Diisopropylethylamine → tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate

HRID 1473109Notes

Reaction equation

HRID 1473109 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36](O)=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[NH4+].[NH4+].C[N:50](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O.O>[NH2:50][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:19][CH:18]=2)[N:26]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 517111Ammonium CarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682828512-(2-(2-(2-((4-(4-(tert-Butoxycarbonyl)morpholin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid

Product 1

HCID 86675724tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylateYield 60.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

2-(2-(2-(2-((4-(4-(tert-Butoxycarbonyl)morpholin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I90) (39 mg, 0.066 mmol) was dissolved in DMF (3 mL) and ammonium carbonate (38 mg, 0.40 mmol), HATU (28 mg, 0.073 mmol) and DIPEA (0.046 mL, 0.27 mmol) were added. The yellow mixture was stirred at room temperature for 18 hours then added to water (30 mL) and brine (10 mL). The mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate phases washed with brine (50 mL), dried over sodium sulfate and evaporated. The residue was chromotographed (4 g deactivated* silica cartridge, 0-100% 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I91) (23.3 mg, 60% yield) as a colourless glass; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.78 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.31-7.19 (m, 5H, overlaps with CHCl3), 5.58 (s, 1H), 5.42 (s, 1H), 4.40 (d, J=8.5 Hz, 1H), 4.08-3.84 (m, 3H), 3.74-3.63 (m, 3H), 3.16-3.00 (m, 5H), 2.85 (s, 1H), 1.48 (s, 9H). LCMS Method C: rt 6.29 min; m/z 586.1 [M+H]+, 530.1 [M−tBu+2H]+, 608.1 [M+Na]+; m/z 584.1 [M−H]−.

Workup

  1. extractionThe mixture was extracted with ethyl acetate (3×30 mL)
  2. washthe combined ethyl acetate phases washed with brine (50 mL)
  3. dry with materialdried over sodium sulfate
  4. customevaporated
  5. custom(4 g deactivated* silica cartridge, 0-100% 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-b3261c75058a44c880472deaecf2b959
Source dataset
uspto-grants-2015_04
Patent number
US09012461B2

Reaction notes

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