tert-Butyl Dimethylphosphonoacetate → 3-[3-(4-Ethyl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4-trifluoromethoxy-phenyl]-acrylic acid tert-butyl ester

HRID 2239241Notes

Reaction equation

HRID 2239241 reaction equation
[C:1]([O:5][C:6]([CH2:8]P(=O)(OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:22]1[C:27]2[CH:28]=[C:29]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=3[O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=O)[C:30]([CH3:32])=[CH:31][C:26]=2[O:25][C:24]([CH3:47])([CH3:46])[C:23]1=[O:48])[CH3:21]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[C:1]([O:5][C:6](=[O:7])[CH:8]=[CH:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][C:42]([F:45])([F:43])[F:44])=[C:33]([C:29]2[C:30]([CH3:32])=[CH:31][C:26]3[O:25][C:24]([CH3:46])([CH3:47])[C:23](=[O:48])[N:22]([CH2:20][CH3:21])[C:27]=3[CH:28]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 3

HCID 4564495tert-Butyl DimethylphosphonoacetateHCID 866116753-(4-Ethyl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4-trifluoromethoxy-benzaldehydeHCID 178418339Butyllithium

Product 1

HCID 685832583-[3-(4-Ethyl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4-trifluoromethoxy-phenyl]-acrylic acid tert-butyl esterYield 60%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22565281tetrahydrofuran 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneSolvent

Conditions

Temperature
-78 °C

Procedure

A flask charged with dimethyl t-butoxycarbonyl-methylphosphonate (0.21 mL, 1.06 mmol) in 2 mL of dry THF/DMPU (10:1) was cooled to −78° C. where 0.52 mL of n-butyl lithium (2.5 M hexane solution, 32 mmol) was added slowly via syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then a solution of Compound 1D (173 mg, 0.43 mmol) in 2 mL of dry THF was added. After warming to room temperature and an additional 20 minutes of stirring, the reaction was quenched with 5 mL of water and passed through a solid phase extraction column (SPE). The column was washed with EtOAc (50 mL) and the collected eluant was evaporated to give crude product which was purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%) to give 126 mg (60%) of product as a white solid. MS (electrospray): mass calculated for C27H30F3NO5, 505.21; m/z found 506.2, [M+H]+.

Workup

  1. additionwas added slowly via syringe
  2. temperatureAfter warming to room temperature and an additional 20 minutes
  3. stirringof stirring
  4. customthe reaction was quenched with 5 mL of water
  5. extractionpassed through a solid phase extraction column (SPE)
  6. washThe column was washed with EtOAc (50 mL)
  7. customthe collected eluant was evaporated
  8. customto give crude product which
  9. customwas purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%)

Sources & evidence

ORD record
ord-eb08c586dafe4d8fa6f5b1483a7b3243
Source dataset
uspto-grants-2010_05
Patent number
US07723326B2

Reaction notes

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