Sodium Hydroxide → tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate

HRID 2362370Notes

Reaction equation

HRID 2362370 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.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:75][C:76]1[CH:81]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=2)[C:79]([F:91])=[CH:78][N:77]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:84]2[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=2)[OH:12])[C:79]([F:91])=[CH:78][N:77]=1

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 77922tert-Butyl carbamateHCID 521297Tert-Butyl hypochloriteHCID 112172021,4-Bis(dihydroquinidine)phthalazineHCID 86673417(E)-2-bromo-5-fluoro-4-(4-fluorostyryl)pyridine

Product 1

HCID 86673418tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamateYield 62.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 10311-PropanolSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl carbamate (189 mg, 1.612 mmol) in propanol (4 mL) was added sodium hydroxide (54.1 mg, 1.352 mmol) in water (2 mL) followed by tert-butyl hypochlorite (172 mg, 1.586 mmol). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (20.26 mg, 0.026 mmol) in propanol (1 mL). To this solution was added a solution of (E)-2-bromo-5-fluoro-4-(4-fluorostyryl)pyridine (154 mg, 0.520 mmol) in propanol (7 mL). To this solution was added potassium osmate dihydrate (7.66 mg, 0.021 mmol) dissolved in water (3 mL) in one portion. The reaction turned light orange and was allowed to stir at 0° C. overnight. The reaction was complete the next morning after warming to room temperature. The reaction was then 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-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (56 mg, 0.130 mmol, 62.7% yield) along with its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.09 min. Mass=431.05 (MH)+.

Workup

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

Sources & evidence

ORD record
ord-da9862c23e074e4d86c86bfeff7e4215
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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