The two possible homologues, with either one or two methyl groups on the methylene carbon of the methylenedioxy group of MDA, are also known. The ethylidene compound (the acetaldehyde addition to the catechol group) has been encoded as EDA, and the acetone (isopropylidine addition to the catechol group) is called IDA. In animal discrimination studies, and in in vitro neurotransmitter studies, they both seem to be of decreased potency. EDA is down two to three-fold from MDA, and IDA is down by a factor of two to three-fold again. Human trials of up to 150 milligrams of the hydrochloride salt of EDA producd at best a threshold light-headedness. IDA remains untested as of the present time. The homologue of MDA (actually of MDMA) with the added carbon atom in, rather than on, the methylenedioxy ring, is a separate entry; see MDMC.
A final isomer to be mentioned is a positional isomer. The 3,4-methylene-dioxy group could be at the 2,3-position of the amphetamine skeleton, giving 2,3-methylenedioxyamphetamine, or ORTHO-MDA. It appears to be a stimulant rather than another MDA. At 50 milligrams, one person was awake and alert all night, but reported no MDA-like effects.
101 MDAL; N-ALLYL-MDA; 3,4-METHYLENEDIOXY-N- ALLYLAMPHETAMINE
SYNTHESIS: A total of about 20 mL allylamine was introduced under the surface of 20 mL concentrated HCl, and the mixture stripped of volatiles under vacuum The resulting 24 g of wet material did not yield any crystals with either acetone or Et2O. This was dissolved in 75 mL MeOH, treated with 4.45 g 3,4-methylenedioxy-phenylacetone (see under MDMA for its preparation), and finally with 1.1 g sodium cyanoborohydride. Concentrated HCl was added as needed over the course of 5 days to keep the pH constant at about 6. The reaction mixture was then added to a large amount of H2O, acidified with HCl, and extracted with 3x100 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from these extracts yielded 3.6 g of an amber oil which, on distillation at 90-95 !C at 0.2 mm/Hg, yielded 2.6 g of an off-white oil. This was dissolved in 10 mL IPA, neutralized with about 25 drops of concentrated HCl, and the resulting clear but viscous solution was diluted with Et2O until crystals formed. These were removed by filtration, washed with IPA/Et2O (1:1), then with Et2O, and air dried to constant weight. There was thus obtained 2.5 g of 3,4-methylenedioxy-N-allylamphetamine hydrochloride (MDAL) with a mp of 174-176 !C and a proton NMR spectrum that showed that the allyl group was intact. Anal. (C13H18ClNO2) N.
DOSAGE: greater than 180 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: Here is another inactive probe, like MDPR, that could possibly serve as a primer to LSD. The three carbon chain on the nitrogen seen with MDPR is almost identical to the three carbon chain on the nitrogen atom of MDAL. And yet, where an RinactiveS
level of 180 milligrams of MDPR is a rather fantastic enhancer of LSD
action, the same weight of this compound not only does not enhance, but actually seems to somewhat antagonize the action of LSD. All this difference from just a couple of hydrogen atoms. Identical carbon atoms, identical oxygen atoms, and an identical nitrogen atom. And all in identical places. Simply C13H18ClNO2 rather than C13H20ClNO2.
So, apparently, almost identical is not good enough!
102 MDBU; N-BUTYL-MDA; 3,4-METHYLENEDIOXY-N-BUTYLAMPHETAMINE
SYNTHESIS: A total of 30 mL butylamine was introduced under the surface of 33 mL concentrated HCl, and the mixture stripped of volatiles under vacuum. The resulting glassy solid was dissolved in 160 mL MeOH and treated with 7.2 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation). To this there was added 50%
NaOH dropwise until the pH was at about 6 as determined by the use of external dampened universal pH paper. The solution was vigorously stirred and 2.8 g sodium cyanoborohydride was added. Concentrated HCl was added as needed, to keep the pH constant at about 6. The addition required about two days, during which time the reaction mixture first became quite cottage-cheese like, and then finally thinned out again.
All was dumped into 1 L H2O acidified with HCl, and extracted with 3x100 mL CH2Cl2. These extracts were combined, extracted with 2x100
mL dilute H2SO4, which was combined with the aqueous fraction above.
This latter mixture was made basic with 25% NaOH, and extracted with 3x150 mL CH2Cl2. Evaporation of the solvent yielded 4.0 g of an amber oil which, on distillation at 90-100 !C at 0.15 mm/Hg, yielded 3.2 g of a white clear oil. This was dissolved in 20 mL IPA, neutralized with 30 drops of concentrated HCl, and the spontaneously formed crystals were diluted with sufficient anhydrous Et2O to allow easy filtration. After Et2O washing and air drying, there was obtained 2.8
g of 3,4-methylenedioxy-N-butylamphetamine hydrochloride (MDBU) as white crystals with a mp of 200-200.5 !C. Anal. (C14H22ClNO2) N.
DOSAGE: greater than 40 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: Straight chain homologues on the nitrogen atom of MDA longer than two carbons are probably not active. This butyl compound provoked no interest, and although the longer chain counterparts were made by the general sodium cyanoborohydride method (see under MDBZ), they were not tasted. All mouse assays that compared this homologous series showed a consistent decrease in action (anesthetic potency and motor activity) as the alkyl chain on the nitrogen atoms was lengthened.
This synthetic procedure, using the hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems to be quite general for ketone compounds related to 3,4-methylenedioxyphenylacetone. Not only were most of the MD-group of compounds discussed here made in this manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P) itself appears to be equally effective. The reaction of butylamine hydrochloride in methanol, with phenyl-2-propanone and sodium cyanoborohydride at pH of 6, after distillation at 70-75 !C at 0.3
mm/Hg, produced N-butylamphetamine hydrochloride (23.4 g from 16.3 g P-2-P). And, in the same manner with ethylamine hydrochloride there was produced N-ethylamphetamine (22.4 g from 22.1 g P-2-P) and with methylamine hydrochloride there was produced N-methylamphetamine hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple ammonia (as ammonium acetate) gives consistently poor yields in these reactions.
103 MDBZ; N-BENZYL-MDA; 3,4-METHYLENEDIOXY-N-BENZYLAMPHETAMINE
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 3x150 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 4x100
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 3x100 mL dillute H2SO4. These pooled extracts were back-washed once with CH2Cl2, made basic with 25% NaOH, and extracted with 3x50 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.
104 MDCPM; CYCLOPROPYLMETHYL-MDA;
3,4-METHYLENEDIOXY-N-CYCLOPROPYLMETHYLAMPHETAMINE
SYNTHESIS: A solution of 9.4 g cyclopropylmethylamine hydrochloride in 30 mL MeOH was treated with 1.8 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 0.5 g sodium cyanoborohydride. Concentrated HCl was added as needed to keep the pH
constant at about 6. After several days stirring, the reaction mixture was added to H2O, acidified with HCl, and washed with 2x100 mL
CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 3x150 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 2.8 g of a crude product which, on distillation at 90-100 !C at 0.1 mm/Hg, yielded 0.4 g of a clear white oil. This was dissolved in a small amount of IPA, neutralized with a few drops of concentrated HCl, and diluted with anhydrous Et2O to the point of turbidity. There was obtained a small yield of crystalline 3,4-methylenedioxy-N-cyclopropylmethylamphetamine hydrochloride (MDCPM) which was filtered off, Et2O washed and air dried. The mp was 218-220 !C, with extensive darkening just prior to melting. Anal.
(C14H20ClNO2) N.
DOSAGE: greater than 10 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: The record of the tasting assay of this compound is pretty embarrassing. The highest level tried was 10
milligrams, which showed no hint of activity. But in light of the rather colorful activities of other cyclopropylmethyl things such as CPM and 2C-T-8 , this compound might someday warrant reinvestigation.
It is a certainty that the yield could only be improved with a careful resynthesis.
105 MDDM; N,N-DIMETHYL-MDA;
3,4-METHYLENEDIOXY-N,N-DIMETHYLAMPHETAMINE
SYNTHESIS: To a well stirred solution of 9.7 g dimethylamine hydr
ochloride in 50 mL MeOH there was added 3.56 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 0.88 g sodium cyanoborohydride. A 1:1 mixture of concentrated HCl and MeOH was added as required to maintain the pH at about 6 as determined with external, dampened universal paper. Twenty drops were called for over the first four h, and a total of 60 drops were added over the course of two days at which time the reduction was complete. After the evaporation of most of the MeOH solvent, the reaction mixture was added to 250 mL H2O and made strongly acidic with an excess of HCl. After washing with 2x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL
CH2Cl2. Removal of the solvent under vacuum yielded a nearly colorless oil that was distilled at 85-90 !C at 0.3 mm/Hg. There was obtained 1.5 g of a water-white oil that was dissolved in 8 mL IPA, neutralized with concentrated HCl and then diluted with 10 mL
anhydrous Et2O. The slightly turbid solution deposited a light lower oily layer which slowly crystallized on scratching. With patience, an additional 75 mL of Et2O was added, allowing the formation of a white crystalline mass. This was removed by filtration and washed with additional Et2O. After air drying there was obtained 1.3 g of 3,4-methylenedioxy-N,N-dimethylamphetamine hydrochloride (MDDM) with a mp of 172-173 !C. The NMR spectrum (60 mH) of the hydrochloride salt (in D2O and with external TMS) was completely compatible with the expected structure. The signals were: 1.25, 1.37 (d) CCH3, 3H; ArCH2
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