Oxalyl chloride → 2-Isopropyl-1-tosylimidazol-5-ylacetyl chloride

HRID 27619Notes

Reaction equation

[Na].[CH:2]([C:5]1[N:6]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:7]([CH2:10][C:11](O)=[O:12])=[CH:8][N:9]=1)([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:27])=O>C1C=CC=CC=1>[CH:2]([C:5]1[N:6]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:7]([CH2:10][C:11]([Cl:27])=[O:12])=[CH:8][N:9]=1)([CH3:4])[CH3:3]

Participants

Conditions

Temperature: 25 °C

Procedure

To 200 ml of cold thionyl chloride is added 0.1 mole of 3-isopropylimidazol-5-ylmethanol. After stirring for 1 hour at 25° C. the excess thionyl chloride is evaporated under reduced pressure to give crude 5-chloromethyl-2-isopropylimidazole hydrochloride. To an ice cold solution of 5 mmole of 5-chloromethyl-2-isopropylimidazole hydrochloride in 25 ml of dry dimethylformamide is added a cold solution of powdered sodium cyanide (18 mmole) in 30 ml of dimethylformamide. The mixture is stirred overnight at 25° C. then diluted with 200 ml of water and neutralized with sodium bicarbonate. The solution is saturated with sodium chloride and extracted with ethylacetate (5×50 ml). The organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a solid residue which is sublimed to give 5-cyanomethyl-2-isopropylimidazole. 5-cyanomethyl-2-isopropylimidazole (10 mmole) is heated with 10 ml of concentrated hydrochloric acid for 12 hours at reflux temperature then concentrated under reduced pressure to give 2-isopropylimidazol-5-ylacetic acid hydrochloride. To an ice cold solution of 0.08 mole of sodium carbonate in 40 ml of water is added 2-isopropylimidazol-5-ylacetic acid hydrochloride followed by 0.025 mole of tosyl chloride dissolved in 30 ml of ethyl acetate. After stirring for 5 hours at 25° C. the reaction mixture is neutralized with hydrochloric acid M and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to yield 2-isopropyl-1-tosylimidazol-5-ylacetic acid. To a suspension of the sodium salt of 2-isopropyl-1-tosylimidazol-5-ylacetic acid in 100 ml of benzene is added 1 equivalent of oxalyl chloride. The reaction mixture is stirred at 25° C. for 12 hours. The precipitate is filtered off and the filtrate concentrated under reduced pressure to give 2-isopropyl-1-tosylimidazol-5-ylacetyl chloride. To a solution of 29 mmole of diazomethane in 84 ml of ether cooled to 0° C. and magnetically stirred is added dropwise over 45 minutes a solution of 14.3 mmole of 2-isopropyl-1-tosylimidazol-5-ylacetyl chloride in 60 ml of ether. After stirring for 11/2 hours at 25° C. the reaction mixture is added to a solution of hydrogen fluoride/pyridine precooled to 0° C. The resulting heterogeneous solution is stirred at 25° C. for 11/2 hours then poured onto 150 g of ice. The organic phase is separated, washed with sodium bicarbonate (pH of 8) then with brine and dried over magnesium sulfate. Concentration of the mixture under reduced pressure yields 2-isopropyl-1-tosylimidazol-5-ylmethyl fluoromethyl ketone.

Workup

filtrationThe precipitate is filtered off
concentrationthe filtrate concentrated under reduced pressure

Sources & evidence

ORD record: ord-70021e0bd0d74ab0acd7aa959b7b7bd5
Source dataset: uspto-grants-1980_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US04221914

Reaction notes

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