SYNTHESIS: To a suspension of 18.6 g benzylamine hydrochloride in 50 mL warm MeOH there was added 2.4 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.0 g sodium cyanoborohydride. Concentrated HCl in MeOH was added over several days as required to maintain the pH at about 6 as determined with external, dampened universal paper. When the demand for acid ceased, the reaction mixture was added to 400 mL H2O and made strongly acidic with an excess of HCl. This was extracted with 3×150 mL CH2Cl2 (these extracts must be saved as they contain the product) and the residual aqueous phase made basic with 25% NaOH and again extracted with 4×100 mL CH2Cl2. Removal of the solvent under vacuum and distillation of the 8.7 g pale yellow residue at slightly reduced pressure provided a colorless oil that was pure, recovered benzylamine. It was best characterized as its HCl salt (2 g in 10 mL IPA neutralized with about 25 drops concentrated HCl, and dilution with anhydrous Et2O gave beautiful white crystals, mp 267-268 °C). The saved CH2Cl2 fractions above were extracted with 3×100 mL dillute H2SO4. These pooled extracts were back-washed once with CH2Cl2, made basic with 25% NaOH, and extracted with 3×50 mL CH2Cl2. The solvent was removed from the pooled extracts under vacuum, leaving a residue of about 0.5 g of an amber oil. This was dissolved in 10 mL IPA, neutralized with concentrated HCl (about 5 drops) and diluted with 80 mL anhydrous Et2O. After a few min, 3,4-methylenedioxy-N-benzylamphetamine hydrochloride (MDBZ) began to appear as a fine white crystalline product. After removal by filtration, Et2O washing and air drying, this weighed 0.55 g, and had a mp of 170-171 °C with prior shrinking at 165 °C. Anal. (C17H20ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

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.

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