Ammonia → 4-(3-Hydroxypropoxy)benzonitrile

Temperature

75 °C

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)).

1. custom) The biphasic reaction mixture
2. temperaturewas heated to 95° C.
3. customwas adjusted to 50° C.
4. temperatureto maintain the temperature at between 50 and 60° C
5. waitto settle after 15 min
6. stirringof stirring (the mixture
7. customis kept at 60° C. during the period in which it
8. customThe lower aqueous layer was separated
9. customwas adjusted to 45° C. before chlorobenzene (133 g, 120 mL)
10. additionwas added
11. extractionextracted
12. customthe phases separated) and the second organic phase
13. distillationChlorobenzene was then distilled (660 mL, 11 volumes) from the product layer at 50 mbar (5 kPa)
14. additionmethanol (470 g, 594 mL) was added over the course of 1 hour
15. additionto fall during this addition
16. temperatureafter which the resulting slurry was cooled to 5° C.
17. waitheld at that temperature for 1 hour
18. filtrationbefore being filtered
19. washThe filter cake was then washed with two portions of methanol (2×47.4 g, (2×60 mL)), at either 5° C. or ambient temperature
20. customsuction dried for 30 mins
21. customdried to constant weight at 40° C.

ORD record

ord-17aeccf75ec84c7aa74af9b14207cf56

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07928225B2