阅读说明：本技术 瑞德西韦中间体(s,s)-氨基磷酸酯的不对称催化合成方法 (Asymmetric catalytic synthesis method of Ruideciclovir intermediate (S, S) -phosphoramidate ) 是由 张万斌 陈建中 张振锋 王沫 吴正兴 于 2020-06-03 设计创作，主要内容包括：本发明提供了一种瑞德西韦中间体(S,S)-氨基磷酸酯的不对称催化合成方法,具体为,在惰性气体下,以(S)-氨基丙酸-(2)-乙基丁酯、二氯化磷酸苯酯和4-硝基苯酚为原料,碱和/或式Ⅰ所示的手性咪唑类化合物为催化剂在溶剂中反应,得到式Ⅱ所示的(S,S)-氨基磷酸酯本发明合成方法原料易得,条件温和,操作简便,成本较低；产物易于分离,收率高,化学纯度和光学纯度高,易于工业化生产,具有好的工业应用前景。(The invention provides an asymmetric catalytic synthesis method of a Reidcciclovir intermediate (S, S) -phosphoramidate, which specifically comprises the steps of taking (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol as raw materials and taking alkali and/or chiral imidazole compound shown as a formula I as a catalyst under inert gas Reaction in a solvent to obtain (S, S) -phosphoramidate represented by formula II)

1. The asymmetric catalytic synthesis method of the (S, S) -phosphoramidate as the intermediate of the Reidcisvir is characterized in that the method comprises the steps of taking (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol as raw materials and taking alkali and/or chiral imidazole compound shown as a formula I as a catalyst under inert gasReaction in a solvent to obtain (S, S) -phosphoramidate represented by formula II

2. The asymmetric catalytic synthesis method of Rudexilvir intermediate (S, S) -phosphoramidate as claimed in claim 1, wherein the chiral imidazole compound catalyst isWherein R is selected from the following substituents: one kind of (1).

3. A process for the asymmetric catalytic synthesis of a reidesavir intermediate, (S, S) -phosphoramidate as claimed in claim 1 wherein the base is an organic or inorganic base.

4. A process for the asymmetric catalytic synthesis of a reidesavir intermediate, (S, S) -phosphoramidate as claimed in claim 3 wherein the organic base is a primary, secondary, tertiary, quaternary amine or diamine thereof with substituents being aliphatic or aromatic substituents containing 1 to 10 carbons; the inorganic base is at least one of sodium carbonate, potassium carbonate, cesium carbonate, disodium hydrogen phosphate, sodium hydrogen carbonate and potassium hydrogen carbonate.

5. A process according to claim 4, wherein the organic base is at least one of triethylamine, ethylenediamine, tetramethylethylenediamine, trimethylethylenediamine, N ' -dimethylethylenediamine, N-dimethylethylenediamine, N-methylethylenediamine, N ' -dimethyl-1, 3-propanediamine, and N, N ' -dimethyl-1, 4-butanediamine.

6. A process for the asymmetric catalytic synthesis of a reidesavir intermediate, (S, S) -phosphoramidate as claimed in claim 1 wherein the solvent is at least one of a non-polar solvent, a polar solvent and an ionic liquid solvent.

7. The asymmetric catalytic synthesis method of the Rudexilvir intermediate (S, S) -phosphoramidate as claimed in claim 6, wherein the non-polar solvent is toluene, diethyl ether or tetrahydrofuran; the polar solvent is dichloromethane, 1, 2-dichloroethane, DMF, DMSO or acetonitrile; the ionic liquid solvent is 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, pyrrolidine onium salt ionic liquid or pyridinium salt ionic liquid.

8. The asymmetric catalytic synthesis method of the ridciclovir intermediate (S, S) -phosphoramidate according to claim 1, wherein the molar ratio of the chiral imidazole compound catalyst to the (S) -aminopropionic acid- (2) -ethylbutyl ester is 1: 5-1000, and the molar ratio of the (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol is 1: (1-1.2): (1-1.2).

9. The asymmetric catalytic synthesis method of the (S, S) -phosphoramidate as the intermediate of the Reed-West according to claim 1, characterized in that the (S) -aminopropionic acid- (2) -ethylbutyl ester is dissolved in the solvent before reaction, and the mass concentration is 5-80%.

10. The asymmetric catalytic synthesis method of the Ruideciclovir intermediate (S, S) -phosphoramidate according to claim 1, wherein the reaction temperature is-100 ℃ to 180 ℃, and the reaction time is 1 to 72 hours.

Technical Field

The invention relates to the technical field of asymmetric catalytic synthesis, in particular to an asymmetric catalytic synthesis method of a Redcciclovir intermediate (S, S) -phosphoramidate, and particularly relates to a method for preparing the important intermediate (S, S) -phosphoramidate of Redcciclovir (Remdesivir) by adopting a chiral imidazole asymmetric catalyst.

Background

(S, S) -phosphoramidate, formula C₂₁H₂₇N₂O₇P is an important intermediate for preparing a medicine of Remdesivir (Remdesivir) for treating new coronavirus (COVID-19). At present, the new coronavirus has a certain treatment effect on the new coronavirus by the researched antiviral medicament Redexilvir except some effective traditional Chinese medicine treatment methods in the world. Therefore, the efficient synthesis of the Reidesciclovir and the important intermediate thereof is valued by researchers and various companies. The asymmetric synthesis of the (S, S) -phosphoramidate by the phenyl dichlorophosphate and the (S) -aminopropionic acid- (2) -ethylbutyl ester has great social value, economic value and research value.

Through the search of the prior art, few documents are reported about the synthesis of (S, S) -phosphoramidate, and all the currently reported methods (US 2013/143835; WO 2013/84165; US 2015/133395; WO 2016/69826; Journal of Medicinal Chemistry,2017,60,1648; WO 2017/184668; US 2017/71964; WO 2018/204198; WO 2020/2469) generate racemic products, namely, chiral raw materials (S) -aminopropionic acid- (2) -ethylbutyl ester react with phenyl dichlorophosphate to carry out resolution. To date, no asymmetric method has been reported for the synthesis of (S, S) -phosphoramidates.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide an asymmetric catalytic synthesis method of a Rudexilvir intermediate (S, S) -phosphoramidate.

The purpose of the invention is realized by the following scheme:

the invention provides an asymmetric catalytic synthesis method of a Reidcciclovir intermediate (S, S) -phosphoramidate, which specifically comprises the steps of taking (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol as raw materials and taking alkali and/or chiral imidazole compound shown as a formula I as a catalyst under inert gasReaction in a solvent to obtain (S, S) -phosphoramidate represented by formula IIThe (S) -aminopropionic acid- (2) -ethyl butyl ester has the purity of 99 wt%, and the ratio of enantiomers (S/R) is 95: 5-99: 1. The (S, S) -phosphoramidate can be preferentially and selectively synthesized under the catalysis of chiral imidazole compound catalysts or under the action of certain alkali respectively, and the obtained dr value is 1: 1-2.5: 1, and simultaneously, under the catalysis of a chiral imidazole compound catalyst and the action of alkali, the better dr value can be obtained, and the maximum dr value can reach 5.5: 1.

in the invention, a chiral imidazole catalyst is used for catalyzing (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol to synthesize (S, S) -phosphoramidate shown in a formula II, wherein the reaction formula is as follows:

further, the chiral imidazole compound catalystR is selected from the following substituents: andone of (1) and (b).

The structural formula of 20 (C1-C20) chiral imidazole compound catalysts is shown as follows:

the chiral imidazole catalyst is preferably C3-C5, C10-C15, C17-C18, more preferably C3, C12, C13, C14, C15, C17, even more preferably C3, C14, C15.

Further, the base is an organic base or an inorganic base.

Further, the organic base is a primary, secondary, tertiary, quaternary amine, or diamine thereof having a substituent which is an aliphatic substituent or an aromatic hydrocarbon substituent containing 1 to 10 carbons; the inorganic base is at least one of sodium carbonate, potassium carbonate, cesium carbonate, disodium hydrogen phosphate, sodium hydrogen carbonate and potassium hydrogen carbonate.

Further, the organic base is at least one of triethylamine, ethylenediamine, tetramethylethylenediamine, trimethylethylenediamine, N ' -dimethylethylenediamine, N-dimethylethylenediamine, N-methylethylenediamine, N ' -dimethyl-1, 3-propanediamine, N ' -dimethyl-1, 4-butanediamine, and the like.

Further, the solvent is at least one of a polar solvent, a non-polar solvent, and an ionic liquid solvent.

Further, the nonpolar solvent is toluene, diethyl ether or tetrahydrofuran; the polar solvent is dichloromethane, 1, 2-dichloroethane, DMF, DMSO or acetonitrile. The ionic liquid solvent is 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, pyrrolidine onium salt ionic liquid or pyridinium salt ionic liquid. The solvent is preferably one or two or more of toluene, dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol and trifluoroethanol, more preferably toluene, dichloromethane, tetrahydrofuran, methanol, ethanol and trifluoroethanol, and further preferably toluene, dichloromethane and ethanol.

Further, the molar ratio of the chiral imidazole compound catalyst to the (S) -aminopropionic acid- (2) -ethylbutyl ester is 1: 5-1000, preferably 1: 50-1000, more preferably 1: 50-400, and particularly preferably 1: 50-200; (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol in a molar ratio of 1: (1-1.2): (1-1.2).

Further, the asymmetric catalytic reaction is carried out by dissolving (S) -aminopropionic acid- (2) -ethylbutyl ester in a solvent, so that the solution is prepared by dissolving (S) -aminopropionic acid- (2) -ethylbutyl ester in the solvent before the reaction, and the concentration of the solution of (S) -aminopropionic acid- (2) -ethylbutyl ester is 5 to 80%, preferably 10 to 60%.

Further, the reaction temperature of the asymmetric catalytic synthesis method is-100 ℃ to 180 ℃, preferably-80 ℃ to 80 ℃, and more preferably-80 ℃ to 30 ℃; 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 (S, S) -phosphoramidate 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 (S, S) -phosphoramidate, directly obtains the predominantly-enriched chiral (S, S) -phosphoramidate, and improves the yield of the product from the prior 26 percent to 63 percent; dr values were from 1: 1 to 5.5: 1;

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.

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 (S, S) -phosphoramidate by asymmetrically catalyzing (S) -aminopropionic acid- (2) -ethylbutyl ester, phenyl dichlorophosphate and 4-nitrophenol. Under the catalysis of chiral imidazole catalyst and/or under the action of alkali, (S, S) -phosphoramidate is stereoselectively synthesized, so that the purpose of asymmetric synthesis of (S, S) -phosphoramidate is realized. The preparation method adopts an asymmetric catalysis method to prepare the (S, S) -phosphoramidate for the first time, 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 20 (C1-C20) chiral imidazole compound catalysts used is as follows:

example 1

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieves (A), (B) and (C)3.0g), chiral imidazole catalyst (C1:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, filtering, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 1.8/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.6g, 35%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36 (m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 2

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C2:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. TLC detection reaction is finished, quenching is carried out by dropping water, filtering, extracting, concentrating and column layerThe product phosphoramidate is obtained by separation. The diastereomer excess (dr) was 2.1/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.9g, 42%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 3

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C3:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 4.8/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.6g, 56%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m, 4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47 (m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz, CDCl₃):δ-3.16。

Example 4

Preparation of chiral (S, S) -phosphoramidates

At one isA50 mL two-necked reaction flask was charged with (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv),molecular sieve (3.0g), chiral imidazole catalyst (C4:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.1/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 52%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 5

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C5:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled, degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 deg.C, and adding dropwise base (triethyl phosphate)Amine, 0.011mol,1.1equiv), stirring for reaction for 3 hours, blowing under nitrogen, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv), stirring for reaction for 3 hours at 78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.5/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 52%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 6

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C6:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 1.7/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.0g, 23%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 7

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C7:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.7/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 51%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 8

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C8:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.4/1. Recrystallization from isopropanol to give chiral (S, S) -phosphoramidate (II, 2.2g, 48%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 9

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C9:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.9/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.6g, 57%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 10

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C10:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.9/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.0g, 45%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 11

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C11:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.1/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.6g, 57%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 12

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C12:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. TLC detection of reaction completionAnd dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 4.6/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.2g, 49%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 13

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C13:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 4.9/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.2g, 49%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 14

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C14:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 5.1/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 51%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 15

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled, degassed DCM (dichloromethane, 15ml), and injecting phosphorus dichloride into the solution at-78 deg.CPhenyl ester (0.011mol,1.1equiv), base (triethylamine, 0.011mol,1.1equiv) was added dropwise, and the mixture was stirred and reacted for 3 hours, 4-nitrophenol (1.5g, 0.011mol,1.1equiv) was added under nitrogen, and the mixture was stirred and reacted for 3 hours at 78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 5.5/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.7g, 61%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 16

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C16:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.7/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 52%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2 Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m, 1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 17

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C17:0.001mol,. 1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding dropwise a base (triethylamine, 0.011mol,1.1equiv), reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, and reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 4.6/1. Recrystallization from isopropanol to give chiral (S, S) -phosphoramidate (II, 2.1g, 46%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 18

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C18:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 4.1/1. Recrystallization from isopropanol to give chiral (S, S) -phosphoramidate (II, 2.4g, 52%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m, 4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47 (m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz, CDCl₃):δ-3.16。

Example 19

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C19:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.7/1. Recrystallization from isopropanol to give chiral (S, S) -phosphoramidatesEster (II, 2.2g, 48%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 20

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C20:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding base (triethylamine, 0.011mol,1.1equiv) dropwise, reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.9/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.3g, 50%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 21

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieves (3.0g) were passed through a vacuum line and replaced with nitrogen 3 times, freshly distilled degassed DCM (dichloromethane, 15ml) was added, phenyl dichlorophosphate (0.011mol,1.1equiv) was injected into the solution at-78 deg.C, followed by dropwise addition of base (triethylamine, 0.011mol,1.1equiv) and stirred for reaction for 3 hours, and under nitrogen gas, 4-nitrophenol (1.5g, 0.011mol,1.1equiv) was added and stirred for reaction at-78 deg.C for 3 hours. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomeric excess (dr) value is 1/1. Recrystallization from isopropanol to give chiral (S, S) -phosphoramidate (II, 1.1g, 24%)¹H NMR(400MHz,CDCl₃):δ 8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m, 2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝ 7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 22

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieves (3.0g) were passed through a vacuum line and replaced with nitrogen 3 times, freshly distilled degassed DCM (dichloromethane, 15ml) was added, phenyl dichlorophosphate (0.011mol,1.1equiv) was injected into the solution at-78 deg.C, and then alkali (N, N-dimethylethylenediamine, 0.0055mol,0.55equiv) was added dropwise, and the mixture was stirred for 3 hours, followed by addition of 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen and stirred for 3 hours at-78 deg.C. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.5/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.4g, 31%)¹H NMR(400 MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H), 4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m, 4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 23

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), charging phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, stirring for reaction for 3 hours, blowing under nitrogen, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv), stirring for reaction at-78 ℃ for 3 hours. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.8/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.6g, 36%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H), 4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m, 3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 24

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.001mol,0.1equiv), by passing the system through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl phosphorodithioate dichloride (0.011mol,1.1equiv) into the solution at-78 ℃, adding dropwise an alkali (N, N-dimethylethylenediamine, 0.0055mol,0.55equiv), reacting for 3 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 3 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 5.5/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.8g, 63%)¹H NMR(400MHz,CDCl₃):δ8.23 (d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H), 4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6 Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 25

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding dropwise a base (ethylenediamine, 0.011mol,1.1equiv), reacting for 5 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 2 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.0/1. By the weight of isopropanolCrystallization to give chiral (S, S) -phosphoramidate (II, 2.4g, 53%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 26

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.001mol,0.1equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding dropwise a base (ethylenediamine, 0.0055mol,0.55equiv), reacting for 5 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, reacting for 2 hours with stirring at-78 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.2/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.5g, 56%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 27

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol,1 equ)iv)，Molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding freshly distilled degassed DCM (dichloromethane, 15ml), injecting phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-78 ℃, adding dropwise a base (ethylenediamine, 0.0055mol,0.55equiv), reacting with stirring for 2 hours, blowing nitrogen, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv), and reacting with stirring at-78 ℃ for 2 hours. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.4/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.6g, 58%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2 Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m, 1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 28

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing through a vacuum line, replacing with nitrogen gas for 3 times, adding 15ml of freshly distilled, degassed toluene, charging phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-90 deg.C, further adding dropwise an alkali (tetramethylethylenediamine, 0.0055mol,0.55equiv), reacting for 2 hours with stirring, blowing under nitrogen gas, adding 4 equivNitrophenol (1.5g, 0.011mol,1.1equiv), the reaction is stirred at 90 ℃ for 2 hours. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.5/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.7g, 59%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Example 29

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding 15ml of freshly distilled, degassed DMF, charging phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-50 ℃, dropwise adding a base (trimethylethylenediamine, 0.0055mol,0.55equiv), reacting for 12 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, and reacting for 24 hours with stirring at-50 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.4/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.6g, 57%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H), 7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H), 1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR (162MHz,CDCl₃):δ-3.16。

Practice ofExample 30

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing through a vacuum line, replacing 3 times with nitrogen, adding 15ml of freshly distilled degassed acetonitrile, charging phenyl dichlorophosphate (0.011mol,1.1equiv) into the solution at-20 ℃, dropwise adding a base (N, N' -dimethylethylenediamine, 0.0055mol,0.55equiv), stirring for 30 hours, blowing nitrogen, adding 4-nitrophenol (1.36g, 0.01mol, 1.0equiv), and stirring for 12 hours at-20 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.6/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.7g, 59%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2 Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m, 1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 31

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing through a vacuum line with nitrogenThe reaction mixture was subjected to substitution 3 times, 15ml of freshly distilled degassed dichloromethane was added, phenyl dichlorophosphate (0.015mol,1.5equiv) was added to the solution at-70 ℃ and then dropwise added with a base (N, N-dimethylethylenediamine, 0.0055mol,0.55equiv) to conduct a reaction with stirring for 30 hours, followed by addition of 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen and a reaction with stirring at-50 ℃ for 12 hours. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 3.7/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 2.5g, 56%)¹H NMR(400MHz,CDCl₃):δ8.23(d, J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H),4.10-4.08(m,2H), 4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m,4H),0.87(t,J＝7.6 Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 32

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,a molecular sieve (3.0g), which was passed through a vacuum line and was replaced with nitrogen gas 3 times, 15ml of 1-methyl-3-propylimidazolium tetrafluoroborate ionic liquid was added, phenyl dichlorophosphate (0.015mol,1.5equiv) was injected into the solution at-25 ℃, alkali (N, N' -dimethyl-1, 3-propanediamine, 0.0055mol,0.55equiv) was added dropwise thereto, the mixture was stirred for reaction for 24 hours, 4-nitrophenol (1.5g, 0.011mol,1.1equiv) was added under nitrogen gas blowing, and the mixture was stirred for reaction for 24 hours at 25 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 1.7/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.6g, 36%)¹H NMR(400MHz,CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H), 4.16-4.13(m,1H),4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m, 3H),1.38-1.28(m,4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 33

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing the system through a vacuum line, replacing 3 times with nitrogen, adding 15ml of 1-ethyl-1-methylpyrrolidinium tetrafluoroborate ionic liquid, injecting phenyl dichlorophosphate (0.015mol,1.5equiv) into the solution at 45 ℃, further adding dropwise an alkali (sodium bicarbonate, 0.0055mol,0.55equiv), reacting for 24 hours with stirring, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv) under nitrogen, and reacting for 24 hours with stirring at 45 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.4/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.7g, 38%)¹H NMR(400MHz, CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H), 4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m, 4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

Example 34

Preparation of chiral (S, S) -phosphoramidates

In a 50mL two-necked reaction flask, (S) -aminopropionic acid- (2) -ethylbutyl ester (2.1g,0.01mol, 1equiv) was added,molecular sieve (3.0g), chiral imidazole catalyst (C15:0.0005mol, 0.05equiv), by passing the system through a vacuum line, replacing 3 times with nitrogen, adding 15ml of butyltrimethylammonium bis (trifluoromethanesulfonyl) imide ionic liquid, injecting phenyl dichlorophosphate (0.015mol,1.5equiv) into the solution at 60 ℃, further adding dropwise an alkali (potassium carbonate, 0.0055mol,0.55equiv), stirring and reacting for 18 hours, blowing nitrogen, adding 4-nitrophenol (1.5g, 0.011mol,1.1equiv), and stirring and reacting for 18 hours at 60 ℃. And after TLC detection reaction is finished, dripping water for quenching, extracting, concentrating and carrying out column chromatography to obtain the product phosphoramidate. The diastereomer excess (dr) was 2.8/1. Recrystallization from isopropanol gave chiral (S, S) -phosphoramidate (II, 1.9g, 42%)¹H NMR(400MHz, CDCl₃):δ8.23(d,J＝9.2Hz,2H),7.36(m,4H),7.24-7.22(m,3H),4.16-4.13(m,1H), 4.10-4.08(m,2H),4.00-3.91(m,1H),1.55-1.47(m,1H)；1.45-1.40(m,3H),1.38-1.28(m, 4H),0.87(t,J＝7.6Hz,6H)；³¹P NMR(162MHz,CDCl₃):δ-3.16。

The preparation method of the chiral imidazole catalyst adopted in the above embodiment is as follows:

example 35: preparation of chiral imidazole catalyst C1

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq), 20mL dichloromethane, and triethylamine (1.08mL,7.2mmol,3.0eq) and stirred for 5 min. Then, acetic anhydride (0.34mL,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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²/g) product C1 was isolated (305mg, 76% yield).¹H NMR(400MHz,CDCl₃)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).¹³C NMR(100MHz,CDCl₃)δ169.8,150.5,134.0, 115.2,66.6,42.4,34.3,20.5。

Example 36: chiral imidazoles as catalystsPreparation of reagent C2

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq) and 30mL tetrahydrofuran, 60% by mass sodium hydride (116mg,2.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then, benzyl bromide (0.43mL,3.6mmol,1.5eq) was added and the reaction was carried out 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, using pure ethyl acetate 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 C2 was isolated (378mg, 73% yield).¹H NMR(400MHz,CDCl₃) 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).¹³C NMR(100MHz,CDCl₃)δ 153.5,137.9,133.8,128.4,128.1,127.7,115.0,71.1,70.8,43.1,35.3。

Example 37: preparation of chiral imidazole catalyst C3

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq) and 30mL tetrahydrofuran, 60% by mass sodium hydride (116mg,2.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. After that, di-tert-butyl dicarbonate (0.83mL,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, using ethyl acetate/methanol volume ratio 10/1 as mobile phase to perform silica gel column chromatography (particle size 100-200 mesh, specific surface area 300-400 m)²The product C3 was isolated (385.0mg, 71% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)δ152.7,150.8,134.9,115.4,82.9,69.3, 42.9,34.9,27.8。

Example 38: preparation of chiral imidazole catalyst C4

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq), 20mL dichloromethane, and triethylamine (1.68mL,12.1mmol,5.0eq) and stirred for 5 min. Then, adamantanoyl chloride (497mg,2.5mmol,1.05eq) was added thereto, and the reaction was carried out 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²The product C4 was isolated (392mg, 57% yield).¹H NMR(500MHz,CDCl₃)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). ¹³C NMR(126MHz,CDCl₃)δ177.3,151.4,134.8,115.5,66.9,43.0,40.9,39.0,38.8,36.7 36.5,35.3,28.2,28.0。

Example 39: 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,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then, 2, 6-diisopropylphenyl isocyanate (0.52mL,2.4mmol,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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²The product C5 was isolated (402mg, 76% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)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 40: 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,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Thereafter, 2,4, 6-trichlorophenyl isocyanate (538mg,2.4mmol,1.5eq) was added thereto, and the reaction was carried out 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, using ethyl acetate/methanol volume ratio 10/1 as mobile phase to perform silica gel column chromatography (particle size 100-200 mesh, specific surface area 300-400 m)²/g) product C6 was isolated (229mg, 41% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)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 41: preparation of chiral imidazole catalyst C7

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (200mg,1.6mmol,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Thereafter, 2-biphenyl isocyanate (472mg,2.4mmol,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, using ethyl acetate/methanol volume ratio 10/1 as mobile phase to perform silica gel column chromatography (particle size 100-200 mesh, specific surface area 300-400 m)²The product C7 was isolated (423mg, 82% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126 MHz,CDCl₃)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 42: preparation of chiral imidazole catalyst C8

A dry reaction flask was charged with bicyclic imidazole C7(319mg,1.0mmol,1.0eq) and 10mL tetrahydrofuran, and 60% by mass sodium hydride (48mg,1.2mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then, methyl iodide (62.3. mu.L, 1.0mmol,1.0eq) 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²/g) product C8 was isolated (185mg, 55% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126 MHz,CDCl₃)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 43: preparation of chiral imidazole catalyst C9

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq) and 30mL tetrahydrofuran, 60% by mass sodium hydride (116mg,2.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then, 3-isopropyl-dimethylbenzyl isocyanate (0.72mL,3.6 mmol,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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²The product C9 (41) is isolated5mg, 53% yield).¹H NMR(400MHz,CDCl₃)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).¹³C NMR(101MHz,CDCl₃)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 44: preparation of chiral imidazole catalyst C10

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq), 20mL dichloromethane, and triethylamine (1.68mL,12.1mmol,5.0eq) 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²Product C9 was isolated (161mg, 27% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)δ154.8,151.9,134.7,115.3,67.6,46.6,45.7,43.0,35.7, 21.5,20.6。

Example 45: preparation of chiral imidazole catalyst C11

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq), 20mL dichloromethane, and triethylamine (1.68mL,12.1mmol,5.0eq) and stirred for 5 min. Then, 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, and performing silica gel column chromatography (granularity) with ethyl acetate/methanol volume ratio 10/1 as mobile phase100 to 200 mesh, and a specific surface area of 300 to 400m²The product C11 was isolated (271mg, 48% yield).¹H NMR(500MHz,CDCl₃)δ7.19(d,J＝1.2 Hz,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).¹³C NMR(126MHz,CDCl₃)δ154.7,151.7,134.6,115.3,68.1,44.9,42.9,35.4,25.6, 24.3。

Example 46: preparation of chiral imidazole catalyst C12

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (300mg,2.4 mmol,1.0eq) and 30mL tetrahydrofuran, 60% by mass sodium hydride (116mg,2.9 mmol,1.2eq) was added portionwise 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, using ethyl acetate/methanol volume ratio 10/1 as mobile phase to perform silica gel column chromatography (particle size 100-200 mesh, specific surface area 300-400 m)²Product C12 was isolated (460mg, 85% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)δ155.0,151.7,134.9,115.5,67.2,50.7,43.1,35.5, 29.0。

Example 47: preparation of chiral imidazole catalyst C13

A dry reaction flask was charged with bicyclic imidazole C12(223mg,1.0mmol,1.0eq) and 10mL tetrahydrofuran, and 60% by mass sodium hydride (48mg,1.2mmol,1.2eq) was added portionwise at 0 deg.C and stirred for 30 minutes. Then, methyl iodide (62.3. mu.L, 1.0mmol,1.0eq) 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, and performing silica gel column chromatography (granularity is 100-2) by taking ethyl acetate/methanol volume ratio 10/1 as a mobile phase00 meshes, and the specific surface area is 300-400 m²/g) product C13 was isolated (193mg, 81% yield).¹H NMR(400MHz,CDCl₃)δ7.19(d,J＝1.2 Hz,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).¹³C NMR (101MHz,CDCl₃)δ155.6,151.9,134.6,115.4,67.7,55.9,43.0,35.6,31.5,28.7。

Example 48: preparation of chiral imidazole catalyst C14

To a dry reaction flask A was added triphosgene (474.8mg,1.6mmol,1.0eq) and 10mL of dichloromethane. 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 added dropwise to the reaction mixture. Then reacted 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 tetrahydrofuran were added portionwise 60% by mass sodium hydride (193mg,4.8mmol,3.0eq) at 0 ℃ and stirred for 30 min. 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²/g) product C14 was isolated (164.8mg, 43% yield).¹H NMR(400MHz,CDCl₃)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＝14.9 Hz,1H),1.38(s,3H),1.34(s,3H),0.99(s,9H).¹³C NMR(101MHz,CDCl₃)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 49: preparation of chiral imidazole catalyst C15

Adding (S) -6, 7-dihydro-5H-pyrrolo [1,2-A ] into a dry reaction bottle]Imidazol-7-ol (200mg,1.6mmol,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Thereafter, 1-adamantane isocyanate (428mg,2.4mmol,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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with petroleum ether/ethyl acetate volume ratio 1/10 as mobile phase²Product C15 was isolated (285mg, 59% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR (126MHz,CDCl₃)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 50: 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,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then, 2- (ethoxycarbonyl) phenyl isocyanate (462mg,2.4mmol, 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²The product C16 was isolated (298mg, 59% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)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 51: 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,1.0eq) and 20mL tetrahydrofuran, 60% by mass sodium hydride (77mg,1.9 mmol,1.2eq) was added portionwise at 0 ℃ and stirred for 30 minutes. Then isopropyl isocyanate (0.18mL,2.4mmol,1.5eq) was added and the reaction was carried out 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, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²Product C17 was isolated (158mg, 47% yield).¹H NMR (500MHz,CDCl₃)δ7.19(s,1H),6.95(s,1H),5.91(dd,J＝7.2,2.7Hz,1H),4.63(d,J＝7.3 Hz,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).¹³C NMR(126MHz,CDCl₃)δ154.7,151.5, 134.8,115.4,67.5,43.2,42.9,35.3,23.0。

Example 52: 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 stirred for 5 min. Thereafter, tert-butyldimethylsilyl trifluoromethanesulfonate (0.74mL,3.2mmol,2.0eq) was added at 0 ℃ and reacted at 20 ℃ for 24 hours. Then directly spin-drying, and performing silica gel column chromatography (granularity is 100-200 meshes, and specific surface area is 300-400 m) with ethyl acetate/methanol volume ratio 10/1 as mobile phase²The product C18 was isolated (287mg, 75% yield).¹H NMR(500MHz,CDCl₃)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).¹³C NMR(126MHz,CDCl₃)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.