3-Amino-5-methylisoxazole → HCID 58236596, compound

HRID 409989Notes

Reaction equation

HRID 409989 reaction equation
[NH2:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:39])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:61][C:62]1[CH:66]=[C:65]([CH3:67])[O:64][N:63]=1>O1CCCC1>[F:39][C:4]1[CH:3]=[C:2]([NH:1][C:50]([NH:61][C:62]2[CH:66]=[C:65]([CH3:67])[O:64][N:63]=2)=[O:52])[CH:38]=[CH:37][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:22](=[O:24])[CH3:23])=[CH:35][CH:36]=3)[S:15][C:8]=12

Participants

6

Reactant 4

HCID 661723-Amino-5-methylisoxazoleHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 58236576HCID 58236576, compound

Product 1

HCID 58236596HCID 58236596, compoundYield 95.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 370 (0.14 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g, 0.61 mmol) in tetrahydrofuran (50 mL) at 0° C. was added triphosgene (0.030 g, 0.10 mmol) and the resulting solution was stirred for 0.5 h at 0° C. 3-Amino-5-methylisoxazole (0.074 g, 0.76 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h, then quenched with 1 mL of water and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic phase was collected, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (10% MeOH in EtOAc), followed by Gilson reverse phase HPLC (35-65% acetonitrile/H2O, Aquasil C18, 30 min) and lyophilized. The residue (containing some formic acid from the HPLC) was partitioned between dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give 371 (65 mg, 38% yield) as a 2:1 mixture of rotamers by 1H NMR. 1H NMR (DMSO-d6) δ (ppm) 1H: 9.64 (s, 1H); 9.19 (s, 1H); 8.50-8.48 (m, 1H); 8.04 (s, 0.4H); 8.01 (s, 0.6H); 7.89 (d, J=8.2, 0.4H); 7.82 (d, J=8.2, 0.6H); 7.72 (dd, J=12.9, 2.5, 1H); 7.45 (t, J=9.2, 1H); 7.33 (d, J=8.4, 2H); 7.27-7.24 (m, 1H); 6.61-6.59 (m, 1H); 6.54 (d, J=0.8, 1H); 4.68 (s, 0.4H); 4.59 (s, 0.6H); 3.52-3.38 (m, 12H); 3.21 (s, 1.8H); 3.20 (s, 1.2H); 2.35 (d, J=0.4, 3H); 2.12 (s, 1.8H); 2.00 (1.2H). LRMS (M+H): 678.8

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. stirringstirred for 3 h
  3. customquenched with 1 mL of water
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was partitioned between ethyl acetate and water
  6. customthe organic phase was collected
  7. washwashed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe product was purified by silica gel chromatography (10% MeOH in EtOAc)
  12. customfollowed by Gilson reverse phase HPLC (35-65% acetonitrile/H2O, Aquasil C18, 30 min)
  13. additionThe residue (containing some formic acid from the HPLC)
  14. customwas partitioned between dichloromethane and 1M NaOH
  15. dry with materialThe organic phase was dried (MgSO4)
  16. filtrationfiltered
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-dca5c126e60f4b26a30d0f28eb4d3b72
Source dataset
uspto-grants-2014_06
Patent number
US08759522B2

Reaction notes

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