Diisopropylethylamine → HCID 57920135, compound

HRID 19420Notes

Reaction equation

HRID 19420 reaction equation
Cl.[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:53][C:52]([O:54][C:55]4[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=4[F:65])=[CH:51][C:50]3=[O:66])CC(C)C)=N2)CO1>C(#N)C>[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([N:17]2[CH2:53][C:52]([O:54][C:55]3[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=3[F:65])=[CH:51][C:50]2=[O:66])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 44252606HCID 44252606, compoundHCID 66899584(S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride

Product 1

HCID 57920135HCID 57920135, compoundYield 16%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

A suspension of (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride salt (2.0 g, 5.8 mmol) in acetonitrile (25 mL) was treated with N,N-diisopropylethylamine (4.0 mL) and stirred at 60° C. for 15 min. At this time N,N-diisopropylethylamine (2.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 1.37 g, 3.75 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 48 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (295 mg, 16%): HR-ES-MS (m/z) calculated for C25H32F2N4O5 [M+H]+ 507.2414, observed 507.2414; 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (br. s., 6H), 1.13 (br. s., 6H), 1.42 (br. s., 3H), 1.48-1.64 (m, 1H), 1.66-1.95 (m, 2H), 3.73 (br. s., 1H), 3.91 (br. s., 2H), 4.01-4.24 (m, 3H), 4.38 (d, J=17.8 Hz, 1H), 4.88 (br. s., 1H), 4.99 (br. s., 1H), 6.66 (br. s., 1H), 6.73-7.00 (m, 2H), 7.27 (br. s., 1H), 8.79 (br. s., 1H).

Workup

  1. temperaturethe resulting solution refluxed for 48 h
  2. concentrationThe mixture was concentrated in vacuo
  3. customthe residue partitioned between ethyl acetate and water
  4. customThe layers were separated
  5. dry with materialthe organic layer was dried over sodium sulfate
  6. filtrationThe mixture was filtered
  7. concentrationconcentrated in vacuo
  8. customthe residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which

Sources & evidence

ORD record
ord-31ae88a5ba674494b06d73350f5f46b1
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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