(R)-2-(tetrazolo[1,5-a]pyrid 6-yl)oxirane → HCID 15137759, compound

A solution of 16 g of 1-(1H-indol-3-yl)-3-butanone, 10.3 g of R(+)-1-phenylethylamine and 0.2 g of TsOH.H2O in 80 ml of benzene is heated at reflux with water removal (Dean-Stark trap) for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue redissolved in 80 ml of methanol. To this solution 8 g of Ra(Ni) catalyst is added and the mixture hydrogenated under positive hydrogen pressure for 32 hours. The reaction mixture is filtered through celite and the filtrate concentrated. The residue is chromatographed on silica gel to afford the (R,R,)-diastereomer. This material (6.2 g) is converted into its hydrochloride salt and dissolved in 50 ml of ethanol and hydrogenated over 1.6 g of 5% Pd(C) for 18 hours. The reaction mixture is then filtered and the filtrate concentrated under reduced pressure to dryness. The residue is chromatographed on silica gel to give 1(R)-methyl-3-(1H-indol-3-yl)propyl amine. This amine (650 mg) is condensed with 650 mg of (R)-2-(tetrazolo-[1,5-a]pyrid-6-yl)oxirane in 15 ml of absolute ethanol at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue purified by chromatography on silica gel to give (R)-α-[[(1(R)-methyl-3-(1H-indol-3-yl)propyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol. This tetrazole (0.6 g) in 15 ml of methanol is treated with 0.6 g of SnCl2.2H2O and the reaction mixture heated at reflux for 18 hours. The reaction solution is partially concentrated under reduced pressure. This concentrated solution is added to a mixture of CH2Cl2 (20 ml) and 12 ml of 2N NaOH solution. The mixture is stirred for twenty minutes and then the layers are separated. The aqueous layer is further extracted with CH2Cl2. The combined organic extracts are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution is concentrated and the residue chromatographed on silica gel to give the titled compound after conversion to its hydrochloride salt with ethanolic HCl.

1. temperatureat reflux for 3 hours
2. concentrationThe reaction mixture is concentrated under reduced pressure
3. customthe residue purified by chromatography on silica gel

ORD record

ord-2b26d5cd58c942c8bdc30ffbf3abf947

Source dataset

uspto-grants-1991_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05030640