Merck Patent DE 274350

IMPERIAL PATENT OFFICE.

PATENT SPECIFICATION No. 274350 — CLASS 12g, GROUP 32/70.

Firm E. Merck, of Darmstadt.

Process for the preparation of alkyloxyaryl-, dialkyloxyaryl- and alkylenedioxyarylaminopropanes, and their N-monoalkylated derivatives.

Patented in the German Reich from 24 December 1912.

The literature has repeatedly described the addition of two atoms of bromine to arylpropylenes of the general formulas R·CH₂·CH:CH₂ and R·CH:CH·CH₃, in which R denotes an etherified aryl radical; the addition of hydrobromic acid to these double bonds, however, had never previously been carried out. It has now been observed, unexpectedly, that hydrohalic acids, under suitable conditions, add to the unsaturated compounds named above to form the hitherto-unknown alkyloxy-, dialkyloxy-, or alkylenedioxyaryl halopropanes, without the cleavage of the alkyloxy group that might have been feared from the outset.

The addition of the hydrogen halide proceeds in such a way that the halogen attaches to the carbon atom nearer the benzene ring. The derivatives of allylbenzene — for example methyleugenol, safrole, apiol — accordingly yield isopropyl halides substituted (arylated) in the β-position: (Ar)·CH₂·CH:CH₂ + HBr = (Ar)·CH₂·CH(Br)·CH₃.

The derivatives of propenylbenzene — for example anethole, isosafrole — add hydrogen halide to form α-substituted (arylated) n-propyl halides: CH₃O·C₆H₄·CH:CH·CH₃ + HBr = CH₃O·C₆H₄·CH(Br)·CH₂·CH₃.

The resulting hydrogen-halide addition products are heavy, faintly coloured oils. They are comparatively unstable and cannot be distilled without decomposition, even in vacuo. Nevertheless, contrary to expectation, they react smoothly with ammonia and with primary aliphatic amines, giving the corresponding alkyloxy-, dialkyloxy-, or alkylenedioxyarylaminopropanes, or their N-monoalkyl derivatives.

This reaction was the less to be expected in that there was a risk that elimination of hydrohalic acid would simply regenerate the starting materials bearing the unsaturated side chain. In fact the reaction does proceed partly in this latter direction; this is, however, immaterial to the final result, since the recovered starting materials can always be returned to the reaction. The alkyloxy-, dialkyloxy-, and alkylenedioxyarylaminopropanes obtainable by reaction with ammonia or with monoalkylated ammonias are important intermediates for the preparation of therapeutically active compounds.

Examples.

1. Hydrobromic acid is added to molten anethole in the manner set out in detail in Example 3, and the crude bromo compound so obtained is reacted, as there described, with alcoholic ammonia.

The resulting α-p-methoxyphenyl-n-propylamine is a colourless oil, boiling at 116–117° under a pressure of 7 mm. The hydrochloride salt melts at 217°.

1. The β-3,4-dimethoxyphenylisopropylamine obtained from methyleugenol in the same way is a colourless oil, boiling point 141–142° under 5 mm pressure. [This pressure figure is uncertain in the scanned original — see textQuality notes.] The hydrochloride salt melts at 150–151°.

1. 150 g of safrole are introduced slowly, with ice-cooling, into 500 cc of a solution of hydrobromic acid in water saturated at 0°, and the mixture is shaken for several hours at the same temperature. The reaction product is taken up in chloroform; this solution is shaken successively with dilute soda solution and water, and dried over calcium chloride. On evaporating off the chloroform under reduced pressure, monobromodihydrosafrole remains, together with some unreacted safrole.

The reaction product is heated with four to five times its volume of strong aqueous ammonia for several hours at 120°, and the resulting base is isolated in the usual manner. [This base is 3,4-methylenedioxyamphetamine, MDA.]

The compound is a colourless liquid boiling at 153° under 19 mm pressure; it forms an acid sulfate that crystallizes readily and well. The hydrochloride salt forms white needles melting at 183–185°.

1. 50 g of the crude bromodihydrosafrole obtained by the method described in Example 3 are heated with five times its volume of a strong alcoholic solution of methylamine for two hours at 130°. After removing the bulk of the methylamine, the residue is worked up in the usual manner. The new secondary base of the formula CH₂O₂:C₆H₃·CH₂·CH(CH₃):NH·CH₃ forms a colourless oil boiling at 155° under 20 mm pressure. [This is N-methyl-3,4-methylenedioxyamphetamine — MDMA.]

The hydrochloride salt forms solid white crystals melting at 148–150°.

1. 50 g of isosafrole are introduced slowly, with ice-cooling, into 100 cc of a solution of hydrobromic acid in glacial acetic acid saturated at 0°, and the mixture is shaken for several hours. Work-up proceeds as described in Example 3.

The crude bromo compound so obtained is heated with four to five times its volume of saturated alcoholic ammonia for two hours at 100°. Ammonia and alcohol are removed in vacuo, and the base is isolated from the residue by the addition of excess alkali.

The α-3,4-methylenedioxyphenyl-n-propylamine boils at 141° under a pressure of 12 mm. The hydrochloride salt melts at 200–201°.

Patent Claim:

A process for the preparation of alkyloxyaryl-, dialkyloxyaryl-, and alkylenedioxyarylaminopropanes, or their N-monoalkylated derivatives, consisting in treating the corresponding unsaturated propylene compounds of the general formulas R·CH₂·CH:CH₂ and R·CH:CH·CH₃ (R = alkoxyaryl, dialkoxyaryl, or alkylenedioxyaryl) with hydrohalic acids, and reacting the resulting halogen-containing reaction products with ammonia or primary aliphatic amines.

Berlin. Printed at the Reichsdruckerei.

[Translation by the proposing research agent (LLM-assisted); not checked against the German by a human translator or chemist. Structural formulas are rendered as linear condensed formulas; the original prints them as multi-line typeset diagrams.]