CN111205294B - Preparation method of Reidesciclovir intermediate - Google Patents
Preparation method of Reidesciclovir intermediate Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to the technical field of medical intermediates, in particular to a preparation method of a ridciclovir intermediate, the chemical name of the preparation method is (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile, and the preparation method comprises the following steps: 1) asymmetrically adding 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone in a solvent to form (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile; 2) (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile is reacted with a hydroxy activator and then with 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine in a solvent to form (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile.
Description
Technical Field
The invention relates to the field of medical intermediates, in particular to a preparation method of a Reidesciclovir intermediate.
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.
(2) Nature 2016 reports a second generation synthesis method, which is scalable to hundredths of grams in the laboratory. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. The route 1 is optimized, during the cyano substitution step, the isomer ratio of the obtained product is 95:5 by adding trifluoromethanesulfonic acid, the ratio of the desired beta-anomer is greatly increased by trifluoromethanesulfonic acid, the chiral purity can be further increased by subsequent recrystallization, and the route 1 has poor selectivity and is only purified by a chiral column.
Disclosure of Invention
The invention aims to provide a novel Rudexilvir intermediate (2R,3R,4R,5R) -2- (4-aminopyrrole [2, 1-f)][1,2,4]A synthetic method of triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile, the structural formula of which is shown in the specification
In both of the above-mentioned routes of the background art, pyrrole triazine is added and then cyano is added, and the mixture is purified by a chiral column or recrystallization. The method firstly adds cyano to improve chiral selectivity as much as possible, and then obtains a single chiral pure compound through recrystallization. The Rudexilvir intermediate (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile is obtained by activating the hydroxy group and then substituting with pyrrolyltriazine iodide.
The specific route is as follows:
a first step of carrying out asymmetric addition on 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone in a solvent to form (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile;
in a second step, (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile is reacted with a hydroxy activator and then with 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine in a solvent to form (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile.
Wherein, the first step of reaction process is as follows:
the solvent used in the reaction is preferably at least one of Dichloromethane (DCM), Tetrahydrofuran (THF) and 1, 2-dichloroethane, and the dosage of the solvent is 2 times to 8 times of the weight of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone;
the temperature for the reaction of this step is preferably 0 ℃ to 50 ℃;
the Lewis acid used in the step of reaction addition is preferably at least one of aluminum trichloride, stannic chloride and titanium tetrachloride;
the cyano reagent used in the step of reaction addition is preferably at least one of trimethylsilyl cyanide and tert-butylcyanodimethylsilane;
in the reaction of the step, the molar ratio of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, Lewis acid and cyano reagent is 1: 0.2: 1 to 1: 2: 5;
the chiral purity is improved by recrystallization of a mixed solvent, wherein the mixed solvent is preferably ethyl acetate: petroleum ether system, ethyl acetate: n-heptane system, acetone: n-heptane system and 4-methyl-2-pentanone: n-heptane system.
The second step of reaction process is:
the solvent used in the substitution reaction is preferably at least one of Tetrahydrofuran (THF) and acetonitrile, and the dosage of the solvent is 2 times to 8 times of the weight of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-nitrile;
the used hydroxyl activating agent is preferably at least one of methylsulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl); in an amount of 1 to 3 times the molar amount of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile;
the temperature used in the substitution reaction in the step is preferably-10 ℃ to 20 ℃;
the base used in the substitution reaction is preferably at least one of triethylamine and DIPEA.
Compared with the prior art, the invention has the beneficial effects that: the method firstly carries out chiral addition on the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, further purifies and improves the chiral purity, and compared with two routes introduced in the background technology, the method further forms a chiral center in advance, reduces the usage amount of 7-iodopyrrole [2,1-f ] [1,2,4] triazine-4-amine and saves the cost.
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
A preparation method of (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile comprises the following specific steps:
1. synthesis of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile
Dissolving 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (41.9g, 0.1mol) in anhydrous dichloromethane (300mL), controlling the temperature to be 0-10 ℃, dropwise adding titanium tetrachloride (5.5mL,0.05mol), and after dropwise adding, adding trimethylsilyl cyanide (19.8g, 0.2 mol). And reacting for 1 hour after the dropwise addition is finished, adding 200mL of saturated sodium bicarbonate aqueous solution into the reaction solution, stirring and separating, drying the organic phase with anhydrous magnesium sulfate for 6 hours, removing the solvent under reduced pressure, adding ethyl acetate (50mL) and petroleum ether (150mL) into the residue, heating to 40 ℃, stirring and dissolving, gradually cooling to room temperature, separating out a solid, and stirring and crystallizing for 2 hours at 0-10 ℃. And (3) carrying out suction filtration, leaching a filter cake by using a small amount of petroleum ether, and carrying out vacuum drying on the filter cake at 40 ℃ to obtain 28g of white-like solid with the molar yield of 64.2%.
2. Synthesis of (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile
(2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile (22.3g, 0.05mol) was dissolved in anhydrous tetrahydrofuran (100mL), cooled to 0-10 ℃ and triethylamine (15.2g, 0.15mol) was added. A solution of methanesulfonyl chloride (8.6g, 0.075mol) in anhydrous tetrahydrofuran (50mL) was added dropwise. After the dropwise addition, the reaction is carried out for half an hour at 10-20 ℃, and then anhydrous tetrahydrofuran (100mL) of 7-iodopyrrole [2,1-f ] [1,2,4] triazine-4-amine (15.6g, 0.06mol) is dropwise added. After reacting for 2 hours, purified water (300mL) was added to the reaction mixture, and ethyl acetate (300mL) was added thereto, 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) to obtain (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile (19g) with the molar yield of 68%.
Example 2
A preparation method of (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile comprises the following specific steps:
1. synthesis of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile
Dissolving 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (41.9g, 0.1mol) in 1, 2-dichloroethane (300mL), controlling the temperature to be 20-30 ℃, adding anhydrous aluminum trichloride (20g,0.15mol), and adding tert-butylcyanodimethylsilane (56g, 0.4mol) after dropwise addition. And reacting for 1 hour after the dropwise addition is finished, adding 200mL of saturated sodium bicarbonate aqueous solution into the reaction solution, stirring and separating, drying the organic phase with anhydrous magnesium sulfate for 6 hours, removing the solvent under reduced pressure, adding 4-methyl 2-pentanone (50mL) into the residue, heating n-heptane (100mL) to 45 ℃, stirring and dissolving, gradually cooling to room temperature, precipitating a solid, and stirring and crystallizing for 2 hours at the temperature of 0-10 ℃. And (3) carrying out suction filtration, leaching a filter cake with a small amount of n-heptane, and carrying out vacuum drying on the filter cake at 40 ℃ to obtain 33g of white-like solid with the molar yield of 74%.
2. Synthesis of (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile
(2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-carbonitrile (22.3g, 0.05mol) was dissolved in acetonitrile (100mL), cooled to 10-20 ℃ and DIPEA (19.4g, 0.15mol) was added. A solution of p-methylbenzenesulfonyl chloride (19.1g, 0.1mol) in acetonitrile (50mL) was added dropwise. After the dropwise addition, the reaction is carried out for half an hour at 10-20 ℃, and then acetonitrile (100mL) of 7-iodopyrrole [2,1-f ] [1,2,4] triazine-4-amine (19.5g, 0.075mol) is dropwise added. After reacting for 2 hours, purified water (300mL) was added to the reaction mixture, and ethyl acetate (300mL) was added thereto, 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) to obtain (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-nitrile (15g) with the molar yield of 55%.
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 (2)
1. A preparation method of a ridciclovir intermediate, wherein the ridciclovir intermediate is (2R,3R,4R,5R) -2- (4-aminopyrrole [, ]2,1-f][1,2,4]Triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile having the structural formula
The method is characterized by comprising the following steps:
(1) in a solvent, carrying out asymmetric addition on 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone to form (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-nitrile, wherein the reaction temperature is 0-50 ℃; the solvent is at least one of Dichloromethane (DCM), Tetrahydrofuran (THF) and 1, 2-dichloroethane; the dosage of the solvent is 2 to 8 times of the mass of the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone; adopting Lewis acid and a cyano reagent, wherein the Lewis acid is at least one of aluminum trichloride, stannic chloride and titanium tetrachloride; the cyano reagent is at least one of trimethyl cyano silane and tert-butyl cyano dimethylsilane; the molar ratio of the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone to the Lewis acid to the cyano reagent is 1: 0.2: 1 to 1: 2: 5; improving chiral purity by recrystallization of a mixed solvent, wherein the mixed solvent is ethyl acetate: petroleum ether system, ethyl acetate: n-heptane system, acetone: n-heptane system and 4-methyl-2-pentanone: any one of n-heptane systems;
(2) in the solvent, the solvent is at least one of tetrahydrofuran and acetonitrile, and the dosage of the solvent is 2 times to 8 times of the mass of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-nitrile; reacting (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-nitrile with a hydroxyl activator, wherein a base is added in the reaction, and the base is at least one of triethylamine and DIPEA;
and then reacting with 7-iodopyrrole [2,1-f ] [1,2,4] triazin-4-amine to form (2R,3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile; the hydroxyl activating agent is at least one of methylsulfonyl chloride and p-methylbenzenesulfonyl chloride, and the dosage of the hydroxyl activating agent is 1-3 times of the molar quantity of (2R,3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) -2-hydroxytetrahydrofuran-2-nitrile.
2. A process for the preparation of a ridciclovir intermediate according to claim 1, characterized in that: the reaction temperature in the step (2) is-10 ℃ to 20 ℃.
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| IL299202A (en) | 2020-06-24 | 2023-02-01 | Gilead Sciences Inc | 1'-cyano nucleoside analogs and uses thereof |
| CN111825641B (en) * | 2020-08-03 | 2022-04-15 | 苏州开元民生科技股份有限公司 | Method for preparing 3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-ketone |
| CA3185450A1 (en) | 2020-08-06 | 2022-02-10 | Istvan Borza | Remdesivir intermediates |
| EP4204421A2 (en) | 2020-08-27 | 2023-07-05 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| CN114105989A (en) * | 2020-08-31 | 2022-03-01 | 中国科学院大连化学物理研究所 | Preparation method and application of iodo-pyrrolotriazine amine compound |
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| CN114989218B (en) * | 2022-07-29 | 2022-12-06 | 山东诚创蓝海医药科技有限公司 | Synthetic method of Ruidecy Wei Lin isomer |
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