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

HRID 2044648Notes

Reaction equation

HRID 2044648 reaction equation
Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.CN1C(=O)CCC1>C(N(CC)CC)C>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[N:26][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH2:30][C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[CH3:27])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=1

Participants

5

Reactant 3

HCID 13387N-methyl-2-pyrrolidoneHCID 39017062-((2-Methylphenyl)methyl)pyrrolidineHCID 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 683933702-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-9-(2-(2-methylbenzyl)pyrrolidin-1-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepineYield 48%

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Conditions

Temperature
160 °C

Procedure

A 10 mL microwave vial was charged with 8-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 (85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq). 0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealed and heated at 160° C. for 24 h. After cooling to room temperature, the solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48% total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08 (s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9 Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89 (m, 2H), 1.81-1.71 (m, 2H)

Workup

  1. customThe vial was sealed
  2. temperatureAfter cooling to room temperature
  3. customthe solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN)
  4. customThe isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic)

Sources & evidence

ORD record
ord-b35cc662545e443581f4b55a4dad998d
Source dataset
uspto-grants-2013_11
Patent number
US08586574B2

Reaction notes

Loading…