5-Tert-butylthiophene-2-carboxylic acid → tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl) pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate

HRID 1775853Notes

Reaction equation

HRID 1775853 reaction equation
[NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])=[O:4].[C:42]([C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43].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>[C:42]([C:46]1[S:50][C:49]([C:51]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:7])=[O:4])=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]

Participants

6

Reactant 3

HCID 4583495-Tert-butylthiophene-2-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 117748653tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate

Product 1

HCID 117748654tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl) pyrimidin-2-yl)phenyl)propanoyl)-D-alaninateYield 70.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Prepared using General Procedure 7. To a stirred solution of tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (418 mg, 0.75 mmol), 5-(tert-butyl)thiophene-2-carboxylic acid (137 mg, 0.75 mmol) in DMF (8 mL) was added TEA (208 μl, 1.49 mmol). The mixture was cooled to 0° C. and HATU (298 mg, 0.78 mmol) was added in 2 portions over 5 mins. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (150 mL) and washed with saturated aqueous NaHCO3 (100 mL), 1N HCl (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 then concentrated. The crude product was purified by chromatography 0-30% ACN in DCM to afford 382 mg (69%) of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate as a white solid. LCMS-ESI (m/z) calculated for C42H54N4O5S: 726.4; no m/z observed, tR=3.47 min (Method 11).

Workup

  1. customPrepared
  2. washwashed with saturated aqueous NaHCO3 (100 mL), 1N HCl (100 mL), and brine (100 mL)
  3. dry with materialThe organic layer was dried over MgSO4
  4. concentrationthen concentrated
  5. customThe crude product was purified by chromatography 0-30% ACN in DCM

Sources & evidence

ORD record
ord-41ef63760d67496982711ebd9c31c7d8
Source dataset
uspto-grants-2016_02
Patent number
US09260427B2

Reaction notes

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