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Method for synthesizing Tegrazan chiral alcohol

A technology of chiral reagents and dihydrogen, which is applied in the field of chiral fragment synthesis of raw materials, can solve the problems of poor chiral purity, high cost, and difficulty in purchasing chiral Ru reagent prices, and achieves simple synthesis methods, easy procurement, and chiral Ru reagents. highly selective effect

Active Publication Date: 2021-06-18
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

CJ Health Care patents CN101341149B and CN107849003A disclose the preparation method of (S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol, but the chiral purity of the method described in CN101341149B is poor (86%ee) (although recrystallization can improve product ee value, recrystallization yield only has 58%), CN107849003A relates to the chiral Ru reagent (expensive) that commercialization is difficult to purchase, the method that patent CN101341149B and CN 107849003A describe as follows:

Method used

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  • Method for synthesizing Tegrazan chiral alcohol
  • Method for synthesizing Tegrazan chiral alcohol
  • Method for synthesizing Tegrazan chiral alcohol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Preparation of (S)-5,7-difluoro-4H-benzopyran-4-ol

[0024] Anhydrous THF (400 mL) and (S)-tetrahydro-1-methyl-,3,3-diphenyl-1H,3H-pyrrolo[1,2-c were added to a 3L reaction flask under nitrogen protection ][1,3,2]oxazaborolane in toluene (1 M in Toluene, 55 mL, 55 mmol). After the addition, the system was cooled to 0±2°C in an ice-salt bath, then borane dimethyl sulfide complex (1M in THF, 575mL, 0.575mol) was added to the system, and the system was stirred at 0±2°C for 10min and then added 5, A solution of 7-difluoro-4H-benzopyran-4-one (100 g, 0.549 mol) in THF (500 mL) was added to maintain the reaction temperature of the system at 0±2 °C. After the addition, the system was reacted to TLC to track the starting material 5,7-Difluoro-4H-benzopyran-4-one disappeared. After completion of the reaction, the system was quenched by adding MeOH (200 mL), and the system was naturally warmed to room temperature and stirred vigorously for 1 hour. The organic solven...

Embodiment 2

[0025] Embodiment 2: the preparation of (S)-5,7-difluoro-4H-benzopyran-4-ol

[0026] Anhydrous THF (80 mL) and (S)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1, (S)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1, 3,2] oxazaborolane in toluene (1 M in Toluene, 11.0 mL, 11.0 mmol). After the addition, the system was cooled to 0±2° C. in an ice-salt bath, and then borane dimethyl sulfide complex (1M inTHF, 121 mL, 121 mmol) was added to the system. The system was stirred at 0±2°C for 10min, and a solution of 5,7-difluoro-4H-benzopyran-4-one (20.0g, 109.8mmol) in THF (100mL) was added, and the reaction temperature of the system was maintained at 0±2°C during the addition. , after the addition, the system reacted until the TLC tracking material 5,7-difluoro-4H-benzopyran-4-one disappeared. After the completion of the reaction, the system was quenched by adding MeOH (50 mL), and the system was naturally warmed to room temperature and stirred vigorously for 1 hour. The org...

Embodiment 3

[0027] Example 3: Preparation of (S)-5,7-difluoro-3,4-dihydro-2H-chromogen-4-ol

[0028] (S)-5,7-difluoro-4H-benzopyran-4-ol (5.0 g, 27.15 mmol) and ethanol (100 mL) were added to the reaction flask, the system was stirred, and then 5% Pd was added under nitrogen protection / C (65% water content, 5.8 g). After the addition, the system was replaced with nitrogen three times, and then hydrogenated at room temperature and normal pressure until HPLC tracked the disappearance of the reaction raw materials. Filter, remove the organic solvent under high vacuum, and purify the residue by column chromatography (n-heptane / EA=5:1) to obtain (S)-5,7-difluoro-3,4-dihydro-2H-chromene -4-ol (4.65 g, 92%).

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Abstract

The present invention relates to a method for preparing Tegoprazan (Tegoprazan) chiral alcohol, in particular to (S)-5,7-difluoro-3,4-dihydro-2 H -Process for the preparation of chromene-4-ol. The method uses 5,7-difluoro-4H-benzopyran-4-one as the starting material, and realizes (S)-5, 7‑difluoro‑3,4‑dihydro‑2 H Preparation of ‑chromene‑4‑ol.

Description

technical field [0001] The invention belongs to the technical field of chiral fragments of synthetic raw materials, in particular to the preparation of tegorazan chiral fluoroalcohol. Background technique [0002] Tegoprazan, also known as Tegoprazan, Tegoprazan, CJ-12420, was approved by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis . [0003] Tegorazan was originally developed by Pfizer, licensed to RaQualia Pharma (separated from Pfizer) in 2008, and licensed to CJ Health Care by RaQualia Pharma in 2014, and was finally successfully developed and marketed by CJ Health Care in South Korea. Tegorazan is a competitive potassium ion acid blocker (P-CAB) and a hydrogen ion / potassium ion exchange ATPase (H + / K + ATPase) inhibitor, the drug was first launched in South Korea and is a new drug for the treatment of gastroesophageal reflux disease and erosive esophagitis. [0004] Gas...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/22C07D405/12
CPCC07B2200/07C07D311/22C07D405/12
Inventor 邱小龙胡林刘文博邹平储玲玲张新刚王平王东辉曹雷陈俊
Owner WISDOM PHARM CO LTD
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