Reaktion #561202

Reaktionsgleichung

6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine

3-cyclopropyl-3-fluoroazetidine hydrochloride

diisopropylethylamine

isopropanol

→

desired product

Ausbeute 80.0%

6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine

Ausbeute 80.0%

Lösungsmittel

Hexane

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe mixture was heated
2. 2
   Temperaturto reflux for 23 hours
3. 3
   Filtrationfiltered
4. 4
   EinengenThe homogeneous solution was concentrated to a minimal volume
5. 5
   workup.ADDITIONEtOAc was then added (1 L)
6. 6
   Einengenthe solution was concentrated to a minimal volume
7. 7
   workup.ADDITIONEtOAc (1 L) and H2O (1 L) were then added
8. 8
   Sonstigethe layers were separated
9. 9
   Sonstigeto crystallize out of the organic layer during the extraction
10. 10
    ExtraktionThe aqueous layer was further extracted with EtOAc (500 ml)
11. 11
    EinengenThe 1st organic layer was concentrated to dryness
12. 12
    Sonstigeto give a white solid
13. 13
    Extraktionorganic extract
14. 14
    Temperaturcooled to 0° C. for 30 min
15. 15
    FiltrationThe slurry was filtered
16. 16
    Waschenwashed with copious Heptane
17. 17
    SonstigeThe filter cake was dried under vacuum
18. 18
    ExtraktionThe filter cake and the white solid from the 1st extraction

Vorschrift

To a mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (150 g, 0.58 mol) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (132.2 g, 0.87 mol) was added diisopropylethylamine (208 g, 1.61 mol) and isopropanol (1.125 L). The mixture was heated to reflux for 23 hours. The reaction was then cooled to 85° C. (a slightly hazy solution) and filtered. The homogeneous solution was concentrated to a minimal volume. EtOAc was then added (1 L) and the solution was concentrated to a minimal volume. EtOAc (1 L) and H2O (1 L) were then added and the layers were separated. Crystallized product began to crystallize out of the organic layer during the extraction. The aqueous layer was further extracted with EtOAc (500 ml). The 1st organic layer was concentrated to dryness to give a white solid. Hexane (750 ml) was added to the second organic extract and the slurry was stirred at ambient temperature, and then cooled to 0° C. for 30 min. The slurry was filtered and washed with copious Heptane. The filter cake was dried under vacuum. The filter cake and the white solid from the 1st extraction were combined to afford 155.1 g of the desired product. (155.1 g, 77%). 1H NMR (DMSO, 400 MHz) 0.44 (2H; m), 0.60 (2H, m), 1.38-1.43 (1H, m), 2.18 (3H, s), 2.42 (3H, s), 3.89-3.97 (4H, m), 5.92 (1H, br s), 6.04 (1H, br s), 9.23 (1H, s), 11.86 (1H, s). ES+335

Quelle