1-Methyl-4-(pyrrolidin-2-yl)piperidine → 9-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-2-(1-(tetrahydrofuran-3-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530620Notes

Reaction equation

HRID 1530620 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:29][CH2:28]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][N:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:2]2[CH:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[N:20]([CH:21]6[CH2:25][CH2:24][O:23][CH2:22]6)[N:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:29][CH2:28]1

Participants

6

Reactant 3

HCID 45663131-Methyl-4-(pyrrolidin-2-yl)piperidineHCID 23676156Sodium t-butoxideHCID 6831305612-bromo-4-[1-(oxolan-3-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene

Product 1

HCID 665587609-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-2-(1-(tetrahydrofuran-3-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 163.4%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 12-bromo-4-[1-(oxolan-3-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (40 mg, 0.010 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (3.0 mg, 0.020 mmol), Pd(PtBu3)2 (1.0 mg, 0.0010 mmol), NaOtBu (2.9 mg, 0.030 mmol) in toluene (2.0 ml) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. The solid was filtered off and the filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to afford 232 (8.0 mg, 16% yield). LCMS (ESI): RT=3.39 min, m/z: 490.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.31 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 6.60 (d, J=9 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 4.54-4.52 (m, 4H), 4.29 (q, J=16 Hz, 1H), 4.16 (q, J=23 Hz, 1H), 4.03-4.01 (m, 1H), 3.97-3.95 (m, 1H), 3.86 (s, 1H), 3.55-3.53 (m, 1H), 3.24 (d, J=8 Hz, 1H), 2.98 (t, J=21 Hz, 2H), 2.56-2.48 (m, 2H), 2.29 (d, J=12 Hz, 3H), 2.04-1.93 (m, 5H), 1.78 (s, 1H), 1.69 (d, J=11.5 Hz, 1H), 1.53-1.44 (m, 3H)

Workup

  1. customwas degassed with N2 for three times
  2. filtrationThe solid was filtered off
  3. concentrationthe filtrate was concentrated
  4. customto give the crude product, which
  5. customwas purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min)

Sources & evidence

ORD record
ord-5920141c72a443219f22e1d5940be1d0
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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