Diisopropylethylamine → 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester

HRID 18982Notes

Reaction equation

HRID 18982 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62][CH:61]=1>ClCCl>[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:62][CH:61]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 66894519(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

Product 1

HCID 442517336-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl esterYield 20%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (as prepared in Example 45, 200 mg, 0.62 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (345 mg, 0.74 mmol), N,N-diisopropylethylamine (240 mg, 1.85 mmol) and 6-aminonicotinic acid methyl ester (115 mg, 0.74 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester (57 mg, 20%) as a light yellow solid: LR-ES-MS m/z calculated for C23H23F2N3O5 [M]+ 459, observed [M+H]+ 460; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H) 0.94 (d, J=6.9 Hz, 3H) 1.39-1.74 (m, 2H) 1.73-1.92 (m, 1H) 3.86 (s, 3H) 4.32 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.95-5.05 (m, 1H) 5.06 (s, 1H) 7.25-7.53 (m, 3H) 8.17 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.34 (s, 1H).

Workup

  1. washwashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
  2. dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-250938e950cb405f80818e488952d7eb
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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