Preparation of Methanol-D3_Industrial Additive

Background and overview^[1]

Deuterated methanol (methanol-D3) is an important chemical raw material and deuterated drug intermediate. The structure of the perdeuterated methanol (methanol-D3) is: CD3OD. It is a commonly used detection reagent for hydrogen nuclear magnetic resonance spectroscopy in chemical synthesis and is widely used in experimental research work. In recent years, as deuterated drugs have become a hot spot in drug research, deuterated methanol has also been widely used in the research of deuterated drugs.

There are currently many deuterated drugs undergoing clinical research, such as deuterated tetrabenazine, deuterated venlafaxine, deuterated tofacitinib, deuterated canagrelor, deuterated pirfenidone, deuterated Deuterated drugs such as paroxetine and deuterated atazanavir. However, the preparation method of ordinary methanol is not suitable for the preparation of fully deuterated methanol (methanol-D3). In the currently disclosed technical data, there are problems such as harsh reaction conditions, complex processes, and low overall yield. There is no method suitable for industrialization. The synthesis technology for producing deuterated methanol (methanol-D3) also limits the steps for the commercial development of deuterated drugs.

Preparation^[1]

The preparation method of fully deuterated methanol (methanol-D3) is as follows: open the valves of deuterium gas and carbon monoxide, control the volume ratio to 1:1 and premix first (deuterium gas and carbon monoxide are 2kg and 14kg respectively, a total of 16kg). Under a pressure of 5.5MPa, at a speed of 2L/second, pass through the catalyst bed of gold oxide: platinum oxide: rhodium oxide = 1:3:2 (mass ratio) at 210~380°C, and after a continuous cycle reaction of 24 hours, The fully deuterated methanol (methanol-D3) reaction liquid was obtained in the separation kettle, and the obtained reaction liquid was distilled to obtain fully deuterated methanol (methanol-D3): 3.2kg, with a yield of 35.5% and a GC purity of 99.8%. Elemental analysis theoretical values: C33.30%, D22.34%, O44.36%; measured values: C33.32%, D22.33%, O44.35%.

Main reference materials

[1] CN108250041