Reaktion #2000634

Reaktionsgleichung

2-chloro-5-ethylpyrimidine

K2CO3

(R)-tert-butyl-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

potassium acetate

→

desired product ( 3-1b )

Ausbeute 92.0%

tert-Butyl 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

Ausbeute 92.0%

Lösungsmittel

dioxane

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe resulting mixture was purged with nitrogen (3×)
2. 2
   Sonstigethe reaction mixture was purged with nitrogen (3×)
3. 3
   workup.ADDITIONto addition, 2M, 5.0 mL)
4. 4
   workup.ADDITIONwere added to the reaction mixture
5. 5
   SonstigeThe reaction was purged with nitrogen (3×)
6. 6
   Temperaturheated for 6 hours at 110° C
7. 7
   TemperaturThe reaction was cooled to room temperature
8. 8
   Sonstigethe dioxane solvent was removed under reduced pressure
9. 9
   SonstigeThe residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution
10. 10
    WaschenThe organic layer was washed with 100 mL of brine
11. 11
    Trocknendried (Na2SO4)
12. 12
    Einengenconcentrated
13. 13
    Sonstigeto afford thecrude product as a dark brown oil
14. 14
    SonstigeThe crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column
15. 15
    Wascheneluted with 0-10% MeOH in CH2Cl2 over 20 minutes

Vorschrift

To an oven-dried round-bottomed flask was added (R)-tert-butyl-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 600 mg, 1.42 mmol), bispinacolatodiboron (398 mg, 1.71 mmol), 559 mg potassium acetate (559 mg, 5.70 mmol) and anhydrous dioxane (20 mL). The resulting mixture was purged with nitrogen (3×). Pd(dppf)Cl2 (58.0 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen (3×). The reaction was heated under nitrogen at 110° C. for 4 hours at which time LCMS showed conversion to the desired boronate intermediate. Pd(dppf)Cl2 catalyst (58.0 mg, 0.07 mmol), 2-chloro-5-ethylpyrimidine (224 mg, 1.57 mmol) and aqueous K2CO3 solution (de-oxygenated with nitrogen for 15 minutes prior to addition, 2M, 5.0 mL) were added to the reaction mixture. The reaction was purged with nitrogen (3×) and heated for 6 hours at 110° C. The reaction was cooled to room temperature and the dioxane solvent was removed under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution. The organic layer was washed with 100 mL of brine, dried (Na2SO4) and concentrated to afford thecrude product as a dark brown oil. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column, eluted with 0-10% MeOH in CH2Cl2 over 20 minutes to afford 583 mg (92%) of the desired product (3-1b) as a brown foam. MS (ES+) 449.5 (M+H)+. 1H NMR (CDCl3) δ 1.23 (t, 3H), 1.40 (s, 9H), 1.56-1.67 (m, 4H), 1.83-1.91 (m, 1H), 2.07-2.16 (m, 1H), 2.59 (q, 2H), 2.76-2.85 (m, 1H), 2.99-3.13 (m, 5H), 3.24-3.31 (m, 4H), 3.91 (dd, 1H), 7.27-7.34 (m, 1H), 8.17-8.23 (m, 2H), 8.56 (s, 2H).

Quelle