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

HRID 1775475Notes

Reaction equation

HRID 1775475 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 86328910tert-butyl (S)-3-amino-3-methylpyrrolidine-1-carboxylateHCID 1184362924,6-Dichloro-2-(4-morpholinyl)-5-pyrimidineethanol

Product 1

HCID 118436528tert-butyl 3-{[6-chloro-5-(2-hydroxyethyl)-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-(S)-3-methylpyrrolidine-1-carboxylateYield 129.3%

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) (7.8 g, 28.0 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (Preparation 4) (8.4 g, 42.1 mmol) in NMP (58 mL) was added DIPEA (18.1 g, 140 mmol) at 15° C. and the resulting mixture was stirred at 130° C. for 60 h. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×5), dried over Na2SO4, filtered and concentrated to give 16 g of a brown gum. The crude product was purified by silica gel column chromatography eluting with a gradient of petroleum ether/EtOAc (20:1 to 8:1) to give the title compound (9.1 g, 73%) as a light yellow solid. m/z (APCI+) for C20H32N5O4Cl 442.0 [M+H]+.

Workup

  1. washwashed with water (100 mL)
  2. extractionThe aqueous layer was extracted with EtOAc (100 mL×2)
  3. washThe combined organic layers were washed with brine (100 mL×5)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-8ddce512c9f4455fa26ed99115ac86a3
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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