Leucinamide → N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-4-((S)-1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamide

HRID 2271399Notes

Reaction equation

HRID 2271399 reaction equation
[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([OH:27])=O)[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:32][C:30](=[O:31])[C@@H:29]([NH:28][C:25](=[O:27])[C:7]1[CH:6]=[C:5]([C@H:2]([OH:1])[CH2:3][OH:4])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]

Participants

6

Reactant 4

HCID 69640LeucinamideHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66668271(S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid

Product 1

HCID 56644318N-((S)-1-amino-4-methyl-1-oxopentan-2-yl)-4-((S)-1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-amino-4-methylpentanamide (0.074 g, 0.44 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.201 g, 0.53 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 25-75% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. The residue was triturated with 5 mL 50% EtOAc/hexanes, filtered and rinsed with additional 50% EtOAc/hexanes. The solid was dried under vacuum at 50° C. to yield N—((S)-1-amino-4-methyl-1-oxopentan-2-yl)-4-((S)-1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamide (compound 63) as an off-white powder (0.105 g, 0.22 mmol, 50% yield, LC/MS: m/z=482.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 8.64 (d, J=9.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 2H), 8.05 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.32-7.24 (m, 2H), 7.21-7.11 (m, 5H), 5.63 (d, J=4.8 Hz, 1H), 4.88-4.82 (m, 1H), 4.76-4.69 (m, 1H), 4.62-4.53 (m, 1H), 3.63-3.49 (m, 2H), 1.76-1.56 (m, 3H), 0.96-0.89 (m, 6H).

Workup

  1. customthen partitioned between 50 mL EtOAc and 50 mL brine
  2. dry with materialThe organics were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was chromatographed over silica gel eluting with 25-75% acetone in hexanes
  6. customThe product fractions were isolated
  7. customevaporated in vacuo
  8. customThe residue was triturated with 5 mL 50% EtOAc/hexanes
  9. filtrationfiltered
  10. washrinsed with additional 50% EtOAc/hexanes
  11. customThe solid was dried under vacuum at 50° C.

Sources & evidence

ORD record
ord-26ad8dd100074528bf49dfabf628fc0d
Source dataset
uspto-grants-2015_09
Patent number
US09120752B2

Reaction notes

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