Réaction #78103

Équation de réaction

2c

3-(4-methyl-1-piperazinyl)aniline

triethylamine

1i

4-Fluoro-3-nitrophenylacetic acid

diethyl ether

→

3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid

Rendement 29.1%

Solvants

NMP

—

petroleum ether

Conditions de réaction

Traitement

1. 1
   Autreresulting in separation of an oily lower phase
2. 2
   AutreThe mixture was decanted
3. 3
   workup.DISSOLUTIONthe oil was dissolved in dichloromethane
4. 4
   Lavageeluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v)

Mode opératoire

To a suspension of 1i (3.0 g, 15.1 mmol) in anhydrous NMP (2 ml) was added 2c (2.88 g, 15.1 mmol) and triethylamine (2.1 ml, 30.2 mmol). The mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was poured into a mixture of diethyl ether and petroleum ether (100 ml, 1:1 v/v) resulting in separation of an oily lower phase. The mixture was decanted and the oil was dissolved in dichloromethane and eluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v) to yield 3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid (1.63 g, 29%). This acid (0.64 g, 1.73 mmol) was dissolved in methanol and concentrated hydrochloric acid (0.2 ml) was added. The mixture was heated to reflux for 4 days. The solvent was removed under reduced pressure and the residue was purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent to leave the ester (0.47 g, 71%) as a red oil. This oil was hydrogenated in methanol at ambient pressure using Pd (5% on activated carbon) as the catalyst to yield the corresponding diamine (0.38 g). This diamine was treated with triethyl orthoformate (0.35 ml, 2.14 mmol) and a catalytic amount of pTSA in THF (5 ml) at 80° C. for 30 min. The solvent was evaporated and the residue was partitioned between aqueous sodium hydroxide (1 M) and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and eluted through a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v). The product precipitated as the hydrochloride by addition of a solution of anhydrous hydrogen chloride in diethyl ether to the eluate. Yield of 4l1: 0.2 g (41%). M.p. 140-142° C.

Source