Anti-HCV drug Boceprevir intermediate II preparation method and application thereof

The technology of a compound and a compound of the general formula is applied in the field of preparation of the anti-hepatitis C drug Boceprevir, which can solve the problems of reaction detection and control of intermediates, side reactions and the like

Inactive Publication Date: 2014-07-23
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing synthetic methods all have the same problem: since there is no obvious chromophoric group in the structure of each intermediate, the reaction detection and intermediate control are relatively troublesome.
In addition, there are exposed hydroxyl groups in the condensation step of strategy 1, which will inevitably lead to side reactions, which is also the case in the actual operation.

Method used

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  • Anti-HCV drug Boceprevir intermediate II preparation method and application thereof
  • Anti-HCV drug Boceprevir intermediate II preparation method and application thereof
  • Anti-HCV drug Boceprevir intermediate II preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1-9

[0068] Embodiment 1-9: R is the preparation of formula 1 compound of hydrogen

Embodiment 1

[0069] Embodiment 1: the preparation of compound B

[0070]

[0071] Compound A (5g, 20.6mmol) was dissolved in 40ml DMF and added to a three-neck flask, cooled to -5°C; NaH (60%, 1.1g, 26.8mmol) was added in batches and stirred for 1h, then added dropwise at -5°C 40ml of BnBr (4.2g, 24.7mmo) DMF solution, after the dropwise addition, stir at this temperature for 2h, add ice water to quench the reaction, extract with ethyl acetate, a small amount of multiple times, combine the organic phases, wash with saturated brine Drying over anhydrous sodium sulfate and distilling off the solvent gave a yellow oil, and column chromatography gave 6.2 g of compound B as a white solid, yield 90.4%, m / z (MH+) 334.16, 1H NMR (400 MHz, CDCl ) δ 1.31 ( t,3H),1.41-1.57(m,4H),1.64-1.74(m,2H),1.77(s,3H),1.96-2.06(m,2H),2.25-2.29(m,1H),3.95( d, 1H), 4.19-4.25(m, 3H), 4.28(d, 1H), 4.81(d, 1H), 5.63(d, 1H), 7.30-7.35(m, 5H).

Embodiment 2

[0072] Embodiment 2: the preparation of compound C

[0073]

[0074] Compound B (5g, 15mmol), DMAP (0.37g, 3mmol) were dissolved in 60ml of THF, added (Boc) 2 After O (6.88ml, 30mmol), the temperature was raised to reflux, and after reflux for about 8 hours, it was lowered to room temperature, and 60ml of methanol and hydrazine hydrate (3g, 60mmol) were added to stir for 4 hours, and then 200ml of dichloromethane was added to dilute, and the reaction solution was sequentially diluted with 1N HCl and copper sulfate solution. , washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent to obtain a yellow oil, column chromatography obtained 4.4g of compound C as a white solid, yield 75.0%, m / z (MNa+) 414.06,1H NMR(400MHz,CDCl3)δ1.32(t,3H),1.44(s,9H),1.48-1.68(m,4H),1.78-1.87(m,2H),2.02-2.11(m,2H ),2.33-2.37(m,1H),3.98(m,1H),4.20-4.32(m,3H),4.43(d,1H),4.65(d,1H),4.81(d,1H),7.30- 7.37 (m, 5H).

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Abstract

The present invention relates to the technical field of a method for preparation of an anti-HCV drug Boceprevir. The present invention provides compounds F of a formula as follows. The preparation of the compounds is simple and of high yield. The compounds can be used for synthesis of the anti-HCV drug Boceprevir. The present invention provides new implication and approach for the synthesis of the anti-HCV drug Boceprevir. Furthermore, a UV chromophore of the compounds makes the compounds more convenient to detect than compounds prepared by a conventional synthetic method, and introduction of a benzyl group to a hydroxyl group avoids side reactions during a condensation step due to the nucleophilicity of the hydroxyl group. There are certain advantages compared to an existing synthesis synthetic method.

Description

technical field [0001] The invention relates to the technical field of preparation methods for 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 of chronic hepatitis C is mainly the combination of pegylated interferon (PEG-IFNα) and ribavirin (RBV), which fails to produce sustained virological response in about 50% of HCV type I patie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/14C07C231/12C07K5/023
CPCY02P20/55
Inventor 姚旻袁哲东杨玉雷张浩宇
Owner SHANGHAI INST OF PHARMA IND CO LTD
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