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#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)-butyl
amphetamine 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)-butyl
amphetamine (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
in
soluble, 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-in
soluble,
ether-in
soluble 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 re
crystallization 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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