in terms of yield. In addition, the carboxylic acid raw material used in this route is generally obtained by hydrolysis of 2-cyanopyrimidine or oxidation of 2-methylpyrimidine, and is also relatively expensive, which is not suitable for commercial production.

[0012]

[0013] Many literatures reported that 2-cyanopyrimidine was used as raw material (route 2) to directly hydrolyze to obtain methyl 2-pyrimidinecarboxylate under the action of methanol-hydrogen chloride. Compared with route 1, the raw material of this route is easy to obtain and cheap, and does not need to go through the process of formic acid. US2010 / 63066 gave a separation yield of 81%, which is the best result in the related reports, but did not give the purity data. However, it was found in the actual scale-up process that the yield stability of this step was very poor, usually 30-50% lower than that in the laboratory.

[0014] SUMMARY

[0015] The technical problem to be solved by the present application is to overcome the defects in the prior art of the preparation method of methyl 2-pyrimidinecarboxylate, and to provide a preparation method of methyl 2-pyrimidinecarboxylate. The preparation method of the present application has one or more advantages of simple operation, high yield, high purity, low cost and suitability for industrial production.

[0016] The present application provides a preparation method of methyl 2-pyrimidinecarboxylate, which comprises the following steps,

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

[0018] Step (2): adding a dehydrating agent to the reaction solution of step (1) to prepare methyl 2-pyrimidinecarboxylate.

[0019] In a certain scheme of the present application, in step (1), the water is purified water.

[0020] In a certain scheme of the present application, in step (1), the acid is hydrogen chloride; for example, hydrogen chloride gas.

[0021] In a certain scheme of the present application, in step (1), the acid and the methanol exist in the form of an alcohol solution of the acid; preferably, a methanol solution of hydrogen chloride; for example, a 2-6M methanol solution of hydrogen chloride; further for example, a 4M methanol solution of hydrogen chloride.

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

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

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

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

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

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

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

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

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

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

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

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

[0034] In some embodiments of the present application, the reaction is terminated when the residual 2-pyrimidinecarboxylic acid is less than 3% in step (2); preferably less than 1%. The detection can be HPLC detection.

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

[0036] In some embodiments of the present application, step (2) further comprises the following post-treatment:

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

[0038] The temperature control is to control the temperature at 15-35 o C.

[0039] The cooling is to cool to -10-20 o C; preferably 0-10 o C.

[0040] The water addition 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 combination of organic phases; preferably,

[0043] The temperature control is to control the temperature at 0-10 o C.

[0044] The pH adjustment is to adjust to pH=7 using sodium carbonate.

[0045] The extraction is first extraction using dichloromethane, and then extraction using 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 at 20-50 o C; preferably 35-40 o C.

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

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

[0050] In a certain aspect of the present application, the raw material of the preparation method of the methyl 2-pyrimidinecarboxylate is the water, the acid, the methanol, the 2-cyanopyrimidine and the dehydrating agent.

[0051] The above-mentioned preferred conditions can be combined arbitrarily without violating the common knowledge in the art, thereby obtaining various preferred examples of the present application.

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

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

[0054] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and the methods are selected according to the conventional methods and conditions or the product instructions.

[0055] Example 1

[0056] 100 g of 2-cyanopyrimidine was added to a reaction kettle, 1 L of 4 M hydrogen chloride methanol solution was added, 17.1 g of purified water (1.0 eq) was added, the temperature was adjusted to 20-30 °C, and stirring was performed until the solution was clear; then the temperature was increased to 42-48 °C and stirring was performed for 14 hours; HPLC detection showed that the remaining raw material was ≤1%; the temperature was controlled at 45 o C, and concentrated to ~200 mL under vacuum;

[0057] The temperature was decreased to 20-25 o C, 226 g of thionyl chloride (2.0 eq) was added dropwise to the concentrated solution; after completion, the temperature was increased to 40-50 o C, stirring was performed for 3 hours, and HPLC detection showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%; the temperature was controlled at 35 o C, and further concentrated to ~100 mL;

[0058] The temperature was adjusted to 0-10 o C, 400 mL of purified water was added dropwise to the kettle, and stirring was performed until the solution was clear; the temperature was controlled at 10 o C, sodium bicarbonate was added to the solution in batches until the pH was ~7; 1 L of dichloromethane was added and stirred to extract the product; the aqueous phase was extracted with a dichloromethane-isopropyl alcohol=7:1 mixed solvent three times, 400 mL each time;

[0059] The organic phase was combined, the temperature was controlled at 35-40 o C, and concentrated to flow cut-off under reduced pressure; the temperature was maintained at 25-35 oC, 400 mL of n-heptane was added dropwise into the reactor, and the temperature was further lowered to 10-15 o C for 4 hours; filtration and vacuum drying gave 125.9 g of white solid, purity 99.6%, molar yield 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 Two

[0061] 0.9 L of methanol was added into the reactor, and the temperature was lowered to 0-10 o C; hydrogen chloride gas was bubbled into the reactor until saturation; 100 g of 2-cyanopyrimidine was added into the reactor, 17.1 g of purified water (1.0 eq) was added, the temperature was adjusted to 20-30 °C, and stirring was performed until the solution was clear; the temperature was then raised to 42-48 °C and stirring was performed for 16 hours; HPLC detection showed that the remaining raw material was ≤1%;

[0062] The temperature was controlled at 45 o C, and the volume was concentrated to ~200 mL; the temperature was lowered to 20-25 o C, 226 g of thionyl chloride (2.0 eq) was added dropwise into the concentrated solution; after completion, the temperature was raised to 40-50 o C for 3 hours, and HPLC detection showed that the remaining 2-pyrimidinecarboxylic acid was ≤1%; the temperature was controlled at 35 o C, and the volume was further concentrated to ~100 mL;

[0063] The temperature was adjusted to 0-10 o C, 400 mL of purified water was added dropwise into the reactor, and stirring was performed until the solution was clear; the temperature was controlled at 10 o C, sodium carbonate was added to the solution in batches until the pH was ~7; 1 L of dichloromethane was added for stirring, and the product was extracted; the aqueous phase was extracted with a dichloromethane-methanol=10:1 mixed solvent three times, 400 mL each time;

[0064] The temperature was controlled at 35-40 o C, and the volume was concentrated to flow cut-off under reduced pressure; the temperature was maintained at 25-35 o C, 400 mL of n-heptane was added dropwise into the reactor, and the temperature was further lowered to 10-15 o C for 4 hours; filtration and vacuum drying gave 123.8 g of white solid, purity 99.1%, molar yield 94.2%.

[0065] Example Three

[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 temperature to 0~10 o C, add 200 kg purified water into the kettle dropwise, and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate into the solution dropwise to pH~7; add 660 kg dichloromethane to stir and extract the product; the aqueous phase is extracted with dichloromethane-isopropyl alcohol=7:1 mixed solvent three times, 520 kg each time;

[0074] Combine the organic phases, control the temperature at 35~40 o C, concentrate under reduced pressure to stop flow; keep the temperature at 25~35 o C, add 400 mL n-heptane into the reaction kettle dropwise, and further cool to 10~15 o C, stir for 4 hours; filter and vacuum dry to obtain 61.1 kg of white solid, purity 99.1%, molar yield 93.0%.

[0075] Comparative Example One

[0076] Add 50 kg of 2-cyanopyrimidine into the reaction kettle, add 395 kg of 4M hydrogen chloride methanol solution, add 8.5 kg of purified water (1.0 eq), adjust the temperature to 20~30℃, and stir to dissolve; then warm to 42~48℃ and stir for 14 hours; HPLC detection of residual raw material ≤1%;

[0077] Control at 45 o C, concentrate under reduced pressure to ~100 L, cool to 20~25 o C; adjust the temperature to 0~10 o C, add 200 kg purified water into the kettle dropwise, and stir to dissolve; control the temperature at 10 o C, add sodium bicarbonate into the solution dropwise to pH~7; add 660 kg dichloromethane to stir and extract the product; the aqueous phase is extracted with dichloromethane-isopropyl alcohol=7:1 mixed solvent three times, 520 kg each time;

[0078] Combine the organic phases, control the temperature at 35~40 o C, concentrate under reduced pressure to stop flow; keep the temperature at 25~35 o C, add 137 kg n-heptane into the reaction kettle dropwise, and further cool to 10~15 o C, stir for 4 hours; filter and vacuum dry to obtain 26.3 kg of white solid, purity 99.2%, molar yield 40.1%.

Claims

1. A process for the preparation of methyl 2-pyrimidinecarboxylate, characterized in that, It comprises the following steps, Step (1): reacting 2-cyanopyrimidine and methanol in the presence of water and acid; Step (2): adding a dehydrating agent to the reaction solution of step (1) to prepare methyl 2-pyrimidinecarboxylate; In the step (1), the acid is hydrogen chloride gas; In the step (1), the acid and the methanol exist in the form of an alcohol solution of the acid; the alcohol solution of the acid is a methanolic hydrogen chloride solution; In the step (1), the molar ratio of the 2-cyanopyrimidine to the water is 1:(1-1.2); In the step (2), the dehydrating agent is thionyl chloride or oxalyl chloride; The molar ratio of 2-cyanopyrimidine in the step (1) to the dehydrating agent in the step (2) is 1:(1.5-2.5).

2. The method of claim 1, wherein the methyl 2-pyrimidinecarboxylate is prepared by the process of: ###00001### 2-pyrimidinecarboxylate It meets one or more of the following conditions, (1) In the step (1), the water is purified water; (2) In the step (1), the molar ratio of the 2-cyanopyrimidine to the acid is 1:(3-5); (3) In the step (1), the mass-volume ratio of the 2-cyanopyrimidine to the methanol is 1g:(8-12)mL; (4) In the step (1), the temperature of the reaction is 30-55 ℃; (5) In the step (1), the time of the reaction is 12-16 h; (6) In the step (1), the reaction is ended when the remaining 2-cyanopyrimidine is detected to be ≤3%; the detection is HPLC detection; and (7) The step (1) further comprises the following post-treatment: temperature control and concentration.

3. The process for the preparation of methyl 2-pyrimidinecarboxylate according to claim 2, characterized in that, It meets one or more of the following conditions, (1) In the step (1), the molar ratio of the 2-cyanopyrimidine to the acid is 1:4.2; (2) In the step (1), the molar ratio of the 2-cyanopyrimidine to the water is 1:1; (3) In the step (1), the mass-volume ratio of the 2-cyanopyrimidine to the methanol is 1g:9mL or 1g:8mL; (4) In the step (1), the temperature of the reaction is 42-48 ℃; (5) In the step (1), the time of the reaction is 14 h; (6) In the step (1), the reaction is ended when the remaining 2-cyanopyrimidine is detected to be ≤1%; the detection is HPLC detection; and (7) In step (1), the temperature control is to control the temperature at 30-45 o C.

4. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, wherein It meets one or two of the following conditions, (1) In the step (1), the methanolic hydrogen chloride solution is a 2-6M methanolic hydrogen chloride solution; (2) In the step (1), the mass-volume ratio of the 2-cyanopyrimidine to the methanolic hydrogen chloride solution is 1g:(8-12)mL.

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

6. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, wherein It meets one or more of the following conditions, (1) In the step (2), the temperature of the reaction is 30-70 ℃; (2) In the step (2), the time of the reaction is 1.5-5 h; (3) the reaction in step (2) is ended when the residual 2-pyrimidinecarboxylic acid is less than or equal to 3%; the detection is HPLC detection; and (4) the step (2) further comprises the following post-treatment: ① temperature control, concentration, temperature reduction, water addition; ② temperature control, pH adjustment, extraction, and organic phase combination; ③ temperature control, crystallization, filtration, and drying.

7. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 6, wherein one or more of the following conditions are met, (1) the molar ratio of 2-cyanopyrimidine in step (1) to the dehydrating agent in step (2) is 1:2; (2) In the step (2), the temperature of the reaction is 40-50 °C or 50-60 °C. o C; (3) the reaction time in step (2) is 3 h or 2 h; (4) the reaction in step (2) is ended when the residual 2-pyrimidinecarboxylic acid is less than or equal to 1%; the detection is HPLC detection; (5) In the above (1), the temperature control is to control the temperature at 15-35 o C; The temperature is lowered to -10 to 20 o C; the water addition is dropwise addition of purified water; the mass-volume ratio of 2-cyanopyrimidine to the purified water is 1 g:(3-5) mL; (6) In the above-mentioned (2), the temperature control is to control the temperature at 0-10 o C. the pH adjustment is sodium carbonate adjustment to pH=7; the extraction is first dichloromethane extraction, and then dichloromethane and methanol mixed solvent extraction; and (7) In the above-mentioned (3), the temperature control is to control the temperature to be 20-50 o C; the crystallization solvent is an alkane solvent; The temperature of the crystallization is 0-25 o C.

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

9. The method for preparing methyl 2-pyrimidinecarboxylate according to claim 1, wherein the raw materials for the preparation method of the methyl 2-pyrimidinecarboxylate are the water, the acid, the methanol, the 2-cyanopyrimidine, and the dehydrating agent.

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