1,4-Dichloro-5,6,7,8-tetrahydrophthalazine → 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

HRID 2361044Notes

Reaction equation

HRID 2361044 reaction equation
Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[NH2:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1>CO>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=4)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:33][CH:34]=2)=[N:3][N:4]=1

Participants

4

Reactant 2

HCID 126224401,4-Dichloro-5,6,7,8-tetrahydrophthalazineHCID 469295414-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine

Product 1

HCID 577562304-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A slurry of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (1.66 g, 8.18 mmol) and 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) in 14 mL 2-BuOH was heated in a sealed pressure vessel to 110° C. The reaction became a thick mass that eventually became a stirring suspension over about 30 min. After 4 h, the reaction was cooled to ambient temperature, and the material was partitioned between 2N NaOH and EtOAc. The aqueous layer was extracted once with EtOAc. The organic layers were dried over anhyd. sodium sulfate, filtered, and concentrated to yield a brown solid. This solid was dissolved in MeOH/MC and adsorbed onto 10 g silica gel, dried, and purified by chromatography (0-100% EtOAc/DCM) to give 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine as an off-white solid. MS m/z=460 [M+H]+. Calc'd for C24H22ClN7O: 459.9.

Workup

  1. customover about 30 min
  2. customthe material was partitioned between 2N NaOH and EtOAc
  3. extractionThe aqueous layer was extracted once with EtOAc
  4. customThe organic layers were dried over anhyd
  5. filtrationsodium sulfate, filtered
  6. concentrationconcentrated
  7. customto yield a brown solid
  8. customdried
  9. custompurified by chromatography (0-100% EtOAc/DCM)

Sources & evidence

ORD record
ord-3a017ea1fdea4b0a8ac205a66cdad265
Source dataset
uspto-grants-2014_04
Patent number
US08686155B2

Reaction notes

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