DE904536C - Process for the preparation of 1- (oxyphenyl) -2-aminobutanes with an analgesic effect - Google Patents

Description

Process for preparing analgesic 1- (oxyphenyl) -2-aminobutanes It is known that i-oxyphenyl-2-aminopropane and its N-alkyl compounds such as i- (p-oxyphenyl) -2-methylamino- propane (known under the trade name Veritol) have pronounced circulatory effects. Recently, analgesic effects of i- (p-oxyphenyl) -2-methylamino-propane have become known (K iessig and Or zechowski, Arch. Exp. Path. And Pharm 197, [194i] p. 39i). The analgesic effects only become apparent at a dose at which the circulatory effects of i- (p-oxyphenyl) -2-methylamino-propane lead to severe disorders (pulse acceleration, increase in blood pressure, risk of collapse). The predominance of the circulatory effects prevents the practical utilization of the analgesic component. It has now surprisingly been found that in compounds of the general formula in which the hydroxyl group in the benzene nucleus can be in the o-, m- or p-position to the side chain and in which the radicals R1 and R2 are hydrogen, alkyl, alkylene, cycloalkyl, cycloalkylene, aralkyl or aralkylene, the circulatory effects recede, while the analgesic Effect comes to the fore. Even the i- (p-oxyphenyl) -2-aminobutane clearly shows analgesic effects, which in the case of the N-alkyl derivatives, e.g. B. the N-methyl and especially the N-butyl derivative, is surprisingly high. The derivatives with branched alkyl radicals on the nitrogen atom, e.g. B. the isobutyl or isoamyl radical, show a predominance of the analgesic effect. The same is true of N-alkylene, e.g. B. -Allyl- or -Crotyl-, -Cycloalkyl-, e.g. B. -Cyclopentyl- or -Cyclohexyl-, -Cycloalkenyl-, z. B. -Cyclopentenyl- or -Cyclohexenyl-, aralkyl, z. B. benzyl, and aralkenyl, e.g. B. cinnamyl derivatives. Tertiary amines with the residues mentioned have a particularly good analgesic effect. For use as analgesics, compounds in which the nitrogen of the amino group is a member of a hydrogenated ring, e.g. B. a piperidine or pyrrolidine or a homogeneous ring, so the group exhibit. Compounds with a radical with more than eight carbon atoms are of less importance in practice. It is extraordinarily surprising that the analgesic effect comes to the fore so strongly in the transition from the oxyphenyl-propane to the oxyphenyl-butane series.

The manufacture of the new analgesics can be done in different ways take place.

You can start from an i-oxyphenyl-2-halo-butane and this react with ammonia or a primary or secondary amine. One can go further of i-oxyphenyl-butanone- (2) and this with 'ammonia or a primary or secondary amine and then or simultaneously z. B. catalytic or reduce with metals.

The compounds according to the invention can also be prepared by that one starts from compounds that in place of the hydroxyl group of the general Formula carry an alkoxy group and in these the alkoxy group according to known Methods, e.g. B. by treatment with hydrohalic acids, especially hydrobromic acid, split. They are also obtained by saponifying compounds of the general species Formula based on oxygen and / or nitrogen through an acid residue, in particular an acyl radical, e.g. B. the acetyl radical, are substituted by acids or alkalis according to methods known per se.

The compounds according to the invention can also from corresponding Compounds of the general formula which contain an amino group in place of the oxy group wear, by diazotizing with nitrous acid and boiling the diazonium compounds getting produced.

They are also obtained from the i-oxyphenyl-2-oxybutanes by this? by known methods in esters of aryl or alkyl sulfonic acids, for. B. the benzene or toluenesulfonic acid, converted and this with ammonia, primary or secondary amines expediently converts under such conditions that not only the sulfonic acid residue bound in the? position of the butane residue is replaced by the amine residue, but also the remainder attached to the hydroxyl group of the benzene nucleus by saponification is split off.

There is another representation for the i-oxyphenyl-2-aminobutane in the known reduction of such nitrogen-containing derivatives of the i-Oxyphenyl-butanons- (2), such as e.g. B. the oxime or phenylhydrazone to the primary Amine are reducible, the reduction z. B. made catalytically or with metals can be.

As far as these methods are primary or secondary i-oxyphenyl-2-aminobutane are obtained, they can optionally also in a manner known per se, for. B. by means of halides of corresponding hydrocarbons, by reaction with the corresponding Aldehydes or stresses and simultaneous or subsequent reduction, e.g. B. after Leuckart-W a 11 a c h, or in another way in the secondary according to the invention or tertiary i-oxyphenyl-2-aminobutanes are converted. Example i i- (p-Oxyphenyl) -2-aminobutane 3.3 g of i- (P-methoxyphenyl) -2-aminobutane are mixed with 15 cc of 48% hydrobromic acid Heated to boiling under reflux for 21/2 hours. It is evaporated to dryness in a vacuum, dissolves the residue in a little water, falls with ammonia and shakes the precipitating Base with ether, which after evaporation the i- (p-oxyphenyl) -2-aminobutane in leaves a practically quantitative yield. It crystallizes from ether with addition of petroleum ether and melts at 127 to i29 °. That in the usual way by cases The hydrochloride produced by the ethereal solution with ethereal hydrochloric acid melts afterwards recrystallization from absolute alcohol with the addition of ether at 162-163 '.

The starting material is z. B. by transferring the from, j. Levy and Dvoleitzka-Gombinska, Bull. Soc. Chim, France (q.) Vol. 49, (193i) p. 1765 i- (p-Methoxyphenyl) -butanons- (2) in the after recrystallization from 5o% Alcohol at 85 to 87 'melting oxime and its reduction with sodium amalgam in acetic acid solution (cf. Mannich and Merz, Arch. für Pharm. 265 [1927] p. 15) obtained by known methods as an oil boiling at 139 to 141 'below 12 mm, characterized by a crystallized hydrochloride melting at 16o to 162 ' is. Example 2 i- (p-Oxyphenyl) -2-methylamino-butane 3.6 g of i- (p-Methoxyphenyl) -2-methylamino-butane are refluxed with 10 ccm q.8% hydrobromic acid for 2 hours under reflux heated. The procedure is as in Example i and i- (p-oxyphenyl) -2-methylamino-butane is obtained than one boiling below 0.1 mm at a bath temperature of 120 'after recrystallization from alcohol with the addition of ether at 124 to 125 'melting compound, whose Hydrochloride represented in the usual way after recrystallization from absolute Alcohol with the addition of ether melts at 158 to 162 '. The source material is z. B. from i- (p-methoxyphenyl) -butanone- (2) by catalytic hydrogenation in Alcohol obtained in a known manner as an oil in the presence of 1.1 mol of 1-ethylamine, which is characterized by a hydrochloride that melts at 121 to i22 °.

Example i- (p-Oxypheny 1) -2-n-butylamino-butane 4.4 g of i- (p-Methoxyphenyl) -2-n-butylamino-butane Earth demethylated as in Example 2 by boiling with 10 cc hydrobromic acid and worked up. The i- (p-oxyphenyl) -2-n-butylamino-butane is obtained as an oil, that boils below 0 mm at a bath temperature of 140 ° and one that melts at 125 to 127 ° Hydrochloride supplies.

The starting material, the hydrochloride of which melts at 134 to 135y, is z. B. shown in the same way as in Example 2.

Example 4 i- (p-Oxyphenyl) -2-n-amylamino-butane 5.4 g hydrochloride des i- (p-methoxyphenyl) -2-n-amylamino-butane are mixed with 2o ccm of concentrated hydrochloric acid Heated to 150 to 16 ° in the containment tube for 4 hours. It is evaporated to dryness in vacuo and the remaining i- (p-oxyphenyl) -2-n-amylamino-butane hydrochloride crystallizes from absolute alcohol with the addition of ether. It melts at 122 ° (sintering from ii9 °).

The starting material is z. B. analogous to example 2 from i- (p-methoxyphenyl) -butanone- (2) and n-amylamine. The hydrochloride melts at 116 to Example 5 i- (p-Oxyphenyl) -2-dimethylamino-butane 3.9 g of i- (p-methoxyphenyl) -2-dimethylamino-butane «earths as in Example 2 with hydrobromic acid demethylated and worked up. The i- (p-oxyphenyl) -2-dimethylamino-butane is obtained than one boiling below 0.1 mm at a bath temperature of 170 to 180 ° to give crystals of Melting point 82 to go @ solidifying compound, its represented in the usual way Hydrochloride melts at 182-184 '.

The starting material is z. B. obtained by the i- (p-methoxyphenyl) -butanone- (2) according to Meerwein-Pondorf with aluminum isopropylate to the one at 154 to 155` under 18 mm boiling i- (p-methoxyphenyl) -butanol- (2) reduced and this in a known manner, z. B. according to the instructions of Sekera and Marwek, Journ. Amer. Chem. Soc. 55 [1933] P. 345, esterified with p-toluenesulfonyl chloride in pyridine. 6 g of the toluenesulfonic acid ester, which after recrystallization from ether with the addition of petroleum ether at 53 '(sintering from 47 °) melts, then in 15 ccm of toluene with 7 g of dimethylamine io hours im Inclusion tube heated to 100 '. The toluene and the excess dimethylamine are evaporated, dissolves the residue in hydrochloric acid, which is used to remove neutral bodies several times is extracted with ether, makes it alkaline and distills the z - (p - Meth oxyphenyl) - 2 - dimethylamino - butane in a high vacuum, in which it is under oj mm passes over at 115 to i20 °. The hydrochloride prepared in the usual way melts after recrystallization from alcohol with the addition of ether at 154 up to i56 °.

Example 6 i- (p-Oxyphenyl) -2-diethylamino-butane 4.4 g of 1- (p-methoxyphenyl) -2-diethylamino-butane are demethylated and worked up as in Example 2. The i- (p-oxyphenyl) -2-diethylaminobucan is obtained than an oil which passes over at a bath temperature of 145 to 150 ° C. below a millimeter, its in more common Way represented hydrochloride after recrystallization from alcohol with addition melts at 166 to 169 ° (sintering from 16o ').

The starting material is analogous to Example 5 as a at iio to i20 ° Obtain bath temperature below ½ mm boiling oil.

Example 7 i- (p-Oxyphenyl) -2-di-n-butylamino-butane 5.5 g of i- (p-Methoxyphenyl) -2-di-n-butylamino-butane are demethylated and worked up as in Example 2. The resulting i- (p-oxyphenyl) -2-din-butylamino-butane boils below 0 mm at 18o to the bath temperature and provides a after recrystallization from alcohol with the addition of ether at 130 to 131 ° (sintering from 126 °) melting Hydrochloride.

The starting material is obtained by heating for 12 hours as in Example s represented p-toluenesulfonic acid ester of i - (p - methoxyphenyl) - butanols- (2) with 8 moles of di-n-butylamine for boiling and work-up as in Example 5 as one 17o to 18o ° bath temperature under oj mm of boiling oil obtained. Example 8 i- (p-Methoxy phenyl) -2-piperidino-butane 4.7 g of i- (P-i # ethoxyphenyl) -2-piperidino-butane demethylated and worked up as in Example 2. One gets in practically quantitative Yield the i- (p-oxyphenyl) -2-piperidino-butane as one at 185 to igo 'bath temperature Compound boiling below mm, its hydrochloride, which is prepared in the usual way after recrystallization from alcohol at 224 to 226 ° (sintering from 218 °) melts.

The starting material is analogous to Example 7 as a bath temperature of 150 ° obtained under 0.1 mm boiling oil, the hydrochloride of which melts at 221 to 222 °.

Claims (1)

PATENT CLAIM: Process for the preparation of analgesic i- (oxyphenyl) -2-aminobutanes of the general formula in which R 1 and R 2 are hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl or aralkenyl, characterized in that i-oxyphenyl-2-halobutane is reacted with ammonia or corresponding primary or secondary amines or x-oxyphenyl-butanone - (2) Reacts with ammonia or a corresponding primary or secondary amine and simultaneously or subsequently reduced or compounds of the general formula given in which the oxy group is etherified, to the compounds with free oxy group z. B. splits by treatment with hydrohalic acids or compounds of the general formula given which carry an acid radical on the oxygen and / or nitrogen, saponified or compounds of the general formula given which carry an amino group instead of the oxy group, diazotized and the diazonium compounds boiled or aryl or Alkyl sulfonic acid esters of i-oxyphenyl-2-oxy = butane with ammonia or corresponding primary or secondary amines or derivatives of i-oxyphenyl-butanone- (2) which can be reducible to the primary amine, e.g. B. the oxime or phenylhydrazone, reduced to the primary amine and the compounds obtained by this process, if they are primary or secondary bases, optionally by methods known per se, eg. B. by treatment with appropriate alkyl halides, alkylated on nitrogen to give the corresponding secondary or tertiary amines.