2-Amino-6-[(E)-α-hydroxyiminobenzyl]-1-(isopropylsulfonyl)-1H-benzimidazole

2-Amino-6-[(E)-α-hydroxyiminobenzyl]-1-(isopropylsulfonyl)-1H-benzimidazole Property

Melting point:

198-199°

Boiling point:

607.2±61.0 °C(Predicted)

Density 

1.41±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO: soluble, Methanol: slightly, heated

form 

A solid

pka

9.85±0.14(Predicted)

color 

White to very dark grey

Hazard and Precautionary Statements (GHS)

2-Amino-6-[(E)-α-hydroxyiminobenzyl]-1-(isopropylsulfonyl)-1H-benzimidazole Chemical Properties,Usage,Production

Description

Enviroxime is an antiviral agent. It inhibits coxsackievirus B3-, rhinovirus-, or poliovirus-induced plaque formation in HeLa monolayer cell cultures when used at concentrations of 0.1, 1, and 10 μg/ml. Enviroxime (1 μg/ml) inhibits production of poliovirus PV1 viral RNA in HeLa monolayer cell cultures. It reduces viral titers in DRAW macrophages infected with the DA strain of Theiler''s murine encephalomyelitis virus.

Originator

Enviroxime,Eli Lilly

Uses

Enviroxime is a benzimidazole derivative that inhibits rhinovirus multiplication.

Manufacturing Process

300 g (1.52 mole) of 4-aminobenzophenone were added in portions to a stirred solution of 250 ml of acetic anhydride in 250 ml of benzene. Thetemperature of the mixture rose to about 70°C. The reaction mixture was stirred overnight. The product was filtered, washed with benzene and dried. The yield of 4-acetamidobenzophenone was 333.8 g (91.5 % yield), melting point 150-152°C (Lit. melting point 155°C).
23 g (0.1 mole) of 4-acetamidobenzophenone, 50 ml of acetic anhydride and 20 ml of acetic acid were stirred together. A solution of 90 % (15 ml), 10 ml of acetic acid and 0.2 g of urea was added dropwise to the mixture. The reaction mixture was maintained at a temperature of about 50°C. The mixture was stirred at ambient temperature whereupon the mixture became very thick. The thick slurry was poured over ice and the insoluble product was filtered to yield 17.7 g (62.5 % yield) of 4-acetamido-3-nitrobenzophenone.
10 g of 4-acetamido-3-nitrobenzophenone were added portion-wise to 40 ml of sulfuric acid. The reaction temperature was moderated with a water bath. After stirring about 45 min the reaction mixture was carefully poured over ice. The precipitated product was filtered to yield 4-amino-3-nitrobenzophenone.
50 g of 4-amino-3-nitrobenzophenone were hydrogenated at room temperature in 945 ml of tetrahydrofuran with 15 g of Raney nickel. After 4 hours 3 equivalents of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to a solid residue. The residue was chromatographed over silica gel using ethyl acetate as eluent. Fractions 5-9 were combined to yield 43.6 g (100 % yield) of 3,4-diaminobenzopheone.
42.4 g (o.2 mole) of 3,4-diaminobenzophenone were dissolved in 100 ml of methanol and mixed into one liter of water. 21.8 g (0.2 mole) of cyanogen bromide were added in portions to the reaction mixture with stirring The reaction was continued overnight. The reaction mixture was filtered and the filtrate was neutralized (pH 7.0) with concentrated ammonium hydroxide. The precipitated product was collected, washed with water, and dried in a vacuum to yield 31 g (68.5%) of 2-amino-5(6)-benzoylbenzimidazole.
4.5 g (20 mmole) of 2-amino-5(6)-benzoylbenzimidazole were dissolved in 30 ml of acetone and 4.0 g of triethylamine. A solution of 2.9 g (20 mmole) of dimethylsulfamoyl chloride in 10 ml of acetone was added dropwise to the reaction mixture. The mixture was heated at reflux overnight. The reaction mixture was poured into 400 ml of water. The product was extracted with chloroform. The extract was washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was crystallized from ethyl acetate to yield 1.06 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole, melting point 206-208°C.
172 mg of 1-dimethylaminosulfonyl-2-amino-5(6)-benzoylbenzimidazole, 100 mg of hydroxylamine hydrochloride and 20 ml of methanol were refluxed for 16 hours. The reaction mixture was concentrated to one-half the original volume by heating on the steam bath. 10 ml of buffer (pH=7.0) were added to the mixture. The product precipitated and was filtered to yield 116 mg of 1- dimethylaminosulfonyl-2-amino-5(6)-(α-hydroxyiminobenzyl)benzimidazole, melting point 180-183°C.

Therapeutic Function

Antiviral

References

[1] B A HEINZ  L M V. The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus.[J]. Journal of Virology, 1995, 69 7: 4189-4197. DOI: 10.1128/jvi.69.7.4189-4197.1995
[2] STEPHANE STEURBAUT. Modulation of viral replication in macrophages persistently infected with the DA strain of Theiler’s murine encephalomyelitis virus.[J]. Virology Journal, 2008: 89. DOI: 10.1186/1743-422x-5-89