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Synthetic method of oxatomide

A synthetic method and ethoxylate technology, applied in the direction of organic chemistry, etc., can solve the problems of harshness, difficult operation, harsh reaction conditions, etc.

Active Publication Date: 2021-09-14
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the molecular structure of the starting material N-(3-chloropropyl)-2-nitroaniline, due to the effect of hydrogen bonds, the nitro group has an inert effect on the ortho-position amine group on the benzene ring, making the first step The conditions of the acylation reaction are relatively harsh, and it needs to be refluxed in xylene for 14-18 hours to complete, and the last step of the cyclization reaction also needs a high temperature of 200 degrees to proceed, so this route has harsh reaction conditions, is not easy to operate, and is not suitable for industrial production
[0013] 3. Patent WO985892 discloses another synthetic method, 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (2) and 1-(3-chloropropyl)-4- After the condensation of benzhydrylpiperazine dihydrochloride (9), the one-pot method of acidolysis to remove the isopropenyl group was obtained to obtain oxamide; Two Ns participate in the alkylation reaction at the same time, but it is still unavoidable that the 2-position oxygen participates in the generated impurity 2 and impurity 5

Method used

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  • Synthetic method of oxatomide
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  • Synthetic method of oxatomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and acetone successively in 50L reactor, then in Add potassium carbonate, 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and inorganic base slowly under stirring The molar ratio is 1:1.2:0.1:3.3. After the addition is completed, the temperature is raised to 55-60°C for reaction, and the reaction is refluxed for 10 hours; after the detection reaction is completed, the acetone is recovered by concentration under reduced pressure, cooled, and 20L of water is added to the residue, and stirred at room temperature for 2 Hour, suction filtration, washing with water, drying, obtain white solid product 1-[3-(4-benzhydryl-1-piperazinyl) propyl group]-2-ethoxy-1H-benzimidazole, yield 74.9%.

[0031] Dissolve 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-ethoxy-1H-benzimidazole in isopropanol, add concentrated hydrochloric acid, ...

Embodiment 2

[0034]Add 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and isopropanol successively in the 50L reactor, Then slowly add sodium carbonate, 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and inorganic The molar ratio of the base is 1:1.0:0.03:3.8. After the addition, the temperature is raised to 55-60°C for reaction, and the reaction is refluxed for 10 hours; after the detection reaction is completed, the isopropanol is recovered by concentration under reduced pressure, cooled, and 20L of water is added to the residue , stirred at room temperature for 2 hours, suction filtered, washed with water, and dried to obtain a white solid product 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-ethoxy-1H-benzo Imidazole, yield 67.1%.

[0035] Dissolve 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-ethoxy-1H-benzimidazole in ethanol, add concentrated hydrochloric acid, 1-[3-( The molar rati...

Embodiment 3

[0038] Add 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and tetrahydrofuran successively in 50L reactor, then in Slowly add sodium hydroxide, 2-ethoxy-1H-benzimidazole, 1-(3-chloropropyl)-4-benzhydrylpiperazine dihydrochloride, sodium iodide and inorganic base under stirring The molar ratio is 1:1.5:0.01:4.0. After the addition, the temperature is raised to 55-60°C for reaction, and the reaction is refluxed for 10 hours; after the detection reaction is completed, the tetrahydrofuran is recovered by concentration under reduced pressure, cooled, and 20L of water is added to the residue, and stirred at room temperature After 2 hours, filter with suction, wash with water, and dry to obtain the white solid product 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-ethoxyl-1H-benzimidazole. The rate is 76.7%.

[0039] Dissolve 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-ethoxy-1H-benzimidazole in tert-butanol, add concentrated hydrochlo...

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Abstract

The invention relates to a synthesis method of oxatomide, and belongs to the technical field of medicine synthesis. According to the preparation method, 2-ethoxy-1H-benzimidazole and 1-(3-chloropropyl)-4-diphenylmethyl piperazine dihydrochloride are taken as initial raw materials, 1-[3-(4-diphenylmethyl-1-piperazinyl) propyl]-2-ethoxy-1H-benzimidazole is obtained through a condensation substitution reaction, and then acidolysis deprotection is carried out to obtain oxatomide. The method has the advantages of few synthesis steps, simple operation, low cost, economy and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of oxamide. Background technique [0002] Oxatomide (Oxatomide) is an H1 receptor antagonist, which was first developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, and was marketed in 1982. It is clinically used for urticaria, allergic rhinitis or conjunctivitis, and food allergy. It can also block the process of airway allergic inflammation in multiple ways, and it can be used to prevent and treat allergic asthma, especially children's asthma. Oxamide and loratadine belong to the second-generation antihistamine drugs, which have the characteristics of high H1 receptor selectivity, no sedative effect, and the separation of anticholinergic and antihistamine effects. The chemical name of oxamide is 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-2-benzimidazolone, CAS is 60607-34-3, molecular formula C 27 h 30 N 4 O, the str...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
CPCC07D235/26
Inventor 杨群力钟强侯绪会张路军吴明昊张龙飞
Owner SHANDONG HUIHAI PHARMA & CHEM
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