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A new method for preparing 4-(2-hydroxyethyl)-1,3-dihydro-2h-indol-2-one

A technology of hydroxyethyl and new method is applied in the field of preparing 4--1,3-dihydro-2H-indol-2-one, which can solve the problem of restricting ropinirole hydrochloride, unfavorable industrial production and price. Expensive and other problems, to achieve the effect of simple operation, simplified operation and low cost

Active Publication Date: 2019-03-22
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But there is following defect in this route: at first must use expensive and toxic big flammable borane reagent, this is unfavorable for suitability for industrialized production
[0013] Therefore, the various defects existing in the prior art have limited the preparation of ropinirole hydrochloride (Ⅱ) on an industrial scale.

Method used

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  • A new method for preparing 4-(2-hydroxyethyl)-1,3-dihydro-2h-indol-2-one
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  • A new method for preparing 4-(2-hydroxyethyl)-1,3-dihydro-2h-indol-2-one

Examples

Experimental program
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Effect test

Embodiment 1

[0051] The synthesis of embodiment one 2-methyl-3-nitrophenyl alcohol (IV)

[0052] At room temperature, 694g of 2-methyl-3-nitrophenylacetic acid (Ⅲ), 676g of sodium borohydride and 15L of tetrahydrofuran were mixed with each other, and 4.5L of boron trifluoride ether was added under thorough stirring. Then reflux reaction for 5h. At 0°C, slowly add 3L of concentrated hydrochloric acid dropwise, and stir at room temperature for 6 hours after the addition. After filtering, the filtrate was dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain 640 g of crude oily product of 2-methyl-3-nitrophenylethanol (IV), which was directly carried out to the next step of reaction.

Embodiment 2

[0053] The synthesis of embodiment two 2-methyl-3-nitrophenethyl alcohol (Ⅳ)

[0054] Mix 500g of 2-methyl-3-nitrophenylacetic acid (Ⅲ), 200g of sodium borohydride and 5L of tetrahydrofuran at room temperature, then add 250g of methanesulfonic acid, stir at room temperature for 24 hours, then add 3L of ethyl acetate and 5L of concentrated hydrochloric acid . The organic phase was obtained by liquid separation, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain 420 g of crude 2-methyl-3-nitrophenylethanol (IV) oil, which was directly carried out to the next reaction.

Embodiment 3

[0055] The synthesis of embodiment three 2-methyl-3-(2-alkoxyethyl) nitrobenzene (Ⅴ)

[0056] The crude compound (IV) obtained in Example 2 and 275 g of sodium hydroxide were added to 2 L of acetone, and then 430 g of benzyl bromide was added dropwise. After the drop was completed, it was stirred at room temperature for 24 hours. After removing the solvent under reduced pressure, 1.5 L of ethyl acetate and 1.5 L of water were added. The layers were separated, and the organic phase was washed with 1.5 L of saturated brine. Liquid separation was obtained to obtain an organic phase, and after drying over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure to obtain 590 g of 2-methyl-3-(2-alkoxyethyl) nitrobenzene (Ⅴ) oil crude product, which was directly used in the following One step reaction.

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PUM

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Abstract

The invention discloses a novel method for preparing a ropinirole hydrochloride key intermediate 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone (I). The reaction process comprises the following steps of: carrying out reduction reaction on 2-methyl-3-nitrobenzene acetic acid (III) to generate 2-methyl-3-nitrobenzene ethanol (IV); protecting the hydroxyl of the compound (IV) to generate 2-methyl-3-(2-alkoxy ethyl) nitrobenzene (V); reacting the compound (V) with diethyl oxalate to generate a 2-nitro-6-(2-alkoxy ethyl)-phenyl acetyl formic acid compound (VI); reacting the compound (VI) with hydrogen peroxide to generate 2-nitro-6-(2-alkoxy ethyl)-phenylacetic acid (VII); and carrying out oxidation reaction on the compound (VII) to obtain 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone (I).

Description

technical field [0001] The present invention relates to a new method for preparing 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I). Background technique [0002] Ropinirole hydrochloride (Ⅱ), the chemical name is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride, produced by GSK A drug developed by the company. The drug, originally approved to treat Parkinson's disease, was later found to be effective in treating moderate to severe restless legs syndrome as well. [0003] [0004] At present, there are many documents and patents introducing the synthesis of ropinirole hydrochloride (II), but the most widely used are still the two routes developed by GSK. Among them, the first route is described in the document JMC, 1985, 1533: [0005] [0006] This route uses 2-methyl-3-nitrophenylacetic acid as the initial raw material, and forms the intermediate 2-methyl-3-nitro-N,N-di-n-propane after acylation, amination and borane reduction phenylethylamine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34C07C201/12C07C205/34
Inventor 陈宇陈欢生袁利
Owner SHANGHAI AOBO PHARMTECH INC LTD
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