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Intermediate I of anti-hepatitis C drug boceprevir and its preparation method and application

A technology of compounds and compounds of general formula, applied in the field of anti-hepatitis C drug Boceprevi, can solve the problems of reaction detection and control of intermediates, side reactions and the like

Inactive Publication Date: 2017-09-29
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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  • Intermediate I of anti-hepatitis C drug boceprevir and its preparation method and application
  • Intermediate I of anti-hepatitis C drug boceprevir and its preparation method and application
  • Intermediate I of anti-hepatitis C drug boceprevir and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1-9

[0066] Embodiment 1-9: R is the preparation of formula 1 compound of hydrogen

Embodiment 1

[0067] Embodiment 1: the preparation of compound B

[0068]

[0069] 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, stirred for 1h, and 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, CDC13) 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

[0070] Embodiment 2: the preparation of compound C

[0071]

[0072] Compound B (5g, 15mmol), DMAP (0.37g, 3mmol) were dissolved in 60ml THF, added (Boc) 2 After O (6.88ml, 30mmol), the temperature was raised to reflux, and after reflux for about 8h, the temperature was lowered to room temperature, and 60ml of methanol and hydrazine hydrate (3g, 60mmol) were added to stir for 4h, 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 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, CDC13) 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...

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Abstract

The invention relates to the technical field of a preparing method of an anti-hepatitis C medicine Boceprevir. A compound 1 provided by the invention has a structural formula shown as the attached drawing. The operation of the compound preparation is simple and convenient, and the yield is higher. The compound can be used for synthesizing the anti-hepatitis C medicine Boceprevir, and a new thought and method can be provided for synthesis of the anti-hepatitis C medicine Boceprevir. In addition, ultraviolet chromophoric groups are contained in molecules of the compound, the detection is more convenient than that of an ordinary synthesis method, and side reaction caused by oxhydryl nucleophilicity in a condensation step is avoided through the introduction of benzyls onto oxhydryls. Compared with the synthesis method in the prior art, the preparing method provided by the invention has certain advantages.

Description

technical field [0001] The present invention relates to the technical field of preparation methods for anti-hepatitis C drug Boceprevir, in particular to a class of (1R, 2S, 5S)-N-[3-amino-1-(cyclobutylmethyl)-2-substituted hydroxy-3-oxo Propyl]-3-((2S)-2-[[[(1,1-dimethylethyl)-amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl ]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide compounds and their preparation methods. 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-infe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/023C07K1/107C07K1/10
Inventor 姚旻袁哲东杨玉雷张浩宇
Owner SHANGHAI INST OF PHARMA IND CO LTD
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