1-Methylpiperazine → 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]furan-3-yl}quinoline-3-carbonitrile

HRID 1454418Notes

Reaction equation

HRID 1454418 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH:29]=O)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH2:29][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32]

Participants

7

Reactant 3

HCID 531671-MethylpiperazineHCID 5049666Sodium triacetoxyborohydrideHCID 11590865HCID 11590865, compound

Product 1

HCID 113418694-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]furan-3-yl}quinoline-3-carbonitrileYield 51%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.43 mmol) and 0.24 mL of N-methylpiperazine (2.2 mmol) in 5 mL of dichloromethane and 1 mL of dimethylformamide is cooled to 0° C. Sodium triacetoxyborohydride (470 mg, 2.22 mmol) is added in portions followed by a few drops of acetic acid. The resulting mixture is stirred at 0° C. for 10 minutes then at room temperature for 5.5 hours. The mixture is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 10% methanol in ethyl acetate to 1% ammonium hydroxide in a 1:4 mixture of methanol and ethyl acetate to provide 120 mg (51%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6 methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-quinolinecarbonitrile as a light yellow solid, mp 179-181° C.; 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.23-2.36 (broad s, 4H), 2.38-2.49 (broad s, 4H), 3.54 (s, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 7.01 (s, 1H), 7.33 (s, 1H), 7.74 (s, 1H), 7.94 (s, 1H), 8.10 (s, 1H), 8.28 (s, 1H), 8.43 (s, 1H), 9.82 (s, 1H); MS 552.1, 554.1 (M+H)+; HRMS calcd: 552.15638, found: 552.15599 (M+H)+.

Workup

  1. waitat room temperature for 5.5 hours
  2. customThe mixture is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate
  3. dry with materialThe organic phase is dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by flash column chromatography
  7. washeluting with a gradient of 10% methanol in ethyl acetate to 1% ammonium hydroxide in a 1:4 mixture of methanol and ethyl acetate

Sources & evidence

ORD record
ord-2aa1ccca1b22484f97afc6e17e413ead
Source dataset
uspto-grants-2009_01
Patent number
US07479561B2

Reaction notes

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