Process for the preparation of 2-trimethylsilyloxy-ethylamines

New 2-trimethylsilyloxy-ethylamines are disclosed. They can be prepared by catalytic hydrogenation of 1-trimethylsilyloxynitriles which are substituted in the 2-position.

The invention relates to new 2-trimethylsilyloxy-ethylamines and a process 
for the preparation of 2-trimethylsilyloxy-ethylamines. These compounds 
can easily be converted into the corresponding 2-hydroxyethylamines by 
hydrolysis. 
In many cases, reduction of cyanohydrins of aldehydes and ketones, which, 
as readily accessible compounds, are potential starting materials for the 
preparation of a large number of homologous, in some cases 
pharmacologically interesting, 2-hydroxyethylamines, presents considerable 
difficulties, both in the case of chemical reduction and in the case of 
catalytic hydrogenation of cyanohydrins (1-hydroxy-nitriles). The 
difficulties are, above all, to be attributed to the fact that the adducts 
of hydrogen cyanide and carbonyl compounds are in equilibrium with the 
starting materials, and to a particularly marked degree in the alkaline pH 
range, their presence leading to the formation of undesired by-products 
or, in the case of catalytic hydrogenation, to poisoning of the catalysts 
by hydrogen cyanide (Houben-Weyl, Methoden der organischen Chemie (Methods 
of Organic Chemistry), Volume XI/1, page 571 et seq. (1957) and Volume 
VI/1c, page 133 (1976)). 
In the known processes for catalytic hydrogenation of 1-hydroxy-nitriles 
(Helv. 30, 1441 (1947), Am. Soc. 82, 4099 (1960), C.A. 67, 53293 (1967) 
and J. Org. Chem. 25, 1658 (1960)), platinum catalysts of palladium 
catalysts are used. In the known cases, large amounts of catalyst and long 
reaction times are required. 
The parent substance of the 2-trimethylsilyloxyethylamine class of 
compounds, that is to say 2-trimethylsilyloxy-ethylamine, is known (Z. 
Obsc. Chem. 39, (1969) No. 7, pages 1462-1467). It is prepared in an 
expensive manner from 2 mols of ethanolamine and 1 mol of trimethylsilyl 
chloride. O,N-Silylated derivatives are formed as by-products. 
The object of the invention is to develop a new process for the preparation 
of 2-trimethylsilyloxyethylamines which are substituted in the 2-position, 
starting from aldehydes or ketones, and hence to provide starting 
materials for an improved and economically acceptable preparation of 
2-substituted 3-hydroxyethylamines on an industrial scale. 
A process has been found for the preparation of 
2-trimethylsilyloxy-ethylamines of the formula (I) 
##STR1## 
in which R.sup.1 and R.sup.2 are identical or different and denote 
hydrogen, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 12 carbon 
atoms, cycloalkyl or cycloalkenyl with in each case 3 to 10 carbon atoms 
or aryl with up to 14 carbon atoms, or together, by linking via methylene 
and, if appropriate, imino or oxo groups, represent a 5-membered or 
6-membered ring, which is characterized in that 
2-trimethylsilyloxy-nitriles, which are substituted in the 2-position, of 
the formula (II) 
##STR2## 
in which R.sup.1 and R.sup.2 have the abovementioned meaning, are reacted 
with hydrogen in the presence of a hydrogenation catalyst in the 
temperature range from 20.degree. to 150.degree. C. under elevated 
pressure. 
The 1-trimethylsilyloxy-nitriles can be reacted with a low catalyst 
consumption and in an unexpectedly selective manner by the process 
according to the invention to give the 2-trimethylsilyloxy-ethylamines 
which are substituted in the 2-position and can easily be converted into 
correspondingly substituted 2-hydroxyethylamines by acid hydrolysis. 
Surprisingly, no complications occur in this process, as is the case in 
catalytic hydrogenation of cyanohydrins, even though formation of hydrogen 
cyanide by hydrogenolysis of the starting materials was to be reckoned 
with. 
The process according to the invention can be illustrated with the aid of 
the following equation: 
##STR3## 
According to the invention, alkyl can be a straight-chain or branched 
hydrocarbon radical with 1 to 18, preferably 1 to 12, carbon atoms. A 
lower alkyl radical with 1 to about 6 carbon atoms is particularly 
preferred. The following alkyl radicals may be mentioned as examples: 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 
hexyl and isohexyl. 
According to the invention, alkenyl can be a straight-chain or branched 
unsaturated hydrocarbon radical with 2 to 12, preferably 2 to 8, carbon 
atoms, and a lower alkenyl radical with 2 to about 6 carbon atoms will be 
particularly preferred. 
The following alkenyl radicals may be mentioned as examples: vinyl, allyl, 
isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl and 
isohexenyl. 
According to the invention, cycloalkyl can be a cyclic hydrocarbon radical 
with 3 to 10, preferably 5 or 6, carbon atoms. The following cycloalkyl 
radicals may be mentioned as examples: cyclopropyl, cyclobutyl, 
cyclopentyl and cyclohexyl. 
According to the invention, cycloalkenyl can be an unsaturated cyclic 
hydrocarbon radical with 3 to 10, preferably 5 or 6, carbon atoms. The 
following cycloalkenyl radicals may be mentioned as examples: 
cyclopentenyl and cyclohexenyl. 
According to the invention aryl can be an aromatic hydrocarbon with 6 to 14 
carbon atoms. The following aryl-radicals may be mentioned as examples: 
phenyl, biphenyl and naphthyl. 
It is also possible for the two radicals R.sup.1 and R.sup.2 to be linked 
together to form a 5-membered or 6-membered ring, which can optionally 
contain a nitrogen or oxygen atom. 
Examples which may be mentioned here are the furan and pyridine rings. 
The radicals according to the invention can be substituted by other 
radicals which do not change under the conditions according to the 
invention. The following radicals may be mentioned as preferred here: 
halogens, such as fluorine and chlorine, alkoxy, preferably lower alkoxy 
(1 to about 6 carbon atoms), such as methoxy, ethoxy, propoxy, isopropoxy, 
butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy, and 
carbalkoxy, such as carbomethoxy and carbethoxy and hydroxy. 
2-Trimethylsilyloxy-nitriles of the formula (III) 
##STR4## 
in which R.sup.3 and R.sup.4 are identical or different and denote 
hydrogen, lower alkyl, lower alkenyl cycloalkyl or cycloalkenyl with in 
each case 5 or 6 carbon atoms, phenyl or naphthyl or together, by linking 
via methylene groups and, if appropriate, an imino or oxo group, represent 
a 5-membered or 6-membered ring, are preferred for the process according 
to the invention. 
The 2-trimethylsilyloxy-nitriles for the process according to the invention 
can be prepared by known methods (Chem. Ber. 106, 589 (1973)). They can be 
prepared, for example, by reacting aldehydes or ketones with 
trimethylsilylcyanide. Examples of aldehydes and ketones which are 
particularly suitable for the preparation are: formaldehyde, acetaldehyde, 
propionaldehyde, butyraldehyde, isobutyraldehyde, acetone, methyl ethyl 
ketone, isopropyl methyl ketone, cyclobutanone, cyclopropanone, 
cyclohexanone, 2-methylcyclohexanone, benzophenone and 
tetramethyl-4-piperidinone. 
The process according to the invention is in general carried out in the 
temperature range from about 20.degree. to 160.degree. C. and under a 
hydrogen pressure of about 10 to 250 bar. It is preferably carried out in 
the temperature range from about 30.degree. to 120.degree. C., and 
particularly preferably in the temperature range from 25.degree. to 
80.degree. C. 
It may be advantageous to carry out the process under a higher hydrogen 
pressure in the range from 50 to 200 bar, and particularly preferably in 
the range from 80 to 120 bar. 
The process according to the invention is carried out in the presence of a 
hydrogenation catalyst. Hydrogenation catalysts for the process according 
to the invention in general contain a metal of group VIII of the Periodic 
Table according to Mendeleeff and/or copper or at least one of these 
metals in combination with vanadium, chromium or manganese. Metals of 
group VIII of the Periodic Table which may be mentioned are: iron, cobalt, 
nickel, ruthenium, rhenium, palladium, osmium, iridium and platinum. 
The metals mentioned can be present in the catalyst in the form of the 
elementary metal or in the form of a hydroxide, hydrated oxide or oxide, 
and can be used together with an inert support material. 
Examples of inert support materials are synthetic and naturally occurring, 
optionally physically or chemically modified substances, such as aluminum 
oxides, silicic acid, kieselguhr, silicates, aluminum silicates, 
montmorillonites, zeolites, spinels, kaolin, clay, magnesium silicate, 
asbestos, pumice, dolomite, alkaline earth metal carbonates, alkaline 
earth metal sulphates, zinc oxide, zirconium oxide, silicon carbide, boron 
phosphate, aluminum phosphate, active charcoal, silk, polyamides, 
polystyrenes, polyurethanes and cellulose. Such supported catalysts in 
general contain about 1 to 65% by weight, preferably 5 to 50% by weight, 
of the catalytically active metal, relative to the total mass of supported 
catalyst. The catalytically active metals can be homogeneously distributed 
in the support material or, preferably, deposited in the outer layer or on 
the surface of the support. The preparation and shaping of the catalysts 
which can be used in the process according to the invention can be 
effected in a known manner (R. L. Augustin, "Catalytic Hydrogenation", 
Marcel Dekker Inc., New York (1965); and Chemical Engineering 81, 98, Book 
No. 20 (1974)). 
Supported catalysts in the form of beads, cylinders, polygons, strands, 
filaments or fibres are in general preferred for carrying out the process 
according to the invention continuously by the fixed bed catalyst method, 
especially in the trickle phase, whilst unsupported catalysts or supported 
catalysts in pulverulent form are preferred for the discontinuous 
procedure in a liquid phase. 
Catalysts which contain nickel are preferred for the process according to 
the invention. These catalysts can contain nickel by itself or in 
combination with at least one other of the abovementioned metals. The 
following are examples of preferred catalysts which may be mentioned: 
catalysts of the Raney type, such as Raney nickel, Raney nickel/iron, 
Raney nickel/cobalt and Raney nickel/copper, metallic nickel prepared by 
reduction of nickel salts with zinc dust, alkali metal hydrides, 
boranates, hydrogen boride, metal-alkyl compounds or hydrazine, such as 
Urushibara nickel, metallic catalysts prepared by reduction of nickel 
oxide or mixtures of nickel oxide and at least one other metal oxide with 
hydrogen, such as nickel oxide/chromium oxide, nickel oxide/manganese 
oxide/copper oxide and nickel oxide/chromium oxide/copper oxide, and 
supported catalysts, such as nickel-on-kieselguhr, nickel-on-aluminum 
oxide, nickel/copper-on-aluminum oxide and nickel/manganese-on-aluminum 
oxide. 
The catalysts can contain, as an accelerator, one or more of the elements 
lithium, sodium, potassium, calcium, barium, silver, gold, beryllium, 
lanthanum, cerium, vanadium, niobium, tantalum, molybdenum and tungsten in 
amounts of up to 10% by weight, preferably up to 1% by weight, based on 
the catalytically active metal. 
Particularly preferred catalysts for the process according to the invention 
are: Raney nickel containing more than 90% by weight of nickel and less 
than 1% by weight of iron, calcium and sodium; Raney nickel/iron 
containing 5 to 30% by weight of iron and less than 1% by weight of 
calcium and sodium; Raney nickel/cobalt containing 5 to 30% by weight of 
cobalt; Raney nickel/copper containing 5 to 20% by weight of copper; 
nickel/copper-on kieselguhr containing 5 to 20% by weight of copper; and 
nickel-on kieselguhr containing 50 to 65% by weight of nickel. 
Mixtures of two or more of the catalysts mentioned can also be used for 
carrying out the process according to the invention. The amount of 
catalyst or catalyst mixture used can vary within wide limits and usually 
depends on the nature of the catalyst or catalyst mixture, the reaction 
conditions and the technological procedure. In general, the catalyst or 
catalyst mixture is used in an amount corresponding to 1 to 100, 
preferably 5 to 50, % by weight of metal, the amount being relative to the 
amount by weight of the 1-trimethylsilyloxy-nitriles employed. A 
corresponding amount of supported catalyst is, of course, used, preferably 
about 1.5 to 150% by weight, particularly preferably 5 to 75% by weight, 
relative to the amount of 1-trimethylsilyloxy-nitriles used. Since the 
catalysts can be reused several times, crude catalyst concentrations are 
also entirely economical. 
The process according to the invention can be carried out in the liquid 
phase in the absence of a diluent. However, the reaction is preferably 
carried out using a diluent. Useful diluents are all the organic solvents 
which are inert under the reaction conditions, for example aliphatic and 
cycloaliphatic hydrocarbons, such as hexane, heptane, octane, cyclohexane, 
methylcyclohexane and decalin; aliphatic and alicyclic ethers, such as 
diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, 
dimethylbutyl ether, methyl butyl ether, ethyl butyl ether, ethylene 
glycol dimethyl ether, 1,3-dioxolane, 1,4-dioxane and tetrahydrofuran; 
lower aliphatic alcohols, such as methanol, ethanol, propanol, 
isopropanol, butanol, iso-butanol, tert.-butanol and ethylene glycol; and 
ether-alcohols, such as diethylene glycol, ethylene glycol monomethyl 
ether, ethylene glycol monobutyl ether and dipropylene glycol. 
One can also use mixtures of the above diluents or solvents. 
Diluents or solvents which are preferred for the process according to the 
invention are cycloaliphatic hydrocarbons, alicyclic ethers and lower 
aliphatic alcohols. Cyclohexane, methylcyclohexane, methanol, ethanol, 
iso-propanol, tetrahydrofuran and 1,4-dioxane are particularly preferred. 
The process according to the invention can be carried out discontinuously 
or continuously in a known manner as bottom-phase hydrogenation in known 
hydrogenation equipment, such as autoclaves, tube reactors, circulatory 
units, for example loop reactors, or cascades of autoclaves. 
It may also be advantageous to carry out the hydrogenation continuously in 
the trickle phase or gas phase on a catalyst, preferably in the form of 
lumps, arranged as a fluidized bed. 
In a simple embodiment, the process according to the invention can be 
carried out, for example, as follows: 
An autoclave is filled with the starting material, the catalyst and the 
diluent are added and the autoclave is closed. The air is then expelled in 
a known manner by flushing with nitrogen and hydrogen and the autoclave is 
then put under the chosen hydrogen pressure. The autoclave is subsequently 
heated to the chosen reaction temperature, with intensive stirring of the 
reaction mixture. 
The course of the hydrogenation can easily be followed by measuring the 
hydrogen consumption, which is compensated by supplying further hydrogen. 
The hydrogenation has ended when no further hydrogen is taken up, the 
amount of hydrogen taken up approximately corresponding to the 
theoretically required amount of hydrogen. 
The reaction time required varies depending on the starting material, 
reaction temperature, hydrogen pressure, intensity of mixing and nature 
and amount of catalyst. In general, it is a half to several hours. 
When the hydrogenation has ended, the reaction mixture can be worked up in 
a known manner, for example by filtering off the catalyst and, if 
appropriate, distilling off the diluent. The resulting crude hydrogenation 
product in general contains only small amounts of impurities and can be 
purified in the usual manner, for example by distillation or extraction. 
By the process according to the invention, 2-trimethylsilyloxy-ethylamines 
can advantageously be prepared in a high yield and purity using 
commercially available catalysts in the reactors usually employed 
industrially for pressure hydrogenation, from readily accessible starting 
materials or industrial mixtures of these starting materials. 
It is surprising that 1-trimethylsilyloxy-nitriles can be converted 
completely and selectively into 2-trimethylsilyloxy-ethylamines, even 
though complications were to be expected as a result of poisoning of the 
hydrogenation catalyst. 
The new 2-trimethylsilyloxy-ethylamines of the formula 
##STR5## 
in which R.sup.1 and R.sup.2 are identical or different and denote 
hydrogen, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 12 carbon 
atoms, cycloalkyl or cycloalkenyl with in each case 3 to 10 carbon atoms, 
or aryl with up to 14 carbon atoms, or together, by linking via methylene 
and, if appropriate, imino or oxo groups, represent a 5-membered or 
6-membered ring, R.sup.2 being other than hydrogen if R.sup.1 is hydrogen, 
can be prepared by the process according to the invention. 
The 2-trimethylsilyloxy-ethylamines which are readily accessible by the 
process according to the invention can easily be converted, with dilute 
acids, into 2-hydroxyethylamines, which, according to Houben-Weyl, Volume 
XI/1, page 571, are pharmacologically interesting compounds. 
In addition, the 2-trimethylsilyloxy-ethylamines which are now readily 
accessible are intermediates for the synthesis of ureas and amides with a 
protected hydroxyl group. 
The 2-trimethylsilyloxy-ethylamines according to the invention can be used 
as stabilizers in a manner similar to the compounds known from German 
Offenlegungsschrift No. 2,642,446 and as light stabilizers in a manner 
similar to the compounds known from Japanese Application No. 55/018,409. 
The 2-trimethylsilyloxy-ethylamines according to the invention can be used 
for the synthesis of sympathominetics, e.g. OCTOPAMIN (Ernst Mutschler, 
"Arzneimittelwirkungen", 4. Auflage, Wissenschaftliche Verlagsgesellschaft 
mbH, Stuttgart 1981). The synthesis can be illustrated with the aid of the 
following equations: 
##STR6##

EXAMPLE 1 
171 g (1 mol) of 1-trimethylsilyloxy-2-methylbutyronitrile are dissolved in 
800 ml of dioxane and are hydrogenated in an autoclave together with 35 g 
of Raney nickel at 60.degree. C. and under 100 bar of hydrogen for 5 
hours. The hydrogen uptake has then ended. The catalyst is filtered off, 
the solvent is distilled off and the residue is fractionated. 
Yield: 143.5 g of 2-trimethylsilyloxy-3-methyl-butylamine (=82% of theory); 
Boiling point: 68.degree. to 70.degree. C. under 18 mbar. 
EXAMPLE 2 
197 g (1 mol) of 1-trimethylsilyloxy-1-cyano-cyclohexane are dissolved in 
600 ml of tetrahydrofuran, 40 g of Raney nickel are added and the mixture 
is hydrogenated in an autoclave at 60.degree. C. and under 90 bar of 
hydrogen for 3 hours. When the uptake of hydrogen has ended, the catalyst 
is removed, the solvent is distilled off and the residue is fractionated. 
Yield: 191 g of 1-trimethylsilyloxy-1-aminomethylcyclohexane (=95% of 
theory); 
Boiling point: 100.degree. to 103.degree. C. under 18 mbar. 
EXAMPLES 3 to 7 
The preparation is carried out in a manner corresponding to that in Example 
2. 
__________________________________________________________________________ 
Starting Yield 
Boiling 
Example 
material End product (%) point 
__________________________________________________________________________ 
##STR7## 
##STR8## 92 131-133.degree. C. under 16 mbar 
4 
##STR9## 
##STR10## 84 46-48.degree. C. under 16 mbar 
5 
##STR11## 
##STR12## 81 130-132.degree. C. under 0.3 mbar 
6 
##STR13## 
##STR14## 87 122-125.degree. C. under 19 mbar 
7 
##STR15## 
##STR16## 91 119-122.degree. C. 
__________________________________________________________________________ 
EXAMPLE 8 
197 g (1 mol) of 1-trimethylsilyloxy-1-cyanocyclohexane are dissolved in 
700 ml of dioxane, 40 g of Ru/Al.sub.2 O.sub.3 are added and the mixture 
is hydrogenated in an autoclave at 130.degree. C. and under 140 bar of 
hydrogen for three hours. When the uptake of hydrogen has ended, the 
catalyst is removed, the solvent is distilled off and the residue is 
fractionated. 
Yield: 170.9 g of 1-trimethylsilyloxy-1-aminomethyl-cyclohexane (=85% of 
theory) 
Boiling point: 100.degree.-103.degree. C. under 18 mbar. 
EXAMPLE 9 
197 g (1 mol) of 1-trimethylsilyloxy-1-cyanocyclohexane are dissolved in 
700 ml of dioxane, 40 g of Ni chromite are added and the mixture is 
hydrogenated in an autoclave at 110.degree. C. and under 90 bar of 
hydrogen for three hours. When the uptake of hydrogen has ended, the 
catalyst is removed, the solvent is distilled off and the residue is 
fractionated. 
Yield: 164.8 g of 1-trimethylsilyloxy-1-aminomethyl-cyclohexane (82% of 
theory) 
Boiling point: 100.degree.-103.degree. C. under 18 mbar.