Triethylamine → HCID 86706160, compound

HRID 2176309Notes

Reaction equation

[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:22][CH2:23][C:24]([CH2:30][F:31])([CH:28]=[CH2:29])[C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)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:1]([O:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](/[CH:29]=[CH:28]/[C:24]([CH2:30][F:31])([CH2:23][F:22])[C:25]([OH:27])=[O:26])=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])=[O:21])([CH3:4])([CH3:3])[CH3:2]

Participants

Conditions

Temperature: 60 °C

Procedure

A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (105 mg, 0.3 mmol), 2,2-bis-fluoromethyl-but-3-enoic acid (50 mg, 0.33 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.13 mL, 0.9 mmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol) as a yellow gum. LCMS (m/z) 421.1 [M+H], Tr=2.27 min. A solution of crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.13 mL, 0.75 mmol), 4-(dimethylamino)-pyridine (73 mg, 0.6 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in anhydrous dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 2:1 to 0:1 to afford the partially purified title compound (26 mg, 10%) as a yellow gum. LCMS (m/z) 834.3, 836.2 [M+H], Tr=3.39 min.

Workup

temperatureThe reaction mixture was cooled to room temperature
filtrationthe mixture was filtered through a hydrophobic frit
customthe filtrate was evaporated

Sources & evidence

ORD record: ord-e6617f48081c4b61820f5c018f01842e
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09062092B2

Reaction notes

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