1. A synthetic method of N-acyl phosphoramide compounds is characterized by comprising the following steps: mixing carboxylic acid, azide, phosphorus chlorine compound, alkali and reaction solvent for reaction to obtain the compound, wherein the reaction structural formula is as follows:

wherein R is selected from phenyl or ethoxy; r' carboxylic acid is selected from benzoic acid, substitutable aryl formic acid or alkyl carboxylic acid, carboxyl-containing drug molecule or natural product; r' is selected from benzyl, aryl, various amino acids and natural product skeleton groups.

2. The synthesis method of claim 1, wherein the reaction solvent is any one or a combination of toluene, chlorobenzene, dichloromethane, diethyl ether or acetonitrile.

3. The method of synthesis of claim 1, wherein the base comprises triethylamine, diisopropylethylamine, diethylamine, triethylenediamine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, or tetramethylguanidine.

4. The method of claim 1, wherein said azide compounds include benzyl azide, phenyl azide, azide derived from various amino acids, azide derived from tartaric acid, azide derived from alpha-D-pyranose, azide derived from uridine.

5. The method of claim 1, wherein the carboxylic acid comprises benzoic acid, benzoic acid substituted at various positions on the phenyl ring, isophthalic acid, 2-naphthoic acid, furan-2-carboxylic acid, thiophene-2-carboxylic acid, pyridine-2, 6-dicarboxylic acid, quinoline-2-carboxylic acid, xanthene-9-carboxylic acid, 4-methylphenylacetic acid, benzoylformic acid, acetic acid, propionic acid, 2-bromo-hexanoic acid, trifluoroacetic acid, cinnamic acid, 1-cyclohexenecarboxylic acid, estrolic acid, febuxostat, indomethacin, sulindac, tretinoin.

6. The method of claim 1, wherein the phosphorus chloride compound comprises diphenylphosphoryl chloride, diethylphosphorous dichloride.

7. The method of claim 1, wherein the molar ratio of azide compound, phosphorus chlorine compound, carboxylic acid and base is 1.0:1.2:1.2:1.2-1.0:1.2:1.2: 1.5.

8. The method of claim 1, wherein the azide compound is present in the reaction system at a reaction concentration of 0.05 to 0.4 moles per liter.

9. The method of synthesis according to any one of claims 1 to 8, wherein the reaction atmosphere is argon; the reaction time is 2-12 hours.

10. The method of synthesis of claim 9, further comprising: after the reaction, carrying out column chromatography on the reaction liquid, wherein the eluent of the column chromatography is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1-1: 2.

Background

Because the phosphoramide skeleton plays an irreplaceable role in the molecular structures of a plurality of drug molecules and functional materials, the phosphoramide compounds become one of the key research objects in the fields of medicine, agriculture, materials, organic synthesis and the like. Among a large number of phosphoramide compounds, N-acyl phosphoramides are a very unique and important class, and many antibiotics have N-acyl phosphoramide skeletons in their molecular structures. The reported synthesis method of the phosphoramide compound is shown as the following formula:

1) the classical synthesis method is: under the action of alkali, one molecule of hydrogen chloride is removed between amine and trivalent phosphorus chloride, and then the corresponding phosphoramide compound is obtained by oxidation. The method needs two steps, most of the methods need to carry out reaction at high temperature, particularly, the method takes amide as a substrate, the reaction time is long, and the application range of the substrate is very limited.

2) And (3) carrying out dehydration condensation reaction on phosphoric acid and amine under the microwave condition. The reaction temperature of the method is about 220 ℃, and the conversion rate is extremely low. Later, by activating the phosphoric acid using propane phosphoric anhydride, the reaction temperature can be lowered to room temperature, however, more than twice as much base is required to catalyze the reaction during the reaction, and the substrate applicability is very limited.

3) Oxidative rearrangement of phosphorus chloride with hydroxylamine: removing one molecule of hydrogen chloride from trivalent phosphorus chloride and hydroxylamine under the action of alkali, and then rearranging under the heating condition to obtain the corresponding phosphoramide compound. The method needs to synthesize the hydroxylamine substrate in advance, and the reaction has higher structural requirement on the hydroxylamine compound and lower universality.

4) Other methods are as follows: coupling of phosphine with benzoylhydroxylamine, phosphhydrogenation of diazo or azo.

The methods usually adopt a step method, the application range of the substrate is narrow, the reaction conditions are harsh, and the conversion rate is low.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a synthesis method of N-acyl phosphoramide compounds, which is simple to operate, high in reaction efficiency and broad in universality.

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

a synthetic method of N-acyl phosphoramide compounds comprises the following steps: mixing carboxylic acid, azide, phosphorus chlorine compound, alkali and reaction solvent for reaction to obtain the compound, wherein the reaction structural formula is as follows:

wherein R is selected from phenyl or ethoxy; r' carboxylic acid is selected from benzoic acid, substitutable aryl formic acid or alkyl carboxylic acid, carboxyl-containing drug molecule or natural product; r' is selected from benzyl, aryl, various amino acids and natural product skeleton groups.

Preferably, the reaction solvent is any one or a combination of toluene, chlorobenzene, dichloromethane, diethyl ether or acetonitrile.

Preferably, the reaction solvent is toluene.

Preferably, the base comprises triethylamine, diisopropylethylamine, diethylamine, triethylenediamine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine or tetramethylguanidine.

Preferably, the base comprises triethylamine.

Preferably, the azide compounds include benzyl azide, phenyl azide, azide derived from various amino acids, azide derived from tartaric acid, azide derived from alpha-D-pyranose, azide derived from uridine.

Preferably, the carboxylic acids include benzoic acid, benzoic acid variously substituted at different positions of the phenyl ring, isophthalic acid, 2-naphthoic acid, furan-2-carboxylic acid, thiophene-2-carboxylic acid, pyridine-2, 6-dicarboxylic acid, quinoline-2-carboxylic acid, xanthene-9-carboxylic acid, 4-methylphenylacetic acid, benzoylcarboxylic acid, acetic acid, propionic acid, 2-bromo-hexanoic acid, trifluoroacetic acid, cinnamic acid, 1-cyclohexenecarboxylic acid, estrolic acid, febuxostat, indomethacin, sulindac, tretinoin.

Preferably, the phosphorus chloride compound comprises diphenyl phosphorus chloride, diethyl phosphorous oxychloride.

Preferably, the molar ratio of the azide compound, the phosphorus chlorine compound, the carboxylic acid and the base is 1.0:1.2:1.2:1.2-1.0:1.2:1.2: 1.5.

Preferably, the molar ratio of the azide compound, the phosphorus chlorine compound, the carboxylic acid and the alkali is 1.0:1.2:1.2:1.2

Preferably, the reaction concentration of the azide compound in the reaction system is 0.05 to 0.4 mol per liter.

Preferably, the reaction concentration of the azide compound in the reaction system is 0.2 mol per liter.

Preferably, the reaction atmosphere is argon; the reaction time is 2-12 hours.

Preferably, when the phosphorus chloride compound is diphenyl phosphorus chloride, the reaction temperature is 25 ℃.

Preferably, when the phosphorus chloride compound is diethylphosphorous acid chloride, the reaction temperature is 50 ℃.

Preferably, the method further comprises: and (2) carrying out column chromatography on the reaction liquid after the reaction, wherein an eluent of the column chromatography is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2: 1-1: 2.

the invention has the beneficial effects that: compared with the prior art, the method has the following advantages: the method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions and high reaction efficiency, triethylamine is used as alkali, no catalyst is needed, byproducts of the reaction are alkali-hydrochloride and nitrogen which are easy to separate and remove, the problems of environmental pollution and the like do not exist, and the method is green and environment-friendly and has better atom economy.

Drawings

FIG. 1 Synthesis of Compound results 1;

FIG. 2 Synthesis of compound results 2.

Detailed Description

The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.

The compounds shown in the figures 1 and 2 are synthesized according to the method, but the invention is not limited to the compounds shown in the figures 1 and 2.

The present examples specifically demonstrate the synthesis of 31 of these compounds.

Example 1

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene, then 0.24 mmol of diphenyl phosphorus chloride and 0.24 mmol of triethylamine were added, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction solution was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give the N-acylphosphoramide compound 4aaa in 96% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.13(dd,J＝12.4,7.6Hz,2H),7.85(dd,J＝13.6,7.2Hz,2H),7.61-7.57(m,1H),7.51-7.46(m,2H),7.40-7.36(m,1H),7.33-7.29(m,2H),7.17-7.12(m,3H),7.06(t,J＝7.4Hz,2H),6.98(d,J＝8.0Hz,2H),6.53(d,J＝7.2Hz,2H),4.76-4.68(m,1H),3.92(s,3H),3.52(dd,J＝14.8,4.0Hz,1H),3.24(dd,J＝14.8,10.4Hz,1H),2.26(s,3H).¹³C NMR(100MHz,CDCl₃)δ174.8(d,J_C-F＝4.0Hz),171.3,141.1,137.1,133.8,133.7,132.8(d,J_C-F＝3.0Hz),131.9(d,J_C-F＝3.0Hz),132.2,131.6,131.5,129.4,128.6,128.5,128.4,128.3,128.1,127.7,126.6,62.8(d,J_C-F＝2.0Hz),52.8,36.9,21.5.³¹P NMR(162MHz,CDCl₃)δ32.63.HRMS(ESI)m/z calcd for C₃₀H₂₉NO₄P[M+H]⁺:498.1829,found 498.1833。

the product has the following structural formula:

example 2

To the reactor, 0.24 mmol of p-toluic acid and 1 ml of toluene were added, followed by 0.24 mmol of diethylphosphorylidene chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 30 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after reacting at 50 ℃ for 6 hours, the reaction mixture was directly used as an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give the N-acylphosphoramide compound 4 aa' a in 82% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.33-7.26(m,2H),7.22(q,J＝7.5Hz,5H),7.10(d,J＝7.6Hz,2H),5.08-5.01(m,1H),4.04-3.92(m,2H),3.82(s,3H),3.76-3.70(m,1H),3.56(dd,J＝14.4,4.4Hz,1H),3.50-3.43(m,1H),3.41-3.34(m,1H),2.35(s,3H),1.11-1.03(m,6H).¹³C NMR(100MHz,CDCl₃)δ172.8(d,J_C-F＝6.0Hz),171.0(d,J_C-F＝1.0Hz),141.3,138.1,133.2,129.8,128.5,128.3,127.7,126.7,64.0(d,J_C-F＝6.0Hz),63.5(d,J_C-F＝6.0Hz),61.4(d,J_C-F＝4.0Hz),52.5,35.2,21.6,15.8(d,J_C-F＝8.0Hz),15.7(d,J_C-F＝8.0Hz).³¹P NMR(162MHz,CDCl₃)δ1.12.HRMS(ESI)m/z calcd for C₂₂H₂₉NO₆P[M+H]⁺434.1727 and found 434.1730. The product has the following structural formula:

example 3

In the reactor, 0.24 mmol of p-vinylbenzoic acid and 1 ml of toluene were added, then 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine were added, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction solution was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aaj in 88% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ6.86(dd,J＝16.6,10.2Hz,2H),6.59(dd,J＝18.0,9.6Hz,2H),6.37-6.33(m,1H),6.27-6.22(m,2H),6.12-6.05(m,3H),5.93-5.90(m,5H),5.86-5.81(m,2H),5.40-5.29(m,3H),4.47(d,J＝23.6Hz,1H),4.02(d,J＝14.8Hz,1H),3.46-3.36(m,1H),2.67(s,3H),2.26(dd,J＝19.6,4.8Hz,1H),1.99(dd,J＝19.6,14.0Hz,1H).¹³C NMR(100MHz,CDCl₃)δ173.3(d,J_C-F＝5.0Hz),170.1,138.7,136.0,134.9,133.1,132.7,132.6,131.8,130.9(d,J_C-F＝4.0Hz),,130.6,129.5,128.3,127.5,127.4,127.4,127.3,127.1,127.1,125.7,124.6,114.8,61.7,51.8,35.7.³¹P NMR(162MHz,CDCl₃)δ31.24.HRMS(ESI)m/z calcd for C₃₁H₂₉NO₄P[M+H]⁺:510.1829,found 510.1833。

the product has the following structural formula:

example 4

0.24 mmol of 2-naphthoic acid and 1 ml of toluene were added to a reactor, followed by 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Acetic acidEthyl ester}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aal in 91% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.92(dd,J＝16.6,10.2Hz,2H),7.61(dd,J＝18.0,9.2Hz,2H),7.47-7.42(m,3H),7.33-7.16(m,7H),7.05-6.92(m,4H),6.81(t,J＝10.0Hz,2H),6.28(d,J＝9.6Hz,2H),4.52-4.42(m,1H),3.67(s,3H),3.27(dd,J＝19.6,5.2Hz,1H),3.06(dd,J＝19.4,14.2Hz,1H).¹³C NMR(100MHz,CDCl₃)δ174.6(d,J_C-F＝4.8Hz),171.1,137.0,133.8,133.7,133.6,132.8,132.5,132.2,131.9,131.8,131.6,131.4,130.8,130.8,129.4,128.9,128.6,128.4,128.3,128.1,127.8,127.6,126.7,126.6,123.9,62.7(d,J_C-F＝3.3Hz),52.8,36.7.³¹P NMR(162MHz,CDCl₃)δ32.37.HRMS(ESI)m/zcalcd for C₃₃H₂₉NO₄P[M+H]⁺:534.1829,found 534.1833。

the product has the following structural formula:

example 5

0.24 mmol cinnamic acid and 1 ml toluene were added to a reactor, then 0.24 mmol diphenylphosphoryl chloride and 0.24 mmol triethylamine were added thereto, and after stirring at room temperature for 10 minutes, 0.2 mmol methyl (S) -2, 6-diazahexanoate was added thereto, and after reaction at 25 ℃ for 4 hours, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aam in 80% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.96(dd,J＝16.0,10.0Hz,2H),7.59-7.53(m,2H),7.48-7.45(m,1H),7.43-7.35(m,5H),7.27-7.22(m,9H),7.04-7.02(m,2H),6.90(d,J＝20.4Hz,1H),4.57-4.37(m,1H),3.83(s,3H),3.54(dd,J＝19.0,6.2Hz,1H),3.30(dd,J＝19.0,12.6Hz,1H).¹³C NMR(100MHz,CDCl₃)δ171.2,168.9(d,J_C-F＝5.6Hz),144.3,137.4,134.3,132.6,132.3,132.2,132.1,130.3,129.9,128.7,128.6,128.2,126.9,120.1,60.7,52.6,36.1.³¹P NMR(162MHz,CDCl₃)δ30.61.HRMS(ESI)m/z calcd for C₃₁H₂₉NO₄P[M+H]⁺:510.1829,found 510.1832。

the product has the following structural formula:

example 6

In the reactor, 0.24 mmol of 1-cyclohexenecarboxylic acid and 1 ml of toluene were added, then 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine were added, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give the N-acylphosphoramide compound 4aan in 79% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.97(dd,J＝16.8,10.4Hz,2H),7.86(dd,J＝16.4,9.6Hz,2H),7.50-7.41(m,6H),7.29-7.27(m,3H),6.93-6.91(m,2H),6.46-6.43(m,2H),4.32-4.25(m,1H),3.83(s,3H),3.47(dd,J＝19.0,5.8Hz,1H),3.16(dd,J＝19.2,13.2Hz,1H),1.93-1.85(m,3H),1.65-1.58(m,1H),1.38-1.23(m,2H),1.15-1.09(m,1H),0.91-0.91(m,1H).¹³C NMR(100MHz,CDCl₃)δ175.3(d,J_C-F＝6.5Hz),171.0,137.6,136.9,133.9,133.0,132.9,132.5,131.9,131.7,131.5,131.1,129.6,128.7,128.5,128.4,127.0,61.8,52.6,36.1,24.8,24.7,21.4,21.0.³¹P NMR(162MHz,CDCl₃)δ27.64.HRMS(ESI)m/z calcd for C₂₉H₃₁NO₄P[M+H]⁺:488.1985,found 488.1990。

the product has the following structural formula:

example 7

In the reactor, 0.2 mmol of m-dibenzoic acid and 1 ml of toluene were added, then 0.4 mmol of diphenylphosphoryl chloride and 0.48 mmol of triethylamine were added, and after stirring at room temperature for 10 minutes, 0.4 mmol of methyl (S) -2, 6-diazahexanoate was added, and after reacting at 25 ℃ for 6 hours, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aao in 93% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.14(dd,J＝14.8,10.8Hz,4H),7.87(dd,J＝17.8,5.4Hz,4H),7.65-7.60(m,2H),7.53-7.49(m,5H),7.35-7.35(m,6H),7.12-7.08(m,2H),6.99-6.89(m,7H),6.44(s,4H),4.61-4.53(m,2H),3.98(s,6H),3.52(dd,J＝20.2,4.6Hz,2H),3.22(dd,J＝19.6,14.0Hz,2H).¹³C NMR(100MHz,CDCl₃)δ173.5(d,J_C-F＝3.6Hz),171.0,137.0,134.7,133.9,133.7,133.2,132.6,132.3,131.8,131.6,130.9,130.8,130.5,129.4,129.1,128.8,128.6,128.5,128.4,126.7,63.0,53.1,36.9.³¹P NMR(162MHz,CDCl₃)δ33.40.HRMS(ESI)m/z calcd for C₅₂H₄₇N₂O₈P₂[M+H]⁺:889.2802,found 889.2807。

the product has the following structural formula:

example 8

0.24 mmol of 4-methylphenylacetic acid and 1 ml of toluene were added to a reactor, followed by 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aap in 80% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.05-7.99(m,2H),7.51-7.44(m,6H),7.35-7.32(m,2H),7.25-7.22(m,3H),7.04(d,J＝10.4Hz,2H),6.93(d,J＝10.4Hz,2H),6.79(d,J＝9.6Hz,2H),4.22(s,1H),3.74(s,4H),3.48-3.40(m,2H),3.14(dd,J＝19.0,12.6Hz,1H),2.26(s,3H).¹³C NMR(100MHz,CDCl₃)δ175.4(d,J_C-F＝7.2Hz),171.3(d,J_C-F＝4.8Hz),137.9,136.9,133.5,133.1,133.0,133.0,132.8,132.6,132.5,131.8,131.1,130.3,130.0,129.4,129.2,129.0,129.0,127.3,62.1,52.9,43.9,36.3,21.5.³¹P NMR(162MHz,CDCl₃)δ31.37.HRMS(ESI)m/z calcd for C₃₁H₃₁NO₄P[M+H]⁺:512.1985,found 512.1989。

the product has the following structural formula:

example 9

0.24 mmol of benzoylformic acid and 1 ml of toluene were charged into a reactor, followed by 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanate was added, and after 4 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aaq in 71% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.83-7.74(m,2H),7.64(dd,J＝12.6,7.8Hz,2H),7.57-7.55(m,2H),7.50-7.42(m,3H),7.30-7.26(m,6H),7.11-7.04(m,5H),5.23-5.16(m,1H),7.77-7.72(m,4H),3.39(s,1H).¹³C NMR(100MHz,CDCl₃)δ187.8,170.4(d,J_C-F＝2.0Hz),169.5(d,J_C-F＝5.0Hz),137.4,134.3,133.4,133.3,133.0(d,J_C-F＝2.0Hz),132.7,132.4,130.1,129.5,128.5,128.4,128.3,128.3,128.2,126.9,59.4,52.7,36.6.³¹P NMR(162MHz,CDCl₃)δ33.90.HRMS(ESI)m/z calcd for C₃₀H₂₇NO₅P[M+H]⁺:512.1621,found 512.1626。

the product has the following structural formula:

example 10

0.24 mmol of trifluoroacetic acid and 1 ml of toluene were added to the reactor, followed by 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 10 minutes, 0.2 mmol of methyl (S) -2, 6-diazahexanoate was added, and after 4 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aar in 32% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.03(dd,J＝12.8,7.6Hz,2H),7.84(dd,J＝13.2,7.2Hz,1H),7.73-7.66(m,2H),7.57-7.54(m,3H),7.45-7.43(m,2H),7.15-7.14(m,3H),6.92-6.92(m,2H),5.07-4.99(m,1H),3.89(dd,J＝14.8,5.6Hz,1H),3.84(s,3H),3.23(dd,J＝14.4,8.0Hz,1H).¹³C NMR(100MHz,CDCl₃)δ170.0,136.9,133.4(d,J_C-F＝3.0Hz),133.2,133.1,132.8(d,J_C-F＝3.0Hz),132.0,131.9,131.5(d,J_C-F＝10.0Hz),129.4,129.0,128.8,128.7,128.6,128.5,128.5,128.3,126.9,60.8,53.0,38.1.³¹P NMR(162MHz,CDCl₃)δ37.30.¹⁹F NMR(376MHz,CDCl₃)δ-68.83.HRMS(ESI)m/z calcd for C₂₄H₂₂F₃NO₄P[M+H]⁺:476.1233,found 476.1237。

the product has the following structural formula:

example 11

In the reactor, 0.24 mmol of Guton-9-carboxylic acid and 1 ml of toluene were added, and then 0.24 mmol of diphenylphosphoryl chloride and 0.24 mmol of triethylamine were added, and the mixture was stirred at room temperature for 10 minutes0.2 mmol of methyl (S) -2, 6-diazahexanoate was added and the mixture was reacted at 25 ℃ for 4 hours, and then an eluent (V) was used as it was for the reaction mixture_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aat in 81% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.48-8.40(m,4H),8.35-7.95(m,4H),7.93-7.62(m,4H),7.52-7.47(m,4H),7.47-7.25(m,3H),7.26-7.20(m,2H),7.16-7.12(m,3H),6.73-6.73(m,1H),6.66(d,J＝9.6Hz,2H),5.70(s,1H),5.61-5.61(m,1H),4.00-3.91(m,1H),3.58(s,3H),3.24(dd,J＝19.6,7.6Hz,1H),2.62(dd,J＝21.2,9.2Hz,1H).¹³C NMR(100MHz,CDCl₃)δ177.0(d,J_C-F＝10.6Hz),171.1,153.2(d,J_C-F＝49.3Hz),138.4,133.8,133.6,133.1(d,J_C-F＝14.4Hz),130.4,130.1,130.0,129.6(d,J_C-F＝16.9Hz),129.2,129.1,128.7,127.3,123.6,123.3,121.0,120.7,117.8,117.6,63.4(d,J_C-F＝2.3Hz),53.1,47.7,36.2.³¹P NMR(162MHz,CDCl₃)δ30.72.HRMS(ESI)m/z calcd for C₃₆H₃₁NO₅P[M+H]⁺:588.1934,found 588.1940。

the product has the following structural formula:

example 12

In the reactor, 0.2 mmol 2, 6-pyridinedicarboxylic acid and 1 ml toluene, then 0.4 mmol diphenylphosphoryl chloride and 0.48 mmol triethylamine were added, and after stirring at room temperature for 10 minutes, 0.4 mmol methyl (S) -2, 6-diazahexanoate was added, and after 6 hours of reaction at 25 ℃, the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:2) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4aaw in 84% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.15-8.10(m,4H),7.85-7.83(m,4H),7.63-7.60(m,2H),7.54-7.48(m,4H),7.35-7.35(m,6H),7.26-7.19(m,3H),7.00-6.82(m,7H),6.57(s,3H),5.41(s,2H),3.82(s,6H),3.65(d,J＝12.4Hz,2H),3.27(t,J＝12.2Hz,2H).¹³C NMR(100MHz,CDCl₃)δ170.6,170.1,150.8,137.4,133.7(d,J_C-F＝10.0Hz),132.9,132.2,131.9,131.8,131.6,131.3(d,J_C-F＝11.0Hz),129.5,129.3,128.4,128.3,128.2,126.4,125.3,61.3,52.7,37.8.³¹P NMR(162MHz,CDCl₃)δ35.68.HRMS(ESI)m/z calcd for C₅₁H₄₆N₃O₈P₂[M+H]⁺:890.2755,found 890.2760。

the product has the following structural formula:

example 13

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene, then 0.24 mmol of diphenyl phosphorus chloride and 0.24 mmol of triethylamine were added, stirred at room temperature for 10 minutes, added 0.2 mmol, reacted at 25 ℃ for 4 hours, and the reaction mixture was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give the N-acylphosphoramide compound 4maa in 71% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.95(dd,J＝13.0,7.0Hz,4H),7.52-7.48(m,2H),7.45-7.41(m,4H),7.29-7.27(m,2H),7.23-7.14(m,5H),6.93(d,J＝8.0Hz,2H),2.19(s,3H).¹³C NMR(100MHz,CDCl₃)δ173.1(d,J_C-F＝3.0Hz),141.6,138.2,132.2,132.1,132.0,131.7,131.6,131.6,130.7(d,J_C-F＝2.0Hz),130.3,129.3,128.9,128.6,128.4,128.3,127.8,21.4.³¹P NMR(162MHz,CDCl₃)δ29.85.HRMS(ESI)m/z calcd for C₂₆H₂₃NO₂P[M+H]⁺:412.1461,found 412.1464。

the product has the following structural formula:

example 14

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene, then 0.24 mmol of diphenyl phosphorus chloride and 0.24 mmol of triethylamine are added, the mixture is stirred for 10 minutes at room temperature, 0.2 mmol of benzyl azide is added, the mixture is reacted for 4 hours at 25 ℃, and then the reaction solution is directly eluted with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4naa in 74% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.83(dd,J＝12.0,8.0Hz,4H),7.48-7.44(m,2H),7.39-7.33(m,6H),7.12-7.12(m,3H),7.09-7.06(m,4H),4.97(d,J＝12.0Hz,2H),2.30(s,3H).¹³C NMR(100MHz,CDCl₃)δ175.3(d,J_C-F＝4.0Hz),141.5,137.7,132.9,132.9,132.1,132.1,132.0,131.8,130.5,128.9,128.3,128.3,128.2,128.1,128.0,127.3,50.3(d,J_C-F＝3.0Hz),21.5.³¹P NMR(162MHz,CDCl₃)δ30.07.HRMS(ESI)m/z calcd for C₂₇H₂₅NO₂P[M+H]⁺:426.1617,found 426.1621。

the product has the following structural formula:

example 15

In the reactor, 0.24 mmol propionic acid and 1 ml toluene, then 0.24 mmol diphenyl phosphorus chloride and 0.24 mmol triethylamine were added, stirred at room temperature for 10 minutes, added 0.2 mmol benzyl azide, reacted at 25 ℃ for 4 hours, and the reaction solution was directly used with eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4nay in 96% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.75(dd,J＝13.0,7.8Hz,4H),7.55-7.51(m,2H),7.44-7.40(m,4H),7.23-7.21(m,3H),7.10-7.08(m,2H),4.89(d,J＝11.2Hz,2H),2.51(q,J＝10.8Hz,2H),0.99(t,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl₃)δ178.3(d,J_C-F＝4.0Hz),137.9,132.4,132.4,132.1,132.0,131.6,130.3,128.5,128.4,127.2,126.9,48.0,29.9,8.8.³¹P NMR(162MHz,CDCl₃)δ31.75.HRMS(ESI)m/z calcd for C₂₂H₂₃NO₂P[M+H]⁺:364.1461,found 364.1465。

the product has the following structural formula:

example 16

In the reactor, 0.24 mmol 2-bromine hexanoic acid and 1 ml toluene, then 0.24 mmol diethyl phosphite chloride and 0.24 mmol triethylamine were added, stirred at room temperature for 30 minutes, added with 0.2 mmol benzyl azide, at 50 ℃ for 4 hours, the reaction solution was directly used with eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give 4 na' z as an N-acylphosphoramide compound in 53% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.29-7.22(m,5H),5.30-5.17(m,3H),4.24-4.10(m,4H),1.42-1.27(m,11H),0.95-0.91(m,4H).¹³C NMR(100MHz,CDCl₃)δ172.1,134.3,128.5,128.1,127.6,64.7(d,J_C-F＝4.0Hz),64.6(d,J_C-F＝3.0Hz),43.8,43.2,33.7,29.4,22.2,16.3,16.2,13.8.³¹P NMR(162MHz,CDCl₃)δ1.54.HRMS(ESI)m/z calcd for C₁₇H₂₈BrNO₄P[M+H]⁺:420.0934,found 420.0936。

the product has the following structural formula:

example 17

In the reactor, the reaction mixture is fed into a reactor,0.24 mmol of acetic acid and 1 ml of toluene were added, followed by 0.24 mmol of diethylphosphorous acid chloride and 0.24 mmol of triethylamine, and after stirring at room temperature for 30 minutes, 0.2 mmol of 2-bromophenyl azide was added, and after reaction at 50 ℃ for 4 hours, the reaction mixture was directly used as an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give 6 oa' a as an N-acylphosphoramide compound in 71% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.68(d,J＝8.0Hz,1H),7.41-7.34(m,2H),7.28-7.24(m,1H),4.32-4.17(m,4H),2.09(s,3H),1.29(q,J＝7.5Hz,6H).¹³C NMR(100MHz,CDCl₃)δ172.6(d,J_C-F＝5.0Hz),138.3,133.7,130.9,130.0,128.7,124.4(d,J_C-F＝3.0Hz),124.3,64.7(d,J_C-F＝6.0Hz),64.6(d,J_C-F＝7.0Hz),24.0(d,J_C-F＝4.0Hz),16.1,16.0.³¹P NMR(162MHz,CDCl₃)δ-0.94.HRMS(ESI)m/z calcd for C₁₂H₁₈BrNO₄P[M+H]⁺:350.0151,found 350.0158。

the product has the following structural formula:

example 18

In the reactor, 0.24 mmol acrylic acid and 1 ml toluene, then 0.24 mmol diethyl phosphorous acid chloride and 0.24 mmol triethylamine were added, stirred at room temperature for 30 minutes, then 0.2 mmol phenyl azide was added, reacted at 50 ℃ for 4 hours, and the reaction solution was directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give 6 ma' b as an N-acylphosphoramide compound in 66% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.45-7.38(m,3H),7.27-7.24(m,2H),6.46(dd,J＝16.8,1.6Hz,1H),6.19(dd,J＝16.6,10.2Hz,1H),5.68-5.64(m,1H),4.27-4.23(m,2H),4.22-4.11(m,2H),1.29-1.25(m,6H).¹³C NMR(100MHz,CDCl₃)δ167.9(d,J_C-F＝5.0Hz),138.0,130.6,129.5,129.4(d,J_C-F＝2.0Hz),128.5,128.4(d,J_C-F＝5.0Hz),64.5,64.5,16.1,16.0.³¹P NMR(162MHz,CDCl₃)δ-1.14.HRMS(ESI)m/z calcd for C₁₃H₁₉NO₄P[M+H]⁺:284.1046,found 284.1051。

the product has the following structural formula:

example 19

In the reactor, 0.4 mmol of p-toluic acid and 1 ml of toluene are added, then 0.4 mmol of diethylphosphorous acid chloride and 0.48 mmol of triethylamine are added, after stirring at room temperature for 30 minutes, 0.2 mmol of tartaric acid-derived azide is added, after reaction at 50 ℃ for 6 hours, the reaction solution is directly subjected to an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4 pa' a in 58% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.49(d,J＝8.4Hz,4H),7.20(d,J＝8.0Hz,4H),4.14-4.09(m,4H),4.07-4.04(m,2H),4.03-3.98(m,4H),3.58(dd,J＝13.2,3.2Hz,2H),3.33(dd,J＝13.0,5.0Hz,2H),2.39(s,6H),1.43(s,3H),1.39(s,3H),1.27(t,J＝7.2Hz,6H),1.23(t,J＝7.0Hz,6H).¹³C NMR(100MHz,CDCl₃)δ173.7(d,J_C-F＝7.0Hz),141.5,133.4,128.6,127.9,109.9,78.1,64.1(d,J_C-F＝6.0Hz),64.0(d,J_C-F＝6.0Hz),51.7,47.9(d,J_C-F＝4.0Hz),27.0,26.9,21.5,16.0(d,J_C-F＝7.0Hz),15.9(d,J_C-F＝7.0Hz).³¹PNMR(162MHz,CDCl₃)δ1.78.HRMS(ESI)m/z calcd for C₃₁H₄₇N₂O₁₀P₂[M+H]⁺:669.2700,found 669.2706。

the product has the following structural formula:

example 20

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene are added, then 0.24 mmol of diethylphosphorous acid chloride and 0.24 mmol of triethylamine are added, after stirring at room temperature for 30 minutes, 0.2 mmol of α -D-pyranose-derived azide is added, after 6 hours of reaction at 50 ℃, the reaction solution is directly subjected to an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4 qa' a in 61% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.51(d,J＝8.4Hz,2H),7.15(d,J＝8.0Hz,2H),5.62(t,J＝9.2Hz,1H),5.13-5.02(m,3H),4.24(dd,J＝12.4,5.2Hz,1H),4.18-4.05(m,5H),3.62-3.58(m,1H),2.33(s,3H),2.04(s,3H),1.96(s,3H),1.94(s,3H),1.91(s,3H),1.27-1.23(m,6H).¹³C NMR(100MHz,CDCl₃)δ173.6,170.4,170.3,169.2,169.0,142.6,132.4,128.9,128.2,85.0,74.3,74.2,69.6,67.7,64.8(d,J_C-F＝6.0Hz),64.1(d,J_C-F＝6.0Hz),62.0,21.6,20.7,20.6,20.5,16.1(d,J_C-F＝7.0Hz),15.9(d,J_C-F＝7.0Hz).³¹P NMR(162MHz,CDCl₃)δ1.12.HRMS(ESI)m/z calcd for C₂₆H₃₇NO₁₃P[M+H]⁺:602.1997,found 602.2001。

the product has the following structural formula:

example 21

In the reactor, 0.24 mmol of p-toluic acid and 1 ml of toluene are added, then 0.24 mmol of diethylphosphorylidene chloride and 0.24 mmol of triethylamine are added, after stirring at room temperature for 30 minutes, 0.2 mmol of uridine-derived azide is added, and after reaction at 50 ℃ for 4 hours, the reaction solution is directly used with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:2) by silica gel column chromatography to obtain N-Acylphosphamide compound 4 ra' a in 47% yield, as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.42(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,2H),5.74(d,J＝8.0Hz,1H),5.58(s,1H),4.94-4.93(m,1H),4.82-4.79(m,1H),4.43-4.39(m,1H),4.17-4.03(m,6H),3.19(s,3H),2.37(s,3H),1.54(s,3H),1.33(s,3H),1.27-1.23(m,6H).¹³C NMR(100MHz,CDCl₃)δ173.8(d,J_C-F＝5.0Hz),162.7,150.6,141.5,140.2,133.3,128.5,128.0,114.4,101.9,95.5,86.8,84.8,82.3,64.0(d,J_C-F＝7.0Hz),64.0(d,J_C-F＝6.0Hz),48.6,27.4,27.1,25.3,21.5,16.0,15.9.³¹P NMR(162MHz,CDCl₃)δ2.19.HRMS(ESI)m/z calcd for C₂₅H₃₅N₃O₉P[M+H]⁺:552.2105,found 552.2110。

the product has the following structural formula:

example 22

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene are added, then 0.24 mmol of diethylphosphorous acid chloride and 0.24 mmol of triethylamine are added, after stirring for 30 minutes at room temperature, 0.2 mmol of L-phenylalanine menthyl ester-derived azide is added, after 4 hours of reaction at 50 ℃, the reaction solution is directly treated with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4 sa' a in 72% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.32-7.29(m,2H),7.27-7.24(m,3H),7.21(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),5.03(td,J＝12.0,4.76Hz,1H),7.84(td,J＝13.0,7.4Hz,1H),3.98-3.88(m,2H),3.64-3.55(m,2H),3.42-3.34(m,2H),2.35(s,3H),2.19-2.13(m,3H),1.70(d,J＝12.0Hz,2H),1.38(s,1H),1.38(t,J＝11.6Hz,1H),1.06(t,J＝7.0Hz,3H),1.00(t,J＝7.0Hz,3H),0.94-0.90(m,8H),0.83(d,J＝6.8Hz,4H).¹³C NMR(100MHz,CDCl₃)δ172.4(d,J_C-F＝6.0Hz),170.0,140.9,138.5,133.5,129.9,128.4,128.1,127.5,126.5,75.5,63.7(d,J_C-F＝6.0Hz),63.3(d,J_C-F＝5.0Hz),61.6(d,J_C-F＝4.0Hz),47.4,40.8,35.1,34.4,31.5,25.8,23.2,22.1,21.5,21.0,16.0,15.8(d,J_C-F＝7.0Hz),15.7(d,J_C-F＝8.0Hz).³¹P NMR(162MHz,CDCl₃)δ1.34.HRMS(ESI)m/z calcd for C₃₁H₄₅NO₆P[M+H]⁺:558.2979,found 558.2984。

the product has the following structural formula:

example 23

In the reactor, 0.24 mmol of methyl benzoic acid and 1 ml of toluene are added, then 0.24 mmol of diethylphosphorous acid chloride and 0.24 mmol of triethylamine are added, after stirring at room temperature for 30 minutes, 0.2 mmol of L-phenylalanine cholesteryl ester-derived azide is added, after reaction at 50 ℃ for 4 hours, the reaction solution is directly subjected to an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 4 ta' a in 69% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.23-7.21(m,2H),7.19-7.17(m,3H),7.15-7.13(m,2H),7.03(d,J＝8.0Hz,2H),5.35(s,1H),4.92(td,J＝12.0,4.5Hz,1H),4.74-4.66(m,1H),3.96-3.85(m,2H),3.67-3.61(m,1H),3.53-3.48(m,1H),3.43-3.37(m,1H),3.32-3.23(m,1H),2.42-2.32(m,2H),2.29(s,3H),1.97-1.89(m,3H),1.84-1.75(m,2H),1.54-1.37(m,8H),1.32-1.19(m,4H),1.10-1.02(m,10H),0.99-0.96(m,8H),0.86(d,J＝6.5Hz,3H),0.80(dd,J＝6.5,1.3Hz,6H),0.62(s,3H).¹³C NMR(100MHz,CDCl₃)δ172.6(d,J_C-F＝6.0Hz),169.8,140.9,139.5,138.4,133.4,129.9,128.4,128.2,127.5,126.6,122.8,75.2,63.9(d,J_C-F＝6.0Hz),63.4(d,J_C-F＝6.0Hz),61.6,56.7,56.2,50.0,42.3,39.7,39.5,38.0,37.0,36.6,36.2,35.8,35.4,31.9,31.9,28.2,28.0,27.8,24.3,23.8,22.8,22.6,21.5,21.1,19.3,18.7,15.8(d,J_C-F＝7.0Hz),15.7(d,J_C-F＝7.0Hz),11.9.³¹P NMR(162MHz,CDCl₃)δ1.21.HRMS(ESI)m/z calcd for C₄₈H₇₁NO₆P[M+H]⁺:788.5014,found 788.5016。

the product has the following structural formula:

example 24

In the reactor, adding 0.24 mmol estriol acid and 1 ml toluene, then adding 0.24 mmol diethyl phosphorous acid chloride and 0.24 mmol triethylamine, stirring at room temperature for 30 minutes, adding 0.2 mmol L-phenylalanine methyl ester derived azide, at 50 ℃ after 4 hours reaction, the reaction liquid directly using eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give 6 aa' c, an N-acylphosphoramide compound, 69% yield, as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ4.12-4.02(m,4H),4.45(dd,J＝13.2,9.2Hz,1H),3.76(s,3H),7.52(d,J＝8.0Hz,2H),7.18(d,J＝7.6Hz,2H),2.43-2.39(m,4H),1.68-1.62(m,1H),1.24(t,J＝7.0Hz,3H),1.19(t,J＝7.4Hz,3H),1.16(d,J＝6.5Hz,3H),0.98-0.88(m,4H).¹³C NMR(100MHz,CDCl₃)δ220.6,172.8(d,J_C-F＝7.0Hz),171.0,142.8,138.1,135.8,133.5,129.9,128.4,128.4,126.7,125.0,124.6,64.0(d,J_C-F＝6.0Hz),63.5(d,J_C-F＝5.0Hz),61.4,52.5,50.5,47.9,44.4,37.8,35.8,35.2,31.5,29.2,26.3,25.5,21.6,15.9(d,J_C-F＝8.0Hz),15.8(d,J_C-F＝8.0Hz),13.8.³¹P NMR(162MHz,CDCl₃)δ2.04.HRMS(ESI)m/z calcd for C₃₃H₄₃NO₇P[M+H]⁺:596.2772,found 596.2775。

the product has the following structural formula:

example 25

In the reactor, adding 0.24 mmol febuxostat and 1 ml toluene, then adding 0.24 mmol diethyl phosphite chloride and 0.24 mmol triethylamine, stirring at room temperature for 30 minutes, adding 0.2 mmol L-phenylalanine methyl ester derived azide, at 50 ℃ after 4 hours reaction, the reaction liquid directly using eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give 6 aa'd N-acylphosphoramide compound in 80% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.07-8.05(m,1H),8.03(d,J＝2.3Hz,1H),7.37-7.33(m,2H),7.30-7.26(m,3H),7.01(d,J＝8.8Hz,1H),5.16-5.09(m,1H),4.13-4.05(m,2H),3.90(d,J＝6.4Hz,2H),3.85(s,3H),3.80-3.74(m,1H),3.61-3.51(m,2H),3.43-3.37(m,1H),2.36(s,3H),2.36-2.17(m,1H),4.45(td,J＝16.0,6.7Hz,3H),1.14-1.09(m,9H).¹³C NMR(100MHz,CDCl₃)δ170.5(d,J_C-F＝1.0Hz),165.0(d,J_C-F＝6.0Hz),165.0,162.2,156.6,137.7,132.4,131.8,129.7,128.7,126.9,125.9,124.0,115.5,112.7,102.8,75.7,64.6(d,J_C-F＝6.0Hz),64.0(d,J_C-F＝5.0Hz),61.7(d,J_C-F＝3.0Hz),52.6,35.2,28.2,19.1,16.7,16.0(d,J_C-F＝3.0Hz),15.9(d,J_C-F＝2.0Hz).³¹P NMR(162MHz,CDCl₃)δ0.37.HRMS(ESI)m/z calcd for C₃₀H₃₇N₃O₇PS[M+H]⁺:614.2084,found 614.2088。

the product has the following structural formula:

example 26

In the reactor, 0.24 mmol of indomethacin and 1 ml of toluene were added, and then 0.24 mmol of diethylphosphorylidene chloride and 0.24 mmol of triethylamine were added, and after stirring at room temperature for 30 minutes, the mixture was added0.2 mmol of L-phenylalanine methyl ester-derived azide at 50 ℃ for 4 hours, and then the reaction mixture was directly subjected to elution with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give 6 aa' e, an N-acylphosphoramide compound, 67% yield, as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.32-7.29(m,2H),7.24-7.21(m,3H),6.85-6.82(m,2H),6.66(dd,J＝8.8,2.4Hz,1H),5.18(td,J＝10.0,5.3Hz,1H),4.35-4.27(m,2H),3.83-3.79(m,5H),3.77-3.72(m,4H),3.49-3.40(m,2H),3.36-3.30(m,1H),2.33(s,3H),1.42(t,J＝7.2Hz,3H),1.18(t,J＝7.0Hz,3H).¹³C NMR(100MHz,CDCl₃)δ172.0(d,J_C-F＝8.0Hz),170.9(d,J_C-F＝3.0Hz),168.3,156.0,139.1,138.0,136.2,134.0,131.2,131.1,130.9,129.8,129.1,128.5,126.6,115.0,113.1,110.9,102.0,64.4(d,J_C-F＝5.0Hz),63.8(d,J_C-F＝5.0Hz),60.9(d,J_C-F＝4.0Hz),55.7,52.4,35.3,31.6,16.2(d,J_C-F＝8.0Hz),16.1(d,J_C-F＝8.0Hz),13.4.³¹P NMR(162MHz,CDCl₃)δ2.78.HRMS(ESI)m/z calcd for C₃₃H₃₇ClN₂O₈P[M+H]⁺:655.1971,found 655.1976。

the product has the following structural formula:

example 27

In the reactor, adding 0.24 mmol sulindac and 1 ml toluene, then adding 0.24 mmol diethyl phosphorous acid chloride and 0.24 mmol triethylamine, stirring at room temperature for 30 minutes, adding 0.2 mmol L-phenylalanine methyl ester derived azide, at 50 ℃ after 4 hours reaction, the reaction liquid directly using eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:2) was subjected to silica gel column chromatography to give 6 aa' f an N-acylphosphoramide compound in 73% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.72(d,J＝8.0Hz,2H),7.67(d,J＝8.4Hz,2H),7.32(t,J＝7.2Hz,2H),7.25-7.20(m,3H),7.15(t,J＝6.8Hz,2H),6.65(dd,J＝8.8,1.6Hz,1H),6.56(td,J＝8.7,1.9Hz,1H),5.19(td,J＝10.7,5.3Hz,1H),4.33-4.28(m,2H),3.84-3.69(m,6H),3.50-3.43(m,2H),3.41-3.34(m,1H),2.81(s,3H),2.15(s,3H),1.42(t,J＝7.0Hz,3H),1.17(t,J＝7.0Hz,3H).¹³C NMR(100MHz,CDCl₃)δ171.4(d,J_C-F＝8.0Hz),170.8(d,J_C-F＝3.0Hz),163.3(d,J_C-F＝244.0Hz),147.0(d,J_C-F＝8.0Hz),145.4,141.8,139.8,138.4,137.9,132.5(d,J_C-F＝2.0Hz),130.3,129.8,129.6(d,J_C-F＝2.0Hz),128.5,128.0,126.7,123.8,123.7(d,J_C-F＝9.0Hz),110.7(d,J_C-F＝23.0Hz),105.8(d,J_C-F＝24.0Hz),64.5(d,J_C-F＝6.0Hz),63.9(d,J_C-F＝5.0Hz),60.8,52.4,43.9,35.2,33.0,16.2(d,J_C-F＝8.0Hz),16.1(d,J_C-F＝8.0Hz),10.6.³¹P NMR(162MHz,CDCl₃)δ2.71.¹⁹F NMR(376MHz,CDCl₃)δ-113.31.HRMS(ESI)m/z calcd for C₃₄H₃₈FNO₇PS[M+H]⁺:654.2085,found 654.2090。

the product has the following structural formula:

example 28

In the reactor, adding 0.24 mmol vitamin A acid and 1 ml toluene, then adding 0.24 mmol diethyl phosphite chloride and 0.24 mmol triethylamine, stirring at room temperature for 30 minutes, adding 0.2 mmol L-phenylalanine methyl ester derived azide, at 50 degrees C reaction for 4 hours, the reaction liquid directly using eluent (V)_{Petroleum ether}:V_{Ethyl acetate}2:1) was subjected to silica gel column chromatography to give 6 aa' g of an N-acylphosphoramide compound in 81% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.28-7.16(m,5H),6.99(dd,J＝15.0,11.4Hz,1H),6.30-6.23(m,3H),6.16-6.11(m,2H),5.09(td,J＝10.5,5.1Hz,1H),4.19-4.12(m,2H),3.76(s,3H),3.59-3.51(m,2H),3.38-3.32(m,1H),3.20-3.14(m,1H),2.27(s,2H),2.06-2.01(m,5H),1.71(s,3H),1.65-1.59(m,2H),1.48-1.45(m,2H),1.26(t,J＝7.0Hz,3H),1.07-1.03(m,9H).¹³C NMR(100MHz,CDCl₃)δ171.4(d,J_C-F＝3.0Hz),167.9(d,J_C-F＝6.0Hz),151.3,139.6,138.3,137.7,137.3,135.4,131.0,130.1,129.8,129.5,128.7,128.4,126.4,120.5,63.8(d,J_C-F＝5.0Hz),63.1(d,J_C-F＝5.0Hz),60.5(d,J_C-F＝4.0Hz),52.3,39.6,35.4,34.3,33.1,29.0,21.8,19.2,16.0(d,J_C-F＝8.0Hz),16.0(d,J_C-F＝7.0Hz),14.6,12.9.³¹P NMR(162MHz,CDCl₃)δ2.22.HRMS(ESI)m/z calcd for C₃₄H₄₉NO₆P[M+H]⁺:598.3292,found 598.3296。

the product has the following structural formula:

example 29

In the reactor, 0.24 mmol 3- (cyclopropyl methoxy) -4- (difluoro methoxy) benzoic acid and 1 ml toluene, then 0.24 mmol diethyl phosphorous acid chloride and 0.24 mmol triethylamine were added, stirring was carried out at room temperature for 30 minutes, then 0.2 mmol 4-azido-3, 5-dichloropyridine was added, reaction was carried out at 50 ℃ for 4 hours, and the reaction solution was directly eluted with an eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give 6 ua' h, a 75% yield, a colorless oily liquid, an N-acylphosphoramide compound.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.51(s,2H),7.15(s,1H),7.11-7.09(m,1H),7.04-7.02(m,1H),6.63(t,J＝74.6Hz,1H),4.36-4.29(m,4H),3.79(d,J＝6.8Hz,2H),1.33(t,J＝7.0Hz,6H),1.27-1.20(m,1H),0.66-0.62(m,2H),0.35-0.33(m,2H).¹³CNMR(100MHz,CDCl₃)δ169.8,149.8,148.8,142.8(q,J_C-F＝3.0Hz),132.7,132.7,131.8,121.4,120.4,118.2,115.6,113.5,113.0,74.0,65.6,65.5,16.1,16.0,9.9,3.2.³¹P NMR(162MHz,CDCl₃)δ-4.42.¹⁹F NMR(376MHz,CDCl₃)δ-82.00.HRMS(ESI)m/z calcd for C₂₁H₂₄Cl₂F₂N₂O₆P[M+H]⁺:539.0712,found 539.0718。

the product has the following structural formula:

example 30

In the reactor, 0.24 mmol acetic acid and 1 ml toluene, then 0.24 mmol diethyl phosphorous acid chloride and 0.24 mmol triethylamine were added, stirred at room temperature for 30 minutes, then 0.2 mmol morpholine derived azide was added, after reaction at 50 ℃ for 4 hours, the reaction solution was directly used with eluent (V)_{Petroleum ether}:V_{Ethyl acetate}1:1) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 6 va' a in 47% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ7.43(dd,J＝14.4,2.4Hz,1H),7.12-7.10(m,1H),6.92(t,J＝9.0Hz,1H),4.92-4.85(m,1H),4.32-4.19(m,4H),4.07-3.99(m,2H),3.88-3.86(m,6H),3.69-3.66(m,1H),3.06-3.04(m,4H),2.40(s,3H),1.41-1.40(m,6H).¹³C NMR(100MHz,CDCl₃)δ172.9(d,J_C-F＝8.0Hz),155.5(d,J_C-F＝245.0Hz),154.0,136.4(d,J_C-F＝9.0Hz),133.3(d,J_C-F＝10.0Hz),118.8(d,J_C-F＝4.0Hz),113.9(d,J_C-F＝3.0Hz),107.5(d,J_C-F＝26.0Hz),70.5,67.0,64.7(d,J_C-F＝6.0Hz),64.2(d,J_C-F＝6.0Hz),51.0(d,J_C-F＝3.0Hz),48.5,48.3(d,J_C-F＝4.0Hz),24.5,16.1(d,J_C-F＝4.0Hz),16.0(d,J_C-F＝4.0Hz).³¹P NMR(162MHz,CDCl₃)δ2.45.¹⁹F NMR(376MHz,CDCl₃)δ-120.42.HRMS(ESI)m/z calcd for C₂₁H₃₁FN₂O₇P[M+H]⁺:473.1847,found 473.1849。

the product has the following structural formula:

example 31

In the reactor, 0.2 mmol of 3,3',3 "- ((((2, 4, 6-trimethylbenzene-1, 3, 5-triyl) tris (methylene)) tris (oxy)) tribenzoic acid and 1 ml of toluene were added, followed by 0.6 mmol of diphenylphosphoryl chloride and 0.72 mmol of triethylamine, and after stirring at room temperature for 10 minutes, 0.6 mmol of L-phenylalanine methyl ester-derived azide was added, and after 8 hours at 25 ℃, the reaction solution was reacted with an eluent (V) as it is_{Petroleum ether}:V_{Ethyl acetate}1:4) was subjected to silica gel column chromatography to give N-acylphosphoramide compound 6aai in 63% yield as a colorless oily liquid.

The product detection data are:¹H NMR(400MHz,CDCl₃)δ8.12(dd,J＝11.8,7.8Hz,6H),7.88(dd,J＝13.6,7.2Hz,6H),7.64-7.60(m,3H),7.54-7.50(m,6H),7.41-7.38(m,3H),7.35-7.31(m,6H),7.20-7.12(m,12H),7.00(d,J＝7.2Hz,3H),6.92(d,J＝6.8Hz,3H),6.81(s,3H),6.66(s,6H),4.95(q,J＝10.0Hz,6H),4.71(t,J＝11.4Hz,3H),3.93(s,9H),3.54(dd,J＝14.6,3.8Hz,3H),3.29(dd,J＝14.6,10.6Hz,3H),2.41(s,9H).¹³C NMR(100MHz,CDCl₃)δ174.3(d,J_C-F＝3.0Hz),171.1,158.5,139.4,137.2,136.4,133.6(d,J_C-F＝11.0Hz),132.8,132.0,131.8,131.7,131.5,129.5,129.1,128.6,128.4,128.3,128.2,126.7,120.3,118.6,112.7,65.0,62.7,52.9,36.6,16.0.³¹P NMR(162MHz,CDCl₃)δ30.99.HRMS(ESI)m/z calcd for C₉₉H₉₁N₃O₁₅P₃[M+H]⁺:1654.5658,found 1654.5661。

the product has the following structural formula:

finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.