Cesium carbonate → [5-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-2-yl]carbamic acid tert-butyl ester

A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv), AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl4 (500 mL) was stirred for 1 h at relfux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixture was stirred at reflux for additional 30 min. The reaction mixture was filtered hot and the filtrate was concentrated. Trituration of the residue in CH3CN afforded of 12.88 g of impure (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2 equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol) and Cs2CO3 (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reaction mixture was stirred for 24 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (150 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 212 mg of the title compound as a white solid. Title compound: ESI-MS: 294.3 [M+H]+; tR=1.95 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).

1. customquenched by addition of a saturated aqueous solution of NaHCO3 (150 mL)
2. extractionextracted with EtOAc
3. washThe organic layer was washed with a saturated aqueous solution of NaHCO3
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated
7. customThe residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1)

ORD-Eintrag

ord-f2a83dbf186840b1b4dc2e68895fb5ed

Quelldatensatz

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08536175B2