反应详情

温度

0 °C

A flask containing methanol (100 mL) was cooled to 0° C. The solution was then charged dropwise with acetyl chloride (16.38 mL, 230.11 mmol) over 1 h maintaining a temperature of 10° C. The resulting mixture was charged with 2-[(R)-5-(6-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1f, 10.0 g, 23.01 mmol) in methanol (50 mL). The resulting mixture was stirred while warming to 20° C. for 18 h. HPLC after 18 h indicated disappearance of starting material. The resulting slurry was concentrated under reduced pressure removing approximately half the total volume. Isopropylacetate (50 mL) was then added and the resulting slurry was stirred for 1 h at 20° C. The solid was filtered and washed with isopropyl acetate (20 mL) under nitrogen. The solids were dried using a filter press with a nitrogen stream followed by drying under vacuum at 45° C. to afford 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 9.6 g, 98%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).

1. temperaturemaintaining a temperature of 10° C
2. temperaturewhile warming to 20° C. for 18 h
3. concentrationThe resulting slurry was concentrated under reduced pressure
4. customremoving approximately half the total volume
5. additionIsopropylacetate (50 mL) was then added
6. stirringthe resulting slurry was stirred for 1 h at 20° C
7. filtrationThe solid was filtered
8. washwashed with isopropyl acetate (20 mL) under nitrogen
9. customThe solids were dried
10. customby drying under vacuum at 45° C.