Diisopropylethylamine → 2-{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-methylpropionic acid methyl ester

HRID 1530361Notes

Reaction equation

HRID 1530361 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[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([SH:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28].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].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>[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([S:36][C:2]2[CH:3]=[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:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[CH:10]4)[C:6]=3[CH:23]=2)[CH2:34][CH2:35]1)([CH3:29])[CH3:28]

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 5820501010-bromo-2-(1-isopropyl-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 683131132-{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-methylpropionic acid methyl esterYield 138%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 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 (326 mg, 0.871 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (284 mg, 1.307 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (50 mg, 10 mol %) and DIPEA (0.60 mL, 3.48 mmol) in dioxane (8 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording 2-{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-methylpropionic acid methyl ester as an orange oil (614 mg, quantitative yield). LCMS: RT 2.23/2.28 min [M+H]+ 511.3.

Workup

  1. customwas purged with nitrogen
  2. custommicrowave irradiation
  3. temperatureAfter cooling to RT
  4. additionthe reaction mixture was diluted with DCM (200 mL)
  5. custompurified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM)

Sources & evidence

ORD record
ord-b09b558cab3941dc91e77f104970298c
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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