Ammonium Chloride → tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

The crude lithium 2-(2-(2-(2-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I97) was dissolved in DMF (2 mL) and ammonium chloride (210 mg, 3.92 mmol), HATU (149 mg, 0.392 mmol) and DIPEA (68.0 μL, 0.392 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, then concentrated. The residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL); the aqueous phase was extracted with further ethyl acetate (2×50 mL) and the combined ethyl acetate phases washed with brine (3×50 mL), dried over sodium sulfate and evaporated. The residue was chromatographed (4 g silica cartridge, 20-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C., then 0-5% gradient methanol/1% isopropylamine in ethyl acetate) to give a residue which was chromatographed (12 g silica cartridge, 80-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I98) (34 mg, 29% yield over two steps from ester) as a white foam; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.29-7.20 (m, 8H), 5.38 (s, 2H), 3.73 (s, 2H), 3.49 (s, 2H), 3.46-3.39 (m, 4H), 3.16-3.04 (m, 4H), 2.44-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.08 min; m/z 599.1 [M+H]+, 499.1 [M-Boc+2H]+; m/z 597.2 [M−H]−.

1. concentrationconcentrated
2. customThe residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL)
3. extractionthe aqueous phase was extracted with further ethyl acetate (2×50 mL)
4. washthe combined ethyl acetate phases washed with brine (3×50 mL)
5. dry with materialdried over sodium sulfate
6. customevaporated
7. customThe residue was chromatographed (4 g silica cartridge, 20-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.
8. custom0-5% gradient methanol/1% isopropylamine in ethyl acetate) to give a residue which
9. customwas chromatographed (12 g silica cartridge, 80-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.)

ORDレコード

ord-970e64499f8c474abaaeb920395c2234

出典データセット

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09421205B2