Acetic Acid → Methyl 3-{[(2R*,6S*)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate

To a stirred mixture of MS3A (1.0 g), methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (350 mg, 1.50 mmol) and (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (359 mg, 1.65 mmol) in chloroform (10 mL) was added acetic acid (500 uL) at 0° C. and stirred at r.t. for 7 hours. To the reaction mixture was added sodium triacetoxyborohydride (670 mg, 3.00 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 1.5 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The MS 3 Å was removed by Celite filtration and the content was extracted with ethylacetate, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1). Target fractions were collected and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (223 mg, 62% yield.). For major isomer; 1H-NMR (400 MHz, CDCl3) δppm; 7.40-7.21 (m, 6H), 6.85 (s, 1H), 4.00-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (d, 2H), 3.84-3.76 (m, 1H), 2.83-2.73 (m, 2H), 2.25 (s, 3H), 1.83-1.69 (m, 4H), 1.13 (d, J=6.4 Hz, 6H).

1. stirringThe reaction mixture was stirred at 23° C. for 1.5 hours
2. customThen the reaction mixture was quenched with aq. NaHCO3 until pH8-9
3. customThe MS 3 Å was removed by Celite filtration
4. extractionthe content was extracted with ethylacetate
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationthe filtrate was concentrated in vacuo
8. customThe residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1)
9. customTarget fractions were collected
10. concentrationconcentrated in vacuo
11. customThe residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1)

ORDレコード

ord-346c22af2de44ed39dcbaacc6d82b582

出典データセット

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09376422B2