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Axial chiral isomers and preparation method and pharmaceutical application thereof

An isomer and axial chirality technology, applied in the field of two axial chiral isomers and their pharmaceutically acceptable salts, can solve the problems of no specific reported separation technology, chiral synthesis technology, no explicit mention of Lesinurad, etc.

Inactive Publication Date: 2016-06-01
MEDSHINE DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] These patents that have been reported have not clearly mentioned that Lesinurad is a mixture of a pair of chiral optical isomers with axial chirality, and have not specifically reported detailed separation techniques and detailed chiral synthesis techniques, as well as the chiral optical isomers. Construct specific parameters

Method used

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  • Axial chiral isomers and preparation method and pharmaceutical application thereof
  • Axial chiral isomers and preparation method and pharmaceutical application thereof
  • Axial chiral isomers and preparation method and pharmaceutical application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Embodiment 1: the preparation of (-)-Lesinurad and (+)-Lesinurad

[0082]

[0083] synthetic route:

[0084]

[0085] Step 1: Synthesis of Compounds 12A and 12B

[0086] Compound 12 was synthesized according to the method reported in patent CN103524440A or patent W2009070740. Compound 12 (330.00mg, 763.31umol) was subjected to supercritical fluid chromatography SFC (chiral column: ChiralpakAS (250mm×30mm, 5um); mobile phase: supercritical CO 2 / ethanol (0.05% DEA)=70 / 30; flow rate: 60mL / min; detection wavelength: 220nm) to separate compound 12A (150.00mg, 346.96umol) and compound 12B (152.00mg, 351.58umol).

[0087] Compound 12A: 1 HNMR (400MHz, DMSO-d 6 )δ: 8.57(d, J=8.4Hz, 1H), 7.78-7.76(m, 1H), 7.69-7.58(m, 2H), 7.43(d, J=7.6Hz, 1H), 7.13(d, J =8.0Hz, 1H), 4.10-4.00(m, 4H), 2.59-2.51(m, 1H), 1.17-1.11(m, 5H), 0.89-0.83(m, 2H).SFC (chiral column: ChiralpakAS -H (250mm×4.6mm, 5um); mobile phase: ethanol (0.05% DEA) / supercritical CO 2 =5~40%; Flow rate: 2.5m...

Embodiment 2

[0119] Embodiment 2: the preparation of (-)-Lesinurad and (+)-Lesinurad

[0120]

[0121] synthetic route:

[0122]

[0123] Step 1: Synthesis of compound 14

[0124]Compound 13 (2.00g, 16.37mmol, 1.00eq) and pyridine (2.59g, 32.74mmol, 2.00eq) were dissolved in toluene (30.00mL), the mixture was cooled to 0°C in an ice-water bath, and 2-bromoethyl Acid chloride (3.09g, 19.64mmol, 1.20eq), the reaction solution was stirred at 0°C for 1 hour, and a large amount of white solid was precipitated. After the reaction was complete, it was filtered, the filter cake was washed with dichloromethane (3 mL), and the obtained filtrate was spin-dried to obtain a yellow oily crude product. The crude product was purified by column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to obtain compound 14 (3.20 g, 13.16 mmol, yield 80.41%) as a colorless oil. 1 HNMR (400MHz, CDCl 3 )δ: 7.45-7.22 (m, 6H), 6.00-5.92 (m, 1H), 4.07 (s, 1H), 3.85 (s, 1H), 1.63-1.55 (d, J=4Hz, 3H)....

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Abstract

The invention discloses two axial chiral isomers, available medicinal salts thereof, a preparation method thereof, and pharmaceutical application of the two axial chiral isomers or medicinal compositions thereof.

Description

field of invention [0001] The present invention relates to two axial chiral isomers and their pharmaceutical salts, their preparation method, and the pharmaceutical use of these two axial chiral isomers or their pharmaceutical compositions. Background of the invention [0002] Lesinurad (CAS: 878672-00-5, RDEA594), as a blood uric acid-lowering reagent, was first reported by Ardea Biosciences Inc in a patent (W2009070740), and its synthesis route is as follows. [0003] Synthetic route 1: [0004] [0005] In subsequent patents (WO2011085009, WO2011126852, WO201159732, WO2012050589, WO2012092395, WO2014008295), Ardea Biosciences Inc. synthesized and produced Lesinurad and its sodium salt, together with colchicines, febuxostat and Febuxostat The combination of drugs such as purinol (Allopurinol) has been reported in detail. [0006] Chinese patent CN103524440A also reported another method for synthesizing Lesinurad and its intermediates, as follows. [0007] Synthetic r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12A61K31/4196A61P19/06A61P7/00
CPCC07B57/00C07B2200/07C07D249/12A61K31/4196A61P7/00A61P19/06Y02P20/54
Inventor 王建非张静张龙张杨黎健陈曙辉
Owner MEDSHINE DISCOVERY INC
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