CN109384702B - Preparation method of N-dithiocarbamate indole compound - Google Patents
Preparation method of N-dithiocarbamate indole compound Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract
The invention discloses a preparation method of an N-dithiocarbamate indole compound, which comprises the following steps: in a DCE solvent or a toluene solvent, potassium tert-butoxide is used as alkali, and indole compounds and thiuram compounds are used as substrates to synthesize the N-dithiocarbamate indole compounds. The method synthesizes the N-dithiocarbamate indole compound for the first time by forming an N-S bond through chemoselectivity. The method has the advantages of cheap and easily-obtained reaction raw materials, simple preparation method, reaction at room temperature by using potassium tert-butoxide as alkali, short reaction time, high yield and simple operation, and is suitable for synthesizing different types of N-dithiocarbamate indole compounds. The method can be used for synthesizing a series of N-dithiocarbamate indole compounds, and the synthesized product can be used as an intermediate compound for further constructing complex active compounds; meanwhile, the compounds have great medicinal activity potential.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing an N-dithiocarbamate indole compound at room temperature promoted by potassium tert-butoxide.
Background
Thioindoles are a very important class of indole compounds, which are widely distributed in natural products and pharmaceutically active molecules as core frameworks, so that the synthesis of the compounds is widely researched. Most of the methods for synthesizing thioindole compounds reported so far are reactions for introducing a thioether at the 3-position of the indole carbon, and disulfide or thiol is generally used as a sulfur source. Dithiocarbamates exist in a wide variety of biologically active molecules, and the pharmaceutical activity of compounds containing a dithiocarbamate structure has received continuous attention and research since the 20 th century. Several classes of heterocyclic compounds containing dithiocarbamates have been demonstrated to have antitumor, antioxidant, antibacterial and anti-pesticidal activity, with indole dithiocarbamates being a potential anticancer agent.
However, few methods for introducing dithiocarbamate groups into heterocyclic rings have been reported, and few methods for synthesizing dithiocarbamate indoles have been reported. In 1997, the Drozd research group first reported a method for synthesizing 3-dithiocarbamate indoles by the Fischer indole synthesis method. Subsequently, the Knochel research group developed a process for synthesizing 3-dithiocarbamate indoles by direct sulfurization at the 3-position of the indole carbon, starting with the N-format reagents indole and thiuram. Recently, the Beier group discovered a method for synthesizing 3-dithiocarbamate indoles from secondary amines, carbon disulfide and indoles under the action of iodine. To our knowledge, the above methods are all reported methods for introducing dithiocarbamates on the indole ring, and the product is 3-dithiocarbamic indole. Therefore, it is important and urgent to develop a direct and efficient sulfurization method for introducing dithiocarbamates at other positions of indole ring. The establishment of the method has important significance and value in synthetic chemistry; meanwhile, the comprehensive research on the biological activity of the dithiocarbamate indole compound is further promoted, and a new pharmaceutically active compound is discovered.
Disclosure of Invention
The invention provides a method for directly synthesizing N-dithiocarbamate indole compounds by taking potassium tert-butoxide as an alkali and indole and thiuram as raw materials.
A preparation method of dithiocarbamate indole compounds comprises the following steps: in a DCE or toluene solvent, reacting an indole compound and thiuram at room temperature by taking potassium tert-butoxide as an accelerator, and performing post-treatment after the reaction to obtain the N-dithiocarbamate indole;
in the formula (I), R1Is hydrogen, C1～C4Alkyl radical, C1～C4Alkoxy, ester group or halogen; r2Is benzyl or C1～C4An alkyl group; in the formula (IV), R3Is C1～C4Alkyl, benzyl or ester groups.
The structure of the indole compound is shown as the formula (VII):
in the formula (VII), R1Is hydrogen, C1～C4Alkyl radical, C1～C4Alkoxy, amino, ester, phenylsulfide, phenylselenide, or halogen; r2Is hydrogen or C1～C4An alkyl group;
the thiuram compound has the structure of the chemical formula (VIII), (IX), (X), (XI), (XII) and XIII:
in the formula (VIII), R2Is benzyl or C1～C4An alkyl group; r in the formula (XI)3Is C1～C4An alkyl, benzyl or ester group;
preferably, the base is potassium tert-butoxide, and other types of bases, including inorganic and organic bases, result in reduced reaction yields or no product formation.
The mol ratio of the indole compound to the potassium tert-butoxide is 1: 2.0, to improve the yield of the reaction. The reaction yield is lowered by decreasing the amount of potassium t-butoxide.
The reaction solvent is DCE or toluene, and other solvents, including polar and non-polar solvents, reduce the reaction yield or produce no product.
The reaction equation of the synthesis is as follows:
preferably, R1Is hydrogen, methyl, methoxy, carbomethoxy, fluorine or bromine; r2Is methyl, ethyl or benzyl; r3Is methyl, benzyl or ethyl formate.
The synthesis reaction principle is as follows: indole loses protons on nitrogen under the action of potassium tert-butoxide to form indole ions with negative charges, and then nucleophilic attack on sulfur-sulfur single bonds of thiuram compounds to form nitrogen-sulfur bonds in chemical selectivity, so that the final product is obtained.
Compared with the prior art, the invention has the following advantages:
the method takes indole and thiuram as raw materials, and synthesizes the N-dithiocarbamate indole compound for the first time through N-S bond formation in a chemoselectivity way. The reaction raw materials are cheap and easy to obtain, and the preparation method is simple; the potassium tert-butoxide is a common alkali, is cheap and easy to obtain, so the reaction cost is low. The reaction is carried out at room temperature, and the reaction condition is mild. Short reaction time, high yield and simple operation. The method can be applied to synthesizing different N-dithiocarbamate indole compounds.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
Example 1
Indole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 43.9mg of the product in 93% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.65(d,J7.69(d,J＝7.7Hz),7.40(dt,J＝17.7,9.2Hz),7.27(dd,J＝13.1,5.6Hz),7.17(d,J＝3.1Hz),6.79(d,J＝3.0Hz),5.51–4.77(m).＝7.7Hz,1H),7.45(d,J＝8.1Hz,1H),7.30(t,J＝7.4Hz,1H),7.22(t,J＝7.3Hz,1H),7.08(d,J＝3.3Hz,1H),6.74(d,J＝3.2Hz,1H),3.51(s,3H),3.36(s,3H)ppm；13C NMR(126MHz,CDCl3)196.15,139.91,133.97,129.64,123.14,121.36,121.18,110.87,106.47,45.60,39.94ppm.
in vitro inhibition of inflammatory factor expression activity test:
extracting ICR mouse primary abdominal cavity macrophage plate, adding a compound to be detected (1 mu M) for pretreatment for 30 minutes after cells are stabilized, adding LPS (0.5 mu g/ml) for stimulation for 24 hours, collecting culture supernatant and cell lysate, and detecting the content of inflammatory factors in the culture supernatant by using TNF-alpha and IL-6ELISA kits (eBioscience, CA, USA) respectively; protein content in cell lysates was determined by Bradford method. The concentration of the inflammatory factor obtained is homogenized by the protein content in the corresponding cell lysate, and the inhibition rate of the inflammatory factor is calculated by comparing with an LPS model group.
The inhibition rate of the compound on inflammatory factors TNF-alpha and IL-6 induced by LPS is respectively as follows: 50% and 65%.
Mouse macrophage cell line (RAW264.7) was cultured in MEM-alpha medium. After the cells were stabilized, the test compound (1. mu.M) and the positive control drug (dissolved in DMSO) were added and treated for 24 hours and 48 hours, then 20. mu.l of MTT (5mg/ml) was added and treated for 4 hours, the culture supernatant was discarded, 150. mu.l of DMSO was added and the purple crystals were dissolved, and the absorbance at 490nm was measured by a microplate reader. After subtracting the blank control group from the obtained OD value, the lethality of the drug to the cells was calculated by comparing with the DMSO control group.
The lethality of the compound to cells was: 10 percent.
These results preliminarily indicate that the compound has anti-inflammatory activity.
Example 2
Indole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 37.3mg of the product in 79% yield, which was obtained as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.65(d,J7.69(d,J＝7.7Hz),7.40(dt,J＝17.7,9.2Hz),7.27(dd,J＝13.1,5.6Hz),7.17(d,J＝3.1Hz),6.79(d,J＝3.0Hz),5.51–4.77(m).＝7.7Hz,1H),7.45(d,J＝8.1Hz,1H),7.30(t,J＝7.4Hz,1H),7.22(t,J＝7.3Hz,1H),7.08(d,J＝3.3Hz,1H),6.74(d,J＝3.2Hz,1H),3.51(s,3H),3.36(s,3H)ppm；13C NMR(126MHz,CDCl3)196.15,139.91,133.97,129.64,123.14,121.36,121.18,110.87,106.47,45.60,39.94ppm
example 3
Indole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and 1, 4-dioxane (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 2 hours, the starting material still remained, but the product did not build up. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 25.0mg of the product in 53% yield, which was as follows:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.65(d,J7.69(d,J＝7.7Hz),7.40(dt,J＝17.7,9.2Hz),7.27(dd,J＝13.1,5.6Hz),7.17(d,J＝3.1Hz),6.79(d,J＝3.0Hz),5.51–4.77(m).＝7.7Hz,1H),7.45(d,J＝8.1Hz,1H),7.30(t,J＝7.4Hz,1H),7.22(t,J＝7.3Hz,1H),7.08(d,J＝3.3Hz,1H),6.74(d,J＝3.2Hz,1H),3.51(s,3H),3.36(s,3H)ppm；13C NMR(126MHz,CDCl3)196.15,139.91,133.97,129.64,123.14,121.36,121.18,110.87,106.47,45.60,39.94ppm.
example 4
Indole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), cesium carbonate (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 29.3mg of the product in 62% yield, which was followed by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.65(d,J7.69(d,J＝7.7Hz),7.40(dt,J＝17.7,9.2Hz),7.27(dd,J＝13.1,5.6Hz),7.17(d,J＝3.1Hz),6.79(d,J＝3.0Hz),5.51–4.77(m).＝7.7Hz,1H),7.45(d,J＝8.1Hz,1H),7.30(t,J＝7.4Hz,1H),7.22(t,J＝7.3Hz,1H),7.08(d,J＝3.3Hz,1H),6.74(d,J＝3.2Hz,1H),3.51(s,3H),3.36(s,3H)ppm；13C NMR(126MHz,CDCl3)196.15,139.91,133.97,129.64,123.14,121.36,121.18,110.87,106.47,45.60,39.94ppm.
example 5
In a 5mL reaction flask, 4-bromoindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 51.1mg of the product in 81% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,DMSO-d6)7.42–7.38(m,3H),7.18(t,J＝7.9Hz,1H),6.66(d,J＝3.4Hz,1H),3.43(s,6H)ppm；13C NMR(126MHz,DMSO-d6)193.93,140.75,136.65,130.17,124.56,124.34,114.25,111.17,105.96,45.85,40.64ppm.
example 6
5-fluoroindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 4 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 34.5mg of the product in 68% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
H NMR(500MHz,CDCl3)7.32(dd,J＝8.8,4.3Hz,1H),7.28–7.24(m,1H),7.09(d,J＝3.1Hz,1H),6.99(t,J＝9.0Hz,1H),6.66(d,J＝3.2Hz,1H),3.49(s,3H),3.35(s,3H)ppm；13C NMR(126MHz,CDCl3)195.92,158.96(d,J＝236.4Hz),136.39,135.86,130.26(d,J＝10.4Hz),111.82(d,J＝9.8Hz),111.31(d,J＝26.2Hz),106.46(d,J＝4.4Hz),106.43(d,J＝24.1Hz),45.69,40.03ppm.
example 7
6-carbomethoxyindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 4 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 41.2mg of the product in 70% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)8.38(s,1H),7.98(d,J＝8.1Hz,1H),7.43(d,J＝8.6Hz,1H),7.10(d,J＝3.3Hz,1H),6.79(d,J＝3.2Hz,1H),3.92(s,3H),3.49(s,3H),3.37(s,3H)ppm；13C NMR(126MHz,DMSO-d6)193.44,166.70,139.14,138.53,133.36,123.94,121.76,120.99,112.22,106.39,51.96,45.34,40.12ppm.
example 8
6-methylindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 48.7mg of the product in 96% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.53(d,J＝7.9Hz,1H),7.26(s,1H),7.05(d,J＝7.9Hz,1H),7.01(d,J＝3.2Hz,1H),6.68(d,J＝3.2Hz,1H),3.52(s,3H),3.36(s,3H),2.50(s,3H)ppm；13C NMR(126MHz,CDCl3)196.49,140.35,133.40,133.18,127.50,123.18,120.87,111.02,106.40,45.65,39.98,21.88ppm
example 9
7-methoxyindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 43.1mg of the product in 81% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.49(d,J＝8.5Hz,1H),6.95(d,J＝3.4Hz,1H),6.91(d,J＝2.0Hz,1H),6.84(dd,J＝8.5,2.2Hz,1H),6.64(d,J＝3.4Hz,1H),3.86(s,3H),3.52(s,3H),3.37(s,3H)ppm；13C NMR(126MHz,CDCl3)196.10,157.45,141.04,132.79,123.63,121.67,110.95,106.33,95.06,55.69,45.56,39.88ppm.
example 10
2, 5-dimethylindole (0.2mmol), N, N, N ', N' -tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 35.9mg of the product in 68% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.51(dd,J＝6.3,2.4Hz,1H),7.38(dd,J＝6.5,2.1Hz,1H),7.24–7.18(m,2H),3.51(s,3H),3.39(s,3H),2.34(s,3H),2.31(s,3H)ppm；13C NMR(126MHz,CDCl3)196.91,139.72,135.96,130.57,122.05,121.01,118.16,110.99,110.37,45.53,39.90,10.55,9.40ppm
example 11
2-methylindole (0.2mmol), N, N, N ', N' -tetraethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask and stirred at room temperature. The reaction was monitored by TLC. After 4 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 40.6mg of the product in 73% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.54(d,J＝7.1Hz,1H),7.37(d,J＝7.6Hz,1H),7.21–7.17(m,2H),6.50(d,J＝12.4Hz,1H),3.86(d,J＝103.4Hz,4H),2.40(d,J＝12.3Hz,3H),1.37(d,J＝69.6Hz,6H)ppm；13C NMR(126MHz,CDCl3)194.71,141.10,140.69,129.67,121.95,121.38,119.94,110.68,104.22,50.00,45.92,13.19,13.07,11.52ppm.
example 12
Indole (0.2mmol), N, N, N ', N' -tetrabenzylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 64.4mg of the product in 83% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.69(d,J＝7.7Hz,1H),7.40(dt,J＝17.7,9.2Hz,12H),7.27(dd,J＝13.1,5.6Hz,1H),7.17(d,J＝3.1Hz,1H),6.79(d,J＝3.0Hz,1H),5.51–4.77(m,4H).ppm；13C NMR(126MHz,CDCl3)198.49,139.99,134.18,129.86,129.03,128.24,123.20,121.47,121.27,110.89,106.62,56.67,53.44ppm.
example 13
Indole (0.2mmol), bis- (N-methylcyclohexylaminothiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 48.1mg of the product in 79% yield, which was obtained as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1HNMR(500MHz,CDCl3)7.62(d,J＝7.7Hz,1H),7.43(d,J＝8.1Hz,1H),7.25(dd,J＝14.4,6.8Hz,1H),7.18(t,J＝7.4Hz,1H),7.06(d,J＝3.3Hz,1H),6.70(d,J＝3.0Hz,1H),3.35–3.15(m,3H),1.87–1.82(m,4H),1.69–1.59(m,3H),1.39(m,3H),1.13–1.11(m,1H)ppm；13C NMR(126MHz,CDCl3)195.25,140.03,134.07,129.65,123.10,121.30,121.14,110.96,106.34,63.25,61.98,37.53,32.58,30.51,29.09,25.34ppm.
example 14
Indole (0.2mmol), di- (pyrrolidinyl-1-thiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 42.5mg of the product in 81% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
H NMR(500MHz,CDCl3)7.65(d,J＝7.8Hz,1H),7.50(dd,J＝8.2,0.6Hz,1H),7.32–7.29(m,1H),7.23–7.20(m,1H),7.12(d,J＝3.4Hz,1H),6.73(dd,J＝3.4,0.7Hz,1H),3.92(t,J＝7.0Hz,2H),3.59(s,2H),2.13–2.08(m,2H),1.98–1.93(m,2H)ppm；13C NMR(126MHz,CDCl3)191.76,139.99,133.99,129.40,123.16,121.31,121.14,110.88,106.26,55.36,48.77,26.47,23.42ppm.
in vitro inhibition of inflammatory factor expression activity test:
extracting ICR mouse primary abdominal cavity macrophage plate, adding a compound to be detected (1 mu M) for pretreatment for 30 minutes after cells are stabilized, adding LPS (0.5 mu g/ml) for stimulation for 24 hours, collecting culture supernatant and cell lysate, and detecting the content of inflammatory factors in the culture supernatant by using TNF-alpha and IL-6ELISA kits (eBioscience, CA, USA) respectively; protein content in cell lysates was determined by Bradford method. The concentration of the inflammatory factor obtained is homogenized by the protein content in the corresponding cell lysate, and the inhibition rate of the inflammatory factor is calculated by comparing with an LPS model group.
The inhibition rate of the compound on inflammatory factors TNF-alpha and IL-6 induced by LPS is respectively as follows: 55% and 60%.
Mouse macrophage cell line (RAW264.7) was cultured in MEM-alpha medium. After the cells were stabilized, the test compound (1. mu.M) and the positive control drug (dissolved in DMSO) were added and treated for 24 hours and 48 hours, then 20. mu.l of MTT (5mg/ml) was added and treated for 4 hours, the culture supernatant was discarded, 150. mu.l of DMSO was added to dissolve the purple crystals, and the absorbance at 490nm was measured by a microplate reader. After subtracting the blank control group from the obtained OD value, the lethality of the drug to the cells was calculated by comparing with the DMSO control group.
The lethality of the compound to cells was: 9 percent.
These results preliminarily indicate that the compound has anti-inflammatory activity.
Example 15
Indole (0.2mmol), bis- (2, 6-dimethyl-1-pyridylthiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, followed by stirring at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 50.5mg of the product in 83% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.64(d,J＝7.8Hz,1H),7.43(d,J＝4.6Hz,1H),7.29–7.26(m,1H),7.21–7.18(m,1H),7.07(d,J＝3.4Hz,1H),6.72(d,J＝3.2Hz,1H),5.56–5.53(m,1H),4.60(m,1H),1.97–1.84(m,3H),1.75–1.69(m,2H),1.65–1.62(m,1H),1.55–1.54(m,3H),1.36(d,J＝6.9Hz,3H)ppm；13C NMR(126MHz,DMSO-d6)190.34,140.21,135.29,129.78,123.27,121.56,121.33,111.38,106.41,55.93,49.45,26.55,23.56ppm.
example 16
Indole (0.2mmol), bis- (4-benzyl-1-pyridylthiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, followed by stirring at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 58.6mg of the product in 80% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.66(d,J＝7.7Hz,1H),7.47(d,J＝8.0Hz,1H),7.37–7.21(m,5H),7.18(d,J＝7.4Hz,2H),7.10(s,1H),6.75(s,1H),5.34(s,1H),4.25(s,1H),3.13(s,2H),2.61(d,J＝6.4Hz,2H),1.91(d,J＝3.73,1H),1.82(d,J＝13.1Hz,2H),1.43(d,J＝11.4Hz,2H)ppm；13C NMR(126MHz,CDCl3)194.72,140.05,139.39,134.13,129.65,128.98,128.36,126.20,123.09,121.31,121.15,110.93,106.39,52.58,49.83,42.43,37.84,31.73ppm.
example 17
Indole (0.2mmol), di- (3-carboethoxy-1-pyridylthiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, followed by stirring at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to give 50.8mg of the product in 73% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.64(d,J＝7.8Hz,1H),7.43(d,J＝8.2Hz,1H),7.28(t,J＝7.6Hz,1H),7.20(t,J＝7.4Hz,1H),7.07(d,J＝3.4Hz,1H),6.73(d,J＝3.4Hz,1H),4.20–4.16(m,2H),3.53–3.37(m,2H),2.69(t,J＝9.8Hz,1H),2.26–2.16(m,1H),1.89–1.68(m,4H),1.30–1.27(m,4H)ppm；13C NMR(126MHz,CDCl3)195.83,172.15,140.07,134.12,129.78,123.22,121.47,121.25,111.00,106.60,61.10,50.79,41.30,27.22,14.20ppm
example 18
Indole (0.2mmol), di- (morpholino-4-thiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 2 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 38.4mg of the product in 69%, which was reacted as shown below:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.65(d,J＝7.8Hz,1H),7.44(dd,J＝8.1,0.5Hz,1H),7.32–7.27(m,1H),7.24–7.19(m,1H),7.07(d,J＝3.4Hz,1H),6.74(dd,J＝3.4,0.7Hz,1H),4.03(s,4H),3.81(t,J＝4.8Hz,4H)ppm；13C NMR(126MHz,CDCl3)196.33,139.98,133.96,129.75,123.33,121.58,121.34,110.91,106.83,66.24,50.66ppm.
example 19
Indole (0.2mmol), bis- (1, 2, 3, 4-tetrahydroisoquinolinyl-2-thiocarbonyl) disulfide (0.22mmol), potassium tert-butoxide (0.4mmol) and toluene (2.0mL) were added to a 5mL reaction flask, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After 1 hour, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to give 47.3mg of the product in 73% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)7.55(d,J＝7.4Hz,1H),7.37(d,J＝7.5Hz,1H),7.27–7.02(m,6H),6.99(d,J＝3.1Hz,1H),6.64(d,J＝2.2Hz,1H),4.97(d,J＝153.1Hz,2H),4.38–3.75(m,2H),2.93(s,2H)ppm；13C NMR(126MHz,CDCl3)195.49,140.10,134.12,129.79,128.04,127.56,127.12,126.58,123.30,121.52,121.31,111.04,106.68,54.07,50.29,28.98ppm.
Claims (6)
1. a preparation method of N-dithiocarbamate indole compounds is characterized in that potassium tert-butoxide is used as an accelerator in a solvent, the indole compounds react with a thiuram compound, and after the reaction is finished, the N-dithiocarbamate indole is obtained through post-treatment;
the structure of the N-dithiocarbamate indole is shown in any one of formulas (I) to (V):
in the formula (I), R1Is hydrogen, C1～C4Alkyl radical, C1～C4Alkoxy, ester group or halogen; r2Is benzyl or C1～C4An alkyl group; in the formula (IV), R3Is C1～C4An alkyl, benzyl or ester group;
the structure of the indole compound is shown as the formula (VII):
in the formula (VII), R1Is hydrogen, C1～C4Alkyl radical, C1～C4Alkoxy, ester group or halogen;
the thiuram compound has the structures of chemical formulas (VIII) to (XII):
in the formula (VIII), R2Is benzyl or C1～C4An alkyl group; r in the formula (XI)3Is C1～C4Alkyl, benzyl or ester groups.
2. The method of preparing an indole N-dithiocarbamate compound according to claim 1, wherein R is1Is hydrogen, methyl, methoxy, carbomethoxy, fluorine or bromine.
3. The method of preparing an indole N-dithiocarbamate compound according to claim 1, wherein R is2Is methyl, ethyl or benzyl; r3Is methyl, benzyl or ethyl formate.
4. The method for preparing indole N-dithiocarbamate compounds according to claim 1, wherein the reaction temperature is 20-30 ℃ and the reaction time is 1-4 hours.
5. A process for preparing an indole N-dithiocarbamate compound as claimed in claim 1, wherein the molar ratio of indole compound to thiuram compound is 1: 1.1 to 1.2; the mol ratio of the indole compound to the potassium tert-butoxide is 1: 2.0 to 2.2.
6. The method of preparing an indole N-dithiocarbamate according to claim 1, wherein the solvent is DCE or toluene.
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