2-(5-Methylisoxazol-3-yl)but-3-yn-2-ol → (5)-10-(3-Hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

HRID 575087Notes

Reaction equation

HRID 575087 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:3]=1.Br[C:13]1[CH:26]=[C:25]2[C:16]([O:17][CH2:18][CH2:19][N:20]3[C:24]2=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)=[CH:15][CH:14]=1>CS(C)=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][C@@:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:18][CH2:19][N:20]3[C:24](=[N:23][C:22]([C:27]([NH2:29])=[O:28])=[CH:21]3)[C:25]=2[CH:26]=1

Participants

6

Reactant 2

HCID 582217592-(5-Methylisoxazol-3-yl)but-3-yn-2-olHCID 6831288310-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Product 1

HCID 86693116(5)-10-(3-Hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 8471TriethylamineSolvent

Procedure

The title compound was prepared according to a procedure similar to that described in Procedure G Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (515 mg, 3.41 mmol, 3.50 equiv), 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (300 mg, 0.97 mmol, 1 equiv) and Pd(PPh3)2Cl2 (205 mg, 0.29 mmol, 0.3 equiv) in DMSO (2 mL) and triethylamine (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 70° C. The resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN. The solids were collected by filtration. The residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003; Phase A:MTBE Phase B:EtOH (0.2% DEA)-HPLC (10.0% EtOH for 60 min, then down to 0%); Detector, uv 254/220 nm. This resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z): 379[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.536 (s, 1H), 7.802 (s, 1H), 7.558 (br s, 1H), 7.340-7.300 (m, 1H), 7.143 (br s, 1H), 7.040 (d, 1H), 6.504 (s, 1H), 6.360 (s, 1H), 4.492 (s, 4H), 2.365 (s, 3H), 1.920 (s, 3H).

Workup

  1. customsealed tube
  2. custompurged
  3. temperaturemaintained with an inert atmosphere of nitrogen
  4. customThe final reaction mixture
  5. customwas irradiated with microwave radiation for 2 h at 70° C
  6. washThe resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN
  7. filtrationThe solids were collected by filtration
  8. customThe residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003
  9. customThis resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z)

Sources & evidence

ORD record
ord-613e6a877468461ca8672abf2787b4cb
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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