Diisopropylethylamine → 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(1-isopropylpiperidin-4-ylthio)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530574Notes

Reaction equation

HRID 1530574 reaction equation
[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30](C)([CH3:33])[CH2:31]O)[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(N1CCC(S)CC1)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23][CH:24]5[CH2:25][CH2:26][N:27]([CH:30]([CH3:33])[CH3:31])[CH2:28][CH2:29]5)[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 199366054-Piperidinethiol, 1-(1-methylethyl)-HCID 683128922-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol

Product 1

HCID 683131242-(1-isopropyl-1H-1,2,4-triazol-5-yl)-10-(1-isopropylpiperidin-4-ylthio)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 90.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 1 (400 mg, 1.07 mmol), 1-isopropylpiperidine-4-thiol (340 mg, 2.14 mmol), Pd2(dba)3 (50 mg, 5 mol %), XantPhos (61 mg, 10 mol %) and DIPEA (0.745 mL, 4.28 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, 0-13% MeOH in DCM) then (C18, 20-45% MeOH in 0.003M HCl/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 176 as a colorless solid (437 mg, 90%). LCMS: RT 3.01 min [M+H]+ 453.3. 1H NMR (MeOD, 400 MHz): δ 8.54 (1H, d, J=2.36 Hz), 7.93 (1H, s), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.49 Hz), 5.96-5.86 (1H, m), 4.55-4.46 (4H, m), 3.11-3.05 (1H, m), 2.94-2.84 (2H, m), 2.75-2.63 (1H, m), 2.28 (2H, t, J=11.32 Hz), 2.05-1.95 (2H, m), 1.69-1.53 (8H, m), 1.04 (6H, d, J=6.57 Hz)

Workup

  1. customwas purged with nitrogen
  2. custommicrowave irradiation
  3. additionThe reaction mixture was diluted with DCM (200 mL)
  4. custompurified by column chromatography (Si-PCC, 0-13% MeOH in DCM)
  5. additionThe product containing fractions
  6. concentrationconcentrated in vacuo
  7. washwas washed with MeOH
  8. washthe product eluted with 0.5M NH3/MeOH
  9. concentrationThe basic fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-eb9ffc76155b4302bdcd62a4b4210507
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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