#103 MDBZN-BENZYL-MDA; 3,4-METHYLENEDIOXY-N-BENZYLAMPHETAMINE
|[3D .mol structure]|
DOSAGE: greater than 150 mg.
EXTENSIONS AND COMMENTARY: The benzyl group is a good ally in the synthetic world of the organic chemist, in that it can be easily removed by catalytic hydrogenation. This is a trick often used to protect (for a step or series of steps) a position on the molecule, and allowing it to become free and available at a later part in a synthetic scheme. In pharmacology, however, it is often a disappointment. With most centrally active alkaloids, there is a two-carbon separation between the weak base that is called the aromatic ring, and the strong base that is called the nitrogen. This is what makes phenethylamines what they are. The phen- is the aromatic ring (this is a shortened form of prefix phenyl which is a word which came, in turn, from the simplest aromatic alcohol, phenol); the ethyl is the two carbon chain, and the amine is the basic nitrogen. If one carbon is removed, one has a benzylamine, and it is usually identified with an entirely different pharmacology, or is most often simply not active. A vivid example is the narcotic drug, Fentanyl. The replacement of the phenethyl group, attached to the nitrogen atom with a benzyl group, virtually eliminates its analgesic potency.
Here too, there appears to be little if any activity in the N-benzyl analogue of MDA. A number of other variations had been synthesized, and none of them ever put into clinical trial. With many of them there was an ongoing problem in the separation of the starting amine from the product amine. Sometimes the difference in boiling points could serve, and sometimes their relative polarities could be exploited. Sometimes, ion-pair extraction would work wonders. But occasionally, nothing really worked well, and the final product had to be purified by careful crystallization.
Several additional N-homologues and analogues of MDA are noted here. The highest alkyl group on the nitrogen of MDA to give a compound that had been assayed, was the straight-chain butyl homologue, MDBU. Six other N-alkyls were made, or attempted. Isobutylamine hydrochloride and 3,4-methylenedioxyphenylacetone were reduced with sodium cyanoborohydride in methanol to give 3,4-methylenedioxy-N-(i)-butylamphetamine boiling at 95-105 °C at 0.15 mm/Hg and giving a hydrochloride salt (MDIB) with a mp of 179-180 °C. Anal. (C14H22ClNO2) N. The reduction with sodium cyanoborohydride of a mixture of (t)-butylamine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol produced 3,4-methylenedioxy-N-(t)-butylamphetamine (MDTB) but the yield was miniscule. The amyl analog was similarly prepared from (n)-amylamine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol to give 3,4-methylenedioxy-N-amylamphetamine which distilled at 110-120 °C at 0.2 mm/Hg and formed a hydrochloride salt (MDAM) with a mp of 164-166 °C. Anal. (C15H24ClNO2) N. A similar reaction with (n)-hexylamine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol, with sodium cyanoborohydride, produced after acidification with dilute sulfuric acid copious white crystals that were water and ether insoluble, but soluble in methylene chloride! This sulfate salt in methylene chloride was extracted with aqueous sodium hydroxide and the remaining organic solvent removed to give a residue that distilled at 110-115 °C at 0.2 mm/Hg to give 3,4-methylenedioxy-N-(n)-hexylamphetamine which, as the hydrochloride salt (MDHE) had a mp of 188-189 °C. Anal. (C16H26ClNO2) N. An attempt to make the 4-amino-heptane analogue from the primary amine, 3,4-methylenedioxyphenylacetone, and sodiumcyanoborohydride in methanol seemed to progress smoothly, but none of the desired product 3,4-methylenedioxy-N-(4-heptyl)-amphetamine could be isolated. This base has been named MDSE, with a SE for septyl rather than HE for heptyl, to resolve any ambiguities about the use of HE for hexyl. In retrospect, it had been assumed that the sulfate salt would have extracted into methylene chloride, and the extraordinary partitioning of the sulfate salt of MDHE mentioned above makes it likely that the sulfate salt of MDSE went down the sink with the organic extracts of the sulfuric acid acidified crude product. Next time maybe ether as a solvent, or citric acid as an acid. With (n)-octylamine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol, with sodium cyanoborohydride, there was obtained 3,4-methylenedioxy-N-(n)-octylamphetamine as a water-insoluble, ether-insoluble sulfate salt. This salt was, however, easily soluble in methylene chloride, and with base washing of this solution, removal of the solvent, and distillation of the residue (130-135 °C at 0.2 mm/Hg) there was eventually gotten a fine hydrochloride salt (MDOC) as white crystals with a mp of 206-208 °C. Anal. (C18H30ClNO2) N.
As to N,N-dialkylhomologues of MDA, the N,N-dimethyl has been separately entered in the recipe for MDDM. Two efforts were made to prepare the N,N-diethyl homologue of MDA. The reasonable approach of reducing a mixture of diethylamine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol with sodium cyanoborohydride was hopelessly slow and gave little product. The reversal of the functionality was successful. Treatment of MDA (as the amine) and an excess of acetaldehyde (as the carbonyl source) with sodium borohydride in a cooled acidic medium gave, after acid-base workup, a fluid oil that distilled at 85-90 °C at 0.15 mm/Hg and was converted in isopropanol with concentrated hydrochloric acid to 3,4-methylenedioxy-N,N-diethylamphetamine (MDDE) with a mp of 177-178 °C. Anal. (C14H22ClNO2) N.
And two weird N-substituted things were made. Aminoacetonitrile sulfate and 3,4-methylenedioxyphenylacetone were reduced in methanol with sodium cyanoborohydride to form 3,4-methylenedioxy-N-cyanomethylamphetamine which distilled at about 160 °C at 0.3 mm/Hg and formed a hydrochloride salt (MDCM) with a mp of 156-158 °C after recrystallization from boiling isopropanol. Anal. (C12H15ClN2O2) N. During the synthesis of MDCM, there appeared to have been generated appreciable ammonia, and the distillation provided a fore-run that contained MDA. The desired product had an acceptable NMR, with the N-cyanomethylene protons as a singlet at 4.38 ppm. A solution of t-butylhydrazine hydrochloride and 3,4-methylenedioxyphenylacetone in methanol was reduced with sodium cyanoborohydride and gave, after acid-basing and distillation at 95-105 °C at 0.10 mm/Hg, a viscous amber oil which was neutralized in isopropanol with concentrated hydrochloric acid to provide 3,4-methylenedioxy-N-(t)-butylaminoamphetamine hydrochloride (MDBA) with a mp of 220-222 °C with decomposition. Anal. (C14H23ClN2O2); N: calcd, 9.77; found, 10.67, 10.84.
|[ Back]||[Main Index]||[Forward ]|