Cesium carbonate → HCID 86680518, compound

HRID 1184602Notes

Reaction equation

HRID 1184602 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][CH:22]3[CH2:31][N:25]4[CH2:26][CH2:27][NH:28][C:29](=[O:30])[CH:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([C:15]2[N:16]=[CH:17][C:18]([O:21][C@H:22]3[CH2:31][N:25]4[CH2:26][CH2:27][N:28]([C:2]5[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=5)[C:29](=[O:30])[C@@H:24]4[CH2:23]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27364342-Bromo-5-(trifluoromethyl)pyridineHCID 86680516HCID 86680516, compound

Product 1

HCID 86680518HCID 86680518, compoundYield 25.5%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
110 °C

Procedure

A 4 mL vial was charged with 2-bromo-5-(trifluoromethyl)pyridine (99 mg, 0.437 mmol), 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](100 mg, 0.365 mmol) from Example 163 Step 3, palladium(II) acetate (4.09 mg, 0.018 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS, 21.09 mg, 0.036 mmol), and cesium carbonate (178 mg, 0.547 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL) was added. The reaction mixture was purged with nitrogen again and was subsequently heated at 110° C. for 16 hours. The mixture was directly loaded and separated by flash chromatography [12 g cartridge, gradient 0-5% methanol/dichloromethane over 20 minutes] to give crude oily product. The crude product was further purified on 12 g cartridge eluted with 100% ethyl acetate over 20 minutes to give the title compound (39 mg, 0.093 mmol, 25.5% yield) as the first eluting diastereomer as a white foam. 1H NMR (500 MHz, CDCl3) δ ppm 8.71-8.63 (m, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.90 (dd, J=8.8, 2.3 Hz, 1H), 5.50 (dd, J=6.5, 5.0 Hz, 1H), 4.45 (ddd, J=5.2, 4.3, 2.5 Hz, 1H), 4.00 (d, J=7.1 Hz, 2H), 3.33 (dd, J=11.0, 5.2 Hz, 1H), 3.32-3.25 (m, 1H), 3.10 (ddd, J=12.2, 6.1, 4.1 Hz, 2H), 2.70-2.60 (m, 1H), 2.47 (dd, J=14.4, 8.0 Hz, 1H), 2.00 (tt, J=8.0, 5.1 Hz, 1H), 1.00-0.90 (m, 4H); MS (ESI+) m/z 420 (M+H)+.

Workup

  1. customThe mixture was purged with nitrogen, and anhydrous dioxane (0.5 mL)
  2. additionwas added
  3. customThe reaction mixture was purged with nitrogen again
  4. customseparated by flash chromatography [12 g cartridge, gradient 0-5% methanol/dichloromethane over 20 minutes]
  5. customto give crude oily product
  6. customThe crude product was further purified on 12 g cartridge
  7. washeluted with 100% ethyl acetate over 20 minutes

Sources & evidence

ORD record
ord-0bb7a7c970964daa98f4166f41ed723c
Source dataset
uspto-grants-2014_03
Patent number
US08669255B2

Reaction notes

Loading…