반응 #1133107

반응 방정식

Sodium tert-butoxide

2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride

8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one

9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

→

2-[4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid

수율 63.0%

용매

1,4-dioxane

반응 조건

후처리

1. 1
   기타sonicated for 5 minutes
2. 2
   기타the resulting suspension was purged with nitrogen
3. 3
   기타the mixture purged with nitrogen
4. 4
   온도to cool to room temperature
5. 5
   기타The mixture was evaporated
6. 6
   기타the residue partitioned between CH2Cl2 (150 mL)
7. 7
   기타The aqueous layer was separated
8. 8
   세척washed with CH2Cl2 (100 mL)
9. 9
   세척The aqueous solution was washed with CH2Cl2 (100 mL)
10. 10
    여과filtered
11. 11
    기타evaporated
12. 12
    기타The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL)
13. 13
    여과the resulting solid filtered
14. 14
    세척washed with a 1:1 mixture of CH2Cl2/MeOH
15. 15
    기타The combined filtrates were evaporated

실험 절차

Sodium tert-butoxide (805 mg, 8.38 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (498 mg, 2.33 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (300 mg, 0.93 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (86 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.075 mmol) was added and the mixture purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was evaporated and the residue partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 with 2N HCl solution. The aqueous solution was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL) and the resulting solid filtered and then washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to leave 2-[4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (250 mg, 63% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.96 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 4.71 (2H, s), 6.81 (1H, s), 6.89 (1H, d), 7.40 (1H, s), 7.43-7.50 (2H, m), 7.90 (1H, d), 8.01 (1H, s), 8.86 (1H, s), 11.23 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=427.33 and 429.29.

출처