Oxalyl chloride → (E)-N-(7-ethoxy-4-((3-ethynylphenyl)amino)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide

HRID 1051121ノート

反応式

HRID 1051121 の反応式
[N:1]1([CH2:7]/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[CH:40])[CH:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[NH2:41])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.C1COCC1>[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[CH:40])[CH:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[NH:41][C:10](=[O:12])/[CH:9]=[CH:8]/[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:20]

参加物

8

反応物 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 10773452(E)-4-(piperidin-1-yl)but-2-enoic acidHCID 867303777-ethoxy-N4-(3-ethynylphenyl)quinazoline-4,6-diamine

生成物 1

HCID 71543353(E)-N-(7-ethoxy-4-((3-ethynylphenyl)amino)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide収率 6.8%

試薬・触媒・溶媒 3

HCID 6228Dimethylformamide触媒HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

(E)-4-(piperidin-1-yl)but-2-enoic acid (550 mg, 3.4 mmol) and 10 drops of DMF were added in 20 ml DCM, and then oxalyl chloride (0.45 ml, 4.9 mmol) was added dropwise at 0° C. The solution was stirred for 1 hour at room temperature, then concentrated to a yellow solid. This intermediate was added in 50 ml THF, and then was added dropwisely into a solution of 7-ethoxy-N4-(3-ethynylphenyl)quinazoline-4,6-diamine (1 g, 3.28 mmol) and DIPEA (1 g, 7.7 mmol) in 200 ml THF in a ice bath. The reaction was stirred at 40° C. for 4 hours. The resulting reaction solution was concentrated to remove the excess of solvent, the residue was separated between 20 ml DCM and 20 ml saturated aqueous NaHCO3. The organic layer was concentrated and applied on a silica gel column (DCM/MeOH=10/1) to get (E)-N-(7-ethoxy-4-((3-ethynylphenyl)amino)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide as white solid 102 mg (6.8% yield). 1H-NMR (DMSO-d6): δ1.41-1.53 (m, 9H), 2.36 (m, 4H), 3.10-3.12 (m, 2H), 4.17 (s, 1H), 4.26-4.33 (m, 2H), 6.55 (d, J=15.3 Hz, 1H), 6.76-6.83 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.26 (s, 1H), 7.35-7.40 (m, 1H), 7.88 (d, J=8.2 Hz, 1H), 8.00 (s, 1H), 8.52 (s, 1H), 8.92 (s, 1H), 9.49 (s, 1H), 9.71 (s, 1H). MS m/z 456 [M+1].

後処理

  1. concentrationconcentrated to a yellow solid
  2. additionThis intermediate was added in 50 ml THF
  3. stirringThe reaction was stirred at 40° C. for 4 hours
  4. customThe resulting reaction solution
  5. concentrationwas concentrated
  6. customto remove the excess of solvent
  7. customthe residue was separated between 20 ml DCM and 20 ml saturated aqueous NaHCO3
  8. concentrationThe organic layer was concentrated

出典と根拠

ORDレコード
ord-52fbfdab374e4278afa46e068d6aef43
出典データセット
uspto-grants-2016_07
特許番号
US09388160B2

反応ノート

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