Low pressure N-debenzylation

[Barium]

This step can sometimes be tricky to perform, but it can nevertheless be a very useful way to make interesting amines. The choice of solvent seems to play a very important role here as does the addition of acid to protonate the liberated amine, thereby preventing it to poison the catalyst.

Patent US6218575

[Aurelius]

US patent 6218575

Process for Preparing Adrenaline

Abstract:

An improved process for preparing adrenaline, or an addition salt thereof, on an industrial scale, with asymmetric hydrogenation as a key step and a special sequence of successive steps, using [Rh(COD)Cl]2 as catalyst and a chiral, bidentate phophine ligand such as (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminocarbonylpyrrolidine as the catalyst system.

Other Related References:

Tet. Lett. 5 (1979), 425-428.  (from 3,4-dihydroxy-2-N-methylaminoacetophenone)
Achiwa, Tet. Lett. 30 (1989), 367-370.  (L-phenylephrine)
Chem. Pharm. Bull. 43 (5) (1995) 738-747. (L-phenylephrine)

Preparation of the Catalyst Solution:

6mg of dichlorobis [(cycloocta-1,5-diene) rhodium (I)] and 8.2mg of RR-MCCPM (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylaminocarbonylpyrrolidine)  are added to 10ml of degassed methanol under protective gas and stirred for 30 minutes at ambient temperature.

Example 1:

7.4g of the hydrochloride of beznyladrenalone 1 are dissolved in about 60 ml of methanol (degassed), 0.07ml of triethylamine and 10 ml of the catalyst solution (corresponding to 6mg of (RhCODCl)2 and 8.2mg of RR-MCCPM) are added and the mixture is hydrogenated at about 50*C under about 20 bar of hydrogen pressure.  After the reaction has ended the methanol is largely distilled off, about 30ml of water and about 0.5g of activated charcoal are added, the mixture is stirred for 30 minutes and filtered.  Then N-benzyladrenaline 2 is precipitated with about 10ml of water and about 15ml of methanol and by adding about 4ml of ammonia (about 25% strength) and then filtered off.  (R.T.) Yield : 6g ~ 90%

Benzyladrenaline 2 is dissolved in about 10ml of water and about 5ml  of 18% sulfuric acid (pH about 5.5), about 50mg of palladium-charcoal (10%) are added and the mixture is hydrogenated at about 60*C under 2 bar of hydrogen pressure.  It is then evaporated down to half its volume, about 20ml of methanol are added and the mixture is cooled.  The crystalline product (adrenaline sulfate 3) is filtered off and dried.

yield over all the steps taken together: about 4.5g  (about 75%) optical purity :> 98% ee (HPLC) chemical purity :>98% (HPLC).