Chloroacetyl chloride → (2S)-3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol

3-Fluorobenzonitrile (3.2 mL, 30 mmol,) and hydroxylamine hydrochloride (4.6 g, 65.8 mmol) in ethanol (30 mL) at 0° C. was treated with triethylamine (9.6 mL, 69 mmol). The solution was allowed to warm to room temperature, then shaken on a J-Kem™. block at 80° C. overnight. Upon cooling, ethyl acetate (40 mL) was added and the precipitate filtered and washed with ethyl acetate (˜100 mL). The filtrate was washed with brine, dried (MgSO4), filtered and concentrated. The crude product (3-fluorophenyl)(hydroxyimino)methylamine (4.96 g, 107%), a compound of formula (9), was used in the next step without further purification. B (3-Fluorophenyl)(hydroxyimino)methylamine (4.96 g, 32.2 mmol) in dichloroethane (45 mL) was cooled to −20° C. and diisopropylethylamine (22.5 mL, 130 mmol) was added dropwise. The solution was stirred for 10 minutes at −20° C., then chloroacetylchloride (11.25 mL, 141 mmol) was added dropwise over ˜5 min. The dark black solution was allowed to warm to room temperature, then shaken on a J-Kem™. block at 85° C. overnight. Upon cooling, the reaction mixture was diluted with dichloromethane (˜200 mL), washed with water (×2) and brine, dried (MgSO4), filtered and concentrated to a black oil. The oil was dissolved in 9:1 hexanes/ethyl acetate and filtered through a plug of SiO2. The plug was washed first with 9:1 hexanes/ethyl acetate, then with ethyl acetate. The combined filtrates were concentrated and the product, 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole, a compound of formula (11), was used in next step without further purification. C. To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 in, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10×, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield (2S)-3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I, (136 mg, 30%). D. Preparation of a Compound of Formula I, varying R1, R2, R3, R4, R5, R6, R7 R8, T, X1, X2, Z1 and Z2

1. customat 80° C.
2. customovernight
3. temperatureUpon cooling
4. filtrationthe precipitate filtered
5. washwashed with ethyl acetate (˜100 mL)
6. washThe filtrate was washed with brine
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated
10. customThe crude product (3-fluorophenyl)(hydroxyimino)methylamine (4.96 g, 107%), a compound of formula (9), was used in the next step without further purification
11. stirringThe solution was stirred for 10 minutes at −20° C.
12. temperatureto warm to room temperature
13. stirringshaken on a J-Kem™
14. customat 85° C.
15. customovernight
16. temperatureUpon cooling
17. washwashed with water (×2) and brine
18. dry with materialdried (MgSO4)
19. filtrationfiltered
20. concentrationconcentrated to a black oil
21. dissolutionThe oil was dissolved in 9:1 hexanes/ethyl acetate
22. filtrationfiltered through a plug of SiO2
23. washThe plug was washed first with 9:1 hexanes/ethyl acetate
24. concentrationThe combined filtrates were concentrated
25. customthe product, 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole, a compound of formula (11), was used in next step without further purification
26. stirringthe reaction was shaken on a J-Kem™ block overnight at 90° C
27. temperatureUpon cooling to room temperature
28. concentrationthe solution was concentrated to an oil
29. custompurified on an Isco™ Combi Flash Si 10×
30. washeluting with ethyl acetate

ORD-Eintrag

ord-06231245923a48b2a9609377b38085a4

Quelldatensatz

uspto-grants-2006_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07001909B2