WATER-SOLUBLE YNAMIDE COUPLING REAGENT AND PREPARATION METHOD AND USE THEREOF

Abstract

The present disclosure discloses a water-soluble ynamide coupling reagent and a method for using the water-soluble ynamide coupling reagent in the synthesis of amide, polypeptide, ester and thioester compound. The ynamide coupling reagent has the structure represented by the following formula (I):

##STR00001##

and in the formula (I), R is one selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups.

Claims

1. A water-soluble ynamide coupling reagent, wherein the ynamide coupling reagent has the structure represented by the following formula (I): ##STR00040## and in the formula (I), R is one selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups.

2. A method for preparing the water-soluble ynamide coupling reagent of claim 1, comprising: 1) mixing N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)amide having the structure represented by formula (II) and ethylene dichloride in solvent I to obtain a mixture; 2) adding an alkali into the mixture obtained in step 1), and subjecting the resultant to a reaction, and separating to obtain the water-soluble ynamide coupling reagent having the structure represented by formula (I); the specific reaction is performed as follows: ##STR00041## and wherein, R is one selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups.

3. The method of claim 2, wherein in step 1), the solvent I is an organic solvent; the solvent I is preferably at least one selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; a molar ratio of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)amide having the structure represented by formula (II) to ethylene dichloride is in a range of 1:(0.8-5), preferably 1:(1-3), and more preferably 1:(1.1-2); and/or in step 2), the alkali is at least one selected from the group consisting of NaH, CaH.sub.2, t-BuONa, KOH, NaOH, EtONa, EtOLi, Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, Ca(OH).sub.2, LiOH and DBU; the reaction is performed at a temperature of 15-100° C., preferably 20-90° C., and more preferably 25-80° C.; the reaction is performed for 0.2-48 h, preferably 0.5-36 h, and more preferably 1-24 h; the separating is performed by filtration, centrifugation or column chromatography; and a molar ratio of the alkali to N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl) amide having the structure represented by formula (II) is in a range of (1-10):1, preferably (2-8):1, and more preferably (3-6):1.

4. A method for using a water-soluble ynamide coupling reagent, wherein the water-soluble ynamide coupling reagent of claim 1 is used in the synthesis of amide, polypeptide, ester compound or thioester compound.

5. The method of claim 4, wherein the process of using the water-soluble ynamide coupling reagent to synthesize an ester compound or a thioester compound is performed as follows: 1a) subjecting a carboxylic acid compound and the water-soluble ynamide coupling reagent having the general molecular formula (I) to a reaction in solvent II to obtain a compound having the structure represented by formula (III); the specific reaction is performed as follow: ##STR00042## 2a) after the reaction in step 1a) completed, dissolving the compound having the structure represented by formula (III) obtained in solvent III, adding one selected from the group consisting of alcohol compound, phenol compound, thiol compound or thiophenol compound thereto, and adding a catalyst thereto, stirring for a reaction to obtain a mixture containing an ester compound or a thioester compound, and a by-product; the specific reaction is performed as follow: ##STR00043## 3a) after the reaction completed, adding a dilute acid aqueous solution into the mixture containing an ester compound or a thioester compound obtained in step 2a), hydrolyzing the unreacted coupling reagent and the by-product produced in the reaction, and separating to obtain the target ester compound or thioester compound; the reaction is performed as follow: ##STR00044## and in the formula, R.sup.1 is one selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic, heterocyclic aryl, protected α-aminoalkyl, protected β-aminoalkyl, protected polypeptide chain alkyl, and R is one selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups, and R.sup.2 is one selected from the group consisting of aliphatic substituent group and aromatic substituent group.

6. The method of claim 5, wherein in step 1a), the carboxylic acid compound is an organic acid formed by the association of a hydrocarbon group and a carboxyl group; the carboxylic acid compound is preferably at least one selected from the group consisting of fatty acid, aromatic acid, heterocyclic acid, acetylenic acid, olefine acid, α-amino acid, and β-amino acid, and the carboxylic acid compound is more preferably one selected from the group consisting of formic acid, acetic acid, phenylacetic acid, lithocholic acid and other aliphatic carboxylic acids, propioic acid, phenylpropioic acid, cinnamic acid, acrylic acid and other unsaturated acids, benzoic acid, p-toluic acid, p-chlorobenzoic acid, pyridine-2-formic acid, furan-2-formic acid and other aromatic acids, benzyloxycarbonyl-protected α-amino acid, tert-butoxycarbonyl-protected α-amino acid, fluorenylmethyloxycarbonyl-protected α-amino acid, acetyl-protected α-amino acid and polypeptide carboxylic acid; a molar ratio of the carboxylic acid compound to the water-soluble ynamide coupling reagent having the general molecular formula (I) is in a range of 1:(1-5), preferably 1:(1.1-4), and more preferably 1:(1.2-3); the solvent II is any one selected from the group consisting of dichloromethane, water, chloroform and 1,2-dichloroethane, or the solvent II is a mixture of water and dimethylsulfoxide, or a mixture of water and N,N-dimethylformamide; and/or in step 2a), the alcohol compound, the phenol compound, the thiol compound and the thiophenol compound are organic compounds with the functional group of —OH or —SH; the alcohol compound, the phenol compound, the thiol compound and the thiophenol compound are preferably organic compounds with the functional group of —OH or —SH in aliphatic alcohol and aromatic alcohol; the alcohol compound, the phenol compound, the thiol compound and the thiophenol compound are more preferably any one selected from the group consisting of ethanol, trifluoroethanol, propanol, butanol, isopropyl alcohol and other aliphatic primary and secondary alcohols, phenol, estrone, p-methoxyphenol, p-chlorophenol, p-nitrophenol and other substituted phenols, ethanethiol, 1-hexanethiol, cyclohexanethiol, 2-methyl-2-propanethiol and other aliphatic thiols, 4-mercaptobenzoic acid, p-methylthiophenol, p-chlorothiophenol, p-bromothiophenol and other substituted thiophenols, amino-protected cysteine esters and sulfhydryl group of polypeptide side chain; a molar ratio of the alcohol compound, the phenol compound, the thiol compound and the thiophenol compound to the carboxylic acid compound is in a range of 1:(1-20), preferably 1:(1.5-15), and more preferably 1:(2-10); the solvent III is at least one selected from the group consisting of water, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, a mixture of acetonitrile and water, a mixture of water and dimethylsulfoxide, a mixture of water and N,N-dimethylformamide; the catalyst is triethylamine or N,N-diisopropylethylamine; a molar ratio of the catalyst to the carboxylic acid compound is in a range of (0.01-10):1, preferably (0.02-5):1, and more preferably (0.03-1):1; and/or in step 3a), the dilute acid is one selected from the group consisting of dilute sulfuric acid, dilute hydrochloric acid, phosphoric acid, acetic acid and citric acid; and the concentration of the dilute acid is in a range of 0.01-5 mol/L, preferably 0.5-2 mol/L, and more preferably 0.1-1 mol/L.

7. The method of claim 5, wherein the step 1a) is performed as follows: adding a carboxylic acid compound, the water-soluble ynamide coupling reagent having the general molecular formula (I) and solvent II into a reactor for mixing, and stirring for a reaction at a temperature of 0-60° C. (preferably 5-50° C.), after the reaction completed, removing the solvent II to obtain a compound having the structure represented by formula (III); and/or the step 2a) is performed as follows: after the reaction in step 1a) completed, dissolving the compound having the structure represented by formula (III) obtained in step 1a) into solvent III, adding one selected from the group consisting of alcohol compound, phenol compound, thiol compound and thiophenol compound thereto, and then adding a catalyst thereto, and stirring, and then stirring for a reaction at a temperature of 0-60° C. (preferably 5-50° C.) to obtain a mixture containing an ester compound or a thioester compound; and/or the step 3a) is performed as follows: optionally adding a diluent into the mixture containing an ester compound or a thioester compound obtained in step 2a) for dilution (preferably, the diluent is dichloromethane or ethyl acetate), and then adding a diluted acid aqueous solution for washing, hydrolyzing the unreacted coupling reagent and the by-product produced in the reaction to precipitate a product, filtering the product, and washing with water to obtain the target ester compound or thioester compound.

8. The method of claim 4, wherein the process of using the water-soluble ynamide coupling reagent to synthesize an amide compound or a polypeptide compound is performed as follows: 1b) subjecting a carboxylic acid compound and the water-soluble ynamide coupling reagent having the general molecular formula (I) to a reaction in solvent II to obtain a compound having the structure represented by the formula (IV); the specific reaction is performed as follow: ##STR00045## 2b) after the reaction in step 1b) completed, adding an amine compound into the obtained compound having the structure represented by formula (IV), and stirring for a reaction to obtain a mixture containing an amide compound or a polypeptide compound and a by-product; the specific reaction is performed as follow: ##STR00046## 3b) adding a diluent and a diluted acid aqueous solution into the mixture containing an amide compound or a polypeptide compound and a by-product obtained in step 2b), hydrolyzing the unreacted coupling reagent and the by-product produced in the reaction, and separating to obtain the target amide compound or polypeptide compound; the reaction is performed as follow: ##STR00047## and in the formula, R.sup.1 is one selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic, heterocyclic aryl, protected α-aminoalkyl, protected β-aminoalkyl and protected polypeptide chain alkyl; R is one selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups; R.sup.3 and R.sup.4 are one selected from the group consisting of selected from aliphatic substituent group and aromatic substituent group.

9. The method of claim 8, wherein in step 1b), the carboxylic acid compound is an organic acid formed by the association of a hydrocarbon group and a carboxyl group; the carboxylic acid compound is preferably any one selected from the group consisting of fatty acid, aromatic acid, heterocyclic acid, acetylenic acid, olefine acid, α-amino acid, β-amino acid; and the carboxylic acid compound is more preferably one selected from the group consisting of formic acid, acetic acid, phenylacetic acid, lithocholic acid and other aliphatic carboxylic acids, propiolic acid, phenylpropynic acid, cinnamic acid, acrylic acid and other unsaturated acids, benzoic acid, p-toluic acid, p-chlorobenzoic acid, pyridine-2-formic acid, furan-2-formic acid and other aromatic acids, benzyloxycarbonyl-protected α-amino acid, tert-butoxycarbonyl-protected α-amino acid, fluorenylmethyloxycarbonyl-protected α-amino acid, acetyl-protected α-amino acid and polypeptide carboxylic acid; a molar ratio of the carboxylic acid compound to the water-soluble ynamide coupling reagent having the general molecular formula (I) is in a range of 1:(1-5), preferably 1:(1.1-4), and more preferably 1:(1.2-3); the solvent II is an organic solvent; the solvent II is preferably any one selected from the group consisting of dichloromethane, water, chloroform, 1,2-dichloroethane, or the solvent II is a mixture of water and dimethylsulfoxide, or a mixture of water and N,N-dimethylformamide; and/or in step 2b), the amine compound is a primary amine or a secondary amine, and the amine compound is preferably any one selected from the group consisting of primary aliphatic amine, secondary aliphatic amine, aromatic amine, α-amino acid methyl ester, α-amino acid ethyl ester, α-amino acid tert-butyl ester, α-amino acid benzyl ester, β-amino acid methyl ester, β-amino acid ethyl ester, β-amino acid tert-butyl ester and β-amino acid benzyl ester; a molar ratio of the carboxylic acid compound to the amine compound is in a range of 1:(1-5), preferably 1:(1.1-4), and more preferably 1:(1.2-3); and/or in step 3b), the dilute acid is any one selected from the group consisting of dilute sulfuric acid, dilute hydrochloric acid, phosphoric acid, acetic acid and citric acid; a concentration of the dilute acid is in a range of 0.01-5 mol/L, preferably 0.5-2 mol/L, and more preferably 0.1-1 mol/L.

10. The method of claim 8, wherein the step 1b) is performed as follows: adding a carboxylic acid compound, the water-soluble ynamide coupling reagent having the general molecular formula (I) and solvent II into a reactor for mixing, and stirring for a reaction at a temperature of 0-60° C. (preferably 5-50° C.) to obtain a compound having a structure represented by formula (IV); and/or the step 2b) is performed as follows: after the reaction in step 1b) completed, adding an amine compound into the compound having the structure represented by formula (IV) obtained in step 1b), and then stirring for a reaction at a temperature of 0-60° C. (preferably 5-50° C.) to obtain a mixture containing an amide compound or a polypeptide compound and a by-product; and/or the step 3b) is performed as follows: adding a diluent (the diluent preferably is dichloromethane or ethyl acetate) into the mixture containing an amide compound or a polypeptide compound obtained in step 2b); and then adding a dilute acid aqueous solution for washing, hydrolyzing the unreacted coupling reagent and the by-product obtained in the reaction to precipitate a product, filtering the product, and washing with water to obtain the target amide compound or polypeptide compound; or the step 3b) is performed as follows: removing the solvent in the mixture containing an amide compound or a polypeptide compound obtained in step 2b), adding solvent IV (the solvent IV preferably is one selected from the group consisting of methanol, ethanol, isopropanol and acetonitrile), and then adding a dilute acid for washing, hydrolyzing the unreacted coupling reagent and the by-product obtained in the reaction to precipitate a product, filtering the product, and washing with water to obtain the target amide compound or polypeptide compound.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0077] The technical solutions of the present disclosure will be illustrated below with reference to the examples, and the protection scope of the present disclosure includes, but is not limited to the following examples.

Preparation Example 1

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)methanesulfonamide

[0078] Under ice bath conditions, 5 mmol of (2,2-dimethyl[1,3]-dioxolane-4-yl)-methylamine and 15 mmol of triethylamine were mixed in a dichloromethane solution, and stirred, and then 5 mol of methylsulfonyl chloride was slowly dropwise added thereto for a reaction. The reaction was detected by TCL. After the reaction completed, water was added into the reaction product, obtaining an aqueous phase and an organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phase was combined, and washed once with saturated brine, and separated, obtaining a separated organic phase. The separated organic phase was dried with anhydrous sodium sulfate and concentrated, obtaining N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)methanesulfonamide. The product is a light yellow liquid with a yield of 98%. The structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00010##

[0079] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.73 (s, 1H), 4.28 (qd, J=6.3, 3.9 Hz, 1H), 4.07 (dd, J=8.5, 6.5 Hz, 1H), 3.75 (dd, J=8.5, 6.0 Hz, 1H), 3.34 (ddd, J=13.3, 6.7, 3.8 Hz, 1H), 3.23-3.16 (m, 1H), 3.00 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H).

[0080] .sup.13C NMR (100 MHz, CDCl.sub.3) δ=109.9, 74.5, 66.6, 45.6, 40.7, 26.9, 25.3.

[0081] HRMS (ESI) m/z calcd. for C.sub.7H.sub.16NO.sub.4S [M+H].sup.+: 210.0795, found: 210.0800.

Preparation Example 2

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)benzenesulfonamide

[0082] Under ice bath conditions, 5 mmol of (2,2-dimethyl[1,3]-dioxolane-4-yl)-methylamine and 15 mmol of triethylamine were mixed in a dichloromethane solution, and stirred, and then 5 mol of benzenesulfonyl chloride was slowly dropwise added thereto for a reaction. The reaction was detected by TCL. After the reaction completed, water was added into the reaction product, obtaining an aqueous phase and an organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phase was combined, and washed once with saturated brine, and separated, obtaining a separated organic phase. The separated organic phase was dried with anhydrous sodium sulfate and concentrated, obtaining N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)benzenesulfonamide. The product is a white solid with a yield of 95%. The structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00011##

[0083] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90-7.83 (m, 2H), 7.80 (s, 1H), 7.66-7.56 (m, 3H), 4.05 (p, J=7.0 Hz, 1H), 3.96 (dd, J=11.4, 7.0 Hz, 1H), 3.71 (dd, J=11.4, 6.9 Hz, 1H), 3.59 (dd, J=12.4, 7.0 Hz, 1H), 3.39 (dd, J=12.4, 7.0 Hz, 1H), 1.39 (s, 3H), 1.34 (s, 3H).

[0084] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 140.0, 133.8, 129.5, 128.2, 109.4, 74.6, 67.0, 46.7, 25.5.

[0085] HRMS (ESI) m/z calcd. for C.sub.12H.sub.18NO.sub.4S [M+H].sup.+: 272.0951, found: 272.0959.

Preparation Example 3

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)p-toluenesulfonamide in the present disclosure

[0086] Under ice bath conditions, 5 mmol of (2,2-dimethyl-[1,3]-dioxolane-4-yl)-methylamine and 15 mmol of triethylamine were mixed in a dichloromethane solution, and stirred, and then 5 mol of p-toluenesulfonyl chloride was slowly dropwise added thereto for a reaction. The reaction was detected by TCL. After the reaction completed, water was added into the reaction product, obtaining an aqueous phase and an organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phase was combined, and washed once with saturated brine, and separated, obtaining a separated organic phase. The separated organic phase was dried with anhydrous sodium sulfate and concentrated, obtaining N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)p-toluenesulfonamide. The product is a white solid with a yield of 97%. The structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00012##

[0087] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.94-4.77 (m, 1H), 4.22-4.14 (m, 1H), 3.99 (dd, J=8.4, 6.4 Hz, 1H), 3.68 (dd, J=8.5, 6.0 Hz, 1H), 3.13 (dddd, J=12.8, 7.0, 4.1, 1.6 Hz, 1H), 3.00-2.93 (m, 1H), 2.43 (s, 3H), 1.35 (s, 3H), 1.30 (s, 3H).

[0088] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 143.7, 136.9, 129.9, 127.2, 109.8, 74.1, 66.7, 45.4, 26.9, 25.3, 21.6.

[0089] HRMS (ESI) m/z calcd. for C.sub.13H.sub.20NO.sub.4S [M+H].sup.+: 286.1108, found: 286.1113.

Preparation Example 4

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)trifluoroacetamide in the present disclosure

[0090] Under ice bath conditions, 5 mmol of (2,2-dimethyl-[1,3]-dioxolane-4-yl)-methylamine and 15 mmol of triethylamine were mixed in a dichloromethane solution, and stirred, and then 5 mol of trifluoroacetyl chloride was slowly dropwise added thereto for a reaction. The reaction was detected by TCL. After the reaction completed, water was added into the reaction product, obtaining an aqueous phase and an organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phase was combined, and washed once with saturated brine, and separated, obtaining a separated organic phase. The separated organic phase was dried with anhydrous sodium sulfate and concentrated, obtaining N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)trifluoroacetamide. The product is a light yellow liquid with a yield of 92%. The structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00013##

[0091] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.69 (s, 1H), 4.52 (p, J=7.0 Hz, 1H), 3.96 (dd, J=11.4, 7.0 Hz, 1H), 3.80 (dd, J=12.4, 7.1 Hz, 1H), 3.71 (dd, J=11.5, 7.0 Hz, 1H), 3.46 (dd, J=12.4, 7.0 Hz, 1H), 1.39 (s, 3H), 1.34 (s, 3H).

[0092] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 159.2, 159.0, 158.7, 158.5, 118.7, 116.5, 114.4, 112.2, 109.4, 74.6, 67.0, 43.1, 43.1, 43.1, 25.5.

[0093] HRMS (ESI) m/z calcd. for C.sub.8H.sub.13F.sub.3NO.sub.3 [M+H].sup.+: 228.0842, found: 228.088.

Preparation Example 5

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide

[0094] N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)methanesulfonamide and 3 times the amount of 1,1-dichloroethylene were mixed in an organic solvent, and an alkali equal to times the molar amount of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)methanesulfonamide was added thereto for a reaction at a temperature of 70° C. The reaction was detected by TLC. After the reaction completed, ice water was added into the reaction solution, The resulting reaction solution was extracted three times with ethyl acetate, obtaining an organic layer. The organic layer was concentrated, and separated by column chromatography, obtaining the pure N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide. The product is a white solid with a yield of 95%. The following are the structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00014##

[0095] .sup.1H NMR (400 MHz, DMSO) δ 4.33 (ddd, J=12.2, 6.8, 5.0 Hz, 1H), 4.05 (dd, J=8.7, 6.4 Hz, 1H), 3.86 (s, 1H), 3.73 (dd, J=8.7, 5.1 Hz, 1H), 3.49 (qd, J=14.1, 6.1 Hz, 2H), 3.25 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H).

[0096] .sup.13C NMR (100 MHz, DMSO) δ 109.1, 75.9, 72.7, 66.0, 61.3, 53.5, 37.9, 26.6, 25.2.

[0097] HRMS (ESI) m/z calcd. for C.sub.9H.sub.16NO.sub.4S [M+H].sup.+:234.0795, found: 234.0797.

Preparation Example 6

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide

[0098] N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)benzenesulfonamide and 3 times the amount of 1,1-dichloroethylene were mixed in an organic solvent, and an alkali equal to times the molar amount of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)benzenesulfonamide was added thereto for a reaction at a temperature of 70° C. The reaction was detected by TLC. After the reaction completed, ice water was added into the reaction solution, The resulting reaction solution was extracted three times with ethyl acetate, obtaining an organic layer. The organic layer was concentrated, and separated by column chromatography, obtaining the pure N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide. The product is a white solid with a yield of 94%. The following are the structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00015##

[0099] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.86 (d, J=7.6 Hz, 2H), 7.62 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.4 Hz, 2H), 4.41-4.30 (m, 1H), 4.10 (dd, J=8.8, 6.1 Hz, 1H), 3.89 (dd, J=8.8, 5.2 Hz, 1H), 3.53 (dd, J=13.4, 5.4 Hz, 1H), 3.30 (dd, J=13.4, 7.2 Hz, 1H), 2.73 (s, 1H), 2.44 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

[0100] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 138.1, 133.8, 129.1, 127.9, 109.9, 76.4, 73.5, 67.4, 59.2, 53.7, 27.0, 25.4.

[0101] HRMS (ESI) m/z calcd. for C.sub.14H.sub.17NNaO.sub.4S [M+H].sup.+: 318.0770, found: 318.0778.

Preparation Example 7

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide

[0102] N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl) p-toluenesulfonamide and 3 times the amount of 1,1-dichloroethylene were mixed in an organic solvent, and an alkali equal to times the molar amount of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)p-toluenesulfonamide was added thereto for a reaction at a temperature of 70° C. The reaction was detected by TLC. After the reaction completed, ice water was added into the reaction solution, The resulting reaction solution was extracted three times with ethyl acetate, obtaining an organic layer. The organic layer was concentrated, and separated by column chromatography, obtaining the pure N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide. The product is a white solid with a yield of 93%. The following are the structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00016##

[0103] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.40-4.31 (m, 1H), 4.09 (dd, J=8.8, 6.1 Hz, 1H), 3.87 (dd, J=8.8, 5.2 Hz, 1H), 3.51 (dd, J=13.4, 5.4 Hz, 1H), 3.32 (dd, J=13.4, 7.2 Hz, 1H), 2.75 (s, 1H), 2.46 (s, 3H), 1.41 (s, 3H), 1.33 (s, 3H).

[0104] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 145.1, 134.4, 130.0, 127.9, 109.9, 76.4, 73.5, 67.4, 59.2, 53.7, 27.0, 25.4, 21.8.

[0105] HRMS (ESI) m/z calcd. for C.sub.15H.sub.20NO.sub.4S [M+H].sup.+: 310.1108, found: 310.1116.

Preparation Example 8

Preparation of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide

[0106] N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl) p-toluenesulfonamide and 3 times the amount of 1,1-dichloroethylene were mixed in an organic solvent, and an alkali equal to times the molar amount of N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)trifluoroacetamide was added thereto for a reaction at a temperature of 70° C. The reaction was detected by TLC. After the reaction completed, ice water was added into the reaction solution, The resulting reaction solution was extracted three times with ethyl acetate, obtaining an organic layer. The organic layer was concentrated, and separated by column chromatography, obtaining the pure N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide. The product is a light yellow liquid with a yield of 90%. The following are the structural formula, and the experimental data of NMR and mass spectrometry of the product are shown as follows:

##STR00017##

[0107] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.52 (p, J=7.0 Hz, 1H), 3.96 (dd, J=11.4, 7.0 Hz, 1H), 3.71 (dd, J=11.5, 7.0 Hz, 1H), 3.44 (dd, J=12.4, 7.0 Hz, 1H), 3.19 (dd, J=12.4, 7.0 Hz, 1H), 2.45 (s, 1H), 1.39 (s, 3H), 1.34 (s, 3H).

[0108] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 160.98, 160.72, 160.47, 160.21, 117.71, 115.57, 113.43, 111.29, 109.38, 77.87, 77.84, 77.81, 77.78, 74.09, 66.98, 57.51, 45.46, 45.45, 45.43, 25.55.

[0109] HRMS (ESI) m/z calcd. for C.sub.10H.sub.12F.sub.3NNaO.sub.3 [M+H].sup.+: 274.0661, found: 274.0657.

Application Example 1

[0110] Phenylpropionic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After phenylpropynic acid consumed completely, 2-hydroxyethylamine (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 90%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00018##

[0111] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.51 (d, J=7.0 Hz, 2H), 7.39 (d, J=7.3 Hz, 1H), 7.33 (t, J=7.4 Hz, 2H), 6.83 (t, J=5.9 Hz, 1H), 3.80-3.75 (m, 2H), 3.52 (q, J=5.4 Hz, 2H).

[0112] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 154.5, 132.6, 130.3, 128.6, 120.2, 85.6, 82.9, 61.5, 42.7.

[0113] HRMS (ESI) m/z calcd. for C.sub.12H.sub.12O.sub.2 [M+H].sup.+:190.0868, found: 190.0867.

Application Example 2

[0114] Phenylpropionic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, piperidine (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 96%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00019##

[0115] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54 (d, J=8.1 Hz, 2H), 7.43-7.33 (m, 3H), 3.80-3.75 (m, 2H), 3.65-3.59 (m, 2H), 1.71-1.64 (m, 4H), 1.62-1.56 (m, 2H).

[0116] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 153.05, 132.41, 129.95, 128.57, 120.85, 90.37, 81.59, 48.33, 42.49, 26.56, 25.50, 24.65.

[0117] HRMS (ESI) m/z calcd. for C.sub.14H.sub.16NO [M+H].sup.+: 214.1226, found: 214.1230.

Application Example 3

[0118] Methyl benzoic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, tetrahydropyrrole (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, the resulting reaction solution was subjected to a reduced pressure distillation to remove the solvent, a small amount of ethanol and 10 mL of 0.5 M dilute hydrochloric acid were added thereto, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 96%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00020##

[0119] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42 (d, J=8.0 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 3.64 (t, J=6.7 Hz, 2H), 3.44 (t, J=6.3 Hz, 2H), 2.37 (s, 3H), 1.94 (q, J=6.2 Hz, 2H), 1.87 (q, J=6.1 Hz, 2H).

[0120] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 169.95, 139.98, 134.40, 128.90, 127.30, 49.75, 46.30, 26.51, 24.55, 21.46.

[0121] HRMS (ESI) m/z calcd. for C.sub.12H.sub.16NO [M+H].sup.+: 190.1226, found: 190.1225.

Application Example 4

[0122] Fmoc-Ala-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 5 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, H-Phe-OtBu (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.2 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and concentrated and then recrystallized with dichloromethane/petroleum ether, obtaining a pure product. The product is a white solid with a yield of 87%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00021##

[0123] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=7.5 Hz, 2H), 7.58 (d, J=7.0 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.29 (t, J=7.4 Hz, 2H), 7.24-7.10 (m, 5H), 6.69-6.48 (m, 1H), 5.60-5.40 (m, 1H), 4.73 (q, J=6.1 Hz, 1H), 4.39 (dd, J=10.3, 7.3 Hz, 1H), 4.36-4.22 (m, 2H), 4.19 (t, J=7.0 Hz, 1H), 3.08 (h, J=8.0, 7.2 Hz, 2H), 1.38 (s, 9H), 1.35 (s, 3H).

[0124] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 171.84, 170.35, 155.94, 143.92, 141.37, 136.09, 129.56, 128.44, 127.80, 127.16, 127.05, 125.17, 120.06, 82.51, 67.20, 53.74, 50.51, 47.21, 38.07, 28.02, 18.87.

[0125] HRMS (ESI) m/z calcd. for C.sub.31H.sub.35N.sub.2O.sub.5[M+H].sup.+: 515.2540, found: 515.2547. dr>99:1.

Application Example 5

[0126] Fmoc-Aib-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 5 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, H-Ala-OtBu (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, the resulting reaction solution was subjected to a reduced pressure distillation to remove the solvent, and a small amount of ethanol and 20 mL of 0.2 M dilute hydrochloric acid were added thereto, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 85%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00022##

[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=7.5 Hz, 2H), 7.61-7.57 (m, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 6.74 (s, 1H), 5.52 (s, 1H), 4.45-4.35 (m, 3H), 4.20 (t, J=6.7 Hz, 1H), 1.53 (s, 6H), 1.44 (s, 9H), 1.35 (d, J=6.9 Hz, 3H).

[0128] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 173.82, 172.23, 155.11, 144.00, 143.96, 141.42, 127.78, 127.17, 125.15, 125.12, 120.06, 82.13, 66.72, 56.84, 49.02, 47.33, 28.06, 25.71, 25.27, 18.54.

[0129] HRMS (ESI) m/z calcd. for C.sub.26H.sub.33N.sub.2O.sub.5[M+H].sup.+: 453,2384, found: 453.2380.

Application Example 6

[0130] Phenylpropionic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and 2-naphthol (0.55 mmol) and triethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 10 mL of 0.5 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 96%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00023##

[0131] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (dd, J=20.9, 9.9 Hz, 3H), 7.70-7.58 (m, 3H), 7.48 (dt, J=14.2, 7.4 Hz, 3H), 7.38 (t, J=7.5 Hz, 2H), 7.32 (d, J=8.8 Hz, 1H).

[0132] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 152.57, 147.92, 133.81, 133.31, 131.81, 131.17, 129.74, 128.79, 127.92, 127.89, 126.86, 126.14, 120.84, 119.39, 118.74, 88.95, 80.46.

[0133] HRMS (ESI) m/z calcd. for C.sub.19H.sub.13O.sub.2[M+H].sup.+: 273.0910, found: 273.0915.

Application Example 7

[0134] Quinoline-2-formic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and n-propanol (2.5 mmol) and triethylamine (0.2 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a light yellow solid with a yield of 93%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00024##

[0135] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.31 (dd, J=10.3, 8.9 Hz, 2H), 8.17 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.64 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 4.46 (t, J=6.9 Hz, 2H), 1.94-1.86 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

[0136] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 165.52, 148.40, 147.77, 137.28, 130.92, 130.27, 129.38, 128.61, 127.59, 121.10, 67.78, 22.21, 10.49.

[0137] HRMS (ESI) m/z calcd. for C.sub.13H.sub.14NO.sub.2[M+H].sup.+: 216.1019, found: 216.1024.

Application Example 8

[0138] Cbz-Phe-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and 4-methoxyphenol (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. 10 mL of 0.5 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 94%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00025##

[0139] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.33-7.19 (m, 10H), 6.91-6.81 (m, 4H), 5.38 (s, 1H), 5.11 (s, 2H), 4.87 (q, J=5.7 Hz, 1H), 3.76 (s, 3H), 3.23 (d, J=5.7 Hz, 2H).

[0140] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 170.63, 157.55, 155.78, 143.85, 136.28, 135.61, 129.53, 128.81, 128.62, 128.29, 128.18, 127.40, 122.08, 114.56, 67.16, 55.65, 55.08, 38.37.

[0141] HRMS (ESI) m/z calcd. for C.sub.24H.sub.24NO.sub.5[M+H].sup.+: 406.1649, found: 406.1653. ee>99%.

Application Example 9

[0142] P-nitrobenzoic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and benzyl mercaptan (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. 10 mL of 0.5 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 90%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00026##

[0143] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (d, J=8.9 Hz, 2H), 8.10 (d, J=8.9 Hz, 2H), 7.32 (ddt, J=22.8, 14.6, 7.4 Hz, 5H), 4.36 (s, 2H).

[0144] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 189.89, 150.69, 141.52, 136.72, 129.12, 128.91, 128.42, 127.79, 124.01, 34.02.

[0145] HRMS (ESI) m/z calcd. for C.sub.14H.sub.12NO.sub.3S[M+H].sup.+: 274.0532, found: 274.0538.

Application Example 10

[0146] Boc-Ala-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl methanesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and 2-naphthylthiophenol (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 20 mL of 0.2 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 94%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00027##

[0147] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.87-7.79 (m, 3H), 7.54-7.47 (m, 2H), 7.43 (d, J=8.3 Hz, 1H), 5.10 (s, 1H), 4.65-4.43 (m, 1H), 1.50 (s, 9H), 1.46 (d, J=7.2 Hz, 3H).

[0148] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 200.34, 155.08, 134.70, 133.70, 133.48, 131.10, 128.91, 128.04, 127.90, 127.25, 126.66, 124.75, 80.56, 56.47, 28.52, 18.83.

[0149] HRMS (ESI) m/z calcd. for C.sub.18H.sub.22NO.sub.3S[M+H].sup.+: 332.1315, found: 332.1319. ee>99%.

Application Example 11

[0150] 4-nitrobenzoic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and trifluoroethanol (0.55 mmol) and triethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 95%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00028##

[0151] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34 (d, J=6.9 Hz, 2H), 8.26 (d, J=9.0 Hz, 2H), 4.76 (q, J=8.3 Hz, 2H).

[0152] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.29, 151.25, 133.82, 131.32, 123.91, 62.10, 61.73, 61.36, 60.99.

[0153] HRMS (ESI) m/z calcd. for C.sub.9H.sub.6F.sub.3NNaO.sub.4 [M+Na].sup.+: 272.0141, found: 272.0135.

Application Example 12

[0154] Boc-Ala-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and 2-naphthylthiophenol (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 20 mL of 0.2 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 94%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00029##

[0155] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.87-7.79 (m, 3H), 7.54-7.47 (m, 2H), 7.43 (d, J=8.3 Hz, 1H), 5.10 (s, 1H), 4.65-4.43 (m, 1H), 1.50 (s, 9H), 1.46 (d, J=7.2 Hz, 3H).

[0156] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 200.34, 155.08, 134.70, 133.70, 133.48, 131.10, 128.91, 128.04, 127.90, 127.25, 126.66, 124.75, 80.56, 56.47, 28.52, 18.83.

[0157] HRMS (ESI) m/z calcd. for C.sub.18H.sub.22NO.sub.3S[M+H].sup.+: 332.1315, found: 332.1319. ee>99%.

Application Example 13

[0158] Pyridine-2-formic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and tert-butylamine (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 97%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00030##

[0159] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=4.7 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.83 (td, J=7.7, 1.5 Hz, 1H), 7.40 (dd, J=7.5, 4.8 Hz, 1H), 1.50 (s, 9H).

[0160] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.56, 150.95, 147.87, 137.48, 125.96, 121.84, 51.05, 28.91.

[0161] HRMS (ESI) m/z calcd. for C10H14N2NaO [M+Na].sup.+: 201.0998, found: 201.1005.

Application Example 14

[0162] Cbz-Ala-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl benzenesulfonamide (0.55 mmol) were dissolved in 5 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, H-Phe-OtBu (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed three times with 15 mL of 0.2 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, concentrated, and then recrystallized with dichloromethane/petroleum ether, obtaining a pure product. The product is a white solid with a yield of 93%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00031##

[0163] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.28 (m, 5H), 7.26-7.19 (m, 3H), 7.13 (d, J=6.8 Hz, 2H), 6.69-6.45 (m, 1H), 5.51-5.34 (m, 1H), 5.10 (t, J=9.4 Hz, 2H), 4.72 (q, J=6.2 Hz, 1H), 4.34-4.16 (m, 1H), 3.11-3.03 (m, 2H), 1.40 (s, 9H), 1.33 (d, J=6.8 Hz, 3H).

[0164] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 171.82, 170.36, 155.93, 136.35, 136.14, 129.60, 128.61, 128.45, 128.25, 128.12, 127.05, 82.52, 67.07, 53.72, 50.56, 38.06, 28.04, 18.69.

[0165] HRMS (ESI) m/z calcd. for C.sub.24H.sub.31N.sub.2O.sub.5 [M+H].sup.+: 427.2227, found: 427.2235. dr>99:1.

Application Example 15

[0166] Quinoline-2-formic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and n-propanol (2.5 mmol) and triethylamine (0.2 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a light yellow solid with a yield of 91%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00032##

[0167] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.31 (dd, J=10.3, 8.9 Hz, 2H), 8.17 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.64 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 4.46 (t, J=6.9 Hz, 2H), 1.94-1.86 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

[0168] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 165.52, 148.40, 147.77, 137.28, 130.92, 130.27, 129.38, 128.61, 127.59, 121.10, 67.78, 22.21, 10.49.

[0169] HRMS (ESI) m/z calcd. for C.sub.13H.sub.14NO.sub.2[M+H].sup.+: 216.1019, found: 216.1024.

Application Example 16

[0170] P-nitrobenzoic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and benzyl mercaptan (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 10 mL of 0.5 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 88%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00033##

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (d, J=8.9 Hz, 2H), 8.10 (d, J=8.9 Hz, 2H), 7.32 (ddt, J=22.8, 14.6, 7.4 Hz, 5H), 4.36 (s, 2H).

[0172] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 189.89, 150.69, 141.52, 136.72, 129.12, 128.91, 128.42, 127.79, 124.01, 34.02.

[0173] HRMS (ESI) m/z calcd. for C.sub.14H.sub.12NO.sub.3S[M+H].sup.+: 274.0532, found: 274.0538.

Application Example 17

[0174] Benzothiophene-2-formic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the phenylpropiolic acid consumed completely, 2-hydroxyethylamine (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 94%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00034##

[0175] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (dd, J=5.9, 3.2 Hz, 1H), 7.80 (dd, J=5.9, 3.2 Hz, 1H), 7.44 (s, 1H), 7.38 (dt, J=6.0, 3.5 Hz, 2H), 3.71-3.64 (m, 4H), 1.73-1.62 (m, 6H).

[0176] .sup.13C NMR (100 MHz, CDCl.sub.3) δ=163.8, 140.2, 138.8, 137.4, 125.6, 124.8, 124.7, 124.6, 122.4, 26.3, 24.7.

[0177] HRMS (ESI) m/z calcd. for C.sub.14H.sub.16NOS [M+H].sup.+: 246.0947, found: 246.0953.

Application Example 18

[0178] Boc-Ala-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl p-toluenesulfonamide (0.55 mmol) were dissolved in 5 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, H-Phe-OtBu (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed three times with 15 mL of 0.2 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, concentrated, and then recrystallized with dichloromethane/petroleum ether, obtaining a pure product. The product is a white solid with a yield of 97%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00035##

[0179] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25 (dt, J=13.1, 6.8 Hz, 3H), 7.15 (d, J=6.8 Hz, 2H), 6.60 (s, 1H), 5.05 (s, 1H), 4.71 (q, J=6.2 Hz, 1H), 4.15 (s, 1H), 3.13-3.04 (m, 2H), 1.43 (s, 9H), 1.39 (s, 9H), 1.32 (d, J=7.0 Hz, 3H).

[0180] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 172.23, 170.41, 155.40, 136.24, 129.64, 128.44, 127.02, 82.44, 80.13, 53.71, 50.28, 38.16, 28.40, 28.03, 18.55.

[0181] HRMS (ESI) m/z calcd. for C.sub.22H.sub.33N.sub.2O.sub.5 [M+H].sup.+: 393.2384, found: 393.2389. dr>99:1.

Application Example 19

[0182] Cbz-Gly-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and estrone (0.55 mmol) and N,N-diisopropylethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 20 mL of 0.2 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 90%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00036##

[0183] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.25 (m, 6H), 6.91-6.72 (m, 2H), 5.46 (s, 1H), 5.14 (s, 2H), 4.20 (d, J=5.5 Hz, 2H), 2.94-2.84 (m, 2H), 2.50 (dd, J=18.9, 8.7 Hz, 1H), 2.42-2.34 (m, 1H), 2.30-2.22 (m, 1H), 2.18-1.94 (m, 4H), 1.65-1.41 (m, 6H), 0.90 (s, 3H).

[0184] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 168.95, 156.37, 148.18, 138.18, 137.80, 136.20, 128.56, 128.23, 128.10, 126.47, 121.28, 118.43, 67.21, 50.43, 47.93, 44.14, 42.99, 37.98, 35.84, 31.56, 29.38, 26.31, 25.76, 21.59, 13.83.

[0185] HRMS (ESI) m/z calcd. for C.sub.28H.sub.32NO.sub.5[M+H].sup.+: 462.2275, found: 462.2281.

Application Example 20

[0186] Pyridine-2-formic (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, the resulting reaction solution was subjected to a reduced pressure distillation to remove dichloromethane, and 3 mL of acetonitrile was added thereto as a solvent, and benzyl mercaptan (0.55 mmol) and triethylamine (0.05 mmol) were added thereto. The process of the reaction was monitored by TLC. 10 mL of 0.5 M dilute hydrochloric acid was added the reaction system, and stirred for 10 min, precipitating an product. The product was filtered, washed with water, obtaining a solid. The solid was collected, obtaining a pure product. The product is a white solid with a yield of 89%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00037##

[0187] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (d, J=4.7 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.83 (td, J=7.7, 1.6 Hz, 1H), 7.50-7.46 (m, 1H), 7.39 (d, J=7.2 Hz, 2H), 7.29 (t, J=7.4 Hz, 2H), 7.26-7.21 (m, 1H), 4.28 (s, 2H).

[0188] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 193.07, 151.99, 149.23, 137.65, 137.31, 129.12, 128.66, 127.93, 127.28, 120.56, 33.29.

[0189] HRMS (ESI) m/z calcd. for C.sub.13H.sub.12NOS [M+H].sup.+: 230.0634, found: 230.0640.

Application Example 21

[0190] Cinnamic acid (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide (0.55 mmol) were dissolved in 3 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, 2-phenethylamine (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed twice with 15 mL of 0.5 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, and subjected to a reduced pressure distillation to remove the solvent, obtaining a pure product. The product is a white solid with a yield of 91%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00038##

[0191] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.61 (d, J=15.6 Hz, 1H), 7.46 (dd, J=6.4, 2.5 Hz, 2H), 7.37-7.28 (m, 5H), 7.23 (t, J=9.5 Hz, 3H), 6.35 (d, J=15.6 Hz, 1H), 5.86 (s, 1H), 3.65 (q, J=6.8 Hz, 2H), 2.88 (t, J=6.9 Hz, 2H).

[0192] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 166.04, 141.08, 139.00, 134.95, 129.74, 128.90, 128.89, 128.78, 127.88, 126.65, 120.83, 40.96, 35.80.

[0193] HRMS (ESI) m/z calcd. for C.sub.17H.sub.18NO [M+H].sup.+: 252.1383, found: 252.1390.

Application Example 22

[0194] Fmoc-Ser(tBu)-OH (0.5 mmol) and N-(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)-N-ethynyl trifluoroacetamide (0.55 mmol) were dissolved in 5 mL of dichloromethane, and stirred for a reaction at room temperature. The process of the reaction was monitored by TLC. After the raw acid consumed completely, H-Leu-OtBu (0.55 mmol) was added thereto. The process of the reaction was monitored by TLC. After the reaction completed, 15 mL of ethyl acetate was added to dilute the reaction solution, obtaining an organic phase. The organic phase was shaken and washed three times with 15 mL of 0.2 M dilute hydrochloric acid, and separated to remove the aqueous phase, obtaining a separated organic phase. The separated organic phase was dried with anhydrous magnesium sulfate, concentrated, and then recrystallized with dichloromethane/petroleum ether, obtaining a pure product. The product is a white solid with a yield of 96%. The structural formula, and the experimental data of NMR and mass spectrometry of the product were shown as follows:

##STR00039##

[0195] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=7.5 Hz, 2H), 7.60 (d, J=6.9 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.30 (t, J=7.4 Hz, 2H), 7.22 (s, 1H), 5.80 (s, 1H), 4.49 (s, 1H), 4.42-4.36 (m, 2H), 4.23 (t, J=7.1 Hz, 2H), 3.83 (dd, J=8.3, 3.4 Hz, 1H), 3.40 (t, J=8.0 Hz, 1H), 1.76-1.59 (m, 3H), 1.58-1.47 (m, 3H), 1.45 (s, 9H), 1.22 (s, 9H), 0.95 (d, J=6.2 Hz, 6H).

[0196] .sup.13C NMR (100 MHz, CDCl.sub.3) δ 171.69, 169.99, 156.11, 143.98, 143.86, 141.36, 127.77, 127.14, 125.20, 120.03, 81.76, 74.31, 67.21, 61.89, 54.41, 51.74, 47.25, 41.96, 28.06, 27.43, 24.95, 22.90, 22.24.

[0197] HRMS (ESI) m/z calcd. for C.sub.32H.sub.45N.sub.2O.sub.6 [M+H].sup.+: 553.3272, found: 553.3279. dr>99:1.

[0198] The above examples are merely the description of the preferred embodiments of the present disclosure, and they should not be limited the scope of the present disclosure. Without departing from the design spirit of the present disclosure, various modifications and improvements made by those skilled in the art to the technical solutions of the present disclosure should be fall within the protection scope determined by the claims of the present disclosure.