Mild and efficient preparation method for α-acyloxyenamide compounds and use thereof in synthesis of amide and polypeptide

Abstract

Disclosed are a mild and efficient preparation method for an -acyloxyenamide compound and a use thereof in the synthesis of an amide and a polypeptide. The -acyloxyenamide compound is obtained by an addition reaction of a ynamide and a carboxylic acid in dichloromethane under conditions where the temperature is 0 C. to 50 C.; the produced -acyloxyenamide compound can react with an amine compound to produce an amide or a polypeptide; the two reactions can be carried out step by step, and can also be carried out in one pot. According to the invention, the reaction conditions are mild and no metal catalyst is required; when the carboxylic acid, which has chirality on an alpha site of carboxyl, forms an amide bond or a peptide bond, no racemization occurs; and the operation is simple and the application range is wide.

Claims

1. A method of synthesizing an amide and a polypeptide by using an -acyloxyenamide, comprising the following steps: (1) adding 0.2-2 mmol of an -acyloxyenamide compound and an appropriate amount of dichloromethane solvent to a clean reaction tube, and then adding 0.2-2 mmol of an amine compound, and stirring at a temperature of 0-50 C.; and (2) detecting the previous step of the reaction by using a TLC analysis; after the previous step of the reaction is completed, and separating and purifying by column chromatography to directly obtain an amide compound; wherein the chemical reaction formula (2) of Step (1) is: ##STR00046## in the formula (2), 3 represents an -acyloxyenamide compound, 4 represents an amine compound, 5 represents an amide compound, 6 represents an amide by-product; R.sup.1 is selected from a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, and the like; the EWG (electron-withdrawing group) is selected from an alkylsulfonyl group, an arylsulfonyl group, an aryl group, an alkanoyl group, a nitro group, a nitrile group, a phosphono group, a sulfonimide, and the like; R.sup.2 may be an alkyl or aryl; R.sup.3 is selected from an alkyl group, an aryl group, an alkenyl group, an alkynyl group, and the like; R.sup.4 is selected from hydrogen, an aliphatic substituent and an aromatic substituent; R.sup.5 is selected from hydrogen, an aliphatic substituent, and an aromatic substituent.

2. The method of synthesizing an amide and a polypeptide by using an -acyloxyenamide compound according to claim 1, wherein the amine compound is an aliphatic primary amine, an aliphatic secondary amine, an aromatic primary amine, or and an aromatic secondary amine.

3. The method of synthesizing an amide and a polypeptide by using an -acyloxyenamide compound according to claim 1, wherein the ratio of the -acyloxyenamide compound to the amine compound is 0.1-10.

4. The method of synthesizing an amide and a polypeptide by using an -acyloxyenamide compound according to claim 1, wherein the dichloromethane solvent is replaced with water, or replaced with an organic solvent such as chloroform or 1,2-dichloroethane, or replaced with a mixture of water and dimethylsulfoxide, or a mixture of water and N,N-dimethylformamide.

5. The method of synthesizing an amide and a polypeptide by using an -acyloxyenamide compound according to claim 1, wherein the temperature is 35 C.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The advantages of the invention are described in detail below with reference to Embodiments 1 to 39, which are intended to help the reader to better understand the essence of the invention, but do not limit the implementation and the scope of the invention.

(2) The first part refers to specific embodiments (Embodiments 1 to 23) of a mild and efficient preparation method for an -acyloxyenamide compound, and the Applicant believes that Embodiment 10 is optimal.

Embodiment 1

(3) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and formic acid (2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 10 C. for 10 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(4) ##STR00004##

(5) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.06 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.33 (t, J=7.5 Hz, 3H), 4.83 (d, J=2.9 Hz, 1H), 4.73 (d, J=2.8 Hz, 1H), 3.01 (s, 3H), 2.43 (s, 3H).

(6) .sup.13C NMR (100 MHz, CDCl.sub.3) 158.2, 146.9, 144.4, 134.1, 129.6, 127.8, 99.7, 36.8, 21.5 ppm.

(7) HRMS m/z (ESI) calcd for C.sub.11H.sub.14NO.sub.4S (M+H).sup.+: 256.0644, found: 256.0647.

Embodiment 2

(8) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and adamantanecarboxylic acid (0.3 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 0 C. for 4 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(9) ##STR00005##

(10) .sup.1H NMR (400 MHz, CDCl3) 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 4.83 (d, J=2.2 Hz, 1H), 4.79 (d, J=2.2 Hz, 1H), 2.95 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.75 (d, J=2.5 Hz, 6H), 1.70 (d, J=12.4 Hz, 3H), 1.63 (d, J=12.1 Hz, 3H).

(11) .sup.13C NMR (100 MHz, CDCl3) 174.8, 146.5, 143.9, 134.1, 129.5, 128.1, 102.0, 41.0, 38.3, 36.6, 36.2, 27.7, 21.5 ppm.

(12) HRMS m/z (ESI) calcd for C.sub.11H.sub.28NO.sub.4S (M+H).sup.+: 390.1739, found: 390.1735.

Embodiment 3

(13) N-methyl-N-ethynyl p-toluenesulfonamide (0.30 mmol) and parachlorobenzoic-acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 6 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(14) ##STR00006##

(15) .sup.1H NMR (400 MHz, CDCl3) 7.83 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.02 (d, J=2.5 Hz, 1H), 4.83 (d, J=2.6 Hz, 1H), 3.10 (s, 3H), 2.40 (s, 3H).

(16) .sup.13C NMR (100 MHz, CDCl3) 163.1, 146.9, 144.0, 140.3, 134.1, 131.5, 129.5, 128.8, 127.9, 127.1, 101.4, 37.3, 21.5 ppm.

(17) HRMS m/z (ESI) calcd for C.sub.17H.sub.17ClNO.sub.4S (M+H).sup.+: 366.0567, found: 366.0563.

Embodiment 4

(18) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and furoic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 30 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 98%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(19) ##STR00007##

(20) .sup.1H NMR (400 MHz, CDCl3) 7.66 (d, J=8.0 Hz, 2H), 7.54 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.02 (d, J=3.2 Hz, 1H), 6.44 (s, 1H), 4.94 (d, J=2.1 Hz, 1H), 4.75 (d, J=2.1 Hz, 1H), 2.99 (s, 3H), 2.32 (s, 3H).

(21) .sup.13C NMR (100 MHz, CDCl3) 155.6, 147.4, 146.3, 144.0, 143.1, 134.0, 129.4, 127.9, 119.8, 112.1, 101.7, 37.2, 21.5 ppm.

(22) HRMS m/z (ESI) calcd for C.sub.15H.sub.16NO.sub.5S (M+H).sup.+: 322.0749, found: 322.0754.

Embodiment 5

(23) N-methyl-N-ethynyl p-toluenesulfonamide (2.0 mmol) and 1-methylindazole-3-carboxylic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of chloroform is added as a solvent. The reaction is carried out at room temperature for 5 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(24) ##STR00008##

(25) .sup.1H NMR (400 MHz, CDCl3) 7.96 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.47 (d, J=2.7 Hz, 2H), 7.34-7.27 (m, 1H), 7.21 (d, J=8.1 Hz, 2H), 5.08 (d, J=2.4 Hz, 1H), 4.90 (d, J=2.4 Hz, 1H), 4.18 (s, 3H), 3.15 (s, 3H), 2.33 (s, 3H).

(26) .sup.13C NMR (100 MHz, CDCl3) 159.8, 146.5, 143.8, 141.0, 134.4, 133.1, 129.4, 128.0, 127.0, 123.7, 123.5, 122.0, 109.6, 101.6, 37.2, 36.5, 21.5 ppm.

(27) HRMS m/z (ESI) calcd for C.sub.19H.sub.20N.sub.3O.sub.4S (M+H).sup.+: 386.1175, found: 386.1173.

Embodiment 6

(28) N-methyl-N-ethynyl p-toluenesulfonamide (1.0 mmol) and 1-benzothiophene-3-carboxylic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 40 C. for 1 hour. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 100%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(29) ##STR00009##

(30) .sup.1H NMR (400 MHz, CDCl3) 7.92 (s, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.50-7.41 (m, 2H), 7.29-7.24 (m, 2H), 5.09 (d, J=2.5 Hz, 1H), 4.92 (d, J=2.5 Hz, 1H), 3.12 (s, 3H), 2.33 (s, 3H).

(31) .sup.13C NMR (100 MHz, CDCl3) 160.0, 146.5, 144.0, 142.7, 138.4, 134.3, 132.1, 131.6, 129.6, 127.9, 127.5, 125.7, 125.1, 122.7, 101.9, 37.1, 21.4 ppm.

(32) HRMS m/z (ESI) calcd for C.sub.19H.sub.18NO.sub.4S.sub.2 (M+H).sup.+: 388.0677, found: 388.0676.

Embodiment 7

(33) N-methyl-N-ethynyl p-toluenesulfonamide (0.80 mmol) and cinnamic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of 1,2-dichloroethane is added as a solvent. The reaction is carried out at 50 C. for 1 hour. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(34) ##STR00010##

(35) .sup.1H NMR (400 MHz, CDCl3) 7.75 (d, J=8.3 Hz, 2H), 7.59 (d, J=16.0 Hz, 1H), 7.51-7.45 (m, 2H), 7.44-7.38 (m, 3H), 7.30 (d, J=8.0 Hz, 2H), 6.31 (d, J=16.0 Hz, 1H), 4.95 (d, J=2.4 Hz, 1H), 4.78 (d, J=2.5 Hz, 1H), 3.08 (s, 3H), 2.36 (s, 3H).

(36) .sup.13C NMR (100 MHz, CDCl3) 164.1, 147.0, 146.9, 144.0, 134.5, 133.9, 130.8, 129.5, 129.0, 128.3, 128.0, 116.3, 101.1, 37.2, 21.5 ppm.

(37) HRMS m/z (ESI) calcd for C.sub.19H.sub.20NO.sub.4S (M+H).sup.+: 358.1113, found: 358.1110.

Embodiment 8

(38) N-methyl-N-ethynyl p-toluenesulfonamide (0.80 mmol) and phenylpropiolic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 0 C. for 10 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(39) ##STR00011##

(40) .sup.1H NMR (400 MHz, CDCl3) 7.76 (d, J=8.2 Hz, 2H), 7.62-7.55 (m, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.99 (d, J=2.7 Hz, 1H), 4.81 (d, J=2.7 Hz, 1H), 3.07 (s, 3H), 2.39 (s, 3H).

(41) .sup.13C NMR (100 MHz, CDCl3) 151.0, 146.4, 144.1, 134.1, 133.1, 131.1, 129.6, 128.6, 128.0, 119.0, 101.8, 89.4, 79.5, 37.2, 21.5 ppm.

(42) HRMS m/z (ESI) calcd for C.sub.19H.sub.18NO.sub.4S (M+H).sup.+: 356.0957, found: 356.0955.

Embodiment 9

(43) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and N-benzyloxycarbonyl-L-serine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 30 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(44) ##STR00012##

(45) .sup.1H NMR (400 MHz, CDCl3) 7.71 (d, J=8.2 Hz, 2H), 7.36-7.32 (m, 7H), 5.84 (d, J=8.4 Hz, 1H), 5.19-5.09 (m, 2H), 4.87 (d, J=2.5 Hz, 1H), 4.46 (dd, J=15.5, 5.5 Hz, 2H), 4.28-4.16 (m, 1H), 3.85 (dd, J=11.8, 3.2 Hz, 1H), 2.98 (s, 3H), 2.43 (s, 3H).

(46) .sup.13C NMR (100 MHz, CDCl3) 168.2, 156.2, 147.0, 144.6, 136.1, 132.0, 129.6, 128.5, 128.1, 128.0, 127.3, 100.5, 67.1, 62.6, 56.3, 38.0, 21.6 ppm.

(47) HRMS m/z (ESI) calcd for C.sub.21H.sub.25N.sub.2O.sub.7S (M+H).sup.+: 449.1382, found: 449.1385.

Embodiment 10

(48) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and Fmoc-L-threonine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 40 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(49) ##STR00013##

(50) 1H NMR (400 MHz, CDCl3) 7.77-7.7 (m, 4H), 7.64 (t, J=7.5 Hz, 2H), 7.43-7.37 (m, 2H), 7.32 (d, J=7.9 Hz, 4H), 5.84 (d, J=9.4 Hz, 1H), 4.89 (d, J=2.8 Hz, 1H), 4.61-4.51 (m, 1H), 4.47-4.39 (m, 4H), 4.26 (t, J=7.2 Hz, 1H), 2.99 (s, 3H), 2.42 (s, 3H), 1.30 (d, J=6.4 Hz, 3H).

(51) 13C NMR (100 MHz, CDCl3) 168.5, 156.7, 147.0, 144.5, 141.2, 141.2, 132.0, 129.5, 128.1, 127.6, 127.0, 125.1, 119.9, 100.7, 67.3, 67.0, 59.6, 47.0, 38.0, 21.5, 19.5 ppm.

(52) HRMS m/z (ESI) calcd for C29H31N2O7S (M+H)+: 551.1852, found: 551.1856.

Embodiment 11

(53) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and N-benzyloxycarbonyl-L-tryptophan (0.24 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 30 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(54) ##STR00014##

(55) .sup.1H NMR (400 MHz, CDCl3) 8.28 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.43-7.26 (m, 6H), 7.23-7.18 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 7.03 (d, J=11.2 Hz, 1H), 5.29 (t, J=25.3 Hz, 1H), 5.08 (q, J=12.2 Hz, 2H), 4.85 (d, J=1.9 Hz, 1H), 4.76-4.55 (m, 2H), 3.47-3.12 (m, 2H), 2.90 (d, J=15.5 Hz, 3H), 2.36 (s, 3H).

(56) .sup.13C NMR (100 MHz, CDCl3) 169.5, 155.7, 146.6, 144.3, 136.1, 133.4, 129.5, 128.5, 128.1, 128.0, 127.9, 127.5, 123.3, 122.2, 119.7, 118.5, 111.3, 109.2, 101.9, 67.0, 54.7, 37.0, 27.3, 21.5 ppm.

(57) HRMS m/z (ESI) calcd for C.sub.29H.sub.30N.sub.3O.sub.6S (M+H).sup.+: 548.1855, found: 548.1856.

Embodiment 12

(58) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and N-tert-butoxycarbonyl-L-phenylalanine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 30 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(59) ##STR00015##

(60) .sup.1H NMR (400 MHz, CDCl3) 7.72 (d, J=8.2 Hz, 2H), 7.33-7.22 (m, 5H), 7.15 (d, J=7.0 Hz, 2H), 4.92-4.87 (m, 2H), 4.70 (s, 1H), 4.53 (dd, J=13.4, 6.9 Hz, 1H), 3.15-3.10 (m, 1H), 3.03-2.90 (m, 4H), 2.42 (s, 3H), 1.40 (s, 9H).

(61) .sup.13C NMR (100 MHz, CDCl3) 169.6, 155.0, 146.6, 144.3, 135.7, 133.7, 129.6, 129.4, 128.6, 128.1, 127.2, 101.8, 80.1, 54.4, 37.6, 37.0, 28.3, 21.6 ppm.

(62) HRMS m/z (ESI) calcd for C.sub.24H.sub.31N.sub.2O.sub.6S (M+H).sup.+: 475.1903, found: 475.1901.

Embodiment 13

(63) N-methyl-N-ethynyl methanesulfonamide (0.20 mmol) and Boc-L-leucine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 20 C. for 40 minutes. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(64) ##STR00016##

(65) .sup.1H NMR (400 MHz, CDCl.sub.3) 5.05 (d, J=1.6 Hz, 1H), 4.90 (d, J=6.8 Hz, 1H), 4.84 (d, J=1.9 Hz, 1H), 4.29 (dd, J=13.4, 8.7 Hz, 1H), 3.08 (s, 3H), 2.98 (s, 3H), 1.78-1.50 (m, 3H), 1.41 (s, 9H), 0.97-0.92 (m, 6H);

(66) .sup.13C NMR (100 MHz, CDCl.sub.3) 171.3, 155.4, 145.6, 100.7, 80.2, 52.2, 40.5, 37.5, 35.6, 28.2, 24.8, 22.8, 21.6 ppm;

(67) HRMS m/z (ESI) calcd for C.sub.15H.sub.29N.sub.2O.sub.6S (M+H).sup.+: 365.1746, found 365.1743.

Embodiment 14

(68) N-methyl-N-phenylethynyl p-toluenesulfonamide (0.20 mmol) and parachlorobenzoic-acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 15 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 93%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(69) ##STR00017##

(70) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.82 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H), 7.65-7.55 (m, 3H), 7.43-7.37 (m, 4H), 7.34-7.28 (m, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.35 (s, 1H), 3.14 (d, J=0.8 Hz, 3H), 2.24 (s, 3H);

(71) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.6, 143.6, 139.9, 136.0, 133.7, 131.9, 130.0, 129.4, 128.6, 128.6, 128.4, 128.3, 127.5, 119.3, 36.6, 21.3 ppm;

(72) HRMS m/z (ESI) calcd for C.sub.23H.sub.22NO.sub.4S (M+H).sup.+: 408.1270, found 408.1273.

Embodiment 15

(73) N-methyl-N-phenylethynyl p-toluenesulfonamide (0.20 mmol) and parachlorobenzoic-acid (1.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 10 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 83%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(74) ##STR00018##

(75) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.82 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H), 7.65-7.55 (m, 3H), 7.43-7.37 (m, 4H), 7.34-7.28 (m, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.35 (s, 1H), 3.14 (d, J=0.8 Hz, 3H), 2.24 (s, 3H);

(76) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.6, 143.6, 139.9, 136.0, 133.7, 131.9, 130.0, 129.4, 128.6, 128.5, 128.4, 128.3, 127.5, 119.3, 36.6, 21.3 ppm;

(77) HRMS m/z (ESI) calcd for C.sub.23H.sub.22NO.sub.4S (M+H).sup.+: 408.1270, found 408.1271.

Embodiment 16

(78) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and parachlorobenzoic-acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 1.5 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(79) ##STR00019##

(80) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.2, 1.0 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.61-7.55 (m, 1H), 7.41 (t, J=7.8 Hz, 2H), 7.28-7.23 (m, 2H), 5.03 (d, J=2.5 Hz, 1H), 4.88 (d, J=2.5 Hz, 1H), 3.10 (s, 3H), 2.38 (s, 3H);

(81) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.0, 146.8, 144.0, 134.3, 133.7, 130.1, 129.5, 128.6, 128.4, 127.9, 101.7, 37.1, 21.5 ppm;

(82) HRMS m/z (ESI) calcd for C.sub.17H.sub.18NO.sub.4S (M+H).sup.+: 332.0957, found 332.0956.

Embodiment 17

(83) N-methyl-N-ethynyl p-toluenesulfonamide (0.20 mmol) and parachlorobenzoic-acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 1.5 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(84) ##STR00020##

(85) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.09 (dd, J=8.3, 1.2 Hz, 2H), 7.68-7.60 (m, 1H), 7.50 (t, J=7.8 Hz, 2H), 5.15 (d, J=2.6 Hz, 1H), 4.99 (d, J=2.6 Hz, 1H), 3.18 (s, 3H), 3.03 (s, 3H);

(86) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.2, 146.1, 134.1, 130.1, 128.8, 128.3, 100.3, 37.7, 36.0 ppm;

(87) HRMS m/z (ESI) calcd for C.sub.11H.sub.14NO.sub.4S (M+H).sup.+: 256.0644, found 256.0645.

Embodiment 18

(88) 3-ethynyl-2-oxazolidinone (1.20 mmol) and benzoic acid (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 10 C. for 12 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 53%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(89) ##STR00021##

(90) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.16 (dd, J=8.4, 1.3 Hz, 2H), 7.76-7.70 (m, 1H), 7.60 (t, J=7.9 Hz, 2H), 5.05 (d, J=2.5 Hz, 1H), 4.81 (d, J=2.5 Hz, 1H), 4.40-4.36 (m, 2H), 3.83-3.79 (m, 2H);

(91) .sup.13C NMR (CDCl.sub.3, 100 MHz) 165.2, 155.4, 137.6, 134.1, 132.1, 128.8, 128.6, 116.3, 63.1, 44.7 ppm;

(92) HRMS (ESI) m/z calculated for C.sub.12H.sub.12NO.sub.4 (M+H).sup.+: 234.0766 found: 234.0763.

Embodiment 19

(93) N-methyl-N-ethynyl methanesulfonamide (0.03 mmol) and 6-carboxyfluorescein diacetate (0.03 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 4 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 90%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(94) ##STR00022##

(95) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.38-8.31 (m, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.13 (d, J=1.8 Hz, 2H), 6.85-6.81 (m, 4H), 5.09 (d, J=2.8 Hz, 1H), 4.96 (d, J=2.8 Hz, 1H), 3.14 (s, 3H), 2.97 (s, 3H), 2.32 (s, 6H).

(96) .sup.13C NMR (100 MHz, CDCl.sub.3) 168.7, 167.8, 162.7, 153.3, 152.3, 151.5, 146.4, 135.1, 131.8, 130.3, 128.7, 125.9, 125.8, 118.0, 115.5, 110.6, 100.2, 81.9, 37.4, 36.4, 21.1 ppm.

(97) LCMS m/z (ESI) calcd for C.sub.29H.sub.23NO.sub.11S (M+H).sup.+: 594.11, found: 594.11.

Embodiment 20

(98) N-methyl-N-ethynyl p-toluenesulfonamide (0.03 mmol) and 6-carboxyfluorescein diacetate (0.03 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 4 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, white solid, with a yield of 93%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(99) ##STR00023##

(100) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-8.09 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 7.06 (d, J=2.1 Hz, 2H), 6.80-6.71 (m, 4H), 4.86 (d, J=2.8 Hz, 1H), 4.60 (d, J=2.8 Hz, 1H), 2.97 (s, 3H), 2.31 (s, 3H), 2.23 (s, 6H).

(101) .sup.13C NMR (100 MHz, CDCl.sub.3) 168.7, 167.8, 162.6, 152.9, 152.4, 151.6, 147.2, 144.3, 135.4, 133.6, 131.8, 130.3, 129.6, 128.8, 128.0, 125.9, 125.5, 118.0, 115.6, 110.6, 101.2, 82.1, 37.6, 21.5, 21.1 ppm.

(102) LCMS m/z (ESI) calcd for C.sub.35H.sub.27NO.sub.11S (M+H).sup.+: 670.14, found: 670.14.

Embodiment 21

(103) N-methyl-N-ethynyl methanesulfonamide (0.03 mmol) and 4-dimethylamine azobenzene-4-carboxylic acid (0.03 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 24 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, red solid, with a yield of 86%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(104) ##STR00024##

(105) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.19-8.16 (m, 2H), 7.93-7.88 (m, 4H), 6.78-6.75 (m, 2H), 5.17 (d, J=2.6 Hz, 1H), 5.01 (d, J=2.5 Hz, 1H), 3.20 (s, 3H), 3.12 (s, 6H), 3.05 (s, 3H).

(106) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.0, 156.8, 153.1, 146.2, 143.8, 131.2, 128.0, 125.8, 122.3, 111.5, 100.3, 40.3, 37.9, 36.0 ppm.

(107) LCMS m/z (ESI) calcd for C.sub.19H.sub.22N.sub.4O.sub.4S (M+H).sup.+: 403.14, found: 403.14.

Embodiment 22

(108) N-methyl-N-ethynyl p-toluenesulfonamide (0.03 mmol) and 4-dimethylamine azobenzene-4-carboxylic acid (0.03 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 24 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, orange solid, with a yield of 89%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(109) ##STR00025##

(110) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94-7.88 (m, 4H), 7.81 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 7.28-7.24 (m, 2H), 6.76 (d, J=9.1 Hz, 2H), 5.06 (d, J=2.4 Hz, 1H), 4.95 (d, J=2.4 Hz, 1H), 3.12 (s, 3H), 3.11 (s, 6H), 2.38 (s, 3H).

(111) .sup.13C NMR (100 MHz, CDCl.sub.3) 163.7, 156.6, 153.1, 146.8, 144.0, 143.8, 134.6, 131.1, 129.6, 128.4, 127.9, 125.7, 122.0, 111.5, 101.9, 40.3, 37.1, 21.5 ppm.

(112) LCMS m/z (ESI) calcd for C.sub.25H.sub.26N.sub.4O.sub.4S (M+H).sup.+: 479.18, found: 479.18.

Embodiment 23

(113) N-methyl-N-ethynyl p-toluenesulfonamide (0.15 mmol) and D-biotin (0.1 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of methanol is added as a solvent. The reaction is carried out at 30 C. for 48 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and the column chromatography are carried out to obtain a pure product, colorless oily liquid, with a yield of 52%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(114) ##STR00026##

(115) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.69 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.49-6.35 (m, 2H), 4.78 (d, J=2.6 Hz, 1H), 4.69 (d, J=2.6 Hz, 1H), 4.35-4.29 (m, 1H), 4.17-4.11 (m, 1H), 3.13-3.06 (m, 1H), 2.95 (s, 3H), 2.86-2.80 (m, 1H), 2.63-2.57 (m, 1H), 2.42 (s, 3H), 2.33-2.27 (m, 2H), 1.66-1.23 (m, 6H).

(116) .sup.13C NMR (100 MHz, DMSO-d.sub.6) 171.0, 163.3, 146.8, 144.7, 134.1, 130.3, 128.0, 100.0, 61.5, 59.7, 55.8, 37.5, 33.5, 28.4, 28.3, 24.5, 21.5 ppm.

(117) LCMS m/z (ESI) calcd for C.sub.20H.sub.27N.sub.3O.sub.5S.sub.2(M+Na).sup.+: 476.13, found: 476.13.

(118) The second part refers to specific embodiments (Embodiments 24 to 29) of use of an -acyloxyenamide compound in the synthesis of an amide and a polypeptide, and the Applicant believes that Embodiment 29 is optimal.

Embodiment 24

(119) Acetoxy-alkenylamide (0.20 mmol) and 2-phenylethylamine (0.3 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 30 C. for 1.5 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 98%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(120) ##STR00027##

(121) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.27 (t, J=7.3 Hz, 2H), 7.21-7.16 (m, 3H), 6.50 (s, 1H), 3.45 (dd, J=13.3, 7.0 Hz, 2H), 2.79 (t, J=7.2 Hz, 2H), 1.90 (s, 3H).

(122) .sup.13C NMR (100 MHz, CDCl.sub.3) 170.2, 138.7, 128.4, 128.3, 126.1, 40.5, 35.3, 22.8 ppm.

(123) HRMS m/z (ESI) calcd for C.sub.10H.sub.14NO (M+H).sup.+: 164.1075, found 164.1070.

Embodiment 25

(124) 1-(N-methyl-p-toluenesulfonylamino) vinyl acetate (0.20 mmol) and 2-phenylethylamine (2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 40 C. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 90%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(125) ##STR00028##

(126) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (d, J=15.6 Hz, 1H), 7.47 (dd, J=6.5, 2.9 Hz, 2H), 7.37-7.29 (m, 5H), 7.28-7.20 (m, 3H), 6.35 (d, J=15.6 Hz, 1H), 5.85 (s, 1H), 3.66 (dd, J=13.0, 6.8 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H).

(127) .sup.13C NMR (100 MHz, CDCl.sub.3) 165.9, 141.0, 138.9, 134.8, 129.6, 128.8, 128.7, 128.6, 127.7, 126.5, 120.7, 40.8, 35.6 ppm.

(128) HRMS m/z (ESI) calcd for C.sub.17H.sub.18NO (M+H).sup.+: 252.1388, found 252.1385.

Embodiment 26

(129) 1-(N-methyl-p-toluenesulfonylamino)-vinyl phenyl acrylate (0.30 mmol) and 2-phenylethylamine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 0 C. for 4 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(130) ##STR00029##

(131) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.33 (t, J=7.3 Hz, 2H), 7.27-7.18 (m, 3H), 5.94 (s, 1H), 3.57 (q, J=6.9 Hz, 2H), 2.85 (t, J=7.0 Hz, 2H), 2.75 (s, 1H).

(132) .sup.13C NMR (100 MHz, CDCl.sub.3) 152.1, 138.2, 128.7, 128.7, 126.7, 79.2, 73.1, 40.9, 35.2 ppm.

(133) HRMS m/z (ESI) calcd for C.sub.11H.sub.12NO (M+H).sup.+: 174.0919, found 174.0916.

Embodiment 27

(134) 1-(N-methyl-p-toluenesulfonylamino) vinyl-benzothiophenecarboxylate (1.0 mmol) and 2-phenylethylamine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at 50 C. for 4 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 98%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(135) ##STR00030##

(136) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90-7.75 (m, 2H), 7.68 (s, 1H), 7.42-7.36 (m, 2H), 7.34-7.30 (m, 2H), 7.26-7.24 (m, 3H), 6.26 (s, 1H), 3.71 (dd, J=13.0, 6.8 Hz, 2H), 2.94 (t, J=6.9 Hz, 2H).

(137) .sup.13C NMR (100 MHz, CDCl.sub.3) 162.2, 140.7, 139.0, 138.7, 138.4, 128.8, 128.7, 126.6, 126.3, 125.1, 125.0, 124.9, 122.7, 41.3, 35.7 ppm.

(138) HRMS m/z (ESI) calcd for C.sub.17H.sub.16NOS (M+H).sup.+: 282.0953, found 282.0950.

Embodiment 28

(139) 1-(N-methyl-p-toluenesulfonylamino) vinyl p-chlorobenzoate (0.20 mmol) and 2-morpholinylamine (0.2 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 5 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 98%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(140) ##STR00031##

(141) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76-7.65 (m, 2H), 7.44-7.35 (m, 2H), 3.76-3.66 (m, 4H), 3.52 (dd, J=11.2, 5.8 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.54-2.43 (m, 4H).

(142) .sup.13C NMR (100 MHz, CDCl.sub.3) 166.3, 137.6, 132.9, 128.8, 128.3, 66.9, 56.8, 53.3, 36.1 ppm.

(143) HRMS m/z (ESI) calcd for C.sub.13H.sub.18ClN.sub.2O.sub.2 (M+H).sup.+: 269.1057, found 269.1058.

Embodiment 29

(144) 1-(N-methyl-methanesulfonamido) vinyl-N-benzyloxycarbonyl-tryptophanate (0.2 mmol) and threonine tert-butyl ester (0.4 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dichloromethane is added as a solvent. The reaction is carried out at room temperature for 15 hours. TLC analysis is then performed. After the completion of the reaction, the solvent was concentrated off and column chromatography are carried out to obtain a pure product, white solid, with a yield of 97%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(145) ##STR00032##

(146) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.29 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.28-7.26 (m, 6H), 7.14 (t, J=7.5 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J=6.2 Hz, 1H), 5.66 (s, 1H), 5.15-4.89 (m, 2H), 4.59 (d, J=4.9 Hz, 1H), 4.40 (dd, J=8.6, 3.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.24 (d, J=5.3 Hz, 2H), 2.86 (s, 1H), 1.42 (s, 9H), 1.04 (d, J=5.3 Hz, 3H);

(147) .sup.13C NMR (100 MHz, CDCl.sub.3) 172.0, 169.6, 156.2, 136.2, 128.4, 128.3, 128.0, 128.0, 127.5, 123.4, 122.1, 119.6, 118.6, 111.2, 110.1, 82.5, 68.3, 67.0, 58.2, 55.7, 28.1, 27.9, 19.8 ppm;

(148) HRMS m/z (ESI) calcd for C.sub.27H.sub.34N.sub.3O.sub.6 (M+H).sup.+: 496.2448, found 496.24484; de: >99%.

(149) We have conducted extensive optimization regarding the racemization during the formation of dipeptides. Serine, which is highly prone to racemization upon activation, was selected as a model substrate to study the racemization by comparing the results with the currently widely used coupling reagents. From the results of Table 1, none of our ynamide coupling reagents such as MYMsA and MYTsA is observed to induce racemization in either an organic solvent or water. In contrast, coupling reagents such as DCC, HATU, HBTU and PyBop, commonly used at current, have very serious racemization. This result shows the advantages of the new coupling reagent ynamide developed by us in the synthesis of peptides.

(150) TABLE-US-00001 TABLE 1 Comparative study of ynamides and the conventional coupling reagents causing racemization in synthesis of dipeptides coupling entry reagent additive solvent time yield de 1 HBTU DIEA DCM 10 min 90% 64% 2 HATU DIEA DCM 10 min 70% 74% 3 PyBop DIEA DCM 10 min 91% 76% 4 DCC DCM 10 min 98% 82% 5 MYMsA DCM 22 h 99% >99% 6 MYTsA DCM 22 h 94% >99% 7 MYMsA H.sub.2O 1.5 h 96% >99% 8 MYTsA H.sub.2O 1.5 h 95% >99% 9 MYMsA DMSO:H.sub.2O 1.5 h 96% >99% 1:1 10 MYTsA DMSO:H.sub.2O 1.5 h 96% >99% 1:1 11 MYMsA DMF:H.sub.2O 2 h 98% >99% 1:1 12 MYTsA DMF:H.sub.2O 2 h 97% >99% 1:1

(151) Abbreviations in the table: HBTU: benzotriazole-N, N, N, N-tetramethylurea hexafluorophosphate; HATU: 2-(7-azabenzotriazole)-N, N, N, N-tetramethylurea hexafluorophosphate; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DCC: cyclohexylcarbodiimide; MYMsA: N-methyl-N-ethynylmethanesulfonamide; MYTsA: N-methyl-N-ethynyl p-toluenesulfonamide; -: no additive; de: diastereoselectivity.

(152) The third part refers to Embodiments 30 to 39 of a method (one-pot method) for synthesizing an amide and a polypeptide by directly using a carboxylic acid and an amine compound as raw materials and under the mediation of ynamides, and the Applicant believes that Embodiment 36 is optimal.

Embodiment 30

(153) 0.2 mmol of 1-adamantanecarboxylic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl p-toluenesulfonamide is added; the mixture is stirred at room temperature for 0.5 hours, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of t-butylamine is added; the mixture is stirred at room temperature for 5 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 98%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(154) ##STR00036##

(155) .sup.1H NMR (400 MHz, CDCl3) 5.35 (br s, 1H), 2.01 (br s, 3H), 1.81-1.78 (m, 6H), 1.73-1.64 (m, 6H), 1.31 (s, 9H).

(156) .sup.13C NMR (100 MHz, CDCl3) 177.6, 50.7, 41.1, 39.6, 36.7, 29.0, 28.4 ppm.

(157) HRMS m/z (ESI) calcd for C.sub.15H.sub.26NO (M+H).sup.+: 236.2014, found 236.2018.

Embodiment 31

(158) 0.2 mmol of phenylpropiolic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl p-toluenesulfonamide is added; the mixture is stirred at 0 C. for 30 minutes, and TLC analysis is then performed; after the reaction is completed, 0.5 mmol of tetrahydropyrrole is added; the mixture is stirred at room temperature for 0.5 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(159) ##STR00037##

(160) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.53 (d, J=6.8 Hz, 2H), 7.41-7.32 (m, 3H), 3.72 (t, J=6.4 Hz, 2H), 3.52 (t, J=6.6 Hz, 2H), 1.99-1.91 (m, 4H).

(161) .sup.13C NMR (100 MHz, CDCl.sub.3) 152.8, 132.5, 130.0, 128.6, 120.8, 88.8, 82.8, 48.2, 45.5, 25.5, 24.8 ppm.

(162) HRMS m/z (ESI) calcd for C.sub.13H.sub.14NO (M+H).sup.+: 200.1075, found 200.1078.

Embodiment 32

(163) 0.2 mmol of phenylpropiolic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl p-toluenesulfonamide is added; the mixture is stirred at room temperature for 30 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of O-benzylhydroxylamine is added; the mixture is stirred at 40 C. for 14 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 90%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(164) ##STR00038##

(165) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.14 (s, 1H), 7.49 (d, J=6.1 Hz, 2H), 7.45-7.24 (m, 8H), 4.97 (s, 2H).

(166) .sup.13C NMR (100 MHz, CDCl.sub.3) 151.9, 134.8, 132.5, 130.3, 129.2, 128.7, 128.5, 128.4, 119.6, 78.0, 78.4, 29.6 ppm.

(167) HRMS m/z (ESI) calcd for C.sub.16H.sub.14NO.sub.2 (M+H).sup.+: 252.1025, found 252.1028.

Embodiment 33

(168) 0.2 mmol of phenylpropiolic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at 0 C. for 50 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of tryptamine is added; the mixture is stirred at room temperature for 40 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 99%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(169) ##STR00039##

(170) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.40-7.32 (m, 2H), 7.30-7.26 (m, 2H), 7.22-7.16 (m, 1H), 7.14-7.08 (m, 1H), 7.01 (d, J=2.1 Hz, 1H), 6.23 (s, 1H), 3.66 (dd, J=12.8, 6.7 Hz, 2H), 3.00 (t, J=6.7 Hz, 2H).

(171) .sup.13C NMR (100 MHz, CDCl.sub.3) 153.5, 136.4, 132.4, 129.9, 128.4, 127.1, 122.3, 122.0, 120.0, 119.3, 118.5, 112.1, 111.4, 84.7, 83.0, 40.1, 25.0 ppm.

(172) HRMS m/z (ESI) calcd for C.sub.19H.sub.17N.sub.2O (M+H).sup.+: 289.1341, found 289.1346.

Embodiment 34

(173) 0.2 mmol of phenylpropiolic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 10 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of diisopropylamine is added; the mixture is stirred at 40 C. for 14 minutes, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 76%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(174) ##STR00040##

(175) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.57-7.45 (m, 2H), 7.41-7.29 (m, 3H), 4.59 (s, 1H), 3.70 (s, 1H), 1.40 (d, J=6.8 Hz, 6H), 1.29 (d, J=6.8 Hz, 6H).

(176) .sup.13C NMR (100 MHz, CDCl.sub.3) 153.5, 132.1, 129.6, 128.4, 121.0, 88.4, 83.1, 50.3, 45.7, 21.0, 20.1 ppm.

(177) HRMS m/z (ESI) calcd for C.sub.15H.sub.20NO (M+H).sup.+: 230.1545, found 230.1559.

Embodiment 35

(178) 0.2 mmol of phenylpropiolic acid and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl p-toluenesulfonamide is added; the mixture is stirred at room temperature for 10 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of cholamine is added; the mixture is stirred at room temperature for 0.5 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 95%. The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(179) ##STR00041##

(180) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52-7.46 (m, 2H), 7.37 (t, J=4.9 Hz, 1H), 7.30 (t, J=7.7 Hz, 2H), 6.92 (s, 1H), 3.75 (s, 2H), 3.49 (dd, J=10.5, 5.5 Hz, 2H).

(181) .sup.13C NMR (100 MHz, CDCl.sub.3) 154.5, 132.6, 130.2, 128.6, 120.2, 85.6, 82.9, 61.4, 42.7 ppm

(182) HRMS m/z (ESI) calcd for C.sub.11H.sub.12NO.sub.2 (M+H).sup.+: 190.0868, found 190.0867.

Embodiment 36

(183) 0.2 mmol of Fmoc-Asp(tBu)-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 30 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of H-Tyr(tBu)-OtBu is added; the mixture is stirred at 35 C. for 24 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 96%.

(184) Alternatively, 0.2 mmol of Fmoc-Asp(tBu)-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 30 minutes, and TLC analysis is then performed. After the reaction is completed, the dichloromethane solvent is dried in a vacuum, an appropriate amount of water is then added as a solvent, and 0.22 mmol of H-Tyr(tBu)-OtBu is then added; the mixture is stirred at 35 C. for 1.5 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 98%.

(185) The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(186) ##STR00042##

(187) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76 (d, J=7.5 Hz, 2H), 7.59 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 7.07 (t, J=8.3 Hz, 3H), 6.89 (d, J=8.3 Hz, 2H), 5.99 (d, J=8.1 Hz, 1H), 4.66 (dd, J=13.4, 6.3 Hz, 1H), 4.55 (d, J=4.5 Hz, 1H), 4.38 (p, J=10.4 Hz, 2H), 4.23 (t, J=7.1 Hz, 1H), 3.10-2.96 (m, 2H), 2.90 (dd, J=17.0, 3.9 Hz, 1H), 2.63 (dd, J=16.7, 5.9 Hz, 1H), 1.45 (s, 9H), 1.36 (s, 9H), 1.29 (s, 9H).

(188) .sup.13C NMR (100 MHz, CDCl.sub.3) 171.0, 169.9, 169.9, 155.9, 154.3, 143.6, 141.2, 130.9, 129.9, 127.7, 127.0, 125.0, 124.0, 119.9, 82.2, 81.8, 78.2, 67.3, 54.0, 51.0, 47.0, 37.4, 37.4, 28.7, 28.0, 27.8 ppm.

(189) HRMS m/z (ESI) calcd for C.sub.40H.sub.51N.sub.2O.sub.8 (M+H).sup.+: 687.3645, found 687.3650.de: >99%.

Embodiment 37

(190) 0.2 mmol of Fmoc-Trp(tBu)-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 50 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of H-Tyr(tBu)-OtBu is added; the mixture is stirred at room temperature for 23 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 97%.

(191) Alternatively, 0.2 mmol of Fmoc-Trp(tBu)-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 50 minutes, and TLC analysis is then performed. After the reaction is completed, the dichloromethane solvent is dried in a vacuum, an appropriate amount of a mixture of water and dimethylsulfoxide (which are in a ratio of 1:1) is then added as a solvent, and 0.22 mmol of H-Tyr(tBu)-OtBu is then added; the mixture is stirred at room temperature for 1 hour, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 96%.

(192) The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(193) ##STR00043##

(194) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14 (d, J=7.3 Hz, 1H), 7.75 (d, J=7.5 Hz, 2H), 7.62 (d, J=7.0 Hz, 1H), 7.57-7.49 (m, 3H), 7.42-7.27 (m, 5H), 7.25-7.21 (m, 1H), 6.85 (d, J=7.3 Hz, 2H), 6.77 (d, J=8.3 Hz, 2H), 6.36 (d, J=6.2 Hz, 1H), 5.50 (s, 1H), 4.55 (dd, J=12.8, 6.0 Hz, 2H), 4.46-4.37 (m, 1H), 4.37-4.29 (m, 1H), 4.20 (t, J=6.7 Hz, 1H), 3.34-3.21 (m, 1H), 3.14 (dd, J=14.2, 7.0 Hz, 1H), 2.94 (d, J=5.4 Hz, 2H), 1.60 (s, 9H), 1.30 (s, 9H), 1.26 (s, 9H).

(195) .sup.13C NMR (100 MHz, CDCl.sub.3) 170.1, 169.7, 155.9, 154.3, 149.4, 143.7, 143.7, 141.2, 135.5, 130.7, 130.2, 129.8, 127.7, 127.1, 125.1, 124.7, 124.6, 123.9, 122.8, 119.9, 118.9, 115.4, 115.1, 83.6, 82.3, 78.3, 67.3, 55.0, 53.9, 47.0, 37.3, 28.8, 28.2, 28.1, 27.8 ppm.

(196) HRMS m/z (ESI) calcd for C.sub.48H.sub.56N.sub.3O.sub.8 (M+H).sup.+: 802.4067, found 802.4065.de: >99%.

Embodiment 38

(197) 0.2 mmol of Fmoc-Ser-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 45 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of H-Tyr(tBu)-OtBu is added; the mixture is stirred at 35 C. for 19 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 98%.

(198) Alternatively, 0.2 mmol of Fmoc-Ser-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 45 minutes, and TLC analysis is then performed. After the reaction is completed, the dichloromethane solvent is dried in a vacuum, an appropriate amount of a mixture of water and N,N-dimethylformamide (which are in a ratio of 1:1) is then added as a solvent, and 0.22 mmol of H-Tyr(tBu)-OtBu is then added; the mixture is stirred at 35 C. for 1 hour, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 98%.

(199) The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(200) ##STR00044##

(201) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76 (d, J=7.5 Hz, 2H), 7.60 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.34-7.28 (m, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.95 (s, 1H), 6.88 (d, J=8.4 Hz, 2H), 5.84 (s, 1H), 4.70 (dd, J=14.1, 6.4 Hz, 1H), 4.47-4.33 (m, 2H), 4.22 (t, J=7.0 Hz, 2H), 4.01 (d, J=10.1 Hz, 1H), 3.64 (d, J=5.0 Hz, 1H), 3.29 (s, 1H), 3.03 (qd, J=14.1, 6.4 Hz, 2H), 1.39 (s, 9H), 1.29 (s, 9H).

(202) .sup.13C NMR (100 MHz, CDCl.sub.3) 170.6, 170.4, 156.4, 154.4, 143.7, 143.6, 141.3, 130.7, 129.8, 127.7, 127.1, 125.1, 124.1, 120.0, 82.7, 78.4, 67.3, 62.9, 55.3, 54.0, 47.0, 37.1, 28.8, 27.9 ppm.

(203) HRMS m/z (ESI) calcd for C.sub.35H.sub.43N.sub.2O.sub.7 (M+H).sup.+: 603.3070, found 603.3070.de: >99%.

Embodiment 39

(204) 0.2 mmol of Z-Ser-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 40 minutes, and TLC analysis is then performed; after the reaction is completed, 0.22 mmol of H-Tyr(tBu)-OtBu is added; the mixture is stirred at 35 C. for 10 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 98%.

(205) Alternatively, 0.2 mmol of Z-Ser-OH and an appropriate amount of dichloromethane are added to a clean 25 mL reaction tube, and then 0.22 mmol of N-methyl-N-ethynyl methanesulfonamide is added; the mixture is stirred at room temperature for 40 minutes, and TLC analysis is then performed. After the reaction is completed, the dichloromethane solvent is dried in a vacuum, an appropriate amount of water is then added as a solvent, and 0.22 mmol of H-Tyr(tBu)-OtBu is then added; the mixture is stirred at 35 C. for 0.5 hours, and TLC analysis is then performed; after the reaction is completed, column chromatography is carried out for separation and purification to directly obtain a pure product, white solid, with a yield of 96%.

(206) The following are the structural formula of the product and the NMR data and mass spectrometry data of the product:

(207) ##STR00045##

(208) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.43-7.29 (m, 5H), 7.04 (d, J=8.4 Hz, 2H), 6.96 (d, J=7.3 Hz, 1H), 6.92-6.85 (m, 2H), 5.79 (d, J=7.3 Hz, 1H), 5.16-5.03 (m, 2H), 4.69 (dd, J=14.2, 6.4 Hz, 1H), 4.23 (s, 1H), 4.08-3.92 (m, 1H), 3.61 (dt, J=11.5, 6.9 Hz, 1H), 3.24 (s, 1H), 3.02 (qd, J=14.0, 6.4 Hz, 2H), 1.39 (s, 9H), 1.31 (s, 9H).

(209) .sup.13C NMR (100 MHz, CDCl.sub.3) 170.6, 170.5, 156.4, 154.4, 136.1, 130.8, 129.9, 128.6, 128.3, 128.1, 124.2, 82.7, 78.5, 67.3, 62.9, 55.4, 54.0, 37.2, 28.8, 28.0 ppm.

(210) HRMS m/z (ESI) calcd for C.sub.28H.sub.39N.sub.2O.sub.7 (M+H).sup.+: 515.2757, found 515.2759.de: >99%.

(211) The embodiments described above are only intended to describe the preferred embodiments of the invention, and are not intended to limit the scope of the invention, and various variants and modifications made to the technical solutions of the invention by those skilled in the art without departing from the design concept of the invention shall fall within the scope of the claims of the invention.