Bromodifluoromethyl diethylphosphonate → N-(7-(Difluoromethoxy)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468800

Reaction equation

[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:19](P(=O)(OCC)OCC)([F:21])[F:20]>C(#N)C.O.C(OCC)(=O)C>[F:20][CH:19]([F:21])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: -78 °C

Procedure

A solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (91.2 mg, 0.40 mmol), diethyl bromodifluoromethylphosphonate (212 mg, 0.80 mmol) in acetonitrile/water (1:1, 5 mL) was mixed and stirred at −78° C. After the reaction mixture was warmed to room temperature and stirred for 20 minutes, the reaction mixture was diluted with ethyl acetate, and the organic phase was separated. The water phase was extracted with ethyl acetate, and the combined organic layer was dried, concentrated and purified by prep-HPLC to give product (42.8 mg, 26%). LCMS (ESI): RT (min)=0.994, M+H+=279.0, method=A. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.54 (s, 1H), 7.43 (dd, J=2.4, 8.8 Hz, 1H), 6.61 (t, J=73.2 Hz, 1H), 1.71-1.57 (m, 1H), 1.15-1.11 (m, 2H), 0.95-0.89 (m, 2H).

Workup

temperatureAfter the reaction mixture was warmed to room temperature
stirringstirred for 20 minutes
customthe organic phase was separated
extractionThe water phase was extracted with ethyl acetate
customthe combined organic layer was dried
concentrationconcentrated
custompurified by prep-HPLC

Sources & evidence

ORD record: ord-aef7cf60683146efa12c723ea2853134
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08623889B2

Linked notes

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