DE854526C - Process for the production of amino alcohols - Google Patents

Description

Process for the production of amino alcohols It is known to produce o-methylaminoacetophenones substituted in the benzene nucleus by reacting the co-bromoacetophenones in question with methylamine -2-ethanone to manufacture, by reducing oxy-4'-phenyl-i-methylamino-2-ethanol produced from that which has become known as a pharmaceutical product. for this purpose, a fairly large amount of the relatively expensive methylamine is required because each Bromketonmolekül at least 2 Methylamine molecules have to be used, while only 1 molecule is consumed to form the methylaminoketone and, in addition, as a result of the formation of tertiary amine, the yield of the desired secondary amine is not high the total consumption of methylamine is nevertheless not reduced.

This disadvantage can be avoided by using a different implementation. According to the invention, a compound ROC, H ″ in which R = hydrogen, acyl, alkyl or aralkyl is used with a compound in a solvent suitable for the reaction in which Ri and R 2 represent hydrogen, alkyl or aralkyl or form a ring with the N atom, or are reacted with a salt thereof formed by means of a strong inorganic acid using aluminum chloride, optionally in the presence of hydrogen chloride.

This reaction produces a salt of the imide by the action of water in an aminoketone or a salt the same converted and then by reduction into an amino alcohol or a Salt of the same is converted.

A solvent suitable for the reaction is used understood, apart from the formation of complex compounds, not with the reacting constituents ih disruptive reaction occurs; as an example of such Solvent can be called nitrobenzene or chlorobenzene.

The yield of the production of aminoketones according to the invention is of the aminonitrile or its salt, the phenol derivative and the solvent as well on the relative amount of each of these substances used and the duration of the reaction and reaction temperature dependent.

The reaction time can vary from a few hours to a few days. The reaction temperature is preferably between 0 and 70 °.

Particularly good yields are obtained when nitrobenzene is used as the solvent and the hydrochloric acid salt can be used as the salt of the aminonitrile. When using of esters or easily cleavable ethers of phenol, it can happen that the Ester or ether group is split off during the reaction. If the invention produced aminoketones unsubstituted or substituted, to the N atom or contain benzyl groups bonded to the phenolic oxygen atom, these groups can be replaced by hydrogen in the reduction of the amino ketones to amino alcohols.

There is no protection here for the production of the aminoketones per se claimed.

The invention is explained in more detail by means of the examples.

Example i In 60 g of nitrobenzene, 30 g of anhydrous aluminum chloride were dissolved, and after cooling to room temperature, a mixture of 14 g of phenol and ii g of N-methylaminoacetonitrile hydrochloride (CX - C H2 - N H - C H, + H CI) was added with stirring . Dry hydrogen chloride gas was then passed in for 3 hours with stirring, the temperature being kept between 20 and 30 ' . 55 cc of water were added to the reaction mixture while cooling with ice; The mixture was then boiled for 10 minutes while stirring, and after cooling the precipitate was filtered off with suction and washed with a mixture of acetone and ethanol. The precipitate was then dissolved in 100 cc of water, a solution of 30 g of sodium potassium tartrate in 50 cc of water was added and just made alkaline with aqueous ammonia. The oxY-4'-phenyl-i-methylamin0-2-ätlianon which had precipitated in crystalline form was filtered off with suction, washed with a little water and dried. Yield 12 g QI 0 /, the amount calculated with respect to N-methylaminoacetonitrile), melting point 143 to 145 'with decomposition.

An experiment carried out in a similar manner, in which the reaction mixture was stored for 6 days at room temperature after the introduction of the hydrogen chloride gas and was further treated as above, gave 11 9 OXY-4'-phenyl-i-methylamino-2-ethanone.

33 g of oxy-4'-phenol-i-methylamin0-2-ethanone prepared in the above manner were dissolved together with 15 g of d-tartaric acid in 125 cc of hot water. On cooling, 313 g of neutral tartrate of the aminoketone crystallized, which melted at 193 to 195 'with decomposition.

18 g of this tartxate were suspended in 75 cc of water, provided with 1.5 g of nickel catalyst (made from a nickel-aluminum alloy) and hydrogenated with hydrogen while shaking until no more hydrogen was absorbed.

The solution separated from the catalyst by filtration gave, after evaporation to a small volume and addition of acetone, 14.5 g of neutral tartrate des. OXY-4'-phenyl-i-methylamino-2-ethanol (melting point 187 to 188 'below Decomposition). After recrystallization from dilute ethanol, the melting point is 189 to igo 'with decomposition.

By way of illustration it should be noted that sodium potassium tartrate is added becomes aluminum, which is otherwise deposited in the form of hydroxide when it is made alkaline would hold in the form of a reflection in solution. To this end, instead Sodium potassium tartrate is also used an alkali salt of citric acid or lactic acid will. The cheapest is to use the alkali salt of lactic acid.

Example 2 To a solution of 30 9 # what erfreiern aluminum chloride in 6o g of nitrobenzene was added to a mixture of 14 9 g of phenol and ii hydrochloride of N-Methylaminoacetonitrils. The mixture was stirred in the dark at approximately 30 'for 3 hours. With cooling, 75 cc of water were added, whereupon the mixture was stirred at 0 to 5 'for a further 1/1 hour. The crystalline precipitate was filtered off with suction and washed with 50 cc of a mixture of 3 parts of acetone and 1 part of ethanol. 4.8 g of the hydrochloride of OxY-4'-phenyl-i-methylamino-2-ethanone were obtained.

A solution of 2 g of the hydrochloride of OxY-4'-phenyl-i-methylamino-2-ethanone prepared in the above manner in water, to which gi mg of palladium oxide and 6 mg of platinum oxide had been added, was shaken with hydrogen until 270 ccm of the same had been absorbed. After filtering off the catalyst, the solution was evaporated to approximately 10 cc and made alkaline with aqueous ammonia. The precipitated OxY-4'-phenyli -methylamiii0-2-ethanol weighed 1.2 g and melted at 184 to 18.9 'with decomposition.

Example 3 To a solution of 33 9 aluminum chloride in 60 g nitrobenzene was added a mixture of 14 9 phenol and 12 g of the neutral, sulfuric acid salt of N-methylaminoacetonitrile (CN-CH, -NH-CH,), H, SO. While the temperature was kept below 30 ' , dry hydrogen chloride gas was introduced for 4',!, Hours with stirring. After the reaction mixture had been kept for one night at room temperature, 6o cem of water was added with stirring and cooling with ice, then boiled for 10 minutes, and after cooling the precipitate was filtered off with suction and washed with acetone.

The washed precipitate was dissolved in 200 CCM water, the solution decolorized with charcoal, a solution of 30 g of sodium potassium tartrate in 100 cc of water was added and the oxy-4'-phenylmetli%, lamino-2 was made slightly alkaline with aqueous ammonia -ethanoii dejected. Yield 7 g; 0.56 g could still be obtained from the mother liquor. 20.5 g of Ox '# - 4'-phenyl-i-methylamino-2-ethanone prepared in the above manner were suspended in 100 cc of water and treated with 10 g of 2601 /' hydrochloric acid, whereby the base was dissolved. The solution was treated with a small amount of decolorizing carbon and then hydrogenated with hydrogen and a nickel catalyst made of a nickel-aluminum alloy. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate was made alkaline with aqueous ammonia. OxY-4'-phenyl-i-methylamino-2-ethanol crystallized from the alkaline solution. Yield 14.3 g; colorless crystals; Melting point at 186 to 187 ' with decomposition.

EXAMPLE 4 A solution of 33 g of anhydrous aluminum chloride in 60 g of nitrobenzene, to which a mixture of 15 g of phenol and 9.3 % of the hydrochloride of aminoacetonitrile had been added, was dried for 3 hours with stirring and cooling at a temperature between 20 and 30 ' Hydrogen chloride gas initiated. The reaction mixture was then introduced into 70 cc of water with cooling and the precipitate formed was filtered off with suction, washed with acetone and dissolved in 500 cc of water. The solution was discolored by coal and, after adding 50 9300!, I sodium citrate with aqueous ammonia? ' Made weakly alkaline, whereby the OxY-4'-phenyl-i-amin0-2-ethanone crystallized out in flakes. Yield 7.7g .

This is done by evaporating dry the solution of the base in dilute hydrochloric acid and subsequent treatment with ethonol and acetone had hydrochloride obtained a CI content of 18.840 / ,. I8, oo () / 0 was prepared for this.

This hydrochloride, when dissolved in water and hardened in The presence of a nickel catalyst in good yield, the hydrochloride of OxY-4'-phenyli-amin0-2-ethanol, after crystallization from a mixture of ethanol and butanone-2 at 177 bis 179o melted with decomposition.

Example 5 A mixture of 25 9 40 0 / # ger formaldehyde solution and a saturated aqueous solution of 26 g of sodium bisulfite was heated on a boiling water bath for% hour. After cooling, 30 g of methylbenzylamine were added with shaking. To the resulting suspension, which was cooled with ice, was /, a solution of 13 g sodium cyanide in 25 cc of water was added dropwise with stirring over 1 hour. The mixture was stirred for a further hour at room temperature, the layer containing the nitrile was separated, the water layer was extracted with ether, the extract was combined with the layer containing the nitrile and dried over sodium sulfate. After the ether had been separated off by distillation, the residue was distilled under reduced pressure, 32 g of -X-methyl-N-benzylaminoacetonitrile being formed, which boils at 10.8 to 112 'at 2 MM.

To a solution of 22 g aluminum chloride in 40 g of nitrobenzene were benzviaminoacetonitrils N-Ivlethyl-N-added 9.3 9 phenol and 13J 9 Hvdrochlorid of what dryer with stirring and cooling to 2o to 3o '6 hours hydrogen chloride was introduced.

A saturated solution of ammonium sulfate in 50 cc of water was then added to the reaction mixture and the mixture was boiled for a short time. After the exhaust cooling, the precipitate was filtered off and washed with acetone, the filtrate, which was consisted of a nitrobenzene layer and an aqueous layer combined with the washing liquid separated after which the aqueous layer and was washed with chloroform to eliminate existing nitrobenzene. The aqueous layer treated in this way, in which the desired reaction product is contained, is now boiled for a short time with decolorizing charcoal, filtered and cooled. 25 g of sodium potassium tartrate were then dissolved in this solution and aqueous ammonia was added until a weakly alkaline reaction. It separated from 4.5 9 OxY-4'-phenyli-N-methvlbenzylamin0-2-ethanone, which was purified by recrystallization from dilute ethanol, from which the base crystallized out with 1 molecule of water of crystallization.

1.27 g of OxY-4'-phenyli-N-methylbenzylamin0-2-ethanone prepared in this way was dissolved in just the required amount of dilute hydrochloric acid, and the solution was hydrogenated with hydrogen using a nickel catalyst made of aluminum-nickel alloy. 2 molecules of hydrogen were absorbed. After filtering the catalyst, the filtrate, which smelled of toluene, was evaporated to a small volume and the resulting oxY-4'-phenyl-i-methylamino-2-ethanol was precipitated by adding ammonia. Yield 0.5 9; Melting point from 183 to 185 'with decomposition.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of amino alcohols and their salts, characterized in that a compound R 0 is C, H, in which R = hydrogen, acyl, alkyl or aralkyl, with a compound in which R, and R, denote hydrogen, alkyl or aralkyl or together with the nitrogen atom form a ring or with a salt thereof formed by means of a strong inorganic acid in the presence of aluminum chloride, optionally with the introduction of hydrogen chloride as a condensing agent, in a suitable solvent brought to reaction and the resulting reaction product is mixed with water and the resulting amin'oketone is reduced. 2. The method according to claim i, characterized in that the starting materials used are preferably phenol on the one hand, and amino, methylamino and isopropylaminoacetonitrile on the other hand. 3. The method according to claim i and 2, characterized in that when the aminoketone is precipitated by making the resulting mixture alkaline, a substance, preferably alkali tartrate, is added which keeps the aluminum in solution as a complex ion. 4. The method according to claim i to 3, characterized in that the solvent used is nitrobenzene and the salt of the aminonitrile is the hydrochloric acid salt.