A green synthesis method of cidofovir

Abstract

The invention discloses a green synthesis method of cidofovir, wherein the specific synthesis process of chiral N4 benzoylcytosine diol compound is: chiral N4 benzoylcytosine epoxy compound, water and ionic liquid catalyst are mixed uniformly and added to autoclave, then CO2 gas is passed through to react at 0 140 DEG C, product and ionic liquid catalyst are separated after reaction, chiral N4 benzoylcytosine diol compound is obtained by column chromatography, it is hydroxyl protection, phospholipidation, deprotection series of reactions to synthesize target product cidofovir, and the isolated ionic liquid catalyst is repeatedly recycled. The present invention does not need to use catalysts such as metals, inorganic bases, does not need to add a large amount of solvents, and the involved operation is simple, reaction conditions are mild, and the catalyst used is ionic liquid, which is relatively friendly to the environment. Meanwhile, the yield of the target product synthesized by the present invention is relatively high, and ee value can be maintained.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of a chiral drug cidofovir, and particularly relates to a green synthesis method of cidofovir. Background Art

[0002] Cidofovir is a nucleoside analog that inhibits viral DNA polymerase and is effective against human cytomegalovirus (CMV) infection. It is a broad-spectrum drug with in vitro activity against human herpesvirus, adenovirus, HPV, polyomavirus, and vaccinia virus. It is currently under clinical investigation and has a variety of potential applications. Due to the specificity of its structure, the synthesis of a single configuration of cidofovir is of great significance. In 1988, Robet et al. (Synthesis of (S)-N 1-(3-hydroxy-2-phosphonylmethoxy)propylcytosine, (S)-HPMPC) uses chiral glyceraldehyde and cytosine as raw materials, DMF and methanol as solvents, and synthesizes the intermediate under the catalysis of cesium carbonate, and then reduces it with palladium hydroxide and esterifies it with TMSBr to obtain the final product. In 1990, Bronson et al. (A New Synthesis of the Potent and Selective Anti-Herpesvirus Agent (S)-1-[3-Hydroxy-2-(Phosphonylmethoxy)Propyl]Cytosine) optimized the synthesis method, replaced cesium carbonate with potassium tert-butoxide, and opened the five-membered ring under the action of concentrated hydrochloric acid to obtain the chiral N4-benzoylcytosine diol intermediate, and then obtained cidofovir through a series of conventional reactions. In 1994, Vemishetti et al. (Apractical synthesis of (S)-HPMPC) also used chiral R-glycidyl alcohol to react with protected cytosine to obtain an intermediate product, and then similar to the above conventional steps, finally obtained the target product with a total yield of 39%. In 2018, Guo et al. (Synthesis of Chiral Acyclic Nucleosides by Sharpless Asymmetric Dihydroxylation: Access to Cidofovir and Buciclovir) used cytosine containing allyl substituents as raw materials, added chiral metal ligands for asymmetric catalysis, and obtained the chiral N4-benzoylcytosine diol intermediate product with a yield of 93% and an ee value of 76%, and then obtained the chiral drug cidofovir through conventional steps. In the method of synthesizing cidofovir from chiral sources, a large amount of alkali metal salts and organic solvents are used; in addition, the chiral metal catalysts used in the asymmetric synthesis strategy have high costs due to their high prices and the pollution caused by their non-recyclability to the environment cannot be ignored. There is still a need to develop an economical, green and pollution-free method for synthesizing the chiral drug cidofovir. At present, there is no report on the method of using carbon dioxide to participate in the synthesis of chiral N4-benzoylcytosine diol as an intermediate for the synthesis of cidofovir. Summary of the invention

[0003] The technical problem solved by the present invention is to provide a green synthesis method of cidofovir. According to the method, a chiral N4-benzoylcytosine epoxy compound is prepared by catalysis of a multifunctional ionic liquid in the presence of carbon dioxide to form a chiral N4-benzoylcytosine diol compound, and then cidofovir is synthesized through a series of reactions including hydroxyl protection, phospholipidation and deprotection.

[0004] The present invention adopts the following technical solution to solve the above technical problems, a green synthesis method of cidofovir, characterized in that the synthesis route is:

[0005]

[0006] The specific synthesis process of the chiral N4-benzoylcytosine diol compound is as follows: the chiral N4-benzoylcytosine epoxy compound, water and ionic liquid catalyst are uniformly mixed and added into a high-pressure reactor, and then CO2 gas is introduced to react at 0-140°C, and after the reaction is completed, the product and the ionic liquid catalyst are separated, and the product is subjected to column chromatography to obtain the chiral N4-benzoylcytosine diol compound, and the separated ionic liquid catalyst is repeatedly recycled;

[0007] The structural formula of the ionic liquid catalyst is:

[0008]

[0009] wherein m and n are both integers between 1 and 16, and X is F, Cl, Br, I or OH.

[0010] It is further defined that the molar ratio of the chiral N4-benzoylcytosine epoxy compound, water and ionic liquid catalyst is 1:10:1-1:45:1, and the pressure of the CO2 gas in the high-pressure reactor is 0.1-10 MPa.

[0011] It is further defined that the reaction temperature during the synthesis process is 60-100°C and the pressure of the CO2 gas is 1-4MPa.

[0012] Compared with the prior art, the present invention has the following advantages: in the synthesis method of the present invention, under the catalysis of an ionic liquid with multiple active sites and a small amount of water, a chiral N4-benzoylcytosine epoxy compound reacts with carbon dioxide in one step to generate a chiral N4-benzoylcytosine diol compound. Compared with the prior art, the method does not require the use of catalysts such as metals and inorganic bases, does not require the addition of a large amount of solvent, and the operation involved is simple, the reaction conditions are mild, and the catalyst used is an ionic liquid, which is relatively environmentally friendly. At the same time, the yield of the target product synthesized by the method is relatively high, and the ee value can be maintained. DETAILED DESCRIPTION

[0013] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0014] Example 1

[0015] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (10mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then the high-pressure reactor was placed in a heating stirrer at a temperature of 60°C and 2MPa of CO2 gas was introduced. After continuous reaction for 24 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product. The chiral N4-benzoylcytosine diol compound was obtained by column chromatography with a yield of 92% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=4, n=4, X=Br.

[0016] Example 2

[0017] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (35mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heating stirrer at a temperature of 80°C and 2MPa of CO2 gas was introduced. After continuous reaction for 18 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 84% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=2, n=3, X=OH.

[0018] Example 3

[0019] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (45mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heating stirrer at a temperature of 70°C and 2MPa of CO2 gas was introduced. After continuous reaction for 12 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was then added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 86% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=6, n=2, X=Br.

[0020] Example 4

[0021] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (27mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heating stirrer at a temperature of 80°C and 4MPa of CO2 gas was introduced. After continuous reaction for 20 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 85% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=8, n=6, X=OH.

[0022] Example 5

[0023] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (35mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heating stirrer at a temperature of 100°C and 2MPa of CO2 gas was introduced. After continuous reaction for 15 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 76% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=3, n=3, X=Cl.

[0024] Example 6

[0025] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (15mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then the high-pressure reactor was placed in a heating stirrer at a temperature of 70°C and 2MPa of CO2 gas was introduced. After continuous reaction for 24 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 54% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=4, n=3, X=I.

[0026] Example 7

[0027] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (30mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then the high-pressure reactor was placed in a heating stirrer at a temperature of 60°C and 2MPa of CO2 gas was introduced. After continuous reaction for 24 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 69% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=4, n=4, X=Cl.

[0028] Example 8

[0029] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (20mmol) were mixed evenly and added to a high-pressure reactor. CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heating stirrer at a temperature of 60°C and 1MPa of CO2 gas was introduced. After continuous reaction for 24 hours, the high-pressure reactor was cooled and excess gas was released. Dichloromethane was added to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried for the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 55% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=6, n=2, X=Br.

[0030] Example 9

[0031] N4-benzoylcytosine epoxy compound (1mmol) (ee value 99%), ionic liquid catalyst (1mmol) and water (25mmol) were mixed evenly and added to a high-pressure reactor, and CO2 gas was replaced three times. Then, the high-pressure reactor was placed in a heated and stirred alkane at a temperature of 60°C to separate the product and the ionic liquid catalyst. The ionic liquid catalyst was washed and dried before the next use. The product was subjected to column chromatography to obtain a chiral N4-benzoylcytosine diol compound with a yield of 94% and an ee value of 99%. The structural formula of the ionic liquid catalyst used in the synthesis process is Wherein m=4, n=2, X=OH.

[0032] The chiral N4-benzoylcytosine diol compound synthesized above is subjected to a series of reactions including hydroxyl protection, phospholipidation, and deprotection to finally obtain the antiviral acyclic nucleoside drug cidofovir. The specific synthesis route is as follows:

[0033]

[0034] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A green synthesis method of cidofovir, characterized in that The synthetic route is: The specific synthesis process of the chiral N4-benzoylcytosine diol compound is as follows: the chiral N4-benzoylcytosine epoxy compound, water and ionic liquid catalyst are uniformly mixed and added into a high-pressure reactor, and then CO2 gas is introduced to react at 0-140°C, and after the reaction is completed, the product and the ionic liquid catalyst are separated, and the product is subjected to column chromatography to obtain the chiral N4-benzoylcytosine diol compound, and the separated ionic liquid catalyst is repeatedly recycled; The structural formula of the ionic liquid catalyst ILs is: wherein m and n are both integers between 1 and 16, and X is F, Cl, Br, I or OH.

2. The green synthesis method of cidofovir according to claim 1, characterized in that: The molar ratio of the chiral N4-benzoylcytosine epoxy compound, water and ionic liquid catalyst is 1:10:1-1:45:1, and the pressure of CO2 gas in the high-pressure reactor is 0.1-10MPa.

3. The green synthesis method of cidofovir according to claim 1, characterized in that: The reaction temperature during the synthesis process is 60-100°C, and the pressure of the CO2 gas is 1-4MPa.

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