Preparation of 2-phenoxyethylamine_Kain Industrial Additive

Background and overview^[1]

2-Phenoxyethylamine, CAS number 1758-46-9, is an important intermediate in the production of nefazodone. Nefazodone is a phenylpiperazine antidepressant. Structurally related to trazodone. It can block the reuptake of 5-HT by presynaptic neurons and is an antagonist of postsynaptic 5-HT2 receptors. Unlike trazodone, this product inhibits the reuptake of norepinephrine. This product can also block α1-receptors, but has no obvious effect on dopamine receptors. Compared with other tricyclic antidepressants, this product does not have significant antimuscarinic effects.

Preparation^[1]

The synthesis routes mainly include the following 7 types:

The first three routes all have the disadvantages of unavailable raw materials, harsh conditions and high costs; route (4) has a yield of only 27% because the product primary amine is easily further substituted into various substituted by-products such as secondary amines and tertiary amines. About; the raw material of route (5), epoxyethylamine, is not easy to obtain, and the reaction yield is low, only about 28%; route (6) is a typical Gabriel reaction method for synthesizing primary amines. Although the product purity is high, the steps are long. , the total yield is low, post-processing is difficult, and pollution is large; route (7) requires a large amount of phosphoric acid to be consumed during hydrolysis and produces a large amount of sewage, making it difficult to achieve industrial production. The technical problem to be solved by CN201210201038.6 is to overcome the defects of the above-mentioned existing technology and provide a preparation method of 2-phenoxyethylamine with a simple process route and easily available raw materials.

To this end, the technical solution adopted by the present invention is: a preparation method of nefazodone intermediate 2-phenoxyethylamine, the steps are as follows: first, the raw material 2-phenoxyacetaldehyde (A) and ammonia The corresponding imine (B) is obtained by gas reaction, and then the imine (B) is reduced to obtain the target product 2-phenoxyethylamine (C). The reaction equation is as follows:

Dissolve 68g (0.5mol) 2-phenoxyacetaldehyde in 300ml toluene, add it to a 1000ml four-neck bottle, add 100g anhydrous magnesium sulfate while stirring, and keep it in a cold water bath at about 10-15°C for drying. 10.2g (0.6mol) ammonia gas, then keep it at about 20°C and stir for 24 hours. The gas phase detects that the raw material is less than 5%, filter it, and the filtrate is directly used for the reduction reaction. Transfer the above reaction liquid into the hydrogenation kettle, add 500 ml of methanol and 1g of palladium carbon catalyst (5% content), fully replace the nitrogen and then replace it with hydrogen three times, maintain the temperature at 30‑40°C, and the hydrogen pressure at 1‑3MPa. The reaction takes about 1.5 hours. Afterwards, the hydrogen gas was absorbed slowly and the reaction was stopped. After the pressure was released and the material was discharged, it was filtered. The filtrate was evaporated to dryness and the residue was analyzed by gas phase. The crude product content was 82.3%. Distillate and collect 50.5g of the 105-113°C/1mmHg fraction, which is a light yellow liquid with a gas phase content of 97.8% and a yield of 73.2%. Product structure confirmation: ¹HNMR (δ, ppm, 400MHz, CDCl₃): 1.461(s,2H,-NH2);3.089(t,3H,J=5.2 Hz, -CH2N);3.992 (t,3H,J=5.2Hz,-OCH2CH2N);6.908-6.974(m,3H, benzene ring);7.263-7.312(m,2H, benzene ring);¹³CNMR (δ, ppm, 400MHz, CDCl₃): 158.9,129.5,120.7,114.4, 69.9,41.5