4-tert-Butylbenzoic acid → (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid

HRID 716409Notes

Reaction equation

HRID 716409 reaction equation
[NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].C(N(C(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.O>[C:37]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([NH:1][C@@H:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=4)=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:47])=[CH:48][CH:49]=1)([CH3:38])([CH3:39])[CH3:40]

Participants

7

Reactant 4

HCID 74034-tert-Butylbenzoic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86689672(S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate

Product 1

HCID 86582069(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acidYield 85%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A stirred solution of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9 (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g, 3.01 mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine (1.01 ml, 5.47 mmol) was treated with HATU (1.09 g, 2.87 mmol). After stirring for 1 h, the mixture was treated with water (60 mL) and iso-hexanes (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×10 mL) then iso-hexanes (10 mL) and dried in the vacuum oven. The ester was taken up in DCM (5 mL) and treated with TFA (5 mL). After 2 h, the mixture was treated with toluene (5 mL) and evaporated. The residue was taken up in DMSO (6 mL) then treated with water (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×15 mL) then acetonitrile (2×5 mL), and dried in the vacuum oven to give 1.40 g (85%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 as a white solid. LCMS-ESI (m/z) calculated for C37H43N3O4: 593.3. found: 594.0 [M+H]+, tR=11.18 min (Method 9) and 97% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br, s, 1H), 9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H), 8.45-8.27 (m, 2H), 7.89-7.69 (m, 4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m, 2H), 4.77-4.62 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.30-3.24 (m, 1H), 3.22-3.12 (m, 1H), 1.80-1.68 (m, 2H), 1.48-1.20 (m, 17H), 0.96-0.82 (m, 3H).

Workup

  1. stirringstirred for 1 h
  2. filtrationThe product was collected by filtration
  3. washwashed with water (3×10 mL)
  4. dry with materialiso-hexanes (10 mL) and dried in the vacuum oven
  5. additiontreated with TFA (5 mL)
  6. waitAfter 2 h
  7. additionthe mixture was treated with toluene (5 mL)
  8. customevaporated
  9. additionthen treated with water (20 mL)
  10. stirringstirred for 1 h
  11. filtrationThe product was collected by filtration
  12. washwashed with water (3×15 mL)
  13. dry with materialacetonitrile (2×5 mL), and dried in the vacuum oven

Sources & evidence

ORD record
ord-1c4ff07eccbc43e3aee0d6b7f330e876
Source dataset
uspto-grants-2015_11
Patent number
US09187522B2

Reaction notes

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