CN112979736B - Preparation method of Reidesciclovir - Google Patents
Preparation method of Reidesciclovir Download PDFInfo
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- CN112979736B CN112979736B CN202110237679.6A CN202110237679A CN112979736B CN 112979736 B CN112979736 B CN 112979736B CN 202110237679 A CN202110237679 A CN 202110237679A CN 112979736 B CN112979736 B CN 112979736B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Abstract
The invention relates to the technical field of medical intermediates, in particular to a preparation method of Reidesciclovir, which comprises the following synthetic route:
Description
Technical Field
The invention relates to the field of medical intermediates, in particular to a preparation method of Reidesvir.
Background
Reddeivir (Remdesivir), an in-process drug of Gilidd chemistry. Reidesciclovir is a nucleoside analogue with antiviral activity having an EC50 value of 74nM for ARS-CoV and MERS-CoV in HAE cells and an EC50 value of 30nM for murine hepatitis virus in delayed brain tumor cells.
At present, the process for synthesizing the Reidesvir at home and abroad roughly comprises two routes, which are as follows:
(1) the route adopted by the original inventor girlidde patent WO2016069826A1 is as follows: the preparation method comprises the steps of taking (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-alcohol as an initial raw material, and performing oxidation, addition, substitution, resolution, debenzylation, protection and substitution, and finally performing resolution to obtain the Reidesvir. The route has poor selectivity, can only be purified by a chiral column, and is not suitable for industrial production.
(2) Nature 2016 (Warren T K, Jordan R, Lo M K, et al. therapeutic efficacy of the small molecule GS-5734 by against Ebola virus in rhesus monkey [ J ] Nature 2016,531(7594):381 and 385) reports a second generation of synthetic methods that can be scaled up to hundredths in the laboratory. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. The route is optimized for the previous route, and during the cyano substitution step, trifluoromethanesulfonic acid is added to obtain a product with an isomer ratio of 95: 5, the triflic acid greatly increases the proportion of the desired beta-anomer, and the chiral purity can be further increased by subsequent recrystallization. However, this method adds protecting group addition and deprotection steps and uses a genotoxic nitro substituent, increasing the risk of the presence of genotoxic impurities.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a preparation method of the Reidesciclovir, which has the advantages of mild reaction conditions, simple operation, high yield and purity, safe production and suitability for industrial large-scale production.
In order to achieve the purpose, the invention provides the following technical scheme:
the preparation method of the Reidesciclovir comprises the following synthetic route:
wherein R is selected from
Any one of the above; x is any one of Cl, Br and I;
the method specifically comprises the following steps:
(1) reacting a compound I with a compound II in a solvent in the presence of a Lewis acid and a base to obtain a compound III;
(2) and reacting the compound III with the compound IV in a solvent in the presence of a hydroxyl activating agent and a base to obtain a compound V.
Further, in the step (1), the lewis acid used is any one of zinc chloride, aluminum chloride, ferric chloride and stannic chloride.
Further, in the step (1), the base is any one of triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-diisopropylethylamine and potassium tert-butoxide.
Further, in the step (1), the solvent used is at least one of tetrahydrofuran, methyl tert-butyl ether, dichloromethane, toluene and dimethylformamide.
Further, in the step (1), the reaction temperature is 20-50 ℃.
Further, in the step (2), the hydroxy activating agent is methylsulfonyl chloride or p-toluenesulfonyl chloride.
Further, in the step (2), the base is any one of triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and N, N-diisopropylethylamine.
Further, in the step (2), the solvent used is at least one of tetrahydrofuran, acetonitrile, dichloromethane and toluene.
Further, in the step (2), the reaction temperature is-10-10 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the invention effectively solves the problems of complicated steps, difficult purification, risk of genotoxic impurities and the like of the synthetic route in the prior art. Meanwhile, the whole route has mild reaction conditions, convenient operation and high yield and purity, and is suitable for industrial large-scale production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(1) Synthesis of Compound III
Under the protection of nitrogen, compound I-1(37g, 75mmol), compound II (12.3g, 57mmol), triethylamine (8.6g, 85mmol), zinc chloride (10.9g, 80mmol) and 100mL of tetrahydrofuran were added to a reactor, the temperature was controlled at 20 ℃ for reaction, and the reaction was monitored by HPLC to be complete. After the reaction, the solvent was concentrated under reduced pressure, dissolved in 100mL of ethyl acetate, washed with 50mL of saturated sodium bicarbonate, washed with 50mL of saturated brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound III (25.6g, 52.7mmol), with a yield of 92.5% and a purity of 99.1%.
(2) Synthesis of Compound V
Adding the compound III (26.3g, 50mmol) and 100mL of tetrahydrofuran into a reactor, stirring to dissolve, cooling to 0-10 ℃, and adding triethylamine (14.2g, 140 mmol). A solution of methanesulfonyl chloride (9.2g, 80mmol) in tetrahydrofuran (50mL) was added dropwise. After the dropwise addition, the reaction is carried out for half an hour at 0-10 ℃, and then a tetrahydrofuran (100mL) solution of the compound IV-1(12.8g, 60mmol) is dropwise added. After completion of the reaction, 300mL of purified water and 300mL of ethyl acetate were added to the reaction mixture, followed by stirring and liquid separation. The organic phase was dried over anhydrous magnesium sulfate for 6 hours and then spin-dried under reduced pressure. And performing column chromatography purification on the residue (eluent: ethyl acetate: petroleum ether 1: 20-1: 5). Adding 50mL of acetone into the obtained product, adding 10% hydrochloric acid to adjust the pH value of the mixture to 3-4, stirring the mixture at room temperature for 2 hours, concentrating the mixture under reduced pressure to remove the solvent, dissolving the solvent with 100mL of ethyl acetate, washing the solvent with 50mL of saturated sodium bicarbonate, washing the solvent with 100mL of saturated sodium chloride, separating the solution, drying the solution with anhydrous sodium sulfate, and concentrating the solution under reduced pressure to obtain a compound V (25.7g, 42.6mmol), wherein the yield is 85.2% and the purity is 98.4%.
Example 2
(1) Synthesis of Compound III
Under nitrogen protection, compound I-2(36.7g, 75mmol), compound II (12.3g, 57mmol), 1, 8-diazabicyclo [5.4.0] undec-7-ene (12.9g, 85mmol), aluminum chloride (10.7g, 80mmol) and 100mL dimethylformamide were added to a reactor, the temperature was controlled at 35 ℃ for reaction, and HPLC monitored for reaction completion. After the reaction, the solvent was concentrated under reduced pressure, dissolved in 100mL of ethyl acetate, washed with 50mL of saturated sodium bicarbonate, washed with 50mL of saturated brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound III (25.3g, 52mmol), with a yield of 91.2% and a purity of 99.2%.
(2) Synthesis of Compound V
Adding the compound III (26.3g, 50mmol) and 100mL of acetonitrile into a reactor, stirring for dissolving, cooling to-10-0 ℃, and adding 1, 8-diazabicyclo [5.4.0] undec-7-ene (21.3g, 140 mmol). A solution of p-toluenesulfonyl chloride (16.5g, 80mmol) in acetonitrile (50mL) was added dropwise. After the dropwise addition, the reaction is carried out for half an hour at the temperature of-10 to 0 ℃, and then an acetonitrile (100mL) solution of a compound IV-2(15.6g, 60mmol) is dropwise added. After completion of the reaction, 300mL of purified water and 300mL of ethyl acetate were added to the reaction mixture, followed by stirring and liquid separation. The organic phase was dried over anhydrous magnesium sulfate for 6 hours and then spin-dried under reduced pressure. And performing column chromatography purification on the residue (eluent: ethyl acetate: petroleum ether 1: 20-1: 5). Adding 50mL of acetone into the obtained product, adding 10% hydrochloric acid to adjust the pH value of the mixture to 3-4, stirring the mixture at room temperature for 2 hours, concentrating the mixture under reduced pressure to remove the solvent, dissolving the solvent with 100mL of ethyl acetate, washing the solvent with 50mL of saturated sodium bicarbonate, washing the solvent with 100mL of saturated sodium chloride, separating the solution, drying the solution with anhydrous sodium sulfate, and concentrating the solution under reduced pressure to obtain a compound V (25.2g, 41.8mmol), wherein the yield is 83.6% and the purity is 98.6%.
Example 3
(1) Synthesis of Compound III
Under nitrogen protection, compound I-3(32g, 75mmol), compound II (12.3g, 57mmol), N-diisopropylethylamine (11g, 85mmol), tin tetrachloride (20.8g, 80mmol) and 100mL of dichloromethane were added to the reactor, the temperature was controlled at 35 ℃ for reaction, and HPLC monitored for completion of the reaction. After the reaction, the solvent was concentrated under reduced pressure, dissolved in 100mL of ethyl acetate, washed with 50mL of saturated sodium bicarbonate, washed with 50mL of saturated brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound III (25.1g, 51.7mmol), with a yield of 90.7% and a purity of 99.1%.
(2) Synthesis of Compound V
Adding the compound III (26.3g, 50mmol) and 100mL of toluene into a reactor, stirring for dissolving, cooling to 0-10 ℃, and adding N, N-diisopropylethylamine (18.1g, 140 mmol). A solution of methanesulfonyl chloride (9.2g, 80mmol) in toluene (50mL) was added dropwise. After the dropwise addition, the reaction is carried out for half an hour at 0-10 ℃, and then a toluene (100mL) solution of a compound IV-3(10.1g, 60mmol) is dropwise added. After completion of the reaction, 300mL of purified water and 300mL of ethyl acetate were added to the reaction mixture, followed by stirring and liquid separation. The organic phase was dried over anhydrous magnesium sulfate for 6 hours and then spin-dried under reduced pressure. And performing column chromatography purification on the residue (eluent: ethyl acetate: petroleum ether 1: 20-1: 5). Adding 50mL of acetone into the obtained product, adding 10% hydrochloric acid to adjust the pH value of the mixture to 3-4, stirring the mixture at room temperature for 2 hours, concentrating the mixture under reduced pressure to remove the solvent, dissolving the solvent with 100mL of ethyl acetate, washing the solvent with 50mL of saturated sodium bicarbonate, washing the solvent with 100mL of saturated sodium chloride, separating the solution, drying the solution with anhydrous sodium sulfate, and concentrating the solution under reduced pressure to obtain a compound V (25g, 41.5mmol), wherein the yield is 83% and the purity is 98.4%.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. The preparation method of the Reidesciclovir is characterized in that the synthetic route is as follows:
wherein R is selected from
Any one of the above; x is any one of Cl, Br and I;
the method specifically comprises the following steps:
(1) reacting a compound I with a compound II in a solvent in the presence of a Lewis acid and a base to obtain a compound III;
(2) and reacting the compound III with the compound IV in a solvent in the presence of a hydroxyl activating agent and a base to obtain a compound V.
2. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (1), the Lewis acid is any one of zinc chloride, aluminum chloride, ferric chloride and stannic chloride.
3. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (1), the base is any one of triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-diisopropylethylamine and potassium tert-butoxide.
4. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (1), the solvent is at least one of tetrahydrofuran, methyl tert-butyl ether, dichloromethane, toluene and dimethylformamide.
5. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (1), the reaction temperature is 20-50 ℃.
6. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (2), the used hydroxyl activating agent is methylsulfonyl chloride or p-methylbenzenesulfonyl chloride.
7. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (2), the base is any one of triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and N, N-diisopropylethylamine.
8. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (2), the solvent is at least one of tetrahydrofuran, acetonitrile, dichloromethane and toluene.
9. A process for preparing ridciclovir according to claim 1, characterized in that: in the step (2), the reaction temperature is-10-10 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107073005A (en) * | 2014-10-29 | 2017-08-18 | 吉利德科学公司 | The method for treating the infection of filamentous virus coe virus |
| CN111233931A (en) * | 2020-03-26 | 2020-06-05 | 宿迁盛基医药科技有限公司 | Synthesis method of Reidesciclovir |
| CN111471070A (en) * | 2020-04-26 | 2020-07-31 | 江苏阿尔法药业有限公司 | Synthetic method of Reidesciclovir |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107073005A (en) * | 2014-10-29 | 2017-08-18 | 吉利德科学公司 | The method for treating the infection of filamentous virus coe virus |
| CN111233931A (en) * | 2020-03-26 | 2020-06-05 | 宿迁盛基医药科技有限公司 | Synthesis method of Reidesciclovir |
| CN111471070A (en) * | 2020-04-26 | 2020-07-31 | 江苏阿尔法药业有限公司 | Synthetic method of Reidesciclovir |
Non-Patent Citations (1)
| Title |
|---|
| "Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir";Tiago Vieira et al.;《ORGANIC PROCESS RESEARCH & DEVELOPMENT》;20201016;第24卷(第10期);2113-2121 * |
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