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A kind of synthetic method of zilpaterol hydrochloride

A technology for the synthesis of zilpaterol hydrochloride and its synthesis method, which is applied in the field of synthesis of zilpaterol hydrochloride, which can solve the problems of potential safety hazards, high hydrogen pressure, and high equipment requirements, and achieve the effects of simple operation, reduced cost, and low activity

Active Publication Date: 2019-11-26
JIANGSU LINGYUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But although in the first step of hydrogenation, it is relatively easy to convert the oxime (hydroxyimino group) at the 6-position into an amino group, but the activation energy required for the reduction of the ketone carbonyl at the 7-position to a hydroxyl group is very large, requiring a higher hydrogen pressure ( 2~5MPa), which requires high equipment and has potential safety hazards

Method used

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  • A kind of synthetic method of zilpaterol hydrochloride
  • A kind of synthetic method of zilpaterol hydrochloride
  • A kind of synthetic method of zilpaterol hydrochloride

Examples

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Embodiment 1

[0044] A kind of synthetic method of zilpaterol hydrochloride provided by the present embodiment, concrete steps are as follows:

[0045] 1. Hydrogenation

[0046]

[0047] Add compound (h) Z gram in the container with stirring; Then add mixed solvent (methanol / DMF=1~9, preferably 2~8, optimal 2.5), the amount of mixed solvent is 10~30Z gram (preferably 10~ 18 times, preferably 12 to 15 times), stirred at room temperature for half an hour to form a slurry, added to the hydrogenation kettle, washed the container with a small amount of methanol (0.75Z g) and put it into the hydrogenation kettle; Raney nickel catalyst, the addition amount is 0.02~0.15Z grams. After sealing the leak with a cover, replace it with nitrogen three times (high pressure 0.5MPa and low pressure 0.1MPa), and then replace it with hydrogen three times (high pressure 0.5MPa and low pressure 0.1MPa). Hydrogen, control the pressure in the kettle to 1-2MPa (gauge pressure, the best 1.2-1.5MPa), react for 2...

Embodiment 2

[0059] According to the method described in Example 1, specifically, 40 grams of compound (h), 480 grams of solvent (80 grams of methanol, 400 grams of DMF), stirred and dissolved into a slurry, added to the autoclave, added Raney nickel washed three times with methanol 5 grams, covered tightly, replaced with nitrogen three times and hydrogen three times, and reacted at 35±2°C and 1.5MPa for 6 hours. After completion, filter and distill under reduced pressure to obtain 445 g of a DMF solution of compound (k).

[0060] Transfer to the alkylation reaction bottle, add 36 grams of potassium carbonate, stir and disperse evenly, add 36 grams of 2-bromopropane dropwise, and steam the excess 2-bromopropane after the reaction is completed according to the above method. The mixture of potassium carbonate and potassium bromide was removed by filtration, and the filter cake was washed with 15 g of DMF. The filtrates were combined and added to a new 1000 ml flask, stirred and added dropwi...

Embodiment 3

[0064] According to the method described in Example 1, specifically, 50 grams of compound (h), 60 grams of solvent (15 grams of methanol, 45 grams of DMF), stirred and dissolved into a slurry, added to the autoclave, added Raney nickel washed three times with methanol 5 grams, covered tightly, replaced with nitrogen three times and hydrogen three times, and reacted at 35±2°C and 1.5MPa for 6 hours. After completion, filter and distill under reduced pressure to obtain 94 g of a DMF solution of compound (k).

[0065] Transfer to the alkylation reaction bottle, add 38 grams of potassium carbonate, add 20 grams of DMF, stir and disperse evenly, add 38 grams of 2-bromopropane dropwise, and steam the excess 2-bromopropane after the reaction is completed according to the above method. The mixture of potassium carbonate and potassium bromide was removed by filtration, and the filter cake was washed with 15 g of DMF. The combined filtrates were added dropwise into a flask prepared wit...

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Abstract

The invention provides a method for synthesizing zilpaterol hydrochloride. The method comprises the following steps: (1) hydrogenating a compound (h) under the action of a nickel-based catalyst to obtain 6-aminobenzimidazolidone azepine-7-one (compound k); (2) carrying out an alkylation reaction on the 6-aminobenzimidazolidinone azepine-7-one and 2-bromopropane to obtain 6-isopropylaminobenzimidazolidoneazepine-7-one (compound m); and (3) reducing the 6-isopropylaminobenzimidazolidinoneazepine-7-one to obtain zilpaterol. The method has the advantages of no high pressure conditions, low cost, simplicity in operation, and suitableness for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for synthesizing zilpaterol hydrochloride. Background technique [0002] Zipaterol hydrochloride is a beta-adrenoceptor agonist. Most of the existing synthetic methods adopt the synthetic route of U.S. Patent US4585770A (1986): [0003] [0004] (1) taking o-phenylenediamine (a) as starting material and ethyl acetoacetate in xylene, and potassium hydroxide as catalyst to synthesize isopropenyl benzimidazolone (b); [0005] (2) condensation reaction of isopropenyl benzimidazolone (b) and ethyl bromobutyrate to generate N-isopropenyl benzimidazolone-N'-ethyl butyrate (c); [0006] (3) N-isopropenyl benzimidazolone-N'-butyric acid ethyl ester (c) is alkaline hydrolyzed to obtain N-isopropenyl benzimidazolone-N'-butyric acid (d); [0007] [0008] (4) N-isopropenylbenzimidazolone-N'-butyric acid (d) is removed through acidic hydrolysis to obtain N-butyric acid benz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/06
CPCC07D487/06
Inventor 凌青云毕亚铃杨玲卫相良斌
Owner JIANGSU LINGYUN PHARMA
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