1,4-Dioxane → 1-(3,3-Dimethylcyclobutyl)-3-(2-fluoro-5-(7-((4-methoxybenzyl)(methyl)amino)-2-methyl-1,6-naphthyridin-3-yl)-4-methylphenyl)urea

HRID 715131Notes

Reaction equation

HRID 715131 reaction equation
[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4](C(O)=O)[CH2:3]1.C1C=CC(P([N:24]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:27][C:28]1[C:29]([F:57])=[CH:30][C:31]([CH3:56])=[C:32]([C:34]2[C:35]([CH3:55])=[N:36][C:37]3[C:42]([CH:43]=2)=[CH:41][N:40]=[C:39]([N:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[CH3:45])[CH:38]=3)[CH:33]=1.[O:58]1[CH2:63]COCC1>>[CH3:9][C:2]1([CH3:1])[CH2:3][CH:4]([NH:24][C:63]([NH:27][C:28]2[CH:33]=[C:32]([C:34]3[C:35]([CH3:55])=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][N:40]=[C:39]([N:44]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[CH3:45])[CH:38]=4)[C:31]([CH3:56])=[CH:30][C:29]=2[F:57])=[O:58])[CH2:5]1

Participants

5

Reactant 4

HCID 312751,4-DioxaneHCID 199401P,P-Diphenylphosphinic azideHCID 2151063,3-Dimethylcyclobutanecarboxylic acidHCID 898277223-(5-amino-4-fluoro-2-methylphenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amine

Product 1

HCID 898142431-(3,3-Dimethylcyclobutyl)-3-(2-fluoro-5-(7-((4-methoxybenzyl)(methyl)amino)-2-methyl-1,6-naphthyridin-3-yl)-4-methylphenyl)ureaYield 69%

Conditions

Temperature
100 °C

Procedure

Heat a mixture of 3,3-dimethylcyclobutane carboxylic acid (0.138 g, 1.080 mmol), DPPA (0.233 ml, 1.080 mmol) and TEA (0.100 ml, 0.720 mmol) in dioxane (3 mL) at 100° C. for 15 minutes, add 3-(5-amino-4-fluoro-2-methylphenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amine (0.15 g, 0.360 mmol) and heat at 100° C. for an additional 2 h. Cool to RT, add satd. NaHCO3, extract with EtOAc (2×), wash the combined organics with H2O, then brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (135 mg, 69%) as an orange pasty solid. MS(ESI) m/z: 542.3 (M+H+).

Workup

  1. temperatureHeat
  2. temperatureCool to RT
  3. additionadd satd
  4. extractionNaHCO3, extract with EtOAc (2×)
  5. washwash the combined organics with H2O
  6. dry with materialbrine, dry over Na2SO4
  7. concentrationconcentrate to dryness
  8. custompurify via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-349f47736338450b96f7ca1d4bf16be6
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

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