DE1443291B - Process for the preparation of N substituted Phenylalkanolaminderi derivatives - Google Patents

Description

(I)

in which X is a hydroxyl group, one of an aliphatic carboxylic acid with 2 to 6 carbon atoms derived acyloxy group or a carbaminoyloxy group, Y is a hydrogen atom, a Hydroxy group, an acyloxy group derived from an aliphatic carboxylic acid with 2 to 6 carbon atoms or a carbaminoyloxy group, where in each case only one Y can be hydrogen, and R denotes an optionally branched alkyl group, characterized in that one acyl cyanide of the general formula

C-CN

(H)

in which X ₁ and Y _{1 have the} same meaning as X or Y, with the exception of the hydroxyl group, in the presence of ketones of the general formula

35

CH ₃
O = CR

(III)

in glacial acetic acid or propionic acid as a solvent with hydrogen using noble metal catalysts catalytically reduced and any acyloxy or carbaminoyloxy groups present if desired, then cleaved off in the usual manner.

2. The method according to claim 1, characterized in that the noble metal catalyst Platinoxvd is used.

It is known that 3,4-dihydroxy- or 3,5-dihydroxyphenylalkanolamines, which are substituted on the nitrogen by a branched hydrocarbon radical, in particular an isopropyl radical, due to their sympathomimetic effectiveness have interesting medicinal properties. For the production these compounds have hitherto been used to convert dihydroxy-cu-haloacetophenones primary amines and subsequent hydrogenation to carbinol. However, this method has the disadvantage that the ω-haloacetophenones are extremely unpleasant are to be handled, as they irritate the mucous membranes, especially those of the eyes, very strongly, which is makes it uncomfortably noticeable especially when it is produced on a larger scale. Also owns this method in the case of the preparation of the 3,5-dihydroxyphenylalkanolamine derivatives nor the disadvantage that the S.S-dihydroxy-cu-halogenacetophenone are very difficult to access because in the 3,5-substituted compounds in contrast to the 3,4-substituted compounds the synthesis according to Friedel - Crafts is not applicable.

It is known that alkanolamines are also obtained by catalytic reduction of cyan ketones Let hydrogen and noble metal catalysts be produced, although only unsubstituted primary ones Amines are obtained. In the case of aromatic cyan ketones, however, it is also known that the reduction with elimination of oxygen up to the araliphatic amines advances, surprisingly Reaction conditions could now be found under which aromatic cyan ketones to phenylalkanolamines are reduced and substituted with simultaneous reductive alkylation on nitrogen Phenylalkanolamines are obtained.

For the production of (3 ', 4'-dihydroxyphenyl) -2-isopropylamino-ethanol it was also proposed that noradrenaline or the corresponding aminoketone be catalytically in the presence of acetone hydrogenate, the amino group present being reductively alkylated by the acetone. But it was Nowhere is any indication that it might be possible to undergo reductive alkylation in the case of phenylalkanolamines to be carried out simultaneously with the formation of the amino group.

Surprisingly, it has now been found that it is possible to use N-substituted phenylalkanolamine derivatives of the general formula I.

CH,

40

45

CH-CH ₂ -NH-CH-R
OH

(I)

in which X is a hydroxyl group, one derived from an aliphatic carboxylic acid with 2 to 6 carbon atoms Acyloxy group or a carbaminoyloxy group, Y a hydrogen atom, a hydroxyl group, a derived from an aliphatic carboxylic acid with 2 to 6 carbon atoms or an acyloxy group Carbaminoyloxy group, where in each case only one Y can be hydrogen, and R one optionally branched alkyl group means on a substantial simpler and shorter route while avoiding C-w-haloacetophenones as intermediates to manufacture. It has been shown that the compounds of formula I in a single Operation can be obtained when using acyl cyanides of the formula II

X ₁ C-CN

(H)

ti a η

in which X ₁ and Y _{1 have the} same meaning as X or

Y, with the exception of the hydroxyl group, in the presence of ketones of the formula III

CH ₃
O = CR

(III)

in which R is defined as stated above, catalytically reduced in glacial acetic acid or propionic acid as solvent using noble metal catalysts. In the process according to the invention, the cyano group is converted into the CH ₂ - NH ₂ group in a single operation, this is reductively alkylated at the same time with the ketone of the formula III, the keto group is reduced to carbinol and any benzyloxy groups present are reductively cleaved. Acyloxy or carbaminoyloxy groups only present in the reaction product have to be split off if desired.

Particularly good results are obtained when using platinum oxide as the catalyst. Furthermore it is favorable to use the ketone of the formula III in excess. The splitting off of what is in the core Acyloxy groups are achieved in the usual way, for example by treatment with alkaline solutions, Alkali carbonates ^ alkali bicarbonates or ammonia in aqueous solution. In the production of 3,5-dioxyphenylalkanolamines of the formula I via the corresponding 3,5-diacyloxy compounds proved to be advantageous, the cleavage of the acyloxy groups by treatment with lower alcohols to be carried out in the presence of mineral acid, preferably hydrochloric acid.

The isolation of the phenylalkanolamines from the reaction solution obtained after the hydrogenation takes place most appropriately in the form of the well crystallizing salts. The reaction solution is evaporated a, the salts of phenylalkanolamines with acetic acid or propionic acid are obtained directly. these can then in the usual way, for example with the help of ammonia, bicarbonate or ion exchange in the Free acids or are converted into salts with other acids, in which case the Hydrohalides the hydrogenation in the presence of benzyl halides, which undergo hydrogen uptake are cleaved in toluene and hydrogen halide, has proven particularly effective.

The acyl cyanides of the formula II can be prepared by known methods. Particularly recommends the use of the reaction of the corresponding acid chlorides with CuCN at increased Temperature. The acyl cyanides obtainable in this way in good yield are consistently well crystallized and can be distilled in a high vacuum without significant decomposition phenomena. In the acids on which the acyl cyanides are based, free hydroxyl groups must be present before the Production of the acid chlorides and reaction with CuCN either acylated or by hydrogenolytic removable radical, for example a benzyl radical or a carbobenzoxy radical, protected will.

The representatives of the compounds of the formula I, which were not previously known, also have a pronounced sympathomimetic effect and thus medically interesting properties.

The parts given in the examples are parts by weight.

example 1

0.70 parts of platinum oxide are hydrogenated out in glacial acetic acid. This will 3,5-diacetoxy cyanide in glacial acetic acid, mixed with 11.6 parts of acetone under continuation of hydrogenation, a solution of 5.0 parts, was slowly added dropwise at 20 ⁰ C. After uptake of 4 mol of hydrogen, the hydrogenation is ended. The catalyst is separated off by filtration, 2.56 parts of benzyl chloride are added to the filtrate and the mixture is hydrogenated with palladium-carbon as a catalyst until the uptake of hydrogen has ceased. After the catalyst has been separated off, the colorless filtrate is concentrated to about 50 parts in vacuo, ether is added until it becomes cloudy and the crystallization is completed by cooling. After filtering off with suction and drying, 5.50 parts of d, ll- (3 ', 5'-diacetoxyphenyl) -2-isopropylamino - ethanol - (1) - hydrochloride, that is 81.8% of theory, are obtained. The substance can be further purified by reprecipitation from glacial acetic acid ether and then has a melting point of 167 to 170 ^° C.

3.30 parts d, l -1 - (3 ', 5' - diacetoxy - phenyl) - 2 - isopropylamino - Ethanol - (I) - hydrochloride are dissolved in 40 parts of methanol, with 5.9 parts more concentrated Added hydrochloric acid and stored at room temperature for 24 hours. Thereupon the solvent distilled off at low temperature in vacuo and the residue to remove the water with Ethanol — benzene redistilled. The oily residue is then dissolved in a little ethanol, mixed with ether until permanent cloudiness, inoculated and ditched. The precipitated crystals are filtered off and dried. 2.0 parts are obtained

35. d, l -1 - (3 ', 5' - dihydroxyphenyl) - 2 - isopropylaminoethanol (l) hydrochloride, that's 81.17% of theory. The raw substance can be removed from ethanol by falling over Ether and then has a micro-melting point of 180 to 182 ° C.

The requisite 3,5-Diacetoxybenzoylcyanid as a starting material can be prepared by reaction of 3,5-diacetoxy-benzoyl chloride are obtained with CuCN · at 180 ⁰ C, whereby care must be taken during the reaction for exclusion of moisture. It has a melting point of 115 to 118 ° C.

Example 2

5.0 parts of 3,5-bis (propionyloxy) -benzoyl cyanide are dissolved in 100 parts of propionic acid, 3.20 parts Acetone are added and this mixture becomes the hydrogenated suspension of 0.70 parts of platinum oxide slowly added dropwise in propionic acid under hydrogen. After uptake of 4 moles of hydrogen the reaction is over. The catalyst is filtered off, the filtrate with 2.30 parts of benzyl chloride and a little palladium-carbon is added and hydrogenation is carried out until the uptake of hydrogen has ceased. After filtering off of the catalyst, the colorless filtrate is concentrated in vacuo at low temperature, seeded and the crystals obtained in this way are filtered off with suction after some time. 4.60 parts of d, l- (3 ', 5'-Dipropionyloxyphenyl) -2-isopropylarnino-ethanol- (l) - are obtained hydrochloride, that's 70.38% of theory.

For further purification, the substance can be reprecipitated from propionic acid ether. she owns then a micro-melting point of 151 to 152 ° C.

The 3,5-bis- (pro-

pionyloxy) benzoyl cyanide can be obtained by reacting

3,5 - bis - (propionyloxy) - benzoyl chloride with CuCN at 180 ° C can be obtained. It has a melting point from 91 to 93 ° C.

B e i s ρ i e 1 3

1.50 parts of platinum oxide are hydrogenated out in glacial acetic acid. This is followed by continuation of the hydrogenation a solution of 12.9 parts of 3,4-diacetoxy-benzoyl cyanide in glacial acetic acid (p. a.), mixed with 9.1 parts Acetone was slowly added dropwise at 20 ° C. After uptake of 5900 ml of hydrogen (volume not at normal proportions reduced) the hydrogenation is stopped and the catalyst is separated off. The colorless one The filtrate is mixed with 6.6 parts of benzyl chloride and after adding a little palladium-carbon as Catalyst hydrogenated until the uptake of hydrogen has ceased. After separating the catalyst the filtrate is concentrated in vacuo at low temperature to a small volume, with ether added and cooled. The precipitated crystals are filtered off with suction after several hours. You get so 12.75 parts d, l-l- (3 ', 4'-diacetoxyphenyl) -2-isopropylamino-ethanol- (l) -hydrochloride, that is 73.64% of theory. The substance can be taken out by falling over Glacial acetic acid ether is purified and then possesses a melting point of 191 to 196 ° C.

The 3,4-diacetoxybenzoyl cyanide required as starting material for the reaction can be prepared by reacting 3,4-diacetoxybenzoyl chloride with CuCN at 180.degree. The substance has a melting point of 87 to 88 ⁰ C.

Example 4

35

0.70 parts of platinum oxide are hydrogenated in glacial acetic acid, then in a hydrogen atmosphere a Solution of 5.0 parts of 3,5-diacetoxy-benzoyIcyanid and 14.6 parts of methyl ethyl ketone in glacial acetic acid Stir added dropwise. After the uptake of 4 mol of hydrogen, the reaction comes to a standstill. the The catalyst is separated off, the filtrate is mixed with 2.56 parts of benzyl chloride and, after adding a little Pd-carbon hydrogenated until the hydrogen uptake ceases. The catalyst is filtered off and the glacial acetic acid is distilled off in vacuo at low temperature. The residue is taken up in acetone, filtered, the filtrate is mixed with ether until it remains turbid, cooled and the precipitated Sucked off crystals after several hours. 4.6 parts of d, l-l- (3 ', 5'-diacetoxyphenyl) -2-sec-butylamino-ethanol- (l) -hydrochloride are obtained, that is 65.9% of theory. The raw substance can be purified by falling over from glacial acetic acid ether and then has a melting point of 145 to 150 ° C.

Example 5

1.0 part of platinum oxide is hydrogenated in glacial acetic acid, then a Solution of 6.50 parts of 3,5-bis (dimethylcarbamoxy) benzoyl cyanide and 12.40 parts of acetone in glacial acetic acid added dropwise with stirring and hydrogenated until the hydrogen uptake ceased. There will be 4 moles Hydrogen added. The catalyst is separated off, the colorless filtrate with 3.50 parts of benzyl bromide added and, after the addition of Pd-charcoal, hydrogenated until the uptake of hydrogen has ceased.

After the catalyst has been separated off, the filtrate is concentrated in vacuo at low temperature, the residue was taken up in ethanol, ether was added until it became cloudy, inoculated, and cooled overnight and sucked off the precipitated crystals. 7.8 parts of d, l -1 - [3 ', 5' - bis (dimethylcarbamoxy) are obtained - phenyl] - 2 - isopropylamino - ethanol - (I) -hydrobromide, that is 84.3% of theory.

The raw substance can be obtained by falling over from ethanol-ether cleaned and then has a melting point of 183.5 to 188 ° C.

The 3,5 - bis - (dimethylcarbamoxy) - benzoyl cyanide required as starting material for the reaction can by reacting 3,5-bis (dimethylcarbamoxy) benzoyl chloride with Cu (I) CN at 180 ° C and purified by distillation and recrystallization. Melting point 115 to 120 ° C.

Example 6

0.70 parts of PtO ₂ are hydrogenated out in 70 parts of glacial acetic acid. Then, while continuing the hydrogenation, a solution of 5.0 parts of 3,5-diisovalerianyloxy-benzoyl cyanide and 8.7 parts of acetone in 80 parts of glacial acetic acid is slowly added dropwise and hydrogenation is carried out _{until the uptake of H 2 is complete.} The catalyst is separated off, the filtrate is acidified with ethereal hydrochloric acid and largely concentrated under reduced pressure at low temperature. Ether is added to the residue and the precipitated crystals are filtered off with suction after a while.

Yield: 3.9 parts d, l -1 - (3 ', 5' - diisovalerianyloxy - phenyl) - 2 - isopropylamino - ethanol - (I) - hydrochloride = 62.2% of theory.

After purification by recrystallization from glacial acetic acid-ether the substance has a melting point of 146 to 150 ° C.

The 3,5-diisovalerianyloxy-benzoyl cyanide required as the starting product can easily be prepared from the corresponding acid chloride by reaction with CuGN at elevated temperature.

Example 7

0.70 parts of PtO ₂ are hydrogenated out in 70 parts of glacial acetic acid and then a solution of 5.0 parts of 3,5-diacetoxybenzoyl cyanide and 20.2 parts of methyl butyl ketone in 80 parts of glacial acetic acid are slowly added dropwise, while the hydrogenation is continued. The reaction comes to a standstill after uptake of 4 moles of H _2.

The catalyst is separated off, and ethereal HCl is added to the filtrate under reduced pressure largely concentrated at a lower temperature, ether is added to the oily residue, the mixture is cooled and that precipitated crystals sucked off after some time.

Yield: 6.30 parts of d, l-l- (3 ', 5'-diacetoxyphenyl) -2-isohexylamino-ethanol- (l) hydrochloride = 83.5% of theory.

Melting point after recrystallization from methanol-ether: 158 to 160 ° C.

B e i s ρ i e 1 8

3.0 parts of Pd-charcoal (10% Pd) are pre-hydrogenated in 250 parts of glacial acetic acid, then 10 parts of 3,5-diacetoxy-benzoyl cyanide, 2.05 parts of H ₂ SO _{4 are} concentrated and 23 parts of acetone are added and initially at room temperature, later at 50 ° C until completion

hydrogenated the H ₂ uptake. After uptake of about ₂ mol of H 2 / mol of acyl cyanide, crystals separate out and go back into solution in the further course of the hydrogenation. After the reaction has ended, the catalyst is separated off, the solvent is distilled off in vacuo and the residue is crystallized from 85% strength aqueous 2-propanol.

Yield: 9.4 parts of 1- (3 ', 5'-diacetoxyphenyl) -2-isopropylamino-ethanol- (l) sulfate = 66.7% of theory.

After recrystallization from 90% ethanol, the l- (3 ', 5'-diacetoxyphenyl) -2-isopropylamino-ethanol (l) sulfate obtained in this way is used found a melting point of 183 to 185 ° C (decomposition).

Example 9

3 parts of Pd-charcoal (10% Pd) are pre-hydrogenated in 500 parts of glacial acetic acid, 20 parts of 3,5-diacetoxy-benzoyl cyanide and 4.0 parts of concentrated H ₂ SO ₄ are added and the mixture is catalytically hydrogenated. After uptake of about 2 moles of H ₂ / mole of acyl cyanide, 60 parts of acetone are added and the mixture is hydrogenated _{at 50 ° C. until the uptake of H 2 has ended.}

After working up as described in Example 8, 24.0 parts of 1 - (3 ', 5' - diacetoxyphenyl) -2-isopropylamino-ethanol (l) sulfate are obtained.

Mp. After recrystallization from 90% ethanol: 185 to 187 ° C.

209 551/545

Claims (1)

Patent claims: 1. Process for the preparation of N-substituted phenylalkanolamine derivatives of the general formula CH ₃ CH-CH ₂ -NH-CH-R
OH 10