Diisopropylethylamine → tert-butyl (S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoate

HRID 1775866Notes

Reaction equation

HRID 1775866 reaction equation
Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[C:27](O)=[O:28])=[CH:21][CH:20]=2)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30][C:31](=[O:42])[C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:36][CH:37]=3)[C:27]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:28])=[CH:21][CH:20]=2)=[N:15][CH:14]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 16218890Tert-butyl 3-aminopropanoate hydrochlorideHCID 89619605(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid

Product 1

HCID 117748659tert-butyl (S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoateYield 72.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Prepared using General Procedure 7. A stirring solution of β-alanine tert-butyl ester hydrochloride (4.9 g, 27.4 mmol), (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid (12.0 g, 24.9 mmol) and DIEA (11.1 mL, 62.0 mmol) in DMF (200 mL) was cooled to 0° C. A solution of HATU (9.9 g, 26.1 mmol) in DMF (75 mL) was added dropwise over 20 min. The reaction mixture was allowed to warm to room temperature over 2 h, then diluted with EA and washed with NaHCO3 (sat aq). The aqueous fraction was back-extracted with EA. The combined organic fractions were dried (Na2SO4) then concentrated onto celite and purified by column chromatography (EA/hexane) to provide 11 g (65%) of tert-butyl (S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanamido)propanoate INT-28. LCMS-ESI (m/z) calculated for C31H37BrN4O4; 609.6. found 610.2 [M+H]+, tR=3.99 min (Method 15), and 87.1% e.e. (Chiral Method, isocratic with 20% Solvent A, 80% Solvent B). 1H NMR (400 MHz, CDCl3) δ8.80 (s, 2H), 8.32 (t, J=6.5 Hz, 2H), 7.74-7.62 (m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 6.91 (d, J=7.7 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 4.93-4.81 (m, 1H), 3.52-3.34 (m, 2H), 3.34-3.14 (m, 2H), 2.46-2.24 (m, 2H), 1.34 (d, J=5.2 Hz, 9H), 1.31 (d, J=5.2 Hz, 9H).

Workup

  1. customPrepared
  2. washwashed with NaHCO3 (sat aq)
  3. extractionThe aqueous fraction was back-extracted with EA
  4. dry with materialThe combined organic fractions were dried (Na2SO4)
  5. concentrationthen concentrated onto celite
  6. custompurified by column chromatography (EA/hexane)

Sources & evidence

ORD record
ord-91417213744244d981ac95d3f3053278
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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