1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 2-[4-[[5-Fluoro-4-[[2-(methylcarbamoyl)phenyl]amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid

Temperatur

150 °C

Reaction performed in 2 batches: Sodium tert-butoxide (773 mg, 8.05 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (0.478 g, 2.23 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 2-[(2-chloro-5-fluoropyridin-4-yl)amino]-N-methylbenzamide (250 mg, 0.90 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (82 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol) was added and the mixture was purged with nitrogen. The mixture was heated to 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. Both batches were combined and then evaporated. The residue was 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 by the addition of a 2N solution of HCl. The aqueous mixture 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 mixture filtered. The solid was washed with a 1:1 mixture of CH2Cl2/MeOH (3×150 mL) and the combined filtrates evaporated to afford 2-[4-[[5-fluoro-4-[[2-(methylcarbamoyl)phenyl]amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (440 mg, 64% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.79 (3H, d), 4.69 (2H, s), 6.70 (1H, d), 7.08 (1H, ddd), 7.33 (1H, s), 7.51 (1H, d), 7.55 (1H, ddd), 7.73 (1H, dd), 7.88 (1H, s), 7.93 (1H, d), 8.57 (1H, s), 8.70 (1H, q), 10.10 (1H, d); Mass spectrum: m/z (ESI+) (M+H)+=385.34.

1. customReaction
2. customsonicated for 5 minutes
3. customthe resulting suspension was purged with nitrogen
4. customthe mixture was purged with nitrogen
5. temperatureto cool to room temperature
6. customevaporated
7. customThe residue was partitioned between CH2Cl2 (150 mL)
8. customThe aqueous layer was separated
9. washwashed with CH2Cl2 (100 mL)
10. additionadjusted to pH4 by the addition of a 2N solution of HCl
11. washThe aqueous mixture was washed with CH2Cl2 (100 mL)
12. filtrationfiltered
13. customevaporated
14. customThe residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL)
15. filtrationthe resulting mixture filtered
16. washThe solid was washed with a 1:1 mixture of CH2Cl2/MeOH (3×150 mL)
17. customthe combined filtrates evaporated

ORD-Eintrag

ord-d5c433e59d39480c8338143a52517456

Quelldatensatz

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08569298B2