1-(3,4,5-TRIMETHOXY-PHENYL)-ETHYLAMINE synthesis

Yield: 73%

Reaction Conditions:

Stage #1:methyl (3,4,5-trimethoxyphenyl) ketone with titanium(IV) isopropylate;ammonia in ethanol at 20; for 6 h;Inert atmosphere;
Stage #2: with sodium tetrahydroborate in ethanol at 0 - 20;
Stage #3: with ammonia in ethanol;water

Steps:

Ti(iPrO)₄ (12 ml; 40 mmol) was added to 3,4,5-trimethoxyacetophenone (4.2 g; 20 mmol). The flask was closed with a septum and 2N solution of NH₃ in EtOH (50 ml; 100 mmol NH₃) was added by syringe. The system was flushed with nitrogen via the septum and subsequently stirred for 6 hours at room temperature in the closed flask.The mixture was cooled in an ice-bath and NaBH₄ (30 mmol; 1.13 g) was added. An exothermic reaction with strong gas evolution occurred. After gas evolution had ceased the cooling bath was removed and the mixture was stirred overnight at room temperature under an atmosphere of nitrogen. After several minutes the mixture turned from a clear solution into a suspension. Work-up:The reaction was quenched with 60 ml of 2M ammonia. The mixture was filtered on a sintered glass filter and washed on the filter with DCM (3x50 ml). After separating the layers, the water layer was extracted with DCM (2x50 ml). The combined DCM fractions were extracted with IM HCl (2x 100 ml) and discarded. The aqueous extracts were washed with DCM (2x50 ml) and subsequently basified with 3 M NaOH till pH>12 followed by extraction with (new) DCM (3x 100 ml). The DCM fractions were dried over Na₂SO₄ and DCM was evaporated. This gave 3.1 g of product z (73 %) as a clear and colorless oil. z: ¹H-NMR (400 MHz₃ CDCl₃): δ 1.31 (d, 2H, J= 6.4 Hz, CH₃), 3.77 (s, 3H, OCH₃), 3.81 (s, 6H₅ 2x OCH₃), 4.02 (q, IH, J= 6.4Hz, CH-Me), 6.53 (s, 2H, aromatic).

References:

NOVOTYR THERAPEUTICS LTD. WO2009/147682, 2009, A1 Location in patent:Page/Page column 59-60