1-[(Pyrrolidin-2-yl)methyl]piperidine → 9-(2-(Piperidin-1-ylmethyl)pyrrolidin-1-yl)-2-(pyridin-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine

HRID 1530510Notes

Reaction equation

HRID 1530510 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[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:28]1([CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][N:22]2[C:2]2[N:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1

Participants

4

Reactant 2

HCID 39738701-[(Pyrrolidin-2-yl)methyl]piperidineHCID 8667145812-Chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene

Product 1

HCID 683130709-(2-(Piperidin-1-ylmethyl)pyrrolidin-1-yl)-2-(pyridin-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

To a solution of 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (200 mg, 0.671 mmol) in NMP (10 mL) was added TEA (10 mL) and 1-(pyrrolidin-2-ylmethyl)piperidine (135 mg, 0.804 mmol). The reaction mixture was stirred at 160° C. for 24 h. After cooling to room temperature, the reaction mixture was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 129 which was further purified by chiral HPLC (AS-H column, 10% EtOH isocratic) to separate 15.9 mg of one enantiomer and 7 mg of the other (8% total yield). LCMS (ESI): RT=4.55 min, m/z: 431.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.50-8.49 (d, J=4.0 Hz, 1H), 7.97-7.95 (d, J=8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.95 (s, 1H), 4.49-4.44 (m, 4H), 4.17 (m, 1H), 3.46-3.44 (m, 1H), 3.28-3.25 (m, 1H), 2.54 (m, 1H), 2.45-2.33 (m, 3H), 2.21-2.16 (m, 1H), 2.01-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.53-1.50 (m, 4H), 1.39-1.38 (m, 2H)

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe reaction mixture was purified by Combi-flash
  3. washeluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3

Sources & evidence

ORD record
ord-90aa2a5b24d94317844f66a1d9b6419f
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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