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Water → tert-butyl 3-({6-chloro-5-(2-hydroxyethyl)-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl}amino)azetidine-1-carboxylate

HRID 1775460
Notes
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Reaction equation

HRID 1775460 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][C@@H:13]2[CH3:18])[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=[C:2]([NH:30][CH:28]2[CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:29]2)[C:7]=1[CH2:8][CH2:9][OH:10]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 1516507Tert-butyl 3-aminoazetidine-1-carboxylateHCID 1184366042-{4,6-dichloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-5-yl}ethanol

Product 1

HCID 118436480tert-butyl 3-({6-chloro-5-(2-hydroxyethyl)-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl}amino)azetidine-1-carboxylateYield 86.2%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
75 °C

Procedure

A solution of 2-{4,6-dichloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-5-yl}ethanol (as prepared in Preparation 2)(0.652 g, 2.23 mmol) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.9 mmol) in DMSO (10.0 mL) was treated with DIPEA (0.7 mL, 4 mmol) and heated at 75° C. for 5 days in a sealed tube. The mixture was poured into a flask containing water and the resulting solids were collected by filtration and rinsed with water. The solids were taken up in DCM, dried over MgSO4 and filtered. The filtrate was purified directly by silica gel chromatography using a gradient of 25-100% EtOAc/heptane as eluent to give 0.823 g (86%) of the title compound as a crisp foam. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=5.6 Hz, 1 H), 4.71 (t, J=5.2 Hz, 1 H), 4.62-4.53 (m, 1 H), 4.47-4.40 (m, 1 H), 4.13-4.04 (m, 3 H), 3.89-3.78 (m, 3 H), 3.66 (d, J=11.4 Hz, 1 H), 3.55-3.44 (m, 3 H), 3.36 (dt, J=11.7, 2.9 Hz, 1 H), 3.04 (dt, J=12.9, 3.7 Hz, 1 H), 2.69 (t, J=6.9 Hz, 2 H), 1.39 (s, 9 H), 1.14 (d, J=6.7 Hz, 3 H).

Workup

  1. additionThe mixture was poured into a flask
  2. filtrationthe resulting solids were collected by filtration
  3. washrinsed with water
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customThe filtrate was purified directly by silica gel chromatography

Sources & evidence

ORD record
ord-f6ebe5c077ec4049b1c1b8e4b8528261
Source dataset
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09260439B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes