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

HRID 1530499Notes

Reaction equation

HRID 1530499 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.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CN1C(=O)CCC1>[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[N:15]=[CH:14][C:13]2[C:12]3[N:8]([CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:11]=3)[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1

Participants

4

Reactant 2

HCID 50165561-Methyl-2-(pyrrolidin-2-yl)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 665583289-((S)-2-((S)-1-methylpiperidin-2-yl)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
150 °C

Procedure

A mixture 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 (300 mg, 1.00 mmol), TEA (0.5 mL), and 1-methyl-2-(pyrrolidin-2-yl)piperidine (507 mg, 3.01 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. After cooling down, the resultant mixture was purified directly by reverse phase Combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to give diastereomeric 111: 15 mg of diasteromer A and 12 mg diasteromer B (48% total yield). Diasteromer A: LCMS (ESI): RT=4.48 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.83-7.79 (m, 2H), 7.22-7.19 (m, 1H), 6.05 (s, 1H), 4.52-4.45 (m, 4H), 4.11 (s, 1H), 3.45-3.34 (m, 2H), 2.78 (s, 1H), 2.17 (s, 3H), 2.11-2.01 (m, 2H), 1.95-1.85 (m, 4H), 1.70 (s, 1H), 1.50-1.35 (m, 3H), 1.30-1.19 (m, 2H). Diasteromer B: LCMS (ESI): RT=4.75 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.50 (d, J=4.0 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.98 (s, 1H), 4.52-4.45 (m, 5H), 3.42 (s, 2H), 2.77 (s, 1H), 2.29 (s, 3H), 2.16-2.13 (m, 2H), 2.00-1.88 (m, 4H), 1.64 (s, 1H), 1.50-1.25 (m, 3H), 1.20-0.90 (m, 2H)

Workup

  1. temperatureAfter cooling down
  2. customthe resultant mixture was purified directly by reverse phase Combiflash
  3. washeluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3
  4. customto give diastereomeric 111
  5. custom15 mg of diasteromer A and 12 mg diasteromer B (48% total yield)

Sources & evidence

ORD record
ord-a57d2a0847d54f4c94d394870b4e1585
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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