A kind of synthetic method of pharmaceutical intermediate 4-aminoquinoline compounds

A synthesis method and aminoquinoline technology, applied in the direction of organic chemistry and the like, can solve the problems such as unreported cyclization synthesis of quinoline compounds, and achieve the effect of good application prospect, industrialization potential and high yield.

Inactive Publication Date: 2017-11-14
厦门法茉维特动物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for CF 3 -The cyclization synthesis of quinoline compounds has not been reported

Method used

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  • A kind of synthetic method of pharmaceutical intermediate 4-aminoquinoline compounds
  • A kind of synthetic method of pharmaceutical intermediate 4-aminoquinoline compounds
  • A kind of synthetic method of pharmaceutical intermediate 4-aminoquinoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] Under nitrogen atmosphere, add 100mmol formula (I) compound and 150mmol formula (II) compound to solvent dichloromethane, stir and mix for 10 minutes, then add 6mmol catalyst PdCl successively 2 (MeCN) 2 , 100mmol additive CuBr 2 , 220mmol base NaHCO 3 , 4mmol of ligand L1 and 10mmol of additives, heated up to 50°C and stirred for 5 hours, cooled to room temperature after the reaction, concentrated in vacuo, and passed through 300-400 mesh silica gel column chromatography (with ethyl acetate in a volume ratio of 1:2 The mixed solution with acetone was used as the eluent) to obtain the compound of formula (III) (wherein t-Bu is tert-butyl) with a yield of 97.3%.

[0043] Wherein, the auxiliary agent is a mixture of polyethylene glycol 400 and butyltriphenylphosphine bromide, wherein the molar ratio of polyethylene glycol 400 to butyltriphenylphosphine bromide is 1:2.

[0044] 1 H NMR (CDCl 3 ,400MHz):δ8.03(d,J=9.2Hz,1H),7.66(s,1H),7.43(d,J=9.1Hz,1H),4.87...

Embodiment 2

[0047]

[0048] Under nitrogen atmosphere, add 100mmol formula (I) compound and 200mmol formula (II) compound to solvent m-dichlorobenzene, stir and mix for 12 minutes, then add 7mmol catalyst PdCl successively 2 (MeCN) 2 , 150mmol additive CuBr 2 , 240mmol base NaHCO 3 , 7mmol of ligand L1 and 12mmol of additives, heated up to 55°C and stirred for 4.5 hours, cooled to room temperature after completion of the reaction, concentrated in vacuo, and passed through 300-400 mesh silica gel column chromatography (with ethyl acetate in a volume ratio of 1:2 (mixture with acetone as eluent) was purified to obtain the compound of formula (III) (wherein t-Bu is tert-butyl) with a yield of 97.7%.

[0049] Wherein, the auxiliary agent is a mixture of polyethylene glycol 400 and butyltriphenylphosphine bromide, wherein the molar ratio of polyethylene glycol 400 to butyltriphenylphosphine bromide is 1:2.5.

[0050] 1 H NMR (CDCl 3 ,400MHz):δ8.28(d,J=12.0Hz,1H),8.14(s,1H),7.53(d,J=12....

Embodiment 3

[0053]

[0054] Under nitrogen atmosphere, add 100mmol formula (I) compound and 250mmol formula (II) compound to solvent chloroform, stir and mix for 15 minutes, then add 8mmol catalyst PdCl successively 2 (MeCN) 2 , 200mmol additive CuBr 2 , 260mmol base NaHCO 3 , 10mmol of ligand L1 and 15mmol of additives, heated up to 60°C and stirred for 5 hours, cooled to room temperature after the reaction, concentrated in vacuo, and passed through 300-400 mesh silica gel column chromatography (with ethyl acetate in a volume ratio of 1:2 (mixture with acetone as eluent) was purified to obtain the compound of formula (III) (wherein t-Bu is tert-butyl) with a yield of 98.1%.

[0055] Wherein, the auxiliary agent is a mixture of polyethylene glycol 400 and butyltriphenylphosphine bromide, wherein the molar ratio of polyethylene glycol 400 to butyltriphenylphosphine bromide is 1:3.

[0056] 1 H NMR (CDCl 3 ,400MHz):δ8.23(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),5.04(s,1H)...

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Abstract

The invention provides a method for synthesizing a 4-aminoquinoline compound shown in the formula (III). The method comprises the following steps: in an atmosphere of inert gas, adding a compound shown in the formula (I) and a compound shown in the formula (II) into a solvent for 10-15 minutes' mixing while stirring; adding a catalyst, an additive, an alkali, a ligand and an auxiliary agent, and heating to 50-60 DEG C and carrying out stirring to trigger a 4-5 hours' reaction; after the reaction is finished, cooling to room temperature; after vacuum concentration, carrying out silica gel column chromatography purification to obtain the 4-aminoquinoline compound shown in the formula (III). In the formula (III), R1 is selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy, and R2 is independently selected from C1-C6 alkyl or C6-C10 naphthenic base. The method is based on the comprehensive selection of various factors, for example, the synergistic action of the catalyst, the alkali, the ligand, the additive and the auxiliary agent, so that the target product can be obtained at high yield; the method has a good application prospect and high potential in industrialized production in the technical field of medical intermediate synthesis.

Description

technical field [0001] The invention relates to a synthesis method of quinoline compounds, more particularly to a synthesis method of 4-aminoquinoline compounds, and belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Quinoline compounds are important structures used to construct natural medicines and synthetic pharmaceutical compounds, and they usually have a wide range of biological activities. Therefore, in the prior art, a variety of medicinal compounds containing quinoline structures and good efficacy have been developed, such as antimalarials such as mefloquine, chloroquine, and amodiaquine. [0003] The oxidative cyclization reaction catalyzed by transition metals has always been the main way to synthesize heterocyclic compounds. The existing literature has recorded that this method can be used to synthesize indole, pyrazole, carbazole, benzofuran, benzo Various heterocyclic compounds such as thiophene. For example, the f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 刘凯卫邵金龙黄卫华
Owner 厦门法茉维特动物药业有限公司
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