A preparation method of 1-alkyl-1,2,4-triazole-3-methanol

Abstract

The present invention relates to a method for preparing 1-alkyl-1,2,4-triazole-3-methanol, and belongs to the field of pharmaceutical chemicals. 1-alkyl-1,2,4-triazole-3-formate is reduced by a sodium borohydride reduction system to obtain 1-alkyl-1,2,4-triazole-3-methanol. The method has low preparation cost, safe scale-up operation, mild reaction conditions, simple post-processing, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry and relates to the preparation of pharmaceutical intermediates, and specifically relates to a method for preparing 1-alkyl-1,2,4-triazole-3-methanol. Background Art

[0002] Ensitrelvir is an oral drug for the treatment of COVID-19 developed by Shionogi Pharmaceuticals of Japan. Ensitrelvir is the first orally active, non-covalent, non-peptide SARS-CoV-2 3CL protease inhibitor. Compared with placebo, it can quickly eliminate the five main symptoms of COVID-19 and reduce viral titers. The structural formula of Ensitrelvir is as follows:

[0003]

[0004] 1-Alkyl-1,2,4-triazole-3-methanol is an important intermediate for the synthesis of Ensitrelvir. With the development and application of Ensitrelvir, the demand for 1-alkyl-1,2,4-triazole-3-methanol is also increasing sharply. Therefore, the efficient and low-cost synthesis of 1-alkyl-1,2,4-triazole-3-methanol has important industrial value and social benefits.

[0005] The traditional methods for synthesizing 1-alkyl-1,2,4-triazole-3-methanol are mainly the following:

[0006] Patent CN107879992A discloses a method for preparing 1-methyl-1,2,4-triazole-3-methanol, which uses 2-hydroxyacetamide as a raw material, uses trityl to protect the hydroxyl group, then reacts with ethyl formate formylation, and then reacts with methylhydrazine for condensation and ring closure to obtain 1-methyl-1,2,4-triazole-3-methanol after deprotection. The reaction route is as follows:

[0007]

[0008] This method has complicated reaction steps, high cost of raw materials and reagents, and low overall yield of products, and is not suitable for industrial production.

[0009] Patent WO2021 / 185256A1 discloses a method for preparing 1-methyl-1,2,4-triazole-3-methanol by reducing 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester with lithium aluminum hydride. The method needs to be carried out at 0°C, the reducing reagent is expensive, there are great safety hazards, post-processing is difficult, the product yield is low, and it is not suitable for industrial scale-up production.

[0010] The document “Development of a manufacturing process toward the convergent synthesis of the COVID-19 antiviral Ensitrelvir” discloses a method for preparing 1-methyl-1,2,4-triazole-3-methanol as follows:

[0011]

[0012] The method uses sodium bis(2-methoxyethoxy)aluminum hydride as a reducing agent to reduce 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester to obtain the target product. The method also has the problems of expensive reducing reagents and complicated post-processing steps, making it difficult to achieve industrial production.

[0013] In view of this, developing an efficient and low-cost method for synthesizing 1-alkyl-1,2,4-triazole-3-methanol has important industrial value. Summary of the invention

[0014] The invention aims to solve the problems existing in the prior art and provides a method for preparing 1-alkyl-1,2,4-triazole-3-methanol. The method has low preparation cost, safe scale-up operation, mild reaction conditions, simple post-treatment and is suitable for industrial production.

[0015] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0016] A method for preparing 1-alkyl-1,2,4-triazole-3-methanol comprises the following steps:

[0017] Reaction of 1-alkyl-1,2,4-triazole-3-carboxylate with sodium borohydride to obtain 1-alkyl-1,2,4-triazole-3-methanol;

[0018] The structures of the 1-alkyl-1,2,4-triazole-3-carboxylate and 1-alkyl-1,2,4-triazole-3-methanol are shown in the following formulas I and II respectively:

[0019]

[0020] Wherein, R1 and R2 are independently a linear or branched C1-10 alkyl group. Further, R1 and R2 are independently a linear or branched C1-4 alkyl group; further, R1 and R2 are independently a methyl group or an ethyl group.

[0021] Furthermore, the preparation method of the 1-alkyl-1,2,4-triazole-3-methanol comprises the following steps:

[0022] (1) dissolving 1-alkyl-1,2,4-triazole-3-carboxylate in a solvent;

[0023] (2) Sodium borohydride is added to react to obtain 1-alkyl-1,2,4-triazole-3-methanol.

[0024] In some embodiments of the present invention, the solvent in step (1) is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran; further, the solvent is methanol or an ethanol / tetrahydrofuran mixed solvent; further, the volume ratio of methanol or ethanol to tetrahydrofuran is 1-9:5; further preferably 3-7:5; most preferably 4-6:5.

[0025] In some embodiments of the present invention, the molar ratio of sodium borohydride added in step (2) to 1-alkyl-1,2,4-triazole-3-carboxylate is 2-9:1; more preferably 4-7:1; most preferably 6:1.

[0026] In some embodiments of the present invention, the reaction temperature in step (2) is 25-65°C; more preferably 40-60°C.

[0027] Generally, the reduction of ester groups is usually carried out using strong reducing agents such as lithium aluminum hydride. If sodium borohydride is used alone, the ester group cannot be reduced under normal circumstances. During the implementation of the present invention, it was found that in the case of a structural substrate such as 1-alkyl-1,2,4-triazole-3-carboxylate, the use of sodium borohydride alone can well reduce the ester group to alcohol. For the present invention, the selection of the reaction solvent is crucial. Using a mixed solvent of methanol or ethanol / tetrahydrofuran and controlling the volume ratio of the two to 4-6:5 can significantly improve the product yield. Using a single solvent will reduce the conversion rate of the reaction and leave a large amount of raw material remaining. Possible reasons are, first, the composition of the solvent affects the solubility of the raw material or reducing agent, and second, an appropriate proportion of protic solvents is conducive to the sodium borohydride reduction reaction. The reduction mechanism of sodium borohydride is as follows:

[0028]

[0029] R = 1-alkyl-1,2,4-triazole.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The preparation method of 1-alkyl-1,2,4-triazole-3-methanol provided by the invention selects sodium borohydride as a reagent for reducing ester groups. Compared with traditional lithium aluminum hydride, the method has the advantages of low cost, safe scale-up operation, mild reaction conditions, simple post-treatment, etc., and is suitable for industrial production. DETAILED DESCRIPTION

[0032] The technical scheme in the embodiment of the present invention will be clearly and completely described below. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. Based on the embodiment in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all common commercial products unless otherwise specified.

[0033] Example 1

[0034] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 14.49g (383.4mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill off the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 5.92g of a white crystalline solid, with a yield of 82.2%.

[0035] Example 2

[0036] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 21.75g ​​(575.1mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 135g of ice water dropwise to quench. Distill off the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 5.04g of a white crystalline solid, with a yield of 70.0%.

[0037] Example 3

[0038] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 14.49g (383.4mmol) of sodium borohydride in batches at room temperature, and react at room temperature for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Evaporate the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 3.96g of a white crystalline solid, with a yield of 55.0%.

[0039] Example 4

[0040] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 18ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 14.49g (383.4mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 3.24g of a white crystalline solid, with a yield of 45.0%.

[0041] Example 5

[0042] Add 9g (57.9mmol) of 1-ethyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 13.17g (348.0mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 4.56g of a white crystalline solid, with a yield of 61.8%.

[0043] Example 6

[0044] Add 9g (57.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid ethyl ester, 180ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 13.17g (348.0mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 4.86g of a white crystalline solid, with a yield of 74.0%.

[0045] Example 7

[0046] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 180ml of tetrahydrofuran and 180ml of ethanol to a 500ml four-necked bottle, stir and dissolve, add 14.49g (383.4mmol) of sodium borohydride in batches at room temperature, heat to 50°C after addition, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill off the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 5.07g of a white crystalline solid, with a yield of 70.4%.

[0047] Example 8

[0048] Add 9g (63.9mmol) of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester, 18ml of tetrahydrofuran and 180ml of methanol to a 500ml four-necked bottle, stir and dissolve, add 14.49g (383.4mmol) of sodium borohydride in batches at room temperature, raise the temperature to 50°C, and react for 3 hours. After the reaction, add 90g of ice water dropwise to quench. Distill the solvent under reduced pressure, add 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, then use 60ml of tetrahydrofuran, extract to obtain a tetrahydrofuran layer, mix the organic layers, evaporate to dryness under reduced pressure to obtain an oily liquid, add 30ml of n-heptane to obtain 3.3g of a white crystalline solid, with a yield of 45.8%.

[0049] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 1-alkyl-1,2,4-triazole-3-methanol, characterized in that: The steps include: React 1-alkyl-1,2,4-triazole-3-carboxylate with sodium borohydride to obtain 1-alkyl-1,2,4-triazole-3-methanol; The structures of the 1-alkyl-1,2,4-triazole-3-carboxylate and 1-alkyl-1,2,4-triazole-3-methanol are shown in Formula I and Formula II respectively: Wherein, R1 is methyl, R2 is methyl or ethyl; The reaction temperature is 40-60°C; The reaction solvent is a mixed solvent of methanol and tetrahydrofuran, and the volume ratio of methanol to tetrahydrofuran is 4-6:5; The molar ratio of sodium borohydride to 1-alkyl-1,2,4-triazole-3-carboxylate is 6:

1.

2. A method for preparing 1-alkyl-1,2,4-triazole-3-methanol, characterized in that: The steps include: (1) dissolving 1-alkyl-1,2,4-triazole-3-carboxylate in a solvent; (2) adding sodium borohydride to react and obtain 1-alkyl-1,2,4-triazole-3-methanol; The structures of the 1-alkyl-1,2,4-triazole-3-carboxylate and 1-alkyl-1,2,4-triazole-3-methanol are shown in the following formulas I and II: Wherein, R1 is methyl, R2 is methyl or ethyl; The reaction temperature is 40-60°C; The solvent is a mixed solvent of methanol and tetrahydrofuran, and the volume ratio of methanol to tetrahydrofuran is 4-6:5; The molar ratio of sodium borohydride to 1-alkyl-1,2,4-triazole-3-carboxylate is 6:1.

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