1-bromo-3-chloro-2-methylpropane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.8 g, 4.12 mmole, Example 1 Part E) in tetrahydrofuran (40 mL) was cooled to -78° C. Butyllithium (1.7 mL of 2.5M in hexanes, 4.2 mmole) was added and the reaction mixture was stirred for 20 minutes. 1-Bromo-3-chloro-2-methylpropane (4.8 mL, 41 mmole) was added and the reaction mixture was allowed to warm to ambient temperature over a period of 1 hour. The reaction mixture was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by flash chromatography (silica gel eluting with 5-20% ethyl acetate in hexanes v/v) to provide 0.65 g of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine. The ether layer was separated dried over magnesium sulfate concentrated under vacuum The resulting residue was purified by flash chromatography (silica gel eluting with 5-20% ethyl acetate in hexanes v/v)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g of anhydrous potassium carbonate and 14.4 ml of 1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at a room temperature for 12 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to obtain 4.67 g of the title compound as a pale yellow oil (yield: 40%). The obtained mixture was reacted at a room temperature for 12 hours The obtained mixture was extracted with ethyl acetate The ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate distilled to remove the solvent The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thiophenol was alkylated with 1-bromo-3-chloro-2-methylpropane in the presence of potassium carbonate (K2CO3) in acetone. The resulting primary chloride was lengthened by one carbon atom using KCN/18 -crown-6 in acetonitrile. Basic hydrolysis, ring closure with polyphosphoric acid in analogy to Example 17(C) and Wolf-Kishner reduction according to Example 17(D) finally gave the required 2,3,4,5-tetrahydro-3-methyl-1-benzothiepine as a colorless oil.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred and warm (40° C.) mixture of 9.5 parts of 1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemethanaminium chloride, 225 parts of a sodium hydroxide solution 50% and 90 parts of tetrahydrofuran are added 17 parts of 1-bromo-3-chloro-2-methylpropane. The whole is heated to about 60° C. and stirring is continued for 15 minutes at this temperature. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloro-2-methylpropyl)-1H-benzimidazole as an oily residue. warm stirring The reaction mixture is cooled the product is extracted with trichloromethane The extract is dried filtered evaporated The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent The pure fractions are collected the eluent is evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred sodium ethoxide solution, prepared starting from 3.5 parts of sodium in 24 parts of ethanol, were added 16.8 parts of 4-fluorophenol. After stirring for 15 minutes, there was added dropwise a solution of 77 parts of 1-bromo-3-chloro-2-methylpropane in 72 parts of ethanol at room temperature. Upon completion, stirring was continued for 20 hours at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in 2,2'-oxybispropane. The organic phase was washed with water and with alkaline water 5%, dried, filtered and evaporated. The residue was distilled, yielding 11.6 parts of 1-(3-chloro-2-methylpropoxy)-4-fluorobenzene; bp. 126° C. (water-jet) (intermediate 82). Upon completion, stirring was continued for 20 hours at reflux temperature The reaction mixture was filtered the filtrate was evaporated The organic phase was washed with water and with alkaline water 5% dried filtered evaporated The residue was distilled