Methane → HCID 25265770, compound

Temperature

0 °C

To a solution of crude [(2R)-3-(2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (assumed 176.57 g, 314.1 mmol) in MeOH (800 mL) was added 20% Pd(OH)2/C (14.13 g). The mixture was hydrogenated under balloon pressure with monitoring every 30 min until the reaction was judged to be complete (7 h). The mixture was then filtered through a glass fiber filter with MeOH washes. The resulting dark filtrate was concentrated in vacuo and purified by preparative reverse phase chromatography (Luna C18 (2) column; 10 microns; 101.6 mm×250 mm; 250 nm UV detection; 480 mL/min; 40 mg/mL sample concentration; 4 g injection mass; mobile phase A: 300 mmol aqueous ammonium formate at pH 4.0; mobile phase B: MeCN; method: 28% B for 9 min; 90% B for 9 min; 28% B for 5 min). The product solution fractions were combined and adjusted to pH 6.8 with aqueous NH4OH, and then stirred with Darco (50% weight load based on crude product) for 30 min at room temperature. The solution was then filtered through Celite. The filtrate was concentrated to a volume of 3.5 L, and the pH was adjusted from 5.6 to 8.5 with NH4OH, affording an orange precipitate. The aqueous phase was extracted 3 times with EtOAc, and then the combined organics were washed with water and brine. The organics were dried (Na2SO4), filtered, and concentrated in vacuo to a volume of 1 L, producing a tan precipitate. An equal volume of heptane (1 L) was added, and the mixture was cooled to 0° C. for 1 h. Then the product was isolated by filtration, washing with heptane, and dried under reduced pressure at 50° C. for 20 h to provide [(2R)-3-(2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (85.5 g, 57% yield for 2 steps) as a white solid. LCMS: (M+H)+: 472.2.

1. custom(7 h)
2. filtrationThe mixture was then filtered through a glass fiber
3. filtrationfilter with MeOH washes
4. concentrationThe resulting dark filtrate was concentrated in vacuo
5. filtrationThe solution was then filtered through Celite
6. concentrationThe filtrate was concentrated to a volume of 3.5 L
7. customaffording an orange precipitate
8. extractionThe aqueous phase was extracted 3 times with EtOAc
9. washthe combined organics were washed with water and brine
10. dry with materialThe organics were dried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo to a volume of 1 L
13. customproducing a tan precipitate
14. customThen the product was isolated by filtration
15. washwashing with heptane
16. customdried under reduced pressure at 50° C. for 20 h

ORD record

ord-17674cf14da54926acee44cf1fb747c9

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893056B2