Water → [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine

HRID 907621Notes

Reaction equation

HRID 907621 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[CH:16]=[N:17][C@H:18]([C:24]12[O:31][CH2:30][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:26][O:25]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].O>CCOCC>[F:39][C:15]([F:14])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C@@H:16]([NH:17][C@H:18]([C:24]12[O:25][CH2:26][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:30][O:31]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 962WaterHCID 99931-Bromo-4-fluorobenzeneHCID 67391427(2,2-Difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amineHCID 178418339Butyllithium

Product 1

HCID 67391815[2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amineYield 17.8%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
40 °C

Procedure

1-Bromo-4-fluorobenzene (1.12 g, 6.4 mmol) of was dissolved in ether (20 ml) and cooled to −78° C. nBuLi (2.56 ml, 2.5M, 6.4 mmol) was added and the reaction mixture was stirred for 1 h. (2,2-Difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (1.18 g, 3.2 mmol) was added and stirring was continued for 2 h while the solution was allowed to warm up to 40° C. Water (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The organic layer was separated, washed with brine and was dried over MgSO4. The solvent was evaporated and the crude was purified by flash column chromatography using silica gel and 20:80 ethylacetate:hexane as an eluent to give [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (265 mg).

Workup

  1. additionwas added
  2. additionwas added
  3. temperatureto warm to room temperature
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialwas dried over MgSO4
  7. customThe solvent was evaporated
  8. customthe crude was purified by flash column chromatography

Sources & evidence

ORD record
ord-8e849e74e92645f5b0445501b57db0b5
Source dataset
uspto-grants-2011_09
Patent number
US08013186B2

Reaction notes

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