反应详情

温度

0 °C

A cooled solution (0° C.) of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, (80 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with 3-(chlorosulfonyl)benzoic acid (30 mg, 0.36 mmol) and diisopropylethylamine (0.09 mL, 0.52 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was then treated with PyBOP (100 mg, 0.31 mmol), diisopropylethylamine (0.15 mL, 0.86 mmol) and 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (107 mg, 0.26 mmol) and stirred at ambient temperature for 16 h. The mixture was treated with water (40 mL) and extracted with dichloromethane (25 mL) and the organic phase was then concentrated to dryness and the intermediate Boc-protected material purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 5 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product containing fractions were concentrated to dryness. The residue was dissolved in methanol, treated with aqueous hydrochloric acid (2M, 2 mL) and stirred at ambient temperature for 16 h. The mixture was then dried (hydrophobic frit), evaporated to dryness and the product purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 2 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product-containing fractions were concentrated to dryness to afford 16 mg of the title compound. LC-MS m/z 783 (M+H)+, 0.92 min (ret time).

1. stirringstirred at ambient temperature for 16 h
2. extractionextracted with dichloromethane (25 mL)
3. concentrationthe organic phase was then concentrated to dryness
4. custompurified
5. extractionProduct-containing fractions were passed though a 5 g SCX solid-phase extraction cartridge
6. washthe product eluted off with a 10% solution of ammonia in methanol, product
7. additioncontaining fractions
8. concentrationwere concentrated to dryness
9. dissolutionThe residue was dissolved in methanol
10. additiontreated with aqueous hydrochloric acid (2M, 2 mL)
11. stirringstirred at ambient temperature for 16 h
12. customThe mixture was then dried (hydrophobic frit)
13. customevaporated to dryness
14. customthe product purified
15. extractionProduct-containing fractions were passed though a 2 g SCX solid-phase extraction cartridge
16. washthe product eluted off with a 10% solution of ammonia in methanol
17. additionproduct-containing fractions
18. concentrationwere concentrated to dryness