Diisopropylethylamine → 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester

HRID 1530377Notes

Reaction equation

HRID 1530377 reaction equation
Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([SH:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].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.C(Cl)Cl.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]>[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:33][CH2:34][CH:35]([S:38][C:2]2[C:3]([F:25])=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=5)=[CH:10]4)[C:6]=3[CH:24]=2)[CH2:36][CH2:37]1)([CH3:31])[CH3:30]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 6831287410-Bromo-9-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineHCID 866714532-(4-Mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester

Product 1

HCID 683130922-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (320 mg, 0.788 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (257 mg, 1.18 mmol), Pd2(dba)3 (36 mg, 0.039 mmol, mol %), XantPhos (46 mg, 0.079 mmol, 10 mol %) and DIPEA (0.55 mL, 3.15 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The crude reaction mixture was diluted with DCM (150 mL) and purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (quantitative yield), impure but taken forward to the next step without further purification. LCMS: RT 2.29 and 2.36 min [M+H]+ 543.2

Workup

  1. customwas purged with nitrogen
  2. custommicrowave irradiation
  3. customThe crude reaction mixture
  4. custompurified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM)

Sources & evidence

ORD record
ord-2951862afc65448e8230da3375e4669d
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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