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Preparation method of 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone

A technology of halobutyryl and halobutyryloxy, applied in organic chemistry and other directions, can solve problems such as unfavorable industrial production, excessive waste brine, etc., to save preparation time, controllable reaction conditions, and high yield. Effect

Pending Publication Date: 2021-07-16
岳阳新华达制药有限公司
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  • Description
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  • Application Information

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Problems solved by technology

Chinese patent CN111217746 adopts 8-hydroxyquinoline nitroxide and 2-bromobutyryl halide to obtain 5-(2-bromobutyryl)-8-hydroxyquinolone, and this reaction condition still needs to use a large amount of Lewis acid, produces too much Waste salt water is not conducive to industrial production

Method used

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  • Preparation method of 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone
  • Preparation method of 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone
  • Preparation method of 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone

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preparation example Construction

[0034] The present invention provides a kind of preparation method of 5-(alpha-halobutyryl)-8-hydroxyquinolin-2-one, comprising the following steps:

[0035] Step 1: In the presence of an acid-binding agent, the 8-hydroxyquinolin-2-one shown in formula (I) is acylated with the acylating agent shown in formula (II) to obtain the formula ( Ⅲ) 8-(α-halobutyryloxy)-quinolin-2-one shown in;

[0036] Step 2: Rearrange 8-(α-halobutyryloxy)-quinolin-2-one in methanesulfonic acid to obtain 5-(α-halobutyrate as shown in formula (IV) Acyl)-8-hydroxyquinolin-2-one;

[0037]

[0038] Preferably, the molar ratio of 8-hydroxyquinolin-2-one to acylating agent is 1:(1-1.5).

[0039] Preferably, the molar ratio of 8-(α-halobutyryloxy)-quinolin-2-one to methanesulfonic acid is 1:(5-15).

[0040] Preferably, the acylating agent includes one or more of 2-chlorobutyryl chloride, 2-bromobutyryl chloride, 2-chlorobutyryl bromide and 2-bromobutyryl bromide.

[0041] Preferably, the acid-binding...

Embodiment 1

[0059] Example 1: 8-(α-chlorobutyryloxy)-quinolin-2-one

[0060] 16.1 g (0.10 mol) of 8-hydroxyquinolin-2-one was put into 150 ml of anhydrous dichloromethane, 34.6 g (0.30 mol) of diisopropylethylamine was added, and 15.5 g of 2-chlorobutyryl chloride was slowly added dropwise at room temperature. g (0.11mol), after the addition, keep stirring at 40°C for 4h, add 200ml of water and stir for 0.5h, filter the mixture directly, wash the filter cake with an appropriate amount of water, and dry the filter cake under vacuum at 50°C to obtain 24.7g of white powder with a yield of 93.0 %.

Embodiment 2

[0061] Example 2: 8-(α-bromobutyryloxy)-quinolin-2-one

[0062] 16.1 g (0.10 mol) of 8-hydroxyquinolin-2-one was dropped into 150 ml of anhydrous dichloromethane, 17.7 g (0.30 mol) of triethylamine was added, and 25.3 g of 2-bromobutyryl bromide was slowly added dropwise at room temperature ( 0.11mol), after the addition, keep stirring at 40°C for 4h, add 200ml of water and stir for 0.5h, filter the mixture directly, wash the filter cake with an appropriate amount of water, and vacuum-dry the filter cake at 50°C to obtain 25.5g of white powder with a yield of 82.2%.

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Abstract

The invention provides a preparation method of 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone, which comprises the following steps: step 1, in the presence of an acid-binding agent, carrying out acylation reaction on 8-hydroxyquinoline-2-ketone as shown in a formula (I) and an acylating agent as shown in a formula (II) to obtain 8-(alpha-halogenated butyryloxy)-quinoline-2-ketone as shown in a formula (III); 2, carrying out a rearrangement reaction on the 8-(alpha-halogenated butyryloxy)-quinoline-2-ketone in methanesulfonic acid to prepare the 5-(alpha-halogenated butyryl)-8-hydroxyquinoline-2-ketone as shown in the formula (IV). The method is simple in process, low in production cost, good in product quality, high in yield and beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of 5-(alpha-halobutyryl)-8-hydroxyquinolin-2-one. Background technique [0002] As a pharmaceutical intermediate, 5-(α-halobutyryl)-8-hydroxyquinolin-2-one is a key intermediate in the synthesis of the drug Procaterol hydrochloride, which is used to prevent and treat bronchial asthma and wheezing Wheezing symptoms due to acute bronchitis and chronic obstructive pulmonary disease. Developed by Otsuka Pharmaceutical, it was launched in Japan in 1981. Japan's Otsuka Haraken patent US4026897 uses 8-hydroxyquinolin-2-one as the starting material, and adopts the Friedel-Crafts reaction to prepare the intermediate 5-(α-bromobutyryl)-8-hydroxyquinolin-2-one. The Friedel-Crafts reaction uses a large excess of 2-bromobutyryl bromide and anhydrous aluminum trichloride, and the reaction product forms viscous oily precipitates, and the post-treatm...

Claims

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Application Information

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IPC IPC(8): C07D215/26
CPCC07D215/26
Inventor 郭凌云潘先良符兆林舒森符德胜廖湘一
Owner 岳阳新华达制药有限公司
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