阅读说明：本技术 一种乙烯基二硫代氨基甲酸酯类化合物的合成方法 (Synthesis method of vinyl dithiocarbamate compound ) 是由 洪志 杨钰莹 吕晓青 黄霄瑜 金瑛 于 2021-09-25 设计创作，主要内容包括：本发明公开了一种乙烯基二硫代氨基甲酸酯类化合物的合成方法,所述的方法是在室温下,将吸电子基取代的炔类、烷基黄原酸盐加到溶有伯胺或仲胺的溶剂混合液中,加料完毕,在25～100℃下反应至结束。反应液加水,滴加0.5mol/L盐酸中和,乙酸乙酯萃取。有机相先水洗,再经饱和食盐水洗,无水硫酸钠干燥。过滤后,滤液蒸馏回收有机溶剂,残留固体经甲苯重结晶,得到产品。本发明具有操作简便、无催化剂、环境友好、安全性较好、产品收率及纯度较高、易于工业化生产等优点。(The invention discloses a method for synthesizing a vinyl dithiocarbamate compound, which comprises the steps of adding an alkyne or alkyl xanthate substituted by an electron-withdrawing group into a solvent mixed solution dissolved with primary amine or secondary amine at room temperature, and reacting at 25-100 ℃ until the reaction is finished. Adding water into the reaction solution, dropwise adding 0.5mol/L hydrochloric acid for neutralization, and extracting by ethyl acetate. The organic phase was washed with water, then with saturated salt water, and dried over anhydrous sodium sulfate. And after filtering, distilling the filtrate to recover the organic solvent, and recrystallizing the residual solid by toluene to obtain the product. The method has the advantages of simple and convenient operation, no catalyst, environmental friendliness, better safety, higher product yield and purity, easy industrial production and the like.)

1. A method for synthesizing a vinyl dithiocarbamate compound comprises the steps of adding an acetylene or alkyl xanthate substituted by an electron-withdrawing group into a solvent mixed solution dissolved with primary amine or secondary amine at room temperature, and reacting at 25-100 ℃ until the reaction is finished. Adding water into the reaction solution, dropwise adding 0.5mol/L hydrochloric acid for neutralization, and extracting by ethyl acetate. Washing the organic phase with water, then with saturated salt water, anhydrous sulfurAnd (5) drying the sodium salt. And after filtering, distilling the filtrate to recover the organic solvent, and recrystallizing the residual solid by toluene to obtain the product. Wherein the substituent R in the structural formula¹Is one of aryl or ester group, substituent R²Is one of hydrogen, methyl, aryl, ester group and carboxyl, and the substituent R³Or R⁴Is one or two of hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, aryl and benzyl, and a substituent R⁵Is one of methyl or ethyl, and M is one of metal elements of sodium or potassium. The reaction equation is:

2. the method for synthesizing a vinyldithiocarbamate compound according to claim 1, wherein: the solvent is one or a mixture of more than two of the following components in any proportion: water, methanol, ethanol, isopropanol, polyethylene glycol 200, dichloromethane, chloroform, tetrahydrofuran.

3. The method for synthesizing a vinyldithiocarbamate compound according to claim 1, wherein: the ratio of the quantity of the electron-withdrawing group-substituted alkyne compound, the quantity of the primary amine or the secondary amine and the quantity of the alkyl xanthate is 1.0: 1.0-2.0: 1.0-5.0.

4. The method for synthesizing a vinyldithiocarbamate compound according to claim 1, wherein: the mass ratio of the solvent to the alkyne compound substituted by the electron-withdrawing group is 5-30: 1.

Technical Field

The invention relates to a synthetic method of a vinyl dithiocarbamate compound, belonging to the technical field of medicines and chemical industry.

Background

The compound of the ethylene dithiocarbamate is an organic molecule with various biological activities, and has wide application in the fields of medicines, minerals, organic synthesis intermediates and the like. In the aspect of medicine, the compounds have the functions of anti-inflammation, antibiosis, disinsection, anti-tumor, antivirus, anti-inflammation and the like; the compound has strong metal bonding capability due to containing various functional groups and heteroatoms such as nitrogen, oxygen, sulfur and the like, can effectively chelate heavy metals, can be used as an antidote for heavy metal poisoning, and is commonly used as a sulfide ore collecting agent in the aspect of ore dressing metallurgy; they are useful as synthetic intermediates, protecting groups in polypeptide synthesis, as linkers for solid phase organic synthesis. In addition, it can also be used as lubricating oil additive, metal corrosion inhibitor, vulcanization accelerator in rubber industry, etc.

At present, the preparation method of the vinyl dithiocarbamate compounds mainly comprises the following four methods:

1) the method for synthesizing the vinyl dithiocarbamate by condensing amine, carbon disulfide and styryl halide catalyzed by nano copper particles in water has the problems of long time, low reaction yield caused by easy oxidation of the nano copper particles, need of storage under argon gas and the like. The reaction formula is shown as formula 1:

2) under the condition of no solvent, synthesizing the compound of the ethylene dithio-formate in one pot by three components of amine, carbon disulfide and alkyne. The method is limited to use of phenylacetylene and propargyl ether/alcohol compounds, and has narrow application range and long reaction time. The reaction formula is shown as formula 2:

3) the alkene lacking electrons reacts with amine and carbon disulfide in dichloromethane solution at room temperature in situ to generate trans-vinyl dithiocarbamate. The allenes required for this reaction are not easily prepared and are not stable in nature, resulting in low yields. The reaction formula is shown as formula 3:

4) reacting 4,5,6, 7-tetrahydroindole with carbon disulfide in a DMSO solution under the action of potassium hydroxide to obtain potassium 1- (4,5,6, 7-tetrahydroindolyl) dithiocarbamate, and then reacting with alkyne in an aqueous solution to obtain a vinyl dithio compound and vinyl thioether. The reaction has the problems of complicated steps, difficult removal of generated by-products and the like. The reaction formula is shown as formula 4:

the carbon disulfide used in the four methods has a low boiling point of only 46.5 ℃, has strong volatility, inflammability, irritation and explosiveness, causes great potential safety hazards in use and storage, and is extremely easy to have great influence on the environment if the carbon disulfide is not properly treated after reaction. Therefore, there is still a need to develop a simple, efficient and safe method for synthesizing the vinyldithiocarbamate compounds.

Disclosure of Invention

The invention aims to overcome the defects of the synthesis method and provide a synthesis method of a vinyl dithiocarbamate compound.

The method takes alkynes, alkyl xanthate, primary amine or secondary amine substituted by electron-withdrawing groups as raw materials, and the raw materials react in a solvent to prepare the vinyl dithiocarbamate compound. In the reaction, primary amine or secondary amine and alkyl xanthate are subjected to ester ammonolysis reaction to obtain substituted dithio ammonium formate, and the product is continuously subjected to nucleophilic addition reaction with alkyne without separation to obtain the vinyl dithio carbamate compound.

The technical scheme adopted by the invention is as follows:

a method for synthesizing a vinyl dithiocarbamate compound comprises the steps of adding an acetylene or alkyl xanthate substituted by an electron-withdrawing group into a solvent mixed solution dissolved with primary amine or secondary amine at room temperature, and reacting at 25-100 ℃ until the reaction is finished. Adding water into the reaction solution, dropwise adding 0.5mol/L hydrochloric acid for neutralization, and extracting by ethyl acetate. The organic phase was washed with water, then with saturated salt water, and dried over anhydrous sodium sulfate. And after filtering, distilling the filtrate to recover the organic solvent, and recrystallizing the residual solid by toluene to obtain the product. The reaction formula is shown as formula 5:

the substituent R in the structural formula¹Is one of aryl or ester group, substituent R²Is one of hydrogen, methyl, aryl, ester group and carboxyl, and the substituent R³Or R⁴Is one or two of hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, aryl and benzyl, and a substituent R⁵Is one of methyl or ethyl, and M is one of metal elements of sodium or potassium.

The solvent is one or a mixture of more than two of the following components in any proportion: water, methanol, ethanol, isopropanol, polyethylene glycol 200, dichloromethane, chloroform, tetrahydrofuran.

The ratio of the quantity of the electron-withdrawing group-substituted alkyne compound, the quantity of the primary amine or the secondary amine and the quantity of the alkyl xanthate is 1.0: 1.0-2.0: 1.0-5.0.

The mass ratio of the solvent to the alkyne compound substituted by the electron-withdrawing group is 5-30: 1.

Compared with the prior art, the invention has the beneficial effects that: the alkyl xanthate adopted by the invention is a solid compound which is cheap and easy to obtain, has stable physicochemical properties and better reaction activity, and replaces carbon disulfide which is extremely easy to burn, explode, volatile, toxic and harmful. The by-product methanol or ethanol produced by the reaction can be recycled and reused. The method has the advantages of simple and convenient operation, no catalyst, high safety, environmental friendliness, higher product yield and purity, easy industrial production and the like.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of 2- (3-fluorophenylethenyl) N, N-diethyldithiocarbamate according to the present invention

FIG. 2 is a nuclear magnetic carbon spectrum of 2- (3-fluorophenylethenyl) N, N-diethyldithiocarbamate according to the present invention

FIG. 3 is an infrared spectrum of 2- (3-fluorophenylethenyl) N, N-diethyldithiocarbamate according to the present invention

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:

example 1

Into a 500mL three-necked flask were successively charged 152mL of water-methanol (volume ratio 1:1), 3.66g (0.05mol) of diethylamine, 26.68g (0.19mol) of sodium ethylxanthate and 6.01g (0.05mol) of 3-fluoro-1-ethynylbenzene, and the reaction was stirred at 70 ℃ for 50 min. After completion of the reaction, 20mL of water was added, followed by dropwise addition of 0.5mol/L HCl to adjust the pH to neutrality, followed by extraction with ethyl acetate (3X 50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was distilled under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 12.90g of N, N-diethyldithiocarbamic acid-2- (3-fluorophenylvinyl) ester. The yield was 95.80% and the HPLC purity was 98.30%. The structural formula of the product is shown as formula 6:

example 2

In a 250mL three-necked flask, 100mL of chloroform, 4.36g (0.05mol) of morpholine, 8.72g (0.067mol) of sodium methylxanthate and 7.31g (0.05mol) of phenylpropanoic acid were sequentially added, and the reaction was stirred at 60 ℃ for 100 min. After the reaction was complete, 40mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (3X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to obtain 14.17g of 3-phenyl-3- (4-morpholinodithioformate-based) acrylic acid. The yield was 91.60% and the HPLC purity was 97.30%.

In this example, the product has the following structural formula 7:

example 3

185mL of ethanol, 6.71g (0.08mol) of morpholine, 15.14g (0.105mol) of sodium ethylxanthate and 5.81g (0.05mol) of 4-ethynyltoluene were successively charged in a 500mL three-necked flask, and the reaction was stirred at 80 ℃ for 110 min. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 60mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 12.57g of 4-morpholinodithio-2- (4-methylstyryl) formate. The yield was 90.00% and the HPLC purity was 97.00%.

In this example, the product has the following structural formula 8:

example 4

80mL of water-ethanol (volume ratio 1:1), 4.83g (0.07mol) of diethylamine, 33.66g (0.05mol) of potassium ethylxanthate and 7.31g (0.05mol) of phenylpropionic acid were sequentially added to a 250mL three-necked flask, and the reaction was stirred at 60 ℃ for 65 min. After the reaction, 20mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 30mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to obtain 13.84g of 3-phenyl-3- (N, N-diethyl-dithiocarbamate) acrylic acid. The yield was 93.70% and the HPLC purity was 97.90%.

In this example, the product has the following structural formula 9:

example 5

141mL of tetrahydrofuran, 5.78g (0.08mol) of diethylamine, 28.05g (0.18mol) of potassium ethylxanthate and 8.71g (0.05mol) of ethyl phenylpropionate were placed in this order in a 500mL three-necked flask, and the reaction was stirred at 60 ℃ for 165 min. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 50mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to obtain 13.78g of ethyl 3-phenyl-3- (N, N-diethyldithiocarbamate) acrylate. The yield was 85.20% with an HPLC purity of 98.40%.

In this example, the product has the following structural formula 10:

example 6

In a 500mL three-necked flask, 105mL of methylene chloride, 5.22g (0.09mol) of cyclopropylamine, 14.63g (0.10mol) of potassium methylxanthate and 8.51g (0.05mol) of diethyl butynedioate were placed in this order, and the reaction was stirred at 40 ℃ for 130 min. After the reaction was complete, 40mL of water was added, the pH was adjusted to neutral by dropwise addition of 0.5mol/L HCl, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (3X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered with suction. The filtrate was distilled under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized, and 13.55g of diethyl 2- (N-cyclopropyl-dithiocarbamate) -butadienoate. The yield was 89.30% with an HPLC purity of 97.30%.

In this example, the product has the following structural formula 11:

example 7

78mL of polyethylene glycol 200, 6.33g (0.09mol) of n-butylamine, 24.43g (0.17mol) of potassium methylxanthate and 5.16g (0.05mol) of 2-acetylpyridine were placed in this order in a 250mL three-necked flask, and the reaction was stirred at 80 ℃ for 89 min. After completion of the reaction, 80mL of water was added, followed by dropwise addition of 0.5mol/L HCl to adjust the pH to neutrality, followed by extraction with ethyl acetate (3X 60 mL). The organic phase was washed with water (2X 80mL), dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 11.81g of 1- (N-N-butyl-dithiocarbamic acid) -2- (2-pyridyl) vinyl ester. The yield was 93.60%, the HPLC purity was 98.50%.

In this example, the product has the following structural formula 12:

example 8

In a 500mL three-necked flask, 112mL of tetrahydrofuran, 5.45g (0.06mol) of aniline, 25.13g (0.19mol) of sodium methylxanthate and 8.71g (0.05mol) of ethyl phenylpropargyrate were placed in this order, and the reaction was stirred at 60 ℃ for 175 min. After the reaction, 60mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 50mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 15.73g of ethyl 3-phenyl-3- (N-phenyl-dithiocarbamate) acrylate. The yield was 93.90% with an HPLC purity of 98.60%.

In this example, the product has the following structural formula 13:

example 9

43mL of polyethylene glycol 200, 3.66g (0.05mol) of n-butylamine, 24.74g (0.19mol) of sodium methylxanthate and 5.11g (0.05mol) of phenylacetylene were successively charged in a 250mL three-necked flask, and the reaction was stirred at 80 ℃ for 60 min. After completion of the reaction, 80mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was extracted (3X 30mL), the organic phase was washed with water (2X 50mL), dried over anhydrous sodium sulfate and filtered with suction. The filtrate was distilled under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 11.92g of N-N-butyl-dithiocarbamate- (2-styryl) ester. The yield was 94.80% with an HPLC purity of 98.80%.

In this example, the product has the following structural formula 14:

example 10

In a 500mL three-necked flask, 110mL of chloroform, 1.55g (0.05mol) of a 40% aqueous methylamine solution, 28.85g (0.18mol) of potassium ethylxanthate and 5.11g (0.05mol) of phenylacetylene were sequentially added, and the reaction was stirred at 60 ℃ for 156 min. After the reaction was complete, 40mL of water was added, the pH was adjusted to neutral by dropwise addition of 0.5mol/L HCl, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (3X 30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 11.76g of N-methyl-dithiocarbamic acid- (2-styryl) ester. The yield was 88.60% with an HPLC purity of 98.60%.

In this example, the product has the following structural formula 15:

example 11

113mL of methanol, 4.96g (0.05mol) of cyclohexylamine, 26.68g (0.19mol) of sodium ethylxanthate and 5.81g (0.05mol) of 1-phenyl-1-propyne were successively charged in a 250mL three-necked flask, and the reaction was stirred at 60 ℃ for 60 minutes. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 50mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 13.43g of 1-methyl-1- (N-cyclohexyl-dithiocarbamic acid) - (2-styryl) ester. The yield was 94.80% with an HPLC purity of 98.80%.

In this example, the product has the following structural formula 16:

example 12

192mL of isopropanol, 6.22g (0.07mol) of piperidine, 20.48g (0.14mol) of potassium methylxanthate and 8.91g (0.05mol) of tolane were sequentially charged in a 500mL three-necked flask, and the reaction was stirred at 80 ℃ for 90 min. After the reaction, 100mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 60mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 16.04g of piperidyl-4-dithio-carboxylic acid-1-phenyl- (2-styryl) ester. The yield was 94.50% and the HPLC purity was 97.50%.

In this example, the product has the following structural formula 17:

example 13

140mL of ethanol, 5.06g (0.05mol) of n-hexylamine, 26.68g (0.19mol) of sodium ethylxanthate and 5.81g (0.05mol) of 1-phenyl-1-propyne were sequentially charged in a 500mL three-necked flask, and the reaction was stirred at 70 ℃ for 90 minutes. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 60mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was distilled under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 13.91g of N-N-hexyl-dithiocarbamate-1-methyl- (2-styryl) ester. The yield was 92.12% and the HPLC purity was 96.70%.

In this example, the product has the following structural formula 18:

example 14

160mL of methanol, 8.89g (0.08mol) of benzylamine, 16.66g (0.13mol) of sodium methylxanthate, and 8.91g (0.05mol) of tolane were placed in this order in a 500mL three-necked flask, and the reaction was stirred at 66 ℃ for 70 minutes. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 60mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 16.58g of N-benzyl-dithiocarbamic acid-1-phenyl- (2-styryl) ester. The yield was 91.70% with an HPLC purity of 97.40%.

In this example, the product has the following structural formula 19:

example 15

In a 500mL three-necked flask, 150mL of tetrahydrofuran, 6.97g (0.08mol) of morpholine, 13.68g (0.09mol) of potassium methylxanthate and 6.83g (0.05mol) of 4-chloro-1-ethynylbenzene were sequentially charged and the reaction was stirred at 60 ℃ for 140 min. After the reaction, 50mL of water was added, 0.5mol/L HCl was added dropwise to adjust the pH to neutrality, ethyl acetate was used for extraction (3X 60mL), and the organic phase was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was subjected to distillation under reduced pressure to recover the organic solvent, and the residual solid toluene was recrystallized to give 12.82g of morpholino-4-dithio-carboxylic acid-2- (4-chlorostyryl) ester. The yield was 85.50% and the HPLC purity was 97.60%.

In this example, the product has the following structural formula 20:

comparative example 1

A250 mL three-necked flask was charged with 3.66g (0.05mol) of diethylamine, followed by addition of 14.09g (11.18mL) (0.18mol) of carbon disulfide and finally 6.01g (0.05mol) of 3-fluoro-1-ethynylbenzene, and the reaction was stirred at room temperature for 180min after the completion of the addition. Vacuum distillation was carried out to recover the low-boiling unreacted raw material, and the residual solid toluene was recrystallized to obtain 11.99g of N, N-diethyl-dithiocarbamic acid-2- (3-fluorophenylvinyl) ester. The yield was 89% and the HPLC purity was 98.70%.¹H NMR(400MHz,CDCl₃)δ:7.56(d,J＝11.2Hz,1H,ArH),7.32(td,J＝8.0,6.1Hz,1H,ArH),7.22-7.15(m,2H,ArH),6.95(td,J＝8.5,1.6Hz,1H,ArH),6.75(d,J＝11.2Hz,1H,ArH),4.07(q,J＝6.9Hz,2H,CH₂),3.81(q,J＝6.9Hz,2H,CH₂),1.37-1.27(m,6H,2CH₃)ppm.¹³C NMR(100MHz,CDCl₃)δ:191.2,163.9,161.5,138.6,129.9,126.9,125.8,124.7,115.4,114.2,50.1,47.0,12.8,11.5ppm.IR(KBr):v＝2980,2933,2874,1607,1578,1352,1271,1204,1009,982,872,824,783cm^-1。

In this example, the product formula 21 is as follows:

the HPLC analysis conditions for the vinyldithioformates were: high performance liquid chromatograph: agilent-1200 Series; the type of the chromatographic column: LlChrospher 60RP-select B (5. mu.L); the mobile phase is methanol and purified water with the ratio of 70: 30; the flow rate is 1mL/min, and the sample injection amount is 20 mu L; a detector: ultraviolet photometric detector, 264 nm; the sample was diluted with methanol and injected (1.00 mg/mL).

The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.

Although the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.