Method for preparing drug intermediate by catalyzing organic silicon supported ion liquid

A technology of ionic liquid and organic silicon, which is applied in the field of medicine and chemical industry, can solve the problems of low production efficiency, long reaction time, low yield, etc., and achieve the effect of realizing recycling and improving production efficiency

Inactive Publication Date: 2018-10-09
刘耿熙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The purpose of the present invention is to overcome the deficiencies in the prior art, provide a kind of organosilicon-loaded alkaline ionic liquid, and catalyze 5-nitrosalicylaldehyde and N-( 2-chloroethyl) pyrrolidine condensation reaction prepares 5-nitro-2-[2-(pyrrolidin-1-yl) ethoxyl] benzaldehyde; the catalytic system of the present invention overcomes the cesium carbonate catalytic process in the prior art Defects such as excessive dosage, long reaction time, low yield and low production efficiency

Method used

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  • Method for preparing drug intermediate by catalyzing organic silicon supported ion liquid
  • Method for preparing drug intermediate by catalyzing organic silicon supported ion liquid
  • Method for preparing drug intermediate by catalyzing organic silicon supported ion liquid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] One, prepare organosilicon-loaded alkaline ionic liquid as follows:

[0039] 1) Ionic liquid preparation process:

[0040] Mix 40mmol of triethylenediamine and 20mmol of 1,4-dichlorobutane, stir at 90-100°C for 3-5h under nitrogen atmosphere, then add 300ml of n-heptane for ultrasonic dispersion for 20-30min, filter, and reduce at 40°C Pressing and drying to obtain the ionic liquid precursor;

[0041] Dissolve 19.8mmol of imidazole in 100ml of anhydrous methanol solution of 0.2mol / L sodium hydroxide at 40-45°C and stir to dissolve for 10-20min, then add 3.51g of ionic liquid precursor (about 19.8mmol by silver nitrate titration). Chloride ion) stirred at 40-45°C for 6-8h, cooled to room temperature and filtered to remove insoluble sodium chloride, and the filtrate was concentrated to obtain an ionic liquid;

[0042] 2) Loading of ionic liquid

[0043] Dissolve 100g of isopropyl orthosilicate in 100ml of isopropanol and heat to 70-80°C, then add 15g of ionic liquid an...

Embodiment 2

[0052] Lithium iodide was selected as metal iodide to prepare organosilicon-supported alkaline ionic liquid as catalyst to catalyze the condensation reaction of 5-nitrosalicylaldehyde and N-(2-chloroethyl)pyrrolidine to prepare 5-nitro -2-[2-(pyrrolidin-1-yl)ethoxyl]benzaldehyde, the present invention further optimizes the solvent type in this catalytic reaction, the method is as follows:

[0053] Add 5-nitrosalicylaldehyde (1.67g, 10mmol), N-(2-chloroethyl)pyrrolidine (1.74g, 13mmol, 1.3eq) and lithium iodide modified organosilicon support to the parallel synthesizer. Loaded alkaline ionic liquid catalyst (0.5g, ~30%wt), 30ml solvent, react at 80°C (solvent with boiling point lower than 80°C, react at reflux temperature), HPLC detects 5-nitrowater in the reaction solution After the concentration of salicylaldehyde no longer changes within 2h, the area percentage of the substrate 5-nitrosalicylaldehyde, the target product 5-nitro-2-[2-(pyrrolidin-1-yl) in the reaction solution...

Embodiment 3

[0058] On the basis of selecting lithium iodide as metal iodide to prepare organosilicon-loaded alkaline ionic liquid as catalyst and acetonitrile as solvent, the present invention has the following requirements for catalyst consumption, N-(2-chloroethyl)pyrrolidine molar consumption (Based on the molar dosage of 5-nitrosalicylaldehyde) further optimization:

[0059] Organosilicon prepared by adding 5-nitrosalicylaldehyde (1.67g, 10mmol), N-(2-chloroethyl)pyrrolidine (11-15mmol, 1.1-1.5eq), and lithium iodide to a parallel synthesizer Loaded alkaline ionic liquid catalyst (0.17-1.67g, 10-100%wt), 30ml of acetonitrile, reacted at 80°C, after the HPLC detection of the concentration of 5-nitrosalicylaldehyde in the reaction solution no longer changed within 2h, The area percentage of substrate 5-nitrosalicylaldehyde, the area percentage of target product 5-nitro-2-[2-(pyrrolidin-1-yl) ethoxyl] benzaldehyde and Its impurity content (using the area normalization method to carry ou...

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals and in particular relates to a method for preparing a drug intermediate by catalyzing organic silicon supported ion liquid. Themethod comprises the following steps: preparing organic silicon supported alkaline ion liquid; connecting triethylene diamine with the mol amount by utilizing 1,4-dichlorobutane to provide a cation part of the alkaline ion liquid; then taking imidazolyl as anion to form ion liquid; supporting the prepared ion liquid by utilizing silica sol; in a supporting process, modifying by utilizing metal iodide to finally prepare the organic silicon supported alkaline ion liquid. The organic silicon supported alkaline ion liquid prepared by the method can be used for efficiently catalyzing condensationreaction of 5-nitrosalicylaldehyde and N-(2-chloroethyl)pyrrolidine to prepare a myelofibrosis treatment medicine Pacritinib intermediate, i.e., 5-nitro-2-[2-(pyrrolidine-1-yl)ethoxy]benzaldehyde; thedefect in a traditional production process that the production efficiency is low is overcome.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for preparing a drug intermediate by catalyzing an organic silicon-loaded ionic liquid. Background technique [0002] Pacritinib hydrochloride (pacritinib hydrochloride) is a Jak type 2 inhibitor developed by CTI Biopharmaceuticals (formerly known as Cell Genomics) of the United States. It is currently used in phase III clinical research for the treatment of moderate-risk and high-risk myelofibrosis. [0003] The molecular weight of Pacritinib is 472.58, the molecular formula is C28H32N4O3, the CAS number is 937272-79-2, and its chemical structural formula is shown in formula (1): [0004] [0005] There are two main synthetic routes of Pacritinib, Shan Hanbin et al. (Chinese Journal of Pharmaceutical Industry, 2015, 46 (12): 1269-1273, the synthesis of Pacritinib hydrochloride) to the two synthetic routes of Pacritinib in the prior ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/088B01J31/02
CPCC07D295/088B01J31/0292
Inventor 刘耿熙陈兰华季辉李靖梁利
Owner 刘耿熙
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