Diisopropylethylamine → N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophene-2-carboxamide

HRID 1968590Notes

Reaction equation

[S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]3[CH2:13][CH:12]([C:2]1=2)[CH2:11][CH2:10]3.[NH2:14][C:15]1[C:16]([CH3:45])=[C:17]([C:21]2[N:22]=[C:23]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[C:41](=[O:42])[N:40]([CH3:43])[CH2:39][CH2:38][N:37]4[CH3:44])=[CH:32][CH:31]=3)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C=O)C>[CH3:44][N:37]1[CH2:38][CH2:39][N:40]([CH3:43])[C:41](=[O:42])[CH:36]1[C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:23]2[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=[C:21]([C:17]3[C:16]([CH3:45])=[C:15]([NH:14][C:6]([C:5]4[S:1][C:2]5[CH:12]6[CH2:13][CH:9]([C:3]=5[CH:4]=4)[CH2:10][CH2:11]6)=[O:8])[CH:20]=[CH:19][CH:18]=3)[N:22]=2)=[CH:31][CH:32]=1

Participants

Conditions

Temperature: 60 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 1e (100 mg, 0.515 mmol), 1p (203 mg, 0.469 mmol), N,N-diisopropylethylamine (242 mg, 1.88 mmol) and anhydrous DMF (2 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 249 mg, 0.563 mmol) was added, and the reaction was heated at 60° C. for 16 h. After this time, the reaction was diluted with water (10 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (20 mL), and the solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was eluted with a gradient from 0% to 20% of methanol in ethyl acetate, and the fractions containing 1q were collected to afford, after concentrating under reduced pressure, a 44% yield (127 mg) of 1q as an off-white solid: mp 178-179° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.35 (s, 1H), 7.85 (d, 1H, J=8.0 Hz), 7.77 (d, 2H, J=8.5 Hz), 7.59 (s, 1H), 7.42 (s, 1H), 7.29-7.22 (m, 4H), 6.76 (s, 1H), 3.68 (td, 1H, J=11.5, 4.5 Hz), 3.62-3.60 (m, 2H), 3.58 (s, 3H), 3.47 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.91 (s, 3H), 2.64 (m, 1H), 2.39 (s, 3H), 2.13 (s, 3H), 1.98-1.90 (m, 3H), 1.67 (dt, 1H, J=9.0, 2.5 Hz), 1.10 (dd, 2H, J=12.5, 3.5 Hz); MS (ESI+) m/z 609.3 (M+H).

Workup

customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer
customwas purged with nitrogen
filtrationthe resulting suspension was filtered
dissolutionThe filter cake was dissolved in methylene chloride (20 mL)
washthe solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL)
dry with materialdried over sodium sulfate
customThe drying agent was removed by filtration
customthe solvent was evaporated under reduced pressure
washThe resulting residue was eluted with a gradient from 0% to 20% of methanol in ethyl acetate
additionthe fractions containing 1q
customwere collected
customto afford
concentrationafter concentrating under reduced pressure

Sources & evidence

ORD record: ord-ce75a70e09f44a3e8797600b2e433244
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08426424B2

Reaction notes

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