CN105237458A - Preparation method for polysubstituted indole derivatives - Google Patents

Preparation method for polysubstituted indole derivatives Download PDF

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CN105237458A
CN105237458A CN201510593614.XA CN201510593614A CN105237458A CN 105237458 A CN105237458 A CN 105237458A CN 201510593614 A CN201510593614 A CN 201510593614A CN 105237458 A CN105237458 A CN 105237458A
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preparation
amino acid
indole derivatives
polysubstituted
derivatives
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CN105237458B (en
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刘烽
张奕
潘仙华
陈晓云
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Beijing Punuo Wang Kang Pharmaceutical Technology Co.,Ltd.
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Shanghai Institute of Technology
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    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention provides a preparation method for polysubstituted indole derivatives. The preparation method comprises employing alkynyl-terminated hydrocarbon, a halogenated aniline derivative and a disulfide as initial raw materials, using an amino acid as an additive and a copper salt as a catalyst, performing a coupling-tandem one-pot reaction in an organic solvent under an alkali-added condition, so as to obtain the corresponding polysubstituted indole derivative, wherein the catalyst is CuX, and X is iodine or bromine. According to the technical scheme, the method for synthesizing the polysubstituted indole derivatives through one-pot process is developed on the basis of a method for synthesizing 2-substituted indole through copper catalysis. The method does not employ an expensive palladium catalyst easily polluting environment. The method enables alkynyl-terminated hydrocarbon, one halogenated aniline derivative and one disulfide to have the coupling-tandem one-pot reaction under a relatively mild condition, is simple in technology and strong in operationality, and possesses industrial application prospect.

Description

A kind of preparation method of polysubstituted indole derivatives
Technical field
The invention belongs to chemical field, relate to a kind of its preparation method of polysubstituted indole derivatives.
Background technology
Polysubstituted indoles is the important organism of a class, because indoles framework compound is extensively present in natural product and has in bioactive compound, is the important intermediate of medicament research and development synthesis.In numerous indole ring skeleton building block synthesis strategies and method, substantially adopt the method for fractional steps, namely first by the Sonogashira linked reaction synthesis 2-substituted indole of precious metal palladium catalysis, then carry out derivatize in the 3-position of indoles.But due to palladium catalyst costly, and comparatively serious to the damage ratio of environment, in the past few years, uses Cu is catalyzer, and some comparatively gentle methods of being synthesized 2-substituted indole by interpolation part obtain very large development.((a)Miura,M.J.Org.Chem.1993,58,4716-4721；(b)Gujiadhur,R.K,；Bates,C.G,；Venkataraman,D.Org.Lett.2001,3,4315.(c)FengLiu,；DaweiMa.J.Org.Chem.2007.)。
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of preparation method of polysubstituted indole derivatives, the preparation method of described this polysubstituted indole derivatives solves preparation method's complex process of the prior art, with serious pollution technical problem.
The invention provides a kind of preparation method of polysubstituted indole derivatives, adopt terminal alkyne and halogeno-benzene sulfonamide derivatives and disulphide as starting raw material, use amino acid as additive, mantoquita is as catalyzer, under the condition of adding alkali, carry out coupling-series connection one pot reaction in organic solvent to obtain, described catalyzer is CuX, X is iodine or bromine, the mol ratio of described catalyst levels and halogeno-benzene sulfonamide derivatives is 0.001 ~ 0.5:1, described amino acid and the mol ratio of catalyzer are 0.1 ~ 3:1, the mol ratio of described terminal alkyne and halogeno-benzene sulfonamide derivatives is 1 ~ 1.5:1, reacting the temperature of carrying out is 30 ~ 150 DEG C,
In formula, X is iodine or bromine;
R is selected from C 1-C 6alkyl, C 1-C 6alkoxyl group, C 1-C 6alkyloyl, halogen, nitro or carboxyl;
R 1for NHCOCF 3;
R 2be selected from C 1-C 6alkyl, C 1-C 6ester group, aryl or substituted aryl;
R 3be selected from aryl or substituted aryl.
Further, described amino acid is replacement or a dibasic a-amino acid on nitrogen, and described substituting group is C 1-C 6alkyl, aryl, substituted aryl or indyl.
Further, described amino acid is selected from proline(Pro), oxyproline, sarcosine, DMG, o-chlorobenzene glycine, adjacent fluorophenyl glycine or tryptophane.
Further, described alkali (described alkali and the mol ratio of terminal alkyne are 1 ~ 2.2:1) is selected from K 2cO 3, Na 2cO 3, Cs 2cO 3, NaOH, K 3pO 4, DBU or DMAP; Described organic solvent be selected from DMSO, DMF, NMP, toluene, acetonitrile, ethanol, pyridine or 2,4-dioxane.
The present invention compares with prior art, and its technical progress is significant.The present invention, on the basis that copper catalysis 2-substituted indole synthesizes, has developed the method for the polysubstituted indoles of one pot process.The present invention does not adopt the palladium catalyst of expensive easy contaminate environment.Method of the present invention makes terminal alkyne and halogeno-benzene sulfonamide derivatives and disulphide under comparatively gentle condition, carry out the one pot reaction of coupling-series connection, and technique is simple, and strong operability, has the prospect of industrial application.
Embodiment
To contribute to understanding the present invention by following examples of implementation, but not limit the present invention.
Embodiment 16-methyl-2-phenyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-2 (282mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain faint yellow solid 274.4mg, yield is 87%.
1HNMR(500MHz,CDCl 3)δ8.48(s,1H),7.78(d,J＝7.4Hz,2H),7.57(d,J＝8.0Hz,1H),7.46(t,J＝7.4Hz,2H),7.41(t,J＝7.1Hz,1H),7.27(s,1H),7.22(t,J＝7.6Hz,2H),7.17(d,J＝7.4Hz,2H),7.11(t,J＝7.2Hz,1H),7.06(d,J＝8.1Hz,1H),2.54(s,3H).
Embodiment 26-nitro-2-phenyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-3 (313mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain yellow solid 294.4mg, yield is 85%.
1HNMR(500MHz,CDCl 3)δ8.54(s,1H),7.80(dd,J＝7.1,1.2Hz,2H),7.62(dd,J＝7.7,5.0Hz,1H),7.51-7.39(m,4H),7.26-7.19(m,4H),7.17-7.07(m,2H).
Embodiment 32-((2-phenyl-1H-indol-3-yl) sulfo-) benzo [d] thiazole
In a 25mL there-necked flask, add B-1 (268mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), benzothiazyl disulfide (166mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain faint yellow solid 272.4mg, yield is 76%.
1HNMR(500MHz,CDCl 3)δ10.63(s,1H),7.81(s,1H),7.55(s,1H),7.47(s,3H),7.39(s,2H),7.30(s,6H).
Embodiment 43-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-1 (268mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), trimethylsilyl acetylene (98mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=15:1), obtain faint yellow solid 219.5mg, yield is 75%.
1HNMR(500MHz,CDCl 3)δ10.69(s,1H),8.40(d,J＝8.3Hz,1H),8.13(d,J＝8.0Hz,1H),7.88(d,J＝7.6Hz,2H),7.65(dq,J＝14.1,7.1Hz,2H),7.56(t,J＝7.7Hz,2H),7.41(t,J＝7.7Hz,1H),7.12(tt,J＝14.3,7.6Hz,1H).
Embodiment 52-(4-p-methoxy-phenyl)-6-methyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-2 (282mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), to Methoxy-phenylacetylene (132mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain brown solid 313.7mg product, yield is 85.8%.
1HNMR(500MHz,CDCl 3)δ8.49(s,1H),7.60(d,J＝8.5Hz,2H),7.48(d,J＝6.1Hz,1H),7.15-7.07(m,6H),7.01(t,J＝7.0Hz,1H),6.96(d,J＝8.0Hz,1H),6.86(d,J＝8.6Hz,2H),3.73(s,3H),2.49-2.36(m,3H).
Embodiment 62-(4-chloro-phenyl-)-6-methyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-2 (282mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), to chlorobenzene acetylene (132mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain light tan solid 290.4mg, yield is 83%.
1HNMR(500MHz,CDCl 3)δ8.45(s,1H),7.69(d,J＝8.3Hz,2H),7.56(d,J＝8.0Hz,1H),7.40(d,J＝8.3Hz,2H),7.22(dd,J＝14.8,7.1Hz,3H),7.12(dd,J＝18.5,7.4Hz,3H),7.06(d,J＝8.0Hz,1H),2.53(s,3H).
Embodiment 76-methyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-2 (282mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), trimethylsilyl acetylene (98mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=15:1), obtain faint yellow solid 201.0mg, yield is 84%.
1HNMR(500MHz,CDCl 3)δ10.65(s,1H),8.22(s,1H),8.00(d,J＝8.2Hz,1H),7.86(d,J＝7.7Hz,2H),7.63(t,J＝7.4Hz,1H),7.54(t,J＝7.8Hz,3H),7.21(d,J＝8.1Hz,1H),2.45(s,3H).
Embodiment 82-(4-p-methoxy-phenyl)-6-methyl-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-3 (313mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), to Methoxy-phenylacetylene (132mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=10:1), obtain yellow solid 294.4mg, yield is 85%.
1HNMR(500MHz,CDCl 3)δ8.90(s,1H),8.40(s,1H),8.06(d,J＝8.8Hz,1H),7.76(d,J＝8.5Hz,2H),7.65(d,J＝8.7Hz,1H),7.18(d,J＝5.8Hz,2H),7.06(d,J＝6.9Hz,3H),7.01(d,J＝8.3Hz,2H),3.86(s,3H).
Embodiment 96-nitro-3-(thiophenyl)-1H-indoles
In a 25mL there-necked flask, add B-3 (313mg, 1mmol), then add Cs 2cO 3(652mg, 2mmol), Diphenyl disulfide ether (109mg, 0.5mmol), L-PROLINE (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), trimethylsilyl acetylene (98mg, 1mmol), 5mLDMF, under the protection of nitrogen, 24h is reacted in the oil bath of 100 DEG C, 5mL water is added after cooling, each 5mL extraction into ethyl acetate, after repeating four times, extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying, filtered fluid underpressure distillation, distillment is crossed silicagel column and is separated (leacheate is sherwood oil: ethyl acetate=15:1), obtain faint yellow solid 207.6mg, yield is 76%.
1HNMR(500MHz,CDCl 3)δ10.83(s,1H),9.31(d,J＝1.9Hz,1H),8.32(d,J＝8.7Hz,1H),8.21(dd,J＝8.8,2.0Hz,1H),7.91(d,J＝7.5Hz,2H),7.73(t,J＝7.5Hz,1H),7.62(t,J＝7.9Hz,3H)。

Claims (4)

1. the preparation method of a polysubstituted indole derivatives, it is characterized in that: adopt terminal alkyne and halogeno-benzene sulfonamide derivatives and disulphide as starting raw material, use amino acid as additive, mantoquita is as catalyzer, under the condition of adding alkali, carry out coupling-series connection one pot reaction in organic solvent to obtain, described catalyzer is CuX, X is iodine or bromine, the mol ratio of described catalyst levels and halogeno-benzene sulfonamide derivatives is 0.001 ~ 0.5:1, described amino acid and the mol ratio of catalyzer are 0.1 ~ 3:1, the mol ratio of described terminal alkyne and halogeno-benzene sulfonamide derivatives is 1 ~ 1.5:1, reacting the temperature of carrying out is 30 ~ 150 DEG C,
In formula, X is iodine or bromine;
R is selected from C 1-C 6alkyl, C 1-C 6alkoxyl group, C 1-C 6alkyloyl or halogen, nitro or carboxyl;
R 1for NHCOCF 3;
R 2be selected from C 1-C 6alkyl, C 1-C 6ester group, aryl or substituted aryl;
R 3be selected from aryl or substituted aryl.
2. the preparation method of a kind of polysubstituted indole derivatives as claimed in claim 1, is characterized in that: described amino acid is replacement or a dibasic a-amino acid on nitrogen, and described substituting group is C 1-C 6alkyl, aryl, substituted aryl or indyl.
3. the preparation method of a kind of polysubstituted indole derivatives as claimed in claim 2, it is characterized in that: described amino acid is selected from proline(Pro), oxyproline, sarcosine, DMG, o-chlorobenzene glycine, adjacent fluorophenyl glycine or tryptophane.
4. the preparation method of a kind of polysubstituted indole derivatives as claimed in claim 3, is characterized in that: described alkali and the mol ratio of terminal alkyne are 1 ~ 2.2:1, and described alkali is selected from K 2cO 3, Na 2cO 3, Cs 2cO 3, NaOH, K 3pO 4, DBU or DMAP; Described organic solvent is selected from DMSO, DMF, NMP, toluene.Acetonitrile, ethanol, pyridine or 2,4-dioxane.
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CN111377917B (en) * 2018-12-29 2022-12-06 武汉朗来科技发展有限公司 Heterocyclic compound, intermediate, preparation method and application thereof
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