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All 4 posts Subject: Synthesis and Evaluation of MDC & MDMC Please login to post Down

imp
(Hive Bee)
05-06-04 05:12
No 505224
      Synthesis and Evaluation of MDC & MDMC

SWIM must first apologize that this had not been posted sooner. It has literally been sitting in one of several forgotten boxes full of papers from the library for over a year... Also please note that Dr. Shulgin uses 'MDMC' to describe another compound in PIHKAL which is not related to the compounds described in this thread. The compounds are often referred to as MDCATH and N-methyl-MDCATH instead of MDC and MDMC.

The synthesis and evaluation of MDC, 3,4-methylenedioxycathinone, and MDMC, 3,4-methylenedioxymethcathinone, are described. Also included are the pharmacologically active substances N-ethylcathinone, N-(n-propyl)cathinone and N,N-dimethylcathinone. Unfortunately, yields for any of the rxns are not provided.

It seems that MDC and MDMC are very similar to MDMA in effects, but will probably be at least 2x less potent. MDMA is characterized at 0.76 mg/kg, which is a very low dose, so for MDMC SWIM would think 3-4 mg/kg would be fully active. Although less potent, these chemicals are still intriguing in the sense that they are very easily synthesized, possibly legal, and also show proof that other cathinone analogs of phenethylamines will most likely be active (although possibly with diminished hallucinogenic activity). SWIM would like to hear people's thoughts on this.

Enjoy...

Pharmacology Biochemistry and Behavior, Vol. 58, No. 4, pp. 1109-1116, 1997.

Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs

[bastards]Terry A. Dal Cason, Richard Young, and Richard A. Glennon.[/bastards]

Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.

Skipping to the experimental...

(+-)N-Monoethylcathinone (N-Et CAT). (+-)N-mono-n-propylcathinone (N-Pr CAT), and (+-)N,N-dimethylcathinone (Di Me CAT) were prepared as their hydrochloride salts from 2-bromopropiophenone (Aldrich Chemical Co., Milwaukee, WI) by reaction with the appropriate aqueous amine (free base) in a 1 to 2 molar ratio. A general procedure, as adapted from the literature (23), will suffice. Previously chilled (5C) bromopropiophenone (0.42 mol) was added in a dropwise manner over a 30-min period to a stirred solution of the aqueous amine (free base, 0.85 mol) immersed in an ice-salt (-8C) bath. The reaction mixture was stirred for 2 h and then allowed to come to room temperature. The mixture was extracted with tap water (4 x 100 ml) to remove any free amine or amine salt. An additional quantity of water (100 ml) and sufficient hydrochloric acid were added to the washed reaction mixture to achieve pH 2. The solution was reextracted with chloroform (4 x 100 ml) to remove any unreacted starting materials. Dilute cold sodium hydroxide solution was added to adjust the pH to 9-10; the reaction mixture was extracted with chloroform (4 x 50 ml) and the solution was filtered through anhydrous sodium sulfate. The hydrochloride salt was formed by addition of a solution of HCl gas in 2-propanol (4.5 N) and the reaction mixture was evaporated to dryness on a steam bath. The recovered solid was dissolved in hot 2-propanol followed by the careful addition of diethyl ether until turbidity was noted. The next day, after having been stored in a freezer overnight, the solution was filtered, and the crystalline material was collected and dried under vaccum for at least 2 days. The melting points (Hoover Unimelt apparatus) were found to be: N-Et CAT, mp 186-188C; N-Pr CAT, mp 180-182.5C; Di Me CAT, mp 206-206.5C.

(+-)3,4-Methylenedioxycathinone hydrochloride (MDC) was prepared from 3,4-methylenedioxypropiophenone (Frinton Laboratories, Vineland, NJ, recrystallized from isooctane to mp 40-41.5C) in a series of steps. Isonitroso-3,4-methylenedioxypropiophenone (mp 149-151C; literature mp 153-154C) was synthesized using the method described by Hartung et al. (20-22) for the synthesis of isonitrosopropiophenone by using butyl nitrite and substituting methylenedioxypropiophenone for propiophenone. The intermediate oxime was catalytically reduced using a low-pressure hydrogenation apparatus (Parr Instrument Co., Moline, IL): the oxime in acidic (HCl gas) ethanol was hydrogenated over a 2-h period with 10% palladium on carbon catalyst (20,24). Removal of the catalyst by filtration and evaporation of the solvent gave MDC after recrystallization from 2-propanol-ether, mp 208-209C. 3,4-Methylenedioxymethcathinone hydrochloride (MDMC) was prepared by brominating 3,4-methylenedioxypropiophenone using the method (option b) of Boyer and Straw (4) to give 2-bromo-3', 4'-methylenedioxypropiophenone (mp 51-53C). This compound in a mixture of absolute ethanol-diethyl ether (5:1) was added in a dropwise manner to an ice-cold 40% aqueous methylamine free base solution using the technique described above in the preparation of N-Et CAT. The recovered material was purified by dissolution in hot 2-propanol followed by precipitation upon the addition of diethyl ether to give the desired product, mp 226-228C. All new compounds analyzed correctly (Atlantic Microlab) for C, H, and N to within 0.4% of theory, were homogeneous by gas-liquid chromatography, and structures were consistent with spectral data.

N-Monoethylcathinone (N-Et CAT; ED50 = 0.77 mg/kg), and N-mono-n-propylcathinone (N-Pr CAT; ED50 = 2.03 mg/kg), racemic N,N-dimethylcathinone and its (-)-isomer [(+-)Di Me CAT, ED50 = 0.61 mg/kg; (-)Di Me CAT (ED50 = 0.44 mg/kg)] and (+)N,N-dimethylamphetamine [(+) Di Me AMPH; ED50 = 2.92 mg/kg] all resulted in stimulus generalization when administered to (+)amphetamine-trained animals (ED50 = 0.33 mg/kg) (Table 1). In some cases [N-Pr CAT, (+)Di Me AMPH)], the animals' response rates were decreased to about 50% of control rates suggesting that the agents may possess some other rate-reducing action. 3,4-Methylenedioxymethcathinone (MDMC; ED50 = 2.36 mg/kg) also resulted in (+)amphetamine-stimulus generalization, whereas 3,4-methylenedioxycathinone (MDC) resulted only in a maximum of 58% (+)amphetamine-appropriate responding (Table 1). In both instances, response rates were reduced at the higher doses tested (Table 1); this may be related to the fact that both agents are capable of producing MDMA-like effects at these doses. The latter two compounds were also examined in DOM-trained and MDMA-trained animals (Table 2). In the DOM-trained rats, neither compound elicited >7% DOM-appropriate responding at 1.5 mg/kg; at 2 mg/kg of MDC only four of seven animals made >5 responses during the extinction session whereas the same dose of MDMC disrupted the majority of animals tested. In the MDMA-trained animals (Table 2), both MDC and MDMC resulted in stimulus generalization (ED50 = 1.64 and 1.60 mg/kg, respectively). Where stimulus generalization occurred, the animals' response rates were decreased by 30-50%.

...it would seem that MDC no longer behaves like MDA but that MDMC retains the amphetamine-like character of MDMA. Interestingly, both MDC and MDMC retain MDMA-like character (Table 2) in that they completely substituted for MDMA (i.e., they produced >80% MDMA-appropriate responding) in MDMA-trained rats. Because MDMC (ED50 = 1.6 mg/kg; 6.9 umol/kg) was about half as potent as MDMA itself (ED50 = 0.76 mg/kg; 3.5 umol/kg), it would seem that here, too, the effect of the carbonyl-oxygen introduction is to decrease potency.

4. Boyer, J.H.; Straw, D.: Azidocarbonyl compounds. The pyrolysis of azidocarbonyl compounds. J. Am. Chem. Soc. 75:1642-1644; 1952.

20. Hartung, W.H.: Palladium catalysts. II. The effect of hydrogen chloride in the hydrogenation of isonitrosoketones. J. Am. Chem. Soc. 53:2248-2253; 1931.

21. Hartung, W.H.; Crossley, F.: Isonitrosopropiophenone. In: Blatt, A.H., ed. Organic synthesis, collective vol. II. New York: John Wiley & Sons; 1943:363-364.

22. Hartung, W.H.; Munch, J.C.: Amino alcohols. I. Phenylpropanolamine and para-tolylpropanolamine. J. Am. Chem. Soc. 51:2262-2266; 1929.

23. Hyde, J.F.; Browning, E.; Adams, R.: Synthetic homologs of ephedrine. J. Am. Chem. Soc. 50:2287-2292; 1928.

24. Iwamoto, H.K.; Hartung, W.H.: Amino alcohols. XIV. Methoxyl derivatives of phenyl propanolamine and 3,5-dihydroxyphenylpropanolamine (1). J. Org. Chem. 9:513-517; 1944.

Rhodium
(Chief Bee)
05-06-04 05:24
No 505228
User Picture       MDMCAT is also known as Methylone

As seen before in Post 475682 (Rhodium: "Cathinone: Investigation of several analogs", Novel Discourse)

Erowid Methylone Vault (http://www.erowid.org/chemicals/methylone)

^{The Hive - Clandestine Chemists Without Borders}

imp
(Hive Bee)
05-06-04 05:28
No 505229
      oops

Sorry, SWIM UTSE too but didn't see it. Should have searched for "methylone" instead. Sorry again!

Rhodium
(Chief Bee)
05-06-04 05:35
No 505231
User Picture       TFSE - Special Techniques

Post 445019 (Rhodium: "How to find already posted articles in TFSE", General Discourse)
Post 445935 (Rhodium: "UTFSE tips", General Discourse)

^{The Hive - Clandestine Chemists Without Borders}

	https://the-hive.archive.erowid.org	the-hive@erowid.org



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	All 4 posts		Subject: Synthesis and Evaluation of MDC & MDMC		Please login to post		Down


		imp (Hive Bee) 05-06-04 05:12 No 505224				Synthesis and Evaluation of MDC & MDMC
						SWIM must first apologize that this had not been posted sooner. It has literally been sitting in one of several forgotten boxes full of papers from the library for over a year... Also please note that Dr. Shulgin uses 'MDMC' to describe another compound in PIHKAL which is not related to the compounds described in this thread. The compounds are often referred to as MDCATH and N-methyl-MDCATH instead of MDC and MDMC. The synthesis and evaluation of MDC, 3,4-methylenedioxycathinone, and MDMC, 3,4-methylenedioxymethcathinone, are described. Also included are the pharmacologically active substances N-ethylcathinone, N-(n-propyl)cathinone and N,N-dimethylcathinone. Unfortunately, yields for any of the rxns are not provided. It seems that MDC and MDMC are very similar to MDMA in effects, but will probably be at least 2x less potent. MDMA is characterized at 0.76 mg/kg, which is a very low dose, so for MDMC SWIM would think 3-4 mg/kg would be fully active. Although less potent, these chemicals are still intriguing in the sense that they are very easily synthesized, possibly legal, and also show proof that other cathinone analogs of phenethylamines will most likely be active (although possibly with diminished hallucinogenic activity). SWIM would like to hear people's thoughts on this. Enjoy... Pharmacology Biochemistry and Behavior, Vol. 58, No. 4, pp. 1109-1116, 1997. Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs [bastards]Terry A. Dal Cason, Richard Young, and Richard A. Glennon.[/bastards] Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation. Skipping to the experimental... (+-)N-Monoethylcathinone (N-Et CAT). (+-)N-mono-n-propylcathinone (N-Pr CAT), and (+-)N,N-dimethylcathinone (Di Me CAT) were prepared as their hydrochloride salts from 2-bromopropiophenone (Aldrich Chemical Co., Milwaukee, WI) by reaction with the appropriate aqueous amine (free base) in a 1 to 2 molar ratio. A general procedure, as adapted from the literature (23), will suffice. Previously chilled (5C) bromopropiophenone (0.42 mol) was added in a dropwise manner over a 30-min period to a stirred solution of the aqueous amine (free base, 0.85 mol) immersed in an ice-salt (-8C) bath. The reaction mixture was stirred for 2 h and then allowed to come to room temperature. The mixture was extracted with tap water (4 x 100 ml) to remove any free amine or amine salt. An additional quantity of water (100 ml) and sufficient hydrochloric acid were added to the washed reaction mixture to achieve pH 2. The solution was reextracted with chloroform (4 x 100 ml) to remove any unreacted starting materials. Dilute cold sodium hydroxide solution was added to adjust the pH to 9-10; the reaction mixture was extracted with chloroform (4 x 50 ml) and the solution was filtered through anhydrous sodium sulfate. The hydrochloride salt was formed by addition of a solution of HCl gas in 2-propanol (4.5 N) and the reaction mixture was evaporated to dryness on a steam bath. The recovered solid was dissolved in hot 2-propanol followed by the careful addition of diethyl ether until turbidity was noted. The next day, after having been stored in a freezer overnight, the solution was filtered, and the crystalline material was collected and dried under vaccum for at least 2 days. The melting points (Hoover Unimelt apparatus) were found to be: N-Et CAT, mp 186-188C; N-Pr CAT, mp 180-182.5C; Di Me CAT, mp 206-206.5C. (+-)3,4-Methylenedioxycathinone hydrochloride (MDC) was prepared from 3,4-methylenedioxypropiophenone (Frinton Laboratories, Vineland, NJ, recrystallized from isooctane to mp 40-41.5C) in a series of steps. Isonitroso-3,4-methylenedioxypropiophenone (mp 149-151C; literature mp 153-154C) was synthesized using the method described by Hartung et al. (20-22) for the synthesis of isonitrosopropiophenone by using butyl nitrite and substituting methylenedioxypropiophenone for propiophenone. The intermediate oxime was catalytically reduced using a low-pressure hydrogenation apparatus (Parr Instrument Co., Moline, IL): the oxime in acidic (HCl gas) ethanol was hydrogenated over a 2-h period with 10% palladium on carbon catalyst (20,24). Removal of the catalyst by filtration and evaporation of the solvent gave MDC after recrystallization from 2-propanol-ether, mp 208-209C. 3,4-Methylenedioxymethcathinone hydrochloride (MDMC) was prepared by brominating 3,4-methylenedioxypropiophenone using the method (option b) of Boyer and Straw (4) to give 2-bromo-3', 4'-methylenedioxypropiophenone (mp 51-53C). This compound in a mixture of absolute ethanol-diethyl ether (5:1) was added in a dropwise manner to an ice-cold 40% aqueous methylamine free base solution using the technique described above in the preparation of N-Et CAT. The recovered material was purified by dissolution in hot 2-propanol followed by precipitation upon the addition of diethyl ether to give the desired product, mp 226-228C. All new compounds analyzed correctly (Atlantic Microlab) for C, H, and N to within 0.4% of theory, were homogeneous by gas-liquid chromatography, and structures were consistent with spectral data. N-Monoethylcathinone (N-Et CAT; ED50 = 0.77 mg/kg), and N-mono-n-propylcathinone (N-Pr CAT; ED50 = 2.03 mg/kg), racemic N,N-dimethylcathinone and its (-)-isomer [(+-)Di Me CAT, ED50 = 0.61 mg/kg; (-)Di Me CAT (ED50 = 0.44 mg/kg)] and (+)N,N-dimethylamphetamine [(+) Di Me AMPH; ED50 = 2.92 mg/kg] all resulted in stimulus generalization when administered to (+)amphetamine-trained animals (ED50 = 0.33 mg/kg) (Table 1). In some cases [N-Pr CAT, (+)Di Me AMPH)], the animals' response rates were decreased to about 50% of control rates suggesting that the agents may possess some other rate-reducing action. 3,4-Methylenedioxymethcathinone (MDMC; ED50 = 2.36 mg/kg) also resulted in (+)amphetamine-stimulus generalization, whereas 3,4-methylenedioxycathinone (MDC) resulted only in a maximum of 58% (+)amphetamine-appropriate responding (Table 1). In both instances, response rates were reduced at the higher doses tested (Table 1); this may be related to the fact that both agents are capable of producing MDMA-like effects at these doses. The latter two compounds were also examined in DOM-trained and MDMA-trained animals (Table 2). In the DOM-trained rats, neither compound elicited >7% DOM-appropriate responding at 1.5 mg/kg; at 2 mg/kg of MDC only four of seven animals made >5 responses during the extinction session whereas the same dose of MDMC disrupted the majority of animals tested. In the MDMA-trained animals (Table 2), both MDC and MDMC resulted in stimulus generalization (ED50 = 1.64 and 1.60 mg/kg, respectively). Where stimulus generalization occurred, the animals' response rates were decreased by 30-50%. ...it would seem that MDC no longer behaves like MDA but that MDMC retains the amphetamine-like character of MDMA. Interestingly, both MDC and MDMC retain MDMA-like character (Table 2) in that they completely substituted for MDMA (i.e., they produced >80% MDMA-appropriate responding) in MDMA-trained rats. Because MDMC (ED50 = 1.6 mg/kg; 6.9 umol/kg) was about half as potent as MDMA itself (ED50 = 0.76 mg/kg; 3.5 umol/kg), it would seem that here, too, the effect of the carbonyl-oxygen introduction is to decrease potency. 4. Boyer, J.H.; Straw, D.: Azidocarbonyl compounds. The pyrolysis of azidocarbonyl compounds. J. Am. Chem. Soc. 75:1642-1644; 1952. 20. Hartung, W.H.: Palladium catalysts. II. The effect of hydrogen chloride in the hydrogenation of isonitrosoketones. J. Am. Chem. Soc. 53:2248-2253; 1931. 21. Hartung, W.H.; Crossley, F.: Isonitrosopropiophenone. In: Blatt, A.H., ed. Organic synthesis, collective vol. II. New York: John Wiley & Sons; 1943:363-364. 22. Hartung, W.H.; Munch, J.C.: Amino alcohols. I. Phenylpropanolamine and para-tolylpropanolamine. J. Am. Chem. Soc. 51:2262-2266; 1929. 23. Hyde, J.F.; Browning, E.; Adams, R.: Synthetic homologs of ephedrine. J. Am. Chem. Soc. 50:2287-2292; 1928. 24. Iwamoto, H.K.; Hartung, W.H.: Amino alcohols. XIV. Methoxyl derivatives of phenyl propanolamine and 3,5-dihydroxyphenylpropanolamine (1). J. Org. Chem. 9:513-517; 1944.



		Rhodium (Chief Bee) 05-06-04 05:24 No 505228				MDMCAT is also known as Methylone
						As seen before in Post 475682 (Rhodium: "Cathinone: Investigation of several analogs", Novel Discourse) Erowid Methylone Vault (http://www.erowid.org/chemicals/methylone) ^{The Hive - Clandestine Chemists Without Borders}



		imp (Hive Bee) 05-06-04 05:28 No 505229				oops
						Sorry, SWIM UTSE too but didn't see it. Should have searched for "methylone" instead. Sorry again!



		Rhodium (Chief Bee) 05-06-04 05:35 No 505231				TFSE - Special Techniques
						Post 445019 (Rhodium: "How to find already posted articles in TFSE", General Discourse) Post 445935 (Rhodium: "UTFSE tips", General Discourse) ^{The Hive - Clandestine Chemists Without Borders}

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