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Substituted pyrimidine type compound as well as preparation method and use thereof

A compound, pyrimidine technology, applied in the field of medicinal chemistry, can solve problems such as druggability, safety and efficacy hidden dangers

Inactive Publication Date: 2019-03-26
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Compounds of formula A and derivatives thereof, such as pharmaceutically acceptable salts, isomers, crystal forms or solvates of compounds of formula A, may contain impurities from various sources as raw materials, which affect their druggability, safety and effectiveness. to hidden danger

Method used

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  • Substituted pyrimidine type compound as well as preparation method and use thereof
  • Substituted pyrimidine type compound as well as preparation method and use thereof
  • Substituted pyrimidine type compound as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 (S)-4-amino-6-((1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl)ethyl)amino) Preparation of pyrimidine-5-cyanomethanesulfonate

[0035] Step 1: Preparation of 3-chloroisatoic anhydride

[0036]

[0037] Add 2-amino-3-chlorobenzoic acid (34.2g, 0.2mol) and 175mL of acetonitrile in a 500mL three-necked flask, cool down to 0°C, then add dropwise a dichloromethane solution of triphosgene (triphosgene (29.6g, 0.1 mol) was dissolved in 150 mL of dichloromethane), and pyridine (50 mL, 0.6 mol) was added dropwise at the same time, and the dropwise addition was completed in about 30 minutes, and the reaction was tracked by TLC until the reaction was complete. After treatment, spin dry directly, add water to make a slurry, and filter to obtain the title compound.

[0038] Step 2: Preparation of 3-acetyl-8-chloro-2-phenylquinolin-4(1H)-one

[0039]

[0040] Add 1-phenyl-1,3-butanedione to the reaction flask, add N,N-dimethylformamide, add sodium methoxide to...

Embodiment 2

[0059] Example 2: (S)-4-amino-6-((1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl)ethyl)amino ) Preparation of pyrimidine-5-methylamide

[0060]

[0061] 5g of (S)-4-amino-6-((1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl)ethyl)amino) Pyrimidine-5-cyano was dissolved in a mixed solvent of 10mL methanol / 40mL water, refluxed at 100°C for 12 hours, turned off the heating and returned to room temperature, concentrated to dryness, and the crude product was obtained by sand-making and rapid column flushing, and the white pure title compound. ESI-MS m / z:457.2[M+Na] + . 1 H NMR (500MHz, DMSO-d 6 )δ: 1.39(3H,J=6.8Hz,d),5.17-5.11(1H,m),6.46(2H,s),7.34(2H,s),7.38-7.36(1H,m),7.56-7.58 (5H,m),7.75(1H,s),7.83(1H,J=7.5Hz,d),8.09(1H,J=8.5Hz,d),8.16(1H,J=8.0Hz,d),10.75 (1H,s).

Embodiment 3

[0062] Example 3: (S)-6-amino-4-(1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl)ethylamino)-5 - Preparation of cyanopyrimidine-1-nitrogen oxide

[0063]

[0064] 4g (S)-4-amino-6-((1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine -5-cyano was dissolved in toluene, 8.3 g of m-chloroperoxybenzoic acid was added, heated and stirred at 80°C for 4 hours, filtered, the mother liquor was concentrated to obtain a yellow solid, and the title compound was obtained by preparative liquid phase separation. ESI-MS m / z:455.2[M+Na] + . 1 H NMR (500MHz, DMSO-d 6 )δ: 1.39(3H,J=6.5Hz,d),5.05(1H,m),7.41(1H,J 1 =J 2 =8.0Hz,dd),7.54-7.52(2H,m),7.59-7.55(3H,m),7.88(2H,J 1 =7.5Hz,J 2 =1.0Hz,dd),8.17(1H,J=9.0Hz,d),8.23(1H,J 1 =7.5Hz,J 2 =1.0Hz,dd),8.35(1H,s),11.10(1H,s).

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Abstract

The invention belongs to the medical chemistry field and particularly relates to a substituted pyrimidine type compound, a preparation method thereof and use thereof as a reference substance for the qualitative and / or quantitative analysis of relevant impurities in quality research of a raw material drug of mesylate of (S)-4-amino-6-((1-(8-chloro-4-oxo-2-phenyl-1,4-dihydroquinolin-3-yl)ethyl)amino)pyrimidine-5-cyano.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a substituted pyrimidine compound, a preparation method thereof and its use as a reference substance in (S)-4-amino-6-((1-(8-chloro-4-oxo- 2-Phenyl-1,4-dihydroquinolin-3-yl)ethyl)amino)pyrimidine-5-cyanomethanesulfonate raw material drug quality research for the use of qualitative and / or quantitative analysis of related impurities. Background technique [0002] PI3K (phosphatidylinositol 3-kinase) is a member of a unique and conserved family of intracellular lipid kinases that phosphorylates the 3'-OH group on phosphatidylinositol. According to the different structures and phosphorylation substrates, PI3K can be divided into three types: I, II, and III. Among them, type I PI3K is the hotspot of current research. Plays an important role in immune cells (Coussens and Werb, Nature, 2002, 420, 860-867) and has therapeutic value in the treatment of various forms of ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 赵立文沙向阳叶仕春丁兆兵陈程李琳毅
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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