Triethylamine → HCID 73672049, compound

HRID 710029Notes

Reaction equation

HRID 710029 reaction equation
[F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([O-:5])=O.CCN(CC)CC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1>C1COCC1.ClC(OCC)=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[CH:33]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 86706740HCID 86706740, compound2×HCID 86706741HCID 86706741, compound

Product 1

HCID 73672049HCID 73672049, compoundYield 217%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 10928Ethyl chloroformateSolvent

Procedure

To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (87.83 g) and Et3N (122 mL) in THF (2000 mL), ethyl chloroformate (30.8 mL) was added at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture, a THF (500 mL) solution of the compound (89.00 g) obtained in Example 1-(1) was added dropwise at room temperature over an hour and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and AcOEt (2 L) and a saturated aqueous solution of NH4Cl (2 L) were added; after filtering the insoluble matter, the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 L), dried (MgSO4), filtered and concentrated to give a crude product (165.0 g). A similar method was applied using 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (34.64 g) and (S)-5-((3,4-dimethoxyphenoxy)methyl)-3-(pyrrolidin-2-yl)isoxazole (35.10 g) to give a crude product (60.10 g), which was combined with the first crude product and further purified by silica gel chromatography (AcOEt/hexane) and NH-form silica gel chromatography (AcOEt/hexane); the purified product was recrystallized (Et2O/pentane) to give the titled compound (134.30 g, colorless powder.)

Workup

  1. additionwas added dropwise at room temperature over an hour
  2. stirringthe mixture was stirred at room temperature for 20 hours
  3. concentrationThe reaction mixture was concentrated
  4. additionAcOEt (2 L) and a saturated aqueous solution of NH4Cl (2 L) were added
  5. filtrationafter filtering the insoluble matter
  6. customthe organic layer was separated
  7. washwashed with saturated aqueous sodium bicarbonate (2 L)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give a crude product (165.0 g)
  12. customto give a crude product (60.10 g), which
  13. customfurther purified by silica gel chromatography (AcOEt/hexane) and NH-form silica gel chromatography (AcOEt/hexane)
  14. customthe purified product was recrystallized (Et2O/pentane)

Sources & evidence

ORD record
ord-3efaf11e8353469bae796f9a5a7cc20c
Source dataset
uspto-grants-2015_11
Patent number
US09181229B2

Reaction notes

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