A kind of synthetic method of pharmaceutical intermediate polysubstituted quinoline derivatives

A synthesis method and a pharmaceutical technology are applied in the field of synthesis of pharmaceutical intermediate quinoline derivatives, and can solve the problems that the reaction conditions need to be improved, the reaction yield needs to be improved, the scope of application of the reaction raw materials needs to be broadened, and the like, and the effect of improving the harsh reaction is achieved.

Inactive Publication Date: 2016-09-07
河北中化鑫宝化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] There are more or less various problems in the above-mentioned synthetic techniques involving quinoline compounds and other prior art that have not been listed one by one, such as the scope of application of reaction raw materials still needs to be broadened, harsh reaction conditions need to be improved, reaction yield rate to be improved, etc.

Method used

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  • A kind of synthetic method of pharmaceutical intermediate polysubstituted quinoline derivatives
  • A kind of synthetic method of pharmaceutical intermediate polysubstituted quinoline derivatives
  • A kind of synthetic method of pharmaceutical intermediate polysubstituted quinoline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] Add 1mmol of the compound of formula (I) and 2.3mmol of the compound of formula (II) in the closed reaction kettle, then add 4ml of toluene and 4ml of acetonitrile, and then add 0.08mmol of Pd(OAc) under stirring 2 And 6mmol trifluoromethanesulfonic acid, finally add 110mg mass ratio of 1:2.5 1,2-bis(diphenylphosphine)ethane (dppe) and 18-crown-6 additive mixture, heat up to 100°C for reaction 12h, TLC monitors the end point of the reaction, after the reaction is completed, the mixture is added to a saturated sodium bicarbonate solution, then extracted with ethyl acetate, the combined organic phases are washed with water, separated, and concentrated in vacuo, and the residue is purified by silica gel column chromatography to obtain the formula (III) compound, the yield is 98.1%, and the purity is 99.3% (HPLC).

[0038] 1 H NMR (400MHz, CDCl 3)δ=8.17(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.53(s,1H),7.41-7.28(m,5H),7.25-7.19(m,3H ), 7.14-7.08 (m, 2H), 7.03-6.96 ...

Embodiment 2

[0040]

[0041] Add 1mmol of the compound of formula (I) and 2mmol of the compound of formula (II) into the closed reaction kettle, then add 4.5ml of toluene and 4.5ml of acetonitrile, and then add 0.05mmol of Pd(OAc) under stirring 2 And 7mmol trifluoromethanesulfonic acid, finally add 100mg mass ratio of 1,2-bis(diphenylphosphine)ethane (dppe) and 18-crown-6 auxiliary agent mixture, heat up to 105°C for reaction 11h, TLC monitors the end point of the reaction, after the reaction is completed, the mixture is added to a saturated sodium bicarbonate solution, then extracted with ethyl acetate, the combined organic phases are washed with water, separated, and concentrated in vacuo, and the residue is purified by silica gel column chromatography to obtain the formula (III) compound, the yield is 99.1%, and the purity is 98.9% (HPLC).

[0042] 1 H NMR (400MHz, CDCl 3 )δ=8.32(m, 1H), 7.74(t, J=7.47Hz, 1H), 7.57(d, J=7.47Hz, 1H), 7.49(t, J=7.47Hz, 1H), 7.37-7.35( m, 2H), 7.26-...

Embodiment 3

[0044]

[0045] Add 1mmol of the compound of formula (I) and 2.5mmol of the compound of formula (II) in the closed reaction kettle, then add 5ml of toluene and 5ml of acetonitrile, and add 0.06mmol of Pd(OAc) successively under stirring 2 And 8mmol trifluoromethanesulfonic acid, finally add 120mg mass ratio of 1:2.5 1,2-bis(diphenylphosphine)ethane (dppe) and 18-crown-6 additive mixture, heat up to 110°C for reaction 12h, TLC monitors the end point of the reaction, after the reaction is completed, the mixture is added to a saturated sodium bicarbonate solution, then extracted with ethyl acetate, the combined organic phases are washed with water, separated, and concentrated in vacuo, and the residue is purified by silica gel column chromatography to obtain the formula (III) compound, the yield is 98.7%, and the purity is 99.0% (HPLC).

[0046] 1 H NMR (400MHz, CDCl 3 )δ=8.25(s,1H),8.19(d,J=8.2Hz,1H),8.03(d,J=8.2Hz,1H),7.91-7.85(m,1H),7.81-7.74(m,2H ), 7.60-7.55 (m, 2H), 7...

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PUM

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Abstract

The invention relates to a preparation method of a medical intermediate multi-substituted quinoline derivative. High-yield preparation of a multi-substituted quinoline compound is achieved by using o-aminoaryl ketone and alkyne as raw materials and screening via an auxiliary / solvent in the presence of a catalyst Pd(OAc)2 / acetic acid. The preparation method has the effects of solving the problem that the prior art has low yield and simultaneously widening the raw material application range, has the advantages of high yield and mild reaction and has very extensive large-scale application prospect and market promotion value.

Description

technical field [0001] The invention relates to a method for synthesizing quinoline derivatives as a pharmaceutical intermediate, more specifically to a method for preparing multi-substituted quinoline compounds by reacting o-aminoaryl ketones and alkyne compounds catalyzed by palladium, and belongs to the field of organic synthesis. Background technique [0002] Quinoline derivatives are the building blocks of many natural products and bioactive compounds. They are also often used as important synthons of pharmaceutical compounds, and can also be used to prepare key ligands for OLED materials, and can also be used to prepare asymmetric catalysts. For this reason, scientific and technological workers have developed many synthetic methods related to quinoline compounds, which have also aroused extensive interest of researchers in the fields of organic, chemical, materials, and especially medicine. [0003] The traditional Conrad-Limpach-Knorr method and the Friedlander method...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/18C07D215/06C07D215/12C07D215/14
CPCC07D215/04C07D215/12C07D215/14C07D215/18
Inventor 杨建疆姬志刚石广柱相东姬志强贾海亮
Owner 河北中化鑫宝化工科技有限公司
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