3-Pyrrolidinemethanamine, 4-methyl-1-(phenylmethyl)- synthesis

Yield:959958-19-1 39%

Reaction Conditions:

with lithium aluminium tetrahydride in tetrahydrofuran at 0 - 25;

Steps:

AE.1

General Procedure AE: Reduction of a nitrile to an amineA flask is charged with a nitrile and an organic solvent such as THF, DCM, 1,4-dioxane, MeOH, toluene (preferably THF), and the mixture may be optionally cooled to about 0 to 10 °C. To the mixture is then added a reducing agent (such as LAH, Raney nickel /?, diborane, tin(II)chloride or cobalt(II)chloride). Optionally, the reducing agent can be added to the solvent followed by the cooling and then the nitrile is added. In cases where Raney nickel/H₂ is used, NH₃ or NH₄OH may be added and water may be used as co-solvent. The mixture is stirred at about 25 to 80 °C (preferably rt) for about 2 to 20 h (preferably about 4 to 8 h). The mixture may optionally be concentrated in vacuo to give the target compound. Alternatively, the mixture is optionally filtered through a media (such as silica gel or Celite) which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, Et₂0, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue as the target compound. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, Et₂0 or DCM). The organic layer is isolated and may optionally be washed in no particular order with water and/or aqueous solutions containing an acid (such as HC1, AcOH or NH₄C1) and/or aqueous solutions containing a base (such as NaHC0₃, Na₂C0₃, NaOH, KOH or NH₄OH) and/or aqueous solutions containing an inorganic salt (such as NaCl Na₂S0₃ or Na₂S₂0₃). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgS0₄ or Na₂S0 ), filtered and concentrated in vacuo to give the target compound.Illustration of General Procedure AE:Preparation No.AE.l (l-Benzyl-4-methylpyrrolidin-3-yl)methanamineTo a mixture of LAH (0.019 g, 0.499 mmol) in THF (5 mL) was added l-benzyl-4- methylpyrrolidine-3-carbonitrile (0.050 g, 0.250 mmol, Tyger) at about 0 °C, then the resulting mixture was stirred at about 25 °C for about 4 h. EtOAc (2 mL) and water (3 mL) were added and the precipitate formed was filtered off. The filtrate was concentrated to give (l-benzyl-4- methylpyrrolidin-3-yl)methanamine (0.05 g, 39 %): LCMS (Table 2 , Method 1) R, = 0.22 min.; MS m/z: 205 (M+H)⁺.

References:

WO2012/48222,2012,A1 Location in patent:Page/Page column 193-194