p-Toluenesulfonic acid monohydrate → (S)-3-(4-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one

HRID 525381Notes

Reaction equation

[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]([CH3:29])([CH3:28])[O:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C@@H:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:20]([CH3:28])([CH3:29])[O:19][C:18]4=[O:30])=[CH:15][CH:16]=3)=[N:9][N:8]=2)[N:7]=1

Participants

Conditions

Temperature: 55 °C

Procedure

(S)—N′-(6-Chloropyridazin-3-yl)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzohydrazide (100 mg, 0.228 mmol) was dissolved in MeOH (2.284 mL). To the reaction mixture was added 4-methylbenzenesulfonic acid hydrate (43.4 mg, 0.228 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.). The mixture was heated at 55° C. and was stirred overnight. LC-MS indicated incomplete conversion. The mixture was then heated at 100° C. in a microwave for 1 hour. LC-MS indicated complete and clean conversion to the desired product. The reaction mixture was then concentrated under reduced pressure and providing a yellow residue. The residue was dissolved in 2 mL of MeOH and 1 mL of NH4OH, and the mixture was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes. The pure fractions were combined and diluted with 30% ammonium hydroxide, and the aqueous layer was extracted with DCM (3×20 mL) to provide (S)-3-(4-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (30 mg, 0.071 mmol, 31.3% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=9.40 Hz, 1H), 8.20 (d, J=8.33 Hz, 2H), 7.74 (d, J=9.19 Hz, 2H), 7.52 (d, J=9.62 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.35 (m, 3H), 5.55 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 420.0 (M+H)+.

Workup

temperatureThe mixture was then heated at 100° C. in a microwave for 1 hour

Sources & evidence

ORD record: ord-8f7d49bee3964219917b79f66c0826cd
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09340549B2

Reaction notes

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