Potassium Carbonate → tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate

HRID 1530560Notes

Reaction equation

HRID 1530560 reaction equation
[CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][CH:14]=[C:15]([C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].CS(O[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([N:27]2[C:23]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11]3[N:21]([CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=3)[CH2:20][CH2:19][O:18]4)=[CH:24][CH:25]=[N:26]2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 683130694-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-(1H-pyrazol-5-yl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene

Product 1

HCID 68313074tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylateYield 7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-(1H-pyrazol-5-yl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.00 g, 2.77 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.95 g, 6.92 mmol), and K2CO3 (1.90 g, 13.8 mmol) in CH3CN (50.0 mL) was stirred at 100° C. for 60 hr. After removal of the solvents, the residue was treated with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated to afford the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient CH3CN in 0.5% NH4HCO3 and followed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 7% yield) as pale yellow solid. LCMS (ESI) m/z: 545.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 8.54 (d, J=10.5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.26, (dd, J=2.5 Hz, 10.5 Hz, 1H), 7.12 (s, 1H), 6.40 (s, 1H), 5.94-5.91 (m, 1H), 4.59-4.56 (m, 4H), 4.42 (s, 1H), 4.02-3.99 (m, 2H), 2.84-2.83 (m, 2H), 1.92-1.85 (m, 4H), 1.50 (s, 6H), 1.40 (s, 9H).

Workup

  1. customAfter removal of the solvents
  2. additionthe residue was treated with water
  3. extractionextracted with ethyl acetate
  4. washwashed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. customto afford the crude product, which
  9. customwas purified by reverse phase combiflash
  10. washeluting with 0-50% gradient CH3CN in 0.5% NH4HCO3
  11. customfollowed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min)

Sources & evidence

ORD record
ord-74aee4b9bb6c46d5bdb616ad122bd3c3
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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