Triethylamine → Tert-butyl 2-(4-bromo-3-fluorophenyl)morpholine-4-carboxylate

HRID 571808Notes

Reaction equation

HRID 571808 reaction equation
[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=1)[OH:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:7]1[CH2:8][CH2:9][O:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([F:21])[CH:15]=2)[CH2:11]1)=[O:22])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 68325535(RS)-[2-(4-bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester

Product 1

HCID 68325716Tert-butyl 2-(4-bromo-3-fluorophenyl)morpholine-4-carboxylateYield 47%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of (RS)-[2-(4-bromo-3-fluoro-phenyl)-2-hydroxy-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (3.88 g) and triethylamine (1.71 ml) in THF (40 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (873 μl). The reaction mixture was then stirred at room temperature for 30 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (6 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (9.05 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 1 hour and then poured into water and extracted twice with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.73 g, 47%) as an orange viscous oil. MS (ISP): 306.1 ([{81Br}M+H—C4H8]+), 304.1 ([{79Br}M+H—C4H8]+), 262.0 ([{81Br}M+H—C4H8—CO2]+), 260.1 ([{79Br}M+H—C4H8—CO2]+).

Workup

  1. customto afford a white suspension
  2. filtrationThe reaction mixture was then filtered
  3. customto remove triethylamine hydrochloride
  4. washwashing the
  5. filtrationfilter with THF (6 ml)
  6. temperatureThe filtrate was cooled to 0-5° C.
  7. additionpotassium 2-methyl-2-butoxide (9.05 ml, 1.7 M solution in toluene) was added
  8. stirringThe reaction mixture was stirred at room temperature for 1 hour
  9. additionpoured into water
  10. extractionextracted twice with EtOAc
  11. dry with materialThe combined organic phases were dried over Na2SO4
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-9aeb2bb1b7194fb5a9e466fd9dd80646
Source dataset
uspto-grants-2015_05
Patent number
US09029370B2

Reaction notes

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