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A kind of (r)‑n‑boc‑5‑bromo‑1‑methylisoindoline and its preparation method and application

A technology of methylisoindoline and -n-boc-5-, which is applied in the field of drug synthesis, can solve problems that no one has raised, and achieve the effects of novel and unique steps, high practical application value, and high yield

Active Publication Date: 2018-01-09
SHANGHAI BALMXY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In this area, no one has proposed a high-conversion preparation method of Boc-5-bromo-1-methylisoindoline, and the preparation of Boc-5-bromo-1-methylisoindoline is the current research the key of

Method used

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  • A kind of (r)‑n‑boc‑5‑bromo‑1‑methylisoindoline and its preparation method and application
  • A kind of (r)‑n‑boc‑5‑bromo‑1‑methylisoindoline and its preparation method and application
  • A kind of (r)‑n‑boc‑5‑bromo‑1‑methylisoindoline and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] (1) Preparation of 4-bromo-phenethylamine

[0057]

[0058] Add 1000g of p-bromoacetophenone and 1445g of ammonium formate into a 5L reaction flask, and slowly heat to 120°C. The two raw materials slowly dissolve and become liquid. Start stirring and keep at 120°C for 2 hours. Then the reaction temperature was raised to 180° C. and kept at this temperature for 5 hours. Stop the reaction, after cooling, add water, dichloromethane, separate layers, concentrate the organic phase, add 670 ml of concentrated hydrochloric acid and 1000 ml of water, reflux, 1-2 hours, the reactant first has solids, then clarifies, and then a large amount of solids are precipitated , the reaction is over, after cooling slightly, add 1000 milliliters of toluene, and cool to room temperature under stirring. Filtration, the solid was fully washed twice with toluene, and the solid was dried to obtain the hydrochloride salt of the product, which was neutralized with sodium hydroxide, extracted w...

Embodiment 2

[0070] (1) Preparation of 4-bromo-phenethylamine

[0071]

[0072] Add 1000g of p-bromoacetophenone and 950g of ammonium formate into a 5L reaction flask, and slowly heat to 120°C. The two raw materials slowly dissolve and become liquid. Start stirring and keep at 120°C for 2 hours. Then the reaction temperature was raised to 180° C. and kept at this temperature for 5 hours. Stop the reaction, after cooling, add water, dichloromethane, separate layers, concentrate the organic phase, add 670 ml of concentrated hydrochloric acid and 1000 ml of water, reflux, 1-2 hours, the reactant first has solids, then clarifies, and then a large amount of solids are precipitated , the reaction is over, after cooling slightly, add 1000 milliliters of toluene, and cool to room temperature under stirring. Filtration, the solid was fully washed twice with toluene, and the solid was dried to obtain the hydrochloride salt of the product, which was neutralized with sodium hydroxide, extracted wi...

Embodiment 3

[0084] (1) Preparation of 4-bromo-phenethylamine

[0085]

[0086] Add 1,000g of p-bromoacetophenone and 1,900g of ammonium formate into a 5L reaction flask, and slowly heat to 120°C. The two raw materials slowly dissolve and become liquid, start stirring, and keep at 120°C for 2 hours. Then the reaction temperature was raised to 180° C. and kept at this temperature for 5 hours. Stop the reaction, after cooling, add water, dichloromethane, separate layers, concentrate the organic phase, add 670 ml of concentrated hydrochloric acid and 1000 ml of water, reflux, 1-2 hours, the reactant first has solids, then clarifies, and then a large amount of solids are precipitated , the reaction is over, after cooling slightly, add 1000 milliliters of toluene, and cool to room temperature under stirring. Filtration, the solid was fully washed twice with toluene, and the solid was dried to obtain the hydrochloride salt of the product, which was neutralized with sodium hydroxide, extracte...

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Abstract

The invention provides (R)-N-Boc-5-bromine-1-methylisoindoline as well as a preparation method and application thereof. Reaction between (R)-4-bromine-phenylethylamine and paraformaldehyde is carried out under an effect of Lewis acid to obtain the (R)-5-bromine-1-methylisoindoline; and a secondary amino group is protected by further utilizing butoxycarbonyl to obtain the (R)-N-Boc-5-bromine-1-methylisoindoline. The cyclization method comprises novel and unique steps, is easy to operate and relatively high in yield. The splitting is carried out firstly by utilizing splitting reagent to obtain the chirally-prepared (R)-4-bromine-phenylethylamine raw material so as to further prepare the (R)-5-bromine-1-methylisoindoline, thereby greatly reducing volumes; and the volumes are greatly reduced, and splitting wastes in the whole process also can be reduced. The whole preparation method disclosed by the invention has easily-available raw materials, is simple in process operation and low in cost and has a relatively practical application value.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to (R)-N-Boc-5-bromo-1-methylisoindoline and its preparation method and application. Background technique [0002] Garafloxacin, English name Gatifloxacin, is a quinolone compound, its chemical name is 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2,3 -dihydro-1H-isoindol-5-yl]-4-oxoquinoline-3-carboxylic acid, its chemical structural formula is as follows: [0003] [0004] Garafloxacin is a new type of broad-spectrum quinolone antibacterial drug. It not only maintains the antibacterial activity of quinolone antibacterial drugs against G-bacteria, but also significantly enhances the antibacterial activity against G+ bacteria. It is mainly used clinically to treat respiratory infections. Urinary system infection and skin, soft tissue infection and other diseases. In its structure, the removal of fluorine at the 6-position of the quinolone core can not only improve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/44C07D401/04
CPCC07D209/44C07D401/04
Inventor 吴天俊
Owner SHANGHAI BALMXY PHARMA CO LTD
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