阅读说明：本技术 一种抗病毒药物Molnupiravir关键中间体及其制备方法 (Antiviral drug Molnopiravir key intermediate and preparation method thereof ) 是由 谢守全 齐伟 梁志寿 高慧丽 于 2021-10-26 设计创作，主要内容包括：本发明提供一种抗病毒药物Molnupiravir关键中间体为2',3'-O-亚异丙基胞苷甲磺酸盐,该关键中间体的制备方法是通过胞苷加入甲磺酸进行丙酮叉保护,同时甲磺酸与胞苷上裸露的胺基形成稳定的甲磺酸盐。本发明解决了现有硫酸盐不稳定的问题,方便放大生产,降低三废量；同时本发明的甲磺酸盐湿料或者干料在空气中放置48小时均不降解,在55℃放置15小时的降解在5％以内。(The invention provides an antiviral drug Molnopiravir key intermediate which is 2',3' -O-isopropylidene cytidine mesylate, and the preparation method of the key intermediate is that the cytidine is added with methanesulfonic acid to carry out acetonylidene protection, and meanwhile, the methanesulfonic acid and the exposed amino on the cytidine form stable mesylate. The invention solves the problem of instability of the existing sulfate, is convenient for large-scale production and reduces the amount of three wastes; meanwhile, the mesylate wet material or dry material of the invention can not be degraded after being placed in the air for 48 hours, and the degradation is within 5 percent after being placed at 55 ℃ for 15 hours.)

1. An antiviral drug Molnbupiravir key intermediate, which is characterized in that the key intermediate has a structural formula (I):

the chemical name of the key intermediate is as follows: 2',3' -O-isopropylidene cytidine mesylate.

2. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 1, which comprises the following steps:

step S1: by dissolving cytidine (III) and 2, 2-dimethoxypropane in an organic solvent, reacting in the presence of methanesulfonic acid; the reaction process is as follows:

step S2: and after the reaction is finished, filtering the solution to obtain a filter cake, and drying the filter cake at the temperature of 10-70 ℃ to obtain the key intermediate (I).

3. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the reaction temperature is-70-80 ℃, and the reaction time is 2-3 hours.

4. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the organic solvent is one or a mixture of dichloromethane, chloroform, chlorobenzene, benzene, toluene, acetonitrile, acetone, DMF, DMSO, THF, diethyl ether, ethyl formate and ethyl acetate.

5. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the mole number of the 2, 2-dimethoxypropane is 1-20 times of that of the cytidine.

6. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the mole number of the methanesulfonic acid is 1-20 times of that of the cytidine.

7. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the weight of the organic solvent is 3-50 times of that of the cytidine.

8. The method for preparing the key intermediate of the antiviral drug Molnupiravir as claimed in claim 2, which is characterized in that: the drying temperature is 20-50 ℃.

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to an antiviral medicine Molnbupiravir key intermediate and a preparation method thereof.

Background

Molnupiarvir (translated in the present invention as mupirovir) is a broad-spectrum oral antiviral drug developed by the combination of University of North Carolina, Vanderbilt University and Emory University. The medicine is a SARS-CoV-2 polymerase inhibitor, and can be used for treating various coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 have prophylactic or therapeutic effects and have potential anti-COVID-19 effects. The study proves that in animal experiments, the mupirovir is used for treating ferrets infected with SARS-CoV-2, can effectively inhibit viruses and prevent the growth of the viruses within 24 hours, thereby inhibiting the virus transmission. The research group believes that if mupirovir can achieve similar effects in human trials, new coronary patients receiving the oral drug therapy can become non-contagious within a day and have a wide market of applications. The chemical name is as follows: methyl ((2R, 3S, 4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxyamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) isobutyrate, formula (IV):

the Molnupiravir original patent WO2019113462 reports a synthesis route (route one), uridine is used as a raw material, and a target compound (IV) is obtained through reactions such as acetonide protection, esterification, substitution, hydroxylamine amination and deprotection, and the route uses an expensive raw material uridine, has a large amount of three wastes, has a low total yield of only 17%, and is not suitable for large-scale production.

In addition, journal of organic synthetic chemistry: synlett, 32(3), 326-328; 2021 reports another synthetic route (route two), which is characterized by taking cytidine as raw material, and carrying out four steps of propylidene protection, esterification, hydroxylamination and deprotection to obtain the target compound (IV), compared with the original starting material in the original route (route one), the synthetic route is cheaper, shorter and higher in yield (44% of total yield), and the advantage of the synthetic route (route two) can be seen.

However, in the actual synthesis of cytidine propylidene sulfate in the second synthetic route, the intermediate (II) is found to be extremely unstable, has self-deprotection function at room temperature and is not suitable for scale-up production, and the intermediate (II) in the second synthetic route still needs to be improved. Therefore, the invention provides an antiviral drug Molnbupiravir key intermediate and a preparation method thereof.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a more optimized preparation method for preparing a Molnopiravir key intermediate of an antiviral drug.

In order to achieve the aim, the invention provides an antiviral drug Molnbupiravir key intermediate, wherein the key intermediate has a structural formula (I):

the chemical name of the key intermediate is as follows: 2',3' -O-isopropylidene cytidine mesylate. Referred to as propylidene cytidine mesylate (or mesylate).

In order to achieve the purpose, the invention also provides a preparation method of the antiviral drug Molnbupiravir key intermediate, which specifically comprises the following steps:

step S1: by dissolving cytidine (III) and 2, 2-dimethoxypropane in an organic solvent, reacting in the presence of methanesulfonic acid; the reaction process is as follows:

step S2: and after the reaction is finished, filtering the solution to obtain a filter cake, and drying the filter cake at 10-70 ℃ to obtain the Molnbupiravir key intermediate (I).

Further, the molar amount of the 2, 2-dimethoxypropane is 1 to 20 times, preferably 1 to 3 times, 1.5 times, 2 times and 2.5 times of that of the cytidine.

Further, the use amount of the methanesulfonic acid is 1 to 20 times, preferably 1 to 3 times, 1.5 times, 2 times, and 2.5 times the mole amount of the cytidine.

Further, the organic solvent is an organic solvent without active hydrogen, and comprises organic solvents containing halogen such as dichloromethane, chloroform or chlorobenzene; or organic solvents containing no halogen, such as benzene and toluene; or organic solvents containing other heteroatoms such as acetonitrile, acetone, DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), THF (tetrahydrofuran) or diethyl ether; or ester organic solvents such as ethyl formate and ethyl acetate.

Further, the weight amount of the organic solvent is 3 to 50 times, preferably 5 to 20 times, 7.5 times, 9.5 times, 10 times, 12.5 times, 15 times, 17.5 times and 20 times of the weight of the cytidine;

further, the reaction temperature is-70-80 ℃, the reaction time is 2-3 hours, and the preferable reaction temperature is-10-40 ℃; the drying temperature is preferably 20 ℃ to 50 ℃.

Compared with the prior art, the invention has the following beneficial effects:

1. the key intermediate mesylate (formula I) obtained by the invention has the advantages of good stability compared with the reported sulfate (formula II); the stability comparison test data is as follows: the sulfate (formula II) is in a wet material state, is placed in the air for 2 hours, and is degraded by 55 percent; the mixture was placed in a nitrogen atmosphere for 15 hours and degraded by 70%. The sulfate (formula II) is in a dry state, is placed in air for 2 hours, is degraded by 20 percent, is heated to 45 ℃, is placed for 15 hours, and is completely degraded. The mesylate (formula I) of the invention is not degraded when the wet material or the dry material is placed in the air for 48 hours; the degradation is within 5 percent after the material is placed at 55 ℃ for 15 hours.

2. According to the preparation method disclosed by the invention, cytidine is added with methanesulfonic acid to carry out acetonide protection, and meanwhile, the methanesulfonic acid and the naked amine group on the cytidine form a salt to form a stable mesylate, so that the problem of unstable sulfate is solved, the large-scale production is convenient, and the amount of three wastes is reduced.

Drawings

FIG. 1 shows the preparation of a key intermediate of the antiviral drug Molnbupiravir¹H-NMR graph;

FIG. 2 is a mass spectrometer MS plot of a key intermediate of the antiviral drug Molnbupiravir of the present invention;

FIG. 3 is an HPLC plot of a key intermediate of the antiviral drug Molnbupiravir of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, so that those skilled in the art can fully understand the technical contents of the present invention. It should be understood that the following examples are intended to further illustrate the present invention and should not be construed as limiting the scope of the present invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing description are intended to be covered by the present invention. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.

Example 1:

the preparation method of the antiviral drug Molnbupiravir key intermediate comprises the following steps: 500ml of acetone, 50g of cytidine and 25.7g of 2, 2-dimethoxypropane were placed in a 1000ml dry three-necked flask under nitrogen protection and stirred. Then, 23.7g of methanesulfonic acid was slowly dropped into the flask, and the mixture was reacted at 20 ℃ for 2 hours. After the reaction is finished, filtering is carried out, a filter cake is rinsed by 100ml of acetone and dried at 45 ℃ to obtain 76g of white solid, the yield is 97 percent, and the purity is 98.6 percent. 1H NMR (400MHz, DMSO-d6) δ 9.58(s, 1H), 8.73(s, 1H), 8.14-8.12(d, 1H, J ═ 8), 6.13-6.11(d, 1H, J ═ 8), 5.79(m, 1H), 4.92-4.90(m, 1H), 4.76-4.74(m, 1H), 4.24-4.22(m, 1H), 3.65-3.54(m, 2H), 2.44(s, 3H), 1.48(s, 3H), 1.29(s, 3H). LCMS: 284.1(M + H).

Example 2:

the preparation method of the antiviral drug Molnbupiravir key intermediate comprises the following steps: 500ml of methylene chloride, 50g of cytidine and 25.7g of 2, 2-dimethoxypropane were placed in a 1000ml dry three-necked flask under nitrogen protection and stirred. Then, 23.7g of methanesulfonic acid was slowly dropped into the flask, and reacted at 80 ℃ for 3 hours. After the reaction, the mixture was filtered, and the filter cake was rinsed with 100ml of dichloromethane and dried at 45 ℃ to obtain 74g of white solid with a yield of 95% and a purity of 98.3%. 1H NMR (400MHz, DMSO-d6) δ 9.58(s, 1H), 8.73(s, 1H), 8.14-8.12(d, 1H, J ═ 8), 6.13-6.11(d, 1H, J ═ 8), 5.79(m, 1H), 4.92-4.90(m, 1H), 4.76-4.74(m, 1H), 4.24-4.22(m, 1H), 3.65-3.54(m, 2H), 2.44(s, 3H), 1.48(s, 3H), 1.29(s, 3H). LCMS: 284.1(M + H).

Example 3:

the preparation method of the antiviral drug Molnbupiravir key intermediate comprises the following steps: 500ml of acetone, 50g of cytidine and 32.1g of 2, 2-dimethoxypropane were placed in a 1000ml dry three-necked flask under nitrogen protection and stirred. Then, 25.6g of methanesulfonic acid was slowly dropped into the flask, and the reaction was carried out at-70 ℃ for 2.5 hours. After the reaction is finished, filtering is carried out, a filter cake is rinsed by 100ml of acetone and dried at 45 ℃ to obtain 72g of white solid, the yield is 92%, and the purity is 98.7%. 1H NMR (400MHz, DMSO-d6) ∈ 9.58(s, 1H), 8.73(s, 1H), 8.14-8.12(d, 1H, J ═ 8), 6.13-6.11(d, 1H, J ═ 8), 5.79(m, 1H), 4.92-4.90(m, 1H), 4.76-4.74(m, 1H), 4.24-4.22(m, 1H), 3.65-3.54(m, 2H), 2.44(s, 3H), 1.48(s, 3H), 1.29(s, 3H). LCMS: 284.1(M + H).

Example 4:

the preparation method of the antiviral drug Molnbupiravir key intermediate comprises the following steps: 500ml of tetrahydrofuran, 50g of cytidine and 25.7g of 2, 2-dimethoxypropane were placed in a 1000ml dry three-necked flask under nitrogen protection and stirred. Then, 23.7g of methanesulfonic acid was slowly dropped into the flask, and the reaction was carried out at-10 ℃ for 2.7 hours. After the reaction is finished, filtering is carried out, a filter cake is rinsed by 100ml of tetrahydrofuran and dried at 45 ℃ to obtain 70g of white solid, the yield is 89.7 percent, and the purity is 98.5 percent. 1H NMR (400MHz, DMSO-d6) ∈ 9.58(s, 1H), 8.73(s, 1H), 8.14-8.12(d, 1H, J ═ 8), 6.13-6.11(d, 1H, J ═ 8), 5.79(m, 1H), 4.92-4.90(m, 1H), 4.76-4.74(m, 1H), 4.24-4.22(m, 1H), 3.65-3.54(m, 2H), 2.44(s, 3H), 1.48(s, 3H), 1.29(s, 3H). LCMS: 284.1(M + H).

Example 5:

the preparation method of the antiviral drug Molnbupiravir key intermediate comprises the following specific steps: 500ml of acetonitrile, 50g of cytidine and 25.7g of 2, 2-dimethoxypropane were placed in a 1000ml dry three-necked flask under nitrogen protection and stirred. Then, 23.7g of methanesulfonic acid was slowly dropped into the flask, and the mixture was reacted at 40 ℃ for 2.2 hours. After the reaction is finished, filtering is carried out, a filter cake is rinsed by 100ml of tetrahydrofuran and dried at 45 ℃ to obtain 71g of white solid, the yield is 91.0 percent, and the purity is 98.3 percent. 1H NMR (400MHz, DMSO-d6) δ 9.58(s, 1H), 8.73(s, 1H), 8.14-8.12(d, 1H, J ═ 8), 6.13-6.11(d, 1H, J ═ 8), 5.79(m, 1H), 4.92-4.90(m, 1H), 4.76-4.74(m, 1H), 4.24-4.22(m, 1H), 3.65-3.54(m, 2H), 2.44(s, 3H), 1.48(s, 3H), 1.29(s, 3H). LCMS: 284.1(M + H).

It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.