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Ledipasvir intermediate preparation method

A unit time, azabicyclic technology, applied in the direction of organic chemistry, can solve the problems of long production cycle, inability to reflect atom economy, cumbersome post-processing, etc., achieve shortened production cycle, high yield, and reduce the use of solvents Effect

Active Publication Date: 2015-04-01
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

PCT application WO 2011091532 changed the synthesis route, which first hydrolyzed compound III, and then reacted with Boc anhydride to prepare compound (V), but these reports all synthesized key intermediate (V) through multi-step reactions, long production cycle and tedious post-processing , and even need to separate and purify the product by column chromatography, these schemes cannot reflect the atom economy

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1 Preparation of (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2,2,1]heptane-3-carboxylic acid

[0035] Under the condition of -10°C to 0°C, (R)-phenethylamine (47.5g) was slowly added dropwise to ethyl glyoxylate (80g), Molecular sieves (30g) in toluene (80g), dropwise, react at -10°C to 0°C for 3 hours, add methanol (63.3g), then slowly drop trimethylchlorosilane (85.02g), dropwise, -10 ℃ to 0 ℃ for 2 hours, and then slowly added dropwise the newly prepared cyclopentadiene (50.0g), dropwise, -10 ℃ to 0 ℃ for 3 hours, then added 10% palladium carbon (5.3g), to the reaction Put hydrogen gas into the bottle, react at room temperature about 27°C for 3 hours, then add sodium hydroxide solution (0.8mL, 2mol / L), dropwise, react at room temperature for 2 hours, then lower the reaction system to -5°C to 0°C, Add Boc anhydride (102g), after the addition is complete, react at -10°C to 0°C for 4 hours. After the reaction is complete, remove the filter residue by filtra...

Embodiment 2

[0036] Example 2 Preparation of (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2,2,1]heptane-3-carboxylic acid

[0037] -10°C to 0°C, (R)-phenethylamine (47.5g) was slowly added dropwise into dichloromethane (80g) containing methyl glyoxylate (80g), anhydrous sodium sulfate (40g) After dropping, react at -10°C to 0°C for 3 hours, add methanol (63.3g), then slowly add trimethylchlorosilane (85.02g), dropwise, react at -10°C to 0°C for 2 hours, then slowly Add freshly prepared cyclopentadiene (50.0g) dropwise, and react at -10°C to 0°C for 3 hours, then add 5% palladium carbon (10.6g), and pass hydrogen gas into the reaction bottle, and the room temperature is about 27°C React at low temperature for 3 hours, then add sodium hydroxide solution (0.8L, 2mol / L), dropwise, react at room temperature for 2 hours, reduce the reaction system to -5°C to 0°C, add Boc anhydride (102g), and add, React at -10°C to 0°C for 4 hours. After the reaction is complete, remove the filter residue by...

Embodiment 3

[0038] Example 3 Preparation of (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2,2,1]heptane-3-carboxylic acid

[0039] Under the condition of -10°C to 0°C, (R)-phenethylamine (47.5g) was slowly added dropwise to ethyl glyoxylate (80g), anhydrous sodium sulfate (40g) in toluene (80g), dropwise After completion, react at -10°C to 0°C for 3 hours, add methanol (63.3g), then slowly drop trimethylchlorosilane (85.02g), dropwise, and react at -10°C to 0°C for 2 hours, then slowly drop Freshly prepared cyclopentadiene (50.0g), dropwise, react at -10°C to 0°C for 3 hours, then add 5% palladium carbon (10.6g), feed hydrogen into the reaction bottle, and react at room temperature at about 27°C After 3 hours, potassium hydroxide solution (0.8L, 2mol / L) was added, and the dropwise reaction was completed at room temperature for 2 hours. React at ℃ to 0℃ for 4 hours. After the reaction is completed, remove the filter residue by filtration. Add 2mol / L hydrochloric acid solution to the fil...

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PUM

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Abstract

The invention relates to a method for preparing (1R,3S,4S)-N-tert-butyloxycarbonyl-2-azabicyclo[2,2,1]heptane-3-carboxylic acid (formula V), wherein the formula V is defined in the instruction. The method comprises: dissolving glyoxylate in a solvent, cooling to a temperature of -10-0 DEG C, adding a dewatering agent and (R)-phenyl ethylamine, and at unit time intervals, sequentially adding an alcohol solvent, an additive, cyclopentadiene and palladium carbon to carry out catalytic hydrogenation and adding an inorganic alkali aqueous solution and Boc anhydride to carry out a reaction. Compared with the method in the prior art, the method of the present invention has the following significant advantages that: the reaction operation is simple, the multi-step reaction is changed into the one-pot method, the production period is shortened, the separation purification is simple, the single configuration target product can be obtained only requiring the recrystallization, the yield is high, the reaction is efficient, the atom economy is reflected, -78 DEG C and other harsh reaction conditions are abandoned, and the method is expected to be used in mass production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of (1R,3S,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2,2,1]heptane-3-carboxylic acid. Background technique [0002] Hepatitis C virus, called hepatitis C for short, is a kind of viral hepatitis caused by hepatitis C virus (HCV). According to the World Health Organization, the global hepatitis C infection rate is about 3%, and it is estimated that about 170 million people carry the hepatitis C virus. Hepatitis C can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients may develop liver cirrhosis or even liver cancer, which poses a great threat to the health and life of patients. [0003] The goal of treatment for chronic hepatitis C is to clear the virus so that complications can be limited or prevented, and successful treatment is defined as undetectable HCV RNA in the patient's serum at 24 weeks after stopping treatment. The cu...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 雷鑫丰亚辉何方
Owner SUNSHINE LAKE PHARM CO LTD
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