Hydrochloric Acid → Carbon Dioxide

The preparation of compound (II) can be accomplished by methods well known to the skilled artisan of organic synthesis, and by methods taught in commonly assigned U.S. patent application Ser. No. 09/056,820, and Tet. Lett. 1994, 35(37), 6811-6814, the disclosures of which are hereby incorporated by reference. Dissolution of compound (II) in THF containing 5% v/v 1N HCl followed by treatment with about 2 equivalents of (R)-(+)-a-methylbenzyl isocyanate between 0° C. and ambient temperature effects condensation of the isocyanate with the aniline nitrogen of (II). The second equivalent of isocyanate is decomposed under the reaction conditions to give CO2 and (R)-(+)-a-methyl-benzylamine hydrochloride salt. The urea condensation product reacts further to condense intramolecularly with the ketone to give the bicyclic urea hemiaminal (IV) as a mixture of diastereomers. The second condensation event takes place only slowly at ambient temperature. However, heating the reaction to reflux (65° C.) completes the conversion to (IV) within a couple of hours. The resulting mixture is washed with water to remove the benzylamine salt, and the THF is replaced with toluene via reduced pressure distillation (75 to 90° C. at 240 to 400 torr) crystallize the product. The mixture is cooled to 0° C., the product filtered, washed with toluene, and dried in an oven at 70° C. under 25 mm Hg vacuum for 15 to 20 hours until constant weight is achieved. Isolated yields are generally about 90%.

1. customwell known to the skilled artisan of organic synthesis

ORD record

ord-c5427d590b6d4ea6b974bc91f6b4c46c

Source dataset

uspto-grants-2001_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06225317B1