Double-sulfhydrylation conjugate of active allyl alcohol acetate as well as preparation method and application of double-sulfhydrylation conjugate

Abstract

The preparation method comprises the following steps: adding mercaptan, an allyl alcohol acetate compound and a catalyst into a reaction solvent, carrying out a stirring reaction at 37 DEG C for 6 h to obtain a reaction solution, carrying out filtering, and removing the reaction solvent of the reaction solution to obtain the dithiolated conjugate of the active allyl alcohol acetate. And purifying by thin layer chromatography / column chromatography to obtain the dithiolated conjugate of the active allyl alcohol acetate. The allyl alcohol acetate compound used in the preparation method is simple in synthesis and good in conversion rate, the applicable substrate range is wide, in addition, the preparation method is simple in step, and has the advantages of being convenient to operate, environmentally friendly, excellent in stereoselectivity and capable of tolerating broad-spectrum functional groups; in addition, the method is high in reaction speed and high in cysteine selectivity, and the reaction is irreversible.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a bis-thiolated conjugate of a reactive allyl alcohol acetate, a preparation method thereof, and an application thereof. Background Art

[0002] Carbon-sulfur bonds are widely present in many natural products, drugs, proteins, and advanced materials. Data analysis of drug compounds approved by the US Food and Drug Administration over the past century found that sulfur-containing drugs account for 22.5% of the top 200 brand-name drugs in the total US prescriptions. Sulfur is the third most important heteroatom in drugs, followed by nitrogen and oxygen, and has been used to treat 12 major disease areas, including infections, cardiovascular diseases, and cancers. Sulfur can expand its valence shell, form more than four covalent bonds, and exhibit oxidation states ranging from -2 to +6, thus allowing many different molecular arrangements. The most common moieties are sulfonamides, sulfones, and thioethers, which are most prominent in penicillins, bicalutamide, or Viagra.

[0003] The formation of carbon-sulfur bonds plays a central role in the mechanism of action of covalent kinase inhibitors. Among the 62 protein kinase inhibitors approved by the US Food and Drug Administration, 7 irreversibly form covalent adducts with their target enzymes. Cysteine is a relatively rare residue containing a nucleophilic side chain and is the most popular target in the field of kinase inhibitors. For example, acrylamides, propargylamides, or epoxy groups covalently bind to the cysteine thiol on the target biomolecule, resulting in the inactivation of pathogenic proteins.

[0004] In addition to small molecule drugs, the formation of carbon-sulfur bonds is also utilized in biopharmaceuticals. In the field of antibody-drug conjugates, which is an emerging cancer immunotherapy. 7 out of 11 antibody-drug conjugates approved by the US Food and Drug Administration are constructed by binding drug molecules to the thiol functional groups of cysteine residues of monoclonal antibodies through the formation of carbon-sulfur bonds.

[0005] Not only in the biomedical field, the formation of carbon-sulfur bonds is also applied in the field of nanotechnology. As excellent σ donors and π acceptors, sulfur atoms are prone to form coordination bonds with metal surfaces such as gold nanoparticles. Therefore, thiol-functionalized aliphatic or poly(ethylene glycol) linkers are used to form self-assembled monolayers.

[0006] Double carbon-sulfur bonds can multiply the advantages on the basis of single carbon-sulfur bonds. Currently, there are linkers for disulfide re-bridging available for the production of antibody-drug conjugates. The dual-reactive linker reacts with two thiol residues from the reduced cysteine disulfide bond, thereby achieving covalent re-bridging of proteins. Such a linker can produce antibody-drug conjugates with more precise antibody and drug ratios and drug distributions, as well as covalent bonds between recombinant antibody chains.

[0007] Currently, the mainstream methods for constructing carbon-sulfur double bonds include: disulfones, divinylpyrimidines, 3-bromo-5-methylenepyrrolidinone, arylidene dicyanides, 3,3-bis(bromomethyl)oxetane, dichlorotetrazine, click reaction of thiol and alkyne coupling, 2H-azin-2-carboxamide, dichloroacetophenone.

[0008] Although the methods for constructing a single carbon-sulfur bond are relatively perfect at present, exploring new synthetic methods for constructing carbon-sulfur double bonds while combining two thiols into a linker is still a developing field, especially in terms of atom economy, high regioselectivity, and mild reaction conditions. Herein, we have developed a thiolation protocol for constructing carbon-sulfur double bonds using allyl alcohol acetate, in which allyl alcohol acetate compounds are cheap and readily available, and the desired dithiolated conjugate can be obtained in high yield in a metal-free manner under mild and efficient conditions. Summary of the Invention

[0009] The primary object of the present invention is to provide a dithiolated conjugate of allyl alcohol acetate.

[0010] Another object of the present invention is to provide a preparation method of the above-mentioned dithiolated conjugate of allyl alcohol acetate, aiming to solve problems such as the lack of construction of double C-S bonds in existing preparation methods.

[0011] Another object of the present invention is to provide an application of the above-mentioned dithiolated conjugate of allyl alcohol acetate.

[0012] The present invention is realized as follows: a dithiolated conjugate of allyl alcohol acetate, its preparation method and application. The method includes the following steps:

[0013] (1) Add thiol, triphenylphosphine, and allyl alcohol acetate compounds to a reaction solvent, and stir and react at 37 °C for 6 h. The chemical equation of the reaction is:

[0014]

[0015] In this reaction formula, compound 1 is an allyl alcohol acetate compound, wherein R 1 is selected from electron-withdrawing groups, including but not limited to: nitro, cyano, trifluoromethyl, sulfonic acid group, carbonyl group, halogen (fluorine, chlorine, bromine, iodine), or heteroaryl (such as pyridyl, pyrimidinyl).

[0016] Compound 2 is thiol, wherein R 2 is selected from any one of thiols with a mercapto group, amino acids, or drug molecules.

[0017] Compound 3 is the product dithiolated conjugate of allyl alcohol acetate.

[0018] (2) Remove the reaction solvent from the reaction solution obtained in step (1), and then purify it by thin layer chromatography / column chromatography to obtain the bis-thiolated conjugate of allyl alcohol acetate.

[0019] In the preparation method of the present invention, under metal-free catalytic conditions, the bis-thiolated conjugate of allyl alcohol acetate is directly synthesized by cross-coupling of allyl alcohol acetate compounds with thiols, amino acids or drug molecules containing thiol groups, so that the reaction occurs in a mild condition in an environmentally friendly manner.

[0020] Compared with the disadvantages and deficiencies of the prior art, the present invention has the following beneficial effects:

[0021] (1) The allyl alcohol acetate compounds used in the preparation method of the present invention are allyl alcohol acetate compounds with simple synthesis and good conversion rate, and have a wide range of applicable substrates. For example, various substituted nitro groups, cyano groups, trifluoromethyl groups, alkynyl groups or sulfonic acid groups can be present on the allyl alcohol acetate, and it has the characteristics of low preparation cost; in addition, the preparation method of the present invention has simple steps, and has the characteristics of convenient operation, environmental friendliness, excellent stereoselectivity, and tolerance to a wide range of functional groups; moreover, the reaction rate of the method of the present invention is fast, has high selectivity for cysteine, and the reaction is irreversible.

[0022] (2) The bis-thiolated conjugate of allyl alcohol acetate prepared by the present invention can utilize its allyl ester and thiol moieties to be used as organic synthesis building blocks for various derivatizations, and is also an important skeleton widely present in natural products, biological and drug molecules, and has potential biological activity and drug activity. Description of the Drawings

[0023] Figure 1 is the 1H NMR spectrum of compound 3 in Example 1 of the present invention;

[0024] Figure 2 is the 13C NMR spectrum of compound 3 in Example 1 of the present invention;

[0025] Figure 3 is the 1H NMR spectrum of compound 5 in Example 2 of the present invention;

[0026] Figure 4 is the 13C NMR spectrum of compound 5 in Example 2 of the present invention;

[0027] Figure 5 is the 1H NMR spectrum of compound 7 in Example 3 of the present invention;

[0028] Figure 6 is the 13C NMR spectrum of compound 7 in Example 3 of the present invention;

[0029] Figure 7It is the 1H NMR spectrum of Compound 9 in Example 4 of the present invention;

[0030] Figure 8 It is the 13C NMR spectrum of Compound 9 in Example 4 of the present invention;

[0031] Figure 9 It is the 1H NMR spectrum of Compound 11 in Example 5 of the present invention;

[0032] Figure 10 It is the 13C NMR spectrum of Compound 11 in Example 5 of the present invention. Detailed implementation manners

[0033] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0034] Example 1

[0035] (1) 0.6 mmol of captopril methyl ester, 0.01 mmol of triphenylphosphine, 1.8 mL of phosphate buffer, 0.2 mmol of methyl 2-(acetyloxymethyl)acrylate, and 0.2 mL of acetonitrile were successively added to a 10 mL Schlenk tube, and the mixture was stirred at 37 °C for 6 h. The reaction equation is:

[0036]

[0037] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by thin layer chromatography. The developing agent was a dichloromethane / methanol system (20 / 1). The product was a pale yellow liquid, Compound 3, with a yield of 57%.

[0038] Compound 3 was characterized, 1 HNMR(400MHz, Chloroform-d)δ4.59 - 4.47(m, 2H), 3.73 - 3.64(m, 13H), 2.93 - 2.67(m, 9H), 2.54(dd, J = 12.5, 5.4Hz, 2H), 2.26 - 2.17(m, 2H), 2.14 - 1.92(m,6H), 1.22(d, J = 6.7Hz, 6H). 13CNMR (101 MHz, Chloroform-d) δ 173.9 (d, J = 4.0 Hz), 173.7, 172.9 (d, J = 11.5 Hz), 58.7, 52.3, 52.1 (d, J = 6.5 Hz), 47.1 (d, J = 2.9 Hz), 46.3, 39.0 (d, J = 10.0 Hz), 36.2, 35.9, 33.9 (d, J = 5.6 Hz), 29.2, 24.9, 17.3 (d, J = 8.1 Hz). IR (KBr): 2953, 2924, 1740, 1644, 1432, 1196, 750, cm -1 . HRMS (ESI) m / z: [M+H] + Calcd. for: C 25 H 41 N 2 O 8 S 2 561.2304; Found 561.2307. The NMR spectrum is as shown in Figures 1 - 2 The characterization results show that compound 3 is ((2S,2'S)-3,3'-((2-(methoxycarbonyl)propane-1,3-diyl)bis(sulfinyl))bis(2-methylpropanoyl))(S)-di-L-proline dimethyl ester.

[0039] Example 2

[0040] (1) 0.6 mmol of ethyl N-acetylcysteinate, 0.01 mmol of triphenylphosphine, 2 mL of phosphate buffer, and 0.2 mmol of methyl 2-(acetyloxymethyl)acrylate were successively added to a 10 mL Schlenk tube and stirred at 37 °C for 6 h. The reaction equation is:

[0041]

[0042] (2) After monitoring the reaction to completion by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by thin-layer chromatography. The eluent was a dichloromethane / methanol system (20 / 1), and the product was a colorless liquid compound 5 with a yield of 90%.

[0043] Compound 5 was characterized. 1 H NMR (400 MHz, ) δ 6.79 (dd, J = 15.8, 7.6 Hz, 2H), 4.87 - 4.78 (m, 2H), 4.32 - 4.19 (m, 4H), 3.74 (s, 3H), 3.08 - 2.96 (m, 3H), 2.89 - 2.75 (m, 5H), 2.08 (d, J = 3.0 Hz, 6H), 1.31 (td, J = 7.2, 1.0 Hz, 6H). 13CNMR (101 MHz, Chloroform-d) δ 173.1, 170.8 (d, J = 4.5 Hz), 170.2 (d, J = 3.3 Hz), 62.1, 52.4, 52.4, 52.3, 46.0, 34.8 (d, J = 23.2 Hz), 33.5 (d, J = 21.6 Hz), 23.2 (d, J = 3.6 Hz), 14.2. IR (KBr): 1736, 1656, 1495, 1438, 1275, 1261 cm - 1 . HRMS (ESI / [M+H] + ) Calcd. for: C 19 H 33 N 2 O 8 S 2 481.1678, found 481.1674. The NMR spectrum is as shown in Figures 3 - 4 . The characterization results show that Compound 5 is 12,4 - diethyl - 8 - methyl (4R,12S) - 2,14 - dioxo - 6,10 - dithia - 3,13 - diazapentane - 4,8,12 - tricarboxylate.

[0044] Example 3

[0045] (1) 0.6 mmol of ethyl N - acetylcysteinate, 0.01 mmol of triphenylphosphine, 2 mL of phosphate buffer, and 0.2 mmol of 2 - benzoylacetate were successively added to a 10 mL Schlenk tube and stirred at 37 °C for 6 h. The reaction equation is:

[0046]

[0047] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by thin - layer chromatography. The eluent was a dichloromethane / methanol system (20 / 1). The product was a pale yellow liquid, Compound 7, with a yield of 83%.

[0048] Compound 7 was characterized. 11H NMR (400 MHz, Chloroform-d) δ 8.00 - 7.93 (m, 2H), 7.67 - 7.58 (m, 1H), 7.55 - 7.47 (m, 2H), 6.61 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 4.81 (dq, J = 7.5, 4.8 Hz, 2H), 4.29 - 4.11 (m, 4H), 3.80 (dt, J = 12.5, 6.2 Hz, 1H), 3.11 - 2.81 (m, 8H), 2.07 (s, 3H), 2.01 (s, 3H), 1.28 - 1.24 (m, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 200.5, 170.8 (d, J = 12.1 Hz), 170.1, 136.4, 133.8, 129.0, 128.5, 62.1, 52.4 (d, J = 17.3 Hz), 46.4, 35.1, 34.2 (d, J = 10.2 Hz), 23.2 (d, J = 7.1 Hz), 14.2 (d, J = 4.3 Hz). IR (KBr): 1715, 1275, 1260, 1204, 1099, 1022, 947, 848 cm -1 . HRMS (ESI) m / z: [M + H] + Calcd. for: C 24 H 35 N 2 O 7 S 2 527.1886; Found 527.1879. As Figures 5 - 6 shown, the characterization results indicate that compound 7 is ethyl S-(2-((((R)-2-acetamido-3-ethoxy-3-oxopropyl)thio)methyl)-3-oxo-3-phenylpropyl)-N-acetyl-D-cysteine.

[0049] Example 4

[0050] (1) 0.6 mmol of ethyl N-acetylcysteine, 0.01 mmol of triphenylphosphine, 2 mL of phosphate buffer, and 0.2 mmol of but-3-yn-1-yl 2-(acetyloxymethyl)acrylate were successively added to a 10 mL Schlenk tube and stirred at 37 °C for 6 h. The reaction equation is:

[0051]

[0052] (2) After monitoring the reaction to completion by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by thin-layer chromatography. The eluent was a dichloromethane / methanol system (20 / 1). The product was a pale yellow liquid, compound 10, with a yield of 56%.

[0053] Characterize compound 9, 1 H NMR (400 MHz, Chloroform-d) δ 6.73 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.86 - 4.80 (m, 2H), 4.27 - 4.22 (m, 6H), 3.08 - 3.01 (m, 4H), 2.88 - 2.79 (m, 5H), 2.56 (td, J = 6.7, 2.7 Hz, 2H), 2.08 (d, J = 1.4 Hz, 6H), 2.04 (t, J = 2.7 Hz, 1H), 1.32 - 1.29 (m, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 172.3, 170.8 (d, J = 2.7 Hz), 170.2 (d, J = 2.2 Hz), 79.9, 70.3, 62.9, 62.1, 52.4 (d, J = 15.0 Hz), 46.1, 34.9 (d, J = 24.5 Hz), 33.6 (d, J = 22.2 Hz), 23.2 (d, J = 2.5 Hz), 19.0, 14.2. IR (KBr): 1738, 1660, 1536, 1373, 1275, 1260, 1208, 1028 cm -1 . HRMS (ESI) m / z: [M + H] + Calcd. for: C 22 H 3s N 2 O 8 S 2 519.1835; Found 519.1827. The NMR spectrum is as Figures 7 - 8 shown, and the characterization results show that compound 9 is 8-(but-3-yn-1-yl)-12,4-diethyl (4R,12S)-2,14-dioxy-6,10-dithia-3,13-diazapentane-4,8,12-tricarboxylate.

[0054] Example 5

[0055] (1) Add 0.6 mmol of ethyl N-acetylcysteine, 0.01 mmol of triphenylphosphine, 2 mL of phosphate buffer, and 0.2 mmol of ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl 2-(acetoxymethyl)acrylate to a 10 mL Schlenk tube in sequence, and stir and react at 37 °C for 6 h. The reaction equation is:

[0056]

[0057] (2) After monitoring the reaction by TLC until completion, the solvent was removed using a rotary evaporator under vacuum. The product was separated by thin-layer chromatography, with the eluent being a petroleum ether / ethyl acetate system (10 / 1). The product was a yellow liquid, compound 11, with a yield of 98%.

[0058] Compound 11 was characterized. 1 H NMR (400 MHz, ) δ 6.89 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.53 (d, J = 4.9 Hz, 1H), 4.86 - 4.77 (m, 2H), 4.63 (dd, J = 7.9, 2.5 Hz, 1H), 4.43 - 4.16 (m, 8H), 3.09 - 2.78 (m, 9H), 2.08 (d, J = 1.6 Hz, 6H), 1.48 (d, J = 23.3 Hz, 6H), 1.35 - 1.28 (m, 12H). 13 C NMR (101 MHz, ) δ 172.1, 170.4, 169.9, 109.3, 108.5, 95.9, 70.6, 70.3, 70.0, 65.6, 63.7, 61.6 (d, J = 3.1 Hz), 52.0 (d, J = 14.1 Hz), 45.7, 34.3 (d, J = 38.5 Hz), 33.1 (d, J = 32.1 Hz), 26.4 - 21.9 (m), 13.8. IR (KBr): 2986, 2935, 1740, 1662, 1529, 1373, 1340, 1276, 1259, 1211, 1116, 1071, 1007 cm -1 . HRMS (ESI) m / z: [M + H] + Calcd. for: C 30 H 49 N 2 O 13 S 2 709.2676; Found 709.2670. The characterization results indicated that compound 11 was 12,4 - diethyl 8 - ((5R,5aS,8aS,8bR)-2,2,7,7 - tetramethyltetrahydro - 5h - bis([1,3]dioxolo)[4,5 - b:4',5'-d]pyran - 5 - yl)methyl)(4R,12S)-2,14 - dioxolo - 6,10 - dithia - 3,13 - diazapentadecane - 4,8,12 - tricarboxylate.

[0059] Example 6

[0060] This Example 6 is basically the same as Example 2, except for step (1): 12 mmol of ethyl N-acetylcysteine, 0.25 mmol of triphenylphosphine, 40 mL of phosphate buffer, and 4 mmol of methyl 2-(acetyloxymethyl)acrylate were successively added to a 250 mL Schlenk tube, and the mixture was stirred and reacted at 37 °C for 26 h. The yield of the obtained product was 88%.

[0061] Examples 7 - 14

[0062] Examples 7 - 14 are basically the same as Example 2, and the differences are shown in Table 1 below:

[0063] Table 1 Comparison of differences

[0064] Number Reaction solvent Reaction time Yield Example 7 PBS (pH = 8.0) 6h 90％ Example 8 PBS (pH = 8.0) / Acetonitrile = 9:1 6h 75％ Example 9 PBS (pH = 8.0) / Dichloromethane = 9:1 6h 52％ Example 10 PBS (pH = 8.0) / Ethanol = 9:1 6h 47％ Example 11 PBS (pH = 8.0) / Dimethyl sulfoxide = 9:1 6h 39％ Example 12 PBS (pH = 8.0) / Tetrahydrofuran = 9:1 6h 66％ Example 13 PBS (pH = 8.0) 18h 70％ Example 14 PBS (pH = 8.0) 72h 87％

[0065] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A dithiolated conjugate of an active allyl acetate, characterized in that: The chemical structure of the compound is shown in the following formula (I): In formula (I), R 1 Any one selected from an electron-withdrawing group, a heteroaryl group containing an electron-deficient heteroatom, and a condensed ring aromatic group; R 2 Any one selected from thiol, amino acid or drug molecule with sulfhydryl group.

2. The dithiolated conjugate of active allyl acetate according to claim 1, characterized in that: The electron-withdrawing group is selected from any one of a nitro group, a cyano group, a trifluoromethyl group, a sulfonic acid group, and a carbonyl group; The heteroaryl group containing an electron-deficient heteroatom is selected from any one of furanyl, indolyl, pyridyl and thienyl; The condensed ring aromatic group is naphthyl or anthracenyl.

3. A method for preparing a dithiolated conjugate of active allyl acetate, characterized in that: The method comprises the following steps: (1) adding a thiol, a catalyst and an allyl acetate compound to a reaction solvent, and stirring the reaction at 37° C. for 6 hours; wherein: The thiol is selected from any one of normal aromatic thiol, heteroaromatic thiol, condensed ring thiol, linear aliphatic thiol and cyclic aliphatic thiol; The catalyst is selected from any one of triphenylphosphine, tri(4-methoxyphenyl)phosphine, 4-dimethylaminopyridine and triethylenediamine. The allyl acetate compound is selected from any one of an electron-withdrawing group-containing allyl ester, an electron-deficient heteroatom-containing heteroaryl allyl ester, and a condensed ring aromatic allyl ester; The reaction solvent is selected from any one of phosphate buffer, tetrahydrofuran, acetonitrile and ethanol; (2) After the reaction time is reached as monitored by TLC, the reaction solution obtained in step (1) is freed of solvent and purified to obtain a dithiolated conjugate of active allyl acetate.

4. The method according to claim 3, characterized in that In step (1), the molar volume ratio of the thiol, the allyl acetate compound, triphenylphosphine, and the reaction solvent is 0.4-0.8 mmol: 0.2-0.4 mmol: 0.01-0.02 mmol: 2-4 mL.

5. The method according to claim 3, characterized in that In step (1), the thiol is selected from any one of cysteine, ethyl 2-mercaptoacetate, ethyl 2-mercaptopropionate, benzyl mercaptan, furfuryl mercaptan, 3-chlorothiophenol, 2-chlorothiophenol, 4-chlorothiophenol, 4-aminothiophenol, 2-aminothiophenol, 4-fluorothiophenol, 2-fluorothiophenol, 3-fluorothiophenol, 4-methylbenzyl mercaptan, 2-thiophenethiol, 4-methoxybenzyl mercaptan, 1-thio-D-glucose tetraacetate, captopril methyl ester, GTP-binding protein fragment, and cysteine-containing polypeptide.

6. The method according to claim 3, characterized in that In step (1), the allyl acetate compound is selected from methyl 2-acetoxymethylacrylate, ethyl 2-acetoxymethylacrylate, 2-(benzylcarbamoyl)allyl acetate, 2-benzoyl acetate, 2-(acetoxymethyl)acrylate but-3-yn-1-yl ester, 2-cyanoallyl acetate, (2S, 5R)-2-isopropyl-5-methylcyclohexyl 2-(acetoxymethyl)acrylate, 4-((tert-butyloxycarbonyl)amino)butyl 2-(acetoxymethyl)acrylate, ((5R, 5aS , 8aS, 8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxol)[4,5-b:4′,5′-d]pyran-5-yl)methyl 2-(acetoxymethyl)acrylate, 2-(1-((2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)ethyl 2-(acetoxymethyl)acrylate.

7. The method according to claim 3, characterized in that In step (1), the reaction was stirred at 37°C for 6 h.

8. The method according to claim 3, characterized in that In step (2), the solvent is removed by extraction, and then the reaction solvent is removed by vacuum rotary evaporator, and the purification is performed by thin layer chromatography / column chromatography, and the developing solvent system is dichloromethane / methanol = 20 / 1 (v / v).

9. Use of the dithiolated conjugate of active allyl acetate according to claim 1 or 2 in modifying drug molecules to synthesize a macromolecular skeleton compound having an allyl structure.

10. The use according to claim 9, characterized in that The drug molecules include captopril methyl ester.

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