Ethyl Acetate → tert-butyl(3S)-3-{[6-chloro-5-(2-hydroxyethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylate

HRID 1775490Notes

Reaction equation

HRID 1775490 reaction equation
Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[NH2:14][C@@:15]1([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH3:13])[N:3]=[C:2]([NH:14][C@@:15]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:7]=1[CH2:8][CH2:9][OH:10]

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 86328910tert-butyl (S)-3-amino-3-methylpyrrolidine-1-carboxylateHCID 1184361184,6-Dichloro-2-(methylthio)-5-pyrimidineethanol

Product 1

HCID 118436348tert-butyl(3S)-3-{[6-chloro-5-(2-hydroxyethyl)-2-(methylsulfanyl)pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylateYield 65%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (1.25 g, 5.23 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (1.57 g, 7.84 mmol) in DMSO (13 mL) was added DIEA (4.6 mL, 26.1 mmol) at room temperature. The reaction mixture was stirred at 110° C. for 42 h, whereupon the mixture was poured into EtOAc and washed with water. The water layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via ISCO normal phase silica gel chromatography (80 g column) eluting with a 0-100% gradient of EtOAc/Heptane to give the title compound (1.37 g, 65%) as a light yellow-white foamy solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J=17.0 Hz, 1 H), 5.06 (br s, 1 H), 3.75 (dd, J=20.6, 11.2 Hz, 1 H), 3.54 (br s, 2 H), 3.50-3.33 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.44 (s, 3 H), 2.40-2.23 (m, 1 H), 2.03-1.93 (m, 1 H), 1.47 (d, J=11.1 Hz, 3 H), 1.38 (d, J=13.4 Hz, 9 H). m/z (APCI+) for C17H27ClN4O3S 403.9 (M+H)+.

Workup

  1. washwashed with water
  2. extractionThe water layer was extracted with EtOAc (3 times)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified via ISCO normal phase silica gel chromatography (80 g column)
  8. washeluting with a 0-100% gradient of EtOAc/Heptane

Sources & evidence

ORD record
ord-1d00e76304f44a10b56cf2471b4d47e8
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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