Hydrochloric Acid → 3-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazole

HRID 2281920Notes

Reaction equation

HRID 2281920 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH3:9])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=O)=[N:22]1.Cl.Cl.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][NH:35][NH2:36]>C1(C)C=CC=CC=1.C(O)C>[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][N:35]1[C:26]([C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[N:36]1.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][N:35]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:9][C:26]([C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[N:36]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 2733832Lithium HexamethyldisilazideHCID 110079401,2-Oxazole-3-carbonyl chlorideHCID 598688311-(5-Fluoropyridin-2-yl)ethan-1-oneHCID 69229193((2-Fluorophenyl)methyl)hydrazine hydrochloride

Product 2

HCID 716222933-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazoleYield 13%HCID 896572533-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazoleYield 14%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a cold solution of 1-(5-fluoropyridin-2-yl)ethanone (1 equiv.) in toluene (9.6 ml) at 0° C., was added 1M LiHMDS in toluene (1 equiv.). The mixture was stirred at 0° C. for 5 min. To this mixture, was added a solution of isoxazole-3-carbonyl chloride (1 equiv.) in toluene (4.8 ml). The mixture was removed from the ice bath and stirred at 25° C. for 5 min. To this mixture, were added 6 N HCl (1 equiv.), followed by (2-fluorobenzyl)hydrazine hydrochloride (1 equiv.) and ethanol (5 ml). The mixture was heated to 100° C. for 2 h. The mixture was cooled to 25° C. and concentrated under vacuum to give a thick red oil. The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes) to give 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (13% yield) as a clear film and its regioisomer 3-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazole (14% yield) as a white solid.

Workup

  1. customThe mixture was removed from the ice bath
  2. stirringstirred at 25° C. for 5 min
  3. temperatureThe mixture was heated to 100° C. for 2 h
  4. temperatureThe mixture was cooled to 25° C.
  5. concentrationconcentrated under vacuum
  6. customto give a thick red oil
  7. customThe oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-d5e7a0443a934f2ababd9d62cc5c2f48
Source dataset
uspto-grants-2015_09
Patent number
US09139564B2

Reaction notes

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