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N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound

A technology based on lactams and quinolines, applied in the field of pharmacy, can solve problems such as harsh conditions, use of toxic reagents, and low yields

Inactive Publication Date: 2014-01-22
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many synthetic methods of reported β-lactam compounds, but many methods have defects of one kind or another, such as multi-step synthetic methods, expensive reagents, low yield, harsh conditions, and the use of toxic reagents, etc.
To date, sp 3 The C-H bond is activated, and then the intramolecular C-N bond is formed. There is no report on the method of one-step synthesis of β-lactam compounds.

Method used

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  • N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound
  • N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound
  • N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] (1) Preparation of 1-(8-quinolyl)-4-phenyl-azetidinone (1a):

[0082]

[0083] Operation is as follows: in the reaction tube of 10ml, add 1 (27.6mg, 0.1mmol) successively, Pd(OAc) 2 (1.1mg, 0.005mmol), AgOAc (20mg, 0.12mmol) and C 6 f 5 I (163mg, 0.55mmol), stirred evenly at room temperature, placed in a microwave reactor and heated to 160°C for 1.5 hours, purified by direct column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 25.5mg of compound 1a, 93% yield. solid; 1 HNMR (400MHz, CDCl 3 )δ8.77(s,1H),8.31(d,J=6.3Hz,1H),8.04(d,J=8.1Hz,1H),7.61–7.47(m,2H),7.41(d,J=7.0 Hz,2H),7.38–7.11(m,4H),6.27(s,1H),3.73(dd,J=15.0and5.2Hz,1H),3.11(d,J=14.7Hz,1H);13 C NMR (100MHz, CDCl 3 )δ166.8, 148.7, 140.5, 135.9, 133.2, 128.9, 128.5, 127.7, 126.5, 126.2, 124.4, 122.0, 121.3, 58.7, 47.8; HRMS (EI) Calcd for C 18 h 14 N 2 O[M + ]:274.1106,Found274.1113;IR(KBr)V(cm -1 ):1744,1638,1503,1344,756.

Embodiment 2

[0085] (2) Preparation of 1-(8-quinolyl)-4-(4-tolyl)-azetidinone (2a):

[0086]

[0087] Operation is as follows: in the reaction tube of 10ml, add 2 (29.0mg, 0.1mmol) successively, Pd(OAc) 2 (1.1mg, 0.005mmol), AgOAc (20mg, 0.12mmol) and C 6 f 5 I (163mg, 0.55mmol), stirred evenly at room temperature, placed in a microwave reactor and heated to 160°C for 1.5 hours, purified by direct column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 23.0mg of compound 2a, 80% yield. solid; 1 H NMR (400MHz, CDCl 3 )δ8.77(dd,J=4.1and1.7Hz,1H),8.27(dd,J=6.9and1.9Hz,1H),8.00(dd,J=8.3and1.6Hz,1H),7.54–7.44(m ,2H),7.35–7.22(m,3H),7.02(d,J=8.0Hz,2H),6.23(dd,J=5.5and2.5Hz,1H),3.70(dd,J=15.1and5.6Hz, 1H),3.09(dd,J=15.1and2.6Hz,1H),2.21(s,3H); 13 C NMR (100MHz, CDCl 3 )δ166.9, 148.7, 140.7, 137.5, 137.3, 136.0, 133.2, 129.2, 128.9, 126.6, 126.2, 124.5, 122.3, 121.3, 58.5, 47.7, 21.1; HRMS (EI) Calcd for C 19 h 16 N 2 O[M + ]:288.1263,Found288.1281;IR(KBr)V(cm -1 ):...

Embodiment 3

[0089] (3) Preparation of 1-(8-quinolyl)-4-(2-methoxyphenyl)-azetidinone (3a):

[0090]

[0091] The operation is as follows: add 3 (30.6mg, 0.1mmol), Pd(OAc) 2 (1.6mg, 0.007mmol), AgOAc (20mg, 0.12mmol) and C 6 f 5 I (163mg, 0.55mmol), stirred evenly at room temperature, placed in a microwave reactor and heated to 160°C for 1.5 hours, purified by direct column chromatography (petroleum ether: ethyl acetate = 12:1) to obtain 23.0mg of compound 3a, 82% yield. solid; 1 H NMR (500MHz, CDCl 3 )δ8.73(d,J=2.7Hz,1H),8.29(dd,J=7.0and1.5Hz,1H),8.02(d,J=8.2Hz,1H),7.58–7.45(m,2H), 7.30–7.25(m,1H),7.24(d,J=7.5Hz,1H),7.15–7.07(m,1H),6.80(d,J=8.2Hz,1H),6.71(t,J=7.5Hz ,1H),6.42(dd,J=5.7and2.6Hz,1H),3.87(s,3H),3.67(dd,J=14.9and5.8Hz,1H),3.13(dd,J=14.9and2.6Hz, 1H); 13 C NMR (100MHz, CDCl 3 )δ167.4, 157.1, 148.6, 140.8, 135.9, 133.9, 128.9, 128.5, 128.3, 127.4, 126.6, 124.1, 121.7, 121.2, 120.3, 110.4, 55.5, 55.4, 46.1; HRMS (EI) Calcd for C 19 h 16 N 2 o 2 [M + ]:304.1212,Fou...

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Abstract

The invention discloses an N-quinolyl substituted beta-lactam compound as shown in a general formula (I), wherein R<1> and R<2> refer to mutually independent H or C1-12 straight-chain or branched-chain hydrocarbonyl, aryl, alkoxy, acyloxy or amino; R<3> refers to H or C1-25 straight-chain or branched-chain hydrocarbonyl or aryl, or R<3> together with R<1> or R<2> forms a substituted or non-substituted five-eight-membered ring containing or without containing heteroatoms, and the heteroatoms can be N, O and S; R<4> and R<5> refer to mutually independent H or C1-12 straight-chain or branched-chain hydrocarbonyl, aryl, alkoxy, acyloxy or amino, nitryl, sulfonyl and halogen, and halogen refers to F, Cl, Br and I. The invention also provides a synthetic method of the N-quinolyl substituted beta-lactam compound, a pharmaceutical composition containing the compound, as well as application of the compound in medicine preparation of beta-lactamase inhibitors.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a class of N-quinolyl-substituted β-lactam compounds, a synthesis method thereof, a pharmaceutical composition containing the compound and its application in preparing medicines. Background technique [0002] β-lactam (2-Azetidinone) is a four-membered ring lactam derived from 3-alanine. Such compounds were first synthesized by Staudinger in 1907. In 1929, Fleming discovered penicillin (compounds 1 and 2), which has strong antibacterial activity. Pharmacological studies have shown that the β-lactam structure is its pharmacophore, and its mechanism of action is that penicillin, as an antibiotic, can block the biosynthesis of bacterial cell walls. There are many kinds of β-lactam compounds as antibiotic drugs, including Cefepime, CefmatilenHydrochlotide Hydrate, CefoselisSilfate, CS-834, DA-1131, ER-35786, Ertapenem Sodium, Faropenem Sodium, RitipenemAcoxil. For example, CS-83...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D405/14C07D401/14C07D507/00A61K31/4709A61P31/04
CPCC07D401/04C07D401/14C07D405/14C07D507/00
Inventor 吴滨孙文武曹沛赵金华杨莲
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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