CN111499551A - Preparation method of β-hydroxyl-substituted alkyl dithiocarbamate - Google Patents

Abstract

The invention provides a preparation method of β -hydroxy-substituted alkyl dithiocarbamate, which belongs to the technical field of organic synthesis and comprises the following steps of (1) adding an alkali catalyst, a styrene derivative and thiuram disulfide into an organic solvent for reaction, and then cooling to room temperature to obtain a reaction liquid, and (2) concentrating, separating and purifying the reaction liquid obtained in the step (1) to obtain the product.

Description

Preparation method of β-hydroxyl-substituted alkyl dithiocarbamate

technical field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a β-hydroxyl-substituted alkyl dithiocarbamate.

Background technique

Over the past decade, transition metal-catalyzed difunctionalization of alkenes has been an effective method to introduce two functional groups into alkenes through a one-step reaction, with the advantages of high efficiency, good regio- and stereoselectivity, and strong tolerance to functional groups . However, the use of transition metals can lead to potential contamination of the product, which is especially important in the pharmaceutical industry.

In view of the above technical problems, in recent years, a transition metal-free synthesis method has been proposed. Transition-Metal-Free Synthesis Although numerous synthetic results for the selective difunctionalization of olefins have been obtained, the synthesis of β-hydroxy-substituted alkyl disulfides is achieved through the regioselective difunctionalization of thiuram disulfides and styrene. A method for substitution of carbamates has not been described so far. The main reason may be due to the lack of effective methods. The product of the reaction is β-hydroxy-substituted alkyl dithiocarbamate, which is a kind of widely used organic synthesis intermediate, and has important application value in the fields of pharmaceutical production, organic synthesis and rubber production.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a preparation method of β-hydroxyl-substituted alkyl dithiocarbamate, the preparation method synthesizes β-hydroxyl through the regioselective bifunctionalization reaction of thiuram disulfide and styrene Substituted alkyl dithiocarbamates.

In order to achieve the above object, the technical scheme adopted in the preparation method of the β-hydroxyl-substituted alkyl dithiocarbamate of the present invention is: the preparation method of the β-hydroxyl-substituted alkyl dithiocarbamate, Include the following steps:

(1) adding alkali catalyst, styrene derivative and thiuram disulfide into an organic solvent for reaction, and then cooling to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is concentrated, separated and purified to obtain β-hydroxydithiocarbamate.

Further, the molar ratio of the base catalyst, the styrene derivative and the thiuram disulfide is 0.2: 0.2: 0.1.

Further, the base catalyst is cesium carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium bicarbonate, potassium acetate, sodium acetate, sodium ethoxide, lithium methoxide, lithium tert-butoxide, potassium tert-butoxide, One or more of sodium tert-butoxide, lithium hydroxide, sodium hydroxide and potassium hydroxide.

Further, the styrene derivatives are styrene, 3-chlorostyrene, 4-chlorostyrene, 3-bromostyrene, 4-bromostyrene, 4-fluorostyrene, 4-methylstyrene, 4-methoxystyrene, 4-tert-butylstyrene or 4-methyl-5-vinylthiazole.

Further, the thiuram disulfide is one or more of tetramethylthiuram disulfide, tetraethylthiuram disulfide, and tetrabutylthiuram disulfide.

Further, the organic solvent is one or more of 1.4-dioxane, toluene, xylene, mesitylene, tetrahydrofuran, acetonitrile, ethanol, and tert-butyl methyl ether.

Further, the consumption of described organic solvent is: every mole of thiuram disulfide uses 10 L of organic solvent

Further, the reaction temperature in the step (1) is 80°C, and the reaction time is 48h.

Further, the specific steps of separation and purification in the step (2) are as follows: the concentrate produced after concentrating the reaction solution is separated by thin-layer chromatography using petroleum ether/ethyl acetate volume ratio 5/1 as a developing solvent.

The preparation method of β-hydroxyl-substituted alkyl dithiocarbamate of the present invention, the reaction principle is as follows (taking 4-chlorostyrene as an example):

Beneficial effects of the present invention:

(1) The present invention adopts the method of one-pot cooking, uses sodium ethoxide as a catalyst, and uses economical and easily available 4-chlorostyrene and tetramethylthiuram disulfide as raw materials, and a coupling reaction directly occurs in the air to generate the corresponding 2 -(4-Chlorophenyl)-2-hydroxyethyldimethylaminodithioate, the product 2-(4-chlorophenyl)-2-hydroxyethyldimethylaminodithioate can be As antibacterial agent, anticancer agent, vulcanization accelerator, etc.;

(2) The synthesis system of the present invention has a wide application range and is compatible with functional groups such as halogenated, alkyl and alkoxy.

(3) The preparation method of the present invention has the advantages of simple process, convenient operation, mild reaction conditions, wide substrate range and high yield, and is suitable for popularization and application.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments.

Example 1

The preparation method of 2-(4-chlorophenyl)-2-hydroxyethyl dimethylamino dithioate comprises the following steps:

(1) Take 0.2 mmol of 4-chlorostyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 15.8 mg of the desired product.

The target product yield of this embodiment is 58%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.46-7.39(d, J = 8.4 Hz, 2H), 7.36-7.31 (d, J = 8.5 Hz, 2H), 5.09-4.98 (d, J = 8.4 Hz, 1H), 3.90-3.79 (dd, J = 14.5, 3.4 Hz, 1H), 3.59 (s, 3H), 3.58-3.50 (t, J =14.5, 6.0 Hz, 1H), 3.42 (s, 3H), 3.28-3.18 (d, J = 2.6 Hz, 1H); 13C NMR (100MHz, CDCl3) 197.4, 141.4, 133.5, 128.6, 127.3, 72.6, 45.9, 45.6, 41.8; IR(KBr) : 3394, 3183, 2920, 2849, 1646, 1492, 1471, 1375, 1252, 1144, 1087, 976cm-1; HRMS (ESI) calcd. for C11H14ClNOS2: [M+Na]+: 298.0103, found: 298.0103.

Example 2

The preparation method of 2-(3-chlorophenyl)-2-hydroxyethyl dimethylamino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-chlorostyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 14.4 mg of the desired product.

The target product yield of this embodiment is 52%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.49 (s,1H), 7.39-7.34 (d, J = 7.3 Hz, 1H), 7.34-7.29 (d, J = 7.8 Hz , 1H), 7.29-7.24(m, 1H), 5.08-4.98 (dd, J = 8.4, 2.6 Hz, 1H), 3.91-3.81 (dd, J = 14.6, 3.4Hz, 1H), 3.59 (s, 3H) ), 3.58-3.50 (dd, J = 14.6, 6.0 Hz, 1H), 3.43 (s, 3H), 3.35-3.25 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) 197.4, 145.0 , 134.4, 129.8, 127.9, 126.0, 124.1, 72.7, 45.9, 45.5, 41.8; IR(KBr): 3203, 2921, 2850, 1646, 1498, 1473, 1429, 1377, 1254, 27 cm-1058, 97 ; HRMS (ESI)calcd. for C11H14ClNOS2: [M+Na]+: 298.0103, found: 298.0102.

Example 3

The preparation method of 2-(4-bromophenyl)-2-hydroxyethyl dimethylamino dithioate, comprises the following steps:

(1) Take 0.4 mmol of 4-bromostyrene, 0.2 mmol of tetramethylthiuram disulfide and 0.4 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of Schlenk In the tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 17.3 mg of target product.

The target product yield of this embodiment is 54%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.54-7.45(d, J = 8.4 Hz, 2H), 7.41-7.32 (d, J = 8.3 Hz, 2H), 5.10-4.96 (dd, J = 8.4, 3.0 Hz, 1H), 3.90-3.79 (dd, J = 14.5, 3.5 Hz, 1H), 3.59 (s, 3H), 3.58-3.48(m, 1H), 3.42 (s, 3H) ), 3.24 (s, 1H); 13C NMR (100 MHz, CDCl3) 197.4, 141.9, 131.6, 127.6, 121.6, 72.6, 45.9, 45.6, 41.8; IR(KBr): 3392, 2922, 2850, 2367, 2333, 1906, 1646, 1590, 1488, 1375, 1252, 1143, 1064, 1008, 976 cm-1; HRMS(ESI) calcd. for C11H14BrNOS2: [M+Na]+: 341.9598, found: 341.9596.

Example 4

The preparation method of 2-(3-bromophenyl)-2-hydroxyethyl dimethylamino dithioester, comprises the following steps:

(1) Take 0.2 mmol of 3-bromostyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 15.3 mg of the desired product.

The target product yield of this embodiment is 48%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.64 (s, 1H), 7.46-7.36 (t, J = 15.3, 7.7 Hz, 2H), 7.28-7.20 (t, J = 15.8, 8.0 Hz, 2H), 5.08-4.98 (dd, J = 8.5, 3.2 Hz, 1H), 3.91-3.81 (dd, J = 14.6, 3.4 Hz, 1H), 3.59 (s, 3H), 3.58-3.50 (dd, J = 14.6, 6.0 Hz, 1H), 3.43 (s, 3H), 3.29(s, 1H); 13C NMR (100 MHz, CDCl3) 197.3, 145.2, 130.8, 130.0, 129.0, 124.6,122.6, 72.6 , 45.9, 45.5, 41.8; IR(KBr): 3391, 3184, 2961, 2920, 2850, 1646, 1500, 1469, 1423, 1379, 1253, 1060, 970 cm-1; HRMS (ESI) calcd. forC11H14BrNOS2: [ M+Na]+:341.9598, found:341.9597.

Example 5

The preparation method of 2-(4-fluorophenyl)-2-hydroxyethyl dimethylamino dithioate comprises the following steps:

(1) Take 0.2 mmol of 4-fluorostyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of Schlenk In the tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 12.2 mg of the desired product.

The target product yield of this embodiment is 47%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.50-7.40(m, 2H), 7.10-7.00 (m, 2H), 5.10-4.98 (dd, J = 8.4, 2.8 Hz, 1H), 3.90-3.78(dd, J = 14.5, 3.4 Hz, 1H), 3.59 (s, 3H), 3.58-3.50 (m, 1H), 3.43 (s, 3H), 3.17 (s, 1H); 13C NMR (100 MHz, CDCl3) 197.4, 162.3 (d, J = 244.1 Hz), 138.7 (d, J = 2.9 Hz), 127.5 (d, J = 8.1 Hz), 115.3 (d, J = 21.2 Hz), 72.7 HRMS (ESI) calcd. for C11H14FNOS2: [M+Na]+:282.0399, found: 282.0400.

Example 6

The preparation method of 2-(4-methoxyphenyl)-2-hydroxyethyl dimethylamino dithioate comprises the following steps:

(1) Take 0.2 mmol of 4-methoxystyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of In a Schlenk tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 13.6 mg of the desired product.

The target product yield of this embodiment is 50%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.45-7.36(d, J = 8.6 Hz, 2H), 6.95-6.85 (d, J = 8.8 Hz, 2H), 5.05-4.94 (dd, J = 8.7, 3.4 Hz, 1H), 3.86-3.77 (m, 4H), 3.67-3.54 (m, 4H), 3.42 (s, 3H), 3.01 (s, 1H); 13C NMR (100 MHz) , CDCl3) 197.6, 159.3, 135.1, 127.1, 113.9, 72.9, 55.3, 45.8, 41.8; IR(KBr): 3389, 2995, 2955, 2920, 2850, 16,11, 1511, 1465, 1377,1 1146, 1032, 976, 833 cm-1; HRMS (ESI) calcd. forC12H17NO2S2: [M+Na]+:294.0598, found: 294.0597.

Example 7

The preparation method of 2-(4-tert-butylphenyl)-2-hydroxyethyl dimethylamino dithioate comprises the following steps:

(1) Take 0.2 mmol of 4-tert-butylstyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of In a Schlenk tube, it was heated in an oil bath at 80 °C, and after 48 h of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 14.4 mg of the desired product.

The target product yield of this embodiment is 48%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.40 (s, 4H), 5.10-4.90 (dd, J = 9.0, 3.3 Hz, 1H), 3.90-3.80 (dd, J = 14.4, 3.4 Hz, 1H), 3.70-3.60 (dd, J = 14.4, 9.1 Hz, 1H), 3.59 (s, 3H), 3.42 (s, 3H), 3.02(s, 1H); 13C NMR (100 MHz) , CDCl3) 197.6, 150.8, 140.0, 125.6, 125.4, 73.1, 45.8, 45.7, 41.8, 34.6, 31.4; IR(KBr): 3415, 2959, 2925, 2867, 1660, 1502,124 1,1 1108, 1057, 977, 838 cm-1; HRMS (ESI) calcd. forC15H23NOS2: [M+Na]+:320.1119, found: 320.1118.

Example 8

The preparation method of 2-hydroxy-2-(4-methylthiazol-5-yl) dimethyl carbamate dithioethyl ester comprises the following steps:

(1) Take 0.2 mmol of 4-methyl-5-vinylthiazole, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture into In a 5ml Schlenk tube, heat in an oil bath at 80 °C, and after 48 hours of reaction, cool to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 14.9 mg of the desired product.

The target product yield of this embodiment is 57%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 8.66 (s, 1H), 5.45-5.35 (dd, J = 7.8, 3.9 Hz, 1H), 3.93-3.82 (dd, J = 14.4, 4.0 Hz, 1H), 3.67 (s, 1H), 3.65-3.60 (d, J = 7.9 Hz, 1H), 3.59 (s, 3H), 3.43 (s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) 196.8, 151.0, 148.9, 134.2, 67.1, 45.9, 45.1, 41.8, 15.7; IR(KBr): 3361, 3199, 2955, 2922, 2851, 1657, 1502, 137668, , 1254, 1145, 1057, 978, 945 cm-1; HRMS (ESI) calcd. forC9H14N2OS2: [M+Na]+: 285.0166, found: 285.0168.

Example 9

The preparation method of 2-(4-chlorophenyl)-2-hydroxyethyl diethyl amino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 4-chlorostyrene, 0.1 mmol of tetraethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of In a Schlenk tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 12 mg of the desired product.

The target product yield of this embodiment is 40%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.44-7.39(d, J = 8.4 Hz, 2H), 7.36-7.31 (d, J = 8.5Hz, 2H), 5.08-5.01 (dd, J = 8.4, 3.4 Hz, 1H), 4.12-3.99 (m, 2H), 3.89-3.81 (dd, J = 14.5, 3.5 Hz, 1H), 3.81-3.74 (m, 2H), 3.60-3.51 (dd, J = 14.5, 8.4Hz, 1H), 3.37 (s, 1H), 1.38-1.23(m, 6H); 13C NMR (100 MHz, CDCl3) 195.8, 141.5, 133.4, 128.6, 127.3, 72.7,50.2 HRMS ( ) calcd.for C13H18ClNOS2: [M+Na]+: 324.0416, found: 324.0414.

Example 10

The preparation method of 2-(3-chlorophenyl)-2-hydroxyethyl diethyl amino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-chlorostyrene, 0.1 mmol of tetraethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 12.4 mg of the desired product.

The target product yield of this embodiment is 41%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.49 (m, 1H), 7.39-7.33 (d, J = 7.3Hz, 1H), 7.33-7.29 (d, J = 7.8 Hz , 1H), 7.29-7.23(m, 1H), 5.10-4.99 (dd, J = 8.4, 3.2 Hz, 1H), 4.13-3.98 (m, 2H), 3.93-3.84(dd, J = 14.6, 3.4 Hz , 1H), 3.84-3.73 (m, 2H), 3.63-3.51 (dd, J = 14.6,8.5Hz, 1H), 3.43 (s, 1H), 1.40-1.20 (m, 6H); 13C NMR (100 MHz) , CDCl3) 195.7, 145.1, 134.4, 129.7, 127.8, 126.1, 124.1, 72.8, 50.2, 47.2, 45.0, 12.5, 11.6; IR(KBr): 3364, 21,74, 2921, 2850, 149, 1647, 1379, 1355, 1270,1205, 1070, 983, 789, 689 cm-1; HRMS (ESI) calcd. for C13H18ClNOS2: [M+Na]+:324.0416, found:324.0414.

Example 11

The preparation method of 2-(3-bromophenyl)-2-hydroxyethyl diethyl amino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-bromostyrene, 0.1 mmol of tetraethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of Schlenk In the tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 11 mg of the desired product.

The target product yield of this embodiment is 32%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.64 (s,1H), 7.45-7.36 (m, 2H), 7.29-7.20 (m, 1H), 5.10-4.98 (t, J = 8.4, 4.2 Hz, 1H), 4.14-3.97 (m, 2H), 3.92-3.84 (dd, J = 14.6, 3.4 Hz, 1H), 3.84-.3.70 (m, 2H), 3.63-3.50 (dd , J = 14.6, 8.4 Hz, 1H), 3.47-3.37 (d, J = 3.6 Hz, 1H), 1.36-1.27 (m, 6H); 13C NMR (100 MHz, CDCl3) 195.7, 145.4, 130.8, 130.0, 129.0, 124.6, 122.6, 72.7, 50.2, 47.2, 45.0, 12.5, 11.6; IR(KBr): 3394, 2957,2922, 2850, 1645, 1489, 1468, 1419, 1379, 12054, 1412 , 982cm-1; HRMS (ESI) calcd. for C13H18BrNOS2: [M+Na]+:369.9911, found: 369.9911.

Example 12

The preparation method of 2-(4-fluorophenyl)-2-hydroxyethyldiethylamino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 4-fluorostyrene, 0.1 mmol of tetramethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, put the mixture in 5 ml of In a Schlenk tube, it was heated in an oil bath at 80°C, and after 48 hours of reaction, it was cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 8.9 mg of the desired product.

The target product yield of this embodiment is 31%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.50-7.40(m, 2H), 7.10-7.00 (t, J = 17.5, 8.8 Hz, 2H), 5.10-4.98 (d, J = 7.7 Hz, 1H), 4.15-3.96 (m, 2H), 3.90-3.82 (dd, J = 14.5, 3.5 Hz, 1H), 3.82-3.73 (m, 2H), 3.64-3.50 (dd, J = 14.5, 8.6 Hz, 1H), 3.31 (s, 1H), 1.37-1.20 (m, 6H); 13CNMR (100 MHz, CDCl3) 195.8, 162.3 (d, J = 244.1 Hz), 138.8 (d, J = 2.3 Hz ), 127.6 (d, J = 8.1 Hz), 115.3 (d, J = 21.4 Hz), 72.7, 50.2, 47.1, 45.3, 12.5, 11.6; IR(KBr): 3394, 2920, 2848, 1644, 1488, 1467, 1418, 1269, 1207, 1142,1068, 982, 835, 541, 525, 509 cm-1; HRMS (ESI) calcd. for C13H18FNOS2: [M+Na]+: 310.0712, found: 310.0713.

Example 13

The preparation method of 2-(4-methylphenyl)-2-hydroxyethyl diethyl amino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-bromostyrene, 0.1 mmol of tetraethylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 7.4 mg of the desired product.

The target product yield of this embodiment is 26%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.41-7.33(d, J = 8.0 Hz, 2H), 7.23-7.13 (d, J = 7.9 Hz, 2H), 5.08-4.93 (t, J = 8.6, 5.0 Hz, 1H), 4.15-3.95 (m, 2H), 3.89-3.81 (dd, J = 14.4, 3.6 Hz, 1H), 3.81-3.72 (m, 2H), 3.69-3.57 (dd, J = 14.4, 8.7 Hz, 1H), 3.20-3.08 (d, J = 3.5 Hz, 1H), 2.40-2.30 (s, 3H), 1.40-1.20 (m, 6H); 13C NMR (100 MHz) , CDCl3) 196.0, 140.1, 137.4, 129.1, 125.8, 73.2, 50.1, 47.1, 45.3, 21.2, 12.5, 11.6; IR(KBr): 3394, 2977, 29,21, 2849, 1646, 14689, 1355, 1268,1205, 1142, 1067, 982, 736 cm-1; HRMS (ESI) calcd. for C14H21NOS2: [M+Na]+:306.0962, found: 306.0963.

Example 14

The preparation method of 2-(4-chlorophenyl)-2-hydroxyethyl dibutylamino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 4-chlorostyrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 15.1 mg of the desired product.

The target product yield of this embodiment is 42%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.47-7.37(d, J = 8.4 Hz, 2H), 7.37-7.30 (d, J = 8.5 Hz, 2H), 5.10-4.96 (d, J = 6.7 Hz, 1H), 4.07-3.89 (m, 2H), 3.89-3.80 (dd, J = 14.6, 3.4 Hz, 1H), 3.76-3.61 (m, 2H), 3.60-3.50 (dd , J = 14.6, 8.5Hz, 1H), 3.37 (s, 1H), 1.80-1.64 (m, 4H), 1.45-1.30 (m, 4H), 1.03-0.90 (m, 6H); 13C NMR (100 MHz) , CDCl3)196.0, 141.6,133.4, 128.6, 127.3, 72.7, 55.7, 52.9, 45.2, 29.4, 28.4, 20.1, 13.8, 13.7; IR(KBr): 3358, 2958, 2926, 2857 1,4 1369, 1290, 1218, 1185,1091, 1064, 1013, 980, 945, 828, 755 cm-1; HRMS (ESI) calcd. forC17H26ClNOS2: [M+H]+: 360.1223, found: 360.1223.

Example 15

The preparation method of 2-(3-chlorophenyl)-2-hydroxyethyl dibutylamino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-chlorostyrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 16.5 mg of the desired product.

The target product yield of this embodiment is 46%.

The NMR characterization of the target product is as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.48 (s, 1H), 7.38-7.33 (m, 1H), 7.33-7.28 (m, 1H), 7.28-7.23 (m, 1H), 5.10-4.98 (t, J= 8.3, 4.9 Hz, 1H), 4.04-3.92 (m, 2H), 3.90-3.80 (dd, J = 14.6, 3.4 Hz, 1H), 3.75-3.64 (m, 2H), 3.62-3.50 (dd, J = 14.6, 8.4Hz, 1H), 3.46-3.36 (d, J = 3.3Hz, 1H), 1.80-1.66 (m, 4H), 1.45-1.32 (m, 4H) , 1.02-0.93 (m, 6H); 13C NMR (100 MHz, CDCl3) 196.0, 145.1, 134.4, 129.7, 127.8, 126.1, 124.1, 72.8, 55.1, 52.9, 45.1, 29.4, 28.4, 3.8.1, 13.8; IR(KBr): 3358, 2959, 2927, 2855, 1657, 1632, 1597, 1537, 1468, 1415, 1367, 1290, 1217, 1184, 1140, 1095, 1061cm-1; [M+H]+: 360.1223, found: 360.1221.

Example 16

The preparation method of 2-(4-bromophenyl)-2-hydroxyethyl dibutylamino dithioate, comprises the following steps:

(1) Take 0.2 mol of 4-bromostyrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 15.1 mg of the desired product.

The target product yield of this embodiment is 38%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.55-7.45(d, J = 8.4 Hz, 2H), 7.40-7.30 (d, J = 8.4 Hz, 2H), 5.08-4.98 (dd, J = 8.4, 3.2 Hz, 1H), 4.06-3.90 (m, 2H), 3.89-3.80 (dd, J = 14.6, 3.4 Hz, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (dd, J = 14.6, 8.5 Hz, 1H), 3.38 (s, 1H), 1.80-1.66(m, 4H), 1.44-1.30 (m, 4H), 1.03-0.90 (m, 6H); 13C NMR ( 100 MHz, CDCl3)196.0, 142.0, 131.5, 127.7, 121.5, 72.8, 55.7, 52.9, 45.1, 29.4, 28.4, 20.1,13.8, 13.7; IR(KBr,): 3360, 2958, 2928, 1486 1368, 1290, 1250,1218, 1069, 1010, 521 cm-1; HRMS (ESI) calcd. for C17H26BrNOS2: [M+Na]+:426.0537, found: 426.0535.

Example 17

The preparation method of 2-(3-bromophenyl)-2-hydroxyethyl dibutylamino dithioate, comprises the following steps:

(1) Take 0.2 mmol of 3-bromostyrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 17.6 mg of the desired product.

The target product yield of this embodiment is 44%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.64 (s, 1H), 7.46-7.36 (t, J = 16.1, 8.1 Hz, 2H), 7.27-7.18 (m, 1H) , 5.08-4.98 (d, J= 8.2 Hz, 1H), 4.07-3.90 (m, 2H), 3.90-3.81 (dd, J = 14.6, 3.4 Hz, 1H), 3.78-3.61 (m, 2H), 3.61 -3.50 (dd, J = 14.6, 8.4 Hz, 1H), 3.49-3.40 (d, J = 2.8 Hz, 1H), 1.80-1.66 (m, 4H), 1.44-1.30 (m, 4H), 1.03-0.90 (m, 6H); 13C NMR (100MHz, CDCl3) 196.0, 145.4, 130.7, 130.0, 129.1, 124.6, 122.6, 72.7, 55.7, 52.9, 45.0, 29.4, 28.4, 20.1, 13.8, 13.7; IR(KBr): 3394, 2957, 2923, 2851,1645, 1484, 1417, 1369, 1291, 1251, 1217, 1186, 1093, 1063 cm-1; HRMS (ESI)calcd. : 426.0536.

Example 18

The preparation method of 2-(4-fluorophenyl)-2-hydroxyethyldibutylamino dithioester, comprises the following steps:

(1) Take 0.2 mmol of 4-fluorostyrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, and place the mixture in a 5 ml Schlenk tube , heated in an oil bath at 80°C, reacted for 48h, cooled to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 14.6 mg of the desired product.

The target product yield of this embodiment is 43%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: 7.51-7.41(m, 2H), 7.13-6.99 (t, J = 17.4, 8.7 Hz, 2H), 5.10-4.98 (dd, J = 8.5, 3.3 Hz, 1H), 4.06-3.88 (m, 2H), 3.88-3.78 (dd, J = 14.5, 3.4 Hz, 1H), 3.78-3.62 (m, 2H), 3.62-3.50 (dd, J = 14.5, 8.6 Hz, 1H), 3.33 (s, 1H), 1.80-1.66 (m, 4H), 1.45-1.31 (m, 4H), 1.04-0.90 (m, 6H); 13C NMR (100 MHz, CDCl3) 196.0, 162.3 (d, J = 244.1 Hz), 138.8 (d, J = 3.0 Hz ), 127.6 (d, J = 8.1 Hz), 115.2 (d, J = 21.4 Hz), 72.8, 55.7, 52.9, 45.3, 29.4, 28.4, 20.1, 13.8, 13.7; IR(KBr): 3360, 2958, 2923, 2852, 1509, 1485, 1467, 1415, 1369, 1290, 1221, 1186, 837cm-1; HRMS (ESI calc) . for C17H26FNOS2: [M+Na]+: 366.1338, found: 366.1339.

Example 19

The preparation method of 2-hydroxy-2-phenylethyl dimethylamino methyl dithioate, comprises the following steps:

(1) Take 0.2 mmol of styrene, 0.1 mmol of tetrabutylthiuram disulfide and 0.2 mmol of sodium ethoxide, add 1 ml of 1.4-dioxane to obtain a mixture, place the mixture in a 5 ml Schlenk tube, and place it in a 5 ml Schlenk tube. Heating in an oil bath at 80 °C, reacting for 48 h, and cooling to room temperature to obtain a reaction solution;

(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate, and the concentrate is separated by thin layer chromatography with ethyl acetate/petroleum ether=1/5 (v/v) as a developing solvent to obtain 15.6 mg of the desired product.

The target product yield of this embodiment is 23%.

The target product was characterized by NMR as follows: 1H NMR (400 MHz, CDCl3) ppm: δ 7.53-7.46(d, J = 7.36 Hz, 2H), 7.42-7.34 (t, J = 14.9, 7.2 Hz, 2H), 7.33-7.27 (t, J =14.6, 7.3 Hz, 1H), 5.10-4.98 (d, J = 8.6 Hz, 1H), 3.92-3.80 (dd, J = 14.5,3.4 Hz, 1H), 3.67-3.60 ( t, J = 14.7, 8.8 Hz, 1H), 3.59 (s, 1H), 3.42 (s, 1H), 3.15 (s, 1H); 13C NMR (100 MHz, CDCl3) 197.6, 142.9, 128.5, 127.8, 125.9 ,73.3, 45.9, 45.7, 41.8; IR (KBr): 3204, 3028, 2921, 1491, 1451, 1373, 1254, 1079, 974, 724, 692 cm-1; HRMS (ESI) calcd. for C11H15NOS2: [M +Na]+:246.0493, found:264.0485.

In the above embodiment, 1.4-dioxane is an organic solvent. In other embodiments, 1.4-dioxane can also be replaced by one or more of toluene, xylene, mesitylene, tetrahydrofuran, acetonitrile, ethanol and tert-butyl methyl ether; of course, the organic solvent is also It can be any one or a combination of 1.4-dioxane and toluene, xylene, mesitylene, tetrahydrofuran, acetonitrile, ethanol, and tert-butyl methyl ether.

In the above embodiment, sodium ethoxide is an alkali catalyst. In other embodiments, the sodium ethoxide can also be cesium carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium bicarbonate, potassium acetate, sodium acetate, lithium methoxide, lithium tert-butoxide, potassium tert-butoxide , one or more of sodium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide to replace; of course, the base catalyst can also be sodium ethoxide and cesium carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, Any one or more of potassium phosphate, sodium bicarbonate, potassium acetate, sodium acetate, lithium methoxide, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide The combination.

In the above embodiment, styrene, 3-chlorostyrene, 4-chlorostyrene, 3-bromostyrene, 4-bromostyrene, 4-fluorostyrene, 4-methoxystyrene, 4-tert-butyl Styrene and 4-methyl-5-vinylthiazole are styrene derivatives. In other embodiments, the styrene derivative may also be 4-methylstyrene.

The present invention has been described in detail above in conjunction with the embodiments, but those skilled in the art can understand that, without departing from the purpose of the present invention, each specific parameter in the above-mentioned embodiments can also be changed to form a plurality of The specific embodiments are all within the common variation range of the present invention, and will not be described in detail here.

Claims (9)

1. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate, is characterized in that, comprises the following steps: (1) adding alkali catalyst, styrene derivative and thiuram disulfide into an organic solvent for reaction, and then cooling to room temperature to obtain a reaction solution; (2) Concentrating the reaction solution obtained in step (1), separating and purifying to obtain β-hydroxydithiocarbamate. 2. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that, the mol ratio of described base catalyst, styrene derivative, thiuram disulfide is 0.2 : 0.2 : 0.1. 3. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that, described base catalyst is cesium carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate , one or more of sodium bicarbonate, potassium acetate, sodium acetate, sodium ethoxide, lithium methoxide, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide . 4. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that, described styrene derivative is styrene, 3-chlorostyrene, 4-chlorobenzene Ethylene, 3-bromostyrene, 4-bromostyrene, 4-fluorostyrene, 4-methylstyrene, 4-methoxystyrene, 4-tert-butylstyrene or 4-methyl-5- Vinylthiazole. 5. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that: described thiuram disulfide is tetramethylthiuram disulfide, tetraethyl disulfide One or more of kithiuram and tetrabutylthiuram disulfide. 6. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that, described organic solvent is 1.4-dioxane, toluene, xylene, mesitylene, One or more of tetrahydrofuran, acetonitrile, ethanol, tert-butyl methyl ether. 7. the preparation method of β-hydroxyl-substituted alkyl dithiocarbamate according to claim 1, is characterized in that, the consumption of described organic solvent is: every mole of thiuram disulfide uses 10 L of organic solvent. 8. The preparation method of β-hydroxy-substituted alkyl dithiocarbamate according to any one of claims 1-8, wherein the reaction temperature in the step (1) is 80°C, and the reaction The time is 48h. 9. The preparation method of β-hydroxy-substituted alkyl dithiocarbamate according to any one of claims 1-8, wherein the specific steps of separation and purification in the step (2) are: The concentrate produced by concentrating the reaction solution was separated by thin layer chromatography using petroleum ether/ethyl acetate volume ratio 5/1 as a developing solvent.