CN113754694B - Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside - Google Patents

Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside Download PDF

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CN113754694B
CN113754694B CN202010495820.8A CN202010495820A CN113754694B CN 113754694 B CN113754694 B CN 113754694B CN 202010495820 A CN202010495820 A CN 202010495820A CN 113754694 B CN113754694 B CN 113754694B
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CN113754694A (en
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张万斌
陈建中
张露
袁乾家
霍小红
张振锋
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Shanghai Jiaotong University
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Abstract

The invention discloses a method for synthesizing Reidesciclovir by asymmetric catalysis of nucleoside without protecting group; in a single or mixed solvent, in a chiral bicyclic imidazole catalyst
Figure DDA0002522769830000011
Under the catalytic action of (2), make the nucleoside without protecting group
Figure DDA0002522769830000012
With chlorophosphoramidates
Figure DDA0002522769830000013
Direct one-step asymmetric synthesis of single-configuration Reidesvir
Figure DDA0002522769830000014
The method has mild reaction conditions, simple and convenient operation, high reaction efficiency and good industrial application prospect, and omits the steps of protecting groups and deprotection.

Description

Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside
Technical Field
The invention belongs to the technical field of asymmetric catalytic synthesis in the technical field of chemical industry, relates to a method for synthesizing ridciclovir by asymmetric catalysis of nucleoside without a protecting group, and particularly relates to a method for preparing single-configuration ridciclovir by directly and asymmetrically catalyzing nucleoside without a protecting group in one step under the action of alkali by using a chiral bicyclic imidazole catalyst.
Background
Reed civir, english name: remdesivir, formula C 27 H 35 N 6 O 8 P, is an antiviral agent in researchA medicine is provided. However, the recombinant human coronavirus has a certain treatment effect on the currently popular new coronary pneumonia virus (COVID-19), and in view of the urgency of treating new coronary pneumonia, the efficient synthesis of the Reidesciclovir and the important intermediate thereof is regarded by scientific researchers and various companies. The single-configuration Ruidexi Wei Ze is directly prepared in one step by catalyzing the nucleoside without the protecting group by adopting the chiral bicyclic imidazole catalyst, and has great economic value, social value and research value.
Through the search of the prior art, the existing literature on the synthesis of the Reidesciclovir is rarely reported, and the reported methods (Nature 2016,531,381, J.Med.chem.2017,60,1648, WO201717184668) are that nucleoside (II) without a protecting group is synthesized into a nucleoside derivative (II ') containing the protecting group, phosphoryl chloride (III) is substituted and resolved by nitrophenol to obtain a chiral phosphate intermediate (III'), then II 'and III' react to generate a Reidesciclovir derivative containing the protecting group, and finally deprotection is carried out to obtain the Reidesciclovir. Alternatively (US 20160122374; CN 103052631) racemic Reiciclovir is obtained in a achiral process by reaction of II and III. This document does not give a specific yield, but the reaction yield of the analogue is only 25%. Thus, to date, there has been no asymmetric method reported for the synthesis of Reidesciclovir.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a method for synthesizing the Reidcisvir by asymmetric catalysis of the nucleoside without the protecting group. In particular to a method for preparing single-configuration Reinecke by one-step asymmetric catalysis of nucleoside without protecting group under the action of alkali by using chiral bicyclic imidazole catalyst.
The purpose of the invention is realized by the following scheme:
the invention provides a method for preparing single-configuration Reinecke by asymmetric catalysis, which directly and asymmetrically synthesizes non-protecting group nucleoside and chloro-phosphoramidate into single-configuration Reinecke in one step under the catalytic action of chiral bicyclic imidazole catalyst.
In the invention, a reaction method for synthesizing the Reidesciclovir by catalyzing protective group-free nucleoside and chloro-phosphoramidate by a chiral imidazole catalyst, a reaction route and comparison of the reaction route with other reaction routes described in other documents are shown in figure 1: in fig. 1, structural formula I represents a chiral bicyclic imidazole catalyst, structural formula II represents a non-protecting group nucleoside, structural formula III represents a chloro phosphoramidate, and structural formula IV represents reiciclovir.
Specifically, under inert gas, nucleoside and chloroaminophosphate without protecting group are taken as raw materials, and chiral imidazole catalyst shown as formula I
Figure BDA0002522769810000021
Reacting in a solvent to obtain the Reidesciclovir shown in formula IV
Figure BDA0002522769810000022
The single isomer purity of the protecting group-free nucleoside was 99wt%. Respectively and preferentially and selectively synthesizing the Ruidexiwei shown in the formula IV under the catalysis of chiral imidazole compound catalysts to obtain a dr value of 1:1-2.2.
In the invention, the maximum ratio (dr) of the Ruidecy Wei Chanlv shown in the formula IV can be up to 63%, and the maximum ratio (dr) of diastereoisomers can be up to 2.2.
In the invention, the chiral bicyclic imidazole catalyst (chiral imidazole catalyst shown in formula I) is any one chiral bicyclic imidazole selected from C1-C18 shown in the following formula:
Figure BDA0002522769810000023
in the present invention, the chiral imidazole catalyst is preferably C3 to C6, C10 to C15, more preferably C3, C4, C10, C14, C15, and even more preferably C3, C4, C15.
In the present invention, the asymmetric synthesis is carried out under the action of a base. The alkali is organic alkali or inorganic alkali.
As an embodiment of the present invention, the organic base is selected from primary, secondary, tertiary, quaternary amines, imidazole and pyridine derivatives having a substituent which is an aliphatic substituent or an aromatic hydrocarbon substituent containing 1 to 15 carbons.
As an embodiment of the present invention, the inorganic base is at least one of sodium carbonate, potassium carbonate, cesium carbonate, disodium hydrogen phosphate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
As an embodiment of the invention, the organic base is at least one of triethylamine, ethylenediamine, N ' -dimethylethylenediamine, N-dimethylethylenediamine, N-methylethylenediamine, N ' -dimethyl-1,3-propylenediamine, N ' -dimethyl-1,4-butylenediamine, pyridine, 2,6-dimethylpyridine, 2,6-diethylpyridine, 2,6-diisopropylpyridine, 2,6-di-tert-butylpyridine, piperidine, pyrrole, 2,5-dimethylpyrrole and 2,5-di-tert-butylpyrrole.
In the present invention, the asymmetric synthesis is carried out in a solvent. The solvent is at least one of a polar solvent, a non-polar solvent and an ionic liquid solvent.
As an embodiment of the present invention, the non-polar solvent is one or more of toluene, diethyl ether, tetrahydrofuran.
As an embodiment of the invention, the polar solvent is one or more of dichloromethane, 1,2-dichloroethane, DMF, DMSO, acetonitrile.
As an embodiment of the present invention, the ionic liquid solvent is one or more of imidazolium salt ionic liquid, ammonium salt ionic liquid, piperidinium salt ionic liquid, sulfonium salt ionic liquid, morpholine salt ionic liquid, quaternary phosphonium salt ionic liquid, pyrrolidinium salt ionic liquid, and pyridinium salt ionic liquid.
In the present invention, the solvent is preferably one or more of toluene, dichloromethane, DMF, DMS, an ammonium salt ionic liquid, an imidazolium salt ionic liquid, and a quaternary phosphonium salt ionic liquid, more preferably toluene, DMF, an ammonium salt ionic liquid, an imidazolium salt ionic liquid, and a quaternary phosphonium salt ionic liquid, and further preferably DMF, an imidazolium salt ionic liquid, and a quaternary phosphonium salt ionic liquid.
In the invention, the molar ratio of the chiral bicyclic imidazole catalyst to the nucleoside without a protecting group is 1:5-1000. Preferably 1. The molar ratio of the unprotected nucleoside to the base to the phosphoroamidate chloride is 1: (1-1.5): (1-1.2).
In the invention, the asymmetric catalytic reaction is carried out by dissolving the nucleoside without the protecting group in a solvent, so that before the reaction, the nucleoside without the protecting group is dissolved in the solvent to prepare a solution, and the concentration of the nucleoside solution without the protecting group is 5-80%, preferably 10-60%.
In the invention, the reaction temperature of the asymmetric synthesis method is-30-180 ℃, preferably 0-120 ℃, and more preferably 25-80 ℃; the reaction time is 1 to 72 hours, preferably 5 to 60 hours, more preferably 5 to 36 hours, still more preferably 6 to 24 hours, and particularly preferably 10 to 24 hours.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention uses chiral catalyst, and obtains the Reidesciclovir with high yield and high enantioselectivity successfully by industrial mature asymmetric technology;
2. the novel chiral imidazole compound catalyst is designed and synthesized, so that the synthetic route is simple, the raw materials are easy to obtain, and the catalyst cost is reduced;
3. the invention adopts chiral imidazole compound catalyst to catalyze and synthesize the Reidesciclovir to directly obtain the Reidesciclovir with enriched advantages, so that the yield of the product is improved to 63% from the prior chiral yield of 44% or racemization low yield in several steps; the dr value is increased from 1:1 to 2.2;
4. the synthetic method has the advantages of easily available raw materials, mild conditions, simple and convenient operation and lower cost; the product is easy to separate, has high yield, high chemical purity and optical purity, is easy for industrial production, and has good industrial application prospect.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is a schematic diagram of the reaction scheme of the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit of the invention. All falling within the scope of the present invention.
The invention provides a reaction method for synthesizing Reidesciclovir by asymmetric catalysis of unprotected nucleoside and chloro phosphoramidate. Under the catalysis of chiral imidazole catalyst and under the action of alkali, the aim of asymmetric synthesis of the Reidcisvir is fulfilled by stereoselectively synthesizing the Reidcisvir. The preparation method adopts an asymmetric catalysis method to prepare the Reidesciclovir for the first time with high efficiency, and has the advantages of simple operation, high yield, good enantioselectivity and the like.
The present invention will be described in further detail with reference to specific examples.
In the following examples, the structural formula of the 18 (C1-C18) chiral imidazole compound catalysts used is as follows:
Figure BDA0002522769810000051
example 1
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000052
molecular sieve (300 mg), chiral imidazole catalyst (C1, 0.1mol, 0.1equiv), passing through vacuum line, replacing with nitrogen gas for 3 times, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dripping chloro phosphoramidate (1.2mmol, 1.2equiv), dripping alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 deg.C for 12 hours, detecting by TLC, dripping water to quench, filtering, extracting, concentrating, and performing column chromatography to obtain diastereomer excess value (d)r) 1.2 of Reidesciclovir (217mg, 36%). 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 2
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000053
molecular sieve (300 mg), chiral imidazole catalyst (C2, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi Wei (253mg, 42%) with diastereomer excess value (dr) of 1.5/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 3
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000061
molecular sieve (300 mg), chiral imidazole catalyst (C3, 0.1mol, 0.1equiv), vacuum line, nitrogen gas displacement 3 times, ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise chloro aminoPhosphate (1.2mmol, 1.2equiv), base (2,6-lutidine, 1.2mol, 1.2equiv) added dropwise, the solution was stirred at 80 ℃ for 12 hours, TLC detection was completed, and the reaction was quenched with dropwise addition of water, filtered, extracted, concentrated, and subjected to column chromatography to obtain Reidesvir (307mg, 51%) having a diastereomer excess value (dr) of 2.0/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 4
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000062
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise, alkali (2,6-lutidine, 1.2mol, 1.2equiv) dropwise, solution at 80 ℃, stirring reaction for 12 hours, TLC detection reaction completion, water dropwise quenching, filtering, extraction, concentration, column chromatography to obtain Rudexilwei (379mg, 63%) with diastereomer excess value (dr) of 2.2/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 5
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000071
molecular sieve (300 mg), chiral imidazole catalyst (C5, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi Wei (301mg, 50%) with diastereomer excess value (dr) of 1.9/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 6
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000072
molecular sieve (300 mg), chiral imidazole catalyst (C6, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise, alkali (2,6-lutidine, 1.2mol, 1.2equiv) dropwise, solution at 80 ℃, stirring reaction for 12 hours, TLC detection reaction ending, water dropwise quenching, filtering, extracting, concentrating, column chromatography to obtain Ruidexiwei (337mg, 56%) with excess number of diastereomers (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 7
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000073
molecular sieve (300 mg), chiral imidazole catalyst (C7, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidsivir (204mg, 34%) with diastereomer excess value (dr) of 1.5/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 8
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000081
molecular sieve (300 mg), chiral imidazole catalyst (C8, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi vir (271mg, 45%) with a diastereomer excess value (dr) of 1.4/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 9
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000082
molecular sieve (300 mg), chiral imidazole catalyst (C9, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi Wei (253mg, 42%) with diastereomer excess value (dr) of 1.2/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 10
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000091
molecular sieve (300 mg), chiral imidazole catalyst (C10, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropping chloroaminophosphate (1.2mmol, 1.2equiv), dropping alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 deg.C for 12 hours, TLC detecting reaction, dropping water for quenching,filtration, extraction, concentration, and column chromatography gave ridciclovir (343mg, 57%) with a diastereomeric excess (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 11
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000092
molecular sieve (300 mg), chiral imidazole catalyst (C11, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidsivir (289mg, 48%) with diastereomer excess value (dr) of 1.9/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 12
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000093
molecular sieve (300 mg), chiral imidazole catalyst (C12, 0.1mol, 0.1equiv), vacuum line, nitrogen gas displacement 3 times, ion additionLiquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), chloro phosphoramidate (1.2mmol, 1.2equiv) is added dropwise, alkali (2,6-lutidine, 1.2mol, 1.2equiv) is added dropwise, the solution is stirred and reacted for 12 hours at 80 ℃, TLC detection reaction is finished, dropwise water is used for quenching, filtration, extraction, concentration and column chromatography are carried out, and the Reidesvir (319mg, 53%) with the diastereomer excess value (dr) of 1.7/1 is obtained. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 13
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000101
molecular sieve (300 mg), chiral imidazole catalyst (C13, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting by TLC to finish the reaction, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidevir (295mg, 49%) with a diastereomer excess value (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 14
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000102
molecular sieve (300 mg), chiral imidazole catalyst (C14, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidsivir (331mg, 55%) with diastereomer excess value (dr) of 1.9/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 15
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000111
molecular sieve (300 mg), chiral imidazole catalyst (C15, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi Wei (343mg, 57%) with diastereomer excess value (dr) of 2.1/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 16
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000112
molecular sieve (300 mg), chiral imidazole catalyst (C16, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting by TLC to finish the reaction, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidevir (295mg, 49%) with a diastereomer excess value (dr) of 1.4/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 17
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000113
molecular sieve (300 mg), chiral imidazole catalyst (C17, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloroaminophosphate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting by TLC to finish the reaction, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain Reidexi Wei (307mg, 51%) with diastereomer excess value (dr) of 1.5/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 18
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000121
molecular sieve (300 mg), chiral imidazole catalyst (C18, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,6-lutidine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 12 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidexi Wei (319mg, 53%) with diastereomer excess value (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 19
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000122
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, toluene (5 ml) addition, chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise addition, alkali (2,6-lutidine, 1.2mol, 1.2equiv) dropwise addition, solution at 80 deg.C, stirring reaction for 18 hours, TLC detection of reaction junctionQuenched by water, filtered, extracted, concentrated, and column chromatographed to give Reidesciclovir (48mg, 8%) with a diastereomeric excess (dr) of 1/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 20
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000131
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, dichloromethane (5 ml) addition, chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise addition, alkali (2,6-lutidine, 1.2mol, 1.2equiv) dropwise addition, solution at-20 ℃, stirring reaction for 36 hours, TLC detection reaction completion, water drop quenching, filtration, extraction, concentration, column chromatography to obtain Reidexi Wer (42mg, 7%) with diastereomer excess value (dr) of 1.1/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 21
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000132
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen displacement 3 times, adding ionic liquid (1-butyl-2,3-twoMethylimidazolium tetrafluoroborate, 5 ml), phosphoroamidate (1.2 mmol,1.2 equiv) was added dropwise, alkali (2,6-di-tert-butylpyridine, 1.5mol,1.5 equiv) was added dropwise, the solution was stirred at 100 ℃ for 24 hours, TLC detection was completed, the reaction was quenched with water, filtered, extracted, concentrated, and column chromatography gave reed civir (337mg, 56%) with a diastereomeric excess value (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 22
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000133
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), the system was passed through a vacuum line, replaced with nitrogen gas 3 times, dichloromethane (2.5 ml) and ionic liquid (1- (2-hydroxyethyl) -3-methyl-1H-imidazol-3-ium tetrafluoroborate, 2.5 ml) were added, chloroaminophosphate (1.2mmol, 1.2equiv) were added dropwise, alkali (piperidine, 1.2mol, 1.2equiv) was added dropwise, the solution was stirred at 40 ℃ for 24 hours, TLC detection reaction was completed, quenching was performed by dropping water, filtration, extraction, concentration, column chromatography gave ridexivir (28mg, 47%) having a diastereomer excess value (dr) of 1.5/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 23
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000141
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (tetrabutyl phosphonium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (2,5-dimethylpyrrole, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 6 hours, detecting by TLC, ending the reaction, dropwise adding water for quenching, filtering, extracting, concentrating, and carrying out column chromatography to obtain Reidsvir (319mg, 53%) with a diastereomer excess value (dr) of 1.7/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 24
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000142
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), alkali (sodium bicarbonate, 1.2mol, 1.2equiv), vacuum line, nitrogen gas replacement for 3 times, ionic liquid (N-butylpyridine tetrafluoroborate, 5 ml), chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise, solution at 80 ℃, stirring reaction for 6 hours, TLC detection reaction finished, water dropping quenching, filtering, extraction, concentration, column chromatography to obtain Reidexilvir (72mg, 12%) with excess value (dr) of 1.3/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 25
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000151
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), passing through a vacuum line, replacing 3 times with nitrogen, adding ionic liquid (tetrabutyl phosphonium tetrafluoroborate, 5 ml), dropwise adding chloro phosphoramidate (1.2mmol, 1.2equiv), further dropwise adding alkali (triethylamine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 6 hours, detecting the reaction by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain Reidexi Wei (283mg, 47%) with a diastereomer excess value (dr) of 1.5/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 26
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000152
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.01mol, 0.01equiv), passing through vacuum line, replacing 3 times with nitrogen, adding ionic liquid (1-ethyl-1-methylpyrrolidinium tetrafluoroborate, 5 ml), dripping chloro phosphoramidate (1.2mmol, 1.2equiv), dripping alkali (N, N' -dimethyl-1,3-propanediamine, 1.2mol, 1.2equiv), stirring the solution at 80 deg.C, reacting for 6 hours, detecting by TLC, quenching by dripping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain Reidsivir (223mg, 37%) with diastereomer excess value (dr) of 1.6/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 27
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000153
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.005mol, 0.005equiv), passing through a vacuum line, displacing 3 times with nitrogen, adding ionic liquid (tetrabutylammonium tetrafluoroborate, 5 ml), dropwise adding phosphoroamidochloridate (1.2mmol, 1.2equiv), further dropwise adding alkali (N, N-dimethylethylenediamine, 1.2mol, 1.2equiv), stirring the solution at 80 ℃ for 6 hours, detecting by TLC that the reaction is finished, quenching by dropping water, filtering, extracting, concentrating, and performing column chromatography to obtain ReideSevir (181mg, 30%) with a diastereomer excess value (dr) of 1.8/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 28
In a 25mL two-port reaction flask, the nucleoside without a protecting group (290mg, 1mmol, 1equiv) was added,
Figure BDA0002522769810000161
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.002mol, 0.002equiv), vacuum line, nitrogen gas replacement for 3 times, adding DMF (5 ml), dropwise adding phosphoroamidate chloride (1.2mmol, 1.2equiv), dropwise adding alkali (N, N' -dimethylethylenediamine, 1.2mol, 1.2equiv), stirring the solution at 80 deg.C for 6 hr, TLC detection reaction, dropwise adding water to quench, filtering, extracting, concentrating, column chromatographyDarescixivir (181mg, 30%) was obtained with a diastereomeric excess (dr) of 1.9/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 29
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000162
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen gas replacement 3 times, ethanol (5 ml) addition, chloro phosphoramidate (1.2mmol, 1.2equiv) dropwise addition, alkali (N, N' -dimethylethylenediamine, 1.2mol, 1.2equiv) dropwise addition, solution at 50 ℃, stirring reaction for 60 hours, TLC detection reaction completion, water dropwise quenching, filtration, extraction, concentration, column chromatography to get Reidexilvir (90mg, 15%) with diastereomer excess value (dr) of 1.0/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 30
A25 mL two-necked reaction flask was charged with a protecting group-free nucleoside (290mg, 1mmol, 1equiv),
Figure BDA0002522769810000171
molecular sieve (300 mg), chiral imidazole catalyst (C4, 0.1mol, 0.1equiv), vacuum line, nitrogen gas displacement 3 times, ionic liquid (butyl trimethyl ammonium bis (trifluoromethanesulfonyl) imide, 5 ml) is added, chloro phosphoramidate (C) (C4, 0.1mol, 0.1equiv) is added dropwise1.2mmol, 1.2equiv), adding alkali (pyridine, 1.2mol, 1.2equiv) dropwise, stirring the solution at 130 ℃ for reaction for 32 hours, detecting by TLC, quenching by dropping water, filtering, extracting, concentrating, and carrying out column chromatography to obtain the Reidesvir (108mg, 18%) with the diastereomer excess value (dr) of 1.4/1. 1 H NMR(400MHz,CD 3 OD):δ7.87(s,1H),7.33-7.27(m,2H),7.21-7.16(m,3H),6.92-6.87(dd,J＝4.0，8.0Hz,1H),4.79(d,J＝5.2Hz,1H),4.40-4.35(m,2H),4.31-4.28(m,1H),4.17(t,J＝5.6Hz,1H),4.02(dd,J＝5.2,10.8Hz,1H),3.95-3.87(m,2H),1.47-1.43(m,1H),1.35-1.27(m,8H),0.85(t,J＝7.2Hz,6H)； 31 P NMR(162MHz,CDCl 3 ):δ3.5。
Example 31: preparation of chiral imidazole catalyst C1
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol, 1.0eq), 20mL methylene chloride and triethylamine (1.08mL, 7.2mmol, 3.0eq) and stirred for 5 min. Then, acetic anhydride (0.34mL, 3.6mmol, 1.5eq) was added thereto, and the reaction was carried out at 20 ℃ for 12 hours. The reaction was quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C1 (305 mg, 76% yield) was isolated. 1 H NMR(400MHz,CDCl 3 )δ7.19(s,1H),6.97(s,1H),5.99(dd,J＝7.2Hz,2.4Hz,1H),4.22-4.11(m,1H),4.05-3.95(m,1H),3.14-3.01(m,1H),2.61-2.49(m,1H),2.11(s,3H). 13 C NMR(100MHz,CDCl 3 )δ169.8,150.5,134.0,115.2,66.6,42.4,34.3,20.5。
Example 32: preparation of chiral imidazole catalyst C2
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol, 1.0eq) and 30mL tetrahydrofuran, 60% by mass of sodium hydride (116mg, 2.9mmol, 1.2eq) was added in portions at 0 ℃ and stirred for 30 minutes. Then, benzyl bromide (0.43mL, 3.6mmol, 1.5eq) was added and reacted at 20 ℃ for 12 hours. The reaction was quenched with 30mL of water, extracted with 30mL of dichloromethane, and the organics combinedThe phases are dried over anhydrous magnesium sulfate. Then spin-drying, using pure ethyl acetate as mobile phase to make silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C2 was isolated (378 mg, 73% yield). 1 H NMR(400MHz,CDCl 3 )δ7.41-7.27(m,5H),7.16(d,J＝1.2Hz,1H),6.93(d,J＝1.2Hz,1H),4.90(d,J＝11.6Hz,1H),4.83(dd,J＝7.2Hz,2.0Hz,1H),4.73(d,J＝11.6Hz,1H),4.21-4.13(m,1H),3.96-3.89(m,1H),2.92-2.82(m,1H),2.67-2.59(m,1H). 13 C NMR(100MHz,CDCl 3 )δ153.5,137.9,133.8,128.4,128.1,127.7,115.0,71.1,70.8,43.1,35.3。
Example 33: preparation of chiral imidazole catalyst C3
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol, 1.0eq) and 30mL tetrahydrofuran, 60% by mass of sodium hydride (116mg, 2.9mmol, 1.2eq) was added in portions at 0 ℃ and stirred for 30 minutes. After that, di-tert-butyl dicarbonate (0.83mL, 3.6mmol,1.5 eq) was added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 /g) the product C3 was isolated (385.0 mg, 71% yield). 1 H NMR(500MHz,CDCl 3 )δ7.18(d,J＝1.2Hz,1H),6.93(d,J＝1.3Hz,1H),5.89(dd,J＝6.8,1.9Hz,1H),4.22–4.14(m,1H),4.03–3.95(m,1H),3.08–2.99(m,1H),2.69–2.61(m,1H),1.50(s,9H). 13 C NMR(126MHz,CDCl 3 )δ152.7,150.8,134.9,115.4,82.9,69.3,42.9,34.9,27.8。
Example 34: preparation of chiral imidazole catalyst C4
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol, 1.0eq), 20mL methylene chloride and triethylamine (1.68mL, 12.1mmol, 5.0eq) and stirred for 5 min. Thereafter, adamantanoyl chloride (497mg, 2.5mmol, 1.05eq) was added and reacted at 20 ℃ for 12 hours. The reaction was quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were washed with brineDried over magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C4 (392 mg,57% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.20(s,1H),6.96(s,1H),5.96(dd,J＝7.4,2.9Hz,1H),4.20–4.10(m,1H),4.03–3.94(m,1H),3.14–3.03(m,1H),2.50–2.40(m,1H),2.03–1.97(m,3H),1.92–1.86(m,6H),1.74–1.64(m,6H). 13 C NMR(126MHz,CDCl 3 )δ177.3,151.4,134.8,115.5,66.9,43.0,40.9,39.0,38.8,36.736.5,35.3,28.2,28.0。
Example 35: preparation of chiral imidazole catalyst C5
Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into a dry reaction bottle]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. 2,6-diisopropylphenyl isocyanate (0.52mL, 2.4mmol,1.5 eq) was then added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 /g) product C5 was isolated (402 mg, 76% yield). 1 H NMR(500MHz,CDCl 3 )δ7.31–7.27(m,1H),7.21(s,1H),7.17(s,1H),7.16(s,1H),6.98(s,1H),6.46(s,1H),5.94(dd,J＝7.1,2.8Hz,1H),4.24–4.16(m,1H),4.04–3.96(m,1H),3.22–3.09(m,3H),2.69–2.60(m,1H),1.23(d,J＝6.9Hz,6H),1.19(d,J＝6.9Hz,6H). 13 C NMR(126MHz,CDCl 3 )δ154.7,151.2,146.8,134.8,130.5,128.4,123.5,115.6,68.4,43.0,35.7,28.6,23.8,23.5。
Example 36: preparation of chiral imidazole catalyst C6
Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into a dry reaction bottle]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Followed by addition of isocyanic acid2,4,6-trichlorophenyl ester (538mg, 2.4mmol, 1.5eq) was reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C6 (229 mg, 41% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ8.18(s,1H),7.38(s,2H),7.16(s,1H),6.94(s,1H),5.98(dd,J＝7.3,2.7Hz,1H),4.22–4.14(m,1H),4.03–3.93(m,1H),3.20–3.07(m,1H),2.74–2.64(m,1H). 13 C NMR(126MHz,CDCl 3 )δ153.3,150.9,134.9,134.7,133.4,131.2,128.6,115.6,100.1,68.9,43.1,35.5。
Example 37: preparation of chiral imidazole catalyst C7
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Thereafter, 2-biphenyl isocyanate (472mg, 2.4mmol, 1.5eq) was added thereto and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C7 (423 mg, 82% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ8.19(d,J＝8.3Hz,1H),7.48–7.41(m,2H),7.41–7.30(m,4H),7.22–7.10(m,3H),6.94(s,1H),6.75(s,1H),5.98(dd,J＝7.3,2.6Hz,1H),4.17–4.09(m,1H),4.02–3.93(m,1H),3.17–3.04(m,1H),2.68–2.57(m,1H). 13 C NMR(126MHz,CDCl 3 )152.8,151.0,138.0,135.0,134.7,130.4,129.4,129.3,128.6,128.1,123.6,115.7,68.3,43.1,35.3。
Example 38: preparation of chiral imidazole catalyst C8
A dry reaction flask was charged with bicyclic imidazole C7 (319mg, 1.0mmol, 1.0eq) and 10mL of tetrahydrofuran, and sodium hydride (4) with a mass fraction of 60% (w/w) was added in portions at 0 deg.C8mg,1.2mmol, 1.2eq) and stirring for 30 minutes. Then, iodomethane (62.3. Mu.L, 1.0mmol,1.0 eq) was added thereto, and the reaction was carried out at 20 ℃ for 12 hours. The reaction was then quenched with 20mL of water, extracted with 20mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C8 (185 mg,55% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.47–7.19(m,20H),7.17–7.12(m,1H),6.93–6.88(m,1H),5.93–5.80(m,2H),4.19–3.80(m,4H),3.08(s,3H),2.98–2.80(m,5H),2.46–2.36(m,1H),2.00–1.91(m,1H). 13 C NMR(126MHz,CDCl 3 )δ174.0,154.6,151.1,150.9,140.8,139.9,139.8,139.6,138.9,134.1,133.8,133.6,130.9,130.6,128.5,128.4,128.3,128.3,128.2,127.8,127.6,127.3,115.6,115.4,115.3,68.2,68.1,43.3,43.0,38.3,37.7,35.6,34.6,21.4。
Example 39: preparation of chiral imidazole catalyst C9
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol, 1.0eq) and 30mL tetrahydrofuran, 60% by mass of sodium hydride (116mg, 2.9mmol, 1.2eq) was added in portions at 0 ℃ and stirred for 30 minutes. Then, 3-isopropyl-dimethylbenzyl isocyanate (0.72mL, 3.6mmol,1.5 eq) was added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C9 (415 mg,53% yield) was isolated. 1 H NMR(400MHz,CDCl 3 )δ7.48(s,1H),7.36–7.27(m,3H),7.18(s,1H),6.94(s,1H),5.82(dd,J＝7.4,2.8Hz,1H),5.38–5.25(m,2H),5.11–5.05(m,1H),4.17–4.07(m,1H),3.99–3.89(m,1H),3.08–2.95(m,1H),2.62–2.49(m,1H),2.15(s,3H),1.70(s,3H),1.66(s,3H). 13 C NMR(101MHz,CDCl 3 )δ153.7,151.4,146.7,143.5,141.3,134.7,128.3,124.1,124.0,122.0,115.4,112.6,67.4,55.4,42.9,35.4,29.5,28.9,22.0。
Example 40: preparation of chiral imidazole catalyst C10
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol,1.0 eq), 20mL dichloromethane, and triethylamine (1.68mL, 12.10 mmol,5.0 eq) and stirred for 5 min. Thereafter, diisopropylcarbamoyl chloride (415mg, 2.5mmol, 1.05eq) was added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C9 (161 mg, 27% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.19(d,J＝1.2Hz,1H),6.95(d,J＝1.3Hz,1H),5.96(dd,J＝7.1,2.8Hz,1H),4.18–4.11(m,1H),4.09–3.95(m,2H),3.76(s,1H),3.12–3.03(m,1H),2.64–2.56(m,1H),1.19(s,12H). 13 C NMR(126MHz,CDCl 3 )δ154.8,151.9,134.7,115.3,67.6,46.6,45.7,43.0,35.7,21.5,20.6。
Example 41: preparation of chiral imidazole catalyst C11
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol,1.0 eq), 20mL dichloromethane, and triethylamine (1.68mL, 12.10 mmol,5.0 eq) and stirred for 5 min. Thereafter, 1-piperidinoyl chloride (0.32mL, 2.5mmol, 1.05eq) was added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C11 (271 mg,48% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.19(d,J＝1.2Hz,1H),6.95(d,J＝1.2Hz,1H),5.91(dd,J＝7.3,2.9Hz,1H),4.20–4.11(m,1H),4.01–3.93(m,1H),3.47–3.32(m,4H),3.14–3.03(m,1H),2.65–2.55(m,1H),1.61–1.45(m,6H). 13 C NMR(126MHz,CDCl 3 )δ154.7,151.7,134.6,115.3,68.1,44.9,42.9,35.4,25.6,24.3。
Example 42: chiral imidazoles as catalystsPreparation of agent C12
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (300mg, 2.4mmol,1.0 eq) and 30mL tetrahydrofuran were added in portions with 60% by mass of sodium hydride (116mg, 2.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Then, tert-butyl isocyanate (0.41mL, 3.6mmol, 1.5eq) was added and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C12 (460 mg, 85% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.18(s,1H),6.94(s,1H),5.88(dd,J＝7.4,2.7Hz,1H),4.78(s,1H),4.19–4.09(m,1H),4.05–3.93(m,1H),3.14–3.00(m,1H),2.68–2.54(m,1H),1.32(s,9H). 13 C NMR(126MHz,CDCl 3 )δ155.0,151.7,134.9,115.5,67.2,50.7,43.1,35.5,29.0。
Example 43: preparation of chiral imidazole catalyst C13
A dry reaction flask was charged with bicyclic imidazole C12 (223mg, 1.0mmol,1.0 eq) and 10mL of tetrahydrofuran, and 60% by mass of sodium hydride (48mg, 1.2mmol,1.2 eq) was added in portions at 0 ℃ and stirred for 30 minutes. Then, iodomethane (62.3. Mu.L, 1.0mmol,1.0 eq) was added thereto, and the reaction was carried out at 20 ℃ for 12 hours. The reaction was then quenched with 20mL of water, extracted with 20mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C13 (193 mg, 81% yield) was isolated. 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝1.2Hz,1H),6.95(d,J＝1.2Hz,1H),5.91(dd,J＝7.2,2.8Hz,1H),4.19–4.10(m,1H),4.02–3.93(m,1H),3.13–3.02(m,1H),2.88(s,3H),2.63–2.54(m,1H),1.38(s,9H). 13 C NMR(101MHz,CDCl 3 )δ155.6,151.9,134.6,115.4,67.7,55.9,43.0,35.6,31.5,28.7。
Example 44: preparation of chiral imidazole catalyst C14
Triphosgene (474.8mg, 1.6mmol, 1.0eq) and 10mL of dichloromethane were added to a dry reaction flask A. Tert-octylamine (0.48mL, 1.6mmol,1.0 eq.) and 3mL of methylene chloride were added to the addition funnel. A solution of tert-octylamine in methylene chloride was slowly added dropwise to a solution of triphosgene in methylene chloride at 0 ℃. After 10 minutes, triethylamine (0.89mL, 6.4mmol, 4.0eq) and 3mL of dichloromethane were added to the dropping funnel, and the mixture was dropped into the above reaction solution. Then, the reaction was carried out at 20 ℃ for 2 hours. Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into another dry reaction bottle B]Imidazol-7-ol (200mg, 1.6mmol, 1.0eq) and 20mL of tetrahydrofuran were added in portions with 60% by mass of sodium hydride (193mg, 4.8mmol, 3.0eq) at 0 ℃ and stirred for 30 minutes. The solution in flask A was then transferred to flask B and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C14 (164.8 mg, 43% yield) was isolated. 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝1.3Hz,1H),6.95(d,J＝1.2Hz,1H),5.86(dd,J＝7.4,2.7Hz,1H),4.75(s,1H),4.19–4.08(m,1H),4.03–3.92(m,1H),3.14–3.01(m,1H),2.64–2.52(m,1H),1.79(d,J＝14.9Hz,1H),1.59(d,J＝14.9Hz,1H),1.38(s,3H),1.34(s,3H),0.99(s,9H). 13 C NMR(101MHz,CDCl 3 )δ153.7,151.7,134.7,115.5,67.3,54.4,51.7,43.1,35.7,31.7,31.6,29.5,29.5。
Example 45: preparation of chiral imidazole catalyst C15
(S) -6,7-dihydro-5H-pyrrolo [1,2-A was added to a dry reaction flask]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Thereafter, 1-adamantane isocyanate (428mg, 2.4mmol, 1.5eq) was added thereto and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking petroleum ether/ethyl acetate volume ratio as 1/10 as mobile phase to carry out silica gelColumn chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m 2 The product C15 (285 mg, 59% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ7.18(d,J＝1.3Hz,1H),6.94(d,J＝1.2Hz,1H),5.86(dd,J＝7.2,2.7Hz,1H),4.72(s,1H),4.19–4.06(m,1H),4.03–3.91(m,1H),3.11–2.98(m,1H),2.66–2.53(m,1H),2.11–2.05(m,3H),1.95–1.90(m,6H),1.68–1.64(m,6H). 13 C NMR(126MHz,CDCl 3 )δ153.5,151.7,134.8,115.5,67.1,51.0,43.1,42.6,41.8,36.6,36.3,35.4,29.7,29.5。
Example 46: preparation of chiral imidazole catalyst C16
Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into a dry reaction bottle]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Thereafter, 2- (ethoxycarbonyl) phenyl isocyanate (462mg, 2.4mmol, 1.5eq) was added thereto and reacted at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 The product C16 (298 mg, 59% yield) was isolated. 1 H NMR(500MHz,CDCl 3 )δ10.60(s,1H),8.47(d,J＝8.5Hz,1H),8.01(dd,J＝8.1,1.6Hz,1H),7.59–7.50(m,1H),7.21(s,1H),7.04(t,J＝7.6Hz,1H),6.97(s,1H),6.07(d,J＝6.3Hz,1H),4.39–4.29(m,2H),4.25–4.17(m,1H),4.06–3.98(m,1H),3.13–3.03(m,1H),2.74–2.66(m,1H),1.38(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ168.0,152.7,141.4,134.5,130.8,121.7,118.9,115.5,115.0,67.8,61.3,43.0,35.1,14.2。
Example 47: preparation of chiral imidazole catalyst C17
Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into a dry reaction bottle]Imidazol-7-ol (200mg, 1.6mmol,1.0 eq) and 20mL tetrahydrofuran were added in portions with a mass fraction of 60% sodium hydride (77mg, 1.9mmol,1.2 eq) at 0 ℃ and stirred for 30 minutes. Then adding isopropyl isocyanate(0.18mL, 2.4mmol, 1.5eq) at 20 ℃ for 12 hours. The reaction was then quenched with 30mL of water, extracted with 30mL of dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate. Then spin-drying, taking ethyl acetate/methanol volume ratio 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 /g) product C17 was isolated (158 mg,47% yield). 1 H NMR(500MHz,CDCl 3 )δ7.19(s,1H),6.95(s,1H),5.91(dd,J＝7.2,2.7Hz,1H),4.63(d,J＝7.3Hz,1H),4.18–4.10(m,1H),4.01–3.94(m,1H),3.89–3.78(m,1H),3.12–3.02(m,1H),2.66–2.56(m,1H),1.15(d,J＝6.4Hz,6H). 13 C NMR(126MHz,CDCl 3 )δ154.7,151.5,134.8,115.4,67.5,43.2,42.9,35.3,23.0。
Example 48: preparation of chiral imidazole catalyst C18
Adding (S) -6,7-dihydro-5H-pyrrolo [1,2-A into a dry reaction bottle]Imidazol-7-ol (200mg, 1.6mmol, 1.0eq), 10mL dichloromethane and 2,6-lutidine (0.56mL, 4.8mmol, 3.0eq) and stirring for 5 min. Then, tert-butyldimethylsilyl trifluoromethanesulfonate (0.74mL, 3.2mmol,2.0 eq) was added at 0 ℃ and reacted at 20 ℃ for 24 hours. Then directly spin-drying, taking ethyl acetate/methanol volume ratio of 10/1 as mobile phase to carry out silica gel column chromatography (granularity is 100-200 meshes, specific surface area is 300-400 m) 2 /g) the product C18 was isolated (287 mg, 75% yield). 1 H NMR(500MHz,CDCl 3 )δ7.13(d,J＝1.3Hz,1H),6.85(d,J＝1.2Hz,1H),5.10(dd,J＝6.8,2.9Hz,1H),4.18–4.11(m,1H),3.91–3.83(m,1H),2.90–2.79(m,1H),2.50–2.42(m,1H),0.92(s,9H),0.21(s,3H),0.13(s,3H). 13 C NMR(126MHz,CDCl 3 )δ155.0,134.0,114.6,66.3,42.8,38.3,25.9,18.4,-4.6,-4.8。
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.

Claims (3)

1. A method for preparing single-configuration Reidesvir through asymmetric catalysis is characterized in that under the catalytic action of a chiral bicyclic imidazole catalyst, nucleoside without a protective group and phosphoroamidate are directly synthesized into single-configuration Reidesvir through one-step asymmetric synthesis; the asymmetric synthesis is carried out under the action of an organic base; the asymmetric synthesis is carried out in a solvent;
the protective group-free nucleoside has a structural formula:
Figure 230465DEST_PATH_IMAGE001
；
the structural formula of the chloro-phosphoramidate is as follows:
Figure 633765DEST_PATH_IMAGE002
；
the chiral bicyclic imidazole catalyst is any one chiral bicyclic imidazole selected from the following formulas:
Figure 955025DEST_PATH_IMAGE003
、
Figure 178196DEST_PATH_IMAGE004
、
Figure 508683DEST_PATH_IMAGE005
、
Figure 766489DEST_PATH_IMAGE006
、
Figure 665175DEST_PATH_IMAGE007
、
Figure 500276DEST_PATH_IMAGE008
、
Figure 244241DEST_PATH_IMAGE009
、
Figure 481187DEST_PATH_IMAGE010
、
Figure 285195DEST_PATH_IMAGE011
、
Figure 607592DEST_PATH_IMAGE012
、
Figure 420827DEST_PATH_IMAGE013
、
Figure 515210DEST_PATH_IMAGE014
；
the solvent is an imidazolium salt ionic liquid solvent;
the organic base is 2,6-lutidine, 2,6-di-tert-butylpyridine, piperidine, 2,5-dimethylpyrrole, N' -dimethyl-1,3-propylenediamine or N, N-dimethylethylenediamine.
2. The method for preparing single-configuration Reidesvir through asymmetric catalysis according to claim 1, wherein the molar ratio of the chiral bicyclic imidazole catalyst to the unprotected nucleoside is 1:5-1000.
3. The asymmetric catalytic preparation method of single-configuration Reineckr according to claim 1, wherein the reaction temperature of the asymmetric synthesis is-30 ℃ to 180 ℃; the reaction time is 1 to 72 hours.
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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
CN111393478A (en) * 2020-03-13 2020-07-10 深圳市前海博扬研究院有限公司 Synthetic method of medicine for treating pneumonia infected by new coronavirus COVID-19

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