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 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 a solvent I to obtain a mixture; 2) Adding an alkali or DBU into the mixture obtained in step 1), and subjecting the resulting mixture 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 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; 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); and/or in step 2), the alkali is 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, and LiOH; the reaction is performed at a temperature of 15-100 C.; the reaction is performed for 0.2-48 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.

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 an ester compound or a thioester compound, wherein the method for 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 a solvent II to obtain a compound having the structure represented by formula (III); the specific reaction is performed as follows: ##STR00042## 2a) after the reaction in step 1a) is completed, dissolving the compound having the structure represented by formula (III) in a solvent III, adding a compound selected from the group consisting of an alcohol compound, an aromatic alcohol compound, a thiol compound and an aromatic thiol compound thereto, adding a catalyst thereto, and 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 follows: ##STR00043## 3a) after the reaction is completed, adding a dilute acid aqueous solution into the mixture containing an ester compound or a thioester compound obtained in step 2a), hydrolyzing unreacted coupling reagent from step 1a) and the by-product produced in the reaction, and separating to obtain the target ester compound or thioester compound; the reaction is performed as follows: ##STR00044## and in the formula, R.sup.1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic, heterocyclic aryl, protected -aminoalkyl, and protected -aminoalkyl; R is selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups; and R.sup.2 is selected from the group consisting of aliphatic substituent group and aromatic substituent group.

5. The method of claim 4, wherein in step 1a), 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); the solvent II is 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), a molar ratio of the alcohol compound, the aromatic alcohol compound, the thiol compound and the aromatic thiol compound to the carboxylic acid compound is in a range of 1:(1-20); the solvent III is 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, and 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; and/or in step 3a), the dilute acid is 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.

6. The method of claim 4, wherein the step 1a) is performed as follows: adding the carboxylic acid compound, the water-soluble ynamide coupling reagent having the general molecular formula (I) and the solvent II into a reactor for mixing, and stirring for a reaction at a temperature of 0-60 C., after the reaction is 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) is completed, dissolving the compound having the structure represented by formula (III) obtained in step 1a) into the solvent III, adding one selected from the group consisting of alcohol compound, aromatic alcohol compound, thiol compound and aromatic thiol compound thereto, adding a catalyst thereto, and then stirring for a reaction at a temperature of 0-60 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, and then adding a diluted acid aqueous solution for washing, hydrolyzing unreacted coupling reagent from step 1a) 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.

7. 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 an amide, or a polypeptide, wherein the method for 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 a solvent II to obtain a compound having the structure represented by the formula (IV); the specific reaction is performed as follows: ##STR00045## 2b) after the reaction in step 1b) is completed, adding an amine compound to 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 follows: ##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 follows: ##STR00047## and in the formula, R.sup.1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic, heterocyclic aryl, protected -aminoalkyl, and protected -aminoalkyl; R is selected from the group consisting of methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoroacetyl and other electron withdrawing groups; R.sup.3 and R.sup.4 are each selected from the group consisting of aliphatic substituent group and aromatic substituent group.

8. The method of claim 7, wherein in step 1b), 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); the solvent II is an organic solvent; and/or in step 2b), a molar ratio of the compound having the structure represented by formula (IV) to the amine compound is in a range of 1:(1-5); and/or in step 3b), the dilute acid is 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.

9. The method of claim 7, wherein the step 1b) is performed as follows: adding the carboxylic acid compound, the water-soluble ynamide coupling reagent having the general molecular formula (I) and the solvent II into a reactor for mixing, and stirring for a reaction at a temperature of 0-60 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) is completed, adding an amine compound to 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. 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 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 any unreacted coupling reagent of formula (I) and any 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, 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

(1) 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

(2) 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:

(3) ##STR00010##

(4) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

(6) 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

(7) 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:

(8) ##STR00011##

(9) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

(11) 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

(12) 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:

(13) ##STR00012##

(14) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

(16) 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

(17) 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:

(18) ##STR00013##

(19) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(20) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(21) 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

(22) 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:

(23) ##STR00014##

(24) .sup.1H NMR (400 MHz, DMSO) 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).

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

(26) 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

(27) 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:

(28) ##STR00015##

(29) .sup.1H NMR (500 MHz, Chloroform-d) 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).

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

(31) 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

(32) 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:

(33) ##STR00016##

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(35) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(36) 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

(37) 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:

(38) ##STR00017##

(39) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(40) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(41) 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

(42) 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 phenylpropynoic 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:

(43) ##STR00018##

(44) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 2

(47) 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:

(48) ##STR00019##

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 3

(52) 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:

(53) ##STR00020##

(54) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 4

(57) 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:

(58) ##STR00021##

(59) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(60) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(61) 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

(62) 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:

(63) ##STR00022##

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(65) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(66) 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

(67) 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:

(68) ##STR00023##

(69) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(70) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

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

Application Example 7

(72) 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:

(73) ##STR00024##

(74) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(75) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

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

Application Example 8

(77) 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:

(78) ##STR00025##

(79) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(80) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(81) 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

(82) 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:

(83) ##STR00026##

(84) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 10

(87) 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:

(88) ##STR00027##

(89) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(90) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(91) 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

(92) 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:

(93) ##STR00028##

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

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

(96) 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

(97) 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:

(98) ##STR00029##

(99) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(100) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(101) 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

(102) 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:

(103) ##STR00030##

(104) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 14

(107) 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:

(108) ##STR00031##

(109) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(110) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(111) 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

(112) 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:

(113) ##STR00032##

(114) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(115) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

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

Application Example 16

(117) 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:

(118) ##STR00033##

(119) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 17

(122) 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 phenylpropionic 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:

(123) ##STR00034##

(124) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 18

(127) 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:

(128) ##STR00035##

(129) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(130) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(131) 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

(132) 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:

(133) ##STR00036##

(134) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(135) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

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

Application Example 20

(137) 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:

(138) ##STR00037##

(139) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

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

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

Application Example 21

(142) 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:

(143) ##STR00038##

(144) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(145) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

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

Application Example 22

(147) 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:

(148) ##STR00039##

(149) .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

(150) .sup.13C NMR (100 MHz, CDCl.sub.3) 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.

(151) 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.

(152) 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.