Water → Di-tert-butyl ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl) phosphate

HRID 1051979Notes

Reaction equation

HRID 1051979 reaction equation
[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:26][C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[P:41]([O:53][CH2:54]Cl)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C.C(OC(C)C)(=O)C>[P:41]([O:53][CH2:54][N:29]1[C:28](=[O:32])[C:27]([CH3:34])([CH3:33])[O:26][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=4)[N:4]=3)=[N:31][C:30]1=2)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 11213558TamatinibHCID 11701630Di-tert-butyl (chloromethyl) phosphate2×

Product 1

HCID 49857796Di-tert-butyl ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl) phosphate

Reagents, catalysts & solvents 3

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 7915Isopropyl AcetateSolvent2×HCID 31374DimethylacetamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 6-[[5-Fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step B) (382 kg, 1.00 mol eq), tetra-n-butylammonium chloride (57.5 kg, 0.25 mol eq) and potassium carbonate (252 kg, 2.25 mol eq) in N,N-dimethylacetamide (1792 kg) is warmed to about 40° C. with stirring. To this is added a solution of ditert-butyl chloromethyl phosphate (Example 2) in isopropyl acetate (229 kg ditert-butyl chloromethyl phosphate, 1.10 mol eq, about 25% w/v solution). The resulting mixture is stirred for about 8 hours and then cooled to about 5° C. Isopropyl acetate (1329 kg) is added and then water (2292 kg) slowly, maintaining the temperature at <25° C. The layers are then separated, retaining the upper layer of the three observed. To this is added acetic acid (99 kg) and the resulting solution of the sub-title compound is used directly in the next step.

Workup

  1. stirringThe resulting mixture is stirred for about 8 hours
  2. temperaturecooled to about 5° C
  3. customThe layers are then separated
  4. additionTo this is added acetic acid (99 kg)

Sources & evidence

ORD record
ord-6353065735a64494a05ccc8821dfeb8c
Source dataset
uspto-grants-2016_07
Patent number
US09388203B2

Reaction notes

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