1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 6-[5-(3-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-N-phenyl-1,3,5-triazine-2,4-diamine

3-Fluoropyridine-2-carboxylic acid (1.75 g, 12.38 mmol) was dissolved in pyridine (15 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.74 g, 14.28 mmol) was added. The mixture was stirred at room temperature for 2 h. 4-Amino-N′-hydroxy-6-(phenylamino)-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 4, 2.33 g, 9.52 mmol) was added and the mixture stirred at room temperature for 16 h. LCMS showed incomplete conversion, so further N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.30 g, 6.8 mmol) was added and the mixture stirred at room temperature for 3 h, before being heated to 60 C under nitrogen for 16 h. Pyridine was removed under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (100 mL), with the addition of brine (100 mL) to aid separation of an emulsion. The aqueous phase was then extracted with DCM (100 mL), which also formed an emulsion. After separation the aqueous phase was filtered to remove an insoluble gum. The aqueous phase was then further extracted with DCM (2×100 mL). The combined DCM and EtOAc layers were dried over sodium sulfate and concentrated under vacuum to yield a pale orange solid. This was purified by FCC using a gradient of 0-8% MeOH in DCM. The crude product was further purified by trituration with DCM to afford the title compound as a white solid (0.425 g, 13%).

1. additionwas added
2. stirringthe mixture stirred at room temperature for 16 h
3. additionwas added
4. stirringthe mixture stirred at room temperature for 3 h
5. temperaturebefore being heated to 60 C under nitrogen for 16 h
6. customPyridine was removed under vacuum and water (100 mL)
7. additionwas added to the residue
8. extractionThe mixture was extracted with EtOAc (100 mL), with the addition of brine (100 mL)
9. customseparation of an emulsion
10. extractionThe aqueous phase was then extracted with DCM (100 mL), which
11. customalso formed an emulsion
12. customAfter separation the aqueous phase
13. filtrationwas filtered
14. customto remove an insoluble gum
15. extractionThe aqueous phase was then further extracted with DCM (2×100 mL)
16. dry with materialThe combined DCM and EtOAc layers were dried over sodium sulfate
17. concentrationconcentrated under vacuum
18. customto yield a pale orange solid
19. customThis was purified by FCC
20. customThe crude product was further purified by trituration with DCM

ORD record

ord-b386c856710a4ef081fafdb95ed07ce7

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08895733B2