2-(Pyridin-2-yl)but-3-yn-2-ol → (+/-)-8-Fluoro-9-(3-hydroxy-3-(pyridin-2-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide

HRID 575089Notes

Reaction equation

HRID 575089 reaction equation
Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CS(C)=O.C(N(CC)CC)C.C(OCC)(=O)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>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1

Participants

7

Reactant 2

HCID 167625022-(Pyridin-2-yl)but-3-yn-2-olHCID 866930599-Bromo-8-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide

Product 1

HCID 86693118(+/-)-8-Fluoro-9-(3-hydroxy-3-(pyridin-2-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

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 a suspension 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 2-(pyridin-2-yl)but-3-yn-2-ol (300 mg, 2.04 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (200 mg, 0.28 mmol, 0.50 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 3 h at 70° C. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×25 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters)): Column, XSelect Prep C18; mobile phase, water with 0.05% NH3H2O and CH3CN (23% CH3CN up to 63% in 10 min, hold 3 min); Detector, uv 254/220 nm. This resulted in 18 mg (7%) of 8-Fluoro-9-(3-hydroxy-3-pyridin-2-yl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid. LC-MS (ES, m/z): 410[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm) δ 8.657 (d, 1H), 8.574 (d, 1H), 8.482 (s, 1H), 7.884 (m, 2H), 7.792 (d, 1H), 7.352 (m, 1H), 7.020 (d, 1H), 6.383 (s, 1H), 4.386 (t, 2H), 3.408 (t, 2H), 1.841 (s, 3H).

Workup

  1. customInto a 8-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 3 h at 70° C
  6. washThe resulting mixture was washed with 3×25 mL of water
  7. dry with materialThe mixture was dried over sodium sulfate
  8. concentrationconcentrated under vacuum
  9. customThe residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-016(Waters))
  10. waithold 3 min
  11. customThis resulted in 18 mg (7%) of 8-Fluoro-9-(3-hydroxy-3-pyridin-2-yl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a light yellow solid

Sources & evidence

ORD record
ord-b8137d7907604af8bc06a013a114c7ae
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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