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A kind of preparation method of quinoline compound and intermediate compound

A compound and quinoline technology are applied in the field of preparation of quinoline compounds and intermediate compounds, can solve the problems of complicated post-processing, complicated operation and high cost, and achieve the effects of low cost, high total yield and short steps

Inactive Publication Date: 2011-12-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the defects of high cost, cumbersome operation and complex post-treatment in the existing method for preparing quinoline compound A with good inhibitory activity against HMG CoA reductase, and provides A kind of preparation method and intermediate compound of quinoline compound A

Method used

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  • A kind of preparation method of quinoline compound and intermediate compound
  • A kind of preparation method of quinoline compound and intermediate compound
  • A kind of preparation method of quinoline compound and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: (3R,5S)-7-[6,7,8-trifluoro-4-(p-isopropylphenylthio)quinolin-3-yl]-3,5-dihydroxy-6 (E)-Heptenoic acid sodium salt

[0049] (3R,5S)-7-[6,7,8-trifluoro-4-(p-isopropylphenylthio)quinolin-3-yl]-3,5-dihydroxy-3,5-O - Isopropylidene-6(E)-tert-butyl heptenoate 0.1g (0.1mmol) with 1ml ethanol, 1ml THF, cool to 0°C, add 6N HCl 0.1ml (0.6mmol), stir at room temperature for 24h, 0°C Add 0.11ml (1.1mmol) of 10N NaOH, stir for 1h, precipitate out solid, filter with suction, wash with water, wash with ethanol, and dry to obtain 0.04g of yellow solid, yield 44.3%, Mp: 118-119°C, [α] D 26 = 18.2 (c 1 , THF). 1 HNMR (400MHz, DMSO-d 6 )δ1.64-1.10 (m, 6H), 1.68-1.61 (m, 2H), 2.43-2.26 (m, 2H), 2.84-2.71 (m, 1H), 4.06-4.02 (m, 1H), 4.41- 4.37(m, 1H), 6.77(dd, 1H, J=16.4, 5.2Hz), 7.16-7.05(m, 4H), 7.31(dd, 1H, J=16.4, 4.0Hz), 8.12-8.07(m, 1H), 9.32(s, 1H). TOF MS(ES+): 1027(2M+H), 514(M+H).

Embodiment 2

[0050] Example 2: (3R,5S)-7-[6-fluoro-7-chloro-4-p-fluorophenoxy-quinoline-3-]3,5-dihydroxy-6E-heptenoic acid tert-butyl ester

[0051] (3R,5S)-7-[6-fluoro-4,7-diphenylthio-quinoline-3-]3,5-dihydroxy-3,5-O-isopropylidene-6E-heptene Mix and stir 14.2 g (13.0 mmol) of tert-butyl ester and 140 ml of THF, add 5 g (78.0 mmol) of acetic acid at 0°C, stir at room temperature at 25°C for 12 hours, filter the solid with suction, dissolve the solid in 100 mL of ethyl acetate and 70 mL of water, and wash with water until Neutral, anhydrous Na 2 SO 4 Dry, concentrate, and dry to obtain 5.6g of solid, yield 42.7%, mp: 136-138°C, [α] D 26 = 27.8 (c 1, methanol). 1 HNMR (400MHz, DMSO-d 6 )δ1.45(s, 9H), 2.81-1.45(m, 2H), 2.37-2.35(m, 2H), 4.15-4.12(m, 1H), 4.68-4.63(m, 1H), 5.77(dd, 1H, J=16.4, 5.1Hz), 6.36(d, 1H, J=16.4Hz), 6.77-6.74(m, 2H), 6.98-6.94(m, 2H), 7.62(d, 1H, J=9.6Hz) 8.21(d, 1H, J=7.2Hz), 8.97(s, 1H).TOF MS(ES+): 1013(2M+H), 506(M+1)

Embodiment 3

[0052] Example 3: (3R,5S)-7-[6-fluoro-7chloro-4-p-fluorophenoxy-quinoline-3-]3,5-dihydroxy-6E-heptenoic acid hemicalcium salt

[0053] 0°C, 5.6ml (56mmol) of 10N NaOH was added dropwise to (3R,5S)-7-[6-fluoro-7-chloro-4-p-fluorophenoxy-quinoline-3-]3,5-dihydroxy - In a solution of 18.8g (37.2mmol) of tert-butyl 6(E)-heptenoate, 190ml ethanol and 190ml THF, stir for 1h, adjust the pH value to 7-8 with 1N HCl at 0°C, and distill off the solvent under reduced pressure. Add 400ml of water and stir to dissolve, add 4.1g (37.2mmol) calcium chloride aqueous solution, stir overnight, precipitate solid, filter with suction, wash with water, recrystallize the obtained solid with 190ml of THF: water (1:1), and place the obtained solid in a vacuum Dry in a drying oven for 24 hours to obtain 14.0 g of off-white solid, yield: 80.0%, mp decomposed at 160°C, HPLC: 99.4%, [α] D 26 =-22.1(c 1,THF:H 2 O=2:1). 1 HNMR (400MHz, DMSO-d 6 )δ1.62~1.54(m, 2H), 2.37-2.20(m, 2H), 3.96-3.92(m, 1H), 4...

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Abstract

The invention discloses a method for preparing (3R,5S)-7-[6,7,8-trisubstituted-4-substituted phenyl sulfide (or oxy)ylquinoline-3-yl]-3,5-dihydroxy-6(E)-heptenoate represented by a formula A, wherein the (3R,5S)-7-[6,7,8-trisubstituted-4-substituted phenyl sulfide (or oxy)ylquinoline-3-yl]-3,5-dihydroxy-6(E)-heptenoate has good activity for inhibiting HMG CoA reductase, and blood lipid reducing effect. The method comprises the following steps that: (1) a compound represented by a general formula B is subjected to a propylidene protecting group removing reaction in an organic solvent under an acidic condition to obtain a compound represented by a formula C; (2) in a solvent, the resulting compound C represented by the formula C from the step (1) reacts with an alkali, or sequentially reacts with an alkali and a salt to prepare the compound represented by the formula A.

Description

technical field [0001] The present invention specifically relates to a preparation method and intermediate compounds of quinoline compounds. Background technique [0002] In the Chinese invention patent applications with application numbers 200610148118.4 and 200710036427.7, novel 4-substituted phenylthio and 4-substituted phenoxyquinoline derivatives with HMG CoA reductase inhibitory activity were disclosed, wherein the side chains were internal ester structure. [0003] In the application number 200810036930.7 Chinese Invention Patent Application, the structure of novel 4-substituted phenylthio and 4-substituted phenoxyquinoline derivative carboxylic acids or their pharmaceutically acceptable salts is disclosed. These compounds are effective in hyperlipidemia quail It has obvious hypolipidemic effect in the model. [0004] This patent also discloses three methods for preparing novel 4-substituted phenylthio and 4-substituted phenoxyquinoline derivatives carboxylic acids ...

Claims

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Application Information

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IPC IPC(8): C07D215/36C07D215/233C07D215/22
CPCY02P20/55
Inventor 蔡正艳郝群潘竞周伟澄
Owner SHANGHAI INST OF PHARMA IND
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