A preparation method of 5-aminoimidazole-4-carboxylic acid methyl ester

Abstract

The invention discloses a preparation method of 5-aminoimidazole-4-methyl formate, comprising the following steps: 1) nitration reaction of 4-imidazole formaldehyde to obtain 5-nitro-1H-imidazole-4-formaldehyde; 2) oxidation reaction of 5-nitro-1H-imidazole-4-formaldehyde with an oxidant under Lewis acid catalysis to obtain 5-nitroimidazole-4-methyl formate; 3) hydrogenation reduction of nitro group of 5-nitroimidazole-4-methyl formate Pd / C to obtain 5-aminoimidazole-4-methyl formate. The preparation method of the present invention is easy to operate, has stable process, high yield, obtains high-quality target product by crystallization, and meets industrial scale production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of 5-aminoimidazole-4-carboxylic acid methyl ester. Background Art

[0002] 5-aminoimidazole-4-carboxylic acid methyl ester belongs to imidazole compounds. Imidazole compounds have proton conjugate acid-base properties, complex coordination properties, etc., and are widely used in medicine, pesticides, surfactants, functional polymer chemistry and other fields.

[0003] 5-aminoimidazole-4-carboxylic acid methyl ester can be used to synthesize drugs or active molecules, mainly used in antibacterial and anticancer drug research. 5-aminoimidazole-4-carboxylic acid methyl ester can be used to synthesize imidazopyridine compounds or imidazopyrimidine compounds, both of which can be used in new drug research and development. Patent WO2005 / 49613, 2005, A1 discloses that it can be used to synthesize ATR kinase inhibitor antitumor drugs.

[0004] At present, there are few methods for 5-aminoimidazole-4-carboxylic acid methyl ester. Among them, the literature [Organic and Biomolecular Chemistry, 2024, vol. 22, # 17, p. 3396-3404] reports the use of methyl cyanoacetate as a raw material, sodium nitrite under the action of acetic acid to form an oxime at the α position, and then reduced to an amino group to obtain 2-amino-2-cyanoacetic acid methyl ester, and finally cyclized with acetic acid formamidine to obtain 5-aminoimidazole-4-carboxylic acid methyl ester. The overall yield of this route is low, the cyclization yield is about 50%, and it is not easy to purify. The reaction route is as follows:

[0005]

[0006] WO2005 / 49613, 2005, A1 discloses using 1H-imidazole-4-carboxylic acid as a raw material, nitrating with ammonium nitrate and concentrated sulfuric acid to obtain 4-nitro-1H-imidazole-5-carboxylic acid, followed by esterification with methanol to obtain 5-nitroimidazole-4-carboxylic acid methyl ester, followed by Pd / C hydrogenation to obtain 5-aminoimidazole-4-carboxylic acid methyl ester, with a total yield of 43.2%. This route has a high nitration temperature and is prone to decarboxylation, resulting in a low yield. The reaction route is as follows:

[0007]

[0008] 5-aminoimidazole-4-methyl formate is soluble in water and generally insoluble in fat-soluble solvents, and is sensitive to temperature, unstable when the temperature is high, so there should be no water in the reduction process (it cannot be extracted, if the water is concentrated under high temperature and reduced pressure, it is easy to go bad). In summary, the current preparation method of 5-aminoimidazole-4-methyl formate has the problems of product operation trouble, target product is not easy to purify and production cost is high. Therefore, in view of the above problems, the present invention adopts different ways to avoid cumbersome operation, make the product easier to purify, and then obtain high-quality product, so as to meet customer needs. Summary of the invention

[0009] In order to solve the above problems, the purpose of the present invention is to provide a preparation method of 5-aminoimidazole-4-carboxylic acid methyl ester, comprising the following steps: 1) nitration reaction of 4-imidazole formaldehyde to obtain 5-nitro-1H-imidazole-4-carboxaldehyde; 2) oxidation reaction of 5-nitro-1H-imidazole-4-carboxaldehyde with an oxidant under the catalysis of Lewis acid to obtain 5-nitroimidazole-4-carboxylic acid methyl ester; 3) hydrogenation reduction of nitro group of 5-nitroimidazole-4-carboxylic acid methyl ester by Pd / C to obtain 5-aminoimidazole-4-carboxylic acid methyl ester. The preparation method of the present invention is easy to operate, has a stable process, a high yield, and obtains a high-quality target product by a crystallization method, which is in line with industrial scale production.

[0010] The preparation method of 5-aminoimidazole-4-carboxylic acid methyl ester of the present invention comprises the following steps:

[0011] Step 1: 4-imidazole carboxaldehyde, an initiator and glacial acetic acid are mixed, fuming nitric acid is added dropwise, and then the temperature is slowly raised and nitrated to obtain 5-nitro-1H-imidazole-4-carboxaldehyde;

[0012] Step 2: Mix 5-nitro-1H-imidazole-4-carboxaldehyde, Lewis acid catalyst and methanol, slowly add oxidant, and heat to react to obtain 5-nitroimidazole-4-carboxylic acid methyl ester;

[0013] Step 3: 5-nitroimidazole-4-carboxylic acid methyl ester, Pd / C and a mixed solvent are mixed, cooled, replaced with hydrogen, and reduced at 15-30 psi to obtain 5-aminoimidazole-4-carboxylic acid methyl ester.

[0014] The reaction route is shown below:

[0015]

[0016] Furthermore, in step 1, the initiator is selected from sodium nitrite.

[0017] Furthermore, in step 1, the molar ratio of 4-imidazolecarboxaldehyde, initiator and fuming nitric acid is 1:0.0015-0.002:1.4-1.6.

[0018] Furthermore, in step 2, the Lewis acid catalyst is selected from tri(pentafluorophenyl)borane or a combination catalyst with lithium tetrafluoroborate, with a molar ratio of 1:1.

[0019] Furthermore, in step 2, the oxidant is selected from urea-hydrogen peroxide complex or hydrogen peroxide.

[0020] Furthermore, the heating temperature in step 2 is selected from 38-42°C.

[0021] Furthermore, in step 2, the molar ratio of 5-nitro-1H-imidazole-4-carboxaldehyde, Lewis acid catalyst and oxidant is 1:0.001-0.0015:1.4-2.0.

[0022] Furthermore, in step 3, the mixed solvent is selected from a mixed solvent consisting of methanol / acetonitrile or ethanol / acetonitrile, wherein the volume ratio of the two in the mixed solvent is 1:1.

[0023] Furthermore, in step 3, Pd / C is selected from 5% Pd / C or 10% Pd / C, and the cooling temperature is selected from 10-15°C.

[0024] Compared with the existing technology, this technology has the following advantages: the raw materials are easily available, easy to operate, high yield, high-quality target products can be obtained through crystal transformation, and it is more suitable for industrialization. DETAILED DESCRIPTION

[0025] The following is a further description of a method for preparing 5-aminoimidazole-4-carboxylic acid methyl ester provided by the present invention in conjunction with specific examples, but the protection scope of the present invention is not limited to the examples.

[0026] Example 1

[0027]

[0028] 115.3 g (1.2 mol) of 4-imidazolecarboxaldehyde, 0.17 g of sodium nitrite and 1100 mL of acetic acid were added into a 2L four-necked bottle. After stirring, the temperature was lowered to 15-18 ° C and 119.2 g (1.74 mol) of fuming nitric acid (92%) was added dropwise. The temperature was then raised to 65-68 ° C and the reaction was carried out for 3 hours. The remaining 0.8% of the raw material was sampled for HPLC. The temperature was lowered to 15 ° C, filtered, and the filter cake was rinsed with water and n-heptane and dried to obtain 150.2 of 5-nitro-1H-imidazole-4-carboxaldehyde with a yield of 88.7% and an HPLC of 99.4%. 1 HNMR (400MHz, DMSO-d6) δ: 13.29 (s, 1H), 9.78 (s, 1H), 8.05 (s, 1H).

[0029] Example 2

[0030]

[0031] 141.1 g (1 mol) of 5-nitro-1H-imidazole-4-carboxaldehyde, 5.1 g (0.01 mol) of tris(pentafluorophenyl)boric acid, 0.9 g (0.01 mol) of lithium tetrafluoroborate and 700 mL of methanol were added into a 2L four-necked bottle. After stirring and dissolving, the temperature was controlled at 20-35° C., 131.7 g (1.4 mol) of urea hydrogen peroxide complex was added in batches, and the temperature was raised to 38-42° C. after addition, and the reaction was carried out for 3 hours. The raw material was sampled and detected by HPLC to have a remaining 3.8%. The temperature was lowered to 15-20° C., added to 3500 g of ice water, filtered, and the filter cake was re-dissolved in ethyl acetate, washed with 5% sodium thiosulfate aqueous solution, washed with saturated sodium chloride aqueous solution, and the organic phase was concentrated under reduced pressure. N-heptane was added and re-pulped to obtain 145.6 g of 5-nitroimidazole-4-methyl carboxylate, with a yield of 85.1% and an HPLC of 99.2%. 1 H NMR (400MHz, DMSO-d6) δ: 14.30 (s, 1H), 7.96 (s, 1H), 3.90 (s, 3H).

[0032] Example 3

[0033]

[0034] 141.1 g (1 mol) of 5-nitro-1H-imidazole-4-carboxaldehyde, 5.1 g (0.01 mol) of tris(pentafluorophenyl)boric acid and 700 mL of methanol were added to a 2L four-necked bottle. After stirring and dissolving, the temperature was controlled at 20-35° C., 131.7 g (1.4 mol) of urea hydrogen peroxide complex was added in batches, and the temperature was raised to 38-42° C. after addition, and the reaction was carried out for 6 hours. The remaining raw material was sampled and detected by HPLC, and 5.2% was found. The temperature was lowered to 15-20° C., added to 3500 g of ice water, filtered, and the filter cake was re-dissolved in ethyl acetate, washed with 5% sodium thiosulfate aqueous solution, washed with saturated sodium chloride aqueous solution, and the organic phase was concentrated under reduced pressure. N-heptane was added and re-pulped to obtain 119.5 g of 5-nitroimidazole-4-methyl carboxylate, with a yield of 69.8% and an HPLC of 98.9%.

[0035] Example 4

[0036]

[0037] 141.1 g (1 mol) of 5-nitro-1H-imidazole-4-carboxaldehyde, 5.1 g (0.01 mol) of tris(pentafluorophenyl)boric acid, 0.9 g (0.01 mol) of lithium tetrafluoroborate and 700 mL of methanol were added into a 2L four-necked bottle. After stirring and dissolving, 198.5 g (1.75 mol) of 30% hydrogen peroxide was added dropwise at a temperature of 20-35 ° C. After addition, the temperature was raised to 38-42 ° C and the reaction was carried out for 4 hours. The remaining raw material was sampled and 3.3% was detected by HPLC. The temperature was lowered to 15-20 ° C. and added to 3500 g of ice water. The filter cake was re-dissolved in ethyl acetate, washed with 5% sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure, and n-heptane was added for heavy pulping to obtain 141.2 g of 5-nitroimidazole-4-methyl carboxylate with a yield of 82.5% and an HPLC of 99.4%.

[0038] Example 5

[0039]

[0040] 85.6 g (0.5 mol) of 5-nitroimidazole-4-carboxylic acid methyl ester, 4.3 g of 5% Pd / C, 850 mL of ethanol and 850 mL of acetonitrile were added to a 3L jacketed autoclave. After stirring, the temperature was lowered to 10°C, and vacuum and hydrogen were replaced 4 times. Hydrogen was introduced at 15-30 PSI. After 6 hours, sampling was performed to detect that the remaining raw material was 0.03%, and the mixture was filtered. The filter cake was rinsed with ethanol, and the filtrate was concentrated under reduced pressure at 20-25°C until no liquid flowed. 160 mL of ethyl acetate and 1500 mL of isopropyl ether were added, and the mixture was slurried and crystallized at 15°C for 24 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl ether and dried at 20-25°C to obtain 63.7 g of 5-aminoimidazole-4-carboxylic acid methyl ester with a yield of 90.3% and an HPLC index of 98.8%. 1 H NMR (400MHz, D2O) δ: 7.12 (s, 1H), 3.71 (s, 3H).

[0041] Example 6

[0042]

[0043] 85.6 g (0.5 mol) of 5-nitroimidazole-4-carboxylic acid methyl ester, 4.3 g of 5% Pd / C, 850 mL of methanol and 850 mL of acetonitrile were added to a 3L jacketed autoclave. After stirring, the temperature was lowered to 10°C, and vacuum and hydrogen were replaced 4 times. Hydrogen was introduced at 15-30 PSI. After 5 hours, sampling was performed to detect the remaining 0.04% of the raw material, and the mixture was filtered. The filter cake was rinsed with methanol, and the filtrate was concentrated under reduced pressure at 20-25°C until no liquid flowed. 160 mL of ethyl acetate and 1500 mL of isopropyl ether were added, and the mixture was slurried and crystallized at 15°C for 24 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl ether and dried at 20-25°C to obtain 60.6 g of 5-aminoimidazole-4-carboxylic acid methyl ester with a yield of 85.9% and an HPLC of 99.0%.

[0044] As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it should not be construed as limiting the present invention itself. Various changes in form and details may be made without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A method for preparing 5-aminoimidazole-4-carboxylic acid methyl ester, characterized in that: The steps include: Step 1: 4-imidazole carboxaldehyde, an initiator and glacial acetic acid are mixed, fuming nitric acid is added dropwise, and then the temperature is slowly raised and nitrated to obtain 5-nitro-1H-imidazole-4-carboxaldehyde; the initiator is selected from sodium nitrite; Step 2: Mix 5-nitro-1H-imidazole-4-carboxaldehyde, Lewis acid catalyst and methanol, slowly add oxidant, and heat to react to obtain 5-nitroimidazole-4-carboxylic acid methyl ester; Step 3: 5-nitroimidazole-4-carboxylic acid methyl ester, Pd / C and a mixed solvent are mixed, cooled, replaced with hydrogen, and reduced at 15-30 psi to obtain 5-aminoimidazole-4-carboxylic acid methyl ester.

2. The method for preparing 5-aminoimidazole-4-methylformate according to claim 1, wherein: In the step 1, the molar ratio of 4-imidazole carboxaldehyde, initiator and fuming nitric acid is 1:0.0015-0.002:1.4-1.

6.

3. The method for preparing 5-aminoimidazole-4-methylformate according to claim 1, characterized in that: In step 2, the Lewis acid catalyst is selected from tri(pentafluorophenyl)borane or a combination catalyst with lithium tetrafluoroborate, and the molar ratio is 1:

1.

4. The method for preparing 5-aminoimidazole-4-methylformate according to claim 1, characterized in that: In step 2, the oxidant is selected from urea-hydrogen peroxide complex or hydrogen peroxide.

5. The method for preparing 5-aminoimidazole-4-methyl carboxylate according to claim 1, characterized in that: The heating temperature in step 2 is selected from 38-42°C.

6. The method for preparing 5-aminoimidazole-4-methyl carboxylate according to claim 1, characterized in that: In the step 2, the molar ratio of 5-nitro-1H-imidazole-4-carboxaldehyde, Lewis acid catalyst and oxidant is 1:0.001-0.0015:1.4-2.

0.

7. The method for preparing 5-aminoimidazole-4-methyl carboxylate according to claim 1, characterized in that: The mixed solvent in step 3 is selected from a mixed solvent consisting of methanol and acetonitrile or ethanol and acetonitrile, wherein the volume ratio of methanol or ethanol to acetonitrile is 1:

1.

8. The method for preparing 5-aminoimidazole-4-methyl carboxylate according to claim 1, characterized in that: In step 3, Pd / C is selected from 5% Pd / C or 10% Pd / C, and the cooling temperature is selected from 10-15°C.

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