S
H
U
L
G
IN
C
H
EMIS
T
R
Y
purification
o
fthebromointermediate,wasdescribedbyincorrectstartingmaterialwouldleadto1-(3,4-
Polishchemistsalmost50yearslater(Biniecki&methylenedioxyphenyl)-3-aminobutane(HMDA)(Shul-
Krajewski196
0
).gin&Jacob1982a,1982b).Thestructureforthisalter-MDMAhasalsobeensynthesizedfromMDAbynate"piperonylacetone"isalsogiveninFigure2.
reactionwithethylchloroformate,followedbyreductionOnlyamodestpharmacologicalliteratureexistson
withRed-Al(Davis&Borne1984).Similarly,MDAcantheset
w
oaminatedh
o
m
o
l
o
g
u
es.Onestudy(Kasuya
beconvertedtotheformamidethatisreducedwithlithium1958)hascomparedHMDMAwithatropineandfoundit
aluminumhydrideintetrahydrofuran(Braun,Shulgin&tobeaweakspasmoly
t
ic.ThetoxicityandpharmacologyBraun1980a).Onereport(O
'
Brien,Bonicamp&Jonesofthishomologueinmice(andofthecorresponding1982)describedthemethylationofMDAwithmethylMDAhomologueHMDA)havebeenstudiedandpub-
iodine.MDMAwasobtained,butthedimethylatedterti-lished(Davis&Borne1984).TheprimaryamineHMDA
aryamineandthetrimethylatedquarternaryproductswasfoundtobeinactive(inratsat10rog
/
kg)inbothopen
w
ereal
s
ogenerate
d
asc
o
ntaminant
s
,field
t
es
t
ingandasastimulant(Buxt
o
n
1
972),bu
t
atTwoproceduresexistforthesyn
t
hesisofMDMAbyhigherdosescausedslightstimulationwithtremors,and
thereductiveaminationofpiperonylacetonewithmethyl-modestinhibitionofmonoamineoxidase(Fellows&amine.Thereducingagentsareeithersodiumcyanoboro-Bemheim1950).hydrideinmethanol(Braun,Shulgin&Braun1980a)or
amalgamatedaluminuminaqueousisopropanol(seePHYSICALPROPERTIES
Nichols
,
inFrith1986b).ThecyanoborohydridemethodOFMDMAhasbeenusedforthepreparationoftritium-labeledThefreebasehasaboilingpoint
i
tl
vacuo
of155°atMDMAusinglabeledmethylamine(Gehlertetal.1985).20mm
/
Hg(Merck1914)andl1
0
°-12
0
°at
0
.4mm
/
Hg
PiperonylacetonemayalsobereactedwithN-(Braun,Shulgin&Braun1980a).Thehydrochloridesalt
methylformamideintheLeuckartreaction,andMDMAcanoccurinanumberofhydratedcrystallineforms,
obtainedbythehydrolysisoftheintermediateN-formylmakingthephysi
c
alpr
o
pertiesandsolidspectraofriskyderivative(Baileyetal.1975).ThisN-formylintermedi-valueforidentificationandascriteriaofpurity.The
ateisalsothetopicofanearlyGermanpatentdescribingfollowingmeltingpoints(m.p.)aregiven:foranhydrous,
itsformationfromMDMAandchloralhydrate(Merck147°-148°(Baileyetal.1975),148°-149°(Biniecki&192
0
).Krajewski
1
960),148
°
.
1
5
0
°
(Davis&Borne1984:MerckThepiperonylacetonerequiredforthesesynthesesis1914),150°-151°(Gaston&Rasmussen197
2
),151°-15
2
°availablecommercially.(Seecommentsbelowforlabel-(Braun,Shulgin&Braun1980a),152%153°(Braun,lngmisidentifications.)It
c
analsobemadeeitherbytheShulgin&Braun1980a),158°-159°(Nichols,In:Frithreductionofthenitroethaneadductofpiperonylwith1968b);forquarter-hydrate,soften132°andm.p.135°-elementalironortheoxidationofisosafrolwithhydrogen139°(Shulgin1986);forhemihydrate,soften9
2°
andperoxideinf
o
rmicacid.m.p.138°-145°(Shulgin1986);forthree-quarterhy
d
rate,soften50°andm.p.90
°
-132
°
(Shulgin1986):formonohy-SyntheticPrecautionsdrate,soften80°andm.p.1
0
7°-133°(Shnlgin1986).
Somepotentialsyntheticmishapsshouldbeconsid-Itisapparentthatwithuncertainhydration,themelt
-
ered.Substitutionofisosafroleforsafrole
l
eads,inthelngpointisnotanacceptablecriterionofiden
t
ityorofereactionwithhydrogenbr
o
mide
,
toanisomericbromo-purity.Ea
c
hofthesepolymorphshas,however,adistinct
propaneintermediatethatonaminationwithammoniaandcharacteristiccrystallinepolymorphicstructure.The
produ
c
esana-aminatedanalogueofMDMA(Merckindexofrefractionhasbeendetermined:
n
_=1.5311
1914).Presumably,thesubstitutionofthemethylamine,(Biniecki&Krajewski1960).
asintheprocedureabo
v
e,wouldproducel-(3,4-methyl-Aconsiderablebodyofspectraldata
e
xis
t
sfor
enedioxyphenyl)-1-methylaminopropane,thebenzyl-MDMA.Asmentionedabove,theseveralpolymorphsof
amineisomerofMDMA.thehydratedhydrochloridesaltshavedistinctinfrared
Inthesynthesesstartingwithpiperonyla
c
et
o
ne,thespectra.SomeoftheseareshowninFigure3.Thespectrasubstitutionof1-(3,4~methylenedioxyphenyi)-3-ofthefreebase(Nichols
,
In:Frith1986b;Baileyetal.
butanonefor1-(3,4-methylenedioxyphenyl)-2-propane1975)andtheanhydroushydrochloridesalt(Baileyetal,(anerrorthatasbeenmadebycommercialsuppliersof1975;Gaston&Rasmussen1972)havebeenpublished,
piperonylacetone)leadstotheformationofI-(3,4-ThelatterareasKBrpellets,aspectralprocedurethatcan
methylenedixoxyphenyl)-3-methylaminobutanedehydrateamaterialduringpreparation.
(HMDMA);withammoniaratherthanmethylamine,thisTheultravioletspectrumischaracteristicofthe
_6
JournalofPsychoactiveDrugs
293Vol.18(4
)
()ct-Dec
.
1986
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