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Palladium catalyzed indolization

A palladium catalyst and reaction technology, applied in organic chemistry, silicon organic compounds, bulk chemical production, etc., can solve expensive problems and achieve the effect of eliminating triazole-based polymerization

Inactive Publication Date: 2002-05-15
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] However, although this alternative is chemically effective, the raw materials, namely butynol and triethylsilyl chloride, are quite expensive

Method used

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  • Palladium catalyzed indolization

Examples

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Effect test

example 1

[0498] Preparation of 2-Trimethylsilylindole

[0499] Iodoaniline (2.19g, 10mmol), acylsilane (26g, 20mmol) prepared according to the procedure of Reference Example A), DABCO (1,4-diazabicyclo[2.2.2]octane, 3.36g, 30mmol) and Pd(OAC) 2 (112.25mg, 0.5mmol) in the mixture in 30ml DMF by N 2 / Vacuum degassed, then heated at 105°C for 36 hours. The mixture was cooled to room temperature, diluted with IPAc (isopropyl acetate, 100ml) and washed with 2 x 50ml of water. The IPAc layer was concentrated in vacuo and purified by silica gel chromatography to obtain 2-trimethylsilylindole and indole.

example 2-8

[0501] Following the procedure of Example 1, starting from appropriately substituted 2-iodoanilines and appropriate acylsilanes, the following compounds were prepared: where R 17 It is a hydroxyl protecting group that can be removed under mild acid hydrolysis conditions.

example 9

[0503] Preparation of indole

[0504] A mixture of the 2-trimethylsilylindole product of Example 1 in 5 mL of methanol was treated with 2.5N HCl (2.11 mL, 5.2 mmol) and the reaction mixture was allowed to mature at room temperature for 2 hours. Additional isopropyl acetate (50ml) and water (10ml) were added. The layers were separated and the organic layer was concentrated in vacuo. The residual oil was chromatographed on silica gel to give indole as a white solid.

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Abstract

We have found that 2-unsubstituted indoles of structural formula (IV) can be cost-effectively synthesized in high yield by the palladium-catalyzed coupling / ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline (I) and an acyl silane derivative (II), followed by deprotection of the silyl protecting groups. The process of the present invention is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a good leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride. When applied to 5-triazolyl substituted indoles, the present process also eliminates the tendency of triazolyl polymerization in the Fischer indole synthesis. Still further, the present invention is also directed to the novel intermediates of structural formulae (V) and (VI).

Description

Background of the invention [0001] The present invention relates to a process for the preparation of 2-silyl-protected indoles from the palladium-catalyzed reaction of haloanilines and acylsilanes (the latter serving as aldehyde synthesis). According to the present invention, such 2-silyl derivatives can be converted into the corresponding unsubstituted indole derivatives at the 2-position. The process of the invention is particularly useful for the preparation of 5-heterocyclic substituted tryptamines, such as 5-(1,2,4-triazol-1-yl)tryptamine. Such compounds are therapeutically active as anti-migraine agents. [0002] Typically, indoles are prepared by the Fischer indole reaction. For example, Chen et al. disclosed in J.Org.Chem, (Journal of Organic Chemistry) 59, 3783 (1994) the use of 4% H 2 SO 4 A method for preparing N,N-dimethyltryptamine from 4-substituted hydrazine compounds and dimethylaminobutyraldehyde dimethyl acetal. However, the yields are often low, especia...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12C07D209/14C07D401/04C07D403/06C07D413/06C07D413/14C07D487/04C07D521/00C07F7/08
CPCC07D231/12C07D413/14C07D209/12C07F7/0818C07D249/08C07D487/04C07D209/14C07D233/56C07D403/06C07F7/083C07D413/06C07D401/04Y02P20/55C07F7/081
Inventor 陈诚义R·D·拉森
Owner MERCK & CO INC
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