[(1R)-1-Cyclohexylethyl](methyl)amine synthesis

Yield:163667-49-0 72%

Reaction Conditions:

Stage #1: N-[(1R)-1-cyclohexyl-ethyl]-formamidewith lithium aluminium tetrahydride in tetrahydrofuran at 0; for 8 h;Heating / reflux;
Stage #2: with sodium hydroxide;water in tetrahydrofuran at 0;

Steps:

17

Ethyl formate (1.2 mL, 15.0 mMol) was added to a round bottom flask containing (1R)-1-cyclohexyl-ethylamine Compound 17a (1.27 g, 10 mMol) at 0° C. and the mixture was stirred at r.t. for 15 hrs. Excess ethyl formate was removed in vacuo to obtain N-[(1R)-1-cyclohexyl-ethyl]-formamide Compound 17b (1.55 g) as a white solid, which was used in the next step without purification. MS m/z 156 (MH⁺). A solution of LAH in THF (1.0 M, 15 mL, 15 mMol) was added dropwise via syringe to a solution of Compound 17b (1.55 g, 10 mMol) in anhydrous THF at 0° C. The mixture was heated to reflux for 8 hrs and provided a grayish suspension. The suspension was cooled to 0° C. and the reaction was quenched carefully by a sequential addition of water (0.6 mL), 2N NaOH (0.6 mL) and water (2.0 mL). A white residue was produced, then filtered through a sintered glass funnel and washed with Et₂O (20 mL). The solvent from the combined filtrate was removed in vacuo to provide [(1R)-1-cyclohexyl-ethyl]-methylamine Compound 17c (1.1 g, 72%) as a pale yellow oil, which was used in the next step without purification. MS m/z 142 (MH⁺). The acid chloride Compound 5e (0.04 g, 0.15 mMol) was added to a solution of the methylamine Compound 17c (0.05 g, 0.035 mMol) in CH₂Cl₂ (2 mL) and triethylamine (0.06 mL, 0.5 mMol). The resulting suspension was stirred at r.t. for 2 hrs, diluted with CH₂Cl₂ (10 mL), then washed with 1N HCl (2×10 mL) and water (2×10 mL). The organic layer was dried over sodium sulfate, then concentrated and purified on a silica gel column (eluted with 20% EtOAc in hexane) to provide Compound 328 (44 mg, 80%). MS m/z 372 (MH⁺).

References:

US2005/228034,2005,A1 Location in patent:Page/Page column 117-118