A New Route to 5-Amino Levulinic Acid

Inventor Sven Aldenkortt was recently awarded US patent #7,319,164 for developing a process for producing 5-azido levulinic acid.  You might be asking yourself about the utility of the compound. The azide moiety can be reduced to the corresponding amine, providing 5-amino levulinic acid hydrochloride, which is a useful synthon.

There have been several attempts at accessing 5-amino levulinic acid, each with its own set of disadvantages.  Some cited procedures involve the use of toxic reagents or require complex workups (Tetrahedron Lett. 1984, 25, 2977-2980, Synthesis 1999, 568-570).  The disadvantage in these cases is dealing with “unwanted chemicals” (which is code "waste").  At least one of the cited previous procedures required used of N-protecting groups (U.S. patent # 5,380,935), which is undesirable because it affects atom economy.  A couple references cite use of photosensitizers such as C60 or rose Bengal (for example see: Synthesis 1995, 303-306).  Having no experience with either chemical, I couldn't tell you if this is good or bad; Aldenkortt claims that they are a disadvantage. 

I thought that Aldenkortt's route was interesting for 2 reasons.  First, the chemistry doesn’t require any wacky reagents or random protocols.  I often encounter across strange procedures that (at least in my mind) could be avoided with careful reagent/solvent/heating choice.  There's something to be said for doing good chemistry with cheap reagents.  Furthermore, there's nothing strange or wacky about crystallizing the products after workup (the purification method of choice in this invention).  Second, the yields are quite high. 

Anyhow, beginning with methyl 5-bromo levulinate (purportedly accessed by direct bromination of methyl levulinate in a whopping 9.5 %), Aldenkortt accessed 5-chloro levulinic acid in 24 h using 3M HCl.  The azide was then installed using sodium azide in warm acetone (similar to a Finkelstein reaction where the resultant NaCl is simply filtered off).  Finally, catalytic hydrogenation in acidic media gave the 5-amino levulinic acid hydrochloride. 

The inventor notes that the serious pitfall in the process involves starting from methyl 5-bromo levulinate (apart from the notably poor yields resulting from direct bromination of either methyl levulinate or levulinic acid).  Methyl 5-bromo levulinate is a nasty lachrymator that has the tendency to decompose and/or isomerize in the presence of acid.  It turns out that 5-chloro levulinic acid is actually stable, crystalline and won’t make you cry. 

The inventor notes that 5-azido levulinic acid has an impact energy (i.e. the total energy absorbed until fracture) of 40 J, which may have “utility as a priming fuse” in motor vehicle airbags.