Ethyl Acetate → HCID 69083834, compound

HRID 2362385Notes

Reaction equation

HRID 2362385 reaction equation
C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1)[C@@H:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])O)(C)(C)C.C(OC(=O)N[C@H](C1C=C(F)C=CC=1F)[C@@H](C1C=NC=C(Br)C=1)O)(C)(C)C.CC(C)([O-])C.[K+].C(OCC)(=O)C>O1CCCC1.O>[Br:25][C:23]1[CH:24]=[C:19]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:26][C:6](=[O:5])[NH:7]2)[CH:20]=[N:21][CH:22]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 23665647Potassium tert-butoxideHCID 69281970HCID 69281970, compoundHCID 69281971HCID 69281971, compound

Product 1

HCID 69083834HCID 69083834, compoundYield 42%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-7 °C

Procedure

A mixture of tert-butyl((1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl((1R,2R)-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6:1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to −7° C. with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert-butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature <3° C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29-7.23 (m, 1H), 7.18-7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for C14H9N2BrF2O2: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S,5S) enantiomer can be purged by recrystallization from methanol to give >99.9 ee with 67% recovery.

Workup

  1. temperaturewhile maintaining the internal temperature <3° C
  2. temperatureto warm up to room temperature
  3. waitAfter 20 h
  4. concentrationThe reaction mixture was concentrated to dryness
  5. customto give crude product
  6. customAnother identical scale reaction
  7. customThe layers were separated
  8. washThe organic layer was washed with brine (1.75 L)
  9. dry with materialdried (sodium sulfate)
  10. customevaporated

Sources & evidence

ORD record
ord-b019ed7a9d264b8485534a83b911d3d0
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

Loading…