Diisopropylethylamine → (S)-2-methyl-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-1-one

Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (8.74 g; 22.6 mmol) is added to a solution of (S)-2-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid (13.0 g; 41.1 mmol, prepared in accordance with Example 67) is a mixture of dichloromethane (540 mL) and dimethylsulfoxide (10 mL). After stiffing for 10 minutes, (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine (11.32 g; 39.1 mmol, free base of Example 8) and diisopropylethyl amine (15.15 g; 39.1 mmol) are added and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and is dissolved in dichloromethane (250 mL). The organic phase is washed with water (2×500 mL), aq. sat. potassium carbonate (250 mL) and with brine (250 mL), is then dried over sodium sulfate and the solvent is removed under reduced pressure. The residue obtained is then diluted in ethyl acetate (250 mL), the organic phase is washed with water (2×1500 mL) is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (ethyl acetate:acetone 1:0 and then 9:1). After concentration of the fractions of interest, the product is dissolved in hot methanol (800 mL), and the solution is concentrated under vacuum. The solid obtained is finally dried at 40° C. under 3 mbar to afford the desired product (15.56 g; 26.5 mmol). The structure was confirmed using Protocol I-B. Calculated mass=588; observed mass=588; HPLC retention time=5.03 min.

1. concentrationThe reaction mixture is then concentrated under reduced pressure
2. dissolutionis dissolved in dichloromethane (250 mL)
3. washThe organic phase is washed with water (2×500 mL), aq. sat. potassium carbonate (250 mL) and with brine (250 mL)
4. dry with materialis then dried over sodium sulfate
5. customthe solvent is removed under reduced pressure
6. customThe residue obtained
7. washthe organic phase is washed with water (2×1500 mL)
8. dry with materialis dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customThe crude product is purified by column chromatography on silica gel (ethyl acetate:acetone 1:0
12. dissolutionAfter concentration of the fractions of interest, the product is dissolved in hot methanol (800 mL)
13. concentrationthe solution is concentrated under vacuum
14. customThe solid obtained
15. customis finally dried at 40° C. under 3 mbar

ORDレコード

ord-dbb26603a27a451ba8fae97179c3afb4

出典データセット

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09096524B2