Piperidine → HCID 178432641, Verbindung

To a room temperature solution of [2-fluoro-1-phenylvinyl]pyrrolidine (freshly prepared before use from 2-fluoro-1-phenyl ethan-1-one (Example 152(a)), pyrrolidine and TiCl4 (see Example 30) (2.44 g, 12.7 mmol) in anhydrous toluene (15 mL) was added N,N-diisopropylethylamine (Aldrich Chemical Company) (2.0 mL, 12.7 mmol) followed by 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.61 g, 12.7 mmol). After stirring at room temperature for 2.5 h the reaction mixture was filtered through a fritted funnel. The residue was washed with hot toluene (2×30 mL) and the filtrate was concentrated under reduced pressure. The residue was dissolved with dioxane/toluene (20 mL:10 mL) and NEt3 (Aldrich Chemical Company) (2.1 mL) and piperidine (Aldrich Chemical Company) (2.0 mL, 20.3 mmol) were added. The mixture was stirred at 80° C. for 2 h under a N atmosphere. The SnCl2 solution was added to the reaction mixture at 80° C. The mixture was stirred at 80° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The reaction mixture was poured onto a mixture of NaOH (5 g) and crushed ice (150 mL) and stirred for 1 h. The resulting slurry was filtered through a Celite® pad, the pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL). The filtrate was transferred to a seperatory funnel. The organic solution was separated, washed with H2O (3×350 mL), saturated NaCl (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant to give 0.51 g (13%) of 7-fluoro-2-methyl-6-piperidylpyrrolo[3,2-d]pyrimidine as a brown colored foam. This compound (0.51 g, 1.60 mmol) was dissolved in 10:1 EtOAc/MeOH (35 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.60 mL, 1.60 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 270 mg (6%) of the title compound as pale green colored needles. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.59 (s, 3), 4.07 (br s, 4), 7.53-7.57 (m, 1), 7.61 (t, 2, J=7.7), 7.87 (d, 2, J=7.5), 12.07 (s, 1), 14.56 (s, 1). MS m/z: 311 (M+1 for free base). Anal. Calcd for C18H19FN4.HCl: C, 62.33; H, 5.81; N, 16.15; Cl, 10.22. Found: C, 62.04; H, 5.95; N, 16.08; Cl, 10.02.

1. filtrationwas filtered through a fritted funnel
2. washThe residue was washed with hot toluene (2×30 mL)
3. concentrationthe filtrate was concentrated under reduced pressure
4. additionwere added
5. stirringThe mixture was stirred at 80° C. for 2 h under a N atmosphere
6. stirringThe mixture was stirred at 80° C. for an additional 16 h
7. temperatureto cool to room temperature
8. stirringstirred for 1 h
9. filtrationThe resulting slurry was filtered through a Celite® pad
10. washthe pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL)
11. customThe filtrate was transferred to a seperatory funnel
12. customThe organic solution was separated
13. washwashed with H2O (3×350 mL), saturated NaCl (300 mL)
14. dry with materialdried (MgSO4)
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant

ORD-Eintrag

ord-1bcfefec89814546ac05e0c3fbbe4e33

Quelldatensatz

uspto-grants-2003_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06583154B1