5-Bromo-2-methoxypyridine → HCID 118276731, compound

HRID 530645Notes

Reaction equation

HRID 530645 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])(C)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28](=[O:33])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][C@H:24]([C:28]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:33])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]

Participants

5

Reactant 3

HCID 27348955-Bromo-2-methoxypyridineHCID 591669901,1-Dimethylethyl (2S)-2-[(methoxymethylamino)carbonyl]-4-morpholinecarboxylateHCID 178418306HCID 178418306, compound

Product 1

HCID 118276731HCID 118276731, compoundYield 89.6%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
-75 °C

Procedure

5-Bromo-2-methoxypyridine (247 mg, 1.31 mmol) was dissolved in toluene (6 mL) and cooled to −75° C. t-Butyl lithium (0.77 mL of 1.7 M in pentane, 1.3 mmol) was added dropwise. Stirring was continued at the same temperature for 15 min and then in an ice bath for 5 min. The reaction was cooled to −75° C. and a solution of (S)-2-(methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (300 mg, 1.09 mmol) in toluene (3 mL) was added dropwise over 5 min. The reaction was stirred at 0° C. for 1.25 h and then poured onto water. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (1:1 EtOAc/heptane eluent) to afford (S)-2-(6-methoxy-pyridine-3-carbonyl)-morpholine-4-carboxylic acid tert-butyl ester (315 mg, 89%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.97-3.25 (m, 2H) 3.63-3.76 (m, 1H) 3.85-3.97 (m, 1H) 4.02 (s and overlapping m, 4H) 4.10-4.32 (m, 1H) 4.50-4.66 (m, 1H) 6.80 (dd, J=8.87, 0.54 Hz, 1H) 8.17 (dd, J=8.87, 2.42 Hz, 1H) 8.91 (d, J=2.42 Hz, 1H).

Workup

  1. additionwas added dropwise
  2. waitin an ice bath for 5 min
  3. stirringThe reaction was stirred at 0° C. for 1.25 h
  4. additionpoured onto water
  5. extractionThe mixture was extracted 3 times with ethyl acetate
  6. washThe combined organic phase was washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe crude product was purified by flash chromatography (1:1 EtOAc/heptane eluent)

Sources & evidence

ORD record
ord-c87b112245a04a5e97d3ba30e85edb5e
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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