Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof

A compound and alkyl technology, applied in the field of α-hydroxy β-amino ester compounds and their preparation, can solve the problems of inability to produce sustained virological response, adverse reactions, etc.

Active Publication Date: 2014-01-15
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current treatment for chronic hepatitis C is mainly the combination of pegylated interferon (PEG-IFNα) and ribavirin (RBV), which fails to produce a sustained virological response in about 50% of HCV type I patients , and have adverse reactions, so it is urgent to develop effective therapeutic drugs

Method used

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  • Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof
  • Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof
  • Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Preparation of Compound C:

[0090]

[0091] At 20°C, NaCN (21.2g, 0.433mol) and DMSO140ml were added to the three-necked flask, the temperature was raised to 60°C, bromomethylcyclobutane (42.4g, 0.285mol) was added dropwise, and the reaction solution remained at 70 Stir at -80°C for 3 hours, stop heating, pour the reaction solution into 500ml of ice water, extract the reaction solution with MTBE (250ml*3), combine the organic phase, wash the organic phase with 150ml of water, then add the organic phase to 150ml of 1M HCl After stirring for 30 min, the organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and evaporated to remove the solvent to obtain 24 g of a slightly yellow liquid, which was the crude compound B, which was directly put into the next reaction without purification.

[0092] N 2 Under protection, compound B (10g, 0.105mol) and 80ml CH 2 Cl 2 Add it into the reaction flask, stir and cool...

Embodiment 2

[0106] where R 1 is benzyl, R 2 Be the preparation of the formula (1) compound of ethyl:

[0107]

[0108] Compound D (0.5g, 2.7mmol) was dissolved in 10ml of phenylacetonitrile, cooled to 0°C, added boron trifluoride diethyl ether (3.6ml, 27.8mmol) dropwise, raised to room temperature and stirred for 4h after the addition, evaporated the solvent under reduced pressure , add 10ml of ethyl acetate to the residue for dilution, add 10ml of saturated sodium bicarbonate and stir for 30min, separate the layers, extract the aqueous phase with ethyl acetate (10ml*3), combine the organic phases and wash with water twice, dry over anhydrous sodium sulfate, After distilling off the solvent, add 20ml of methanol, and add 20ml of 0.5mol / L dilute hydrochloric acid and stir for 90min. After stirring, add saturated sodium bicarbonate solution to adjust the pH to 7, and stir overnight. The liquid was separated and the aqueous phase was extracted with ethyl acetate (20ml*3). The combined o...

Embodiment 3

[0110] where R 1 is phenyl, R 2 Be the preparation of the formula (1) compound of ethyl:

[0111]

[0112] Compound D (0.5g, 2.7mmol) was dissolved in 9ml of benzonitrile, cooled to 0°C, added boron trifluoride diethyl ether (3.6ml, 27.8mmol) dropwise, raised to room temperature and stirred for 4h after the addition, evaporated under reduced pressure Solvent, add 10ml of ethyl acetate to the residue to dilute, add 10ml of saturated sodium bicarbonate and stir for 30min, separate the layers, extract the aqueous phase with ethyl acetate (10ml*3), combine the organic phases and wash with water twice, dry over anhydrous sodium sulfate After evaporating the solvent, add 20ml of methanol, and add 20ml of 0.5mol / L dilute hydrochloric acid and stir for 90min. After stirring, add saturated sodium bicarbonate solution to adjust the pH to 7, and stir overnight. The liquid was separated and the aqueous phase was extracted with ethyl acetate (20ml*3). The combined organic phases were ...

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Abstract

The invention provides a cyclobutyl-containing alpha-hydroxy-beta-amino ester compound. The invention discloses the novel compound with the formula (1), wherein R1 is alkyl, aryl or aralkyl, and R2 is alkyl. The invention also discloses a preparation method of the compound represented by the formula (1). The compound can be used in the synthesis of an anti-hepatitis C drug Boceprevir.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a novel α-hydroxyl β-amino ester compound with a cyclobutyl group and a preparation method thereof. The compound can be used in the synthesis of the intermediate of the anti-hepatitis C drug Boceprevir. Background technique [0002] Globally, the infection rate of hepatitis C virus (HCV) is about 3%, and the total number of infected people is about 200 million. Because of the high infection rate of HCV and the serious potential complications such as liver cirrhosis and liver cancer, HCV is a serious threat to human life and health. According to the Simmonds naming system, HCV can be divided into six main genotypes, namely I-VI, and each type can be divided into several subtypes (such as Ia, Ib, IIa, IIb, IIIa, IIIb, etc.). There are about 40 million HCV-infected people in my country, 69% of which are type I infections (mainly type Ib). The current treatment for chronic hepatitis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C233/51C07C233/84C07C231/06C07C271/20C07C269/04C07D303/48C07C69/608C07C67/343
Inventor 姚旻袁哲东杨玉雷胡雪峰
Owner SHANGHAI INST OF PHARMA IND CO LTD
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