反应详情

温度

120 °C

To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (50 mg, 0.161 mmol, prepared as described above) and 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (99 mg, 0.161 mmol; see Example 5, Alternative Preparation, Step 2) in i-PrOH (2 ml) was added N,N-diisopropylethylamine (0.056 ml, 0.322 mmol). The vessel was sealed under argon atmosphere and heated in a microwave for 1 hr at 120° C. LC/MS found: (M+H)+=523.3 as the major product peak. The reaction was repeated on the same scale in a separate vessel. The two reactions were combined and evaporated to give an oily residue, which was purified by automated flash chromatography (40 g silica gel) with elution by 8:92 (10% cNH4OH in MeOH). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was crystallized from CH2Cl2 and hexane. The two crops were combined and dried under vacuum to afford 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (101 mg). Analysis by 1H-NMR showed that this material contained ˜0.6 molar equivalents of CH2Cl2. LC/MS found: [M+H]+=523.30. 1H-NMR (400 MHz, CD3OD), δ ppm: 9.00 (s, 1H), 8.80 (s, 1H), 8.61 (d, J=9.0 Hz, 1H), 8.32 (dd, J=9.0, 1.6 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H), 4.57 (brs, 1H), 4.02 (brd, 1H), 3.65-3.51 (m, 2H), 3.24 (brs, 1H), 2.59-2.51 (m, 1H), 2.34-2.20 (m, 1H), 2.04 (s, 3H), 2.04 (m, 1H), 1.89 (brs, 3H), 1.74 (brs, 2H), 1.20 (s, 9H).

1. customThe vessel was sealed under argon atmosphere
2. customThe reaction was repeated on the same scale in a separate vessel
3. customevaporated
4. customto give an oily residue, which
5. customwas purified by automated flash chromatography (40 g silica gel) with elution by 8:92 (10% cNH4OH in MeOH)
6. additionThe fractions containing the desired product
7. concentrationconcentrated in vacuo
8. customThe residue was crystallized from CH2Cl2 and hexane
9. customdried under vacuum