Diisopropylethylamine → Tert-butyl 3-{[6-chloro-5-(2-hydroxyethyl)-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylate

HRID 1775465Notes

Reaction equation

HRID 1775465 reaction equation
Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([NH:18][C:19]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:7]=1[CH2:8][CH2:9][OH:10]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 57415917tert-Butyl 3-amino-3-methylpyrrolidine-1-carboxylateHCID 1184362924,6-Dichloro-2-(4-morpholinyl)-5-pyrimidineethanol

Product 1

HCID 118436089Tert-butyl 3-{[6-chloro-5-(2-hydroxyethyl)-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylateYield 80%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1)(3.47 g, 12.5 mmol) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (racemic from a commercial source or Preparation 3 for a chirally pure enantiomer) (5.00 g, 24.97 mmol) in NMP (40 mL) was added DIPEA (8.07 g, 62.44 mmol) at 10° C. The resulting mixture was stirred at 130° C. for 30 h. The mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (1:1) to give the title compound (4.40 g, 80%) as a light yellow gum. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 6.48 (s, 1 H), 4.76 (t, J=5.0 Hz, 1 H), 3.76 (d, J=11.1 Hz, 1 H), 3.68-3.53 (m, 10 H), 3.45-3.28 (m, 3 H), 2.69 (t, J=6.24 Hz, 2 H), 2.35-2.26 (m, 1 H), 2.01-1.92 (m, 1 H), 1.49 (s, 3 H), 1.40 (s, 9 H). m/z (APCI+) for C20H32ClN5O4 442.2 (M+H)+.

Workup

  1. washwashed with brine (20 mL×3)
  2. dry with materialThe organic layer was dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customto give a residue, which
  6. customwas purified by silica gel chromatography
  7. washeluting with petroleum ether/EtOAc (1:1)

Sources & evidence

ORD record
ord-e31acf3d090d40f88cfedbcef7e1a121
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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