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Method for reducing diastereomer impurity content in ledipasvir intermediate

A technology of diastereoisomers and enantiomers, which is applied in the field of diastereoisomer impurity content, achieves the effects of mild method, reduced production cost, and simple post-treatment

Active Publication Date: 2018-12-21
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 diastereomer impurity content in ledipasvir intermediate
  • Method for reducing diastereomer impurity content in ledipasvir intermediate
  • Method for reducing diastereomer impurity content in ledipasvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Preparation of crude compound of formula (I)

[0044] Route 1:

[0045] Using methyl ester compound (SM) as the starting material, the specific route is as follows:

[0046]

[0047] Take the 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℃ for 20 hours, concentrate, Add 1Kg methanol, 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, naturally warm to room temperature, add DCM (dichloro Methane) extraction, collecting the organic phase, and concentrating 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 to a 5L three-necked flask and reacted at 50°C for 24 hours. The reaction solution was washed with 1L of dichloromethane. Cool the water phase to 0-10°C, ...

Embodiment 2

[0054] Example 2 Purification of the compound of formula (I)

[0055] The specific route is as follows:

[0056]

[0057] The crude product (10g) of the compound of formula (I) obtained in Example 2 was dissolved in 30mL of ethanol, the temperature was raised to 80°C, and (R)-(+)-1-phenylethylamine (5.2g) was added and stirred evenly. React for 2h, cool to 20℃, filter with suction, the resulting filter cake is dissolved in 100mL of 0.5N hydrochloric acid solution at 0℃, adjust the pH=1 to 1.5, add an equal volume of dichloromethane for extraction, take the organic phase, concentrate, and 20℃ Crystallized and filtered to obtain 8.1 g of white solid, yield 81%, de value 99.8%, content of diastereomeric impurity (Ia) 0.1%; mass spectrum: MS (M-H+): m / z 240.3. 1 HNMR (400MHz, DMSO-d6): δ 12.47 (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 diastereoisomeric impurities (Ia) (1R, 3R, 4S)-N-tert-butoxyc...

Embodiment 4

[0059] Example 4: Preparation of pure compound of formula (I)

[0060] The crude product (10g) of the compound of formula (I) obtained in Example 1 was dissolved in 80mL ethyl acetate, the temperature was raised to 70°C, (R)-(+)-1-phenylethylamine (7.5g) was added and stirred The reaction is uniform, the reaction is 2h, the temperature is lowered to 40°C, and the filter cake is filtered by suction. The resulting filter cake is dissolved in 150mL of 0.1N sulfuric acid solution at 0°C, adjusted to pH=1-1.5, and 100mL of 1,2-dichloroethane is added to the water phase. After extraction, the organic phase was taken, concentrated, crystallized at 0°C, and filtered 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 technical field of medicine, in particular to a method for reducing the intermediates of Radipavir (1R, 3S, 4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylate The method of diastereomeric impurity content in acid. Background technique [0002] In 2014, the compound Radipavir / Sofosbuvir compound (trade name Harvoni) developed by Gillard 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 redipavir intermediate. The above-mentioned patents mainly disclose the following two s...

Claims

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Application Information

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Patent Type & Authority Patents(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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