N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine CAS#93102-05-7 is used in the preparation of trans-phenyl pyrrolidine ethers which are tachykinin receptor antagonists.
To a solution of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)-phosphonate and 18-crown-6 THF is added potassium hexamethyldisilazide solution at -78 °. After 5 min a compound of formula V is added. The reaction mixture is stirred at -78 °C for about 20min and consequently allowed to warm to room temperature over a period of about 1 h, followed by quenching with a saturated aqueous solution of ammonium chloride and by extraction in conventional manner. The obtained compound of formula VI is dissolved in dichloromethane and consecutively treated with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (96%, Aldrich) and a solution of dichloromethane and trifluoroacetic acid is added at 0 °C. Another portion of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (96%, Aldrich) is added after one hour if necessary to drive conversion to completion. The reaction mixture is diluted with dichloromethane and washed with saturated sodium carbonate solution. After concentration and purification a compound of formula VII is obtained. A solution of a compound of formula VII and 1-chloroethyl chloroformate in 1,2-dichloroethane is heated at about 50 °C over night. After cooling to room temperature the solvent is evaporated. The residue is redissolved in MeOH and the resulting solution is heated at reflux for 30 min. The reaction mixture is concentrated in vacuo. The residual hydrochloride salt is redissolved in THF. The mixture is cooled to 0 °C and treated with triethylamine and a solution of di-tert.-butyl dicarbonate in THF. After stirring for about 90 min the reaction mixture is worked up in conventional manner to obtain a compound of formula VIII. Then a mixture of a compound of formula VIII and hydrochloric acid solution is heated at reflux for about 4 h. The reaction mixture is cooled to 0 °C and basified by the addition of sodium hydroxide. Dilution with dioxane is followed by addition of a solution of di-tert.-butyl dicarbonate in 1,4-dioxane. The reaction mixture is concentrated and purified in conventional manner to obtain a compound of formula IX.