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Starting with piperonal, one would perform a Grignard alkylation with n-butylmagnesium bromide, oxidation of the resulting alcohol back into a ketone with pyridinium chlorochromate, followed by bromination and subsequent amination with pyrollidine.
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One method for preparation involving only four steps would involve alkylation of piperonal via a Grignard reaction using n-butylmagnesium bromide, oxidation of the resulting alcohol back into a ketone with pyridinium chlorochromate, followed by bromination and subsequent amination with pyrollidine.
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The best synthetic route probably involves the 4-step alkylation-oxidation-bromination-amination methodology. One possible preparation involves alkylation of piperonal in a Grignard reaction using n-butylmagnesium bromide or 1-bromobutane and magnesium metal in diethyl ether and under anhydrous conditions using an inert atmosphere such as nitrogen. The second step would involve oxidation of the resulting alcohol back into a ketone by adding it (without the ether phase) to a suspension of pyridinium chlorochromate in chloroform. The use of an optional organometallic scavenger such as nano-porous silica gel will make workup easier. After workup and redissolving residue in fresh chloroform, third-step addition of bromine will create a haloketone with bromide at the alpha position, and acts as the leaving group during subsequent (fourth-step) amination with pyrollidine in ether, which should take 12 hours and proceed at room temperature (20°C). Several washes with cold water, keeping the ethereal phase, will draw off most of the excess pyrollidine. Dissolve in absolute ethanol and salt with HCl. Recrystallize from a mixture of ethanol and ether. M.P. 229-231°C
α,α-Dibrominated Organohalide Intermediates
The α,α-dibrominated or α-mono-brominated intermediate from the 3rd step bromination, and left behind by an expedited or incomplete final workup is the most likely contaminant/impurity to be seen in the final product using this method. Bromination is likely to in excess, since excess pyrollidine amine will form a black precipitate that is difficult to separate. The Beilstein test is used to test for the presence of halogenated intermediates.
Such brominated halo-aromatic ketones are of particular concern to eukaryote macro-biological organisms, and special consideration must be made when preparing MDPV for purposes of long-term biological testing on lab animals, especially in mammals, and especially where the possibility exists for diversion and subsequent ingestion by humans for recreational purposes. Preparation for biological purposes and testing must ensure a complete and through workup, including several washes with saturated NaHCO3 solution after washing with water to remove the brominated intermediates before final salting of the freebase for recrystallization. Aside from the bromine ion being highly electronegative and reactive, the alkyl-bromine compounds often being alkylating agents, and brominated aromatic derivatives being implicated as hormone disruptors, there also exists the mechanism for bromine substituting for the methyl group in the nitrogenous base 5-methyluracil of DNA, creating the base-analog 5-bromouracil, which can be incorporated into DNA and induce a point mutation via base substitution.
MDPV undergoes CYP450 2D6, 2C19 and COMT phase 1 metabolism (liver) into methylcatechol and pyrrolidine, which in turn are glucuronated (uridine 5'-diphospho-glucuronosyl-transferase) allowing it to be excreted by the kidneys, with only a small fraction of the metabolites being excreted into the fecal matter. No free pyrrolidine could be detected in the urine.
First, methylenedioxypyrovalerone undergoes demethylenation via the CYP2D6 enzyme, followed by methylation of the aromatic ring via catechol-O-methyl transferase. Then hydroxylation of both the aromatic ring and side chain takes place followed by and oxidation of the pyrimidine ring to the corresponding lactam, with subsequent detachment and ring opening to the corresponding carboxylic acid.
Crystalline Structure (HCl)
MDPV HCl has a granular particle size between 9 and 12 mesh. 10 mesh powdered sugar is approximately the same granule size and has a similar appearance and behavior. One might describe the appearance of MDPV by comparing it to powdered sugar.
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