Diisopropylethylamine → Isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate

HRID 718373Notes

Reaction equation

[CH:1]1([CH:4]2[CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:6]2[CH2:7][CH2:8][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of 3-cyclopropylpyrrolidine (250 mg, 2.25 mmol) and DIEA (1.178 mL, 6.74 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (752 mg, 2.25 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h before being cooled, concentrated, and charged (DCM) to a 40 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 745 mg (81%). 1H NMR (500 MHz, DMSO-d6) δ 5.05-5.00 (m, 1H), 3.25-3.19 (m, 2H), 3.15-3.11 (m, 1H), 2.94-2.90 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.06 (br. s., 1H), 1.73-1.69 (m, 2H), 1.29-1.27 (m, 6H), 0.72-0.69 (m, 1H), 0.45-0.40 (m, 2H), 0.16-0.10 (m, 2H). UPLC (M+H)=411.1.

Workup

customThe resulting mixture was placed in a pre-heated oil bath
temperaturebefore being cooled
concentrationconcentrated
additioncharged (DCM) to a 40 g ISCO silica gel cartridge and gradient
washeluted (5-35% EtOAc/hexanes)

Sources & evidence

ORD record: ord-a26cc4fd6d64445eba84af5aa9f53735
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09193720B2

Reaction notes

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