Hydrochloric Acid → 3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4-(4-methoxythiazol-2-yl)isoxazole

HRID 1805261Notes

Reaction equation

[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([OH:19])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.[CH3:36]I.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([O:19][CH3:36])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:26])[F:27])[O:11][N:10]=1

Participants

Conditions

Temperature: 45 °C

Procedure

To a stirred solution of 52 mg (0.1 mmol) hydroxyl thiazole (example 9) in 5 ml dioxane were added alternately in small portions 0.140 g (1.0 mmol) of CH3I and a solution of 40 mg (1.0 mmol) NaOH in 1 mL water. The pH has to be kept at 8-9 and the temperature at 40-50° C. Then the reaction mixture was stirred for 1 hour at 40-50° C., diluted with 15 mL water, neutralized with HCl to pH 6-7. Thick oil was extracted with CCl4, dried with MgSO4 and purified by column chromatography on silica gel, using CCl4, then CHCl3/CCl4 (1:1, v/v) as eluents. Yield of glassy substance of example 10 is 20 mg (37%). Result of LC/MS MH+: 539.03; 1H NMR (DMSO-d6; CCl4): 3.73 (3H, s, CH3), 6.59 (1H, s, CH-thiazole), 7.52-7.78 (7H, m, CH-arom.), 8.62 (1H, s, CH-pyraz.)

Workup

customat 40-50° C
extractionThick oil was extracted with CCl4
dry with materialdried with MgSO4
custompurified by column chromatography on silica gel
customResult of LC/MS MH+

Sources & evidence

ORD record: ord-b7e657a64ed24a8093cad3171c20a3bd
Source dataset: uspto-grants-2013_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08354436B2

Reaction notes

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