2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound as well as intermediate, preparation method and application thereof

A technology of methyl anilino group and methyl substitution, which is applied in the fields of metabolic diseases, organic chemistry, drug combination, etc.

Inactive Publication Date: 2012-06-27
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the 4-position of the quinoline ring is generally directly connected to p-fluorophenyl. Two Chinese patents, CN101210011 and CN101220021, respectively disclose two compounds that connect the 4-position of the quinoline ring to the aromatic ring through a sulfur atom or an oxygen atom to the benzene ring. Compounds with good inhibitory activity against HMG-CoA reductase, but the compounds linked by nitrogen atom and introduced cyclopropyl group at the 2-position have not been reported

Method used

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  • 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound as well as intermediate, preparation method and application thereof
  • 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound as well as intermediate, preparation method and application thereof
  • 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound as well as intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1 (4-fluoroanilino-cyclopropyl-methylene) diethyl malonate (T2)

[0061] (Chloro-cyclopropyl-methylene)diethyl malonate (4.93g, 0.02mol), 4-fluoroaniline (2.66g, 0.024mol), potassium carbonate (2.76g, 0.02mol) were added to DMF (60ml ), stirred and heated to 100°C for 11 h. Cooled, poured into ice water (100ml), extracted with ethyl acetate, concentrated, and obtained 5.79g (4-fluoroanilino-cyclopropyl-methylene) diethyl malonate crude product yellow oil through column chromatography ( T2), yield 90.2%.

[0062] Wherein, the synthesis of (chloro-cyclopropyl-methylene) diethyl malonate is synthesized with reference to the method in the document Org syn, 1993, Coll.Vol.8, 247: diethyl malonate (150ml, 1mol) was dissolved in absolute ethanol (300ml), slowly dripped into a reaction flask equipped with magnesium chips (25.0g, 1.04mol) and carbon tetrachloride (1ml), and stirred vigorously to keep the system under stable reflux. After the addition is complete, h...

Embodiment 2

[0065] Example 2 2-cyclopropyl-6-fluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester (L2)

[0066] T2 (5.79g, 0.018mol), add heat conduction oil (60ml), heat up to 200°C, and stir vigorously for 0.5h. After cooling and suction filtration, washing with toluene, and recrystallization from ethanol, 4.58 g of white needle-like crystal L2 was obtained, with a yield of 92.3%.

[0067] According to the above method, T2 was replaced by T1 and T3 respectively to obtain L1-3 respectively. Yields, physical properties and 1 H-NMR identification results are shown in Table 2.

Embodiment 3

[0068] Example 3 2-cyclopropyl-4-chloro-6-fluoroquinoline-3-carboxylic acid ethyl ester (M2)

[0069] L2 (4.58g, 16.6mmol) was added to toluene (50ml) and POCl was added dropwise 3(5.10g, 3.1ml, 33.3mmol), reflux for 4h, pour into saturated sodium bicarbonate solution, separate the organic layer, wash with water and saturated brine respectively, dry over anhydrous sodium sulfate, and concentrate to obtain 4.57g 2-cyclo Propyl-4-chloro-6-fluoroquinoline-3-carboxylic acid ethyl ester solid (M2), yield 93.5%.

[0070] According to the above method, L2 was replaced by L1 and L3 respectively to obtain M1-3 respectively. Yields, physical properties and 1 H-NMR identification results are shown in Table 3.

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Abstract

The invention discloses a 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound shown as formula (A), a pharmaceutically acceptable solvate thereof, an optical isomer or polymorph and reaction intermediate compounds shown as formulas D and K, wherein R1 is H or F; R2 is H, F or a group shown as formula Q; R3 is H, F or C1-C3 alkoxy; and R4 is H or F. The invention also discloses a preparation method of the 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound and application thereof for preparing medicines for inhibiting HMG-CoA reductase and / or treating diseases associated with hyperlipidemia. Compared with pitavastatin, rosuvastatin and atorvastatin in the prior art, the 2-cyclopropyl-4-(N-methyl substituted anilino) quinoline compound has better or at least equivalent activity to inhibit the HMG-CoA reductase and can be applied to treating diseases associated with hyperlipidemia.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a class of novel 2-cyclopropyl-4-(N-methyl-substituted anilino)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 (HMG-CoA) reductase inhibitors (also known as "statins") are the mainstream products of hypolipidemic drugs (Cai Zhengyan, Zhou Weicheng, HMG CoA reductase inhibitors research Progress, 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/44C07D405/06A61K31/4706A61P43/00A61P3/06
Inventor 赵士魁周伟澄孟祥国茅迪李泳佳
Owner SHANGHAI INST OF PHARMA IND CO LTD
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