1-Methyl-4-(pyrrolidin-2-yl)piperidine → 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530562Notes

Reaction equation

HRID 1530562 reaction equation
Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=2)=[CH:10]3)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]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>[CH:21]([N:20]1[C:16]([C:11]2[N:12]=[C:13]3[C:14]4[CH:15]=[C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:3]=[CH:4][C:5]=4[O:6][CH2:7][CH2:8][N:9]3[CH:10]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]

Participants

6

Reactant 3

HCID 45663131-Methyl-4-(pyrrolidin-2-yl)piperidineHCID 23676156Sodium t-butoxideHCID 5820501010-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Product 1

HCID 683129792-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 13-bromo-4-[1-(propan-2-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 (200 mg, 0.540 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (108 mg, 0.640 mmol), Pd(PtBu3)2 (7 mg, 0.015 mmol), NaOtBu (155 mg, 1.62 mmol) in toluene (2 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 through Celite. 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/10 mm/L NH4HCO3, 17 min) to afford 161. The (R) and (S) enantiomers were further purified and separated by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-Hexane isocratic) to give 6 mg of one enantiomer and 11 mg of the other (5% total yield)

Workup

  1. customwas degassed with N2 for three times
  2. filtrationThe solid was filtered off through Celite
  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/10 mm/L NH4HCO3, 17 min)

Sources & evidence

ORD record
ord-2e4aceb37dfb4201aabcfbaab6157373
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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