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[3D .mol structure]
SYNTHESIS: To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for the preparation) and 29.2 g malonic acid in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this was heated on the steam bath for several h. The mixture was added to a solution of 125 mL concentrated HCl in 500 mL H2O at 0 °C, and the solid product that was formed was removed by filtration, and washed with H2O. Recrystallization from aqueous EtOH yielded 31 g 2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 °C. Anal. (C12H14O4) C,H.

In a cooled high-pressure reaction vessel there was placed a suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL liquid isobutene. This was treated dropwise with 0.6 mL concentrated H2SO4, then sealed and brought to room temperature. After 48 h shaking, the vessel was cooled again to -10 °C, opened, and poured into 200 mL of 10% Na2CO3. This was extracted with hexane, the pooled extracts washed with H2O, and the solvent removed to yield 17.0 g of (t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal. (C16H22O4) C,H.

The cyclopropane ester was prepared by the reaction between 16 g (t)-butyl 2,5-dimethoxy-4-methylcinnamate and dimethylsulfoxonium methylide, prepared as described in the Kaiser reference in the acknowledgements. Hydrolysis of this ester gave 53% trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid which, after recrystallization from a MeOH/H2O mixture, had a mp of 136 °C. Anal. (C13H16O4) C,H.

A suspension of 4 g of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in an equal volume of H2O, was treated with sufficient acetone to effect complete solution. This was cooled to 0 °C and there was added, first, 2.0 g triethylamine in 35 mL acetone, followed by the slow addition of 2.5 g ethyl chloroformate in 10 mL acetone. This was stirred for 0.5 h, and then there was added a solution of 1.7 g NaN3 in 6 mL H2O, dropwise. After 1 h stirring at 0 °C, the mixture was quenched by pouring into H2O at 0 °C. The separated oil was extracted with Et2O, and extracts dried with anhydrous MgSO4. Removal of the solvent under vacuum gave a residue of the azide, which was dissolved in 10 mL anhydrous toluene. This solution was heated on the steam bath until the nitrogen evolution was complete, and the removal of the solvent under vacuum gave a residue of crude isocyanate as an amber oil. This intermediate isocyanate was dissolved in 5.4 g benzyl alcohol and the reaction mixture was heated on the steam bath for 6 h. The excess benzyl alcohol was removed by distillation, yielding trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as a crystalline residue. This was recrystallized from an EtOAc/hexane mixture to give 6.13 g of a crystalline product with a mp of 107-108 °C. Anal. (C20H23NO4) C,H,N.

A solution of 1.5 g trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in 120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas at 35 psig for 45 min. The solution was filtered through celite, and a sufficient amount of a solution of 5% HCl in EtOH was added to the filtrate to make it acidic. Removal of all volatiles under vacuum gave a solid residue that was recrystallized from an EtOH/ether mixture to give 0.98 g of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride (DMCPA) as white crystals with a mp of 210-211 °C.

DOSAGE: 15 - 20 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 10 mg) The effects were quite real at an hour, but very hard to define. Nothing left at four hours, but my sleep was filled with bizarre and colorful dreams. Something was still working somewhere, at some level.

(with 20 mg) I found myself lightheaded, and the thinness seemed to be, rather remarkably, on the left side of my brain. The experience was flighty. I was reminded of the aura that has been described preceding a convulsion. I was decoupled from my experience and from my environment. Not all of the control is there, and I am uncomfortable. But in an hour, there is complete control again, and I can relax my conscious guard which allows an easy plus three. With this, there was easy fantasy, erotic, quite a bit of movement in the visual field, and mild anorexia. The residual hyperreflexive thinness is largely gone, and not at all worrisome. This stuff is complicated, with a little too much of the physical. The next day was without any residues at all.

EXTENSIONS AND COMMENTARY: Most of the human trials took place in the fifteen to twenty milligram range. Several reports describe some muscular tremor, especially in the earliest part of the experience, but this never seemed to be a concern. The efforts to lock imagery to music were not too successful. All of these clinical studies were conducted on the trans-compound, but on the racemic mixture. This has been resolved into the two optical isomers, but they have not been compared in man. The cis-mixture is unknown.

This material is intimately related to tranylcypromine, a clinically proven antidepressant. This drug is a known monoamine oxidase inhibitor, and it is certainly possible that some of this pharmacological property might be found in DMCPA if it were to be looked for. The hints of physical toxicity at the higher doses assayed might suggest some such activity.

This compound, DMCPA, was modeled directly after the structure of DOM, with the 2,5-dimethoxy-4-methyl substitution pattern. Another analogue of tranylcypromine, similarly modeled, is 3,4,5-trimethoxytranylcypromine, or trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been evaluated at levels of only 13 milligrams orally, and at this dose there were no hints of central activity.

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