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Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate

A technology of diastereoisomers and enantiomers, applied in the field of diastereoisomer impurity content, to achieve the effects of reducing production costs, mild methods, and simple post-processing

Active Publication Date: 2016-03-23
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no literature reports on how to prepare high-purity ledipasvir intermediates

Method used

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  • Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate
  • Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate
  • Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 formula (I) compound crude product

[0044] Route 1:

[0045] Taking methyl ester compound (SM) as initial raw material, concrete route is as follows:

[0046]

[0047] Take starting materials SM (500g), methanol (2.5kg) and Pd / C (5% w / w, 100g), replace with nitrogen, fill with hydrogen to 0.8-1.0MPa, react with 45-55°C for 20 hours, concentrate, Add 1Kg methanol and 2Kg water, adjust the pH to 8 with sodium carbonate, keep the temperature below 5°C, slowly add di-tert-butyl dicarbonate (90g) dropwise, stir and react for 2 hours, then naturally rise to room temperature, add DCM (dichloro methane) extraction, the organic phase was collected and concentrated to obtain 300 g of the crude product of compound 3.

[0048] The crude compound 3 (300g), water (1.5Kg), LiOH (50g) and tetrahydrofuran (1.5L) were added into a 5L three-necked flask, and reacted at 50°C for 24 hours, and the reaction solution was washed with 1L of dichloromethane,...

Embodiment 2

[0054] The purification of embodiment 2 formula (I) compound

[0055] The specific route is as follows:

[0056]

[0057] The crude product (10 g) of the compound of formula (I) obtained in Example 2 was dissolved in 30 mL of ethanol, the temperature was raised to 80 ° C, (R)-(+)-1-phenylethylamine (5.2 g) was added and stirred evenly, React for 2 hours, cool down to 20°C, filter with suction, dissolve the obtained filter cake in 100 mL of 0.5N hydrochloric acid solution at 0°C, adjust pH=1-1.5, add an equal volume of dichloromethane for extraction, take the organic phase, concentrate, and store at 20°C Crystallization and filtration gave 8.1 g of white solid with a yield of 81%, a de value of 99.8%, and a diastereomer impurity (Ia) content of 0.1%; mass spectrum: MS (M-H+): m / z 240.3 . 1 HNMR (400MHz, DMSO-d6): δ12.47(s, 1H), 4.12-4.05(d, 1H), 3.60(s, H), 2.58(s, 1H), 1.73-1.38(m, 5H), 1.31(s, 4H), 1.25(s, 3H), 1.23-1.20(t, 1H).

[0058] The diastereomer impurity (Ia) ...

Embodiment 4

[0059] Embodiment 4: the preparation of the pure product of formula (I) compound

[0060] The crude product (10 g) of the compound of formula (I) obtained in Example 1 was dissolved in 80 mL of ethyl acetate, the temperature was raised to 70 ° C, and (R)-(+)-1-phenylethylamine (7.5 g) was added and stirred Evenly, react for 2 hours, cool down to 40°C, filter with suction, and dissolve the obtained filter cake in 150mL of 0.1N sulfuric acid solution at 0°C, adjust pH=1-1.5, add 100mL of 1,2-dichloroethane to the water phase, Extract, take the organic phase, concentrate, crystallize at 0°C, and filter to obtain 8.5 g of white solid with a yield of 85%, a de value of 99.8%, and a diastereomeric impurity (Ia) content of 0.1%.

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Abstract

The invention discloses a method for reducing content of a diastereoisomer impurity (Ia) in a Ledipasvir intermediate (1R,3S,4S)-N-t-butyloxycarboryl-2-azabicyalo[2.2.1]heptane-3-carboxylic acid (I). The method comprises the steps of firstly taking a crude product of a compound shown as a formula (I) and containing the diastereoisomer impurity (Ia), dissolving in an organic solvent, adding alkaline organic amine to react with the crude product, separating out a solid, and filtering to obtain an amine salt of the compound shown as the formula (I); acidizing the obtained amine salt in an aqueous phase solution; extracting an obtained aqueous phase, separating out a solid, and separating to obtain the high-purity Ledipasvir intermediate (I). The product obtained by the method has a de value up to more than 99.5 percent, and the yield of more than 80 percent; reaction conditions in the method are mild, raw materials are easy to get, and the method is suitable for industrial application.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a method for reducing the concentration of ledipasvir intermediate (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylate Method for Diastereomeric Impurity Content in Acids. Background technique [0002] In 2014, the compound preparation ledipasvir / sofosbuvir compound (trade name Harvoni) developed by Gilead was launched in the United States. This drug is mainly suitable for genotype I chronic hepatitis C infection. [0003] Among them, (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid is the key intermediate of Ledipasvir. The CAS registration number of the compound is 291775-59-2, and the specific structural formula is as follows: [0004] [0005] At present, patents WO2011 / 091532A1, WO2012 / 040923A1 and US2013 / 0287731A1 have reported the synthesis method of the ledipasvir intermediate, and the above-mentioned pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/02
CPCC07D209/02
Inventor 陈兴王灿辉孙秋何帅杰庄明晨杨佑喆郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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