Diisopropylethylamine → (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol

HRID 57475

Reaction equation

HRID 57475 reaction equation
F[C:2]1[CH:7]=[C:6]([F:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=2)[CH3:11])[N:3]=1.[NH2:24][C@@H:25]([C@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:29])[CH2:26][OH:27].C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+]>[C:31]([O:30][C@H:28]([CH3:29])[C@H:25]([NH:24][C:2]1[CH:7]=[C:6]([F:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=2)[CH3:11])[N:3]=1)[CH2:26][OH:27])([CH3:34])([CH3:32])[CH3:33]

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 87698345(2R,3R)-2-amino-3-(tert-butoxy)butan-1-olHCID 90414038(S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine

Product 1

HCID 90416255(2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-olYield 50.4%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 5234Sodium ChlorideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (80 mg, 0.25 mmol), (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (55 mg, 0.28 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.63 mmol, 2.5 equiv) in DMSO (1.3 mL) was heated at 85° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (0.058 g, white solid) in 50% yield. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.61 (m, 2H), 7.13 (t, J=8.6 Hz, 2H), 5.35 (s, 1H), 5.30-5.14 (m, 2H), 5.04 (m, 1H), 3.94 (m, 1H), 3.77-3.65 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.21 (s, 9H), 1.15 (d, J=6.0 Hz, 3H). MS m/z 461.3 (M+H)+; Rt-0.88 min.

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted with ethyl acetate (20 mL)
  3. dry with materialThe combined organic extracts were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-017e1f87c813466585d0d3d9e2e4e694
Source dataset
uspto-grants-2016_09
Patent number
US09434719B2

Linked notes

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