Nitrogen → N-(4-[{4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-4-methyl-3-[(2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)ethynyl]benzamide

HRID 1527888Notes

Reaction equation

HRID 1527888 reaction equation
[CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[CH:29])[CH:22]=3)=[CH:15][C:14]=2[C:31]([F:34])([F:33])[F:32])[CH2:8][CH2:7]1)([CH3:4])=[O:3].Br[C:36]1[CH:45]=[N:44][C:43]2[NH:42][C:41](=[O:46])CO[C:38]=2[CH:37]=1.N#N.C(N(CC)C(C)C)(C)C.C[CH2:59][O:60]C(C)=O>[Cu]I.O.CN(C=O)C>[CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[C:29][C:36]4[CH:45]=[N:44][C:43]5[NH:42][C:41](=[O:46])[O:60][CH2:59][C:38]=5[CH:37]=4)[CH:22]=3)=[CH:15][C:14]=2[C:31]([F:34])([F:32])[F:33])[CH2:8][CH2:7]1)([CH3:4])=[O:3]

Participants

9

Reactant 5

HCID 947NitrogenHCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 159259837-bromo-2H,3H,4H-pyrido(3,2-b)(1,4)oxazin-3-oneHCID 86632313N-[4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-3-ethynyl-4-methylbenzamide

Product 1

HCID 68911400N-(4-[{4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-4-methyl-3-[(2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)ethynyl]benzamide

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

N-[4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-3-ethynyl-4-methylbenzamide (0.22 mmol), 7-bromo-4H-Pyrido[3,2-b][1,4]oxazin-3-one (45.8 mg, 0.2 mmol), Pd[(PPh3)]4 (11.6 mg, 0.01 mmol), CuI (2.9 mg, 0.015 mmol) is placed in a vial capped with rubber septa. This vial is subjected to 3 cycles of vacuum-refilling with N2. To this mixture is added anhydrous N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and DMF (1.0 mL). The resulting solution is stirred at 80° C. for 24 h. After the reaction mixture is cooled, water and EtOAc are added to facilitate the extraction. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue is purified on a silica gel column (eluent: 10% MeOH in CH2Cl2, MeOH is pre-saturated with NH3 gas).

Workup

  1. customa vial capped with rubber septa
  2. temperatureAfter the reaction mixture is cooled
  3. extractionthe extraction
  4. dry with materialThe combined organic layers are dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated on a rotavap
  7. customthe residue is purified on a silica gel column (eluent: 10% MeOH in CH2Cl2, MeOH is pre-saturated with NH3 gas)

Sources & evidence

ORD record
ord-b20ddbfaed664054b15f4d237505616f
Source dataset
uspto-grants-2015_07
Patent number
US09090561B2

Reaction notes

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