2,5-Dimethoxyphenethylamine (2C-H) via Darzen Condensation
Methyl Chloroacetate
94.5g (1 mole) of chloroacetic acid was dissolved in 350ml (10 moles) of methanol, 2.5ml (5g) of 98% H2SO4 was added, and the mixture was refluxed for 12 hours. The solution was neutralized with Na2CO3, filtered, and most of the methanol was removed by evaporation. The residue was washed with 100ml of water, dried over Na2SO4 and distilled, pure methyl chloroacetate was collected at 130-132°C. (Caution: Methyl Chloroacetate is a lachrymator!)
Methyl 2,5-Dimethoxyphenylglycidate
0.12 moles of sodium methoxide as a 15% solution in methanol (made by cautiously dissolving 2.75 g small pieces of sodium metal in 50ml of MeOH) is added with stirring during one hour to a solution of 0.1 mole of 2,5-dimethoxybenzaldehyde (16.6g) in 0.14 moles of methyl chloroacetate (10.9g) while keeping the temperature between 15-20°C. After the addition is finished, the stirring is continued at room temperature for one more hour.
2,5-Dimethoxyphenylglycidic acid
During two hours, the above ester solution is added dropwise to a solution of 9.8g 85% KOH (0.15 moles) in 13ml water, keeping the temperature between 15-20°C. The reaction mixture is stirred for three more hours at this temp, then at room temp for 12 hours, then cooled to 10°C and filtered.
2,5-Dimethoxyphenylacetaldehyde
The solid is washed with 2x15ml of methanol, and subsequently it is added to a mixture consisting of 50ml water, 50ml methylene chloride and 14g KH2PO4, while keeping the reaction mixture under stirring for two hours at room temp. The two layers are then separated, the aqueous phase is extracted twice with 25ml methylene chloride, then discarded, while the organic layers are collected and washed with 25ml of dH2O.
2,5-Dimethoxyphenylacetaldoxime
The pooled organic extracts are added dropwise with strong stirring into a 25% aqueous solution of 0.3 moles hydroxylamine (from 20.9 g hydroxylamine hydrochloride and 12g NaOH in 100 ml water) while keeping the temperature at -5°C for about two hours. Then 0.4 grams of sodium chloride is added, and the layers are separated, the aqueous layer is extracted with 3x10ml of DCM, and the pooled organic extracts are added to 50ml of methanol.
The aldoxime is then finally reduced to the amine using any known method.
Reference: US Pat. 5,057,624
