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 기록

ord-4e53dce41fac45c39b106caf3e59f9fe

출처 데이터셋

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09012461B2