Diisopropylamine → 3-fluoro-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide

HRID 1641137Notes

Reaction equation

HRID 1641137 reaction equation
C([O:5][C:6](=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:28][CH:29]1COCC(C2C(C(O)=O)=CC=CC=2)N1.[Cl-].ClC1N(C)[CH2:49][CH2:48][NH+]1C.[CH:53]([NH:56][CH:57]([CH3:59])[CH3:58])([CH3:55])C.[O:60]1[CH2:65][CH2:64]OCC1>Cl.C(Cl)Cl>[F:28][C:29]1[CH:48]=[C:49]([CH:58]=[C:57]([N:56]2[CH2:64][CH2:65][O:60][CH2:55][CH2:53]2)[CH:59]=1)[C:6]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:10][CH:9]=1)=[O:5]

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 312751,4-DioxaneHCID 109867151H-Imidazolium, 2-chloro-4,5-dihydro-1,3-dimethyl-, chlorideHCID 59553280t-Butyl(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)carbamateHCID 667380893-Fluoro-5-morpholinebenzoic acid

Product 1

HCID 595530703-fluoro-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of t-butyl(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)carbamate (1.0 g, 2.61 mmol) in 4.0 M HCl in dioxane (10 ml) is stirred at room temperature for 1 h. The mixture is then evaporated to dryness. The residue is then dissolved in CH2Cl2 (5 ml) containing diisopropylamine (1.0 ml). To this mixture is added a solution of 3-fluoro-5-morpholinebenzoic acid (0.70 g, 3.13 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (0.525 g, 3.13 mmol) and diisopropylamine (1.27 ml) in CH2Cl2 (10 ml) at room temperature. The mixture is stirred at room temperature overnight and then washed with saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel (10-60% EtOAc in hexane) to give 3-fluoro-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide as an off-white solid (0.75 g). Mp: 189-190° C.; 1H NMR (300 MHz, CDCl3) δ 2.29(s, 3H), 3.25(t, J=4.8 Hz, 4H), 3.87(t, J=5.1 Hz, 4H), 6.53(d, J=6.0 Hz, 1H), 6.75-6.80(m, 1H), 7.07(d, J=8.4 Hz, 1H), 7.30-7.33(m, 2H), 7.49-7.56(m, 2H), 7.89-7.97(m, 3H), 8.16(s, 1H), 8.36(d, J=5.7 Hz, 1H); MS: 491 (M+1).

Workup

  1. customThe mixture is then evaporated to dryness
  2. dissolutionThe residue is then dissolved in CH2Cl2 (5 ml)
  3. additioncontaining diisopropylamine (1.0 ml)
  4. washwashed with saturated NaHCO3 solution, brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue is purified by column chromatography on silica gel (10-60% EtOAc in hexane)

Sources & evidence

ORD record
ord-a8e96da9f68b4572beeee5680a63b417
Source dataset
uspto-grants-2012_02
Patent number
US08114873B2

Reaction notes

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