Synthesis method of 2-indolone-3-carboxylate derivatives

A synthesis method and derivative technology, applied in the field of synthesis of 2-indolinone-3-carboxylate derivatives, can solve the problems of potential environmental hazards and high commercial prices, and achieve environmental friendliness, simple operation, The effect of mild reaction conditions

Active Publication Date: 2014-01-22
BIRDO (SHANGHAI) PHARM R&D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The disadvantage of this method is that the organometallic reagent rhodium acetate is used in the preparation process, which is potentially harmful to the environment and commercially expensive

Method used

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  • Synthesis method of 2-indolone-3-carboxylate derivatives
  • Synthesis method of 2-indolone-3-carboxylate derivatives
  • Synthesis method of 2-indolone-3-carboxylate derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Monoethyl malonate amide derivative (ethyl 3-oxo-3-[(2,4-dimethoxybenzyl)(4-methoxyphenyl)amino]propionate) (IV) preparation

[0024] Dissolve monoethylmalonyl chloride (III) (2.6g, 17.6mmol) in anhydrous dichloromethane (130mL), cool the resulting solution to 0°C, and add substituted aniline (N-(2 , 4-dimethoxybenzyl)-4-methoxyaniline) (II) (4.0g, 16.6mmol), stirred until dissolved, slowly added triethylamine (2.5 mL), after the dropwise addition was completed, the stirring was continued for 30 minutes, and the reaction was completed. Add saturated ammonium chloride solution (100mL) to the reaction solution, place the mixture in a separatory funnel to collect the organic layer, wash with water (150mL), dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude product , the crude product was separated and purified by column chromatography to obtain 5.5 g of light yellow oily liquid, yield: 85%.

[0025] 1 H NMR (4...

Embodiment 2

[0028] Enol compound (ethyl 2-[(2,4-dimethoxybenzyl)(4-methoxyphenyl)carbamoyl]-3-hydroxy-2-butenoate) (V) preparation

[0029] Suspend sodium hydride (524 mg, 13 mmol) in a mixed solution of anhydrous tetrahydrofuran / acetonitrile (33 mL, V THF :V MeCN =1:1) and stir evenly, add 3-oxo-3-[(2,4-dimethoxybenzyl)(4-methoxyphenyl) dropwise to the mixture at 0°C Ethyl amino]propionate (IV) (1.5 g, 3.95 mmol) in dry THF / acetonitrile (33 mL, V THF :V MeCN =1:1), continue to stir for 30 minutes after the dropwise addition. Acetyl chloride (340uL) was slowly added dropwise to the obtained mixture at 0°C, and the obtained mixture was protected with nitrogen, stirred for 6 hours and gradually warmed to room temperature. After the completion of the reaction monitored by TLC, ethyl acetate (100 mL) was added to the reaction system and transferred to a separatory funnel, washed with water (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under redu...

Embodiment 3

[0033] 2-indolinone-3-carboxylate derivatives (1-(2,4-dimethoxybenzyl)-5-methoxy-2-[(triisopropylsilyl)oxy] -1-H-indole-3-carboxylic acid ethyl ester) (I)

[0034] 2-[(2,4-dimethoxybenzyl)(4-methoxyphenyl)carbamoyl]-3-hydroxy-2-butenoic acid ethyl ester (V) (622mg, 1.45mmol) Dissolve in acetonitrile (30 mL), add iodobenzene acetate powder (562 mg, 1.75 mmol) to the resulting solution at one time, stir and react at room temperature for 30 minutes, until the disappearance of the raw material as monitored by TLC. Add ethanol (5 mL) and sodium acetate powder (2.4 g, 29 mmol) to the reaction solution, and stir at room temperature for 48 hours. The solvent was removed under reduced pressure, ethyl acetate (50 mL) was added to the reaction system and transferred to a separatory funnel, washed with water (50 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in anhydrous di...

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Abstract

The invention discloses a synthesis method of 2-indolone-3-carboxylate derivatives (I), which comprises the following steps: reacting substituted aniline (II) used as a raw material and triethylamine as an acid-binding agent with ethyl malonyl chloride (III) to generate ethyl malonyl chloride (IV); reacting the ethyl malonyl chloride (IV) with acetyl chloride in an acetonitrile-tetrahydrofuran mixed solution under the action of sodium hydride to generate an enol form compound (V); carrying out intramolecular cyclization on the enol form compound (V) under the action of iodosobenzene diacetate to remove acetyl group, thereby obtaining 2-indolone-3-carboxylate; and reacting the 2-indolone-3-carboxylate with triisopropyl trifluoromethanesulfonates under the action of triethylamine to generate the 2-indolone-3-carboxylate derivatives (I). The synthesis method is simple to operate, and has the advantages of mild reaction conditions, accessible reaction raw materials and reaction reagents, no need of toxic metal reagents, environment friendliness and the like.

Description

technical field [0001] The invention relates to a synthesis method of 2-indolinone-3-carboxylate derivatives. Background technique [0002] 2-indolinone-3-carboxylate (I) is an important synthetic intermediate used in the synthesis of the product Horsfiline [1] . [0003] [0004] There is only one synthetic method of 2-indolinone-3-carboxylate (I) reported in the literature at present, as follows: [0005] In 2006, Trost and Brennan reported the total synthesis of Horsfiline, an indolinone alkaloid. This method uses 2-indolinone-3-carboxylate (I) as an important synthetic intermediate. The specific preparation method As follows: [0006] [0007] In this method, substituted aniline (II) is used as a raw material, and triethylamine is used as an acid-binding agent to react with monoethyl diazomalonate acid chloride (III') to generate monoethyl diazomalonate amide derivative (IV '); compound (IV') undergoes intramolecular ring closure under the action of rhodium ace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
Inventor 杜云飞吕晶磊赵康
Owner BIRDO (SHANGHAI) PHARM R&D CO LTD
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