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Preparation method of high-purity Ledipasvir intermediate

An intermediate and high-purity technology, applied in the field of medicine, to achieve safe production process, high reaction yield, and improve the effect of drug safety

Active Publication Date: 2016-04-06
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Preparation method of high-purity Ledipasvir intermediate
  • Preparation method of high-purity Ledipasvir intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] 1) Preparation of (1R,3S,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid: take compound 1 (50g), methanol (250g) and Pd / C (5% w / w, 9.8g), replaced with nitrogen, filled with hydrogen to 0.8-1.0MPa, reacted at 45-55°C for a period of time (2-4 hours), concentrated, added 100g methanol, 200g water, and used carbonic acid Adjust the pH to 8 with sodium, keep the temperature below 5°C, slowly add di-tert-butyl dicarbonate (86g) dropwise, and stir for half an hour to react. Rise naturally to room temperature, add DCM for extraction, collect the organic phase, concentrate to obtain compound 3 (28g, yield=77%, de is 80-86%), repeat three times, the results of the three batches are as follows: The table below Show:

[0061]

[0062] 2) Preparation of optically pure (1R,3S,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid: Compound 3 (10g, 39mmol), water (50mL) , triethylamine (1.2 mL), and porcine pancreatic lipase (50 mg) were...

Embodiment 2

[0069] Compound 3 (10g, 39mmol, de 83%), water (50mL), triethylamine (6mL), and porcine pancreatic lipase (55mg) were added to a 100mL three-neck flask, and reacted at 55°C for 24 hours. After the reaction is complete, extract the reaction liquid with dichloromethane (50 mL), collect the water phase, continue to add an equal volume of dichloromethane to the water phase, cool down to 0-10 ° C, add a certain amount of 6N HCl, and adjust the pH to about 2 . The organic phase was collected, concentrated until a solid precipitated, cooled to room temperature, crystallized by adding petroleum ether (5 mL), suction filtered, and dried to obtain a white solid 6 (7.18 g). The yield was 69.2%, and the de was 99.7%. The isomer impurity content was 0.17%. The white solid was confirmed to be the target product by structural characterization, and the specific data are as follows:

[0070] Mass Spectrum: MS (M-H+): m / z 240.3.

[0071] 1 HNMR(400MHz,DMSO-d6):δ12.45(s,1H),4.12-4.05(d,1H),3...

Embodiment 3

[0072] The screening of embodiment 3 enzymes

[0073] Compound 3 (10g), water (50mL), and triethylamine (1.2mL) were added to a 100mL three-necked flask, and different hydrolytic enzymes were added, and reacted at 50°C for 24 hours, and the reaction results as table 1 .

[0074] Table 1 Hydrolysis of compound 3 catalyzed by different hydrolases

[0075]

[0076] The results show that the above hydrolases can effectively obtain products with high de value, and the de value is 98.6%-99.7%. Among them, porcine pancreatic lipase and Novozymes 435 are better, and the yields are both greater than 70%.

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Abstract

The invention discloses a preparation method of a high-purity Ledipasvir intermediate (1R, 3S and 4S)-N-t-butylcarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylic acid. According to the method, (1R, 3S and 4S)-N-t-butylcarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylate serves as an initial raw material, and the Ledipasvir intermediate is obtained through enzymatic hydrolysis. A test proves that the high-purity Ledipasvir intermediate is obtained and a feasible path is provided for reducing production cost and improving drug use safety. Meanwhile, the method has the advantages that operation is easy, environment friendliness is achieved, the yield is high, selectivity is high and cost is low; large-scale production can be achieved, and industrial application and popularization are facilitated.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a ledipasvir intermediate, high-purity (1R,3S,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3 - Process for the preparation of carboxylic 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 patents mainly disclose the following two synthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/02C12P17/10
CPCC07D209/02C12P17/10
Inventor 陈兴孙大召孙秋何帅杰王灿辉庄明晨杨佑喆谢开龙郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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