Toluene → HCID 9841284, compound

Temperature

65 °C

A mixture of 270.6 g of inosine-2',3',5'-tripropionate, 240 ml of N,N-dimethylformamide and 600 ml of toluene is heated to 65° C.; and over a period of 1 hour, 67.84 ml of thionyl chloride are added at a rate which maintains the internal temperature between 62°-65° C. The mixture is stirred at this temperature for an additional 2.5 hours and then cooled to 10° C. with an ice bath. After addition of 600 ml of water precooled to 10°-15° C. in an ice bath at a rate which maintains the temperature below 20° C., the organic layer is separated and washed with a total of 800 ml of 10% aqueous sodium chloride in four equal portions of 200 ml each. The organic layer containing crude 6-chloro-9-(2,3,5-tri-O-propionyl-β-ribofuranosyl)-9H-purine is added with stirring to 620 ml of cyclohexylamine heated to 105° C. over a period of 2 hours at a rate which maintains the internal temperature at 105° C. After this mixture is stirred at this temperature for an additional 17 hours, it is cooled to room temperature (25° C.) over approximately 2 hours with efficient stirring and then filtered in a Buchner funnel with suction. The solid containing N6 -cyclohexyladenosine and cyclohexylamine hydrochloride is washed with a total of 460 ml of toluene in four equal portions of 115 ml. each and transferred damp to a 5-liter flask equipped with a mechanical stirrer. After addition of 2 liters of aqueous saturated sodium bicarbonate solution and 2.5 liters of ethyl acetate, the mixture is stirred until all the solid dissolve (approximately 10-15 min.). The organic layer is separated; and the aqueous layer is extracted with 1.5 liters of ethyl acetate in two portions of 1 liter and 500 ml., respectively. The organic layers are combined and evaporated until about 3 liters of ethyl acetate (at 40° C., 100-200 mbar) is removed. To the residue, 500 ml. of heptane is added; and the resulting mixture is stirred for 30 minutes. The solids are separated on a Buchner funnel, and washed with a total of 300 ml of heptane in three equal portions of 100 ml each. The solids are then dried at 45°-50° C. (30-35 mbar) for approximately 3 hours to yield 148 g of crude N6 -cyclohexyladenosine as a white solid. This is transferred to a 1 liter round-bottomed flask equipped with a mechanical stirrer, and 175 ml. of 95% ethanol are added. The suspension is stirred for 15-20 min and 175 mL of tert-butyl ethyl ether are added. After stirring for 5 min, the suspension is cooled in an ice bath and stirred for an additional 15 minutes. This suspension is filtered in a Buchner funnel and washed with a total of 50 ml. of tert-butyl methyl ether in two equal portions of 25 ml. each. The solid is dried at 45°-50° C. (30-35 mbar) for 14 hours to yield 130 g of N6 -cyclohexyladenosine as a white solid (m.p. 185°-187° C.; yield 60.0%).

1. custombetween 62°-65° C
2. temperaturecooled to 10° C. with an ice bath
3. customprecooled to 10°-15° C. in an ice bath at a rate which
4. customthe temperature below 20° C.
5. customthe organic layer is separated
6. washwashed with a total of 800 ml of 10% aqueous sodium chloride in four equal portions of 200 ml each
7. additionThe organic layer containing crude 6-chloro-9-(2,3,5-tri-O-propionyl-β-ribofuranosyl)-9H-purine
8. additionis added
9. stirringwith stirring to 620 ml of cyclohexylamine
10. temperatureheated to 105° C. over a period of 2 hours at a rate which
11. customat 105° C
12. stirringAfter this mixture is stirred at this temperature for an additional 17 hours
13. temperatureit is cooled to room temperature (25° C.) over approximately 2 hours
14. stirringwith efficient stirring
15. filtrationfiltered in a Buchner funnel with suction
16. additionThe solid containing N6 -cyclohexyladenosine and cyclohexylamine hydrochloride
17. washis washed with a total of 460 ml of toluene in four equal portions of 115 ml
18. customeach and transferred damp to a 5-liter flask
19. customequipped with a mechanical stirrer
20. additionAfter addition of 2 liters of aqueous saturated sodium bicarbonate solution and 2.5 liters of ethyl acetate
21. stirringthe mixture is stirred until all the solid
22. dissolutiondissolve (approximately 10-15 min.)
23. customThe organic layer is separated
24. extractionand the aqueous layer is extracted with 1.5 liters of ethyl acetate in two portions of 1 liter and 500 ml
25. customevaporated until about 3 liters of ethyl acetate (at 40° C., 100-200 mbar)
26. customis removed
27. additionof heptane is added
28. stirringand the resulting mixture is stirred for 30 minutes
29. customThe solids are separated on a Buchner funnel
30. washwashed with a total of 300 ml of heptane in three equal portions of 100 ml each
31. customThe solids are then dried at 45°-50° C. (30-35 mbar) for approximately 3 hours

ORD record

ord-a1467fc5f9784f858d423712c7473b82

Source dataset

uspto-grants-1997_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05596094