阅读说明：本技术 一种瑞德西韦中间体的合成方法 (Synthetic method of Reidesciclovir intermediate ) 是由 夏青青 于 2020-12-01 设计创作，主要内容包括：本发明公开了一种瑞德西韦中间体的合成方法,包括以下步骤：S1、将7-碘吡咯并[2,1-f][1,2,4]三嗪-4-胺加入至有机溶剂中,加入四甲基乙二胺搅拌混合,再加入硅保护试剂反应,随后加入苯基氯化镁保护胺基；S2、向体系中加入异丙基氯化镁,再加入2,3,5-三苄氧基-D-核糖酸-1,4-内酯反应制得(3R,4R,5R)-2-(4-胺基吡咯[2,1-f][1,2,4]三嗪-7-yl)-3,4-双(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-醇)。通过该合成方法制得的产物收率高达50-60％,利于瑞德西韦原料药的工业化生产。(The invention discloses a synthesis method of a Rudexilvir intermediate, which comprises the following steps: s1, adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine into an organic solvent, adding tetramethyl ethylenediamine, stirring and mixing, adding a silicon protection reagent for reaction, and then adding phenylmagnesium chloride for protecting an amino group; s2, adding isopropyl magnesium chloride into the system, adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, and reacting to obtain (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol). The yield of the product prepared by the synthesis method is as high as 50-60%, and the industrial production of the bulk drug of the Reidesciclovir is facilitated.)

1. A synthesis method of a Reidesciclovir intermediate is characterized in that the Reidesciclovir intermediate is (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), and the structural formula of the Reidesciclovir intermediate is shown as a formula I

The method is characterized by comprising the following steps:

s1, adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine into an organic solvent, adding tetramethyl ethylenediamine, stirring and mixing, adding a silicon protection reagent for reaction, and then adding phenylmagnesium chloride for protecting an amino group;

s2, adding isopropyl magnesium chloride into the system, and then adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone to react to prepare (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol);

wherein, in the step S1, the water content of the organic solvent is 135-450 ppm.

2. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S1, the molar ratio of 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine to tetramethylethylenediamine is 1: (2.8-3.2).

3. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S1, the mole ratio of the silicon protecting reagent, phenylmagnesium chloride and 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine is (1.8-2.2): (1.8-2.2): 1.

4. a synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S2, the molar ratio of isopropyl magnesium chloride, 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone and 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine is (0.9-1.2): (0.8-1.2): 1.

5. a synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S1, the silicon protecting reagent is trimethylchlorosilane or tetramethyldichlorodisilane.

6. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in the step S1, the organic solvent is any one or a combination of several of tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethyl sulfoxide and N, N-dimethyl imine.

7. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S1, the temperature is room temperature when tetramethylethylenediamine is added into the system, the temperature is reduced to 10 ℃ to 15 ℃ when silicon protecting reagent is added, and the temperature is reduced to-35 ℃ to-45 ℃ when phenylmagnesium chloride is added.

8. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that in step S2, when 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is added, the temperature is reduced to below-40 ℃.

Technical Field

The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthetic method of a Reidesciclovir intermediate.

Background

Reddeivir (Remdesivir) is a nucleoside analog 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. Meanwhile, the Reidesciclovir is a broad-spectrum medicine, and has ideal effects on coronavirus, filovirus and paramyxovirus at present, so that research and production of Reidesciclovir are of great significance for treating new coronavirus.

Currently, the synthesis route of the ridciclovir is shown in fig. 1, and in the synthesis route, the synthesis of a ridciclovir intermediate GS-6, namely (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol) is a crucial step. The patent document WO2012142085 describes a synthetic route of a Reidesciclovir intermediate GS-6, which is to dissolve Reidesciclovir intermediate GS-5 (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine) in tetrahydrofuran, add a silicon protective reagent, protect amino groups under the action of phenyl magnesium chloride, exchange the amino groups with iodine under the action of isopropyl magnesium chloride to obtain a carbanion intermediate state, and then react with 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone to obtain a Reidesciclovir intermediate GS-6. However, the yield of the final preparation of the ridciclovir intermediate GS-5 by the above synthesis method is very low, and particularly, under the condition that the water content of the tetrahydrofuran solvent is high, a product can hardly be obtained, and when the reaction is carried out by using the commercially available tetrahydrofuran solvent with low water content (the water content is 135ppm), the yield of the product is 15-25%, and the yield is also low, so that the method is not suitable for industrial production.

Therefore, a method for synthesizing the ridciclovir intermediate with higher yield is sought, and the method has important practical significance for the industrial production of the ridciclovir bulk drug.

Disclosure of Invention

In order to solve the problems that the yield of the existing Reidesciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol) is low and the industrial production is difficult, the invention aims to provide a synthetic method of the Reidesciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), the yield of the product is as high as 50-60%, the industrial production of the bulk drug of the Reidesciclovir is facilitated, and the development of the economic technology of the Reidesciclovir is promoted.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a synthesis method of a Reidesciclovir intermediate, wherein the Reidesciclovir intermediate is (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), and the structural formula of the Reidesciclovir intermediate is shown as a formula I

The method comprises the following steps:

s1, adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine into an organic solvent, adding tetramethyl ethylenediamine, stirring and mixing, adding a silicon protection reagent for reaction, and then adding phenylmagnesium chloride for protecting an amino group;

s2, adding isopropyl magnesium chloride into the system, and then adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone to react to prepare (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol);

wherein, in the step S1, the water content of the organic solvent is 135-450 ppm.

In step S1, the molar ratio of 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine to tetramethylethylenediamine is 1: (2.8-3.2).

Wherein, in the step S1, the molar ratio of the silicon protective reagent, the phenylmagnesium chloride and the 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine is (1.8-2.2): (1.8-2.2): 1.

wherein, in the step S2, the molar ratio of isopropyl magnesium chloride, 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone and 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine is (0.9-1.2): (0.8-1.2): 1.

in step S1, the silicon protecting agent is trimethylchlorosilane or tetramethyldichlorodisilane. Trimethylchlorosilane is preferred.

In step S1, the organic solvent is any one or a combination of several of tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethyl sulfoxide and N, N-dimethyl imine. Tetrahydrofuran is preferred.

In the step S1, the temperature is room temperature when tetramethylethylenediamine is added into the system, the temperature is reduced to 10 ℃ to 15 ℃ when a silicon protective reagent is added, and the temperature is reduced to-35 ℃ to-45 ℃ when phenylmagnesium chloride is added.

Wherein, in the step S2, the temperature is reduced to below-40 ℃ when the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is added for reaction.

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

the research on the reaction mechanism shows that the reason that the yield of the existing synthesis method is low is that carbanion intermediates generated in the reaction process are easily damaged by the moisture of the system, iodine is removed from the structures, and the carbanion intermediates cannot further react with 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone; according to the invention, the tetramethylethylenediamine substance is added into the reaction system, and forms a stable ion pair (or salt formation) with the carbanion intermediate to play a role in stabilizing the carbanion intermediate, so that the influence of trace moisture in the reaction system on the overall reaction is reduced, the moisture in the organic solvent in the reaction system is controlled to be 135-450ppm, the yield of the finally synthesized product is up to 50-60%, the industrial production of the bulk drug of the Reidesciclovir is facilitated, and the development of the economic technology of the Reidesciclovir bulk drug is promoted.

Drawings

The invention is described in further detail below with reference to specific embodiments and with reference to the following drawings.

FIG. 1 is a schematic diagram of a synthetic route for Redcixvir in the prior art;

fig. 2 is a schematic diagram of a synthetic route of the ridciclovir intermediate of the invention.

Detailed Description

The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.

Example 1

This example provides a method for synthesizing a ridciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), which includes the following steps:

s1, weighing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (1300g, 5mol), adding into a reaction kettle, adding 13L tetrahydrofuran (with the water content of 240ppm), stirring at room temperature to dissolve the tetrahydrofuran, adding 1740g, 15mol tetramethylethylenediamine (1740g, 15mol) into the reaction kettle, stirring at room temperature for about 10min, cooling to 10 ℃, adding 1080g, 10mol trimethylchlorosilane (for reaction for 30 min), replacing air under reduced pressure, slowly cooling to-40 ℃, slowly adding 2mol/L phenylmagnesium chloride (5L,10mol) dropwise, and continuing to stir for reaction for 15 min;

s2, adding 1.3mol/L isopropyl magnesium chloride lithium chloride complex (4.0L, 5.2mol) into the system, stirring for 30min, controlling the temperature of the reaction system to be below-40 ℃, adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (2009g, 5mol) in batches, and continuing to react for 2 h;

s3, detecting reaction by TLC (thin layer chromatography), after the reaction is finished, adding 1.3L of acetic acid into a reaction system for quenching, taking out and collecting reaction liquid, adding 10L of water and 15L of ethyl acrylate into the reaction liquid for extraction, carrying out liquid separation treatment, respectively collecting an organic phase and an aqueous phase, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, combining the organic phases obtained by two extractions, washing the combined organic phase by using 18L of 1mol/L hydrochloric acid, carrying out liquid separation treatment, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, and combining the organic phase with the organic phase obtained by the previous liquid separation;

s4, washing the obtained organic phase with a saturated sodium carbonate solution and a saturated saline solution respectively, concentrating under reduced pressure, performing sample mixing and column passing twice, wherein a solvent used in the first sample mixing and column passing is a mixed solution of petroleum ether and ethyl acrylate with a molar ratio of 2:1, a solvent used in the second sample mixing and column passing is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and drying to obtain 1462g of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol with a molar yield of 52.9%.

Example 2

This example provides a method for synthesizing a ridciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), which includes the following steps:

s1, weighing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (1300g, 5mol), adding into a reaction kettle, adding 15L tetrahydrofuran (with the water content of 135ppm), stirring at room temperature to dissolve the tetrahydrofuran, adding 1624g, 14mol tetramethylethylenediamine (1624g, 14mol), stirring at room temperature for about 15min, cooling to 10 ℃, adding trimethylchlorosilane (972g, 9mol), reacting for 30min, replacing air under reduced pressure, slowly cooling to-40 ℃, slowly adding 2mol/L phenylmagnesium chloride (5.5L,11mol) dropwise, and continuing to stir for 15 min;

s2, adding 1.3mol/L isopropyl magnesium chloride lithium chloride complex (3.46L, 4.5mol) into the system, stirring for 30min, controlling the temperature of the reaction system to be below-40 ℃, adding 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone (1607.2g, 4mol) in batches, and continuing to react for 2 h;

s3, detecting reaction by TLC (thin layer chromatography), after the reaction is finished, adding 1.3L of acetic acid into a reaction system for quenching, taking out and collecting reaction liquid, adding 10L of water and 15L of ethyl acrylate into the reaction liquid for extraction, carrying out liquid separation treatment, respectively collecting an organic phase and an aqueous phase, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, combining the organic phases obtained by two extractions, washing the combined organic phase by using 18L of 1mol/L hydrochloric acid, carrying out liquid separation treatment, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, and combining the organic phase with the organic phase obtained by the previous liquid separation;

s4, washing the obtained organic phase with a saturated sodium carbonate solution and a saturated saline solution in sequence, concentrating under reduced pressure, performing sample mixing and column passing twice, wherein the solvent used in the first sample mixing and column passing is a mixed solution of petroleum ether and ethyl acrylate with a molar ratio of 2:1, the solvent used in the second sample mixing and column passing is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and drying to obtain 1636g of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol) with a molar yield of 59.2%.

Example 3

This example provides a method for synthesizing a ridciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), which includes the following steps:

s1, weighing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (1300g, 5mol), adding into a reaction kettle, adding 12L tetrahydrofuran (with the water content of 310ppm), stirring at room temperature to dissolve the tetrahydrofuran, adding tetramethylethylenediamine (1856g, 16mol), stirring at room temperature for about 15min, cooling to 15 ℃, adding tetramethyldichlorodisilane (1685g, 9mol), reacting for 30min, replacing air under reduced pressure, slowly cooling to-40 ℃, slowly adding 2mol/L phenylmagnesium chloride (4.5L,9mol) dropwise, and continuing to stir for reaction for 15 min;

s2, adding 1.3mol/L isopropyl magnesium chloride lithium chloride complex (3.85L, 5mol) into the system, stirring for 25min, controlling the temperature of the reaction system to be below-40 ℃, adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (2009g, 5mol) in batches, and continuing to react for 2 h;

s3, detecting reaction by TLC (thin layer chromatography), after the reaction is finished, adding 1.3L of acetic acid into a reaction system for quenching, taking out and collecting reaction liquid, adding 10L of water and 15L of ethyl acrylate into the reaction liquid for extraction, carrying out liquid separation treatment, respectively collecting an organic phase and an aqueous phase, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, combining the organic phases obtained by two extractions, washing the combined organic phase by using 18L of 1mol/L hydrochloric acid, carrying out liquid separation treatment, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, and combining the organic phase with the organic phase obtained by the previous liquid separation;

s4, washing the obtained organic phase with a saturated sodium carbonate solution and a saturated saline solution in sequence, concentrating under reduced pressure, performing sample mixing and column passing twice, wherein the solvent used in the first sample mixing and column passing is a mixed solution of petroleum ether and ethyl acrylate with a molar ratio of 2:1, the solvent used in the second sample mixing and column passing is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and drying to obtain 1509g of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol with a molar yield of 54.6%.

Example 4

This example provides a method for synthesizing a ridciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), which includes the following steps:

s1, weighing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (1300g, 5mol), adding into a reaction kettle, adding 13L of acetone (with the water content of 150ppm), stirring at room temperature to dissolve the acetone, adding 1740g, 15mol of tetramethylethylenediamine, stirring at room temperature for about 10min, cooling to 10 ℃, adding 1080g, 10mol of trimethylchlorosilane, reacting for 25min, replacing air under reduced pressure, slowly cooling to-40 ℃, slowly adding 2mol/L phenylmagnesium chloride (5.5L,11mol) dropwise, and continuing to stir for 15 min;

s2, adding 1.3mol/L isopropyl magnesium chloride lithium chloride complex (4.23L, 5.5mol) into the system, stirring for 30min, controlling the temperature of the reaction system to be below-40 ℃, adding 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone (2410.8g, 6mol) in batches, and continuing to react for 2 h;

s3, detecting reaction by TLC (thin layer chromatography), after the reaction is finished, adding 1.3L of acetic acid into a reaction system for quenching, taking out and collecting reaction liquid, adding 10L of water and 15L of ethyl acrylate into the reaction liquid for extraction, carrying out liquid separation treatment, respectively collecting an organic phase and an aqueous phase, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, combining the organic phases obtained by two extractions, washing the combined organic phase by using 18L of 1mol/L hydrochloric acid, carrying out liquid separation treatment, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, and combining the organic phase with the organic phase obtained by the previous liquid separation;

s4, washing the obtained organic phase with a saturated sodium carbonate solution and a saturated saline solution respectively, concentrating under reduced pressure, mixing and passing through a sample-mixing column twice, wherein a solvent used in the first sample-mixing column is a mixed solution of petroleum ether and ethyl acrylate with a molar ratio of 2:1, a solvent used in the second sample-mixing column is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and drying to obtain 1586g of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol with a molar yield of 57.4%.

Example 5

This example provides a method for synthesizing a ridciclovir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol), which includes the following steps:

s1, weighing 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (1300g, 5mol), adding into a reaction kettle, adding 9L of dichloromethane (with the water content of 450ppm), stirring at room temperature to dissolve the dichloromethane, adding 1856g, 16mol of tetramethylethylenediamine, stirring at room temperature for about 10min, cooling to 10 ℃, adding chlorotrimethylsilane (1188g, 11mol), reacting for 35min, replacing air under reduced pressure, slowly cooling to-35 ℃, slowly adding 2mol/L phenylmagnesium chloride (5L,10mol) dropwise, and continuing to stir for 20 min;

s2, adding 1.3mol/L isopropyl magnesium chloride lithium chloride complex (4.62L, 6mol) into the system, stirring for 35min, controlling the temperature of the reaction system to be below-40 ℃, adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (2009g, 5mol) in batches, and continuing to react for 2 h;

s3, detecting reaction by TLC (thin layer chromatography), after the reaction is finished, adding 1.3L of acetic acid into a reaction system for quenching, taking out and collecting reaction liquid, adding 10L of water and 15L of ethyl acrylate into the reaction liquid for extraction, carrying out liquid separation treatment, respectively collecting an organic phase and an aqueous phase, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, combining the organic phases obtained by two extractions, washing the combined organic phase by using 18L of 1mol/L hydrochloric acid, carrying out liquid separation treatment, carrying out back extraction on the aqueous phase once by using 5L of ethyl acrylate, and combining the organic phase with the organic phase obtained by the previous liquid separation;

s4, washing the obtained organic phase with a saturated sodium carbonate solution and a saturated saline solution respectively, concentrating under reduced pressure, performing sample mixing and column passing twice, wherein the solvent used in the first sample mixing and column passing is a mixed solution of petroleum ether and ethyl acrylate with a molar ratio of 2:1, the solvent used in the second sample mixing and column passing is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and drying to obtain 1400g of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol with a molar yield of 50.7%.

According to the invention, the tetramethylethylenediamine substance is added into the reaction system, and forms a stable ion pair (or salt formation) with the carbanion intermediate to play a role in stabilizing the carbanion intermediate, so that the influence of trace moisture in the reaction system on the overall reaction is reduced, the moisture in the organic solvent in the reaction system is controlled to be 135-450ppm, the yield of the finally synthesized product is up to 50-60%, the industrial production of the bulk drug of the Reidesciclovir is facilitated, and the development of the economic technology of the Reidesciclovir bulk drug is promoted.

The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. For a person skilled in the art to which the invention pertains, several simple deductions, modifications or substitutions may be made according to the idea of the invention.