Methylamine → HCID 71737482, compound

HRID 715141Notes

Reaction equation

HRID 715141 reaction equation
C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH3:31][NH2:32].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[C:45]([C:51]3[C:52]([CH3:67])=[CH:53][C:54]([F:66])=[C:55]([NH:57][C:58]([NH:60][CH2:61][CH2:62][CH:63]4[CH2:65][CH2:64]4)=[O:59])[CH:56]=3)[C:46]([CH3:50])=[N:47]2)=[CH:42][N:41]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:63]1([CH2:62][CH2:61][NH:60][C:58]([NH:57][C:55]2[CH:56]=[C:51]([C:45]3[C:46]([CH3:50])=[N:47][C:48]4[C:43]([CH:44]=3)=[CH:42][N:41]=[C:40]([NH:32][CH3:31])[CH:49]=4)[C:52]([CH3:67])=[CH:53][C:54]=2[F:66])=[O:59])[CH2:65][CH2:64]1

Participants

7

Reactant 4

HCID 6329MethylamineHCID 10796Cesium carbonateHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 89815965HCID 89815965, compound

Product 1

HCID 71737482HCID 71737482, compoundYield 59.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

Add Pd2(dba)3 (0.020 g, 0.022 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl [t-butyl X-Phos] (0.019 g, 0.045 mmol), methylamine (2.0M in THF, 1.114 mL, 2.228 mmol) and Cs2CO3 (0.436 g, 1.337 mmol) to a solution of 1-(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(2-cyclopropylethyl)urea (0.184 g, 0.446 mmol) in dioxane (4 mL) and heat at 90° C. for 3 h. Cool to RT, remove the solids via filtration, rinse with DCM, then THF, concentrate the filtrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 1-(2-cyclopropylethyl)-3-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea (108 mg, 59%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.16 (d, J=12.4 Hz, 1H), 6.78-6.72 (m, 1H), 6.59 (m, 1H), 6.52 (s, 1H), 3.10 (q, J=6.5 Hz, 2H), 2.82 (d, J=5.0 Hz, 3H), 2.26 (s, 3H), 1.95 (s, 3H), 1.37 (m, 2H), 0.70 (m, 1H), 0.35 (m, 2H), 0.04 (m, 2H); MS(ESI) m/z: 408.2 (M+H+). Suspend 1-(2-cyclopropylethyl)-3-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)urea, (0.108 g, 0.265 mmol) in acetonitrile (4 mL), treat with 0.5 M HCl (0.53 mL, 0.265 mmol), freeze and lyophilize the resulting clear solution to provide the title compound. MS(ESI) m/z: 408.2 (M+H+).

Workup

  1. temperatureCool to RT
  2. customremove the solids
  3. filtrationvia filtration
  4. washrinse with DCM
  5. concentrationTHF, concentrate the filtrate to dryness
  6. custompurify via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-8fbfcce30d9e4ad1b27874690eeca713
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

Loading…