Diisopropylethylamine → 6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}--nicotinic acid methyl ester

HRID 19011Notes

Reaction equation

HRID 19011 reaction equation
[Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:33]([F:36])=[CH:34][CH:35]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]([NH:14]C2C=CN(CC(O)(C)C)N=2)=[O:13])[C:8](=[O:32])[CH:7]=1.[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44](N)=[N:43][CH:42]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([NH:14][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]([O:5][C:4]3[C:33]([F:36])=[CH:34][CH:35]=[C:2]([Cl:1])[C:3]=3[F:37])=[CH:7][C:8]2=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:43][CH:42]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 44251878(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

Product 1

HCID 442518796-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}--nicotinic acid methyl esterYield 24%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 510 mg, 1.28 mmol) in dichloromethane (20 mL) was treated with 6-amino-nicotinic acid methyl ester (252 mg, 1.67 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (1.20 g, 2.57 mmol) and N,N-diisopropylethylamine (438 mg, 2.52 mmol). The reaction mixture was stirred for 5 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium 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 50% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (160 mg, 24%) as a tan solid: HR-ES-MS m/z calculated for C26H26ClF2N3O5 [M+H]+ 534.1602, observed 534.1606; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.36 (m, 6H) 1.37-1.93 (m, 7H) 3.86 (s, 3H) 4.33 (d, J=18.5 Hz, 1H) 4.64 (d, J=18.5 Hz, 1H) 5.04 (dd, J=11.3, 5.0 Hz, 1H) 5.27 (s, 1H) 7.45 (td, J=9.5, 2.1 Hz, 1H) 7.68 (ddd, J=9.5, 8.1, 5.6 Hz, 1H) 8.13-8.19 (m, 1H) 8.29 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (dd, J=2.4, 0.8 Hz, 1H) 11.32 (s, 1H).

Workup

  1. washwashed with saturated ammonium chloride, water
  2. dry with materiala saturated sodium chloride solution and dried over sodium 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 50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-470ea19d043f4565a34628d01b5db2a2
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

Loading…