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Method for preparing (3R, %S)-Fluvastatin

A technology of fluvastatin and fluorophenyl, which is applied in the production of bulk chemicals and organic chemistry, and can solve the problems of high catalyst price, great impact on the environment, and no industrial value

Inactive Publication Date: 2007-06-13
四川抗菌素工业研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Adopt chiral ruthenium (Ru) when this method ketone carbonyl is reduced into hydroxyl to form first chiral carbon, rhodium (Rh), iridium (Ir) catalyst, this type of catalyst price is high, and the impact on environment is bigger, so this One method does not currently have industrial value

Method used

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  • Method for preparing (3R, %S)-Fluvastatin
  • Method for preparing (3R, %S)-Fluvastatin
  • Method for preparing (3R, %S)-Fluvastatin

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Example 1 (+)-(E)-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)indol-2'-yl]-5-carbonyl - Preparation of 3-tert-butyldimethylsilyloxy-6-heptenoic acid methyl ester (IV)

[0020] At room temperature, under the protection of nitrogen, add 2.3g of chiral side chain (II), 15ml of absolute ethanol, and 832mg of potassium carbonate to the reaction flask in sequence, stir for 25 minutes, then add 1.52g of parent nucleus aldehyde (III), and stir for about 48 hours at room temperature (TLC tracking, hexane:ethyl acetate=9.5:2), add 40ml of ethyl acetate, 20ml of water and stir, separate the organic layer, wash the ethyl acetate layer twice with water, once with saturated sodium chloride, and concentrate to dryness to obtain 3.2 g of crude orange-red oil was separated by silica gel column chromatography, eluting with petroleum ether: ethyl acetate = 10:1 to give 1.8 g of orange-red oil

[0021] 1H-NMR (CDCl3, 400NHz): δ0.02(s, 3H), 0.06(S, 3H), 0.8(s, 9H), 1.7(d, 6H), 2.5(m, 2H), 2...

Embodiment 2

[0024] Example 2 (+)-(E)-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)indol-2'-yl]-5-carbonyl - Preparation of 3-tert-butyldimethylsilyloxy-6-heptenoic acid methyl ester (IV)

[0025] At room temperature, under the protection of nitrogen, add 33.0g of chiral side chain (II), 200ml of isopropanol, 12.0g of potassium carbonate, 14.9g of parent nucleus aldehyde (III) to the reaction bottle, stir and react at room temperature for about 45 hours, then add 600ml of water , extracted twice with ethyl acetate 300ml and 100ml, separated the organic layer, washed the ethyl acetate layer twice with 500ml water, once with saturated sodium chloride, concentrated and dried to obtain 40.0g of crude red oil (IV).

Embodiment 3

[0026] Example 3 (+)-(E)-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)indol-2'-yl]-3-hydroxy - Preparation of 5-oxo-6-heptenoic acid methyl ester (V)

[0027] At room temperature, under the protection of nitrogen, add 0.6g of the product of the previous step, 5ml of acetocyanide, and 0.4ml of 40% hydrofluoric acid to the reaction bottle and stir for about 1 hour (TLC tracking, hexane:ethyl acetate=10:3), add Ethyl acetate 30ml, washed with saturated sodium bicarbonate 2×30ml, washed with water, washed once with saturated sodium chloride, dried over magnesium sulfate, and the organic layer was concentrated to dryness to obtain 0.6g of crude orange-red oil, separated by silica gel column chromatography, hexane: Elution with ethyl acetate=6:4 gave 0.4 g of light yellow solid.

[0028] 1H-NMR (CDCl3, 400MHz): δ1.7(d, 6H), 2.5(m, 2H), 2.7(d, 2H), 3.6(s, 3H), 4.5(m, 1H), 4.9(m, 1H), 6.2(d, 1H), 7.1(m, 1H), 7.2(m, 2H), 7.3(m, 1H), 7.4(m, 2H), 7.5(d, 1H), 7.6(d, 1H ), 7.7(d, 1H)

[...

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Abstract

This invention discloses a method of preparing (3R,5S)- fluvastatin(I). The method includes using aldehyde of formula (III) and chiral side chain of formula (II) to carry out condensation reaction. Then obtain (3R,5S)- fluvastatin(I) by undoing protecting group, disoxidation and hydrolysis.

Description

Technical field: [0001] The invention relates to a preparation method of (3R, 5S)-fluvastatin compound. technical background: [0002] The (3R,5S)-fluvastatin compound has the structure of the following formula (I). [0003] [0004] Fluvastatin is known to be a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and a blood lipid-lowering drug. The enzyme inhibitory activity of the two enantiomers of fluvastatin is very different. It is reported that (3R, 5S)-fluvastatin is 30 times more active in inhibiting HMG-CoA reductase than (3S, 5R)-fluvastatin . There are two disclosed methods for preparing (3R, 5S)-fluvastatin: [0005] 1. Synthetic method 1 of (3R, 5S)-fluvastatin: [0006] [0007] In this method, the indole acrolein nucleus substituted by fluorobenzene reacts with a chiral reagent to form a chiral center, and then undergoes cis-reduction, and the reduced product is purified by recrystallization, and further hydrolyzed to obtain (3R, 5S)-fluo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/24
CPCY02P20/55
Inventor 陈宇瑛黎鹏平原
Owner 四川抗菌素工业研究所有限公司
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