Potassium Phosphate, Tribasic → (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

温度

90 °C

A mixture of 180 mg (0.370 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and Intermediate 9 using the method described in Step 1 of Example 52), (6-((2-methoxyacetamido)methyl)pyridin-3-yl)boronic acid (332 mg, 1.480 mmol), potassium phosphate, tribasic, 2M (0.925 mL, 1.850 mmol) and PdCl2(dppf) (54.2 mg, 0.074 mmol) in DMA (2.5 mL) was stirred at 90° C. for 45 minutes. After cooling to rt, the reaction mixture was diluted with ˜40 ml of EtOAc. The resulting dark mixture was filtered through celite and the filtrate was washed with water (40 ml), 10% LiCl solution (2×40 ml) and brine (40 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a brown oil that was chromatographed on a 4 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient, followed by a 0-10% MeOH/CH2Cl2 gradient. The pure fractions were concentrated to afford a brown oil that was triturated with ethyl ether. Filtration and drying afforded (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (203 mg, 0.347 mmol, 94% yield) as a tan solid. The material will be used as is in the next step. MS (ES+) m/z: 586.3 (M+H); LC retention time: 2.388 min (analytical HPLC Method O).

1. customprepared
2. temperatureAfter cooling to rt
3. filtrationThe resulting dark mixture was filtered through celite
4. washthe filtrate was washed with water (40 ml), 10% LiCl solution (2×40 ml) and brine (40 ml)
5. customAfter drying
6. filtration(MgSO4) and filtration
7. concentrationthe organic layer was concentrated to a brown oil that
8. customwas chromatographed on a 4 gm ISCO silica gel cartridge
9. washeluting with a 0-100% EtOAc/Hex gradient
10. concentrationThe pure fractions were concentrated
11. customto afford a brown oil that
12. customwas triturated with ethyl ether
13. filtrationFiltration
14. customdrying

ORDレコード

ord-820d7632fa15439f89d3bef8d3f3dbad

出典データセット

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08987268B2