Water → Tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate

HRID 78716Notes

Reaction equation

HRID 78716 reaction equation
Br[C:2]1[N:3]=[C:4]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)O1.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:11]([O:10][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[N:3][C:4]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]

Participants

6

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 59472363tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamateHCID 86682773Tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate

Product 1

HCID 86682772Tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylateYield 109.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
65 °C

Procedure

tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (750 mg, 1.393 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (691.5 mg, 1.532 mmol) were suspended in MeCN (7.500 mL)/water (7.500 mL) and Na2CO3 (1.393 mL of 2 M, 2.786 mmol) was added. The reaction mixture was degassed with 3× nitrogen/vacuum cycles. Pd(tBu3P)2 (71.19 mg, 0.1393 mmol) was added and the reaction mixture again degassed 3 times then heated to 65° C. (Dry Syn Temp) for 1.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethylacetate/water. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 30% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate as a yellow solid (1.01 g, 93% Yield). H NMR (400.0 MHz, DMSO) δ 9.53 (s, 1H), 8.67 (d, 2H), 8.12 (d, 2H), 8.05-8.03 (m, 3H), 7.60-7.57 (m, 3H), 3.76 (br d, 1H), 3.47-3.41 (m, 1H), 3.02-2.95 (m, 1H), 2.81-2.77 (m, 1H), 2.09-2.04 (m, 1H), 1.77-1.63 (m, 2H) and 1.42-1.21 (m, 29H) ppm

Workup

  1. additionwas added
  2. customThe reaction mixture was degassed with 3× nitrogen/vacuum cycles
  3. customthe reaction mixture again degassed 3 times
  4. custom(Dry Syn Temp) for 1.5 hours
  5. temperatureThe reaction mixture was cooled to ambient temperature
  6. additiondiluted with ethylacetate/water
  7. extractionThe aqueous layer was extracted with ethylacetate (×1)
  8. washthe combined organic extracts washed with brine (×2)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 30% Petroleum/Petroleum Ether, loaded in DCM)

Sources & evidence

ORD record
ord-54db9fe7666f47708867f157cf84b132
Source dataset
uspto-grants-2014_09
Patent number
US08841449B2

Reaction notes

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