Phenyl vinyl sulfone → HCID 59459699, compound

Temperature

100 °C

To a stirred suspension of 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(31)-one (31.62 g), as prepared in Example 1 (c) above, in butyronitrile (150 ml) at room temperature was added diisopropylethylamine (16 ml, 1.0 eq), forming a solution. A butyronitrile line wash was applied (10 ml). Phenylvinylsulfone (20 g, 1.3 eq) was dissolved in butyronitrile (80 ml) in a separate flask and this solution was added to the vessel, followed by a line wash with butyronitrile (70 ml). The orange solution was heated to an internal temperature of 100° C. After 18 hours HPLC showed almost complete consumption of the starting material (3.36% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one remained)*. At this point further diisopropylethylamine (16 ml, 1.0 eq) was added to the mixture at 50° C., followed by a small line wash of butyronitrile (5 ml). D-alaninol (9.25 mLs, 1.3 eq) was added, followed by a line wash of butyronitrile (5 ml). After 6.5 hrs HPLC showed almost complete conversion of the reaction intermediate (2.52% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2-(3H)-one remained). The reaction was allowed to cool from 100 to 50° C. over 6.5 hrs and held at 50° C. under nitrogen for 64 hrs. In order to get a homogeneous sample the reaction was re-heated to 100° C. (1.19% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one present by HPLC). The reaction was cooled from 100 to 50° C. over 1 hr and water (200 mLs) was added. A precipitate was observed. The mixture was cooled from 50° C. to 20° C. over 2 hrs. The precipitate was ‘aged’ at 20° C. for 1 hr and collected by filtration. The ‘cake’ was washed with 1:1 water/butyronitrile (70 ml) twice, then with butyronitrile (35 ml). The solid was then dried on the filter for 30 mins, collected and dried in a vacuum oven overnight at 50° C. A pale yellow solid 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one was obtained with 88% yield (44.33 g, HPLC area=98.75%).

1. customat room temperature
2. customforming a solution
3. washA butyronitrile line wash
4. additionthis solution was added to the vessel
5. washwash with butyronitrile (70 ml)
6. customconsumption of the starting material (3.36% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one remained)*
7. washwash of butyronitrile (5 ml)
8. washwash of butyronitrile (5 ml)
9. waitAfter 6.5 hrs HPLC showed almost complete
10. temperatureto cool from 100 to 50° C. over 6.5 hrs
11. waitheld at 50° C. under nitrogen for 64 hrs
12. customIn order to get a homogeneous sample the reaction
13. temperatureThe reaction was cooled from 100 to 50° C. over 1 hr
14. temperatureThe mixture was cooled from 50° C. to 20° C. over 2 hrs
15. customat 20° C.
16. customfor 1 hr
17. filtrationcollected by filtration
18. washThe ‘cake’ was washed with 1:1 water/butyronitrile (70 ml) twice
19. customThe solid was then dried on the
20. filtrationfilter for 30 mins
21. customcollected
22. customdried in a vacuum oven overnight at 50° C

ORD record

ord-a85e5742209c4d96bfe0673476cf2d84

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07790883B2