Triethylamine → tert-Butyl (2R,5S)-2-[(3-amino-5-fluoropyridin-4-yl)ethynyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate

HRID 629735Notes

Reaction equation

HRID 629735 reaction equation
[C:1]([C@H:3]1[O:8][CH2:7][C@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)#[CH:2].[F:25][C:26]1[C:27](I)=[C:28]([NH2:32])[CH:29]=[N:30][CH:31]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:28]1[CH:29]=[N:30][CH:31]=[C:26]([F:25])[C:27]=1[C:2]#[C:1][C@H:3]1[O:8][CH2:7][C@@H:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 867263335-Fluoro-4-iodopyridin-3-amineHCID 131735383tert-butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate

Product 1

HCID 86726336tert-Butyl (2R,5S)-2-[(3-amino-5-fluoropyridin-4-yl)ethynyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylateYield 166.9%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalyst

Procedure

tert-Butyl (2R,5R)-2-ethynyl-5-(tert-butyldimethylsilyloxy-methyl)morpholine-4-carboxylate (2.75 g, 7.73 mmol), 5-fluoro-4-iodopyridin-3-amine (1.84 g, 7.73 mmol), bis(triphenylphosphine)palladium(II) chloride (0.380 g, 0.541 mmol), triethylamine (32.3 mL, 232 mmol), and copper(I) iodide (0.147 g, 0.773 mmol) were heated at 70° C. for 2 hours. The reaction was quenched with saturated aqueous KH2PO4 and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (330 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (2.20 g, 12.9 mmol, 42% yield) as a viscous oil, MS (ESI): m/z=466.45 (MH+); 68% pure by LCMS, remainder is un-reacted 5-fluoro-4-iodopyridin-3-amine, taken onto next reaction as mixture.

Workup

  1. customThe reaction was quenched with saturated aqueous KH2PO4
  2. extractionthe mixture was extracted with ethyl acetate (×3)
  3. dry with materialThe combined organic fractions were dried (MgSO4)
  4. filtrationfiltered
  5. customthe solvent was evaporated under reduced pressure
  6. customPurification on silica gel (330 g)
  7. washeluting with a gradient of 0-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-d5392badedfb4fe2b73c3dc5cd8b65af
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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