slothrop
(Stranger)
01-06-02 18:26
No 253386
      5-Methyl-MDA
(Rated as: excellent)
    

5-Methyl-MDA

5-Methyl-MDA is mentioned in Journal of Medicinal Chemistry, 1998, 41(6), pp1001-1005 and does look like a pretty interesting compound. It substitutes for (+)MBDB, MMAI, and DOI in their rat models suggesting effects something like a combination of MDMA and LSD perhaps. It has less than one-tenth the potency of MDA as a dopamine uptake inhibitor, which would prevent the serototoxic effects associated with MDA due to extracellular dopamine. It is more than 5 times more potent than MDA in inhibiting uptake of serotonin suggesting a suitable human dosage of 15-25 mg. It would be interesting to hear reports of human consumption of this novel substance. [The Safety of this compound has not been determined. This is an educated guess.] An open question Is the dopamine uptake inhibition of MDA and MDMA an essential component of their empathogenic properties.

Due to its 5-methyl subsitution it can't be metabolized to 2,4,5-trihydroxyamphetamine which is a metabolite of MDA, MDMA, and MDE. 2,4,5-THA is suspected serototoxic and it is the amphetamine analogue of the dopamine neurotoxin 6-OH-DA. Maybe this is an issue with TMA-2?

A little side note... I skimmed through Pihkal and found 6-Me-MDA mentioned and in the last paragraph of the extension and commentary Dr S raises the question on the potency of 2-Me-MDA and outlines a synthesis. That compound has about the same pharmacological profile as 5-Me-MDA and should therefore be about 5 times the potency of MDA. Wonder why he never tried it out?   

The experimental is enclosed here and it seems pretty straight-forward.


5-Dimethylaminomethyl-4-hydroxy-3-methoxybenzaldehyde
To a stirred solution of 37 % aqueous CH2O (120 g, 1.50 mol) and 40 % aqueous Me2NH (180 g, 1.50 mol) in 900 mL of EtOH was added vanillin (152 g, 1.00 mol). The mixture was refluxed for 30 min, stirred at 25C for 24 h and then refrigerated overnight. The white granular solid was collected by filtration, washed with ice-cold acetone and then dried under vacuum to give 179.8 g (86%) of 5-dimethylaminomethyl-4-hydroxy-3-methoxybenzaldehyde: mp 139-141C. [5]


4-Hydroxy-5-methoxy-3-methylbenzaldehyde (5-Methyl-vanillin)
A solution of 5-dimethylaminomethyl-4-hydroxy-3-methoxybenzaldehyde (104.5 g, 500 mmol), in 500 mL of Ac2O was refluxed for 24 h protected from moisture. Volatile materials were removed by distillation (bp 55-80C) under aspirator vacuum. After cooling the residue (which was the crude diacetate) to ~40C, 500 mL of conc. HCl was added gradually and then the mixture was stirred at ambient temperature for 1.5 h by which time most of the chloromethyl derivative had precipitated. Enough p-dioxane (~400 mL) was added to ensure dissolution of the solid at 60-70C. Then with efficient (mechanical) stirring 337.5 g (1.5 mol) of SnCl2 2 H2O was added and the mixture was refluxed for 30 min. After cooling to 25C and dilution with 200 mL conc. HCl, the mixture was extracted with CHCl3 (5 x 150 mL). The combined organic layers were washed with 6 N HCl, water, 10 % NaCl solution and then evaporated in vacuo to dryness. The crude residue was adsorbed on silica gel (63-200 mesh, 70 g) by adding silica gel to a solution of the crude in CHCl3 and then evaporating the solvent in vacuo. A slurry of the mixture in CHCl3 was then applied on a column of silica gel (100 g) and eluted with ether-hexane (2:1). Evaporation of eluents followed by sublimation (0.1 mm, 120C) of the grey solid residue gave 70.6 g (85%) of 4-Hydroxy-5-methoxy-3-methylbenzaldehyde as a white granular solid: mp 99-101C. [5]


4,5-Dihydroxy-3-methylbenzaldehyde
Anhydrous AlCl3 (32.4 g, 0.242 mol) was suspended in a solution of 36.6 g (0.220 mol) of 4-hydroxy-5-methoxy-3-methylbenzaldehyde in 300 mL of CH2Cl2 in an apparatus protected from atmospheric moisture. While stirring briskly and cooling to maintain the temperature at 30-35C, 76.6 g (0.970 mol) of pyridine was added slowly. The reaction was vigorous; the solution of the reaction complex was heated to reflux (45C) and maintained at that temperature with stirring for 24 hours. The solution, which had darkened only slightly during the reflux period, was cooled to 25C and the product was hydrolyzed, while stirring and maintaining the temperature at 25-30C, by the addition of dilute (15-20%) HCl until the mixture was definitely acidic to congo red indicator. Extraction of the aqueous phase with ether followed by evaporation of the ether left 25.4 g (76 %) of 4,5-dihydroxy-3-methylbenzaldehyde. An analytical sample was prepared from recrystallization from EtOAc-cyclohexane: mp 186-188C. [3], [4]


4-Methyl-1,3-benzodioxole-6-carboxaldehyde (5-Methylpiperonal)
To a mechanically stirred suspension of 4,5-dihydroxy-3-methylbenzaldehyde (12.84 g, 84.5 mmol) and cesium carbonate (41.28 g, 126.7 mmol) in anhydrous DMF (200 mL) was added BrCH2Cl (8.23 mL = 16.39 g, 126.7 mmol), and the resulting mixture was heated to 110C for 2 h. The reaction was then cooled to room temperature and filtered through a pad of Celite with EtOAc washing. The Filtrate was concentrated almost to dryness, diluted with H2O, and extracted three times with EtOAc. The Extracts were washed with H2O and brine, dried with MgSO4, filtered, and evaporated, yielding 13.54 g (98%) of product as a tan solid of sufficient purity to be carried on to the condensation step. An analytical sample of 1.27 g gave after bulb-to-bulb distillation (120C, 0.25 Torr) 1.05 g of a white solid: mp 45-46C. [1]


4-Methyl-6-(2-nitro-1-propenyl)-1,3-benzodioxole (5-methyl -3,4-methylenedioxyphenyl-2-nitropropene)
A mixture of 11.0 g (67.1 mmol) of 4-methyl-1,3-benzodioxole-6-carboxaldehyde, 40 mL of nitroethane, 10.9 g (134 mmol) of dimethylamine hydrochloride, 0.58 g (10 mmol) of potassium fluoride, and 40 mL of toluene was placed in a flask equipped with a Dean-Stark trap and heated at reflux under N2 for 24 h. Solvents were evaporated, yielding 14.12 g (95%) of product as an orange-yellow solid. An analytical sample was recrystallized from MeOH to give pale-orange crystals: mp 97-98C. [1]


1-(4-Methyl-1,3-benzodioxol-6-yl)-2-aminopropane Hydrochloride (5-Methyl-MDA HCl)
A solution of 2.21 g 4-methyl-6-(2-nitro-1-propenyl)-1,3-benzodioxole (10 mmol) in 20 mL THF was added dropwise to a suspension of 2.66 g of LiAlH4 (70 mmol) in 35 mL of THF while stirring under N2. The reaction mixture was stirred and heated under reflux for 5 h and cooled to room temperature, and the reaction was quenched carefully by the sequential addition of 2 mL of 2-propanol, 2 mL of 15 % aqueous NaOH, and 7 mL of H2O. The precipitate was removed by filtration, and the resulting solution was evaporated. The residue was suspended in H2O, acidified with concentrated HCl, and washed three times with Et2O. The resulting acidic solution was then made basic with aqueous NaOH and extracted three times with Et2O. The Et2O solution was evaporated, and the resulting oil was dissolved in 10 mL of 2-propanol, neutralized with ethanolic HCl, and diluted with Et2O to yield 1.26 g (65%) of the hydrochloride salt: mp 222-223C. [1], [2]


References
[1] Journal of Medicinal Chemistry, 1998, 41(6), pp1001-1005
[2] Journal of Medicinal Chemistry, 1993, 36(23), pp3700-3706
[3] Journal of Medicinal Chemistry, 1985, 28(9), pp1273-1279
[4] Journal of Organic Chemistry, 1962, 27, pp2037-2039
[5] Synthetic Communications, 1983, 13(8), p677

//Tyrone Slothrop

  

 
 
 
 
    Rhodium
(Chief Bee)
08-17-03 17:48
No 454222
      More MDA analogs from Dave Nichols
(Rated as: excellent)
    

Nonneurotoxic tetralin and indan analogs of 3,4-(methylenedioxy)amphetamine (MDA)
David E. Nichols, William K. Brewster, Michael P. Johnson, Robert Oberlender, Robert M. Riggs
J. Med. Chem. 33(2), 703-710 (1990) (../rhodium/pdf /nichols/nichols-tetralin.indan.non-neurotoxic.mda-analogs.pdf)

Abstract

Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5- (methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3anor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.

Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)
Michael P. Johnson, Stewart P. Frescas, Robert Oberlender, and David E. Nichols
J. Med. Chem. 34, 1662-1668 (1991) (../rhodium/pdf /nichols/nichols-mmai-mma.pdf)

The Experimental part can also be found in Post 122807 (dormouse: "Benzofuran, indan and tetralin analogues of MDA.  -Nemesis", Serious Chemistry)

Abstract

The racemate and the enantiomers of 1-(3-methoxy-4-methyphenyl)-2-aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Both 6 and 11 were found to substitute with high potency in 3,4-(methylenedioxy)methamphetamine (1) and (S)-1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (2) trained rats. In the latter assay, both enantiomers of 6 had identical potencies, but their dose-response curves were not parallel. Racemic 6, but not 11, partially substituted for LSD. Racemic 6 and 11 did not substitute in (S)-amphetamine-trained rats. All of the test compounds were potent inhibitors of [3H]-5-HT uptake into synaptosomes in vitro, with the S enantiomer of 6 being most active. Rat brain monoamine levels were unaltered 1 week following a single high dose (10 or 20 mg/kg, sc) of 6 or 11, or two weeks following a subacute dosing regimen (20 mg/kg, sc, twice a day for 4 days). In addition, radioligand-binding parameters in rat brain homogenate with the 5-HT uptake inhibitor [3H]paroxetine were unchanged after subacute dosing with either racemic 6 or 11. The results indicate that compounds 6 and 11 have animal behavioral pharmacology similar to the methylenedioxy compounds 1 and 2, but that they do not induce the serotonin neurotoxicity that has been observed for the latter two drugs.


Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine
Monte AP; Marona-Lewicka D; Cozzi NV; Nichols DE
J. Med. Chem. 36(23), 3700-6 (1993) (../rhodium/pdf /nichols/nichols-benzofuran.indan.tetralin.mda-analogs.pdf)
The Experimental part can also be found in Post 122807 (dormouse: "Benzofuran, indan and tetralin analogues of MDA.  -Nemesis", Serious Chemistry)

Abstract

Benzofuran, indan and tetrahydronaphthalene analogs of 3,4-(methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB (1c), MMAI (3), and (S)-(+)-amphetamine and for the ability to inhibit the uptake of [3H]serotonin, [3H]dopamine, and [3H]norepinephrine into crude synaptosome preparations. Behaviorally, the benzofuran and indan analogs 4-6 produced similar discriminative cues, whereas the tetralin derivative 7 did not fully substitute for the training drugs. The results in the in vitro pharmacology studies indicate that selectivity for 5-HT versus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms. However, the nonoxygenated isostere 6 possessed high potency at all uptake sites examined. Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.
 
 
 
 
    Rhodium
(Chief Bee)
02-05-04 10:33
No 486611
      Reference #5: C-Methylation of Vanillin
(Rated as: excellent)
    

Selective Ring C-Methylation of Hydroxybenzaldehydes via Their Mannich Bases
Achintya K. Sinhababu and Ronald T. Borchardt
Synthetic Communications, 13(8), 677-683 (1983) (../rhodium/chemistry /5-methyl-vanillin.html)

In connection with our synthesis of analogs of serotonin neurotoxins1 we needed access to 4-hydroxy-3-methoxy-5-methylbenzaldehyde (1) in quantities. The only previous method2 for the synthesis of 1 involved conversion of o-vanillin to 2-hydroxy-3-methoxytoluene followed by formylation using CHCl3/NaOH in 12% overall yield. We thought a more efficient process would result if we could introduce a methyl group selectively in the position ortho to the hydroxyl group of vanillin (2). However, no direct and selective method for introducing a methyl group into a benzene ring containing a hydroxyl as well as an aldehyde group has been described in the literature. In this paper we describe the development of a method for the synthesis of 1 from vanillin (2) without requiring the protection of either the hydroxyl or the aldehyde function and demonstrate the generality of such a method.
 
In devising the present method we took advantage of the selectivity and the high yield that can often be realized in the Mannich reaction of phenols3. Thus in the first step in the synthesis of 1 from 2, the methyl group equivalent, dimethylaminomethyl group, was introduced in vanillin in 86% yield to give crystalline Mannich base 3. Previous methods for the synthesis of C-methylated phenols from phenolic Mannich bases have involved catalytic hydrogenolysis of the Mannich base itself4, its hydrochloride salt5 or its acetolysis product6 (cf. 4) and NaBH3CN reduction of the methiodide of the Mannich base7. None of these procedures, due to their incompatibility with the aldehyde function, could be applied to the conversion of 3 to 1

We next considered the conversion of the dimethylaminomethyl group of 3 to a methyl group equivalent that can be reduced to a methyl group in the presence of a free aldehyde function. The chloromethyl group appeared to be such a group based on Sandin and Fieser's8 observation that the iodomethyl group of 9-methyl-10-iodomethyl-1,2-benzanthracene can be converted to a methyl group using SnCl2 in conc. HCl. 



For the synthesis of the chloromethyl derivative9 5. Mannich base 3 was first treated with excess acetic anhydride under reflux to give the diacetate 4. Without its isolation, but after the removal of excess acetic anhydride, the diacetate 4 was treated with conc. HCl at ambient temperature for 1.5 h to generate the chloromethyl derivative 5 which precipitated out of the reaction mixture. 1H-NMR spectrum of the crude precipitate suggested it to be 5, however, due to its instability, an analytical sample could not be prepared The chloromethyl derivative, in turn, without its isolation was reacted with SnCl22 H2O in a mixture of conc. HCl and p-dioxane under reflux for 30 min to give, after sublimation of the crude product, the desired C-methylated product 1 in 85% yield based on the Mannich base. To determine the generality of the procedure, we studied three other examples (Eq. 1-3). In each case the Mannich base was converted to the corresponding C-methylated derivative without the isolation of the intermediate acetolysis product (cf. 4) or the chloromethyl derivative (cf. 5). These examples show that the method is suitable for the introduction of the methyl group para to the hydroxyl group (Eq. 1-2) and also suitable for bis-C-methylation (Eq. 2-3).

Experimental Section




5-Dimethylaminomethyl-4-hydroxy-3-methoxybenzaldehyde (2)

To a stirred solution of 37% aqueous CH2O (120 g, 1.5 mol) and 40% aqueous Me2NH (180 g, 1.5 mol) in 900 mL of EtOH was added vanillin (2, 152 g, 1 mol). The mixture was refluxed for 30 min, stirred at 25C for 24 h and then refrigerated overnight. The white granular solid was collected by filtration, washed with ice-cold acetone and then dried under vacuum to give 179.8 g (86%) of 3: mp 139-141C. 


4-Hydroxy-3-methoxy-5-methylbenzaldehyde (1)

A solution of the Mannich base 3 (104.5 g, 500 mmol), in 500 mL of Ac2O was refluxed for 24 h protected from moisture. Volatile materials were removed by distillation (bp 55-80C) under aspirator vacuum. After cooling the residue (which was the crude diacetate 4) to ~40C, 500 mL of conc. HCl was added gradually and then the mixture was stirred at ambient temperature for 1.5 h by which time most of the chloromethyl derivative 5 had precipitated. Enough p-dioxane (~400 mL) was added to ensure dissolution of the solid at 60-70C. Then with efficient (mechanical) stirring 337.5 g (1.5 mol) of SnCl22 H2O was added and the mixture was refluxed for 30 min. After cooling to 25C and dilution with 200 mL conc. HCl, the mixture was extracted with CHCl3 (5 x 150 mL). The combined organic layers were washed with 6 N HCl, water, 10% NaCl solution and then evaporated in vacuo to dryness. The crude residue was adsorbed on silica gel (63-200 mesh, 70 g) by adding silica gel to a solution of the crude in CHCl3 and then evaporating the solvent in vacuo. A slurry of the mixture in CHCl3 was then applied on a column of silica gel (100 g) and eluted with ether-hexane (2:1). Evaporation of eluents followed by sublimation (0.1 mm, 120C) of the grey solid residue gave 70.6 g (85%) of 1 as a white granular solid: mp 99-101C (lit.2 mp 99-100C).


5-Dimethylaminomethyl-2-hydroxy-3-methoxybenzaldehyde (7) was prepared from o-vanillin (6, 3 g) as described for 3 except that reflux was carried out for 4 h and then the mixture was evaporated in vacuo to dryness. The residue was triturated with Et2O whereby a light yellow solid was formed which was thoroughly washed with Et2O and dried (yield 78%): mp 110-112C; mp of HCl salt 170-172C (lit.11 mp 169-172C).
 
2-Hydroxy-3-methoxy-5-methylbenzaldehyde (8) was produced from 7 (2.8 g) in 63% yield: mp 74-76C (lit.12 mp 76C).
 
3,5-Bis(dimethylaminomethyl)-2-hydroxybenzaldehyde (10) was prepared from 9 (4 g) as described for 7 except that three equivalents each of CH2O and Me2NH were used and was isolated as an oil (87%).
 
3,5-Dimethyl-2-hydroxybenzaldehyde (11) was produced from 10 (3.8 g) using six equivalents of SnCl22H2O at the reduction step, in 55% yield: mp 12-14C (lit.13 mp 12-14C).

3,5-Bis(dimethylaminomethyl)-4-hydroxybenzaldehyde (13) was prepared from 12 (4 g), as described above for 10, as a syrup in 83% yield.

3,5-Dimethyl-4-hydroxybenzaldehyde (14) was prepared from 13 (3.8 g) as described above for 11 in 63% yield: mp 113-115C (lit.14 mp 114-115C).


Notes and References

[1] Sinhababu, A. K. and Borchardt, R. T., manuscripts in preparation: for example, synthesis of 7-methyl-5,6-dihydroxytryptamine from 1; for a review on serotonin neurotoxins, see: "Serotonin Neurotoxins;" Jacoby, J. H., Lytle, L. D., eds., Ann. N. Y. Acad. Sci., 1978, 305, 1-702.
[2] Koetschet, J. P., Helv. Chim. Acta, 1930, 13, 474-482.
[3a] Tramontini, M., Synthesis, 1973, 703-775.
[3b] Mathieu, J. and Weill-Raynal, J. "Formation of C-C Bonds," Vol. 1. Thieme, Stuttgart, 1973; pp 95-101.
[4] Fields, D. L., Miller, J. B. and Reynolds, D. D., J. Org. Chem., 1964, 29, 2640-2647.
[5] Previc, E. P., U. S. Patent 3461172 (1969); C. A. 1969, 71, 101520.
[6] Sinhababu, A. K. and Borchardt, R. T., Synth. Commun., 1982, 12, 983-988.
[7] Yamada, K., Itoh, N. and Iwakuma, T., Chem. Commun., 1978, 1089-1090.
[8] Sandin, R. B. and Fieser, L. F., J. Am. Chem. Soc., 1940, 62, 3098-3105.
[9] Attempts to produce 5 by the direct chloromethylation of 2, under a variety of conditions10 were not successful. Attempts to produce the corresponding iodomethyl derivative using ClCH2OCH3 and HI8 were also unsuccessful. These findings are not surprising since, in general, phenols are so highly activated that direct halomethylation reactions are difficult to control and diarylmethanes as well as polymers are formed10.
[10] Fuson, R. C. and McKeever, C. H., Org. Reactions, 1942, 1, 63-90.
[11] Profft, E. and Mrker, P., J. Prakt. Chem., 1959, 280, 199-206.
[12] Krajniak, E. R., Ritchie, E. and Taylor, W. C., Aust. J. Chem., 1973, 26, 1337-1351.
[13] Casiraghi, G., Casnati, G., Puglia, G., Cartori, G. and Terenghi, G., J. Chem. Soc. Perkin Trans. 1, 1980, 1862-1865.
[14] Becker, H. D., J. Org. Chem., 1965, 30, 982-989.

The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Rhodium
(Chief Bee)
03-15-04 11:15
No 495325
      Nichols Review: Novel Serotonergic Agents
(Rated as: excellent)
    

Novel Serotonergic Agents
David E. Nichols, Danuta Marona-Lewicka, Xuemei Huang And Michael P. Johnson
Drug Design and Discovery, Vol. 9, 299-312 (1993) (../rhodium/pdf /nichols/nichols-novel.serotonergic.agents.pdf)

Abstract
The preliminary structure-activity relationships are described for a series of substituted phenethylamines that induce the release of neuronal serotonin. Structures that also have the ability to release neuronal catecholamines are toxic to serotonin neurons, leading to long-term reductions in serotonin markers in rat brain. Conversely, compounds that are selective for the serotonin uptake carrier. and do not affect catecholamines, are not neurotoxic. It is suggested that these novel, selective serotonin releasing agents may find therapeutic utility in disorders where serotonin uptake inhibitors are currently employed.

The Hive - Clandestine Chemists Without Borders