Cyclobutanone → 6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid

HRID 927602

Reaction equation

[Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:18]([OH:20])=[O:19])=[N:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:15]1([CH2:14][O:13][C:12]2[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:7]=2[C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1

Participants

Conditions

Temperature: -78 °C

Procedure

Under nitrogen atmosphere, BuLi (0.58 mL, 0.89 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 0.2 g, 0.74 mmol) in THF (20 mL) at −78° C. The reaction mixture was stirred for 1 h at −78° C. then cyclobutanone (CAN 1191-95-3, 1.11 mL, 1.47 mmol) in THF (3 mL) was added to the above solution at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then quenched with NH4Cl and the pH was adjusted to 2 by addition of 1 N HCl. The mixture was extracted with ethyl acetate (3×10 mL); the organic layers were combined, washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was used for the next step without further purification; MS (EI): m/e=264.1 [M+H]+.

Workup

temperatureto warm to ambient temperature
stirringstirred for 1 h
customThe reaction mixture was then quenched with NH4Cl
additionthe pH was adjusted to 2 by addition of 1 N HCl
extractionThe mixture was extracted with ethyl acetate (3×10 mL)
washwashed with brine (2×10 mL)
dry with materialdried over Na2SO4
customThe solvent was removed under reduced pressure
customthe crude product was used for the next step without further purification

Sources & evidence

ORD record: ord-32711dfe128a4b648a33bb022b52d9a5
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09290451B2

Linked notes

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