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Quinolines compounds and their intermediates, preparation method and application

A compound, quinoline technology, applied in the field of medicinal chemistry synthesis

Inactive Publication Date: 2008-07-02
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 4-position of the quinoline ring is generally directly connected to p-fluorophenyl, and the compounds connected through heteroatoms (such as O, S, N, etc.) have not been reported in the literature

Method used

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  • Quinolines compounds and their intermediates, preparation method and application
  • Quinolines compounds and their intermediates, preparation method and application
  • Quinolines compounds and their intermediates, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Preparation of 4-chloro-6,7,8-trifluoroquinoline-3-carboxylic acid ethyl ester

[0048] 59.0 g of ethyl 4-hydroxy-6,7,8-trifluoroquinoline-3-carboxylate and POCl 3 500ml was refluxed for 8 hours. Atmospheric pressure evaporation to remove POCl 3 (Recoverable and applicable), the resulting residue was transferred to a vigorously stirred mixture of ice and water, solid NaHCO 3 Alkalinize to pH 7-8, filter with suction, and recrystallize from toluene to obtain 41.3 g of the product, yield 65.6%, mp: 110-112°C.

[0049] 4-hydroxy-quinoline-3-carboxylic acid ethyl ester, 4-hydroxy-6-fluoro-7-chloroquinoline-3-carboxylic acid ethyl ester and 4-hydroxy-7-chloroquinoline-3-carboxylic acid ethyl Esters are raw materials, and 4-chloro-quinoline-3-carboxylic acid ethyl ester, 4-chloro-6-fluoro-4,7-dichloroquinoline-3-carboxylic acid ethyl ester and 4,7- Dichloroquinoline-3-carboxylic acid ethyl ester.

Embodiment 2

[0050] Example 2 Preparation of 4-substituted phenylthio-quinoline-3-carboxylic acid ethyl ester (E1~4)

[0051] 4-Chloro-quinoline-3-carboxylic acid ethyl ester 8.0g (34mmol), 4-fluorothiophenol 5.2g (41mmol) and Et 3 N 6.9g (68mmol) was stirred in THF at room temperature for 30min. The insoluble matter was filtered off, the mother liquor was concentrated, and the mixed solvent (toluene and petroleum ether) was recrystallized to obtain 10.0g 4-(4-fluorophenylthio)quinoline-3- Ethyl carboxylate (E2).

[0052] According to the above method, 4-fluorothiophenol was replaced by thiophenol, m-methoxythiophenol and p-isopropylthiophenol respectively to obtain 4-phenylthio-quinoline-3-carboxylic acid ethyl Ester (E1), ethyl 4-(4-methoxyphenylthio)-quinoline-3-carboxylate (E3) and 4-(4-p-isopropylphenylthio)-quinoline-3- Ethyl carboxylate (E4). Yield, melting point (Mp.) and 1 H-NMR identification results are shown in Table 1.

Embodiment 3

[0053] Example 3 Preparation of ethyl 7-chloro-4-substituted phenylthioquinoline-3-carboxylate (E5-8)

[0054] With 4,7-dichloroquinoline-3-carboxylate ethyl ester as raw material, by the method for embodiment 2, respectively with thiophenol, 4-fluorothiophenol, m-methoxythiophenol and p-cymene Thiophenol was reacted to obtain compound E5~8 respectively, yield, melting point (Mp.) and 1 H-NMR identification results are shown in Table 2.

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PUM

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Abstract

The invention discloses a quinolinic compound showed in the formula A and pharmacy acceptable solvate, optical isomers or polymorphic substance and a reaction intermediate compound showed in the formula D; wherein, R1, R2 and R3 are respective and independent H, halogen or group showed in the formula H; wherein, the R is H, the halogen, alkyl of C1-C4 or alkoxide of C1-C4. The invention further discloses a preparation method thereof and application for preparing medicines for inhibiting HMG CoA reductase and treating hyperlipemia related diseases. Compared with the existing fuvastatin, rosuvastatin and pitavastatin in the prior art, the quinolinic compound of the invention can better inhibiting the activity of the HMG CoA reductase and can be used for treating hyperlipemia related diseases.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a class of novel quinoline compounds and their intermediates, preparation methods and applications in the field of medicine. Background technique [0002] Since hypercholesterolemia was recognized as a major risk factor for atherosclerosis and cardiovascular disease, the research on lipid-lowering drugs has developed rapidly. 3-Hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (also known as "statins") are mainstream products of hypolipidemic drugs (Cai Zhengyan, Zhou Weicheng, Research progress of HMG CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15(22): 1907-1911). Fully synthetic statin drugs that have been marketed include fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. But relative to the needs of human beings, new and more efficient drugs must be found. [0003] In the prior art, the structu...

Claims

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Application Information

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IPC IPC(8): C07D405/06A61K31/4709A61P3/06A61P9/10
CPCC07D405/06A61P3/06A61P9/10
Inventor 蔡正艳周伟澄郝群
Owner SHANGHAI INST OF PHARMA IND
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