Diisopropylethylamine → 10-(1-Tert-butylpiperidin-4-ylthio)-2-(pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530549Notes

Reaction equation

HRID 1530549 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].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]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 683129989-Bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azuleneHCID 866714621-tert-Butylpiperidine-4-thiol

Product 1

HCID 6655875510-(1-Tert-butylpiperidin-4-ylthio)-2-(pyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

A mixture of 9-bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.10 mmol), 1-tert-butylpiperidine-4-thiol (53 mg, 0.30 mmol), Pd2(dba)3 (9 mg, 10 mol %), XantPhos (12 mg, 20 mol %) and DIPEA (72 μL, 0.41 mmol) in dioxane (2 mL) was purged with argon and heated at 120° C. for 40 min, then 130° C. for 1 h and 140° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc then C18, gradient 2-20% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%). LCMS: RT 2.42 min [M+H]+ 435.1. 1H NMR (CDCl3, 400 MHz): δ 9.03-9.02 (1H, m), 8.75-8.72 (1H, m), 8.51 (1H, dd, J=4.82, 1.67 Hz), 8.21 (1H, d, J=7.88 Hz), 7.35-7.33 (3H, m), 6.99 (1H, d, J=8.26 Hz), 4.52-4.50 (2H, m), 4.46-4.44 (2H, m), 3.03-2.98 (2H, br m), 2.20 (2H, br m), 2.06-1.94 (3H, br m), 1.66-1.62 (2H, br m), 1.06 (9H, br m)

Workup

  1. customwas purged with argon
  2. wait140° C. for 1 h using
  3. custommicrowave irradiation
  4. washwas washed with MeOH
  5. washthe product eluted with 2M NH3/MeOH
  6. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc
  7. washwas washed with MeOH
  8. washthe product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%)

Sources & evidence

ORD record
ord-621ff40974d543e2ac2d469bde5ab8c4
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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