9-Bromo-8-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide → (+/-)-8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide

HRID 575084Notes

Reaction equation

HRID 575084 reaction equation
Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][C:9]3[S:10][C:11]([C:16]([NH2:18])=[O:17])=[N:12][C:13]=32)=[CH:4][C:3]=1[F:19].[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>CS(C)=O.C(N(CC)CC)C.O>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[S:10][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=1

Participants

6

Reactant 2

HCID 866930599-Bromo-8-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamideHCID 866931131-Fluoro-2-methylbut-3-yn-2-ol

Product 1

HCID 71715339(+/-)-8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8471TriethylamineSolvent

Procedure

The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 13-bromo-12-fluoro-9-oxa-5-thia-3-azatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2(6),3,10,12-pentaene-4-carboxamide (200 mg, 0.58 mmol, 1.00 equiv), 1-fluoro-2-methylbut-3-yn-2-ol (360 mg, 1.76 mmol, 3.00 equiv) and Pd(PPh3)Cl2 (82 mg, 0.20 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (10:1). This resulted in 0.06 g (28%) of 8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide. LC-MS: (ES, m/z): 365[M+H]+; 1H-NMR: (400 MHz, CD3OD, ppm) δ 8.708 (d, 1H), 6.857 (d, 1H), 4.427 (t, 2H), 4.410 (d, 2H), 3.442 (t, 2H), 1.601 (s, 3H).

Workup

  1. customInto a 10-mL sealed tube
  2. custompurged
  3. temperaturemaintained with an inert atmosphere of nitrogen
  4. customThe final reaction mixture
  5. customwas irradiated with microwave radiation for 1 h at 70° C
  6. extractionThe resulting solution was extracted with 3×15 mL of dichloromethane
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under vacuum
  9. customThis resulted in 0.06 g (28%) of 8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide

Sources & evidence

ORD record
ord-855854d108cb4c54a84f1099ea32d084
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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