1-Methyl-4-(pyrrolidin-2-yl)piperidine → 2-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine

HRID 1530644Notes

Reaction equation

HRID 1530644 reaction equation
Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]([CH3:26])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[CH2:30][CH2:29]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:26][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=1

Participants

6

Reactant 3

HCID 45663131-Methyl-4-(pyrrolidin-2-yl)piperidineHCID 23676156Sodium t-butoxideHCID 866523128-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene

Product 1

HCID 683131332-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepineYield 12%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 12-chloro-4-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (50.0 mg, 0.130 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (30.0 mg, 0.178 mmol), Pd(P-t-Bu3)2 (6.00 mg, 0.0120 mmol), and NaOt-Bu (40.0 mg, 0.412 mmol) in toluene (20.0 mL) in a seal tube was stirred at 110° C. for 3 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3 to afford 253 (8 mg, 12% yield) as white solid. LCMS (ESI): RT=4.70 min, m/z: 517.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.66 (s, 1H), 5.85 (s, 1H), 5.70 (dd, J=8.5 Hz, J=23.5 Hz, 2H), 4.46-4.43 (m, 4H), 4.06 (s, 1H), 3.38 (s, 1H), 3.26 (s, 1H), 2.09 (s, 3H), 1.95 (s, 9H), 1.84-1.72 (m, 2H), 1.52-1.34 (m, 3H), 1.19-1.12 (m, 2H)

Workup

  1. concentrationAfter concentration
  2. customthe residue was purified by reverse phase Combiflash
  3. washeluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3

Sources & evidence

ORD record
ord-a39e1d2df09845279be6a4b27a4511b1
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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