Benzaldehyde, Min 98%, SD Fine Chem
Aminoethanol, 98%, Commercial
Sodium borohydride, 98%, Commercial
Ammonium chloride, Lab reagent
Dichloromethane, commercial
Sodium hydroxide, 98%, SD Fine Chem
Maleic acid, 99%, commercial
Dichloromethane, commercial, 98%
Ethyl acetate, 99%, commercial
Sodium sulfate, Lab reagent
Ammonia, Lab reagent

A 1-liter 3 necked round bottomed flask containing a mechanical stirrer, thermometer pocket, water/oil heating bath was assembled under an atmosphere of dinitrogen. Ethanol (400 mL) and aminoethanol (61 g, 1 mol) were charged. The reaction temperature was raised to about 45 ^oC. To this solution, benzaldehyde (106 g, 1 mol) was added over a period of 30 min. The reaction mass was further refluxed for 3 h. At this point, TLC of the reaction mixture shows almost conversion of benzaldehyde to corresponding imine (2:8, ethylacetate: hexane). The reaction mass was cooled to about 35-40oC and a solution of sodium borohydride (19 g, 0.5 mol) in 40 mL aqueous sodium hydroxide solution (400 mg NaOH in 40 ml water) was added over a period of 90 min keeping the reaction temperature below 40oC. The reaction mixture was stirred at the same temperature for 4 h. The ethanol was distilled off almost completely under vacuum. The reaction mass was added to about 250 mL water containing ammonium chloride (50 g) and extracted with dichloromethane at least 4 times (500 mL each). The dichloromethane extracts were washed with sodium carbonate solution (500 mL, 10%), dried with sodium sulfate and evaporated thoroughly to leave an oily mass (140 g, 92.7%) about 95% pure by GC. This can be further purified by vacuum distillation (one can get about 75% main fraction). Alternatively, this can be purified by converting to maleate salt - please find details below. The maleate can be bascified and extracted in dichloromethane.

 

Purification of the product by converting into Maleate salt:

The crude product from above reaction (~ 140 g , 0.92 mol) was dissolved in ethyl acetate (800 mL ) by warming to about 50 oC. Maleic acid (107 g, 0.92 mol) was added all at once and the mixture was stirred for 15 min then cooled to 20 ^oC. The almost white solid was filtered off (~ 325 g, wet) and washed with ethyl acetate (200 mL). The solid thus isolated was added to 5 l flask containing water ( 900 mL) and dichloromethane (750 mL) under stirring. The mixture was chilled to 10oC and treated with aqueous ammonia (~200 mL) . The dichloromethane layer thus obtained was separated and the water layer extracted with further dichloromethane (750 mL). The combined organic extracts were washed with water ( 500 mL) and dried over sodium sulphate ( 200g). Finally, dichloromethane was removed under reduced pressure to get about 110-113 g (~ 75%) pure product.

1. Direct monoalkylation of aminoethanol is difficult. It always gives varied amont of di-benzyl amino ethanol (10-70%) depending on the batch size.

2. This procedure under mild basic condition gives better quality product compared to all the literature procedure.

1H NMR (400 MHz, CDCl3): δ 7.25-7.38 (m, 5H), 3.79 (s, 2H) 3.58-3.72 (m, 2H), 2.60-2.70 (m, 2H), 2.54 (s, 1H).

13 C NMR (100 MHz, CDCl3): δ 139.70, 128.30, 128.0, 126.90, 60.40, 53.40, 50.60.

 

 

1. Chong, H-S, Ma X, Lee H, Bui P, Song, H. A., Birch, N. J Med. Chem. 2008, 51, 2208-2215. http://dx.doi.org/10.1021/jm701307j

2. Huskens, J., Sherry, A. D. J. Am. Chem. Soc., 1996, 118, 4396-4404. http://dx.doi.org/10.1021/ja953771p