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Preparation method of boceprevir intermediate

A boceprevir and intermediate technology, which is applied in the field of chemical drug intermediate preparation, can solve the problems of low yield, shortened synthetic route of target compound, and high cost of intermediates, and achieves easy availability of raw materials, low cost of raw materials, and synthetic route. short effect

Inactive Publication Date: 2016-02-17
JIANGSU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The method uses cheap and easy-to-obtain 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride as the starting material, which greatly shortens the synthetic route of the target compound, but the method involves Chemical resolution, so the yield is low, resulting in high cost of intermediates

Method used

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  • Preparation method of boceprevir intermediate
  • Preparation method of boceprevir intermediate
  • Preparation method of boceprevir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Add 147.7g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (1.0mol, 1.0eq) and 138g of potassium carbonate (1.0mol) into 1.5L of water, stir well, and then Slowly add 218.3 g of di-tert-butyl dicarbonate (1.0 mol) dropwise under an ice bath. After completion, warm up to room temperature and stir for 3 hours, stop stirring, let stand for liquid separation, and separate the upper organic layer, and the water layer with methyl tert-butyl Butyl ether (MTBE) was extracted once, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 205 g of intermediate A with a yield of 97.0%.

[0035] Add 200g of intermediate A (0.95mol, 1.0eq) to the three-necked flask successively, and add 108.5g of (1S,2S)-(+)-1,2-cyclohexanediamine (0.95mol, 1.0eq) as the chiral ligand body, add 2.0L methyl tert-butyl ether as anhydrous organic solvent, replace the air three times, N 2 For protection, cool the flask to -70°C with...

Embodiment 2

[0038] Add 147.7g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (1.0mol) and 200.2g of potassium bicarbonate (2.0mol) into 1.5L of water, stir well, then ice Slowly add 256.0g of benzyl chloroformate (1.5mol) dropwise in the bath, after completion, rise to room temperature and stir for 3 hours, stop stirring, let stand for liquid separation, separate the upper organic layer, and extract the aqueous layer with MTBE once to obtain the organic phase , the organic layers were combined, dried using anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 239.2 g of intermediate A with a yield of 97.5%.

[0039] Add 239g intermediate A (0.97mol, 1.0eq), 171.3g (1S,2S)-(+)-1,2-cyclohexanediamine (1.5mol) as chiral ligand and 2.0L Methyl tert-butyl ether, three air replacements, N 2 For protection, cool the three-necked flask to -70°C with liquid nitrogen, slowly add 1.07L of sec-butyllithium cyclohexane solution with a concentration of 1.4mol / L dropwise, ...

Embodiment 3

[0042] Add 147.7g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (1.0mol) and 112.2g of potassium hydroxide (2.0mol) into 1.5L of water, stir well, then ice Slowly add 327.5 g of di-tert-butyl dicarbonate (1.5 mol) dropwise in the bath. After completion, rise to room temperature and stir for 3 hours, stop stirring, let stand for liquid separation, separate the upper organic layer, and extract the aqueous layer with MTBE once to obtain The organic phase was combined, dried using anhydrous sodium sulfate, and concentrated to remove the solvent to obtain 200 g of intermediate A with a yield of 94.7%.

[0043] Add 200g of intermediate A (0.95mol, 1.0eq) and 135.1g of chiral ligand (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanedi Amine (0.95mol, 1.0eq) and 2.0L tetrahydrofuran, three air replacements, N 2 For protection, cool the flask to -70°C with liquid nitrogen, and add dropwise 0.68L of 1.4mol / L sec-butyllithium cyclohexane solution, wherein the amount of sec-butyllithium...

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Abstract

The invention provides a preparation method of a boceprevir intermediate. 6,6-dimethyl-3-azabicyalo [3.1.0] hexane hydrochloride is adopted as a raw material and reacts with an amino protective agent under the effect of inorganic base, and an intermediate A is obtained; the intermediate A is dissolved in an anhydrous organic solvent, a chiral organic ligand is added, nitrogen protection is conducted, lithium alkylide is added at the temperature of -70 DEG C and reacts for 2 hours, dry carbon dioxide is introduced, and an intermediate B is obtained; the intermediate B is added to a saturated hydrochloric acid solution, heating reflux is conducted for 3 h, and the target compound, namely, (1R, 2S, 5S)-6,6-dimethyl-3-azabicyalo [3.1.0] hexane-2-carboxylic acid ester hydrochloride is obtained. The preparation method has the advantages that the synthetic route is short, cost is low, and the yield and optical purity are high, and mass production can be smoothly achieved.

Description

technical field [0001] The invention relates to a preparation method of a boceprevir intermediate, belonging to the field of preparation methods of chemical drug intermediates. Background technique [0002] Boceprevir (trade name Boceprevir) chemical name is (1S,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3- [(2S)-2-(tert-Butylcarbamoylamino)-3,3-dimethylbutyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -Formamide is a pseudo-hepatitis C protease inhibitor developed by Schering-Ploug (Schering-Ploug), which can be used as the main drug of triple therapy (combined with pegylated α-interferon and ribavirin) for Treatment of CHC genotype I chronic disease hepatitis. The combined use of the three drugs can cure more than 60% of patients, which is 2 to 3 times the cure rate of pegylated α-interferon or ribavirin alone, and boceprevir can also improve the cure rate while improving the cure rate. Can shorten treatment time. The drug was approved by the U.S. Food and Dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 赵晓华杨睿张振亚
Owner JIANGSU UNIV
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