Ammonia → 4-(3-Hydroxypropoxy)benzonitrile

Participants

Reaction Conditions

Reaction Steps

Chlorobenzene (598 g, 9 volumes) and water (7.2 g, 0.4 moles) were added to a solution of chirally enriched 5-benzyl-3(S),7(S)-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane in chlorobenzene (0.382 moles; see step (ii), Alternative 1 above) and heated to 75° C. Sulfric acid (98%, 134 g, 1.337 moles) was then added over 1 hour, whilst maintaining the temperature in the range 75-90° C. (In an alternative embodiment, chirally enriched 5-benzyl-3(S),7(S)-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane may be added to sulfuric acid.) The biphasic reaction mixture was heated to 95° C. and stirred for 3 hours. The temperature was adjusted to 50° C. and methanol (57 g, 1.2 volumes) was added at such a rate as to maintain the temperature at between 50 and 60° C. The reaction mixture was basified by adding aqueous ammonia (17.5%, 346 g, 372 mL) over 2 hours at between 60 and 70° C., and then allowed to settle after 15 min of stirring (the mixture is kept at 60° C. during the period in which it is allowed to settle). The lower aqueous layer was separated and the upper organic layer transferred to the crystallising vessel. The aqueous layer was returned to the reaction vessel and the temperature was adjusted to 45° C. before chlorobenzene (133 g, 120 mL) was added. The separation process was repeated (i.e. the aqueous layer extracted and the phases separated) and the second organic phase combined with the first organic phase in the crystallising vessel. Chlorobenzene was then distilled (660 mL, 11 volumes) from the product layer at 50 mbar (5 kPa) and then methanol (470 g, 594 mL) was added over the course of 1 hour. The temperature was allowed to fall during this addition, after which the resulting slurry was cooled to 5° C. and held at that temperature for 1 hour before being filtered. The filter cake was then washed with two portions of methanol (2×47.4 g, (2×60 mL)), at either 5° C. or ambient temperature, and then suction dried for 30 mins. The product was transferred to a vacuum oven and dried to constant weight at 40° C. to provide the sub-title compound (yield 31% (42.5 g) over Alternative 1 of steps (i), (ii) and (iii)).

Provenance & Evidence