Preparation method of 3-thiocyano indole derivative

Abstract

The invention discloses a preparation method of a 3-thiocyano indole derivative. According to the method, indole or substituted indole is taken as a substrate, ammonium thiocyanate is taken as a reactant, N-fluorobenzenesulfonamide (NFSI) is taken as an accelerant, reaction is carried out for 0.5-3 hours at room temperature, and C3-thiocyanated indole can be obtained. The method has the advantages of easily available reaction raw materials, mild reaction conditions and short reaction time, is suitable for industrial production, and provides a new method and different reaction mechanisms for thiocyanation of the C3 site of the indole compound.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a 3-thiocyanatoindole derivative. Background Art

[0002] In the past few years, sulfur-containing indole derivatives have attracted much attention, mainly because they are widely present in many natural products and active pharmaceutical ingredients. For example, through structural modification, they can be transformed into antiviral drugs, HIV inhibitors, tubulin polymerization inhibitors, and 5HT6 receptor antagonists. It is worth noting that in the field of anti-tumor applications, some sulfur-containing indoles have shown strong anti-tumor activity, such as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.

[0003] In the field of medicinal chemistry, the indole skeleton plays a vital role in the construction of pharmacophores by forming an important framework. It is worth noting that the thiocyanates derived from indole can be easily converted into indole thioethers, and after further manipulation, they can be converted into sulfoxides and sulfones. This unique reactivity characteristic has made the thiocyanation reaction of indole attract the attention of many researchers. As an electron-rich heteroaromatic ring, indole has the potential to be converted into indole thioethers by electrophilic substitution at its C 3 In view of these potential factors, the C 3 The in-situ thiocyanation reaction has therefore received more attention in the scientific community.

[0004] Typically, researchers introduce cyanate groups into the C of the indole ring by direct functionalization. 3 position, thereby obtaining indole thiocyanate. In recent years, researchers have developed a variety of methods for the preparation of indole 3-indole thiocyanate. There are two main categories: 1. Reagents containing a thiocyanate moiety, such as sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, and N-thiocyanate-substituted succinimide, saccharin, diphenylsulfonimide thiocyanate, etc., in the presence of oxidants such as selective fluoride reagent (Selectfluor), potassium persulfate (K 2 S 2 O 8 ), hydrogen peroxide (H 2 O 2 ), oxygen, high-valent iodine (such as diiodine pentoxide, PIDA, etc.), graphene oxide, 1,1,2,2-tetrahydroperoxy-1,2-diphenylethane, potassium peroxymonosulfate complex salt, cerium ammonium nitrate, 2,2′-(1,2-diazenediyl)bis[benzothiazole], bromine (Br 2 ) and iodine (I 2) and other oxidants, thiocyanate cations are generated as electrophilic reagents, and electrophilic substitution reactions occur under the catalysis of ferric chloride, cerium bromide, thiourea, citric acid, silicon dioxide and other substances, thereby obtaining 3-thiocyanatoindole. In addition, photocatalytic, electrochemical and ultrasound-assisted methods for synthesizing 3-indole thiocyanate have also been reported. These methods all use the method of obtaining thiocyanate cations to perform electrophilic substitution reactions. 2. Obtaining C through free radical reactions 3 Indole thiocyanate. In 2024, Pooja K. Bagad et al. reported the use of ammonium thiocyanate and tert-butyl hydroperoxide (TBHP) as oxidants to selectively construct carbon-sulfur bonds through a free radical pathway, and applied this method to the synthesis of indole-3-thiocyanate (see Formula 1).

[0005]

[0006] Formula 1: Synthesis of 3-indolethiocyanide reported in the literature

[0007] However, these existing methods have several defects. First, metal thiocyanates are toxic. Second, thiocyanates exist in the form of anions after dissociation, requiring strong oxidants (explosive) or weaker oxidants + metal catalysts to oxidize them into cations. In some methods, thiocyanation reagents are difficult to obtain and difficult to prepare. Third, these reactions usually require relatively harsh conditions (such as acidic environments and relatively high reaction temperatures). Under mild conditions, the electrophilic thiocyanation reaction of indole is difficult to proceed. If thiocyanation is carried out by free radical reaction, the yield is low. In view of the wide application of thiocyanoindole in the pharmaceutical field, it is necessary to develop a safe, mild and efficient C 3 The in situ thiocyanation method has significant technical value for subsequent innovative drug research. Summary of the invention

[0008] In view of the wide application of indole thiocyanate in the pharmaceutical field, the present invention aims to develop a safe, mild and efficient C 3 -Indole thiocyanate, promoting subsequent innovative drug research.

[0009] The present invention provides a method for preparing a 3-thiocyanatoindole derivative, comprising:

[0010]

[0011] Compound 2 is synthesized by reacting compound 1 with ammonium thiocyanate in a solvent via a promoter.

[0012] Wherein, R is H or C1-C6 alkyl, R 1 is H, C1-C6 alkyl, trifluoromethyl, nitro, cyano, methoxy, F, Cl, Br, I, carboxyl or carboxylate, R2 is H, C1-C6 alkyl. Wherein R is preferably H, C1-C3 alkyl; preferably R 1 H, C1-C3 alkyl, trifluoromethyl, nitro, cyano, methoxy, F, Cl, Br, I, carboxyl or COOCH 3 , R 2 H, CH 3 .

[0013] The accelerator used was N-fluorobisbenzenesulfonamide.

[0014] The reaction solvent is selected from a combination of one or more solvents of toluene, N,N'-dimethylformamide, tetrahydrofuran, 1,4'-dioxane, dichloromethane, ethylene glycol dimethyl ether, acetonitrile, water, methanol and ethanol; preferably a combination of one or more solvents of N,N'-dimethylformamide, tetrahydrofuran, 1,4'-dioxane, dichloromethane, ethylene glycol dimethyl ether, acetonitrile, methanol and ethanol; further preferably a combination of one or more solvents of N,N'-dimethylformamide, tetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, methanol and ethanol; further preferably a combination of one or more solvents of acetonitrile, methanol and ethanol.

[0015] The molar ratio of compound 1, ammonium thiocyanate and accelerator is 1:1.0-2.0:1.0-2.0; preferably 1:1.0-1.1:1.0-1.1.

[0016] The reaction temperature is 0°C to 80°C; preferably 15°C to 80°C; more preferably 20°C to 50°C.

[0017] The reaction time is 0.5-3 hours; the reaction time is preferably 1-3 hours.

[0018] Compared with the literature, the preparation method of the invention has the advantages of easy availability of raw materials, wide substrate adaptability, short reaction time, high yield, etc.

[0019] In order to obtain a safe, mild and efficient C 3 -Thiocyanation of indole, to promote the subsequent innovative drug research, we used ethanol as solvent, indole or substituted indole as substrate, ammonium thiocyanate as reactant, NFSI as promoter, and obtained a series of 20 3-thiocyanato indole derivatives in a simple and high yield at room temperature under oxidant-free conditions. The relevant reaction mechanism shows that this reaction is similar to the previous indole C 3 The reaction mechanism of -thiocyanate is different, it undergoes electrophilic substitution of halogen and subsequent bimolecular nucleophilic substitution.

[0020]

[0021] Different reaction mechanisms provide technical support for the synthesis of 3-thiocyanatoindole derivatives. The beneficial effects of this technical solution are as follows:

[0022] (1) The yield of 3-thiocyanatoindole derivatives prepared by this method is relatively high. After being scaled up 10 times, the yield does not decrease. The highest yield of 3-thiocyanatoindole series compounds reaches 97%;

[0023] (2) The raw materials are relatively economical, and the amount of ammonium thiocyanate and accelerator is 1.1 equiv;

[0024] (3) The reaction does not require the use of dangerous oxidants or metal catalysts, making it safer;

[0025] (4) The reaction temperature is room temperature, the reaction time is 1 to 3 hours, and the conditions are mild.

[0026] The method was scaled up to gram levels for the preparation of 3-thiocyanatoindole derivatives, and the structures of all compounds were confirmed by H NMR and MS. This strategy has the advantages of good process safety, easy availability of raw materials, wide substrate adaptability, short reaction time, mild reaction and easy scale-up. DETAILED DESCRIPTION

[0027] The present invention is described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0028] Example 1

[0029] 3-Thiocyanato-1H-indole

[0030] 3-thiocyanato-1H-indole

[0031]

[0032] Indole (117 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 169 mg of a white powdery solid with a yield of 97%.

[0033] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):8.75(s,1H),7.83(dt,J=7.1,3.6Hz,1H),7.49(d,J=2.9Hz,1H),7.47-7.42(m,1H),7.37-7.32(m,2H).

[0034] MS(ESI):[MH] - calcd.for C 9 H 5 N 2 S, 173.0; found, 173.1.

[0035] Example 2

[0036] 1-Methyl-3-thiocyanato-1H-indole

[0037] 1-methyl-3-thiocyanato-1H-indole

[0038]

[0039] 1-Methyl-indole (131 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 171 mg of off-white solid, with a yield of 91%.

[0040] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):7.83(dt,J=7.4,0.9Hz,1H),7.44-7.33(m,4H),3.85(d,J=2.1Hz,3H).

[0041] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 S, 187.0; found, 187.1.

[0042] Example 3

[0043] 4-Nitro-3-thiocyanato-1H-indole

[0044] 4-nitro-3-thiocyanato-1H-indole

[0045]

[0046] 4-Nitroindole (162 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at 40±2°C for 3 h. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 204 mg of brown needle-shaped solid, with a yield of 93%.

[0047] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):12.81(s,1H),8.28(s,1H),7.97(dd,J=12.6,8.0Hz,2H),7.44(t,J=8.0Hz,1H).

[0048] MS(ESI):[MH] - calcd.for C 9 H 4 N 3 O 2 S, 218.0; found, 218.1.

[0049] Example 4

[0050] 5-Nitro-3-thiocyanato-1H-indole

[0051] 5-nitro-3-thiocyanato-1H-indole

[0052]

[0053] 5-Nitroindole (162 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at 40±2°C for 3 h. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 197 mg of an orange solid with a yield of 90%.

[0054] 1 H NMR (400 MHz, DMSO-d 6 )δ (ppm): 12.65 (s, 1H), 8.53 (d, J = 2.3Hz, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.14 (dd, J = 8.9, 2.3Hz, 1H), 7.72 (d, J = 9.0Hz, 1H).

[0055] MS(ESI):[MH] - calcd.for C 9 H 4 N 3 O 2 S, 218.0; found, 218.1.

[0056] Example 5

[0057] 6-Nitro-3-thiocyanato-1H-indole

[0058] 6-nitro-3-thiocyanato-1H-indole

[0059]

[0060] 6-Nitroindole (162 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at 40±2°C for 3 h. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 199 mg of a light yellow solid with a yield of 91%.

[0061] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):12.64(s,1H),8.40(d,J=2.0Hz,1H),8.36(s,1H),8.07(dd,J=8.8,2.1Hz,1H),7.81(d,J=8.8Hz,1H).

[0062] MS(ESI):[MH] - calcd.for C 9 H 4 N 3 O 2 S,218.0;found,218.1..

[0063] Example 6

[0064] 7-Nitro-3-thiocyanato-1H-indole

[0065] 7-nitro-3-thiocyanato-1H-indole

[0066]

[0067] 7-Nitroindole (162 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at 40±2°C for 3 h. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 188 mg of a yellow solid with a yield of 86%.

[0068] 1 H NMR ((400 MHz, DMSO-d 6 )δ(ppm): 1 H NMR (400MHz, DMSO) δ12.65 (s, 1H), 8.26 (dd, J = 8.1, 1.0Hz, 1H), 8.24-8.14 (m, 2H), 7.49 (t, J = 7.9Hz, 1H).

[0069] MS(ESI):[MH] - calcd.for C 9 H 4 N 3 O 2 S,218.0;found,218.0.

[0070] Example 7

[0071] 4-Methoxy-3-thiocyanato-1H-indole

[0072] 4-methoxy-3-thiocyanato-1H-indole

[0073]

[0074] Indole (117 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 177 mg of off-white powdery solid, with a yield of 87%.

[0075] 1 H NMR (400 MHz, DMSO-d 6)δ (ppm): 11.92 (s, 1H), 7.79 (d, J = 2.8Hz, 1H), 7.15 (t, J = 7.9Hz, 1H), 7.08 (d, J = 8.2Hz, 1H), 6.67 (d, J = 7.7Hz, 1H), 3.92 (s, 3H).

[0076] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 OS, 203.2; found, 203.1.

[0077] Example 8

[0078] 5-Methoxy-3-thiocyanato-1H-indole

[0079] 5-methoxy-3-thiocyanato-1H-indole

[0080]

[0081] Indole (117 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 193 mg of a white powdery solid with a yield of 95%.

[0082] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):8.66(s,1H),7.48(d,J=2.9Hz,1H),7.33(d,J=8.9Hz,1H),7.21(d,J=2.4Hz,1H),6.98(dd,J=8.9,2.4Hz,1H),3.94(s,3H).

[0083] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 OS, 203.2; found, 203.1.

[0084] Example 9

[0085] 6-Methoxy-3-thiocyanato-1H-indole

[0086] 6-methoxy-3-thiocyanato-1H-indole

[0087]

[0088] Indole (117 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 173 mg of a light yellow solid with a yield of 85%.

[0089] 1 H NMR (400 MHz, DMSO-d 6 )δ (ppm): 11.80 (s, 1H), 7.85 (d, J = 2.8Hz, 1H), 7.53 (d, J = 8.7Hz, 1H), 7.01 (d, J = 2.2Hz, 1H), 6.90 (dd, J = 8.7, 2.2Hz, 1H), 3.80 (s, 3H).

[0090] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 OS, 203.2; found, 203.1.

[0091] Example 10

[0092] 2-Methyl-3-thiocyanato-1H-indole

[0093] 2-methyl-3-thiocyanato-1H-indole

[0094]

[0095] 2-Methyl-indole (131 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 156 mg of a light yellow solid with a yield of 83%.

[0096] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):11.98(s,1H),7.60-7.53(m,1H),7.46-7.40(m,1H),7.23-7.17(m,2H),2.54(s,3H).

[0097] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 S, 187.0; found, 187.1.

[0098] Embodiment 11

[0099] 5-Methyl-3-thiocyanato-1H-indole

[0100] 5-methyl-3-thiocyanato-1H-indole

[0101]

[0102] 5-Methyl-indole (131 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 167 mg of a light yellow solid with a yield of 89%.

[0103] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):11.91(s,1H),7.94(d,J=2.9Hz,1H),7.48-7.39(m,2H),7.10(dd,J=8.3,1.6Hz,1H),2.46(s,3H).

[0104] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 S, 187.0; found, 187.1.

[0105] Example 12

[0106] 7-Methyl-3-thiocyanato-1H-indole

[0107] 7-methyl-3-thiocyanato-1H-indole

[0108]

[0109] 7-Methyl-indole (131 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 177 mg of a white solid with a yield of 94%.

[0110] 1 H NMR (400 MHz, CDCl 3 )δ(ppm):8.63(s,1H),7.68(d,J=8.0Hz,1H),7.53(d,J=2.9Hz,1H),7.26(t,J=7.5Hz,1H),7.15(d,J=7.2Hz,1H),2.51(s,3H).

[0111] MS(ESI):[MH] - calcd.for C 10 H 7 N 2 S, 187.0; found, 187.1.

[0112] Embodiment 13

[0113] 3-Thiocyanato-1H-indole-5-carboxylic acid

[0114] 3-thiocyanato-1H-indole-5-carboxylic acid

[0115]

[0116] Indole-5-carboxylic acid (189 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 203 mg of a white solid with a yield of 93%.

[0117] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):12.82(s,1H),12.33(s,1H),8.31(d,J=1.6Hz,1H),8.14(d,J=2.1Hz,1H),7.89(dd,J=8.6,1.6Hz,1H),7.61(d,J=8.6Hz,1H).

[0118] MS(ESI):[MH] - calcd.for C 10 H 5 N 2 O 2 S, 217.0; found, 217.2.

[0119] Embodiment 14

[0120] 5-Fluoro-2-methyl-3-thiocyanato-1H-indole

[0121] 5-fluoro-2-methyl-3-thiocyanato-1H-indole

[0122]

[0123] 2-Methyl-5-fluoro-indole (149 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 181 mg of a light yellow solid with a yield of 88%.

[0124] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):12.09(s,1H),7.43(dd,J=8.8,4.4Hz,1H),7.29(dd,J=9.3,2.6Hz,1H),7.04(td,J=9.2,2.6Hz,1H),2.53(s,3H).

[0125] MS(ESI):[MH] - calcd.for C 10 H 6 FN 2 S, 205.0; found, 205.1.

[0126] Embodiment 15

[0127] 5-Bromo-3-thiocyanato-1H-indole

[0128] 5-bromo-3-thiocyanato-1H-indole

[0129]

[0130] 5-Bromo-indole (196 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 244 mg of a white solid with a yield of 97%.

[0131] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):12.22(s,1H),8.07(d,J=2.9Hz,1H),7.81(d,J=1.9Hz,1H),7.51(d,J=8.6Hz,1H),7.40(dd,J=8.7,1.9Hz,1H).

[0132] MS(ESI):[MH] - calcd.for C 9 H 4 Bn 2 S,250.9;found,251.0,253.1.

[0133] Example 16

[0134] 5-Iodo-3-thiocyanato-1H-indole

[0135] 5-iodo-3-thiocyanato-1H-indole

[0136]

[0137] 5-iodo-indole (273 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 287 mg of an off-white solid with a yield of 96%.

[0138] 1 H NMR (400 MHz, DMSO-d 6)δ(ppm):12.19(s,1H),8.00(dd,J=8.2,2.3Hz,2H),7.55(dd,J=8.5,1.7Hz,1H),7.39(d,J=8.5Hz,1H).

[0139] MS(ESI):[MH] - calcd.for C 9 H 4 IN 2 S,298.9;found,299.1..

[0140] Embodiment 17

[0141] 3-Thiocyanato-1H-indole-5-carboxycyanide

[0142] 3-thiocyanato-1H-indole-5-carbonitrile

[0143]

[0144] 5-Cyanine-indole (142 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 183 mg of a white solid with a yield of 92%.

[0145] 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm):12.52(s,1H),8.21(d,J=8.5Hz,2H),7.71(d,J=8.3Hz,1H),7.64(d,J=8.8Hz,1H).

[0146] MS(ESI):[MH] - calcd.for C 10 H 4 N 3 S, 198.0; found, 198.1.

[0147] Embodiment 18

[0148] 3-Thiocyanato-5-(trifluoromethyl)-indole

[0149] 3-thiocyanato-5-(trifluoromethyl)-1H-indole

[0150]

[0151] 5-Trifluoromethyl-indole (185 g, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 230 mg of a white needle-like solid with a yield of 95%.

[0152] 1 H NMR (400MHz, DMSO) δ (ppm): 12.45 (s, 1H), 8.22 (d, J = 2.8Hz, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.6Hz, 1H), 7.58 (dd, J = 8.6, 1.8Hz, 1H).

[0153] MS(ESI):[MH] - calcd.for C 10 H 4 F 3 N 2 S, 241.0; found, 241.1.

[0154] Embodiment 19

[0155] 4-Chloro-3-thiocyanato-1H-indole

[0156] 4-chloro-3-thiocyanato-1H-indole

[0157]

[0158] 4-Chloroindole (152 g, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 h. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 195 mg of a yellow solid with a yield of 94%.

[0159] 1 H NMR (400MHz, DMSO) δ (ppm): 12.35 (s, 1H), 8.10 (s, 1H), 7.50 (p, J = 4.0Hz, 1H), 7.23 (d, J = 4.5Hz, 2H).

[0160] MS(ESI):[MH] - calcd.for C 9 H 4 C1N 2 S, 207.0; found, 207.1.

[0161] Embodiment 20

[0162] 3-Thiocyanato-1H-indole-2-carboxylic acid methyl ester

[0163] methyl 3-thiocyanato-1H-indole-2-carboxylate

[0164]

[0165] Indole-2-carboxylic acid methyl ester (175 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), N-fluorobisbenzenesulfonamide (347 mg, 1.1 mmol) and 10 mL of ethanol were added to a 25 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 197 mg of a white solid with a yield of 85%.

[0166] 1 H NMR (400MHz, DMSO) δ (ppm): 12.85 (s, 1H), 7.81 (d, J = 8.2Hz, 1H), 7.58 (d, J = 8.3Hz, 1H), 7.43 (t, J = 7.6Hz, 1H), 7.32 (t, J = 7.6Hz, 1H), 3.98 (s, 3H).

[0167] MS(ESI):[MH] - calcd.for C 11 H 7 N 2 O 2 S, 231.0; found, 231.1.

[0168] Embodiment 21

[0169] This example compares the effect of solvents on reaction yield. The difference from Example 1 is that the type of solvent is different. See Table 1 below for details:

[0170] Table 1 Effect of different solvents on the yield of 3-thiocyanato-1H-indole

[0171] Solvents Yield Toluene 48％ N,N-Dimethylformamide 81％ Tetrahydrofuran 82％ 1,4'-Dioxane 77％ Dichloromethane 73％ Ethylene glycol dimethyl ether 80％ Acetonitrile 90％ water 45％ Methanol 90％

[0172] Embodiment 22

[0173] The difference between this embodiment and embodiment 1 is that the molar ratio of indole, ammonium thiocyanate and N-fluoro-bis-benzenesulfonamide is 1:1.0:1.0, as follows: indole (117 mg, 1.0 mmol), ammonium thiocyanate (76 mg, 1.0 mmol), N-fluoro-bis-benzenesulfonamide (315 mg, 1.0 mmol) and 10 mL of ethanol are added to a 25 ml reaction bottle, and stirred at room temperature for 1 hour. After the reaction, the crude product is concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1), and 161 mg of off-white solid is obtained, with a yield of 86%.

[0174] Embodiment 23

[0175] The difference between this embodiment and embodiment 1 is that the molar ratio of indole, ammonium thiocyanate and N-fluoro-bis-benzenesulfonamide is 1:2.0:2.0, as follows: indole (117 mg, 1.0 mmol), ammonium thiocyanate (152 mg, 2.0 mmol), N-fluoro-bis-benzenesulfonamide (630 mg, 2.0 mmol) and 10 mL of ethanol are added to a 25 ml reaction bottle, and stirred at room temperature for 1 hour. After the reaction is completed, the crude product is concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1), and 169 mg of off-white solid is obtained, with a yield of 90%.

[0176] Embodiment 24

[0177] The difference between this embodiment and embodiment 1 is that the reaction temperature is different. See Table 2 below for details.

[0178] Table 2 Effect of reaction temperature on the yield of 3-thiocyanato-1H-indole

[0179] temperature Yield 0℃ 60％ 15℃ 73％ 50℃ 92％ 80℃ 85％

[0180] Embodiment 25

[0181] The difference between this example and Example 1 is that the promoter is 30% hydrogen peroxide, which is as follows: indole (117 mg, 1.0 mmol), ammonium thiocyanate (84 mg, 1.1 mmol), 30% hydrogen peroxide (125 mg, 1.1 mmol) and 10 mL of ethanol are added to a 25 ml reaction bottle, and the mixture is stirred at room temperature for 1 hour. After the reaction is completed, the crude product is concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain 17 mg of an off-white solid with a yield of 9%.

[0182] Embodiment 26

[0183] The difference between this embodiment and embodiment 1 is that the reaction time is 0.5 h, and 156 mg of off-white solid is obtained, with a yield of 83%.

[0184] Embodiment 27

[0185] The reaction system of Example 1 was enlarged 10 times to investigate the industrial feasibility of the reaction, as follows: indole (1.17 g, 10 mmol), ammonium thiocyanate (840 mg, 11 mmol), N-fluorobisbenzenesulfonamide (1.25 mg, 11 mmol) and 100 mL of ethanol were added to a 250 ml reaction bottle and stirred at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure and recrystallized from 95% ethanol to obtain 1.78 g of a white solid with a yield of 94.7%.

[0186] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a 3-thiocyanatoindole derivative, characterized in that: The method comprises the following steps: dissolving compound 1 and ammonium thiocyanate in a solvent, reacting in the presence of a promoter to obtain a 3-thiocyanatoindole derivative 2; ， Wherein, R is H, C1~C6 alkyl, R 1 is H, C1~C6 alkyl, trifluoromethyl, nitro, cyano, methoxy, F, Cl, Br, I, carboxyl or carboxylate, R 2 is H, C1~C6 alkyl; the promoter is N -Fluorobisbenzenesulfonamide.

2. The method for preparing 3-thiocyanatoindole derivatives according to claim 1, characterized in that: The molar ratio of compound 1, ammonium thiocyanate and accelerator is 1:1.0~2.0:1.0~2.

0.

3. The method for preparing 3-thiocyanatoindole derivatives according to claim 1, characterized in that: The reaction temperature is 0℃~80℃.

4. The method for preparing 3-thiocyanatoindole derivatives according to claim 1, characterized in that: The reaction time is 0.5-3 hours.

5. The method for preparing 3-thiocyanatoindole derivatives according to claim 1, characterized in that: The reaction solvent is selected from toluene, N,N' - one or more of dimethylformamide, tetrahydrofuran, 1,4'-dioxane, dichloromethane, ethylene glycol dimethyl ether, acetonitrile, water, methanol, and ethanol.

6. The method for preparing 3-thiocyanatoindole derivatives according to claim 1, characterized in that: R is H, C1~C3 alkyl; R 1 is H, C1~C3 alkyl, trifluoromethyl, nitro, cyano, methoxy, F, Cl, Br, I, carboxyl or COOCH3, R 2 It is H and CH3.

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