Trifluoroacetic acid → 2-(6-(((2S,4S)-2-Methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

HRID 1027190Notes

Reaction equation

CC(C)([O-])C.[K+].[CH3:7][C@H:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][CH2:10][NH:9]1.Cl[C:16]1[N:21]=[N:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][C:23]=2[OH:33])=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C1COCC1>[CH3:7][C@H:8]1[CH2:13][C@@H:12]([O:14][C:16]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[OH:33])=[CH:18][CH:17]=2)[CH2:11][CH2:10][NH:9]1

Participants

Conditions

Temperature: 50 °C

Procedure

Potassium tert-butoxide (1.0 M in THF, 1.4 mL, 1.4 mmol) was added to cis-2-methylpiperidin-4-ol (0.10 g, 0.68 mmol) in THF (3 mL) and the mixture was stirred for 10 min at 50° C. 2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (0.08 g, 0.28 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 days at RT. Trifluoroacetic acid (0.3 mL) was added and the solvent was evaporated under reduced pressure. The crude material was purified via preparative HPLC (5 to 95% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Two solids (10 mg (10%) and (15 mg (16%)) were afforded.

Workup

stirringthe mixture was stirred for 2 days at RT
customthe solvent was evaporated under reduced pressure
customThe crude material was purified via preparative HPLC (5 to 95% acetonitrile in water, 0.1% trifluoroacetic acid as modifier)
customEnantiomer 1 and Enantiomer 2 were isolated via preparative SFC
customTwo solids (10 mg (10%) and (15 mg (16%)) were afforded

Sources & evidence

ORD record: ord-145eaa66c4a44c018c9ceca2b6f80865
Source dataset: uspto-grants-2014_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08729263B2

Reaction notes

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