Toluene → HCID 11237883, compound

A solution of 1-N-Boc-4-amino piperidine (300 mg, 1.49 mmol) (Astatech) and triethylamine (840 μL, 606 mg, 5.99 mmol) (Aldrich) in anhydrous dichloromethane (10 mL) was treated at 0° C. with a 20% solution of phosgene in toluene (1.47 mL, 2.99 mmol) (Fluka). After stirring for 30 minutes the mixture was partitioned between 0.5 M aqueous hydrochloric acid and dichloromethane. The organic layer was then collected, washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in diethyl ether (approx. 6 mL) and the resulting solution was filtered and concentrated. The residue was then dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL) and transferred via cannula to a −78° C. solution of [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine (300 mg, 1.06 mmol) (from Example 1d supra) and n-butyllithium (2.5 M solution in hexanes, 0.51 mL, 1.27 mmol) in anhydrous tetrahydrofuran (20 mL). The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours before it was partitioned between ethyl acetate and brine. The organic layer was then collected, dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography on a silica gel column with 0–60% ethyl acetate in hexanes. The product from this purification was then dissolved in aniline (2 mL) (Aldrich) and the resulting solution was heated at 80° C. for a period of 12 hours. The reaction mixture was then cooled, and purified by silica gel column chromatography using a 0–70% ethyl acetate in hexanes gradient to afford the product. After a precipitation out of THF with excess of pentane, 4-[3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was isolated as an off white solid. (Yield 74 mg, 13%).

1. customwas partitioned between 0.5 M aqueous hydrochloric acid and dichloromethane
2. customThe organic layer was then collected
3. washwashed with brine
4. dry with materialdried over sodium sulfate
5. concentrationconcentrated
6. dissolutionThe residue was dissolved in diethyl ether (approx. 6 mL)
7. filtrationthe resulting solution was filtered
8. concentrationconcentrated
9. dissolutionThe residue was then dissolved in a small volume of anhydrous tetrahydrofuran (approx. 3 mL)
10. customtransferred via cannula to a −78° C.
11. stirringstirred for 4 hours before it
12. customwas partitioned between ethyl acetate and brine
13. customThe organic layer was then collected
14. dry with materialdried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated
17. customthe residue was purified by chromatography on a silica gel column with 0–60% ethyl acetate in hexanes
18. customThe product from this purification
19. dissolutionwas then dissolved in aniline (2 mL) (Aldrich)
20. temperaturethe resulting solution was heated at 80° C. for a period of 12 hours
21. temperatureThe reaction mixture was then cooled
22. custompurified by silica gel column chromatography
23. customto afford the product
24. customAfter a precipitation out of THF with excess of pentane

ORD record

ord-99f5665d23374b10925b8e7887a4dd15

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07115740B2