Trifluoroacetic acid → HCID 71053028, compound

HRID 869961Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH3:32][S:33]([CH2:36][CH2:37][N:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:39]1=[O:53])(=[O:35])=[O:34].FC(F)(F)C(O)=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:25])=[C:2]([C:42]5[CH:41]=[CH:40][C:39](=[O:53])[N:38]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:34])=[O:35])[CH:43]=5)[N:7]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1

Participants

Conditions

Temperature: 80 °C

Procedure

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (325 mg, 0.886 mmol), tetrakis(triphenylphosphine)palladium (0) (51.20 mg, 0.044 mmol), potassium carbonate (1.1 mL of 2 M, 2.21 mmol), and 1-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (377 mg, 1.15 mmol) were combined in a scintillation vial containing 1,2-dimethoxyethane (8 mL). The reaction mixture was then stirred and heated to 80 degrees C. for 16 hours. The reaction was then allowed to cool to room temperature. The layers were then separated and the organic layer was evaporated to dryness, re-dissolved in 1 mL of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile (containing 0.035% trifluoroacetic acid (v/v)) in water (containing 0.05% trifluoroacetic acid (v/v)) to yield the product. The resulting trifluoroacetic acid salt was then dissolved in a minimum of dichloromethane (5 mL). This solution was then washed two times with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride, followed by two washes of water. The organic layer was dried over sodium sulfate and then evaporated to dryness. The product was then further purified on 4 g of silica utilizing a gradient of 0-10% methanol in dichloromethane to yield the pure product (16.7 mg, 3.5%). ESI-MS m/z calc. 531.1. found 532.1 (M+1)+. Retention time 1.52 minutes. 1H NMR (400 MHz, CD3CN) δ 7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.62-7.55 (m, 2H), 7.36-7.32 (m, 2H), 7.22 (d, J=8.2 Hz, 1H), 6.42 (d, J=9.4 Hz, 1H), 4.29 (t, J=6.7 Hz, 2H), 3.49 (t, J=6.7 Hz, 2H), 2.90 (s, 3H), 2.32 (s, 3H), 1.62-1.58 (m, 2H), 1.19-1.15 (m, 2H).

Workup

temperatureto cool to room temperature
customThe layers were then separated
customthe organic layer was evaporated to dryness
dissolutionre-dissolved in 1 mL of N,N-dimethylformamide
custompurified by reverse-phase preparative liquid chromatography
customto yield the product
washThis solution was then washed two times with a saturated aqueous solution of sodium bicarbonate
dry with materialThe organic layer was dried over sodium sulfate
customevaporated to dryness
customThe product was then further purified on 4 g of silica utilizing a gradient of 0-10% methanol in dichloromethane

Sources & evidence

ORD record: ord-49e15088c9b34ea08d89193ecdf061af
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08969386B2

Reaction notes

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