Background and overview[1]
Deuterated methanol is an important chemical raw material and deuterated drug intermediate. 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, and deuterated paroxetine , deuterated atazanavir and other deuterated drugs.
Preparation[1]
A method for preparing fully deuterated methanol, specifically: opening the valves of deuterium gas and Huntsman polyetheramine carbon oxide, controlling the volume ratio to 1:1 and first premixing (deuterium gas and carbon monoxide respectively) are 2kg and 14kg, totaling 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. After a continuous cycle reaction of 24 hours, The separation kettle obtained the fully deuterated methanol reaction liquid, and the obtained reaction liquid was distilled to obtain fully deuterated methanol: 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%.
Apply[2]
Deuterated dimethylamine salt is a widely used organic chemical raw material. It is often used in the synthesis of pharmaceutical and pesticide intermediates. It can be used as a deuterated raw material to synthesize deuterated drugs. The method for preparing deuterated dimethylamine salt using deuterated methanol is as follows:
(1) Preparation of deuterated methyl p-toluenesulfonate
In a 250ml three-necked flask, add 90g sodium hydroxide, 144ml water, 16.2g deuterated methanol, drop the ice water bath to 0 degrees, add 144ml of tetrahydrofuran solution of 103g p-toluenesulfonyl chloride, and let it naturally Warm to room temperature and stir overnight. Filter, extract the mother liquor with ethyl acetate, wash with water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 82.5g of deuterated methyl p-toluenesulfonate as a colorless oil.
(2) Preparation of N,N-deuterated dimethylformate tert-butyl ester
Weigh 1.2g (30mmol, 3.0eq) sodium hydride (60%) and add it to 15mL of dried tetrahydrofuran. Under nitrogen protection, cool to 0°C and add 1.17g of raw material tert-butyl carbamate (10mmol, 1.0 eq), after stirring for 30 minutes, add 3.8g of deuterated methyl p-toluenesulfonate (20mmol, 2.0eq). After the addition is completed, heat to 65-70°C and stir under reflux overnight. TLC monitors the reaction. After the raw materials disappear, cool to room temperature, slowly add ice water dropwise to quench the reaction, extract with 30 mL of ethyl acetate, wash with water (3*20 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil. 0.95g of N,N-deuterated dimethylformate tert-butyl ester, yield: 62.9%. LCMS (ESI, m/z): calcdforC7H9D6NO2[M+H]+151.2.
(3) Preparation of deuterated dimethylamine hydrochloride
Add 0.95g of raw material N,N-deuterated dimethylformate tert-butyl ester (6.3mmol, 1.0eq) into 10mL of ethyl acetate, add dry hydrogen chloride gas, and stir at room temperature overnight. TLC monitors the reaction. After the raw materials disappear, filter and rinse with ethyl acetate to obtain 0.35g of deuterated solvent dye manufacturer’s dimethylamine hydrochloride, yield: 64%. ESI-MSm/z(%):52.10(100%)[M+H]+.
Main reference materials
[1][Chinese invention] CN201810159452.2 A preparation method of fully deuterated methanol
[2][Chinese invention] CN201711130719.7 A method for synthesizing deuterated dimethylamine salt using deuterated methanol
