Synthesis of MMA (3-Methoxy-4-Methylamphetamine)

Translation by Chimimanie
(format & minor edits by metanoid)
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Synthesis of the 3-hydroxy-4-methyl derivative of amphetamine.   from V.Valenta and M.Protiva, Coll Czech Chem Commun 42, 1977


p-Toluic acid was converted in seven steps to (3-methoxy-4-methylphenyl)acetonitrile (VIII) which underwent Claisen's reaction with ethyl acetate and subsequent acid hydrolysis to the phenylacetone derivative XI. Leuckart's reaction and alkaline hydrolysis of the product gave rise to 3-methoxy-4-methylamphetamine (XIII) which was demethylated with hydrobromic acid to the title compound I.


Carlsson and coworkers (ref 1,2) prepared the 3-hydroxy-4-methyl derivative of amphetamine I which in histochemical and biochemical experiments on rats and mice, depresses with extraordinary intensity the levels of norepinephrine in central and peripheral neurones {brain and heart)

Chimimanie's voice: So it's a vile compound BUT if you don't do the last step (demethylation) you have got 3-methoxy-4-methyl-amphetamine which is an acceptable analogue of MDA


ref 1,2 desribe its preparation in two parallel ways which proceed from 3-methoxy-4-methylbenzaldehyde and from 3-benzyloxy-4-methylbenzaldehyde (obtained from the corresponding acids by Rosenmund's reaction) which react wIth nitroethane to yield the corresponding substituted nitrostyrenes. Reduction with lithium aluminium hydride yielded 1-(3-methoxy-4-methyl)-2-propylamine and 1-(3-benzyloxy-4-methyl)-2-propylamine; to obtain I, the first of these was demethylated with hydrobromic acid, the other was debenzylated by catalytic hydrogenation. We developed an alternative synthesis which, although somewhat longer as to the number of steps, is advantageous because it employs simple reactions and gives a high yield.


3-amino-4-methylbenzoic acid (III)

Raney nickel (10 g) was added to a warm solution of 121 g 4-methyl-3-nitrobenzoic acid (produced from the nitration of p-toluic acid (ref 14,15)) (II, m.p. 185-190°C) in 1 litre ethanol and the mixture was hydrogenated at normal pressure and with gentle heating. Theoretical consumption of hydrogen was reached in 5 h; it was filtered and the solution was evaporated. A total of 93.8 g (94%) crystalline product was obtained; mp 166.5-167.5°C. Ref.16 reports for a product obtained by reduction of II with stannous chloride a mp. of 164-165°C.

3-methoxy-4-methylbenzoic acid (V)

Dimethyl sulfate (54.2 g) was added to a suspension of 26.9 g 3-hydroxy-4-methylbenzoic acid (from III see ref 17) (IV mp 206-210°C) in 110 ml methanol, and 117 ml 30% NaOH was then added dropwise under stirrIng over a period of 40 min. The temperature of the mixture rose spontaneously to the boiling point and a clear solution was formed. It was refiuxed for 4 h, methanol was evaporated at reduced pressure and the residue was diluted with water until the sodium salts formed dissolved. After filtration, the filtrate was acidified with 70 ml 5M-HCI, the precipitated product was cooled, filtered, washed with water and dried in air; 23.9 g (82%), m,p, 158 -160°C.

3-methoxy-4-methylbenzyl alcohol (VI)

Supension of 47.4 g V in 500 ml ether was added dropwise under stirring over a period of 30 min to a suspension of 21.5 g LiAlH4 in 250 ml ether. The mixture was refluxed for 2 h, cooled, decomposed by adding 75 ml water and 25 ml 5M-NaOH, stirred for a while and combined with 25 g K2CO3. After brief stirring, the solid was filtered and washed with ether. Treatment of the filtrate yielded 34.4g (80%) product boiling at 96-102°C/0.2-0.5 Torr (bp of 107-110°C/3 Torr).

3-methoxy-4-methylbenzyl chloride (VII)

A solution of 87.5 g SOCl2 in 75 ml benzene was added dropwise over a period of 30 min to a solution of 53.4 g VI In 200 ml benzene. The mixture was stirred for 30 mln at 50°C and refiuxed for 1.5 h. After evaporation of the volatile fractions the residue was dissolved in 200 ml benzene, the solution was filtered with charcoal and CaCl2 and the filtrate was distilled; 44.8 g (75%), bp 76-78°C/0.5 Torr. (bp of 123°C/17 Torr).

3-Methoxy-4-methylphenyl)acetonitrile (VIII)

Sodium cyanide (19.9 g) was added under stirring to a solution of 35.2 g VII in 75 ml dimethylformamide. After cessation of the exothermic reaction the mixture was stirred for 4 h at room temperature. After standing overnight it was diluted with 300 ml water and extracted with chloroform. The extract was washed with water, dried with Na2SO4 and distilled: 30.3 g (91%), bp. 106-108°C/0.5 Torr. Analytical sample, b.p. 99°C/0.1 Torr.

l-Cyano-l-(3-methoxy-4-methylphenyl)acetone (IX)

Compound VIII (12.6 g) was added to a warm solution of C2H5ONa (2.36 g Na and 35 ml ethanol) and then 14.5 g ethyl acetate was added under stirring over a period of 20 min at 70 to 75°C. The mixture was refiuxed under stirring for 2.5 h and left to stand overnight at room temperature. The precipitated substance was dissolved by adding 250 mI water, the pH of the solution was adjusted to 10-12 with 20% NaOH and the turbid solution was washed with ether. Acidification of the alkaline aqueous layer with 30 ml acetic acid (pH 4.5) released a product which was isolated by extraction with chloroform; 14.6 g (92%), mp. 80-81°C. An analytical sample was obtained by crystallization from a mixture of benzene and light petroleum, mp. 83.5-84.5°C.

(3-Methoxy-4-methylphenyl)acetone (XI)

Hydrochloric acid (30 ml) was added to a solution of 8.5 g IX in 40 ml acetic acid and the mixture was refluxed for 6 h. After cooling, it was diluted with 500 ml water and extracted with chloroform. Processing of the extract yielded 4.9 g (67%) product boiling at 100-110°C/1 Torr. The analytical sample boiled at 101°C/1 Torr.

1-(3-Methoxy-4-methylphenyl)-2-propylamine (XIII)

A mixture of 18.2 g XI, 140 g formamide and 14 g formic acid was refluxed for 12 h in a 190 to 200°C bath. After partial cooling, it was diluted with 250 ml water and the product was isolated by extraction with chloroform. Processing of the extract yielded 15.5 g (75%) oily N-[1-(3-methoxy-4-methylphenyl)-2-propyl]formamide (XII) which was processed further without characterization.

A mixture of 15.5 g XII, 30 ml ethanol and 28g KOH was refluxed for 3 h in a 135-140°C bath. After cooling, it was diluted with 100 ml water and the product was isolated by extraction with ether. The extract was dried with K2CO3 and evaporated. Base XIII was obtained in a theoretical yield (13.4 g) as a viscous oil. After dissolving in ethanol, it was neutralized with an ether solution of hydrogen chloride. A total of 10.5 g (65%) hydrochloride was obtained, melting at 181.5-183.5°C. Analytical sample. mp. 182.5-183-5°C (ethanol-ether); crystal modification takes place at 166-169°C.

Ref.1,2 describe the preparation of the compound in a different way without characterizing it.

1-(3-Hydroxy-4-methylphenyl)-2-propylamine (I)

A mixture of 10.5 g XIII-HCI and 60 ml 48% hydrobromic acid was refluxed for 5 h, the solution formed was evaporated in vacuo, the residue was made alkaline with NH4OH and the product was isolated by extraction with chloroform; 7.6 g (94%), mp. 134-138°C. Analytical sample mp. 137.5- 138.5°C (light petroleum)


1. Carlsson A., Lindqvist M., Wysokowski J., Corrodi H., Junggren U.: Acta Pharm. Suec. 7, 293 (1970); Chem. Abstr. 73, 64 633 (1970).

2. Carlsson P. A. E., Junggren U. K., Hallhagen S. G., Corrodi H. R.: (Aktiebolag. Hassle): Neth. Appl. 69/5061; Ger. Offen. 1 915 230 (Swed. Appl. 1. IV. 1968); Chem. Abstr. 72, 121 177 (1970).

14. Kloppel E.: Ber. Deut. Chem. Ges. 26, 1733 (1893).

l5. Giacolone A.: Gazz. Chim. Ital. 65, 840 (1935); Chem. Zentr. 1936, 1, 3137.

16. Ahrens F.: Z. Chem. 1869, 104.

17. Vongerichten E., Rossler W .: Ber. Deut. Chem. Ges.ll, 705 (1898).

20. Julian P. L., Oliver J. J., Kimball R. H., Pike A. B., Jefferson G. D.: Org. Syn. Coll. Vol. 2. 487 (1943). and see also

21. Ruggli P., Weis P., Rupe H.: Helv. Chim. Acta 29, 1788 (1946).

Pharmacology of the 3-Methoxy-4-methyl-amphetamine (XIII):

see 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).

J Med Chem, May 1, 1991; 34(5): 1662-8.

link at rhodium:

:) Note the reaction from VIII to XI: the Claisen's reaction followed by hydrolysis transform a phenylacetonitrile to a phenylacetone! That's rock! (see ref 20,21 too). 8)

Synthesis of 3-methoxy-4-methylbenzaldehyde

W. Flitsch, P. Russkamp und W. Langer, Liebigs Annalen der Chemie, (7), 1413 (1985),
retrieved by Chimimanie and translated from german by GC_MS


36.0 g (0.3 mol) 4-methylbenzaldehyde is nitrated with KNO3 in concentrated H2SO4 [20]. Recrystallization from ether gave brightly yellow coloured needles; yield 45.0 g (91%), mp: 47°C (from ether) (literature [20] 43-44°C from ether, 48-49°C from petroleum ether).


60.0 g (0.36 mol) 4-methyl-3-nitrobenzaldehyde was reduced applying SnCl2.2H2O (according [13]), subjected to a diazotation reaction involving NaNO2 and HCl, and boiled down to the phenol. When there was no more nitrogen gas evolution, the mixture was treated with activated coal. It was filtered while hot and allowed to cool down for 16 h, after which the precipitated phenol was sucked away. Some more phenol can be obtained by extracting the filtrate with DCM. Crystallization of the raw product from benzene yields 29.0 g (60%) of the phenol (literature [13] 60%), mp: 71-72°C (from benzene) (literature [13] 73°C)


40 mL (30.0 g, 0.42 mol) dimethyl sulfate (DMS) is added to 25.0 g (16.7 mmol) 3-hydroxy-4-methylbenzaldehyde dissolved in 45 mL 33% KOH. Fierce stirring is necessary, and the temperature is not allowed to exceed 45°C. Otherwise, cooling is necessary. After 20 minutes, 15 mL 33% KOH and 10.5 g (14 mL, 0.15 mol) DMS are simultaneously drop-wise added. This is repeated after 10 min, and the reaction mixture is stirred for 30 more min. The mixture is diluted with 60 mL 33% KOH and allowed to rest at room temperature for two hours. The mixture is extracted with 1 x 200 mL and 2 x 100 mL chloroform, the combined extracts washed zith water, dried over Na2SO4 and freed from solvent in vacuo. The residue is crystallized from ether/n-hexane, yielding 29.0 g (91%) (literature [13] 87%), mp: 45-46°C (from ether/n-hexane) (literature [13] 42-43°C).


[13] H. Fukumi, H. Kurihara und H. Mishima, Chem. Pharm. Bull. 26, 2175 (1978)

[20] L. Gattermann, Liebigs Ann. Chem. 347, 354 (1906)

Synthesis of 3-methoxy-4-methylbenzaldehyde

H Fukumi, H Kurihara, H Mishima. Chem Pharm Bull 26(7) (1978) 2175-2180.,
retrieved by GC_MS

4-methyl-3-nitrobenzaldehyde (110 g) was added at once to a solution of SnCl2.2H2O (450 g) in 35% HCl (600 mL). The reaction was highly exothermic. As soon as the inner temperature of the reaction mixture reached at 100°C, the mixture was cooled to 0-5°C with ice-cooling. The resulting precipitates (stannic complex of 3-amino-4-methylbenzaldehyde) were filtered off and used to the following diazotization reaction without purification.

To the suspended mixture of the complex in 35% HCl (600 mL) was added dropwise at 4-5°C a solution of NaNO2 (46 g) in H2O (50 mL) for 50 min. The mixture was stirred at the same temperature for 2 h, and the resulting pale yellow precipitates were filtered off. A solid of the dizaonium salt was added in portions to refluxing water (1.71) over 30 min and after evolution of nitrogen gas ceased, the mixture was cooled and extracted with DCM. Concentration of DCM extracts gave a crude product, which was purified by DCM elution through a short silica gel layer and by recystallization from benzene. Yield of 3-hydroxy-4-methylbenzaldehyde [1] was 54.5 g (60%).

To a solution of 3-hydroxy-4-methylbenzaldehyde (10.6 g) in 2 N NaOH (60 mL) was added dropwise at 40-45°C Me2SO4 (15.9 g) for 10 min. The mixture was stirred at the same temperature for 1 h, cooled to 20°C and extracted with ether (150 mL). Usual work-up and recrystallization from n-hexane gave colorless needles (8.6 g, 88.5%) of 3-methoxy-4-methylbenzaldehyde, which melted at 45-46°C (lit [2] bp 101-103°C/10^-4 mmHg).


[1] NV Sidgwick e.a. JCS 123 (1923) 2819

[2] K Tsuda e.a. Chem Pharm Bull 10 (1962) 856