Dibenzyl amine compounds and derivatives
A technology of compounds, chemical formulas, applied in the field of dibenzylamine compounds and derivatives
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Embodiment 1
[0387] Example 1: (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl- Benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
[0388]
[0389] Step A: Preparation of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4- Trifluoromethyl-phenyl)-cyclohexyl-methanol
[0390]
[0391] To 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino in THF (3 mL) at 0°C To a solution of ]-methyl}-4-trifluoromethyl-benzaldehyde (244 mg, 0.48 mmol) was added cyclohexylmagnesium bromide (18% solution in THF, 0.6 mL, 0.57 mmol), And the reaction was warmed to room temperature and stirred overnight. The reaction mixture was dissolved in aqueous NH 4 Quenched with Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on a 25+S Biotage silica column (eluting with 0-30% ethyl acetate in hexanes) to yield 110 mg (39%) ...
Embodiment 2 and 3
[0395] Examples 2 and 3: (R)- and (S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl Base)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
[0396]
[0397] The enantiomers of Example 1 were prepared as follows. A racemic mixture (110 mg) of the alcohol from step A of Example 1 was dissolved in methanol and injected onto a Chiralpak AD column (2.1 cm x 25 cm) (Chiral Tech Inc. Westchester, PA, USA) using heptane / 2-propanol (90:10, 20 mL / min) eluted. On the Chiralpak AD-H column, enantiomer 1 (37 mg, 97.5% ee) eluted at 7.364 minutes and enantiomer 2 (18.8 mg, 85% ee) at 8.948 minutes. Each enantiomer was converted to the title compound according to the procedure described in Example 1, Step B. Found MS for each enantiomer: 610.4 (M+1).
Embodiment 4
[0398] Example 4: (S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoro Methyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
[0399]
[0400] Step A: Preparation of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4- Trifluoromethyl-phenyl)-cyclohexyl-methanol
[0401]
[0402] To (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrafluoromethyl-benzyl)-(2-methyl-2H-tetra To a solution of azol-5-yl)-amine (from Preparation 6, 6.08 g, 10.8 mmol) was added isopropylmagnesium chloride / lithium chloride in THF (21 mL, 27 mmol). The isopropylmagnesium chloride / lithium chloride reagent was prepared according to the procedure described in Angew. Chem. Int. Ed. 2004, 43, 3333. The mixture was stirred at 0°C for 3.5 hours. Cyclohexanecarbaldehyde (3.3 g, 29 mmol) was added. The mixture was stirred at 0°C for 3.5 hours, quenched with saturated aqueous ammonium chloride, and extracted wit...
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