CN109384702B - Preparation method of N-dithiocarbamate indole compound - Google Patents

Abstract

The invention discloses a preparation method of N-dithiocarbamate indole compounds. Compounds are used as substrates to synthesize N-dithiocarbamate indole compounds. In the method of the invention, N-dithiocarbamate indole compounds are synthesized for the first time by forming N-S bonds with chemical selectivity. The reaction raw materials of the invention are cheap and easy to obtain, the preparation method is simple, potassium tert-butoxide is used as the base, and the reaction is carried out at room temperature, the reaction time is short, the yield is high, and the operation is simple, and is suitable for different types of N-dithiocarbamate indoles Synthesis of Indoles. The method of the invention can be used to synthesize a series of N-dithiocarbamate indole compounds, and the synthesized products can not only be used as intermediate compounds to further construct complex active compounds; active potential.

Description

A kind of preparation method of N-dithiocarbamate indole compounds

technical field

The invention belongs to the field of organic synthesis, in particular to a method for preparing N-dithiocarbamate indole compounds at room temperature promoted by potassium tert-butoxide.

Background technique

Thioindoles are a very important class of indole compounds, which are widely distributed as core skeletons in natural products and pharmaceutical active molecules, so the synthesis of these compounds has been extensively studied. Most of the reported methods for synthesizing thioindole compounds are the reaction of introducing a thioether at the 3-position of the indole carbon, usually using disulfide or thiol as the sulfur source. Dithiocarbamates exist in many classes of biologically active molecules, and the pharmaceutical activity of compounds containing dithiocarbamate structures has received continuous attention and research since the 20th century. A variety of heterocyclic compounds containing dithiocarbamates have been shown to have antitumor, antioxidant, antibacterial and anti-insecticide activities, among which indole dithiocarbamates have been used as a Potential anticancer agent.

However, there are few reports on the introduction of dithiocarbamate groups on heterocycles, and there are few reports on the synthesis of dithiocarbamate indole. In 1997, Drozd's group first reported the synthesis of 3-dithiocarbamate indole by the Fischer indole synthesis method. Subsequently, Knochel's research group developed a method for the synthesis of 3-dithiocarbamate indole by direct sulfidation at the 3-position of the indole carbon using the N-Gallen reagents indole and thiuram as raw materials. Recently, Beier's group discovered a method to synthesize 3-dithiocarbamate indole with secondary amine, carbon disulfide and indole under the action of iodine. To the best of our knowledge, the above methods are all reported methods for the introduction of dithiocarbamate on the indole ring, and the products are all 3-dithiocarbamate indole. Therefore, it is particularly important and urgent to develop a direct and efficient vulcanization method for introducing dithiocarbamate into other positions of the indole ring. The establishment of this method is not only of great significance and value in synthetic chemistry; at the same time, it will further promote the comprehensive study of the biological activity of dithiocarbamate indole compounds and discover new medicinally active compounds.

SUMMARY OF THE INVENTION

The invention provides a method for directly synthesizing N-dithiocarbamate indole compounds using potassium tert-butoxide as a base and indole and thiuram as raw materials. The raw materials of the method are easy to obtain and the preparation method is simple. .

A method for preparing a dithiocarbamate indole compound, comprising: in DCE or a toluene solvent, at room temperature, using potassium tert-butoxide as a promoter, reacting the indole compound and thiuram, and reacting After finishing, the N-dithiocarbamate indole is obtained through post-processing;

In chemical formula (I), R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, ester group or halogen; R ² is benzyl or C ₁ -C ₄ alkyl; in chemical formula In (IV), R ³ is a C ₁ -C ₄ alkyl group, a benzyl group or an ester group.

The structure of the indole compound is shown in formula (VII):

In formula (VII), R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, amino, ester group, phenyl sulfide group, phenyl selenide group or halogen; R ² is hydrogen or C ₁ -C ₄ alkyl;

The thiuram compounds have the structures of chemical formulae (VIII), (IX), (X), (XI), (XII), (XIII):

In formula (VIII), R ² is benzyl or C ₁ -C ₄ alkyl; in formula (XI), R ³ is C ₁ -C ₄ alkyl, benzyl or ester group;

Preferably, the base is potassium tert-butoxide, and other types of bases, including inorganic bases and organic bases, reduce the reaction yield or produce no product.

The molar ratio of the indole compound and the potassium tert-butoxide is 1:2.0, so as to improve the yield of the reaction. Reducing the amount of potassium tert-butoxide reduces the reaction yield.

The reaction solvent is DCE or toluene, and other kinds of solvents, including polar solvents and non-polar solvents, reduce the reaction yield or produce no product.

The reaction equation of the described synthesis is:

Preferably, R ¹ is hydrogen, methyl, methoxy, methyl formate, fluorine or bromine; R ² is methyl, ethyl or benzyl; R ³ is methyl, benzyl or ethyl formate.

The synthesis reaction principle is as follows: indole loses the proton on nitrogen under the action of potassium tert-butoxide to form a negatively charged indole ion, and then it nucleophilically attacks the sulfur-sulfur single bond of the thiuram compound, chemical selection Nitrogen-sulfur bonds are naturally formed to obtain the final product.

Compared with the prior art, the present invention has the following advantages:

The method of the invention takes indole and thiuram as raw materials, and chemically selectively forms N-dithiocarbamate indole compounds for the first time. The reaction raw materials are cheap and easy to obtain, and the preparation method is simple; potassium tert-butoxide is a common base, which is cheap and easy to obtain, so the reaction cost is low. The reaction is carried out at room temperature under mild reaction conditions. The reaction time is short, the yield is high, and the operation is simple. The method of the present invention can be suitable for synthesizing different kinds of N-dithiocarbamate indole compounds.

Detailed ways

The present invention will be described in detail below with reference to the embodiments, 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, respectively. Stir at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 43.9 mg of the product with a yield of 93%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J δ 7.69 (d, J=7.7 Hz), 7.40 (dt, J=17.7, 9.2 Hz), 7.27 (dd, J=13.1, 5.6 Hz) ,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; ¹³ C NMR (126MHz, CDCl ₃ )δ 196.15, 139.91, 133.97, 129.64, 123.14, 121.36, 121.18, 110.87, 106.47, 45.60, 39.94 ppm.

In vitro inhibition of inflammatory factor expression activity test:

ICR mouse primary peritoneal macrophages were extracted and plated. After the cells were stabilized, the test compound (1 μM) was added for pretreatment for 30 minutes, and then LPS (0.5 μg/ml) was added to stimulate for 24 hours. The culture supernatant and cell lysate were collected. The content of inflammatory factors in the culture supernatant was detected by TNF-α and IL-6 ELISA kits (eBioscience, CA, USA) respectively; the protein content in the cell lysate was detected by Bradford method. The obtained inflammatory factor concentrations were normalized with the protein content in the corresponding cell lysate, and the inhibition rate of inflammatory factors was calculated compared with the LPS model group.

The inhibition rates of the compounds on LPS-induced inflammatory factors TNF-α and IL-6 were 50% and 65%, respectively.

A mouse macrophage cell line (RAW264.7) was cultured in MEM-α medium. After the cells were stabilized, the compound to be tested (1 μM) and the positive control drug (dissolved in DMSO) were added for 24 hours and 48 hours, and then 20 μl MTT (5 mg/ml) was added for treatment for 4 hours, the culture supernatant was discarded, and 150 μl DMSO was added to dissolve the cells. Purple crystals, use a microplate reader to detect the absorption value at 490nm. After subtracting the blank control group from the obtained OD value, the lethality of the drug to the cells was calculated compared with the DMSO control group.

The lethality of the compound to cells: 10%.

These results preliminarily suggest 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, respectively. Stir at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 37.3 mg of the product with a yield of 79%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J δ 7.69 (d, J=7.7 Hz), 7.40 (dt, J=17.7, 9.2 Hz), 7.27 (dd, J=13.1, 5.6 Hz) ,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; ¹³ C NMR (126 MHz, CDCl ₃ ) δ 196.15, 139.91, 133.97, 129.64, 123.14, 121.36, 121.18, 110.87, 106.47, 45.60, 39.94 ppm

Example 3

Indole (0.2 mmol), N,N,N',N'-tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and 1,4-dioxane were added to a 5mL reaction flask. Hexacyclic (2.0 mL), stirred at room temperature. The detection reaction was followed by TLC. After 2 hours, starting material remained, but the product was no longer increasing. 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 25.0 mg of the product with a yield of 53%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J δ 7.69 (d, J=7.7 Hz), 7.40 (dt, J=17.7, 9.2 Hz), 7.27 (dd, J=13.1, 5.6 Hz) ,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; ¹³ C NMR (126MHz, CDCl ₃ )δ 196.15, 139.91, 133.97, 129.64, 123.14, 121.36, 121.18, 110.87, 106.47, 45.60, 39.94 ppm.

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 stirred at room temperature . The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 29.3 mg of the product with a yield of 62%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J δ 7.69 (d, J=7.7 Hz), 7.40 (dt, J=17.7, 9.2 Hz), 7.27 (dd, J=13.1, 5.6 Hz) ,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; ¹³ C NMR (126MHz, CDCl ₃ )δ 196.15, 139.91, 133.97, 129.64, 123.14, 121.36, 121.18, 110.87, 106.47, 45.60, 39.94 ppm.

Example 5

4-Bromoindole (0.2mmol), N,N,N',N'-tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0 mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 51.1 mg of the product with a yield of 81%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500MHz, DMSO-d ₆ ) δ 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; ¹³ C NMR (126MHz, DMSO-d ₆ ) δ 193.93, 140.75, 136.65, 130.17, 124.56, 124.34, 114.25, 111.17, 105.96, 45.85, 40.64 ppm.

Example 6

5-fluoroindole (0.2mmol), N,N,N',N'-tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0 mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 34.5 mg of the product with a yield of 68%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

H NMR (500 MHz, CDCl ₃ ) δ 7.32 (dd, J=8.8, 4.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.09 (d, J=3.1 Hz, 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 )δ 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

Into a 5mL reaction flask were added 6-carbonate methyl indole (0.2mmol), N,N,N',N'-tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) and DCE (2.0 mL), stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 41.2 mg of the product with a yield of 70%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.10 (d, J=3.3 Hz , 1H), 6.79(d, J=3.2Hz, 1H), 3.92(s, 3H), 3.49(s, 3H), 3.37(s, 3H) ppm; ¹³ C NMR (126MHz, DMSO-d ₆ )δ193 .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 ( 2.0 mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 48.7 mg of the product with a yield of 96%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53 (d, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 7.01 (d, J=3.2 Hz) , 1H), 6.68(d, J=3.2Hz, 1H), 3.52(s, 3H), 3.36(s, 3H), 2.50(s, 3H) ppm; ¹³ C NMR (126MHz, CDCl ₃ )δ 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 were added to a 5mL reaction flask, respectively. (2.0 mL), stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 43.1 mg of the product with a yield of 81%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49 (d, J=8.5 Hz, 1H), 6.95 (d, J=3.4 Hz, 1H), 6.91 (d, J=2.0 Hz, 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; ¹³ C NMR (126MHz) , CDCl ₃ )δ196.10,157.45,141.04,132.79,123.63,121.67,110.95,106.33,95.06,55.69,45.56,39.88ppm.

Example 10

2,5-dimethylindole (0.2mmol), N,N,N',N'-tetramethylthiuram (0.22mmol), potassium tert-butoxide (0.4mmol) were added to the 5mL reaction flask respectively. and toluene (2.0 mL), and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 35.9 mg of the product with a yield of 68%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.51 (dd, J=6.3, 2.4 Hz, 1H), 7.38 (dd, J=6.5, 2.1 Hz, 1H), 7.24-7.18 (m, 2H), 3.51 ( s, 3H), 3.39 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H) ppm; ¹³ C NMR (126 MHz, CDCl ₃ ) δ 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 ( 2.0 mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 40.6 mg of the product with a yield of 73%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.54 (d, J=7.1 Hz, 1H), 7.37 (d, J=7.6 Hz, 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; ¹³ C NMR (126MHz, CDCl) ₃ ) δ194.71, 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, respectively. Stir at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 64.4 mg of the product with a yield of 83%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500MHz, CDCl ₃ ) δ 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=3.1 Hz, 1H), 6.79 (d, J=3.0 Hz, 1H), 5.51-4.77 (m, 4H).ppm; ¹³ C NMR (126 MHz, CDCl ₃ ) δ 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 (0.2 mmol), bis-(N-methylcyclohexylaminothiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and DCE (2.0 mL) were added to a 5 mL reaction flask, respectively. , and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 48.1 mg of the product with a yield of 79%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

1HNMR(500MHz, CDCl3)δ7.62(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) δ 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 (0.2 mmol), bis-(pyrrolidinyl-1-thiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and toluene (2.0 mL) were added to a 5 mL reaction flask, respectively. Stir at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 42.5 mg of the product with a yield of 81%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J=7.8 Hz, 1H), 7.50 (dd, J=8.2, 0.6 Hz, 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 )δ191.76,139.99,133.99,129.40,123.16,121.31,121.14,110.88,106.26,55.36,48.77,26. ,23.42ppm.

In vitro inhibition of inflammatory factor expression activity test:

ICR mouse primary peritoneal macrophages were extracted and plated. After the cells were stabilized, the test compound (1 μM) was added for pretreatment for 30 minutes, and then LPS (0.5 μg/ml) was added to stimulate for 24 hours. The culture supernatant and cell lysate were collected. The content of inflammatory factors in the culture supernatant was detected by TNF-α and IL-6 ELISA kits (eBioscience, CA, USA) respectively; the protein content in the cell lysate was detected by Bradford method. The obtained inflammatory factor concentrations were normalized with the protein content in the corresponding cell lysate, and the inhibition rate of inflammatory factors was calculated compared with the LPS model group.

The inhibition rates of the compounds on LPS-induced inflammatory factors TNF-α and IL-6 were 55% and 60%, respectively.

A mouse macrophage cell line (RAW264.7) was cultured in MEM-α medium. After the cells were stabilized, the compound to be tested (1 μM) and the positive control drug (dissolved in DMSO) were added for 24 hours and 48 hours, and then 20 μl MTT (5 mg/ml) was added for 4 hours, the culture supernatant was discarded, and 150 μl DMSO was added to dissolve the purple color. Crystal, use a microplate reader to detect the absorption value at 490nm. After subtracting the blank control group from the obtained OD value, the lethality of the drug to the cells was calculated compared with the DMSO control group.

The lethality of the compound to cells: 9%.

These results preliminarily suggest that the compound has anti-inflammatory activity.

Example 15

Indole (0.2 mmol), bis-(2,6-dimethyl-1-pyridylthiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and Toluene (2.0 mL), stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 50.5 mg of the product with a yield of 83%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.64 (d, J=7.8 Hz, 1H), 7.43 (d, J=4.6 Hz, 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; ¹³ C NMR (126MHz, DMSO- d ₆ ) δ190.34, 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 (0.2 mmol), bis-(4-benzyl-1-pyridylthiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and toluene (2.0 mmol) were added to a 5 mL reaction flask, respectively. mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 58.6 mg of the product with a yield of 80%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.66 (d, J=7.7 Hz, 1H), 7.47 (d, J=8.0 Hz, 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=13.1 Hz, 2H), 1.43 (d, J=11.4 Hz, 2H) ppm; ¹³ C NMR (126 MHz, CDCl ₃ ) δ 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 (0.2 mmol), bis-(3-ethylcarboxylate-1-pyridylthiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and toluene were added to a 5 mL reaction flask. (2.0 mL), stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (17% ethyl acetate in petroleum ether) to obtain 50.8 mg of the product with a yield of 73%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.64 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.28 (t, J=7.6 Hz, 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; ¹³ C NMR (126MHz, CDCl ₃ ) δ195.83,172.15,140.07,134.12,129.78,123.22,121.47,121.25,111.00,106.60,61.10,50.79,41.30,27.22,14.20ppm

Example 18

Indole (0.2 mmol), bis-(morpholinyl-4-thiocarbonyl) disulfide (0.22 mmol), potassium tert-butoxide (0.4 mmol) and toluene (2.0 mL) were added to a 5 mL reaction flask, respectively. Stir at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 38.4 mg of the product with a yield of 69%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J=7.8 Hz, 1H), 7.44 (dd, J=8.1, 0.5 Hz, 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 ; ¹³ C NMR (126MHz, CDCl ₃ )δ196.33,139.98,133.96,129.75,123.33,121.58,121.34,110.91,106.83,66.24,50.66ppm.

Example 19

Indole (0.2mmol), bis-(1,2,3,4-tetrahydroisoquinolinyl-2-thiocarbonyl)disulfide (0.22mmol), potassium tert-butoxide were added to a 5mL reaction flask, respectively. (0.4 mmol) and toluene (2.0 mL) and stirred at room temperature. The detection reaction was followed 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 with anhydrous sodium sulfate, concentrated, and separated by column chromatography (9% ethyl acetate in petroleum ether) to obtain 47.3 mg of the product with a yield of 73%. The reaction process is shown in the following formula:

The products prepared in this example were subjected to nuclear magnetic resonance analysis:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.55 (d, J=7.4 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.27-7.02 (m, 6H), 6.99 (d, J= ^13C NMR (126MHz, CDCl ₃ )δ195.49,140.10,134.12,129.79,128.04,127.56,127.12,126.58,123.30,121.52,121.31,111.04,106.68,54.07,50.29,28.98ppm.

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.