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

HRID 1051121Notes

Reaction equation

HRID 1051121 reaction equation
[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]

Participants

8

Reactant 4

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

Product 1

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

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

(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].

Workup

  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

Sources & evidence

ORD record
ord-52fbfdab374e4278afa46e068d6aef43
Source dataset
uspto-grants-2016_07
Patent number
US09388160B2

Reaction notes

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