Diisopropylethylamine → 3-(3-amino-4-fluorophenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amine

HRID 715099Notes

Reaction equation

HRID 715099 reaction equation
Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][CH3:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:29])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:20]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 4854071-(4-methoxyphenyl)-N-methylmethanamine3×HCID 898155055-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline

Product 1

HCID 898157773-(3-amino-4-fluorophenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amineYield 68%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
170 °C

Procedure

Treat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.353 g, 1.227 mmol) and 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) in NMP (6 mL) in a sealed tube with N,N-diispropylethylamine (DIEA) (0.429 mL, 2.454 mmol), sparge with argon and heat at 170° C. overnight. Add additional 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) and heat at 185° C. for 24 h. Add more 4-methoxy-N-methylbenzylamine (0.15 g, 1 mmol) and heat the mixture overnight at 185° C. Cool to RT, dilute with EtOAc and wash with satd. NaHCO3, water, and then brine. Dry the organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (334 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 7.95 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.05 (dd, J=11.5, 8.2 Hz, 1H), 6.85 (m, 2H), 6.78 (dd, J=8.8, 2.3 Hz, 1H), 6.71 (s, 1H), 6.54 (ddd, J=8.2, 4.4, 2.2 Hz, 1H), 5.24 (s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.08 (s, 3H), 2.47 (s, 3H); MS (ESI) m/z: 403.2 (M+H+).

Workup

  1. customsparge with argon
  2. temperatureheat at 185° C. for 24 h
  3. temperatureheat the mixture overnight at 185° C
  4. temperatureCool to RT
  5. washwash with satd
  6. dry with materialDry the organics over MgSO4
  7. concentrationconcentrate to dryness
  8. custompurify via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-b0c07163b5cf465ba1a9a9ac22c07ebc
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

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