Formic Acid → HCID 71247648, compound

Temperature

100 °C

To racemic N-(4,4-dimethylpent-1-en-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 89a, (0.105 g, 0.211 mmol) and rhodium(II) acetate (0.019 g, 0.042 mmol) in dichloromethane (6.2 mL) was added dropwise a solution of ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in 2 mL dichloromethane over 30 minutes. Pd(OAc)2 (0.019 g, 0.042 mmol) in dichloromethane (2 mL) was added followed by ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in dichloromethane (2 mL) dropwise. The reaction was stirred overnight and the solvent was concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes gradient) to afford a racemic mixture of diasteromeric esters, 90a. The mixture of esters was dissolved in dioxane (2 mL) and 2N LiOH (1 mL). After heating at 100° C. for 2 h and cooling to room temperature, the mixture was acidified pH 6.5 with 2N HCl. The aqueous phase was extracted twice with EtOAc and once with dichloromethane. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography (0-20% MeOH/EtOAc gradient) to isolate the mixture of diastereomeric acids, which were further purified by preparatory HPLC (CH3CN/H2O—TFA modifier) to afford 3 diastereomers. Two of the diastereomers, 51 and 52, were isolated as a single diastereomer each. The third diastereomer, 50, was isolated as a mixture of diastereomers. All three diastereomers showed same LCMS: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 402.45.

1. concentrationthe solvent was concentrated in vacuo
2. customThe resulting crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes gradient)
3. customto afford
4. temperaturecooling to room temperature
5. extractionThe aqueous phase was extracted twice with EtOAc and once with dichloromethane
6. dry with materialThe combined organic phases were dried (MgSO4)
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customto isolate
10. additionthe mixture of diastereomeric acids, which
11. customwere further purified by preparatory HPLC (CH3CN/H2O—TFA modifier)
12. customto afford 3 diastereomers
13. customTwo of the diastereomers, 51 and 52, were isolated as a single diastereomer each
14. customThe third diastereomer, 50, was isolated as a mixture of diastereomers

ORD record

ord-e29ffd240b274e7bbb55f358a379fdd3

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09394302B2