Hydrochloric Acid → (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride

HRID 19009

Reaction equation

HRID 19009 reaction equation
[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[NH2:33].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:33][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[O:13])[C:7](=[O:21])[CH:6]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 78747AminopyrazineHCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 66893500(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid

Product 1

HCID 44251873(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochlorideYield 33%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 200 mg, 0.52 mmol) in dichloromethane (5 mL) was treated with pyrazin-2-ylamine (65 mg, 0.68 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 mmol). The reaction mixture was stirred for 4 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 100% ethyl acetate/hexanes) to give a waxy material. This material was dissolved in dichloromethane (2 mL). The clear solution was treated with hydrogen chloride in diethyl ether (1M, 4 mL) and solvents were evaporated. The residue was triturated with diethyl ether and filtered to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride (28 mg, 33%) as a orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.37 (m, 6H) 1.43-1.95 (m, 7H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.02-5.12 (m, 1H) 7.36-7.57 (m, 3H) 8.38 (d, J=2.4 Hz, 1H) 8.40-8.47 (m, 1H) 9.27 (d, J=1.2 Hz, 1H) 11.20 (s, 1H). HR-ES-MS m/z calculated for C23H24ClFN4O3 459.1594, observed 459.1593 [M+H]+.

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 100% ethyl acetate/hexanes)
  5. customto give a waxy material
  6. customwere evaporated
  7. customThe residue was triturated with diethyl ether
  8. filtrationfiltered

Sources & evidence

ORD record
ord-740c58233cc64e52b71a49e6f4a7df9b
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

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