1,1'-Carbonyldiimidazole → N-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)-1-methyl-1H-indazole-3-carboxamide

A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2×30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147°-149° C.

1. customAfter a few minutes bubbling
2. dissolutionthe solid dissolved
3. waitafter a few more minutes
4. customa precipitate formed
5. customdegassed over 15 minutes under a stream of nitrogen
6. stirringthe mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr
7. concentrationconcentrated in vacuo
8. customThe residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml)
9. additioncontaining some 2-propanol
10. customThe organic layer was separated
11. extractionthe aqueous solution was extracted with toluene (2×30 ml)
12. additioncontaining some 2-propanol)
13. concentrationThe combined organic solution was concentrated in vacuo
14. washthe residual gum washed with water (50 ml)
15. customto remove most of the imidazole
16. dry with materialdried azeotropically with toluene
17. filtrationfiltered through alumina (eluted with 20% methanol/tetrahydrofuran)
18. customthe concentrated filtrate was recrystallized from acetonitrile

ORDレコード

ord-fb425ccac5f04ed6a606885c9dd23272

出典データセット

uspto-grants-1992_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US05137895