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A kind of method for preparing fluvastatin key intermediate

A fluvastatin and intermediate technology, applied in the field of organic synthetic pharmaceuticals, can solve the problems of high cost, low total yield, long reaction steps, etc., and achieve the effects of reducing raw material costs, short synthetic routes, and good chemical selection

Active Publication Date: 2016-04-13
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method can construct key intermediates, but there are the following problems: (1) raw materials are expensive; (2) key raw materials or intermediates such as phenyl diazonium salts are dangerous, and large-scale production is not used; (3) ester group reduction Using DIBAL, the cost price is high
The method has long reaction steps and low overall yield, so it is not suitable for large-scale production which is difficult to realize

Method used

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  • A kind of method for preparing fluvastatin key intermediate
  • A kind of method for preparing fluvastatin key intermediate
  • A kind of method for preparing fluvastatin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: a kind of method for preparing fluvastatin key intermediate, is characterized in that concrete preparation steps are as follows:

[0033] (1) Halogenation reaction: Control the temperature at 25±5°C, add 504.0kg (5mL / g) of 1,2-dichloroethane into a 2000L reactor, and the main raw material 3-(4-fluorophenyl)-1 - Isopropyl-1H-indole 80 kg (315.8 mol, 1.0 equiv.) and N-bromosuccinimide 67.5 kg (379.0 mol, 1.2 equiv.). The system was heated to reflux for reaction, and detected by HPLC until the reaction was completed. The system was pressed into 480.0 kg of saturated aqueous sodium bisulfite solution (5 mL / g) to terminate the reaction. Stand still, separate the liquid, concentrate the organic phase, and then add 126.4kg (2mL / g) of ethanol to recrystallize to obtain the halogenated product 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole 89.2 kg, the liquid phase purity was 96.0%, and the yield was 85.0%.

[0034] (2) Hydroxymethylation reaction: Control the...

Embodiment 2

[0036] Embodiment 2: a kind of method for preparing fluvastatin key intermediate, is characterized in that concrete preparation steps are as follows:

[0037] (1) Halogenation reaction: Control the temperature at 25±5°C, add 665.0kg (10mL / g) of dichloromethane to a 2000L reactor, and the main raw material 3-(4-fluorophenyl)-1-isopropyl -1H-indole 50kg (197.4mol, 1.0equiv.) and tribromopyridine 62.3kg (197.4mol, 1.0equiv.). The system was heated to reflux for reaction, followed by HPLC detection until the end of the reaction. Press the system into 600.0 kg (10 mL / g) of saturated aqueous sodium bisulfite solution to terminate the reaction. Stand still, separate the liquid, concentrate the organic phase, add methanol 197.5kg (5mL / g) to recrystallize to obtain the halogenated product 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole 62.3 kg, the liquid phase purity was 99.0%, and the yield was 95.0%.

[0038] (2) Hydroxymethylation reaction: control the temperature at 25±5°C, ad...

Embodiment 3

[0040] Embodiment 3: a kind of method for preparing fluvastatin key intermediate, is characterized in that concrete preparation steps are as follows:

[0041] (1) Halogenation reaction: Control the temperature at 25±5°C, add 499.5kg (15mL / g) of chlorobenzene into a 2000L reactor, and the main raw material 3-(4-fluorophenyl)-1-isopropyl-1H - Indole 30 kg (118.4 mol, 1.0 equiv.) and bromine 28.4 kg (177.6 mol, 1.5 equiv.). The system was heated to reflux for reaction, followed by HPLC detection until the end of the reaction. Press the system into 540.0 kg (15 mL / g) of saturated aqueous sodium bisulfite solution to terminate. Stand still, separate the liquid, concentrate the organic phase, and then add 355.5kg (15mL / g) of isopropanol for recrystallization to obtain the halide 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-ind Indole (Compound 2) 35.4kg, HPLC purity 97.0%, yield 90.0%.

[0042] (2) Hydroxymethylation reaction: Control the temperature at 25±5°C, add tetrahydrofuran 4...

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Abstract

The invention discloses a method for preparing a fluvastatin key intermediate. The method adopts easy-to-synthesize 3-(4-fluorophenyl)-1-isopropyl-1H-indole (compound 1) as a raw material and prepares a fluvastatin key intermediate dimethyl(3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-yl)methyl phosphate (compound 4) through halogenation, hydroxymethylation and phosphate esterification. The method disclosed by the invention has the advantages of stable technology, mild reaction conditions, good selectivity, simple after-treatment operation, easiness for separation of the intermediate and high product purity and yield, and provides a new idea and method for large-scale production of the fluvastatin key intermediate.

Description

(1) Technical field: [0001] The invention relates to the field of organic synthesis and pharmacy, in particular to a method for preparing a key intermediate of fluvastatin. (2) Background technology: [0002] Fluvastatin, chemical name: [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H- Indol-2-yl] sodium 3,5-dihydroxy-6-heptanoate is a fully synthetic cholesterol-lowering drug and an inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. The action site of this product is in the liver, which can inhibit the synthesis of endogenous cholesterol, reduce the content of cholesterol in liver cells, stimulate the synthesis of low-density lipoprotein (LDL) receptors, increase the intake of LDL particles, and reduce the concentration of total plasma cholesterol. effect. Since the listed fluvastatin drug is a racemate, how to construct the indole ring is the key to the synthesis of fluvastatin. The synthetic method of existing fluvastatin mother nucleus mainly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/572
Inventor 洪浩马建国李九远黄俊
Owner ASYMCHEM LAB TIANJIN
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