Sodium Hydroxide → tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate

HRID 2362362Notes

Reaction equation

HRID 2362362 reaction equation
[C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:21]([F:24])=[N:22][CH:23]=1>C(O)CC.O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[Br:17][C:18]1[CH:19]=[C:20]([C@@H:25]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:12])[C:21]([F:24])=[N:22][CH:23]=1

Participants

8

Reactant 4

HCID 14798Sodium HydroxideHCID 77922tert-Butyl carbamateHCID 521297Tert-Butyl hypochloriteHCID 69082804(E)-5-Bromo-2-fluoro-3-(3-fluorostyryl)pyridine

Product 1

HCID 70958019tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamateYield 52%

Reagents, catalysts & solvents 3

HCID 112172021,4-Bis(dihydroquinidine)phthalazineCatalystHCID 962WaterSolventHCID 10311-PropanolSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl carbamate (363 mg, 3.10 mmol) in propanol (10 mL) was added sodium hydroxide (122 mg, 3.05 mmol) in water (4 mL) followed by tert-butyl hypochlorite (331 mg, 3.05 mmol). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (38.9 mg, 0.050 mmol) in propanol (4 mL). To this solution was added a solution of (E)-5-bromo-2-fluoro-3-(3-fluorostyryl)pyridine (296 mg, 1.0 mmol) in propanol (10 mL). To this solution was added potassium osmate dihydrate (14.73 mg, 0.040 mmol) in one portion. The reaction turned light orange and was allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with a 10% solution of sodium thiosulfate and stirred for 30 min. The reaction was then extracted with diethylether (3×). The combined organic extracts were combined washed with water, then brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography 25% EtOAc/75% Hexanes to 50%/50% EtOAc/Hexanes to afford tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate (223 mg, 0.520 mmol, 52.0% yield) along with its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.11 min. Mass=453.14 (MNa)+.

Workup

  1. customThe ice bath was then removed
  2. temperatureto warm to room temperature
  3. stirringstirred overnight
  4. customThe reaction was quenched with a 10% solution of sodium thiosulfate
  5. stirringstirred for 30 min
  6. extractionThe reaction was then extracted with diethylether (3×)
  7. washThe combined organic extracts were combined washed with water
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. customevaporated in vacuo
  11. customThe crude residue was purified by silica gel chromatography 25% EtOAc/75% Hexanes to 50%/50% EtOAc/Hexanes

Sources & evidence

ORD record
ord-7d17f74cfdc54f0bb267451b3439fa9c
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

Loading…