trans-4-Hydroxy-Crotonic Acid (T-HCA) [13,19]
Comment: T-HCA is 16% more potent as a GHB receptor agonist than GHB itself, and most T-HCA (trans-4-hydroxy-2-butenoic acid) derivatives are more
active than the corresponding GHB homologs. The 4-CH3 analog is 9%, and the 4-Ph analog is 27% more potent than GHB itself. The 4-C6H11 analog is 16%
less potent than GHB, and cis-4-Hydroxy-Crotonic Acid (C-HCA) is inactive. T-HCA has also been identified as a naturally occurring substance in the
CNS, which dismisses the theory of T-HCA just being a synthetic semi-rigid analog of GHB, but as a possible endogenous receptor ligand, which also
competes at GHB receptors, and possibly possesses specific functions of its own.
Synthesis:
To a solution of 20g (0.23 mole) of crotonic acid (2-butenoic acid) in 200ml of dry benzene, 45.6g (0.25 mole) of N-bromosuccinimide was added under
nitrogen. The solution was brought to a gentle reflux with stirring and was treated with 0.5g (3.7 mmol) of 2,2'-azobisisobutyronitrile as a radical
initiator. Refluxing was continued for 2 h, and the solution was cooled to 10°C. The resulting white precipitate was filtered off, and the filtrate
was evaporated in vacuo. The residue was taken up with 200ml of carbon tetrachloride and the mixture was cooled to 0°C and filtered. The filtrate was
evaporated in vacuo to give 38 gram of a mixture consisting of 85% 4-bromocrotonic acid and the rest unreacted starting material. Pure 4-bromocrotonic
acid can be obtained by multiple recrystallizations from petroleum ether.
To a cold solution of 12g (72 mmol) of 4-bromocrotonic acid in 120 ml of water was added dropwise 240 ml of a 2M KOH solution in water. After the
addition was completed, the solution was successively heated under reflux for 5 minutes (oil bath temp 120°C), cooled in an ice bath, and acidified
with dilute H2SO4. The medium was evaporated under vacuum, and extracted with ethyl ether. After the drying and evaporation of the solvent, the
residue was chromatographed on a silica gel column eluted with a mixture of EtOAc:MeOH (97:3) to yield 5.22 g (71%) of pure T-HCA. After
recrystallization from EtOAc, the mp was found to be 108°C.
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