4,6-Dichloropyrimidine → (3R*,5S*)-5-(6-Chloro-pyrimidin-4-ylamino)-piperidine-3-carboxylic acid cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amide

To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DMF (0.5 mL) are added i-Pr2NEt (26 uL, 0.15 mmol) and 4,6-dichloropyrimidine (23 mg, 0.15 mmol). After stirring for 16 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc/Et2O (c.a. 1:1, 60 mL). The organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give Boc protected title compound. MS: 604 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.88 min. The Boc protected compound is treated with 4N HCl-1,4-dioxane to give the title compound as a white amorphous solid. MS: 504 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.66 min.

1. customthe reaction mixture is quenched by H2O (30 mL)
2. extractionextracted with EtOAc/Et2O (c.a. 1:1, 60 mL)
3. washThe organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine
4. dry with materialdried over Na2SO4
5. filtrationThe solution is filtered
6. customthe solvent is evaporated in vacuo
7. customThe residue is purified by silica gel column chromatography
8. customto give Boc

ORDレコード

ord-3ff5546d74ef4a879a0d8bfba3bca1a7

出典データセット

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08163773B2