Diisopropylethylamine → HCID 57920147, compound

HRID 19416Notes

Reaction equation

HRID 19416 reaction equation
Cl.[NH2:2][CH:3]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:56][C:55]([O:57][C:58]4[C:63]([F:64])=[CH:62][CH:61]=[C:60]([O:65][CH2:66][CH3:67])[C:59]=4[F:68])=[CH:54][C:53]3=[O:69])CC(C)C)=N2)CO1>C(#N)C>[CH2:66]([O:65][C:60]1[C:59]([F:68])=[C:58]([C:63]([F:64])=[CH:62][CH:61]=1)[O:57][C:55]1[CH2:56][N:2]([CH:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:53](=[O:69])[CH:54]=1)[CH3:67]

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 44252606HCID 44252606, compoundHCID 675036222-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride

Product 1

HCID 57920147HCID 57920147, compoundYield 14%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

A suspension of 2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride salt (766 mg, 2.0 mmol) in acetonitrile (15 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and the resulting mixture stirred at 60° C. for 15 min. After this time N,N-diisopropylethylamine (0.5 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, 705 mg, 1.93 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 20 h. The resulting 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 anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (4 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 6 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (148 mg, 14%): HR-ES-MS (m/z) calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2520; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.07 (br. s., 3H), 1.13-1.31 (m, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.55-1.74 (m, 3H), 1.75-1.88 (m, 1H), 3.09-3.31 (m, 2H), 3.82 (br. s., 2H), 3.90 (s, 2H), 4.14 (q, J=6.9 Hz, 2H), 4.32 (d, J=18.6 Hz, 1H), 4.66 (br. s., 1H), 4.64 (d, J=18.6 Hz, 1H), 4.91 (dd, J=10.8, 4.4 Hz, 1H), 5.06 (s, 1H), 6.45 (d, J=1.8 Hz, 1H), 7.17 (td, J=9.4, 4.9 Hz, 1H), 7.27 (td, J=9.4, 1.3 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 10.81 (s, 1H).

Workup

  1. temperaturethe resulting solution refluxed for 20 h
  2. concentrationThe resulting 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 anhydrous sodium sulfate
  6. filtrationThe mixture was filtered
  7. concentrationconcentrated in vacuo
  8. dissolutionthe residue dissolved in tetrahydrofuran (4 mL)
  9. custommicrowaved at 160° C. for 6 h
  10. concentrationThe mixture was concentrated in vacuo
  11. customthe residue was purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which

Sources & evidence

ORD record
ord-3e4376d0404f443589d20438245d1255
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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