Diisopropylethylamine → 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidine-1-carboxylic acid tertbutyl ester

HRID 1530363Notes

Reaction equation

HRID 1530363 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(C)(C)CO)[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:35]([O:39][C:40](N1CCC(S)CC1)=[O:41])([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.BrC1C=CC2OCCN3C(=NC(C4N(C(C)C)N=CN=4)=C3)C=2C=1>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].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.C(Cl)Cl>[C:35]([O:39][C:40]([N:27]1[CH2:28][CH2:29][CH:24]([S:23][C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][N:11]4[C:17](=[N:18][C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)=[CH:10]4)[C:16]=3[CH:19]=2)[CH2:25][CH2:26]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]

Participants

9

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 21906090tert-Butyl 4-sulfanylpiperidine-1-carboxylate2×HCID 5820501010-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineHCID 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 683130254-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidine-1-carboxylic acid tertbutyl esterYield 931.5%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)Catalyst2×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

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 (100 mg, 0.267 mmol), 4-mercaptopiperidine-1-carboxylic acid tertbutyl ester (87 mg, 0.401 mmol), Pd2(dba)3 (13 mg, 5 mol %), XantPhos (15 mg, 10 mol %) and DIPEA (0.19 mL) in dioxane (3 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The same process was repeated using 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 (400 mg, 1.068 mmol), 4-mercaptopiperidine-1-carboxylic acid tertbutyl ester (348 mg, 1.604 mmol), Pd2(dba)3 (50 mg, 5 mol %), XantPhos (61 mg, 10 mol %) and DIPEA (0.745 mL) in dioxane (10 mL). The two crude reaction mixtures were combined into DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-7% MeOH in DCM) affording the title compound as an orange gum (1.27 g, quantitative). LCMS: RT 4.15 min [M+H]+ 511.3. (110174852)

Workup

  1. customwas purged with nitrogen
  2. custommicrowave irradiation
  3. customThe two crude reaction mixtures
  4. custompurified by column chromatography (Si-PCC, gradient 0-7% MeOH in DCM)

Sources & evidence

ORD record
ord-dcc16e2492a94483b63603486cb8d528
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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