Method for efficiently preparing various substituted chiral phosphamides

Abstract

The invention provides a method for efficiently preparing various substituted chiral phosphoramides, which comprises the following steps: in the presence of an organic solvent, alkali, a chiral ligand and a catalyst, reacting a nucleoside compound or alcohol with racemic amino phosphoryl dichloride or alkoxy phosphoryl dichloride to generate chiral phosphoryl chloride; and reacting the chiral phosphoryl chloride with a nucleophilic reagent to obtain the chiral phosphamide. The synthesis method provided by the invention is simple to operate, high in yield and good in diastereoselectivity or enantioselectivity, and the obtained target compound has the characteristics of good functional group compatibility and wide substrate universality. The obtained product is diversified in structure and good in controllability, and has good application potential in the field of medicine synthesis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and pharmaceutical intermediate synthesis technology, specifically relating to a method for efficiently preparing various substituted chiral phosphoramides. Background Technology

[0002] Compounds with one or more stereophosphorus atoms in the P(V) oxidation state play a vital role in chemistry, biology, and medicine. These include well-known antiviral drugs, such as remdesivir, originally designed to combat Ebola and also approved for the treatment of SARS-CoV-2. Other relevant compounds include fosinopril, a compound used to treat hypertension and heart failure, and cyclophosphamide, a chemotherapy drug listed as an essential medicine by the World Health Organization (WHO).

[0003]

[0004] The synthetic methods for enantiomeric pure P(V) compounds can be divided into five categories: (1) chiral resolution strategy of racemic phosphine oxides; (2) chiral prosthetic group-induced strategy; (3) strategy of tertiary phosphine oxidation to synthesize P-chiral phosphine oxides; (4) asymmetric catalytic strategy based on phosphine oxides; and (5) enantioselective desymmetry by chiral catalysts to separate the prochiral groups attached to the phosphorus center, for which several reactions have been developed. However, to date, a highly efficient and universal synthetic method for chiral phosphoramides has not been reported. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for the efficient preparation of various substituted chiral phosphoramides.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] In a first aspect, the present invention provides a chiral phosphoric acid chloride having a compound structure as shown in Formula I:

[0008]

[0009] Among them, R 1Derived from dimethylamine, diethylamine, diallylamine, di(2-chloroethyl)amine, diisobutylamine, N-benzylglycine isopropyl ester, N-methylbenzylamine, N-methylbenzylamine, N-[(trimethylsilyl)methyl]benzylamine, diethyl iminodiacetate, N-(2-furanylmethyl)benzylamine, tetrahydropyrrole, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrothieno[3,2-c] Pyridine, 4-methylhexahydropyridine, methyl 4-piperidine acetate, morpholine, N-phenylpiperazine, 1-(2-pyrimidinyl)piperazine, cycloheptamine, 4,4'-difluorobenzylpiperazine, 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole, 4-(1,2-benzisothiazol-3-yl)-1-piperazine, duloxetine (3-(1-naphthoxy)-3-(2-thienyl)propyl, nortriptyline, vortioxetine, atomoxetine, sertraline;

[0010] R 2 Derived from 2',3'-isoproterenol, 2',3'-isoproterenol, 5-fluoro-2',3'-isoproterenol, 5-bromo-2',3'-isoproterenol, 5-iodo-2',3'-isoproterenol, 2',3'-isoproterenol, 6-chloro-2',3'-isoproterenol, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, 1-((3a'R, 4'R, 6'R) 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furano[3,4-d][1,3]dioxacyclopentene]-6-yl)pyrimidin-2,4(1H,3H)-dione, 1-((2R,6S)-6-(hydroxymethyl)-4-triphenylmethylmorpholino-2-yl)pyrimidin-2,4(1H,3H)-dione, (2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) 2-(hydroxymethyl)tetrahydrofuran, fructose diacetone, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (2R,3R,4R,5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-trimethyltribenzoate, (3-phenoxyphenyl)methanol, 4-nitrobenzyl alcohol, methyl 4-(hydroxymethyl)benzoate, 1-naphthalenemethanol, 2-naphthalenemethanol, 3 - Morpholinylbenzyl alcohol, (5-nitrofuran-2-yl)methanol, 2-naphthylethanol, 1-(2-methoxyphenyl)ethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, 2-thiopheneethanol, 2-phenylthioethanol, N-BOC-2-(4-aminophenyl)ethanol, 4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester, and idebenone.

[0011] Secondly, the present invention provides a method for preparing chiral phosphoryl chloride, comprising the following steps:

[0012] Chiral phosphoryl chloride is generated by reacting nucleoside compounds or alcohols with racemic aminophosphoryl dichloride or alkoxyphosphoryl dichloride in the presence of organic solvents, bases, chiral ligands and catalysts.

[0013] Preferably, the nucleoside compound is selected from 2',3'-isopropylideneuridine, 5-fluoro-2',3'-isopropylideneuridine, 5-bromo-2',3'-isopropylideneuridine, 2',3'-isopropylidene thymidine, 5-iodo-2',3'-isopropylideneuridine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine. At least one of the following: 1-((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furano[3,4-d][1,3]dioxane]-6-yl)pyrimidin-2,4(1H,3H)-dione, (2R, 3S, 5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran, and fructose diacetone.

[0014] Preferably, the alcohol is selected from 4-nitrobenzyl alcohol, (5-nitrofuran-2-yl)methanol, 1-(2-methoxyphenyl)ethanol, 2-thiopheneethanol, 2-phenylthioethanol, N-BOC-2-(4-aminophenyl)ethanol, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (3-phenoxyphenyl)methanol, 1-naphthalenemethanol, 2-naphthalenemethanol, etc. At least one of methanol, 3-morpholinobenzyl alcohol, 2-naphthylethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, (2R, 3R, 4R, 5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-trimethyltribenzoate, methyl 4-(hydroxymethyl)benzoate, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, benzyl 4-(hydroxymethyl)piperidine-1-carboxylate, and idebenone.

[0015] Preferably, the aminophosphoryl dichloride is selected from at least one of dibenzylaminophosphoryl dichloride, dimethylaminophosphoryl dichloride, di(2-chloroethyl)phosphoramide dichloride, diallylphosphoramide dichloride, benzyl(furan-2-ylmethyl)phosphoramide dichloride, and (S)-methyl-(3-(1-naphthoxy))-3-(thiophen-2-yl)propyl)phosphoramide dichloride.

[0016] Preferably, the alkoxyphosphoryl dichloride is selected from at least one of pyrrolidine-1-ylphosphonyl dichloride, morpholine phosphoryl dichloride, azircyclopentane-1-phosphonyl dichloride, (4-(6-fluorobenzo[d]trimethylandrosadieneisoxazol-3-yl))piperidin-1-yl)phosphine dichloride, and ethyl dichlorophosphate.

[0017] Preferably, the organic solvent is selected from tetrahydrofuran.

[0018] Preferably, the base is selected from triethylamine.

[0019] Preferably, the catalyst is selected from copper hexafluoroacetylacetonate.

[0020] Preferably, the chiral ligand is selected from ligand L1 and ligand L2, and the ligand structure is as follows:

[0021]

[0022] Preferably, the molar ratio of the nucleoside-containing compound or alcohol to the chiral ligand and catalyst is 1:0.075-0.15:0.05-0.1.

[0023] Preferably, the molar ratio of the nucleoside-containing compound or alcohol to aminophosphoryl dichloride or alkoxyphosphoryl dichloride is 1:1.0 to 1.5.

[0024] Preferably, the reaction temperature is -60℃ to -30℃, and the reaction time is 18 to 28 hours.

[0025] Thirdly, the present invention provides a method for preparing chiral phosphoramide, comprising the following steps: reacting chiral phosphoryl chloride with a nucleophilic reagent to obtain chiral phosphoramide.

[0026] Preferably, the nucleophile is selected from any one of sodium phenolate, sodium methoxide, sodium 1-naphthol, sodium 4-fluorophenolate, sodium thiophene, sodium ethanethiol, cyclohexylamine, benzamide, 4-methoxyaniline, benzylamine, dimethylamine, morpholine, 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane, L-alanine isopropyl ester, 1,2,3,4-tetrahydroisoquinoline, magnesium methyl bromide, and lithium amino.

[0027] Preferably, the reaction temperature is -60℃ to -30℃, and the reaction time is 2 to 6 hours.

[0028] Fourthly, the present invention provides a chiral phosphoramide prepared according to the aforementioned method, said chiral phosphoramide comprising compounds having the structures shown in formulas II to X as follows:

[0029]

[0030] Among them, R 3Derived from dimethylamine, diethylamine, diallylamine, di(2-chloroethyl)amine, diisobutylamine, N-benzylglycine isopropyl ester, N-methylbenzylamine, N-methylbenzylamine, N-[(trimethylsilyl)methyl]benzylamine, diethyl iminodiacetate, N-(2-furanylmethyl)benzylamine, tetrahydropyrrole, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- The following are listed: tetrahydrothieno[3,2-c]pyridine, 4-methylhexahydropyridine, methyl 4-piperidine acetate, morpholine, N-phenylpiperazine, 1-(2-pyrimidinyl)piperazine, cycloheptylamine, 4,4'-difluorobenzylpiperazine, 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole, 4-(1,2-benzisothiazol-3-yl)-1-piperazine, duloxetine, nortriptyline, vortioxetine, atomoxetine, and sertraline.

[0031] R 4 It is any one of methyl, 1-naphthol, 4-fluorophenol, phenol, methoxy, thiophene, ethylthio, cyclohexylamine, benzylamine, benzamide, 4-methoxyaniline, dimethylamine, morpholine, tert-butyloxy, 2-tert-butyloxycarbonyl-2,7-diazaspiro[3.5]nonane;

[0032] R 5 It is any one of 2',3'-isoproterenylthymidine, 5-fluoro-2',3'-isoproterenyluridine, 5-bromo-2',3'-isoproterenyluridine, 5-iodo-2',3'-isoproterenyluridine, 2',3'-isoproterenyl adenosine, (2R, 3S, 5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran;

[0033] R 6 It is any one of hydrogen, acetoxy, tert-butyldimethylsiloxy, and azide;

[0034] R 7 It is either thymidine or uridine;

[0035] R 8Derived from fructose diacetone, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (2R,3R,4R,5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triyltribenzoate, (3-phenoxyphenyl)methanol, 4-nitrobenzyl alcohol, methyl 4-(hydroxymethyl)benzoate, 1-naphthalenemethanol, 2-naphthalene The following is a list of methanol, 3-morpholinobenzyl alcohol, (5-nitrofuran-2-yl)methanol, 2-naphthylethanol, 1-(2-methoxyphenyl)ethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, 2-thiopheneethanol, 2-phenylthioethanol, 4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester, and idebenone.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The synthesis method provided by the present invention is simple to operate, has a high yield, good diastereoselectivity or enantioselectivity, and the target compound obtained has the characteristics of good functional group compatibility and broad substrate universality.

[0038] (2) The synthesis method provided by this invention has a short chiral ligand synthesis process and uses inexpensive and readily available raw materials. The products have diverse structures and good controllability, and have good application potential in the field of pharmaceutical synthesis. Detailed Implementation

[0039] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0040] This invention constructs P(V) species through enantioselective desymmetry involving enantioselective nucleophilic substitution of the leaving group. Through the rational selection of the leaving group, nucleophile, and catalyst, desired enantiomeric enrichments can be obtained in high yields and with good enantioselectivity (Stage 1). The desymmetric substrate, still possessing another leaving group, then undergoes a second (potentially optical isomer) nucleophilic substitution reaction, thereby achieving diversified subsequent derivatization (Stage 2). This two-phase strategy allows for the acquisition of a wide range of P(V) compounds from a common intermediate, overcoming one of the major limitations of current enantioselective desymmetry methods.

[0041]

[0042] In a specific embodiment of the present invention, a method for preparing chiral phosphoryl chloride is provided, comprising the following steps:

[0043] In the presence of an organic solvent, a base, a chiral ligand, and a catalyst, a nucleoside compound or an alcohol is reacted with racemic aminophosphoryl dichloride or alkoxyphosphoryl dichloride to generate chiral phosphoryl chloride; the chiral phosphoryl chloride has the compound structure shown in Formula I:

[0044]

[0045] Among them, R 1 Derived from dimethylamine, diethylamine, diallylamine, di(2-chloroethyl)amine, diisobutylamine, N-benzylglycine isopropyl ester, N-methylbenzylamine, N-methylbenzylamine, N-[(trimethylsilyl)methyl]benzylamine, diethyl iminodiacetate, N-(2-furanylmethyl)benzylamine, tetrahydropyrrole, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- The following are listed: tetrahydrothieno[3,2-c]pyridine, 4-methylhexahydropyridine, methyl 4-piperidine acetate, morpholine, N-phenylpiperazine, 1-(2-pyrimidinyl)piperazine, cycloheptylamine, 4,4'-difluorobenzylpiperazine, 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole, 4-(1,2-benzisothiazol-3-yl)-1-piperazine, duloxetine, nortriptyline, vortioxetine, atomoxetine, and sertraline.

[0046] R 2Derived from 2',3'-isoproterenol, 2',3'-isoproterenol, 5-fluoro-2',3'-isoproterenol, 5-bromo-2',3'-isoproterenol, 5-iodo-2',3'-isoproterenol, 2',3'-isoproterenol, 6-chloro-2',3'-isoproterenol, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, 1-((3a'R, 4'R, 6'R) 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furano[3,4-d][1,3]dioxacyclopentene]-6-yl)pyrimidin-2,4(1H,3H)-dione, 1-((2R,6S)-6-(hydroxymethyl)-4-triphenylmethylmorpholino-2-yl)pyrimidin-2,4(1H,3H)-dione, (2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) 2-(hydroxymethyl)tetrahydrofuran, fructose diacetone, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (2R,3R,4R,5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-trimethyltribenzoate, (3-phenoxyphenyl)methanol, 4-nitrobenzyl alcohol, methyl 4-(hydroxymethyl)benzoate, 1-naphthalenemethanol, 2-naphthalenemethanol, 3 - Morpholinylbenzyl alcohol, (5-nitrofuran-2-yl)methanol, 2-naphthylethanol, 1-(2-methoxyphenyl)ethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, 2-thiopheneethanol, 2-phenylthioethanol, N-BOC-2-(4-aminophenyl)ethanol, 4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester, and idebenone.

[0047] In one specific embodiment, the aminophosphoryl dichloride is selected from at least one of dibenzylaminophosphoryl dichloride, dimethylaminophosphoryl dichloride, di(2-chloroethyl)phosphoramide dichloride, diallylphosphoramide dichloride, benzyl(furan-2-ylmethyl)phosphoramide dichloride, and (S)-methyl-(3-(1-naphthoxy))-3-(thiophen-2-yl)propyl)phosphoramide dichloride; the alkoxyphosphoryl dichloride is selected from at least one of pyrrolidine-1-ylphosphonyl dichloride, morpholinephosphoryl dichloride, azircyclopentane-1-phosphonyl dichloride, (4-(6-fluorobenzo[d]trimethylandrosadienisoxazol-3-yl))piperidin-1-yl)phosphine dichloride, and ethyl dichlorophosphate.

[0048] In one specific embodiment, the organic solvent is selected from tetrahydrofuran; the base is selected from triethylamine; the catalyst is selected from copper hexafluoroacetylacetonate; and the chiral ligand is selected from ligands L1 and L2.

[0049] In the following specific embodiments, the synthesis methods of ligands L1 and L2 are as follows:

[0050] Step 1: Take a dried 250 mL flask and add 80 mL of THF, 5-fluoro-2-pyridinecarboxylic acid (18 mmol, 2.54 g, 1.0 equiv.), (S)-tert-leucine (2.15 g, 18 mmol), and TBTU (5.85 g, 18 mmol), respectively. Add 5 mL of NEt3 and stir for 24 h. Remove the solvent under reduced pressure. Dissolve the residue in DCM (3 × 20 mL), wash with 1 M HCl solution, combine the organic layers, wash with brine, dry with anhydrous Na2SO4, filter, and concentrate. Purify the residue by silica gel column chromatography.

[0051] Step 2: Dissolve (S)-5-fluoro-N-(1-hydroxy-3,3-dimethylbutane-2-yl)pyrcolinamide (5.0 mmol, 1.2 g, 1.0 equiv.) in chloroform (5.0 mL, 1.0 M). Under N2 protection, add 0.4 mL, 5.5 mmol, 1.1 equiv. of thionyl chloride dropwise at room temperature and reflux for 2 hours. After cooling to room temperature, add phosphorus pentachloride (1.145 g, 5.5 mmol) at room temperature and reflux the resulting suspension overnight. Cool the solution to 0 °C and add dropwise a chloroform solution of 3,5-ditrifluoromethylaniline (6.0 mmol, for preparing ligand L1) and triethylamine (15 mmol) or a chloroform solution of 3,5-di-tert-butylaniline (6.0 mmol, for preparing ligand L2) and triethylamine (15 mmol). Stir the mixture at 0 °C for 30 min and then reflux for 12 hours. After removing volatiles, an aqueous solution of NaOH (20% w / v, 10 mL) was added to the residue. The mixture was extracted with dichloromethane and washed with saturated brine. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give products L1 and L2, respectively.

[0052]

[0053] 1 H NMR(500MHz,Chloroform-d)δ8.29(d,J=2.7Hz,1H),7.99(dd,J=8.6,4.5Hz,1H),7.53(ddd,J=8.7,7.9,2.9Hz,1 H),7.41(dd,J=1.5,0.8Hz,1H),6.99–6.96(m,2H),4.19–4.06(m,2H),3.86(dd,J=8.9,7.5Hz,1H),1.01(s,9H). 13C NMR(126MHz,Chloroform-d)δ159.9(d,J=261.1Hz),157.4,145.8(d,J=4.1Hz),143.4,137.5(d,J=24.4Hz),131.7(q,J=33.1Hz),126.0(d,J=5.1Hz),123.9(d,J=18.8Hz),123.0(q,J=272.9Hz),120.2(d,J=3.7Hz),115.6–115.3(m),74.3,54.1,34.2,25.9. 19 F NMR(471MHz,Chloroform-d)δ-63.30,-122.63.HRMS(ESI)m / z calcd.for C 20 H 19 F7N3[M+H] + m / z 434.1462found434.1465.

[0054]

[0055] 1 H NMR(500MHz,Chloroform-d)δ8.26(d,J=2.9Hz,1H),7.62(dd,J=8.7,4.4Hz,1H),7.28(td,J=8.3,2.8Hz,1H),6.92(t,J=1.8Hz,1H),6.43(d,J=1.8Hz,2H),4.04(dd,J=10.9,8.9Hz,1H),3.97(dd,J=10.9,8.2Hz,1H),3.72(t,J=8.5Hz,1H),1.06(s,18H),0.93(s,9H). 13 C NMR(126MHz,Chloroform-d)δ159.79,159.31(d,J=259.2Hz),150.94,147.55(d,J=4.2Hz),141.90,137.49(d,J=24.4Hz),125.40(d,J=4.6Hz),123.06(d,J=18.8Hz),117.20,116.37,74.44,54.70,34.65,34.15,31.23,26.03. 19 F NMR(471MHz,Chloroform-d)δ-124.87.HRMS(ESI)m / z calcd.for C 26 H 37FN3[M+H]+m / z410.2966found410.2965.

[0056] In one specific embodiment, the reaction temperature is -60℃ to -30℃, and the reaction time is 18 to 28 hours.

[0057] Based on the above preparation method, different nucleoside compounds or alcohols can be used to react and obtain the corresponding chiral phosphoryl chlorides, which will not be listed one by one in the embodiments of the present invention.

[0058] In a specific embodiment of the present invention, a method for preparing chiral phosphoramide is also provided, comprising the following steps: reacting chiral phosphoryl chloride with a nucleophilic reagent to obtain chiral phosphoramide.

[0059] In one specific embodiment, the nucleophile is selected from any one of sodium phenolate, sodium methoxide, sodium 1-naphthol, sodium 4-fluorophenolate, sodium thiophene, sodium ethanethiol, cyclohexylamine, benzamide, 4-methoxyaniline, benzylamine, dimethylamine, morpholine, 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane, L-alanine isopropyl ester, 1,2,3,4-tetrahydroisoquinoline, magnesium methyl bromide, and lithium amino.

[0060] In one specific embodiment, the reaction temperature is -60℃ to -30℃, and the reaction time is 2 to 6 hours.

[0061] Based on the above preparation method, different chiral phosphoryl chlorides can be used to react and obtain the corresponding chiral phosphoramides, which will not be listed one by one in the embodiments of the present invention.

[0062] Example 1

[0063] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidine-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-dibenzylphosphamide (compound II-1), the structure of which is shown below:

[0064]

[0065] The specific preparation steps for compound II-1 are as follows:

[0066] 1) In an 8 mL reaction flask, add ligand L1 (6.8 mg, 0.015 mmol), copper hexafluoroacetylacetonate (4.8 mg, 0.01 mmol), and 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol). Place the reaction system in a glove box, then add tetrahydrofuran (0.3 mL) and triethylamine (72.0 μL, 0.5 mmol, NEt3) sequentially. Seal the reaction apparatus, remove it from the glove box, and stir at room temperature for half an hour. Then, cool the mixture to -30°C and stir for another half hour. Next, add a pre-cooled solution of dibenzylphosphonate dichloride (47 mg, 0.15 mmol) in tetrahydrofuran (0.2 mL) to the above-stirred solution and react for 20 h. The resulting reaction solution was separated by column chromatography (DCM:MeOH = 20:1, Rf = 0.50) to obtain a white solid intermediate product, compound I-1 (54.0 mg, yield 96%), with the structure shown below:

[0067]

[0068] 1 H NMR(500MHz,Chloroform-d)δ9.56(s,1H),7.26(t,J=7.9Hz,2H),7.20(d,J=7.9Hz,1H),7.13(dd,J=11.4,7.6Hz,3H),5.64(dd,J=9.2,2.6Hz,2H),4. 70(dd,J=6.6,3.1Hz,1H),4.58(dd,J=6.5,2.7Hz,1H),4.33–4.23(m,3H), 3.56–3.47(m,4H),3.41(dt,J=14.2,7.0Hz,4H),1.48(s,3H),1.25(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.43,150.46(d,J=6.9Hz),150.04,141.78,129.92,125.40,119.99(d,J=5.1Hz),11 4.66, 102.58, 93.93, 85.24 (d, J = 7.8Hz), 84.22, 80.62, 66.54 (d, J = 5.5Hz), 49.33 (d, J = 4.6Hz), 41.91, 27.07, 25.19. 31 P NMR (202 MHz, Chloroform-d) δ 4.34. Phosphoramide I-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50% iPrOH / hexanes, 1.0 mL / min, 250 nm, t R (Minor) = 20.9 min, tR (Main) = 21.9 min).

[0069] 2) Add a cold sodium phenolate (58 mg, 0.50 mmol) tetrahydrofuran (0.5 mL) solution to the reaction solution from step 1), and stir at -30°C for 4 hours. After the reaction is complete, the resulting reaction solution is separated by column chromatography (DCM:MeOH = 20:1, Rf = 0.50) to obtain the final product as a white solid, namely compound II-1 (57.5 mg, yield 93%). 1 H NMR(500MHz,Chloroform-d)δ9.54(s,1H),7.37(d,J=7.3Hz,1H),7.35–7.27(m,10H),7.21(dd ,J=7.4,2.2Hz,5H),5.79(d,J=2.9Hz,1H),5.60(d,J=7.9Hz,1H),4.77(dd,J=6.6,3.4Hz,1H),4 .52(dd,J=6.4,2.9Hz,1H),4.46–4.40(m,1H),4.40–4.37(m,1H),4.30(ddd,J=10.8,5.4,3.2H z,1H),4.24(dd,J=15.3,10.6Hz,2H),4.16(dd,J=15.4,11.0Hz,2H),1.58(s,5H),1.34(s,5H). 13 C NMR(126MHz,Chloroform-d)δ163.46,150.94(d,J=6.9Hz),150.11,141.16,136.48(d,J=2.8Hz),129.86,128.59,127.71,125.19,1 20.30(d,J=4.6Hz),114.61,102.49,92.99,84.93(d,J=7.8Hz),84.21,80.48,66.34(d,J=5.5Hz),48.50(d,J=4.6Hz),27.09,25.21. 31 P NMR (162MHz, Chloroform-d) δ 5.43. Phosphoramide II-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50% iPrOH / hexanes, 1.0 mL / min, 220 nm, t R (Main) = 28.0 min, t R (Minor) = 41.4 min).

[0070] Example 2

[0071] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-dimethylphosphoramide (compound II-2), the structure of which is shown below:

[0072]

[0073] The specific preparation steps of compound II-2 are basically the same as those in Example 1, except that in step 1), dibenzylamine phosphoryl dichloride (47 mg, 0.15 mmol) is replaced with dimethylphosphoramide dichloride (24.2 mg, 0.15 mmol), ligand L1 is replaced with ligand L2, and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product obtained as a white solid is compound II-2 (33 mg, yield 71%). 1 H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.38(d,J=8.1Hz,1H),7.32(t,J=7.9Hz,2H ),7.17(dd,J=15.9,7.9Hz,3H),5.83(d,J=3.1Hz,1H),5.68(dd,J=8.1,2.2Hz,1H),4.8 2(dd,J=6.4,3.3Hz,1H),4.58(dd,J=6.4,3.0Hz,1H),4.39(dt,J=5.3,2.6Hz,1H),4.3 5–4.28(m,1H),4.28–4.21(m,1H),2.75(s,3H),2.73(s,3H),1.57(s,3H),1.33(s,3H). 13 C NMR(101MHz,Chloroform-d)δ162.86,150.83,149.91,141.04,129.83,125.02,119.81(d,J=5.1Hz),114.6 3,102.48,92.86,84.92(d,J=7.6Hz),84.35,80.54,65.91(d,J=5.4Hz),36.71(d,J=4.0Hz),27.12,25.24. 31 P NMR (162MHz, Chloroform-d) δ 6.27. Phosphoramide II-2 was analyzed by chiral HPLC to be 99.1 d.r. (CHIRALPAK IBN-3, 40% iPrOH / hexanes, 1.0 mL / min, 254 nm, tR (Main) = 13.2 min, t R (Minor) = 14.3 min).

[0074] Example 3

[0075] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-bis(2-chloroethyl)phosphoramide ester (compound II-3), and its structure is shown below:

[0076]

[0077] The specific preparation steps of compound II-3 are basically the same as those in Example 1, except that in step 1), the dibenzylamine phosphoryl dichloride (47 mg, 0.15 mmol) used is replaced with di(2-chloroethyl)phosphamide dichloride (38.6 mg, 0.15 mmol). The final product, a white solid, was compound II-3 (54 mg, 96% yield); ¹H NMR (500 MHz, Chloroform-d) δ 9.56 (s, 1H), 7.26 (t, J = 7.9 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.16–7.07 (m, 3H), 5.64 (dd, J = 9.2, 2.6 Hz, 2H), 4.70 (dd, J = 6.6, 3.1 Hz, 1H), 4.58 (dd, J = 6.5, 2.7 Hz, 1H), 4.33–4.22 (m, 2H), 3.57–3.46 (m, 4H), 3.41 (dt, J = 14.2, 7.0 Hz, 4H), 1.48 (s, 3H), 1.25 (s, 3H). 13 C NMR(126MHz,Chloroform-d)δ163.43,150.46(d,J=6.9Hz),150.04,141.78,129.92,125.40,119.99(d,J=5.1Hz),11 4.66, 102.58, 93.93, 85.24 (d, J = 7.8Hz), 84.22, 80.62, 66.54 (d, J = 5.5Hz), 49.33 (d, J = 4.6Hz), 41.91, 27.07, 25.19. 31PNMR (202 MHz, Chloroform-d) δ 4.34. Phosphoramide II-3 was analyzed by chiral HPLC to be 99.1 d.r. (CHIRALPAKIE, 60% iPrOH / hexanes, 1.0 mL / min, 220 nm, t) R (Main) = 20.1 min, t R (Minor) = 24.3 min).

[0078] Example 4

[0079] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-diallyl phosphoramide (compound II-4), the structure of which is shown below:

[0080]

[0081] The specific preparation steps of compound II-4 are basically the same as in Example 1, except that in step 1), dibenzylaminophosphoryl dichloride (47 mg, 0.15 mmol) is replaced with diallylphosphoramide dichloride (32.1 mg, 0.15 mmol). The final product obtained as a white solid is compound II-4 (40 mg, yield 77%). 1 H NMR(500MHz,Chloroform-d)δ9.30(s,1H),7.31(t,J=8.0Hz,3H),7.21(dt,J=8.7,1.2Hz,2H),7.16(t,J= 7.6Hz,1H),5.80(d,J=3.1Hz,1H),5.67(dd,J=8.1,2.3Hz,1H),5.65–5.56(m,2H),5.18–5.16(m,2H),5.1 5–5.11(m,2H),4.77(dd,J=6.6,3.2Hz,1H),4.48(dd,J=6.4,3.1Hz,1H),4.36(dt,J=4.1,2.1Hz,1H),4.3 2(dt,J=7.8,3.8Hz,1H),4.24(ddd,J=11.1,5.4,2.9Hz,1H),3.74–3.58(m,4H),1.55(s,3H),1.31(s,3H). 13C NMR(101MHz,Chloroform-d)δ150.83(d,J=6.9Hz),150.02,141.02,133.59(d,J=2.2Hz),129.79,125.07,120.00(d,J=5.1H z),118.59,114.61,102.49,92.76,84.82(d,J=7.6Hz),84.26,80.47,66.04(d,J=5.1Hz),47.81(d,J=4.7Hz),27.10,25.21. 31 P NMR (202 MHz, Chloroform-d) δ 5.24. Phosphoramide II-4 was analyzed by chiral HPLC as 98:2d.r. (CHIRALPAK IBN-3, 40% iPrOH / hexanes, 1.0 mL / min, 250 nm, t R (Main) = 8.5 min, t R (Minor) = 9.8 min).

[0082] Example 5

[0083] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)–benzyl(furan-2-ylmethyl)phosphoramide (compound II-5), and its structure is shown below:

[0084]

[0085] The specific preparation steps of compound II-5 are basically the same as in Example 1, except that in step 1), the dibenzylamine phosphoryl dichloride (47 mg, 0.15 mmol) used is replaced with benzyl(furan-2-ylmethyl)phosphamide dichloride (45.5 mg, 0.15 mmol). The final product obtained as a white solid is compound II-5 (52 mg, yield 86%). 1HNMR(500MHz,Chloroform-d)δ9.20(s,1H),7.35(d,J=2.1Hz,1H),7.34–7.28(m,6H ),7.24–7.21(m,4H),7.18(t,J=7.4Hz,1H),6.30(dd,J=3.2,1.8Hz,1H),6.14(d,J=3 .2Hz,1H),5.79(d,J=3.1Hz,1H),5.58(d,J=8.1Hz,1H),4.75(dd,J=6.4,2.9Hz,1H) ,4.41–4.36(m,3H),4.31–4.26(m,2H),4.18–4.07(m,3H),1.55(s,3H),1.30(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.16,150.89(d,J=6.9Hz),150.44(d,J=2.3Hz),150 .00,142.63,140.90,136.45(d,J=3.2Hz),129.82,128.61,128.47,127.73,125.18,1 20.14(d,J=4.6Hz),114.52,110.38,109.50,102.34,92.76,84.83(d,J=7.8Hz),84. 33, 80.50, 66.19 (d, J = 5.5Hz), 49.09 (d, J = 4.6Hz), 41.37 (d, J = 5.5Hz), 27.09, 25.20. 31 P NMR (202 MHz, Chloroform-d) δ 5.05. Phosphoramide II-5 was analyzed by chiral HPLC as 98:2d.r. (CHIRALPAK AD-H, 50% iPrOH / hexanes, 1.0 mL / min, 250 nm, t R (Minor) = 20.5 min, t R (Main) = 26.3 min).

[0086] Example 6

[0087] This embodiment provides ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)–methyl(phenyl)phosphate (compound II-6), the structure of which is shown below:

[0088]

[0089] The specific preparation steps of compound II-6 are basically the same as in Example 1, except that in step 1), ligand L1 is replaced with L2, and the dibenzylamine phosphoryl chloride (47 mg, 0.15 mmol) is replaced with N,P-dimethyl-N-phenylphosphine chloride (30.6 mg, 0.15 mmol); in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product obtained as a white solid is compound II-6 (40 mg, yield 81%). 1 H NMR(500MHz,Chloroform-d)δ9.08(s,1H),7.35–7.28(m,4H),7.24(dd,J=16.6,8.2Hz,3H),7.19–7.13(m,4H),5.79(d,J=3.1Hz,1H),5. 56(d,J=8.1Hz,1H),4.72(dd,J=6.4,3.1Hz,1H),4.45–4.35(m,3H),4.35–4.26(m,1H),3.24(d,J=9.3Hz,3H),1.55(s,3H),1.31(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.04,150.56(d,J=6.9Hz),149.93,143.20,140.89,129.85,129.30,129.20,125.27(d,J=4.1Hz),123.54(d,J =3.7Hz),119.93(d,J=5.1Hz),114.61,102.44,92.78,84.67(d,J=7.8H z),84.29,80.48,66.31(d,J=5.5Hz),37.87(d,J=5.5Hz),27.09,25.19. 31 P NMR (202 MHz, Chloroform-d) δ 1.34. Phosphoramide II-6 was analyzed by chiral HPLC as 99.1 d.r. (CHIRALPAK IBN-3, 30% iPrOH / hexanes, 1.0 mL / min, 250 nm, t R (Minor) = 18.3 min, t R (Main) = 19.4 min).

[0090] Example 7

[0091] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-diketone-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)–pyrrolidine-1-yl phosphate (compound II-7), and its structure is shown below:

[0092]

[0093] The specific preparation steps of compound II-7 are basically the same as in Example 1, except that in step 1), dibenzylaminophosphoryl dichloride (47 mg, 0.15 mmol) is replaced with pyrrolidine-1-ylphosphoryl dichloride (28.1 mg, 0.15 mmol); and in steps 1) and 2), the reaction temperature is replaced with -60°C instead of -30°C. The final product obtained as a white solid is compound II-7 (40 mg, yield 81%). 1 H NMR(400MHz,Chloroform-d)δ8.92(s,1H),7.42(d,J=8.1Hz,1H),7.35–7.28(m,2H),7.20( dt,J=8.6,1.3Hz,2H),7.16(d,J=7.6Hz,1H),5.86(d,J=3.1Hz,1H),5.68(dd,J=8.1,2.3Hz, 1H),4.81(dd,J=6.4,3.1Hz,1H),4.55(dd,J=6.4,3.1Hz,1H),4.41–4.37(m,1H),4.36–4.29 (m,1H),4.29–4.21(m,1H),3.32–3.17(m,4H),1.85–1.79(m,4H),1.56(s,3H),1.32(s,3H). 13 C NMR(101MHz,Chloroform-d)δ162.96,150.88(d,J=6.5Hz),149.97,140.96,129.80,124.93,119.79(d,J=5.1Hz),114.59,1 02.45, 92.62, 84.84 (d, J = 7.6Hz), 84.37, 80.53, 65.84 (d, J = 5.4Hz), 47.10 (d, J = 5.1Hz), 27.13, 26.34 (d, J = 9.4Hz), 25.24. 31P NMR (162MHz, Chloroform-d) δ 2.96. Phosphoramide II-7 was analyzed by chiral HPLC as 98.5:1.5dr (CHIRALPAK IBN-3, 30% iPrOH / hexanes, 1.0mL / min, 250nm, t R (Main) = 35.9 min, t R (Minor) = 42.0 min).

[0094] Example 8

[0095] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-morpholine phosphate (compound II-8), the structure of which is shown below:

[0096]

[0097] The specific preparation steps of compound II-8 are basically the same as those in Example 1, except that in step 1), dibenzylamine phosphoryl dichloride (47 mg, 0.15 mmol) is replaced with morpholine phosphoryl dichloride (30.5 mg, 0.15 mmol); and in steps 1) and 2), the reaction temperature is replaced with -60°C instead of -30°C. The final product obtained as a white solid is compound II-8 (47 mg, yield 92%). 1 H NMR(400MHz,Chloroform-d)δ8.85(s,1H),7.36–7.28(m,3H),7.23–7.14(m,3H),5.75(d,J=2.6Hz,1H),5.68(dd,J=8.0,2.3Hz,1H),4.83(dd,J=6.4,3 .4Hz,1H),4.69(dd,J=6.4,2.7Hz,1H),4.40–4.35(m,1H),4.34–4.24(m,2H ),3.63–3.56(m,4H),3.21(qd,J=4.8,3.3Hz,4H),1.56(s,3H),1.33(s,3H). 13CNMR(101MHz,Chloroform-d)δ162.86,150.69(d,J=6.9Hz),149.86,141.51,129.87,125.17,119.90(d,J=5.1Hz),11 4.70,102.57,93.58,85.19(d,J=7.6Hz),84.25,80.63,66.82(d,J=5.4Hz),66.15(d,J=5.4Hz),44.64,27.12,25.26. 31 P NMR (162MHz, Chloroform-d) δ 3.04. Phosphoramide II-8 was analyzed by chiral HPLC to be 99.1 d.r. (CHIRALPAK IBN-3, 40%). i PrOH / hexanes,0.8mL / min,220nm,t R (Minor) = 34.2 min, t R (Main) = 29.3 min).

[0098] Example 9

[0099] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-azacycloheptane-1-yl phosphate (compound II-9), the structure of which is shown below:

[0100]

[0101] The specific preparation steps of compound II-9 are basically the same as those in Example 1, except that in step 1), dibenzylaminophosphoryl dichloride (47 mg, 0.15 mmol) is replaced with azircyclopentane-1-phosphonyl dichloride (32.3 mg, 0.15 mmol). The final product obtained as a white solid is compound II-9 (47 mg, yield 90%). 1H NMR(500MHz,Chloroform-d)δ9.45(s,1H),7.37(d,J=8.2Hz,1H),7.30(t,J=7.9Hz,2H),7.21( d,J=8.4Hz,2H),7.14(t,J=7.4Hz,1H),5.84(d,J=3.1Hz,1H),5.67(dd,J=8.1,2.3Hz,1H),4.78 (dd,J=6.4,3.1Hz,1H),4.44(dd,J=6.4,3.2Hz,1H),4.40–4.36(m,1H),4.35–4.28(m,1H),4.2 5–4.18(m,1H),3.21(dt,J=9.9,5.9Hz,4H),1.68–1.62(m,4H),1.56–1.50(m,7H),1.30(s,3H). 13 C NMR (126MHz, Chloroform-d) δ 163.31, 151.01 (d, J = 6.9Hz), 150.10, 140.87, 129.77, 124.88, 119.81 (d, J = 5.1Hz), 114.55, 102. 44, 92.46, 84.74 (d, J = 7.8Hz), 84.31, 80.49, 65.78 (d, J = 5.1Hz), 47.57 (d, J = 4.1Hz), 29.95 (d, J = 4.1Hz), 27.11, 26.79, 25.21. 31 P NMR (202 MHz, Chloroform-d) δ 5.60. Phosphoramide II-9 was analyzed by chiral HPLC to be 99.1 d.r. (CHIRALPAK IBN-3, 60%). i PrOH / hexanes,1.0mL / min,250nm,t R (Main) = 13.1 min, t R (Minor) = 14.0 min).

[0102] Example 10

[0103] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3a R,4R,6R,6a R)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)–(4-(6-fluorobenzo[d]trimethylandrostadienisoxazol-3-yl)piperidin-1-yl)-1-yl phosphate (compound II-10), the structure of which is shown below:

[0104]

[0105] The specific preparation steps of compound II-10 are basically the same as those in Example 1, except that in step 1), the dibenzylaminophosphoryl dichloride (47 mg, 0.15 mmol) used is replaced with (4-(6-fluorobenzo[d]trimethylandrostadienisoxazol-3-yl))piperidin-1-yl)phosphine dichloride (50.4 mg, 0.15 mmol), and the final product of the white solid obtained is compound II-10 (62 mg, yield 96%). 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),7.44(dd,J=8.8,5.1Hz,1H),7.33(dt,J=7.3,3.9Hz,3H),7.25(s,1H) ,7.23–7.19(m,2H),7.16(t,J=7.3Hz,1H),7.00(td,J=8.9,2.3Hz,1H),5.75(d,J=2.6Hz,1H),5.67(d,J=8.0Hz, 1H), 4.85 (dd, J=6.4, 3.3Hz, 1H), 4.71 (dd, J=6.4, 2.6Hz, 1H), 4.38 (d, J=4.0Hz, 1H), 4.36–4.27 (m, 2H), 3.83–3. 71(m,2H),3.24–3.13(m,1H),3.03–2.91(m,2H),2.04–1.95(m,2H),1.94–1.77(m,2H),1.54(s,3H),1.31(s,3H). 13 C NMR(126MHz,Chloroform-d)δ164.17(d,J=250.9Hz),163.88(d,J=13.3Hz),160.39,150.87(d ,J=6.9Hz),150.06,141.69,129.90,125.02,122.27(d,J=11.0Hz),119.90(d,J=5.1Hz),116. 98,114.60,112.58(d,J=25.3Hz),102.52,97.56(d,J=26.7Hz),93.69,85.31(d,J=7.8Hz),84 .34, 80.66, 66.13 (d, J = 5.5Hz), 44.63 (d, J = 3.2Hz), 34.06, 30.28 (d, J = 4.6Hz), 27.13, 25.26. 1 P NMR(162MHz,Chloroform-d)δ3.65. 19F NMR (377MHz, Chloroform-d) δ-109.12. Phosphoramide II-10 was analyzed by chiral HPLC to be 99.1d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,250nm,t R (Minor) = 17.4 min, t R (Main) = 18.8 min).

[0106] Example 11

[0107] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(S)–methyl((R)-3-(1-naphthoxy)-3-(2-thienyl)propyl)phosphoramide (compound II-11), the structure of which is shown below:

[0108]

[0109] The specific preparation steps of compound II-11 are basically the same as those in Example 1, except that in step 1), dibenzylamine phosphoryl dichloride (47 mg, 0.15 mmol) is replaced with (S)-methyl-(3-(1-naphthoxy))-3-(thiophen-2-yl)propyl)phosphamide dichloride (62 mg, 0.15 mmol). The final product obtained as a white solid is compound II-11 (62 mg, yield 86%). 1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),8.26–8.20(m,1H),7.71–7.65(m,1H),7.42–7.37(m,2H),7.30(d,J=8.3Hz,1H),7.23–7.15 (m,3H),7.13–7.07(m,4H),7.05(t,J=7.3Hz,1H),6.95(dd,J=3.6,1.0Hz,1H),6.83(dd,J=5.1,3.4Hz,1H),6.71(d,J=7.6Hz,1H),5.61 (d,J=2.9Hz,1H),5.60–5.56(m,1H),5.50(dd,J=8.1,2.2Hz,1H),4.63(dd,J=6.4,3.3Hz,1H),4.43(dd,J=6.4,2.9Hz,1H),4.19–4.10 (m,2H),4.08–3.99(m,1H),3.33–3.22(m,2H),2.69(d,J=10.3Hz,3H),2.44–2.31(m,1H),2.21–2.09(m,1H),1.44(s,3H),1.19(s,3H). 13 C NMR (101MHz, Chloroform-d) δ 163.33, 153.06, 150.77 (d, J = 6.9Hz), 150.06, 144.57, 141.22, 134. 59,129.82,127.59,126.71,126.42,126.05,125.70,125.38,125.06,124.96,124.89,121.99,12 0.85,119.99(d,J=5.1Hz),114.58,107.06,102.47,92.94,84.87(d,J=7.3Hz),84.19,80.52,73. 86, 66.04 (d, J = 5.4Hz), 46.17 (d, J = 4.4Hz), 37.48 (d, J = 2.9Hz), 34.03 (d, J = 4.0Hz), 27.10, 25.23. 31 P NMR (162MHz, Chloroform-d) δ 5.93. Phosphoramide II-11 was analyzed by chiral HPLC to be 99.1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,250nm,t R (Minor) = 13.9 min, t R (Main) = 16.4 min).

[0110] Example 12

[0111] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(5-methyl-2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)tetrahydrofuran[3,4-d][1,3]-dioxacyclopenten-4-yl)methylphenyl(R)-dibenzylphosphamide (compound IV-1), and its structure is shown below:

[0112]

[0113] The specific preparation steps of compound IV-1 are basically the same as in Example 1, except that in step 1), 2',3'-isoproterenidine (28.4 mg, 0.1 mmol) is replaced with 2',3'-isoproterenidine (29.8 mg, 0.1 mmol). The final product, a white solid, is compound IV-1 (42 mg, yield 66%). 1 H NMR(500MHz,Chloroform-d)δ8.73(s,1H),7.34–7.27(m,3H),7.25(q,J=2.2Hz,5H),7.22(d,J=8.1H z,2H),7.18(d,J=7.2Hz,1H),7.16–7.13(m,4H),7.12(s,1H),5.74–5.71(m,1H),4.74(dd,J=7.2,3. 9Hz,1H),4.53(dd,J=6.9,4.0Hz,1H),4.41–4.34(m,1H),4.32(q,J=3.8Hz,1H),4.30–4.24(m,1H),4 .20(dd,J=15.3,10.5Hz,2H),4.08(dd,J=15.3,10.6Hz,2H),1.80(s,3H),1.53(s,3H),1.28(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.54,150.92(d,J=7.4Hz),149.98,137.06,136.48(d,J=2.8Hz),129.80,128.58(d,J=5.1Hz),127.67,125.14 ,120.34(d,J=4.6Hz),114.66,111.09,92.81,84.57(d,J=7.4Hz),83.9 0, 80.51, 66.36 (d, J = 5.5Hz), 48.43 (d, J = 4.6Hz), 27.13, 25.24, 12.39.31 P NMR (202MHz, Chloroform-d) δ 5.40. Phosphoramide IV-1 was analyzed by chiral HPLC as 98:2d.r. (Shimadzu LC-2030) (Agilent XDB-C18, H2O:MeOH = 30.0:70.0, 0.3mL / min, 40℃, 254nm), t R (Main) = 29.2 min, t R (Minor) = 30.7 min).

[0114] Example 13

[0115] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-dibenzylphosphamide (compound IV-2), and its structure is shown below:

[0116]

[0117] The specific preparation steps of compound IV-2 are basically the same as those in Example 1, except that in step 1), 2',3'-isoproterenol (28.4 mg, 0.1 mmol) is replaced with 2',3'-isoproterenol (30.7 mg, 0.1 mmol). The final product, a white solid, is compound IV-2 (50.6 mg, yield 82%). 1 H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.85(s,1H),7.29–7.21(m,9H),7.18(q,J=2.3,1.8Hz ,1H),7.17–7.10(m,6H),6.06(d,J=2.6Hz,1H),5.80(s,2H),5.08(dd,J=6.3,2.7Hz,1H),4.95(d d,J=6.4,2.8Hz,1H),4.53–4.47(m,1H),4.32(dd,J=7.1,4.6Hz,1H),4.25(ddd,J=11.1,5.6,4.6 Hz, 1H), 4.16 (dd, J=15.3, 10.6Hz, 2H), 4.06 (dd, J=15.4, 10.9Hz, 2H), 1.60 (s, 3H), 1.34 (s, 3H). 13C NMR(101MHz,Chloroform-d)δ155.49,153.20,150.89(d,J=6.9Hz),149.38,139.34,136.58(d,J=2.5Hz),129.69,128.60,128.47,127.5 6,125.00,120.32(d,J=4.7Hz),114.47,91.15,85.24(d,J=8.4Hz),84.01,81.37,66.16(d,J=5.4Hz),48.42(d,J=5.1Hz),27.09,25.21. 31 P NMR (162MHz, Chloroform-d) δ 5.42. Phosphoramide IV-2 was analyzed by chiral HPLC as 95:5 d.r. (CHIRALPAK IBN-3, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 41.0 min, t R (Main) = 43.6 min).

[0118] Example 14

[0119] This embodiment provides ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2,6a-trimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl(R)-dibenzylphosphamide (compound V), the structure of which is shown below:

[0120]

[0121] The specific preparation steps of compound V are basically the same as in Example 1, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with 1-((4R,6R,6aR)-6-(hydroxymethyl)-2,2,3A-trimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)pyrimidine-2,4(1H,3H)-dione (29.8 mg, 0.1 mmol). The final product obtained as a white solid is compound V (28 mg, yield 45%). 1HNMR(500MHz,Chloroform-d)δ8.99(s,1H),7.38(d,J=8.2Hz,1H),7.27(t,J=7.9Hz,2H),7.22–7.18(m,8H),7.14–7.08(m,5H),5.97(s,1H),5.42(d ,J=8.2Hz,1H),4.35–4.27(m,2H),4.26(s,2H),4.15(dd,J=15.3,10.7Hz, 2H), 4.05 (dd, J=15.3, 11.0Hz, 2H), 1.52 (s, 3H), 1.29 (s, 3H), 1.01 (s, 3H). 13 C NMR(126MHz,Chloroform-d)δ162.97,150.86(d,J=6.9Hz),149.97,140.00,136.31(d,J=2.8Hz),129.91,128.61(d,J=7.8Hz),127.82,125.20 ,120.23(d,J=5.1Hz),114.95,101.81,92.23,89.51,84.95,81.47(d,J =7.8Hz), 65.99 (d, J = 5.5Hz), 48.53 (d, J = 5.1Hz), 28.22, 27.12, 19.05. 31 P NMR (202 MHz, Chloroform-d) δ 5.48. Chiral HPLC analysis of phosphoramide V showed a 95:5 d.r ratio (CHIRALPAK IE, 60%). i PrOH / hexanes,1.0mL / min,40℃,254nm,t R (Main) = 34.6 min, t R (Minor) = 44.3 min).

[0122] Example 15

[0123] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((2S,3S,5R))-3-azido-5-(5-methyl-2,4-dione-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methylphenyl(R)-dibenzylphosphamide (compound VI-1), and its structure is shown below:

[0124]

[0125] The specific preparation steps of compound VI are basically the same as those in Example 1, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with zidovudine (26.7 mg, 0.1 mmol). The final product, a white solid, is compound VI-1 (54.8 mg, 91% yield). 1 H NMR(500MHz,Chloroform-d)δ9.29(s,1H),7.38–7.34(m,2H),7.33–7.26(m,9H),7.23(t,J=7.3Hz,1H),7.19(dd,J=6.5,3.1Hz,4H),6.18(dd,J=7.6 ,6.0Hz,1H),4.38(ddd,J=10.7,7.5,3.1Hz,1H),4.29–4.13(m,6H),4.06– 4.02(m,1H),2.33–2.26(m,1H),1.98–1.90(m,1H),1.84(d,J=1.2Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ163.68,150.79(d,J=6.9Hz),150.24,136.33(d,J=3.2Hz),135.06,129.94,128.59(d,J=16.5Hz),127 .84,125.37,120.24(d,J=5.1Hz),111.36,84.64,82.40(d,J=7.4Hz),65.78(d,J=5.5Hz),60.42,48.60(d,J=5.1Hz),37.19,12.54. 31 P NMR (202 MHz, Chloroform-d) δ 5.79. Phosphoramide VI-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK IBN-3, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 34.6 min, t R (Main) = 37.3 min).

[0126] Example 16

[0127] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((2S,5R))-5-(5-methyl-2,4-dione-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)methylphenyl(R)-dibenzylphosphamide (compound VII), and its structure is shown below:

[0128]

[0129] The specific preparation steps of compound VII are basically the same as those in Example 1, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with stavudine (22.4 mg, 0.1 mmol). The final product obtained as a white solid is compound VII (48 mg, yield 86%). 1 H NMR(500MHz,Chloroform-d)δ9.03(s,1H),7.35–7.30(m,2H),7.28–7.24(m,7H), 7.23–7.18(m,3H),7.16–7.11(m,4H),6.98(dt,J=3.7,1.8Hz,1H),6.31(dt,J=6. 1,1.8Hz,1H),5.85(dt,J=6.1,2.1Hz,1H),5.01(dq,J=3.7,2.0Hz,1H),4.43–4.3 6(m,1H),4.23–4.14(m,3H),4.07(dd,J=15.4,10.8Hz,2H),1.72(d,J=1.4Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ163.67,150.81,150.71(d,J=6.9Hz),136.37(d,J=3.2Hz),135.57,133.28,129.80,128.60,128.57 ,127.73,127.28,125.14,120.35(d,J=5.1Hz),111.16,89.73,84.80(d,J=8.7Hz),66.70(d,J=5.1Hz),48.43(d,J=4.6Hz),12.38. 31 P NMR (202 MHz, Chloroform-d) δ 6.00. Phosphoramide VII was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK IBN-3, 30%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 26.7 min, t R (Main) = 28.9 min).

[0130] Example 17

[0131] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aS,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrothiophene-[3,4-d][1,3]dioxacyclopenten-4-yl)methylphenyl)methylphenyl(R)-dibenzylphosphamide (compound VIII), the structure of which is shown below:

[0132]

[0133] The specific preparation steps of compound VIII are basically the same as those in Example 1, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with 1-((3aR,4R,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydrothiophene[3,4-d][1,3]dioxacyclopenten-4-yl)pyrimidine-2,4(1H,3H)-dione (30.0 mg, 0.1 mmol). The final product obtained as a white solid is compound VIII (54 mg, yield 85%). 1 HNMR(500MHz,Chloroform-d)δ9.55(s,1H),7.35(d,J=8.1Hz,1H),7.25(t,J=7.9Hz,2H),7.2 1–7.15(m,8H),7.13–7.07(m,5H),5.81(d,J=2.9Hz,1H),5.59(dd,J=8.0,2.4Hz,1H),4.77(d d,J=5.7,2.8Hz,1H),4.64(dd,J=5.6,2.7Hz,1H),4.33–4.22(m,2H),4.15(dd,J=15.3,10.7H z,2H),4.04(dd,J=15.5,10.8Hz,2H),3.77(td,J=6.3,2.8Hz,1H),1.48(s,3H),1.20(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.20,150.87(d,J=6.9Hz),150.17,141.75,136.52(d,J=2.8Hz),129.83,128.60(d,J=9.7Hz),127.65,125 .10,120.37(d,J=5.1Hz),112.60,103.10,88.81,85.02,70.28,67.60(d,J=6.0Hz),54.23(d,J=7.8Hz),48.52(d,J=4.6Hz),27.41,25.18. 31P NMR (202 MHz, Chloroform-d) δ 5.23. Phosphoramide VIII was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 23.1 min, t R (Minor) = 33.1 min).

[0134] Example 18

[0135] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((2R,6S)-6-(4-dione-3,4-dihydropyrimidin-1(2H))-yl)-4-tris(hydroxymethylmorpholino-2-yl)methylphenyl(R)-dimethylphosphoramide (compound IX-1), and its structure is shown below:

[0136]

[0137] The specific preparation steps for compound IX-1 are as follows:

[0138] 1) In an 8 mL reaction flask, add ligand L2 (6.3 mg, 0.015 mmol), copper hexafluoroacetylacetonate (4.8 mg, 0.01 mmol), and 1-((2S,6R))-6-(hydroxymethyl)-4-triphenylmethylmorpholino-2-yl)pyrimidine-2,4-(1H,3H)-dione (46.9 mg, 0.1 mmol). Place the reaction system in a glove box, then add tetrahydrofuran (0.3 mL) and triethylamine (72.0 μL, 0.5 mmol, NEt3) sequentially. Seal the reaction apparatus, remove it from the glove box, and stir at room temperature for half an hour. Then, cool the mixture to -40 °C and stir for half an hour. Finally, add a pre-cooled solution of dimethylamine phosphoryl dichloride (25 mg, 0.15 mmol) in tetrahydrofuran (0.2 mL) to the above-stirred solution and react for 20 h. The resulting reaction solution was separated by column chromatography (DCM:MeOH = 20:1, Rf = 0.50) to obtain a white solid intermediate product, namely compound I-2 (58.0 mg, yield 98%), with the structure shown below:

[0139]

[0140] 1H NMR(400MHz,Chloroform-d)δ9.3(s,1H),7.6–7.4(m,6H),7.3(q,J=6.8,5.9Hz,6H),7.2(t,J=7.5Hz,4H),6.1(dd,J=9.6,2.6Hz,1H),5.6(d,J=8.1Hz, 1H),4.5–4.4(m,1H),4.2–4.0(m,2H),3.4(d,J=11.1Hz,1H),3.1(d,J=12.0 Hz,1H),2.6(d,J=13.9Hz,6H),1.5(t,J=11.4Hz,1H),1.4(t,J=10.4Hz,1H). 31 P NMR (162 MHz, δ 18.5). Phosphoramide I-2 was analyzed by chiral HPLC as 93:7 d.r. (CHIRALPAK IBN-3, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 19.7 min, t R (Minor) = 22.4 min). After separation with ethyl acetate, a ratio of approximately 99:1 d.r can be obtained.

[0141] 2) The method is the same as step 2) in Example 1. The final product of the resulting white solid is compound IX-1 (74 mg, yield 92%). 1 H NMR(500MHz,Chloroform-d)δ9.33(s,1H),7.43(s,6H),7.29–7.22(m,13H),7.20–7.07(m,11H ),7.04(d,J=8.2Hz,1H),6.07(d,J=8.1Hz,1H),5.48(d,J=8.1Hz,1H),4.36(dt,J=11.3,5.9Hz, 1H), 4.15 (tt, J=10.5, 5.3Hz, 3H), 4.06 (tt, J=7.3, 4.0Hz, 1H), 3.99 (dd, J=15.4, 10.8Hz, 2H), 3.36(d,J=11.3Hz,1H), 3.12(d,J=11.7Hz,1H), 1.56(t,J=11.2Hz,1H), 1.31(t,J=10.5Hz,1H). 13C NMR(126MHz,Chloroform-d)δ163.16,156.53,150.90(d,J=7.4Hz),149.79,139.78,136.55(d,J=3.2Hz),129.50,128.56,128.47,127.97,127.59 ,126.65,124.95,120.45(d,J=5.1Hz),119.96,115.46,102.18,80.62,7 5.07(d,J=6.9Hz),66.86(d,J=6.0Hz),52.01,48.78,48.45(d,J=4.6Hz). 31 P NMR (202 MHz, Chloroform-d) δ 5.00. Phosphoramide IX-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK IBN-3, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 19.6 min, t R (Minor) = 21.1 min).

[0142] Example 19

[0143] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is phenyl((3aS,5aR,8Ar,8bS)-2,2,7,7-tetramethylhexahydro-3aH-[1,3]dioxolane[4,5-b]pyran[3,2-d]pyran-3a-yl)methyl)(R)-dibenzylphosphamide (compound X-1), and its structure is shown below:

[0144]

[0145] The specific preparation steps of compound X-1 are basically the same as in Example 1, except that in step 1), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) is replaced with fructose diacetone (26 mg, 0.1 mmol). The final product obtained as a colorless oily liquid is compound X-1 (52 mg, yield 87%). 1H NMR(500MHz,Chloroform-d)δ7.26–7.16(m,10H),7.13(d,J=8.7Hz,4H),7.08(t, J=7.2Hz,1H),4.53(dd,J=7.8,3.4Hz,1H),4.32(d,J=3.4Hz,1H),4.23–4.12(m,4H ),4.07(dd,J=10.6,4.5Hz,1H),3.98(dd,J=15.2,10.9Hz,2H),3.84(d,J=13.0Hz ,1H),3.67(d,J=12.8Hz,1H),1.42(s,3H),1.31(s,3H),1.27(s,3H),1.06(s,3H). 13 C NMR(126MHz,Chloroform-d)δ151.17(d,J=6.9Hz),136.64(d,J=3.2Hz),129.64,128.85,128.48,127.56,124.65,120.21(d,J=5.5Hz),109 .04(d,J=24.8Hz),101.53(d,J=12.0Hz),70.89,70.09,69.76,66.93(d,J=5.1Hz),61.36,48.36(d,J=4.6Hz),26.53,25.91,25.17,24.11. 31 P NMR (202 MHz, Chloroform-d) δ 4.71. Phosphoramide VI-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 10%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 27.2 min, t R (Main) = 34.5 min).

[0146] Example 20

[0147] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is (5-phenoxyfuran-2-yl)methylphenyl(R)-dibenzylphosphamide ester (compound X-2), and its structure is shown below:

[0148]

[0149] The specific preparation steps of compound X-2 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with 4-nitrobenzyl alcohol (15.3 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product, a colorless oily liquid, is compound X-2 (44 mg, yield 91%). 1 H NMR(500MHz,Chloroform-d)δ8.18–8.13(m,2H),7.40(d,J=7.6Hz,2H),7.34(t,J=7.2Hz, 2H),7.27(dd,J=5.3,2.7Hz,8H),7.23–7.14(m,5H),5.28–5.13(m,2H),4.28–4.11(m,4H). 13 C NMR(126MHz,Chloroform-d)δ150.88(d,J=7.4Hz),147.70,143.48(d,J=7.4Hz),136.59(d,J=2.8Hz),129.81, 128.62, 128.55, 127.79, 127.68, 125.12, 123.74, 120.51 (d, J = 4.6Hz), 67.11 (d, J = 5.1Hz), 48.58 (d, J = 4.6Hz). 31 P NMR (202 MHz, Chloroform-d) δ 5.58. Phosphoramide X-2 was analyzed by chiral HPLC to be 98:2 e.r. (CHIRALPAK IBN-3, 30%). i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 12.2 min, t R (Main) = 14.5 min).

[0150] Example 21

[0151] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is (5-nitrofuran-2-yl)methylphenyl(R)-dibenzylphosphamide ester (compound X-3), and its structure is shown below:

[0152]

[0153] The specific preparation steps of compound X-3 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) is replaced with (5-nitrofuran-2-yl)methanol (14.3 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product obtained as a red oily liquid is compound X-3 (44 mg, yield 92%). 1 H NMR(500MHz,Chloroform-d)δ7.33(t,J=7.9Hz,3H),7.30–7.27(m,5H),7.25–7.22(m,2H),7.22–7.19(m,2H),7.19–7.14( m, 4H), 6.51 (d, J = 3.7Hz, 1H), 5.10 (dd, J = 10.6, 9.1Hz, 2H), 4.22 (dd, J = 15.3, 10.9Hz, 2H), 4.13 (dd, J = 15.4, 11.0Hz, 2H). 13 C NMR(126MHz,Chloroform-d)δ152.69(d,J=7.4Hz),150.67(d,J=7.4Hz),136.47(d,J=2.8Hz),129.78, 128.58(d,J=7.4Hz),127.67,125.15,120.45,112.85,111.98,60.10(d,J=5.1Hz), 48.49(d,J=4.6Hz). 31 P NMR (202 MHz, Chloroform-d) δ 5.59. Phosphoramide X-3 was analyzed by chiral HPLC and found to be 98.5:1.5 er (CHIRALPAK IBN-3, 30%). i PrOH / hexanes,1.0mL / min,40℃,254nm,t R (Minor) = 11.0 min, t R (Main) = 15.9 min).

[0154] Example 22

[0155] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is 2-methoxyphenethylphenyl(R)-dibenzylphosphamide ester (compound X-4), and its structure is shown below:

[0156]

[0157] The specific preparation steps of compound X-4 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) is replaced with 1-(2-methoxyphenyl)ethanol (15.2 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product, a colorless oily liquid, is compound X-4 (34 mg, yield 70%). 1 H NMR(500MHz,Chloroform-d)δ7.31(t,J=7.8Hz,2H),7.27–7.23(m,6H),7.19(q,J=10.1,8.2Hz,4H),7.13(dd,J=6.6,2.8Hz,4H),7.09(d,J=7.3Hz ,1H),6.83(t,J=8.2Hz,2H),4.39–4.29(m,2H),4.12(dd,J=15.3,10.5Hz ,2H),4.03(dd,J=15.3,10.5Hz,2H),3.76(s,3H),3.02(t,J=7.1Hz,2H). 13 C NMR(126MHz,Chloroform-d)δ157.64,151.24(d,J=7.4Hz),136.92(d,J=3.2Hz),131.09,129.59,128.72,128.37,127.99,127 .37,125.49,124.60,120.56(d,J=4.6Hz),120.38,110.19,66.40(d,J=6.0Hz),55.19,48.29(d,J=4.6Hz),31.75(d,J=7.4Hz). 31 P NMR (202 MHz, Chloroform-d) δ 5.14. Phosphoramide X-4 was analyzed by chiral HPLC as 98:2 e.r. (CHIRALPAK IBN-3, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 8.9 min, t R (Main) = 9.6 min).

[0158] Example 23

[0159] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is tert-butyl(R)-(4-(2-((dibenzylamino))(phenoxy)phosphoryl)OXY)ethyl)phenyl)carbamate (compound X-5), and its structure is shown below:

[0160]

[0161] The specific preparation steps of the X-5 compound are basically the same as those in Example 2, except that: in step 1), the 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) used is replaced with tert-butyl (4-(2-hydroxyethyl)phenyl)carbamate (23.7 mg, 0.1 mmol); in steps 1) and 2), the reaction temperature -30℃ is replaced with -40℃. The final product, a white solid, was compound X-5 (47 mg, 82% yield). ¹H NMR (500 MHz, Chloroform-d) δ 7.31 (t, J = 7.3 Hz, 3H), 7.26–7.23 (m, 7H), 7.22–7.15 (m, 3H), 7.15–7.10 (m, 4H), 7.05 (d, J = 8.2 Hz, 2H), 6.58 (s, 1H), 4.32–4.21 (m, 2H), 4.09 (dd, J = 28.0, 10.5 Hz, 4H), 2.90 (t, J = 7.1 Hz, 2H), 1.51 (s, 9H). 13 C NMR(126MHz,Chloroform-d)δ152.84,151.15(d,J=7.4Hz),137.02,136.85(d,J=2.8Hz),131.82,129.66,129.55,128.69,128 .43,127.46,124.74,120.55(d,J=5.1Hz),118.68,80.42,67.62(d,J=6.0Hz),48.35(d,J=4.6Hz),36.10(d,J=7.4Hz),28.38. 31 PNMR (202 MHz, Chloroform-d) δ 5.19. Phosphoramide X-5 was analyzed by chiral HPLC as 97:3 e.r. (CHIRALPAK AD-H, 40%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 10.4 min, t R (Minor) = 11.2 min).

[0162] Example 24

[0163] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylphenyl(R)-dibenzylphosphamide ester (compound X-6), the structure of which is shown below:

[0164]

[0165] The specific preparation steps of compound X-6 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) is replaced with metronidazole (17.1 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product, a white solid, is compound X-6 (48.6 mg, yield 96%). 1 H NMR(500MHz,Chloroform-d)δ7.90(s,1H),7.31(t,J=7.9Hz,2H),7.28–7.21(m,6H),7.19(d,J=7.2Hz,1H),7.18–7.13(m, 2H),7.08(dd,J=6.5,3.1Hz,4H),4.53–4.46(m,2H),4.45–4.39(m,1H),4.36–4.27(m,1H),4.12–3.99(m,4H),2.25(s,3H). 13 C NMR(126MHz,Chloroform-d)δ151.46,150.68(d,J=7.4Hz),138.32,136.30(d,J=3.2Hz),133.31,129.87,128.58, 128.49, 127.74, 125.17, 120.19 (d, J = 4.6Hz), 65.05 (d, J = 5.5Hz), 48.44 (d, J = 4.6Hz), 46.38 (d, J = 7.8Hz), 14.21. 31 P NMR (202 MHz, Chloroform-d) δ 5.46. Phosphoramide X-6 was analyzed by chiral HPLC to be 99:1 e.r. (CHIRALPAK IBN-3, 30%). i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 13.2 min, t R (Main) = 16.4 min).

[0166] Example 25

[0167] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is phenyl(2-(thiophen-2-yl))ethyl)(R)-dibenzylphosphamide ester (compound X-7), and its structure is shown below:

[0168]

[0169] The specific preparation steps of compound X-7 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with 2-thiopheneethanol (12.9 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product, a colorless oily liquid, is compound X-7 (39 mg, yield 84%). 1 H NMR(500MHz,Chloroform-d)δ7.32(t,J=7.6Hz,2H),7.27–7.21(m,8H),7.20–7.11(m,6H),6.91(t ,J=4.6Hz,1H),6.80(d,J=4.0Hz,1H),4.39–4.25(m,2H),4.20–4.03(m,4H),3.18(t,J=7.2Hz,2H). 13 C NMR(126MHz,Chloroform-d)δ151.15,139.35,136.83,129.68,128.71,128.44,127.48, 126.92,125.84,124.79,124.11,120.55(d,J=5.1Hz),67.29,48.39(d,J=4.6Hz),30.99. 31 P NMR (202 MHz, Chloroform-d) δ 5.19. Phosphoramide X-7 was analyzed by chiral HPLC as 98:2 e.r. (CHIRALPAK IBN-3, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 11.2 min, t R (Main) = 15.3 min).

[0170] Example 26

[0171] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is phenyl(2-(phenylthio)ethyl)(R)-dibenzylphosphatamide ester (compound X-8), and its structure is shown below:

[0172]

[0173] The specific preparation steps of compound X-8 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) is replaced with 2-phenylthioethanol (15.4 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product obtained as a white solid is compound X-8 (44 mg, yield 90%). 1 H NMR(500MHz,Chloroform-d)δ7.38–7.29(m,4H),7.29–7.24(m,8H),7.20(dd,J=16.2,8.2Hz ,4H),7.15(dd,J=6.6,2.7Hz,4H),4.31–4.20(m,2H),4.20–4.04(m,4H),3.23–3.08(m,2H). 13 C NMR(126MHz,Chloroform-d)δ151.02(d,J=7.4Hz),136.75(d,J=2.8Hz),134.92,130.01,129.70,129.13,128.71, 128.47, 127.53, 126.68, 124.86, 120.53 (d, J = 4.6Hz), 65.39 (d, J = 6.0Hz), 48.44 (d, J = 4.6Hz), 33.76 (d, J = 7.4Hz). 31 PNMR (202 MHz, Chloroform-d) δ 5.25. Chiral HPLC analysis of phosphoramide X-8 yielded a result of 98:2 e.g. (CHIRALPAKIBN-3, 20%). i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 9.6 min, t R (Main) = 12.7 min).

[0174] Example 27

[0175] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is tert-butyl(R)-(4-(2-((dibenzylamino))(ethylthio)phosphoryloxy)ethyl)phenyl)carbamate (compound X-9), and its structure is shown below:

[0176]

[0177] The specific preparation steps of compound X-9 are basically the same as in Example 2, except that in step 1), 2',3'-isopropylidene uridine (28.4 mg, 0.1 mmol) is replaced with N-BOC-2-(4-aminophenyl)ethanol (23.7 mg, 0.1 mmol); and in steps 1) and 2), the reaction temperature is replaced with -40°C instead of -30°C. The final product obtained as a white solid is compound X-9 (51 mg, yield 94%). 1 H NMR(500MHz,Chloroform-d)δ7.36–7.19(m,12H),7.08(d,J=8.4Hz,2H),6.76–6.58(m,1H),4.25(p,J=7.6Hz ,2H),4.17–4.04(m,4H),2.93(t,J=7.9Hz,2H),2.86–2.69(m,2H),1.50(d,J=2.7Hz,9H),1.34–1.28(m,3H). 13 C NMR(126MHz,Chloroform-d)δ152.87,137.08(d,J=3.2Hz),131.78,129.51,128.73,128.45,127.46,118.70,80 .36, 67.01 (d, J = 6.4Hz), 48.23 (d, J = 4.6Hz), 36.14 (d, J = 7.4Hz), 28.39, 25.20 (d, J = 3.7Hz), 16.26 (d, J = 6.9Hz). 31 P NMR (202 MHz, Chloroform-d) δ 35.25. Phosphoramide X-9 was analyzed by chiral HPLC to be 97:3 e.r. (CHIRALPAK AD-H, 20%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 13.7 min, t R (Minor) = 16.8 min).

[0178] Example 28

[0179] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(5-methyl-2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)tetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methylnaphthol-1-yl(R)-dibenzylphosphamide (compound III-1), the structure of which is shown below:

[0180]

[0181] The specific preparation steps of compound III-1 are basically the same as in Example 1, except that in step 2), sodium phenolate (58 mg, 0.50 mmol) is replaced with sodium 1-naphthol (83 mg, 0.50 mmol). The final product obtained as a white solid is compound III-1 (57.5 mg, yield 93%). 1 H NMR(500MHz,Chloroform-d)δ9.02(s,1H),7.92(d,J=8.4Hz,1H),7.76(d,J=8.2Hz,1H),7.64(d,J=7.6Hz, 1H),7.60(d,J=8.2Hz,1H),7.42(t,J=7.6Hz,1H),7.35(q,J=7.2Hz,2H),7.26–7.11(m,10H),6.70(d,J=8.1 Hz,1H),5.59–5.55(m,1H),5.18(d,J=8.1Hz,1H),4.47(dt,J=5.6,2.2Hz,1H),4.40–4.33(m,1H),4.26(d,J =10.1Hz,1H),4.23–4.16(m,4H),4.16–4.10(m,1H),3.91(dt,J=5.8,2.1Hz,1H),1.43(s,3H),1.17(s,3H). 13 C NMR(126MHz,Chloroform-d)δ162.90,149.86,147.00(d,J=7.8Hz),140.21,136.47 (d,J=2.8Hz),134.76,128.68,128.52,128.09,127.78,126.87,126.62,126.31(d,J =6.4Hz),125.58,124.99,121.19,115.24(d,J=3.2Hz),114.70,102.50,91.96,84.2 0(d,J=7.8Hz),83.56,80.11,66.19(d,J=5.5Hz),48.72(d,J=4.6Hz),27.08,25.18. 31 P NMR (202 MHz, Chloroform-d) δ 5.98. Phosphoramide III-1 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 18.3 min, tR (Main) = 21.4 min).

[0182] Example 29

[0183] This embodiment provides an efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(S)-dibenzylphosphamide methyl ester (compound III-2), the structure of which is shown below:

[0184]

[0185] The specific preparation steps of compound III-2 are basically the same as in Example 1, except that in step 2), sodium phenolate (58 mg, 0.50 mmol) is replaced with sodium methoxide (54 mg, 1.0 mmol). The final product obtained as a white solid is compound III-2 (30 mg, yield 54%). 1 H NMR(500MHz,Chloroform-d)δ9.20(s,1H),7.31(d,J=8.1Hz,1H),7.26(t,J=7.1Hz,4H),7.22(d,J=7.0Hz,2H),7.18(d,J=8.2Hz,4H),5.69(s,1H),5. 54(d,J=8.2Hz,1H),4.77(s,2H),4.27(t,J=5.3Hz,1H),4.22–4.11(m,2H) ,4.01(d,J=10.5Hz,4H),3.66(d,J=11.3Hz,3H),1.50(s,3H),1.27(s,3H). 13 C NMR (126MHz, Chloroform-d) δ 163.17, 150.00, 141.52, 137.00 (d, J = 2.8Hz), 128.59, 127.65, 114.68, 102.59, 93. 43, 85.28 (d, J = 7.8Hz), 84.43, 80.56, 65.84 (d, J = 5.5Hz), 53.52 (d, J = 6.0Hz), 48.38 (d, J = 4.6Hz), 27.16, 25.32. 31 PNMR (202 MHz, Chloroform-d) δ 11.34. Phosphoramide III-2 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) iPrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 9.2 min, t R (Minor) = 14.4 min).

[0186] Example 30

[0187] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is O-(((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methyl)S-ethyl(R)-dibenzylthiophosphoramide (compound III-3), and its structure is shown below:

[0188]

[0189] The specific preparation steps of compound III-3 are basically the same as in Example 1, except that in step 2), sodium phenolate (58 mg, 0.50 mmol) is replaced with sodium ethanethiol (86 mg, 1.0 mmol). The final product obtained as a white solid is compound III-3 (52 mg, yield 91%). 1 H NMR(500MHz,Chloroform-d)δ9.58(s,1H),7.34(dd,J=3.3,1.6Hz,1H),7.33–7.3 0(m,4H),7.29(t,J=1.7Hz,1H),7.28–7.26(m,3H),7.25(d,J=1.4Hz,2H),5.75(d, J=2.1Hz,1H),5.62(d,J=8.1Hz,1H),4.88–4.80(m,2H),4.37–4.30(m,2H),4.28–4 .21(m,1H),4.20–4.09(m,4H),2.94–2.75(m,2H),1.55(s,3H),1.36–1.31(m,6H). 13 C NMR(126MHz,Chloroform-d)δ163.43,150.09,141.69,136.82(d,J=2.8Hz),128.70,128.58,127.67,114.63,102.65,93.59 ,85.46(d,J=7.8Hz),84.48,80.67,65.73(d,J=6.0Hz),48.37(d,J=4.6Hz),27.14,25.31(d,J=2.8Hz),16.30(d,J=6.9Hz).31 P NMR (202 MHz, Chloroform-d) δ 36.51. Phosphoramide III-3 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 16.9 min, t R (Main) = 19.8 min).

[0190] Example 31

[0191] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is O-(((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methyl)S-phenyl(R)-dibenzylthiophosphoramide (compound III-4), and its structure is shown below:

[0192]

[0193] The specific preparation steps of compound III-4 are basically the same as in Example 1, except that in step 2), sodium phenoxide (58 mg, 0.50 mmol) is replaced with sodium thiophene (58 mg, 0.50 mmol). The final product, a white solid, is compound III-4 (62 mg, 97% yield). 1 H NMR(500MHz,Chloroform-d)δ9.23(s,1H),7.63–7.56(m,2H),7.40–7.35(m,1H),7.34–7.28 (m,3H),7.27–7.23(m,6H),7.11(dd,J=6.4,3.1Hz,4H),5.75(d,J=2.9Hz,1H),5.64(d,J=8. 1Hz,1H),4.65(dd,J=6.6,3.5Hz,1H),4.59(dd,J=6.4,2.9Hz,1H),4.39–4.32(m,1H),4.30( q,J=3.9Hz,1H),4.26–4.15(m,3H),4.03(dd,J=15.3,11.4Hz,2H),1.54(s,3H),1.30(s,3H). 13C NMR(126MHz,Chloroform-d)δ163.14,149.98,141.32,136.39(d,J=2.8Hz),134.79(d,J=5.5Hz),129.45(d,J=1.8Hz),129.11(d,J=2.8Hz),128.70,1 28.53,127.67,126.80(d,J=6.4Hz),114.64,102.61,93.18,85.12(d,J=7. 8Hz),84.35,80.45,65.92(d,J=6.9Hz),48.71(d,J=4.6Hz),27.12,25.28. 31 P NMR (202 MHz, Chloroform-d) δ 32.21. Phosphoramide III-4 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Minor) = 31.8 min, t R (Main) = 44.4 min).

[0194] Example 32

[0195] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((R)-(dibenzylamino)(((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]-dioxacyclopenten-4-yl)methoxy)phosphoryl)methyl benzocarbamate (compound III-5), and its structure is shown below:

[0196]

[0197] The specific preparation steps of compound III-5 are basically the same as those in Example 1, except that in step 2), sodium phenolate (58 mg, 0.50 mmol) is replaced with benzylamine (21.4 mg, 0.20 mmol). The final product, a white solid, was compound III-5 (56 mg, 89% yield). ¹H NMR (500 MHz, Chloroform-d) δ 9.52 (s, 1H), 7.33–7.22 (m, 15H), 7.16 (d, J = 8.1 Hz, 1H), 5.63 (d, J = 2.4 Hz, 1H), 5.53 (dd, J = 8.0, 1.6 Hz, 1H), 4.82–4.75 (m, 2H), 4.32–4.24 (m, 2H), 4.17–4.10 (m, 5H), 4.07–3.98 (m, 1H), 3.29 (dt, J = 10.4, 6.9 Hz, 1H), 1.52 (s, 3H), 1.30 (s, 3H). 13 CNMR(126MHz,Chloroform-d)δ163.19,149.90,141.75,139.69(d,J=6.9Hz),137.57(d,J=2.8Hz),128.63,128.56,127.45,127.3 8,127.36,114.67,102.59,94.02,85.77(d,J=6.9Hz),84.27,80.76,65.17(d,J=4.6Hz),48.64(d,J=5.1Hz),45.03,27.12,25.31. 31 P NMR (202 MHz, Chloroform-d) δ 17.06. Phosphoramide III-5 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 20.4 min, t R (Minor) = 27.3 min).

[0198] Example 33

[0199] This embodiment provides a highly efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((R)-(dibenzylamino)(((3aS,4S,6S,6aS)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]-dioxacyclopenten-4-yl)methoxy)phosphoryl)benzoylcarbamate (compound III-6), and its structure is shown below:

[0200]

[0201] The specific preparation steps of compound III-6 are basically the same as in Example 1, except that in step 2), the sodium phenolate (58 mg, 0.50 mmol) used is replaced with an aminolithium solution generated by reacting benzamide (36 mg, 0.30 mmol) and n-butyllithium (0.33 mmol) at -30°C for 30 minutes. The final product, a white solid, is compound III-6 (50.4 mg, yield 78%). 1 H NMR(500MHz,Chloroform-d)δ10.15(s,1H),8.92(d,J=8.4Hz,1H),7.94(d,J=7.6Hz,2H),7.56 (t,J=7.4Hz,1H),7.45(t,J=7.1Hz,2H),7.28–7.18(m,10H),7.15–7.05(m,1H),5.55(t,J=2.6H z,1H),5.52(d,J=7.9Hz,1H),4.89(dt,J=6.0,2.7Hz,1H),4.83–4.78(m,1H),4.55(dd,J=15.9, 9.6Hz,2H),4.46–4.39(m,1H),4.39–4.29(m,2H),4.20–4.10(m,2H),1.52(s,3H),1.30(s,3H). 13 C NMR (126MHz, Chloroform-d) δ168.42, 163.64, 150.19, 142.17, 137.28 (d, J = 2.3Hz), 132.88 (d, J = 9.7Hz), 132.73, 128.63, 128. 51,128.19,128.10,127.34,114.47,102.76,94.57,85.66(d,J=6.9Hz),84.05,80.99,65.96,49.47(d,J=5.5Hz),27.07,25.19. 31 P NMR (202 MHz, Chloroform-d) δ 7.76. Phosphoramide III-6 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 20.0 min, t R (Minor) = 23.9 min).

[0202] Example 34

[0203] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((R)-(dibenzylamino)(((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]-dioxacyclopenten-4-yl)methoxy)phosphonyl)-4-methoxyphenylcarbamate (compound III-7), and its structure is shown below:

[0204]

[0205] The specific preparation steps of compound III-7 are basically the same as in Example 1, except that in step 2), the sodium phenolate (58 mg, 0.50 mmol) used is replaced with an aminolithium solution generated by reacting 4-methoxyaniline (37 mg, 0.30 mmol) and n-butyllithium (0.33 mmol) at -30°C for 30 minutes. The final product, a white solid, is compound III-7 (51.2 mg, yield 82%). 1 H NMR(500MHz,Chloroform-d)δ9.55(s,1H),7.27–7.24(m,6H),7.19–7.12(m,5H),6.97(d ,J=8.9Hz,2H),6.74(d,J=9.0Hz,2H),5.88(d,J=9.3Hz,1H),5.59–5.52(m,2H),4.87(s, 2H),4.42(dt,J=10.5,6.9Hz,1H),4.36(t,J=6.3Hz,1H),4.26–4.20(m,1H),4.17(dd,J= 15.3,10.1Hz,2H),4.03(dd,J=15.3,11.1Hz,2H),3.75(s,3H),1.54(s,3H),1.32(s,3H). 13 C NMR(126MHz,Chloroform-d)δ163.21,155.11,149.92,142.28,137.06(d,J=2.8Hz),132.83,128.68,128.45,127.41,120.12(d ,J=6.9Hz),114.57,114.45,102.59,95.37,86.26(d,J=6.9Hz),84.25,81.26,65.49,55.56,48.64(d,J=5.1Hz),27.08,25.20. 31P NMR (202 MHz, Chloroform-d) δ 11.11. Phosphoramide III-7 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 15.2 min, t R (Minor) = 20.4 min).

[0206] Example 35

[0207] This embodiment provides a highly efficient method for preparing chiral phosphoramide, wherein the chiral phosphoramide is tert-butyl2-((R)-(dibenzylamino)(((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methoxy)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid ester (compound III-8), the structure of which is shown below:

[0208]

[0209] The specific preparation steps of compound III-8 are basically the same as in Example 1, except that in step 2), the sodium phenoxide (58 mg, 0.50 mmol) tetrahydrofuran (0.5 mL) solution is replaced with 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (68 mg, 0.30 mmol); and the stirring time in step 2) is 2 h. The final product obtained as a white solid is compound III-8 (58 mg, yield 78%). 1 H NMR(500MHz,Chloroform-d)δ9.51(s,1H),7.35–7.30(m,5H),7.29–7.24(m,6H),5.75(d,J=2.4 Hz,1H),5.63(dd,J=8.1,2.0Hz,1H),4.85(dd,J=6.5,2.4Hz,1H),4.81(dd,J=6.6,3.7Hz,1H),4 .31(q,J=4.4Hz,1H),4.28–4.22(m,1H),4.16(dd,J=15.4,10.4Hz,2H),4.09–3.98(m,3H),3.55 –3.44(m,4H),3.29(t,J=5.6Hz,4H),1.70–1.62(m,4H),1.56(s,3H),1.44(s,9H),1.34(s,3H). 13C NMR(126MHz,Chloroform-d)δ163.21,154.79,149.98,141.50,137.48(d,J=2.3Hz),128.56(d,J=3.7Hz),127.51,114.61,102.52,93.59, 85.58(d,J=7.4Hz),84.48,80.73,79.68,64.85(d,J=4.6Hz),57.92,48.42(d,J=4.6Hz),35.37(d,J=17.5Hz),35.09,28.43,27.17,25.34. 31 P NMR (202 MHz, Chloroform-d) δ 16.93. Phosphoramide III-8 was analyzed by chiral HPLC as 99:1 d.r. (CHIRALPAK AD-H, 50%) i PrOH / hexanes,1.0mL / min,40℃,250nm,t R (Main) = 18.9 min, t R (Minor) = 27.3 min).

[0210] Example 36

[0211] This embodiment provides an efficient method for preparing chiral phosphoramides, wherein the chiral phosphoramide is ((3aR,4R,6R,6aR)-6-(2,4-dione-3,4-dihydropyrimidin-1(2H))-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxacyclopenten-4-yl)methyl(R)-N,N-dibenzyl-P-methylphosphonamide (compound III-10), and its structure is shown below:

[0212]

[0213]

[0214] The specific preparation steps of compound III-10 are basically the same as in Example 1, except that in step 2), the sodium phenoxide (58 mg, 0.50 mmol) tetrahydrofuran (0.5 mL) solution is replaced with methyl magnesium bromide (0.3 mL, 0.30 mmol); step 2) is followed by stirring at room temperature for 2 hours. The final product, a white solid, is compound III-10 (36.9 mg, yield 68%). 1H NMR (500 MHz, Chloroform-d) δ7.37–7.30(m,5H),7.31–7.28(m,2H),7.24(dd,J=6.8,1.8 Hz,4H),5.70(d,J=1.7 Hz,1H),5.63(d,J=7.9 Hz,1H),4.86(d,J=2.6 Hz,2H),4.31–4.27(m,1H),4.27–4.21(m,1H),4.10(d,J=10.1 Hz,4H),3.99–3.92(m,1H),1.56–1.50(m,6H),1.33(s,3H). 13 CNMR(126 MHz,Chloroform-d)δ163.09,149.91,141.54,136.98(d,J=2.8 Hz),128.68,128.45,127.62,114.57,102.45,93.95,85.67(d,J=7.4 Hz), 84.51, 80.74, 63.26 (d, J = 6.0 Hz), 47.70 (d, J = 4.6 Hz), 27.16, 25.31, 12.83 (d, J = 133.3 Hz). 31 P NMR (202 MHz, Chloroform-d) δ 35.40. Phosphoramide III-10 was analyzed by chiral HPLC as 97:3 dr (CHIRALPAK AD-H, 50%). i PrOH / hexanes,1.0 mL / min,40℃,250 nm,t R (Main) = 51.9 min,t R (Minor) = 81.0 min).

[0215] Example 37

[0216] This example examines the yield and dr value of the final product prepared using different ligands. The specific preparation steps are basically the same as in Example 1, except that the L3-L14 ligands shown below are used instead of ligand L1:

[0217]

[0218] Table 1

[0219] experimental group ligands Yield (%) dr value 1-1 L3 54 8:1 1-2 L4 22 2:1 1-3 L5 Trace -- 1-4 L6 23 3:1 1-5 L7 28 4:1 1-6 L8 42 3:1 1-7 L9 Trace -- 1-8 L10 36 5:1 1-9 L11 Trace -- 1-10 L12 Trace -- 1-11 L13 Trace -- 1-12 L14 Trace --

[0220] Example 38

[0221] This example examines the yield and dr value of compound I-1 prepared using different temperatures, different catalyst types, and different bases. The specific preparation steps are basically the same as in Example 1, except that the variables shown in Table 2 below are used.

[0222] Table 2

[0223] experimental group variable Yield (%) dr value 2-1 T＝-5℃ 45 3:1 2-2 <![CDATA[Cu(OAc)2]]> 46 10:1 2-3 <![CDATA[Cu(hfac)2]]> 53 13:1 2-4 <![CDATA[Cu(acac)2]]> trace -- 2-5 <![CDATA[Cu(OTf)2]]> 50 8:1 2-6 DBU trace -- 2-7 DIPEA 35 4:1 2-8 <![CDATA[K2CO3]]> 32 4:1

[0224] The yield and dr values ​​for each experimental group are shown in Table 2. In experimental group 2-1, when stirred at -5℃, the dr value decreased significantly compared to Example 1, only 3:1. In experimental groups 2-2 to 2-5, when different catalysts were used, both the yield and dr value decreased significantly compared to Example 1, indicating that copper hexafluoroacetylacetonate (Cu(hfac)2) is more favorable than other anionic copper catalysts. In experimental groups 2-6 to 2-8, when different bases were used, both the yield and dr value decreased significantly compared to Example 1, indicating that the use of a strong organic base (DBU) significantly inhibits the reaction, while the use of other weak organic bases (DIPEA) or inorganic bases (K2CO3) leads to a decrease in dr value.

[0225] Example 39

[0226] In an 8 mL reaction flask, ligand L1 (6.8 mg, 0.015 mmol), copper hexafluoroacetylacetonate (4.8 mg, 0.01 mmol), and 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) were added. The reaction system was placed in a glove box, followed by the addition of tetrahydrofuran (0.3 mL) and triethylamine (72.0 μL, 0.5 mmol, NEt3). The reaction apparatus was sealed, removed from the glove box, and stirred at room temperature for half an hour. Then, the mixture was cooled to -30 °C and stirred for another half hour. A pre-cooled solution of dibenzylamine dichloride (38 mg, 0.12 mmol) in tetrahydrofuran (0.2 mL) was added to the solution, and the reaction was allowed to proceed for 20 h. Finally, a cold solution of sodium phenolate (58 mg, 0.50 mmol) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and the mixture was stirred at -30 °C for another 4 hours. After the reaction was complete, the resulting reaction solution was separated by column chromatography (DCM:MeOH = 20:1, Rf = 0.50) to obtain the final product, a white solid, namely compound II-1 (50.5 mg, yield 82%). Chiral HPLC analysis showed a product ratio of 95:1 d.r. (CHIRALPAK IBN-3, 40% iPrOH / hexanes, 1.0 mL / min, 254 nm, t). R (Main) = 13.2 min, t R (Minor) = 14.3 min).

[0227] Example 40

[0228] In an 8 mL reaction flask, ligand L1 (3.4 mg, 0.0075 mmol), copper hexafluoroacetylacetonate (2.4 mg, 0.005 mmol), and 2',3'-isopropylideneuridine (28.4 mg, 0.1 mmol) were added. The reaction system was placed in a glove box, followed by the sequential addition of tetrahydrofuran (0.3 mL) and triethylamine (72.0 μL, 0.5 mmol, NEt3). The reaction apparatus was sealed, removed from the glove box, and stirred at room temperature for half an hour. Then, the mixture was cooled to -30 °C and stirred for another half hour. A pre-cooled solution of dibenzylamine dichloride (47 mg, 0.15 mmol) in tetrahydrofuran (0.2 mL) was added to the solution, and the reaction was allowed to proceed for 20 h. Finally, a cold solution of sodium phenolate (58 mg, 0.50 mmol) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and the mixture was stirred at -30 °C for another 4 hours. After the reaction was complete, the resulting reaction solution was separated by column chromatography (DCM:MeOH = 20:1, Rf = 0.50) to obtain the final product, a white solid, namely compound II-1 (45.2 mg, yield 73%). Chiral HPLC analysis showed that the product was 98.1 d.r. (CHIRALPAK IBN-3, 40% iPrOH / hexanes, 1.0 mL / min, 254 nm, t). R (Main) = 13.2 min, t R (Minor) = 14.3 min).

[0229] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A chiral phosphoryl chloride, characterized in that, The chiral phosphoryl chloride has the compound structure shown in Formula I: Among them, R 1 Derived from dimethylamine, diethylamine, diallylamine, di(2-chloroethyl)amine, diisobutylamine, N-benzylglycine isopropyl ester, N-methylbenzylamine, N-methylbenzylamine, N-[(trimethylsilyl)methyl]benzylamine, diethyl iminodiacetate, N-(2-furanylmethyl)benzylamine, tetrahydropyrrole, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- The following are listed: tetrahydrothieno[3,2-c]pyridine, 4-methylhexahydropyridine, methyl 4-piperidine acetate, morpholine, N-phenylpiperazine, 1-(2-pyrimidinyl)piperazine, cycloheptylamine, 4,4'-difluorobenzylpiperazine, 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole, 4-(1,2-benzisothiazol-3-yl)-1-piperazine, duloxetine, nortriptyline, vortioxetine, atomoxetine, and sertraline. R 2 The following are listed: 2',3'-isopropylidene uridine, 2',3'-isopropylidene thymidine, 5-fluoro-2',3'-isopropylidene uridine, 5-bromo-2',3'-isopropylidene uridine, 5-iodo-2',3'-isopropylidene uridine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, 1-((3 a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furano[3,4-d][1,3]dioxacyclopentene]-6-yl)pyrimidin-2,4(1H,3H)-dione, (2R, 3S, 5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran, fructose diacetone, ((2S, 3) (R, 4S, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (2R, 3R, 4R, 5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triyltribenzoate, (3-phenoxyphenyl)methanol, 4-nitrobenzyl alcohol, methyl 4-(hydroxymethyl)benzoate, 1-naphthalenemethanol, 2-naphthalenemethanol, 3-morpholinophenylmethanol, (5-nitro) Any one of the following: furan-2-yl)methanol, 2-naphthylethanol, 1-(2-methoxyphenyl)ethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, 2-thiopheneethanol, 2-phenylthioethanol, N-BOC-2-(4-aminophenyl)ethanol, benzyl 4-(hydroxymethyl)piperidine-1-carboxylate, and idebenone.

2. A method for preparing chiral phosphoryl chloride according to claim 1, characterized in that, Includes the following steps: Chiral phosphoryl chloride is generated by reacting nucleoside compounds or alcohols with racemic aminophosphoryl dichloride or alkoxyphosphoryl dichloride in the presence of organic solvents, bases, chiral ligands and catalysts.

3. The method for preparing chiral phosphoryl chloride according to claim 2, characterized in that, The nucleoside compounds are selected from 2',3'-isopropylideneuridine, 5-fluoro-2',3'-isopropylideneuridine, 5-bromo-2',3'-isopropylideneuridine, 2',3'-isopropylidenethymidine, 5-iodo-2',3'-isopropylideneuridine, 2',3'-isopropylidene adenosine, 6-chloro-2',3'-isopropylidene adenosine, zidovudine, 3'-O-(tert-butyldimethylsilyl)thymidine, 3'-O-benzylthymidine, stavudine, 1 At least one of -((3a'R, 4'R, 6'R, 6a'R)-4'-(hydroxymethyltetrahydrospiro[cyclohexane-1,2'-furano[3,4-d][1,3]dioxacyclopentene]-6-yl)pyrimidin-2,4(1H,3H)-dione, (2R, 3S, 5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran, and fructose diacetone; The alcohol is selected from 4-nitrobenzyl alcohol, (5-nitrofuran-2-yl)methanol, 1-(2-methoxyphenyl)ethanol, 2-thiopheneethanol, 2-phenylthioethanol, N-BOC-2-(4-aminophenyl)ethanol, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (3-phenoxyphenyl)methanol, 1-naphthalenemethanol, 2-naphthalenemethanol At least one of the following: 3-morpholinylbenzyl alcohol, 2-naphthylethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, (2R, 3R, 4R, 5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-trimethyltribenzoate, methyl 4-(hydroxymethyl)benzoate, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, benzyl 4-(hydroxymethyl)piperidine-1-carboxylate, and idebenone.

4. The method for preparing chiral phosphoryl chloride according to claim 2, characterized in that, The aminophosphoryl dichloride is selected from at least one of dibenzylaminophosphoryl dichloride, dimethylaminophosphoryl dichloride, di(2-chloroethyl)phosphoramide dichloride, diallylphosphoramide dichloride, benzyl(furan-2-ylmethyl)phosphoramide dichloride, and (S)-methyl-(3-(1-naphthoxy))-3-(thiophen-2-yl)propyl)phosphoramide dichloride; The alkoxyphosphoryl dichloride is selected from at least one of pyrrolidine-1-ylphosphonyl dichloride, morpholine phosphoryl dichloride, azircyclopentane-1-phosphonyl dichloride, (4-(6-fluorobenzo[d]trimethylandrosadieneisoxazol-3-yl))piperidin-1-yl)phosphine dichloride, and ethyl dichlorophosphate.

5. The method for preparing chiral phosphoryl chloride according to claim 2, characterized in that, The organic solvent is selected from tetrahydrofuran; The base is selected from triethylamine; The catalyst is selected from copper hexafluoroacetylacetone; The chiral ligand is selected from ligand L1 and ligand L2, and the ligand structure is as follows:

6. The method for preparing chiral phosphoryl chloride according to claim 2, characterized in that, The molar ratio of the nucleoside-containing compound or alcohol to aminophosphoryl dichloride or alkoxyphosphoryl dichloride is 1:1.0 to 1.5; The reaction temperature is -60℃ to -30℃, and the reaction time is 18 to 28 hours.

7. A method for preparing chiral phosphoramide, characterized in that, The method includes the following steps: reacting the chiral phosphoric acid chloride of claim 1 with a nucleophilic reagent to obtain chiral phosphoramide.

8. The method for preparing chiral phosphoramide according to claim 7, characterized in that, The nucleophile is selected from any one of sodium phenolate, sodium methoxide, sodium 1-naphthol, sodium 4-fluorophenolate, sodium thiophene, sodium ethanethiol, cyclohexylamine, benzamide, 4-methoxyaniline, benzylamine, dimethylamine, morpholine, 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane, L-alanine isopropyl ester, 1,2,3,4-tetrahydroisoquinoline, magnesium methyl bromide, and lithium amino.

9. The method for preparing chiral phosphoramide according to claim 7, characterized in that, The reaction temperature is -60℃ to -30℃, and the reaction time is 2 to 6 hours.

10. A chiral phosphoramide prepared according to any one of claims 7-9, characterized in that, The chiral phosphoramide includes compounds having the structures shown in formulas II to X: Among them, R 3 Derived from dimethylamine, diethylamine, diallylamine, di(2-chloroethyl)amine, diisobutylamine, N-benzylglycine isopropyl ester, N-methylbenzylamine, N-methylbenzylamine, N-[(trimethylsilyl)methyl]benzylamine, diethyl iminodiacetate, N-(2-furanylmethyl)benzylamine, tetrahydropyrrole, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- The following are listed: tetrahydrothieno[3,2-c]pyridine, 4-methylhexahydropyridine, methyl 4-piperidine acetate, morpholine, N-phenylpiperazine, 1-(2-pyrimidinyl)piperazine, cycloheptylamine, 4,4'-difluorobenzylpiperazine, 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole, 4-(1,2-benzisothiazol-3-yl)-1-piperazine, duloxetine, nortriptyline, vortioxetine, atomoxetine, and sertraline. R 4 It is any one of methyl, 1-naphthol, 4-fluorophenol, phenol, methoxy, thiophene, ethylthio, cyclohexylamine, benzylamine, benzamide, 4-methoxyaniline, dimethylamine, morpholine, tert-butyloxy, 2-tert-butyloxycarbonyl-2,7-diazaspiro[3.5]nonane; R 5 It is any one of 2',3'-isoproterenylthymidine, 5-fluoro-2',3'-isoproterenyluridine, 5-bromo-2',3'-isoproterenyluridine, 5-iodo-2',3'-isoproterenyluridine, 2',3'-isoproterenyl adenosine, (2R, 3S, 5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran; R 6 It is any one of hydrogen, acetoxy, tert-butyldimethylsiloxy, and azide; R 7 It is either thymidine or uridine; R 8 Derived from fructose diacetone, ((2S,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methanol, (2R,3R,4R,5S)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triyltribenzoate, (3-phenoxyphenyl)methanol, 4-nitrobenzyl alcohol, methyl 4-(hydroxymethyl)benzoate, 1-naphthalenemethanol, 2-naphthalene The following is a list of methanol, 3-morpholinobenzyl alcohol, (5-nitrofuran-2-yl)methanol, 2-naphthylethanol, 1-(2-methoxyphenyl)ethanol, 1-(3-methoxyphenyl)ethanol, 1-(4-methoxyphenyl)ethanol, tert-butyl(4-(2-hydroxyethyl)phenyl)carbamate, metronidazole, 2-thiopheneethanol, 2-phenylthioethanol, 4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester, and idebenone.

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