Ethyl formate → 2,6-Dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde

HRID 251635

Reaction equation

[N:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=1)C(O)=O.[Li+].CC([N-]C(C)C)C.[CH:27](OCC)=[O:28]>C1COCC1>[Cl:18][C:16]1[C:15]([CH:27]=[O:28])=[C:11]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH:10]=[C:9]([Cl:8])[N:17]=1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of 2,6-dichloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone (2.0 g, 8.2 mmol, prepared from commercially available 2,6-dichloro-isonicotinic acid) in THF (50 mL) is added slowly LDA (4 mL, 2M in heptane/THF/ethylbenzene), maintaining an internal temperature below −65° C. The solution is stirred at −78° C. for 1 hour, then treated dropwise ethyl formate (640 mg, 8.6 mmol), again maintaining an internal temperature below −65° C. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is quenched with saturated NH4Cl, extracted with ether and the combined extracts are washed with brine, dried over sodium sulfate and concentrated to give crude 2,6-dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde, which is used directly for the next step.

Workup

temperaturemaintaining an internal temperature below −65° C
temperatureagain maintaining an internal temperature below −65° C
temperatureThe resulting mixture is gradually warmed to room temperature
stirringstirred overnight
customThe mixture is quenched with saturated NH4Cl
extractionextracted with ether
washthe combined extracts are washed with brine
dry with materialdried over sodium sulfate
concentrationconcentrated

Sources & evidence

ORD record: ord-ab08aba5d4564124a395abc09f3f602e
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07863454B2

Linked notes

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