CN110938027B - Synthetic method of indole derivatives - Google Patents
Synthetic method of indole derivatives Download PDFInfo
- Publication number
- CN110938027B CN110938027B CN201911141336.9A CN201911141336A CN110938027B CN 110938027 B CN110938027 B CN 110938027B CN 201911141336 A CN201911141336 A CN 201911141336A CN 110938027 B CN110938027 B CN 110938027B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- indole
- dimethyl sulfoxide
- cdcl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of indole derivatives, which comprises the following steps: dissolving a raw material o-ethynylaniline derivative (II) in dimethyl sulfoxide or deuterated dimethyl sulfoxide, dropwise adding thionyl chloride, and reacting to obtain an indole derivative (I);
Description
Technical Field
The invention relates to a synthesis method of indole derivatives.
Background
Indole derivatives are heterocyclic compounds with important value, and the skeleton of the indole derivatives is one of the scaffold structures with obvious advantages in a plurality of biological activity and functional molecules and natural products. [1] The sulfenyl and substituted indole functional groups play an important role in pharmaceutical chemistry and drug development, and researches show that the indole derivatives have remarkable physiological activities of resisting cancer, fungi, viruses, inflammation, depression, epilepsy and the like. [2-3] For example: indomethacin is a non-steroidal anti-inflammatory drug used for treating fever, diminishing inflammation, relieving pain and relieving stiffness; [4] l-737 can be used to treat HIV; [5] MK-886 is a drug (see formula III, formula IV, formula V) for the treatment of arteriosclerosis, leukemia, cancer. [6] The indole skeleton is a common heterocyclic pharmacophore and has very important significance for pharmaceutical chemistry research. [7] So far, chemical synthesis of indole derivatives has been reported, [8-9] however, o-ethynylbenzene is not found in these synthesesThe amine derivative (II) compound is used as a raw material, and forms the indole derivative (I) under the combined action of thionyl chloride and dimethyl sulfoxide.
See in particular the following references:
[1]T.Feng,X.H.Cai,Y.P.Liu,Y.Li,Y.Y.Wang,X.D.Luo,J.Nat.Prod.,2010,73,22.
[2]S.Cacchi,G.Fabrizi,Chem.Rev.,2005,105,2873.
[3]Z.Zhao,S.E.Wolkenberg,P.E.J.Sanderson,M.Lu,V.Munshi,G.Moyer,Bioorg.Med.Chem.Lett.,2008,18,554.
[4]C.Zhu,S.M.Ma,Org.Lett.,2013,15,2782.
[5]R.Ragno,M.Artico,G.D.Martino,G.L.Regina,A.Coluccia,A.D.Pasquali,R.Silvestri,J.Med.Chem.,2005,48,213.
[6]J.H.Hutchinson,Y.Li,J.M.Arruda,C.Baccei,G.Bain,C.Chapman,L.Correa,J.Darlington,C.D.King,C.Lee,D.Lorrain,P.Prodanovich,H.Rong,A.Santini,N.Stock,P.Prasit,J.F.Evans,J.Med.Chem.,2009,52,5803.
[7]R.Silvestri,G.De Martino,G.La Regina,M.Artico,S.Massa,L.Vargiu,M.Mura,A.G.Loi,T.Marceddu,P.La Colla,J.Med.Chem.,2003,46,2482.
[8]L.M.Tao,W.Q.Liu,Y.Zhou,A.T.Li.J.Chem.Res.,2012,36,644.
[9]Y.J.Guo,R.Y.Tang,J.H.Li,P.Zhong,X.G.Zhang,Adv.Synth.Catal.,2009,351,2615.
disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthesis method of indole derivatives for simply realizing intramolecular cyclization and methionine tandem cyclization.
The technical scheme of the invention is summarized as follows:
a synthetic method of indole derivatives comprises the following steps: dissolving a raw material o-ethynylaniline derivative (II) in dimethyl sulfoxide or deuterated dimethyl sulfoxide, dropwise adding thionyl chloride, and reacting to obtain an indole derivative (I);
wherein:
R 1 is a hydrogen atom, a methyl group, a fluorine atom or a bromine atom;
R 2 is phenyl, 2-bromophenyl, 3-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 1-naphthyl, 2-thienyl, cyclopropyl or 2- (p-toluenesulfonylamino) phenyl;
R 3 are p-toluenesulfonyl and methanesulfonyl;
R 4 is methyl or deuterated methyl.
The molar ratio of the o-ethynylaniline derivative (II) to thionyl chloride is preferably 3.
The method has the advantages of simple operation, cheap and easily obtained raw materials, mild reaction conditions, short reaction time, ideal yield and the like.
Detailed Description
Thionyl chloride (SOCl) 2 ) Analytically pure thionyl chloride purchased commercially.
Dimethyl sulfoxide (DMSO) is a commercially available absolute anhydrous dimethyl sulfoxide.
Deuterated dimethyl sulfoxide (DMSO-d) 6 ) Commercially available deuterated dimethyl sulfoxide of 99.9% purity.
The reaction starting material required in the examples, o-ethynylaniline (II), was prepared by the literature method. ([ 1 ]) Y.yin, W.Y.Ma, Z.Chai, G.ZHao, J.org.Chem.2007,72, 5731.)
The present invention will be further illustrated by the following specific examples.
Example 1
Preparation of 3-methylthio-2-phenyl-1-p-toluenesulfonyl-1H-indole-a
4-methyl-N- (2- (phenylethynyl) phenyl) benzenesulfonamide ll-a (0.5 mmol, 174mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 173mg of a white solid, 88% yield, melting point 104-105 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.36(d,J＝8.3Hz,1H),7.68(d,J＝7.4Hz,1H),7.50-7.40(m,4H),7.37(d,J＝7.0Hz,3H),7.29(d,J＝8.4Hz,2H),7.07(d,J＝8.2Hz,2H),2.31(s,3H),2.06(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.9,142.8,137.1,135.2,131.8,131.2,130.7,129.5,129.1,127.3,126.9,125.6,124.4,119.9,117.5,116.2,21.6,18.4.HRMS(ESI)calcd for C 22 H 19 NNaO 2 S 2 + [M+Na + ]416.0749, found 416.0750 is l-a.
Example 2
Preparation of 3-methylthio-2-phenyl-1-methanesulfonyl-1H-indole l-b
N- (2- (phenylethynyl) phenyl) methanesulfonamide ll-b (0.5 mmol, 136mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to column chromatography silica gel to dryness, and the organic phase was separated by column chromatography (ethyl acetate: petroleum ether = 10) to give 139mg of a white solid with a yield of 88% and a melting point of 136-137 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.20–8.08(m,1H),7.86–7.74(m,1H),7.52–7.46(m,5H),7.46–7.39(m,2H),2.82(s,3H),2.16(s,3H). 13 C NMR(151MHz,CDCl 3 )δ142.5,136.7,131.3,131.0,130.5,129.3,127.7,125.8,124.6,120.2,117.3,115.5,40.7,18.4.HRMS(ESI)calcd for C 16 H 15 NNaO 2 S 2 + [M+Na + ]341.0436, found 340.0436, is l-b.
Example 3
Preparation of 2- (2-bromophenyl) -5, 7-dimethyl-3- (methylthio) -1-p-toluenesulfonyl-1H-indole l-c
N- (2- ((2-bromophenyl) ethynyl) -4, 6-dimethylphenyl) -4-methylbenzenesulfonamide ll-c (0.5mmol, 227mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5mmol, 179mg) was added dropwise at 0 ℃ and the reaction was carried out at 70 ℃ until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column chromatography silica gel to dryness, and the organic phase was separated by column chromatography (ethyl acetate: petroleum ether = 5) to give 225mg of a white solid with a yield of 90% and a melting point of 118-119 ℃. 1 H NMR(600MHz,CDCl 3 )δ7.65-7.62(m,1H),7.37-7.34(m,1H),7.31(s,1H),7.29(dd,J＝7.8,1.7Hz,1H),7.23-7.20(m,3H),7.08-7.04(m,3H),2.73(s,3H),2.43(s,3H),2.32(s,3H),2.05(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.4,143.7,136.6,135.5,134.8,133.7,133.4,133.3,132.7,131.3,130.2,129.2,128.4,126.8,126.2,125.6,121.2,118.1,22.2,21.6,21.2,17.9.HRMS(ESI)calcd for C 24 H 22 79 BrNNaO 2 S 2 + [M+Na + ]522.0168, found 522.0169 is l-c.
Example 4
Preparation of 2- (2-bromophenyl) -5-methyl-3- (methylthio) -1-toluenesulfonyl-1H-indole l-d
N- (2- ((2-bromophenyl) ethynyl) -4-methylphenyl) -4-methylbenzenesulfonamide ll-d (0.5 mmol, 220mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 ℃ and the reaction was carried out at 70 ℃ until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 10) to give 199mg of a white solid with a yield of 82% and a melting point of 141-144 ℃. 1 H NMR(600MHz,CDCl3)δ8.19(d,J＝8.5Hz,1H),7.68(dd,J＝7.9,1.1Hz,1H),7.51(s,1H),7.47(d,J＝8.4Hz,2H),7.43–7.32(m,2H),7.25(m,2H),7.14(d,J＝8.1Hz,2H),2.49(s,3H),2.33(s,3H),2.15(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.9,140.5,135.8,134.6,133.7,133.5,132.7,132.5,130.7,130.6,129.6,127.2,127.1,126.4,126.2,119.8,116.9,115.0,21.6,21.4,18.0.HRMS(ESI)calcd for C 23 H 20 BrNNaO 2 S 2 + [M+Na + ]509.0011, found509.0011, l-d.
Example 5
Preparation of 6-methyl-3- (methylthio) -2- (p-tolyl) -1-toluenesulfonyl-1H-indole-e
4-methyl-N- (5-methyl-2- (p-tolylethynyl) phenyl) benzenesulfonamide ll-e (0.5 mmol, 188mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was continued at 70 deg.C until TLC indicated complete reaction of the substrate. Extracting the reaction solution with water (20 mL) and dichloromethane (20 mL. Times.3), combining the organic phases, washing the organic phase with saturated sodium bicarbonate, washing the organic phase with saturated brine, adding anhydrous sodium sulfate, drying, adding the organic phase into column silica gel, evaporating to dryness,column chromatography (ethyl acetate: petroleum ether =5 = 95) gave 162mg of a white solid in 77% yield, melting point 163-164 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.16(s,1H),7.53(d,J＝7.9Hz,1H),7.28(d,J＝8.3Hz,2H),7.26(s,1H),7.18(d,J＝7.9Hz,1H),7.07(d,J＝8.2Hz,2H),2.55(s,3H),2.45(s,3H),2.31(s,3H),2.06(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.7,142.2,138.9,137.4,135.6,135.3,131.6,129.4,129.0,128.0,127.9,126.9,125.8,119.4,117.2,116.4,22.1,21.6,21.6,18.3.HRMS(ESI)calcd for C 24 H 23 NNaO 2 S 2 + [M+Na + ]444.1062, found 444.1064, l-e.
With N- (2- (((4-chlorophenyl) ethynyl) -5-methylphenyl) -4-methylbenzenesulfonamide
This example was repeated except that, in place of 4-methyl-N- (5-methyl-2- (p-tolylethynyl) phenyl) benzenesulfonamide, prepared were:
2- (4-chlorophenyl) -6-methyl-3- (methylthio) -1-tolyl-1H-indole
Example 6
Preparation of 2- (4-methoxyphenyl) -3- (methylthio) -1-p-toluenesulfonyl-1H-indole-e
N- (2- ((4-methoxyphenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide ll-f (0.5mmol, 189mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to yield 181mg of a white solid, 86% yield, mp 147-148 ℃. 1 HNMR(600MHz,CDCl 3 )δ8.35(d,J＝8.3Hz,1H),7.66(d,J＝7.4Hz,1H),7.45-7.38(m,1H),7.38-7.32(m,1H),7.28(dd,J＝11.2,8.5Hz,4H),7.06(d,J＝8.1Hz,2H),6.97(d,J＝8.7Hz,2H),3.90(s,3H),2.30(s,3H),2.06(s,3H). 13 C NMR(151MHz,CDCl 3 )δ160.2,144.8,142.8,137.0,135.3,133.1,131.3,129.4,126.9,125.3,124.3,122.7,119.8,117.0,116.3,112.8,55.3,21.6,18.3.HRMS(ESI)calcd for C 23 H 21 NNaO 3 S 2 + [M+Na + ]446.0855, found446.0856, is l-f.
Example 7
Preparation of 2- (4-bromophenyl) -3- (methylthio) -1-toluenesulfonyl-1H-indole-g
N- (2- ((4-bromophenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide ll-g (0.5 mmol, 213mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 155mg of a white solid, yield 66%, melting point 146-147 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.35(d,J＝8.4Hz,1H),7.67(d,J＝7.7Hz,1H),7.57(d,J＝8.2Hz,2H),7.42(t,J＝7.8Hz,1H),7.36(t,J＝7.5Hz,1H),7.26(m,4H),7.07(d,J＝8.1Hz,2H),2.30(s,3H),2.06(s,3H). 13 C NMR(151MHz,CDCl 3 )δ148.6,145.1,141.4,137.2,135.0,133.3,131.1,130.6,129.6,129.5,126.8,125.8,124.5,123.6,120.0,118.1,116.3,21.6,18.3.HRMS(ESI)calcd for C 22 H 18 BrNNaO 2 S 2 + [M+Na + ]494.9855, found494.9855, l-g.
With N- (2- ((3-fluorophenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide
In place of the N- (2- ((4-bromophenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide of this example, the following was prepared:
2- (3-fluorophenyl) -3- (methylthio) -1-tosyl-1H-indole
Example 8
Preparation of 5-fluoro-3- (methylthio) -2-phenyl-1-tosyl-1H-indole-H
N- (4-fluoro-2- (phenylethynyl) phenyl) -4-methylbenzenesulfonamide ll-h (0.5 mmol, 183mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 ℃, and the reaction was carried out at 70 ℃ until TLC showed complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 176mg of a white solid with 81% yield and melting point 120-121 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.30(dd,J＝9.1,4.4Hz,1H),7.47-7.50(m,1H),7.46-7.41(m,2H),7.36(dd,J＝5.1,3.3Hz,2H),7.32(dd,J＝8.4,2.6Hz,1H),7.26(d,J＝8.4Hz,2H),7.11-7.15(m,1H),7.07(d,J＝8.1Hz,2H),2.31(s,3H),2.04(s,3H). 13 C NMR(151MHz,CDCl 3 )δ161.2,159.6,145.0,144.6,135.0,133.2,132.8,132.7,131.7,130.3,129.4,129.3,127.3,126.9,117.5,117.2,113.3,105.5,21.5,18.2.HRMS(ESI)calcd for C 22 H 18 FNNaO 2 S 2 + [M+Na + ]434.0655, found434.0656, l-h
Example 9
Preparation of 6-bromo-3- (methylthio) -2-phenyl-1-tosyl-1H-indole-i
N- (5-bromo-2- (phenylethynyl) phenyl) -4-methylbenzenesulfonamide ll-i (0.5mmol, 213mg) was dissolved inTo dimethylsulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 ℃ to react at 70 ℃ until TLC showed complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 224mg of a white solid with 95% yield and 138-139 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.55(d,J＝1.5Hz,1H),7.54(d,J＝8.3Hz,1H),7.48(m,2H),7.43(t,J＝7.5Hz,2H),7.35–7.30(m,2H),7.27(d,J＝8.4Hz,2H),7.09(d,J＝8.1Hz,2H),2.33(s,3H),2.02(s,3H). 13 C NMR(151MHz,CDCl 3 )δ145.2,143.2,137.6,135.1,131.8,130.1,130.0,129.5,129.3,127.6,127.3,127.0,121.0,119.1,119.0,117.0,21.6,18.3.HRMS(ESI)calcd for C 22 H 18 BrNNaO 2 S 2 + [M+Na + ]493.9855, found494.9855, is l-i
Example 10
Preparation of 2-cyclopropyl-3- (methylthio) -1-tosyl-1H-indole-l-f
N- (2- (cyclopropylethynyl) phenyl) -4-methylbenzenesulfonamide ll-j (0.5 mmol, 156mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed first with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 162mg of a white solid with a yield of 91% and a melting point of 66-68 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.21(d,J＝8.3Hz,1H),7.65(d,J＝8.4Hz,2H),7.63-7.57(m,1H),7.36-7.30(m,1H),7.30-7.26(m,1H),7.19(d,J＝8.1Hz,2H),2.35(s,3H),2.28(s,3H),2.19(tt,J＝8.2,5.9Hz,1H),1.22-1.00(m,4H). 13 C NMR(151MHz,CDCl 3 )δ144.7,143.1,136.6,131.1,129.7,126.5,125.0,123.7,119.3,115.6,115.0,21.5,19.2,9.3,9.0.HRMS(ESI)calcd for C 19 H 19 NNaO 2 S 2 + [M+Na + ]380.0749, found 380.0748, is l-j
Example 11
Preparation of 3- (methylthio) -2- (thiophen-2-yl) -1-tosyl-1H-indole-k
4-methyl-N- (2- (thien-2-ylethynyl) phenyl) benzenesulfonamide ll-k (0.5mmol, 177mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5mmol, 179mg) was added dropwise at 0 ℃ and the reaction was carried out at 70 ℃ until TLC showed complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate, then with saturated brine, dried by adding anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography on silica gel, and the mixture was separated by column chromatography (ethyl acetate: petroleum ether = 5. 1 H NMR(600MHz,CDCl 3 )δ8.35(d,J＝8.4Hz,1H),7.71–7.66(m,1H),7.53(dd,J＝5.0,1.2Hz,1H),7.42(m,1H),7.39–7.32(m,3H),7.16(m,2H),7.08(d,J＝8.1Hz,2H),2.31(s,3H),2.13(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.9,137.3,135.3,135.0,132.2,130.8,130.2,129.4,128.6,126.9,126.4,125.9,124.3,120.0,119.7,116.1,21.6,18.6.HRMS(ESI)calcd for C 20 H 17 NNaO 2 S 3 + [M+Na + ]423.0314, found423.0314, and is l-k
Example 12
Preparation of 3- (methylthio) -2- (naphthalen-1-yl) -1-tosyl-1H-indol-l
4-methyl-N- (2- (naphthalen-1-ylethynyl) phenyl) benzenesulfonamide ll-l (0.5 mmol, 199mg) was dissolved in dimethyl sulfoxide (1 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 10) to give 205mg of a white solid with a yield of 93% and a melting point of 142-143 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.45(d,J＝8.4Hz,1H),7.98(d,J＝8.2Hz,1H),7.88(t,J＝12.4Hz,1H),7.78(d,J＝7.7Hz,1H),7.55(t,J＝7.6Hz,1H),7.48(dd,J＝8.3,7.3Hz,1H),7.42(q,J＝7.6Hz,2H),7.38(d,J＝7.0Hz,1H),7.24(m,4H),6.92(d,J＝8.2Hz,2H),2.24(s,3H),2.00(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.7,140.2,137.0,133.5,133.0,130.6,130.4,129.9,129.3,128.4,128.2,127.1,126.2,125.9,125.7,125.5,124.4,124.0,119.8,117.7,115.6,21.5,18.4.HRMS(ESI)calcd for C 26 H 21 NNaO 2 S 2 + [M+Na + ]467.0906, found 467.0906, l-l
Example 13
Preparation of 3- (deuterated methylthio) -2-phenyl-1-tosyl-1H-indole-m
4-methyl-N- (2- (phenylethynyl) phenyl) benzenesulfonamide ll-a (0.5 mmol, 174mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC showed complete reaction of the substrate. Extracting the reaction solution with water (20 mL) and dichloromethane (20 mL × 3), mixing organic phases, washing the organic phase with saturated sodium bicarbonate solution, washing the organic phase with saturated saline solution, adding anhydrous sodium sulfate, drying, passing through silica gel column, and performing column chromatography (ethyl acetate: petroleum oil)Ether = 5) was isolated to yield 152mg of a white solid with a yield of 76% and a melting point of 111-112 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.36(d,J＝8.3Hz,1H),7.76-7.64(m,1H),7.57-7.41(m,4H),7.41-7.32(m,3H),7.29(d,J＝8.4Hz,2H),7.07(d,J＝8.1Hz,2H),2.31(s,3H). 13 C NMR(151MHz,CDCl 3 )δ144.9,142.7,137.0,135.2,131.8,131.2,130.7,129.5,129.1,127.3,126.9,125.6,124.4,119.9,117.4,116.2,77.4,77.2,77.0,21.6.HRMS(ESI)calcd for C 22 H 16 D 3 NNaO 2 S 2 + [M+Na + ]419.0938, found 419.0936, is l-m
With N- (2- (phenylethynyl) phenyl) methanesulfonamide
In place of the 4-methyl-N- (2- (phenylethynyl) phenyl) benzenesulfonamide of this example, the following was prepared in the same manner as in this example:
3- (deuterated methylthio) -2-phenyl-1-methylsulfonyl-1H-indole.
Example 14
Preparation of 6-bromo-3- (deuterated methylthio) -2-phenyl-1-tosyl-1H-indole-n
N- (5-bromo-2- (phenylethynyl) phenyl) -4-methylbenzenesulfonamide ll-i (0.5 mmol, 213mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol,179 mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed first with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography over silica gel, and column chromatography (ethyl acetate: petroleum ether = 10) separated to give 201mg of a white solid with 85% yield and 136-137 ℃. 1 HNMR(600MHz,CDCl 3 )δ8.55(d,J＝1.3Hz,1H),7.54(d,J＝8.3Hz,1H),7.48(t,J＝7.7Hz,2H),7.42(t,J＝7.5Hz,2H),7.32(d,J＝7.2Hz,2H),7.27(d,J＝8.3Hz,2H),7.09(d,J＝8.2Hz,2H),2.32(s,3H). 13 C NMR(151MHz,CDCl 3 )δ145.2,143.2,137.6,135.1,131.8,130.2,130.1,129.5,129.3,127.6,127.3,127.0,121.0,119.1,119.1,117.0,21.6.HRMS(ESI)calcd for C 22 H 15 D 3 79 BrNNaO 2 S 2 + [M+Na + ]497.0043, found497.0044 is l-n
With N- (4-fluoro-2- (phenylethynyl) phenyl) -4-methylbenzenesulfonamide
In place of N- (5-bromo-2- (phenylethynyl) phenyl) -4-methylbenzenesulfonamide of this example, the following was prepared:
5-fluoro-3- (deuterated methylthio) -2-phenyl-1-tosyl-1H-indole.
Example 15
Preparation of 2- (4-methoxyphenyl) -3- (deuterated methylthio) -1-toluenesulfonyl-1H-indole l-o
N- (2- ((4-methoxyphenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide ll-f (0.5 mmol, 189mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 ℃ and the reaction was carried out at 70 ℃ until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate, then with saturated brine, dried over anhydrous sodium sulfate, added to a column, silica gel evaporated to dryness, and column chromatographed (ethyl acetate: petroleum ether = 5) to give 184mg of a white solid with 86% yield and 146-147 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.35(d,J＝8.3Hz,1H),7.66(dd,J＝7.7,0.5Hz,1H),7.44-7.38(m,1H),7.37-7.32(m,1H),7.28(dd,J＝11.6,8.6Hz,4H),7.05(d,J＝8.1Hz,2H),6.97(d,J＝8.7Hz,2H),3.89(s,3H),2.30(s,3H). 13 C NMR(151MHz,CDCl 3 )δ160.2,144.7,142.7,137.0,135.3,133.1,131.3,129.3,126.9,125.3,124.2,122.7,119.7,116.9,116.3,112.7,55.3,21.4.HRMS(ESI)calcd for C 23 H 18 D 3 NNaO 3 S 2 + [M+Na + ]449.1043, found 449.1044 to l-o
With N- (2- (cyclopropylethynyl) phenyl) -4-methylbenzenesulfonamide
In place of the N- (2- ((4-methoxyphenyl) ethynyl) phenyl) -4-methylbenzenesulfonamide of this example, the following was prepared:
2-cyclopropyl-3- (deuterated methylthio) -1-tosyl-1H-indole.
Example 16
Preparation of 4-methyl-N- (2- (3- (deuterated methylthio) -1-toluenesulfonyl-1H-indol-2-yl) phenyl) benzenesulfonamide l-p
N, N' - (ethyne-1, 2-diylbis (2, 1-phenylene)) bis (4-methylbenzenesulfonamide) ll-p (0.5 mmol, 258mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise at 0 deg.C, and the reaction was carried out at 70 deg.C until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3), the organic phases were combined, washed first with saturated sodium bicarbonate and then with saturated brine, dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography on silica gel, and separated by column chromatography (ethyl acetate: petroleum ether = 10) to give 257mg of a white solid with a yield of 91% and a melting point of 161-163 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.39(d,J＝8.4Hz,1H),7.71-7.68(m,2H),7.67-7.64(m,1H),7.49(td,J＝7.3,3.7Hz,2H),7.38-7.42(m,2H),7.31-7.27(m,2H),7.17-7.07(m,5H),6.95(dd,J＝7.6,1.5Hz,1H),6.75(s,1H),2.34(d,J＝9.2Hz,6H). 13 C NMR(151MHz,CDCl 3 )δ145.6,143.7,137.3,137.1,136.8,136.8,134.7,132.9,130.9,130.6,129.7,129.6,127.2,127.0,126.2,124.5,123.2,122.0,120.1,119.8,119.6,116.1,21.6,21.5.HRMS(ESI)calcd for C 29 H 23 D 3 N 2 NaO 4 S 3 + [M+Na + ]588.1135, found 588.1136, is l-p
With N- (2- ((2-bromophenyl) ethynyl) -4, 6-dimethylphenyl) -4-methylbenzenesulfonamide
In place of the N, N' - (ethyne-1, 2-diylbis (2, 1-phenylene)) bis (4-methylbenzenesulfonamide) of this example, otherwise as in this example, there was prepared:
2- (2-bromophenyl) -5,7 dimethyl-3- (deuterated methylthio) -1-p-toluenesulfonyl-1H-indole.
The above description is only a part of the embodiments of the present invention, and is not intended to limit the present invention in any way, and all simple modifications, equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (1)
1. A synthetic method of indole derivatives is characterized by comprising the following steps: dissolving a raw material o-ethynylaniline derivative (II) in dimethyl sulfoxide or deuterated dimethyl sulfoxide, dropwise adding thionyl chloride, and reacting to obtain an indole derivative (I);
wherein:
R 1 is a hydrogen atom, a methyl group, a fluorine atom or a bromine atom;
R 2 is phenyl, 2-bromophenyl, 3-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 1-naphthyl, 2-thienyl, cyclopropyl or 2- (p-toluenesulfonylamino) phenyl;
R 3 are p-toluenesulfonyl and methanesulfonyl;
R 4 is methyl or deuterated methyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911141336.9A CN110938027B (en) | 2019-11-20 | 2019-11-20 | Synthetic method of indole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911141336.9A CN110938027B (en) | 2019-11-20 | 2019-11-20 | Synthetic method of indole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110938027A CN110938027A (en) | 2020-03-31 |
| CN110938027B true CN110938027B (en) | 2022-11-25 |
Family
ID=69907797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911141336.9A Active CN110938027B (en) | 2019-11-20 | 2019-11-20 | Synthetic method of indole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110938027B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358432B (en) * | 2020-11-02 | 2022-06-10 | 天津大学 | Synthetic method of indole derivatives |
| CN115093360B (en) * | 2022-07-06 | 2023-11-17 | 都创(上海)医药科技股份有限公司 | Synthesis method of indole derivatives |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009057733A1 (en) * | 2007-10-31 | 2009-05-07 | Santen Pharmaceutical Co., Ltd. | Novel indole derivative having anti-angiogenic activity |
| CN105693589A (en) * | 2014-11-26 | 2016-06-22 | 中国科学院大连化学物理研究所 | Synthesis method of indole derivative |
| CN105859725A (en) * | 2016-05-11 | 2016-08-17 | 天津大学 | 5,10-dihydroindolo[3,2-b]indole derivative synthesis method |
| CN108752363A (en) * | 2018-08-15 | 2018-11-06 | 天津大学 | A kind of synthetic method of benzothiophene [3,2-b] indole derivatives |
| CN109232366A (en) * | 2018-09-29 | 2019-01-18 | 华中师范大学 | The preparation method and applications of 2- acyl group -3- amino indole class compound |
| CN109851608A (en) * | 2019-01-21 | 2019-06-07 | 中国科学院兰州化学物理研究所 | A kind of preparation method of indole-2-carboxylic acid ester |
| CN111004164A (en) * | 2019-11-28 | 2020-04-14 | 浙江工业大学 | Preparation method of polysubstituted 2-aryl indole derivative |
-
2019
- 2019-11-20 CN CN201911141336.9A patent/CN110938027B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009057733A1 (en) * | 2007-10-31 | 2009-05-07 | Santen Pharmaceutical Co., Ltd. | Novel indole derivative having anti-angiogenic activity |
| CN105693589A (en) * | 2014-11-26 | 2016-06-22 | 中国科学院大连化学物理研究所 | Synthesis method of indole derivative |
| CN105859725A (en) * | 2016-05-11 | 2016-08-17 | 天津大学 | 5,10-dihydroindolo[3,2-b]indole derivative synthesis method |
| CN108752363A (en) * | 2018-08-15 | 2018-11-06 | 天津大学 | A kind of synthetic method of benzothiophene [3,2-b] indole derivatives |
| CN109232366A (en) * | 2018-09-29 | 2019-01-18 | 华中师范大学 | The preparation method and applications of 2- acyl group -3- amino indole class compound |
| CN109851608A (en) * | 2019-01-21 | 2019-06-07 | 中国科学院兰州化学物理研究所 | A kind of preparation method of indole-2-carboxylic acid ester |
| CN111004164A (en) * | 2019-11-28 | 2020-04-14 | 浙江工业大学 | Preparation method of polysubstituted 2-aryl indole derivative |
Non-Patent Citations (2)
| Title |
|---|
| "2-叔丁基-3-苯硫基-1H-吲哚的合成研究";李爱桃等;《化学世界》;20130925;第54卷(第9期);第551-553页 * |
| "Microwave assisted metal-/oxidant-free cascade electrophilic sulfenylation/5-endo-dig cyclization of 2-alkynylanilines to generate diversified 3-sulfenylindoles";Sharma, Shivani等;《Tetrahedron Letters》;20171231;第58卷(第40期);第3823-3826页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110938027A (en) | 2020-03-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110938027B (en) | Synthetic method of indole derivatives | |
| CN1543455B (en) | 3-phenoxy-4-pyridazinol derivative and herbicide composition containing the same | |
| CN111825585B (en) | Aryl sulfide containing benzylamine structure and synthesis method and application thereof | |
| JPS5939428B2 (en) | Method for producing a 5(6)-benzene ring-substituted benzimidazole-2-carbamate derivative having anthelmintic effect | |
| CA2457676A1 (en) | Chemotherapeutic agents | |
| Wróbel | Silane-mediated direct condensation of nitroarenes with cinnamyl-type sulfones. The way to 2-aryl-4-X-quinolines and their hetero analogs | |
| CN112321481B (en) | Chiral indole compound and preparation method thereof | |
| Liu et al. | Non-directed copper-catalyzed regioselective C–H sulfonylation of phenothiazines | |
| Knight et al. | 5-endo-dig Cyclisations of homopropargylic sulfonamides: a new route to 2, 3-dihydropyrroles and β-iodopyrroles | |
| Hu et al. | Copper‐Catalyzed Hydrosulfonylation of Alkynes Employing Sulfonohydrazides toward the Synthesis of Vinyl Sulfones | |
| CN112358432B (en) | Synthetic method of indole derivatives | |
| US20200030303A1 (en) | Compositions and methods for inhibiting protein kinases | |
| JP2014505043A (en) | Process for producing N-sulfonyl-substituted oxindoles | |
| CN109320503A (en) | Benzimidazole alkynes aminated compounds without metal one-pot synthesis method | |
| CN112341368B (en) | Method for synthesizing alpha-fluorinated thioacrylamide derivative | |
| CN115093360B (en) | Synthesis method of indole derivatives | |
| Adam et al. | Sulfoxides of penicillanates with non classical substituents in the 6-position | |
| Ren et al. | Synthesis and potent biological activity of 1-sulfonyl substituted imidazole and benzo [d] imidazole compounds | |
| JP2022545773A (en) | Process for preparing carboxylic acid derivatives of 3-bromo-4,5-dihydro-1H-pyrazole | |
| CN109485611A (en) | A kind of preparation method of triazole derivatives | |
| CN112159364B (en) | Synthetic method of isothiazole derivative | |
| CN108003103B (en) | Synthetic method of sulfonylated 5-aminopyrazole compound | |
| KR102325534B1 (en) | Synthesis of Sulfones and Sulfonyl Derivatives using Sodium (tert-butyldimethylsilyl)oxymethanesulfinate | |
| CN108586406A (en) | A kind of preparation method of 3- sulfuryls coumarin compound | |
| CN116041251A (en) | Synthesis method of sulfonyl tetrahydropyridine derivative containing halogen atom |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20221021 Address after: No. 156, Taxi Street, Circular Chemical Industry Park, Shijiazhuang City, Hebei Province 050,099 Applicant after: Hebei Kainuo Zhongxing Technology Co.,Ltd. Address before: 300072 Tianjin City, Nankai District Wei Jin Road No. 92 Applicant before: Tianjin University |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |