Silanol condensation products

Product of condensation of a silanol or a silanol derivative, which comprises an Si atom carrying two organic radicals and two oxygen atoms connected to organic groups other than the radicals; at least one of these organic groups carries at least one NH and a NH.sub.2.

The present invention relates to a new series of silanol condensation 
products and their derivatives; it relates more particularly to those 
products formed by the condensation of silanols with organic compounds, 
carrying at least one carboxylic function, which also have one or more 
hydroxyls and one or more aminio groups. They can comprise siloxanic 
groups in their molecule. 
The usefulness of silanols, siloxanes and their various derivatives is well 
known. It is known for example that alkyl silanols, such as methyl 
silanetriol, and their salicylates have a very beneficial action on 
conjunctive tissues; they prevent sclerosis, stimulate the regeneration of 
tissue and ensure its stabilisation. Moreover, organic polysiloxanes are 
employed as additives for plastics materials, as they facilitate removal 
from moulds; they are also used for the lubrication of organic fibres and 
as emulsifiers and foaming agents. 
The present invention provides an advance over the known art relating to 
organic compounds of silicon, in that it concerns condensation products 
which are highly stable to heat, which can be manipulated, transported and 
stored in the solid or oily state and not necessarily in solution, as are 
the products mentioned above. It is possible to have according to the 
invention compounds which hydrolyse or alcoholise in solution, thus giving 
products in the nascent state, which are particularly active. Very 
effective products having therapeutic and cosmetic action are obtained 
according to the invention with hydroxylated aminoacids. 
The new products according to the invention, which comprise an Si atom 
carrying two organic radicals and two oxygen atoms connected to organic 
groups other than these radicals, are characterised in that at least one 
of these groups carries at least one --NH.sub.2 or =NH groups. 
One of or the two organic groups of these products can be cyclic or 
together can form a ring. 
The products according to the invention can be represented by the general 
formula: 
##STR1## 
where the radicals R and R.sup.1, the same or different, are aliphatic or 
aryl hydrocarbon or oxyhydrocarbon radicals; R.sup.2 and R.sup.3, the same 
or different between themselves or each different from R and R.sup.1, are 
linear or cyclic organic groups at least one of which carries one or more 
--NH.sub.2 or =NH groups. 
R and R.sup.1 can in particular be alkyls or alkenyls, preferably from 
C.sub.1 to C.sub.18, benzene or naphthalene aryls which can carry 
substituents, in particular alkyls, halogens, hydroxyls, alkoxyls or 
acyls; they can be C.sub.1 to C.sub.8 alkoxy, benzene or naphthalene 
aryloxy, if required substituted as indicated above, or C.sub.4 to C.sub.8 
cycloalkyls or cycloalkenyls. 
Also R.sup.2 and R.sup.3 can be C.sub.1 to C.sub.18 alkyls or alkenyls, 
aryls, alkoxy, aryloxy, cycloalkyls or cycloalkenyls, defined as above, 
but different from R and R.sup.1. 
R.sup.2 and R.sup.3 can be connected to one another in which case they form 
a ring with the part 
##STR2## 
of the molecule. An important case is that where R.sup.2 and R.sup.3 
together form a ring, for example having 5 or 6 elements. 
When the products according to the invention are intended for biological 
uses, particularly as medicaments or in cosmetics, it is highly preferable 
for one of the radicals R and R.sup.1 to be hydrocarbon namely alkyl, 
alkenyl or aryl, the second being of a different nature, in particular 
alkoxy, alkenoxy, aryloxy, hydroxy-alkyl or amino. It is in effect 
considered that the silanols and their derivatives, where the silicon atom 
carries more than one hydrocarbon radical connected to Si by a C-Si bond, 
have a lower efficacy than that of compounds having a single bond of this 
type. 
This is the reason why those of the products according to the invention 
which are intended for pharmaceutical uses preferably correspond to the 
formula (1) in which R, as indicated above, can be a hydrocarbon or 
oxyhydrocarbon radical, while R.sup.1 is never a hydrocarbon radical. In 
other words in this form of the invention, preferred for pharmaceutical 
products, in the part of the molecule 
##STR3## 
derived from a mono- alkyl, alkenyl- or aryl- (R) silane di- or tri-ol, 
R.sup.1 can be a group of the type R.sup.4 0-(bond-O-Si) where R.sup.4 is 
an alkyl, alkenyl, aryl, cycloalkyl, hydrogen, ether or polyether possibly 
hydroxylated, the group R.sup.4 O possibly being blocked for example with 
an acid molecule, R.sup.1 can on the other hand comprise an amine or amide 
function possibly blocked. 
Thus by way of purely illustrative examples, the formulae of the part 
##STR4## 
of some of the condensation products according to the invention 
particularly utilisable for pharmaceutical purposes are: 
##STR5## 
This example it will be understood has no limitative nature. 
Products according to the invention of particular interest correspond to 
the general formula: 
##STR6## 
where each of R and R.sup.1 same or different is a C.sub.1 to C.sub.4 
alkyl or a C.sub.1 to C.sub.4 alkoxy group, while R.sup.2 is H or a 
C.sub.1 to C.sub.4 alkyl. 
The condensation products according to the invention can be prepared by the 
action of a silane, silanol or siloxane having at least reactive groups, 
with a carboxylic acid having an hydroxyl and an amino group, the reaction 
taking place within an anhydrous organic solvent in the presence of a 
neutraliser. The preparation is terminated by elimination of the solvent 
by boiling. 
Another procedure, generally allowing the attainment of better yields, 
comprises reacting the active groups of the Si compound with a metal 
derivative of the carboxylic acid indicated above. 
Silanes having at least two reactive groups are in particular the di- and 
tri-halides respectively of di- and mono-hydrocarbyl silicon, namely 
R.sub.2 SiX.sub.2 and RSiX.sub.3, R being a hydrocarbon radical and X a 
halogen. Such silanes are for example (CH.sub.3).sub.2 SiCl.sub.2 and 
CH.sub.3 SiCl.sub.3. However dihalogen compounds are more preferred, 
because of subsequent complications, namely the cross-linking 
polymerisation which can be caused by the third halogen. 
Siloxanes utilisable in the process according to the invention are 
organosilicons of the R'.sub.2 SiQ.sub.2 and R'SiQ.sub.3 types, R' being a 
hydrocarbon or oxyhydrocarbon radical such as for example --CH.sub.3 or 
CH.sub.3 O--, while Q is --OH or --OR, R indicating as above a hydrocarbon 
radical. Examples of such siloxanes, without any limitation are: 
##STR7## 
The compounds preferred for the process of the invention are those where R 
is a lower alkyl (C.sub.1 to C.sub.4) leading to the formation of the 
corresponding alcohol, easily separable by distillation. 
As carboxylic acids to be condensed with the siloxane, various aliphatic or 
aryl acids can be used, including diacids carrying OH and NH.sub.2 or NH 
functions. 
These are in particular serine, diserine, threonine, hydroxyproline, 
tyrosine, casein or amino phenyl lactic acid. 
By way of non-limitative examples, these two diagrams give an idea of the 
condensation reaction in the case of the invention: 
##STR8## 
As regards anhydrous organic solvents employed in the preparation of the 
condensation products according to the invention, these are selected from 
liquids dissolving the silicon compound and the acid utilised and, 
preferbly, boiling at temperatures which do not exceed about 150.degree. 
C. Thus these are liquids which do not react with the reactants present. 
Thus use can be made depending upon the case of aliphatic hydrocarbons 
particularly from C.sub.6 to C.sub.12, aromatics such as benzene, toluene, 
xylene etc, chlorinated solvents, terpenes, ethers such as dioxane, 
tetrahydrofuran etc. It is particularly practical to use as the solvent a 
silane or silanol, in particular the same one as is used for the reaction. 
As indicated for terminating the reaction by heating preferably between 
50.degree. and 100.degree. C., this heating serves at the same time to 
eliminate the solvent and it is carried out under a pressure, possibly 
reduced, under which the solvent boils at an adequate temperature. 
Naturalisers which are well known in the chemical art do not need to be 
mentioned here; reference is merely made to various amines for example 
trimethylamine, dibutylamine or pyridine which are utilisable in the 
process according to the invention.

The invention is illustrated by the non-limitative examples which follow: 
EXAMPLE 1 
Condensation of the sodium salt of serine with dichloro dimethyl silane 
Preparation of the sodium derivative of serine is first carried out by the 
action of Na ethanolate. For this, 0.2 atom of Na or 4.6 g is reacted with 
200 ml of absolute ethanol in an ice bath; when all the sodium is 
dissolved, the solution of Na ethanolate obtained is removed from the ice 
bath and then 0.1 mole or 10.5 g of serine is added. After 1/2 hour, a 
precipitate of the sodium derivative appears. The ethanol is then 
distilled to dryness in order to obtain a white powder formed by the Na 
salt of serine. 
This powder is put into suspension in chloroform and then 0.1 mol, namely 
12.9 g of Cl.sub.2 Si(CH.sub.3).sub.2 is added and the whole is boiled 
under reflux for 24 hours which produces the reaction: 
##STR9## 
The condensate is obtained in a yield of 97% with respect to the serine 
used, after separation by filtration of the precipitate of NaCl and 
rinsing with chloroform. The solid product so prepared has the following 
characteristics: 
______________________________________ 
IR NMR .sup.1 H 
______________________________________ 
C.dbd.O 
1720 cm.sup.-1 CH.sub.3 --Si 
0,38 ppm 
singulet 
CH.sub.3 --Si 
800 cm.sup.-1 
1260 cm.sup.-1 
CH--N 4,52 ppm 
triplet 
NH.sub.2 
3220 cm.sup.-1 CH.sub.2 --O 
3,20 ppm 
doublet 
CH 2900 cm.sup.-1 NH.sub.2 
7,25 ppm 
multiplet 
______________________________________ 
EXAMPLE 2 
Condensation of serine with Cl.sub.2 Si(CH.sub.3).sub.2 in the presence of 
a neutraliser 
0.1 mole of serine is put into suspension in 200 ml of CH.sub.2 Cl.sub.2 to 
which is added 0.2 mole of triethylamine. Then there is added drop by drop 
0.11 mole of dichlorodimethylsilane. The mixture is taken to reflux in the 
solvent for 12 hours and then allowed to return to the ambient 
temperature. The reaction mixture is filtered, the precipitate formed is 
washed with dichloromethane and then dried under reduced pressure. The 
solid product obtained in a yield of 71% over the serine corresponds to 
the cyclic siloxane according to the reaction scheme: 
##STR10## 
The characteristics of this condensate are partically the same for those 
of Example 1: 
______________________________________ 
IR NMR .sup.1 H 
______________________________________ 
C.dbd.O 
1730 cm.sup.-1 CH.sub.3 --Si 
0,35 ppm 
singulet 
CH.sub.3 --Si 
815 cm.sup.-1,1260 cm.sup.-1 
CH--N 4,52 ppm 
triplet 
NH.sub.2 
3200 cm.sup.-1 CH.sub.2 --O 
3,25 ppm 
doublet 
NH.sub.2 
7,3 ppm 
multiplet 
______________________________________ 
EXAMPLE 3 
Product of condensation of a monoalkyl trialkoxy silane with an amino acid 
alcohol the NH.sub.2 function of which is protected by acetylation. 
According to the mode of operation of Example 2, mono-methyl triethoxy 
silane is reacted with acetyl serine. The reaction can be written: 
##STR11## 
EXAMPLE 4 
Another aminated condenation product according to the invention. 
Preparation according to Example 3 with acetyl-threonine in place of 
serine: 
##STR12## 
EXAMPLE 5 
Condensation of a silanol with an aromatic amino-acid having a phenol 
function. 
To a solution of 1 mole of acetyl-tyrosine 
##STR13## 
in 500 ml of benzene, 100 ml of pyridine, 100 ml of ethyl acetate and 1.5 
mole of CH.sub.3 -Si(OC.sub.2 H.sub.5).sub.3 or 267 g (300 ml) are added. 
The solvent is slowly distilled under atmospheric pressure. Then by 
distillation under vacuum, 338 g of an oil is recovered which is dissolved 
in ethyl acetate; the solution is passed through a silica column which is 
then eluated with a mixture of 60 vol. ethyl acetate and 40 vol. ethyl 
ether. Evaporation of the eluate leaves a yellow solid of the following 
characteristics: 
______________________________________ 
M. P. .perspectiveto. 62.degree. C. 
IR: 3300-2900-1730-1630-1050-920-780 
NMR: 6,8 ppm multiplet 4H 
4,5 ppm multiplet 1H 
2,3 ppm multiplet 2H 
1,9 ppm singulet 3H 
0,3 ppm singulet 3H 
______________________________________ 
The formula indicated for this compound is: 
##STR14## 
EXAMPLE 6 
Following the technique of Example 1, a condensation was effected according 
to the reaction: 
##STR15## 
The solid product obtained in a yield of 96% has the following 
characteristics. 
______________________________________ 
IR NMR .sup.1 H 
______________________________________ 
C.dbd.O 1730 cm.sup.-1 (CH.sub.3).sub.3 --Si 
0,39 ppm, 
singulet 
relative integration 18 
Si--O--C 1090 cm.sup.-1 NH.sub.2 
7,2 ppm, 
multiplet 
relative integration 2 
CH.sub.3 --Si 
800 cm.sup.-1, 
CH--N 4,5 ppm, 
1250 cm.sup.-1 triplet 
relative integration 1 
NH.sub.2 3200 cm.sup.-1 CH.sub.2 --O 
3,2 ppm, 
doublet 
relative integration 2 
______________________________________ 
It can be seen that the process of the invention allows the preparation of 
the desired compound with a free NH.sub.2 group in a very good yield. 
EXAMPLE 7 
In a manner analogous to that of Example 1, the condensation is effected: 
##STR16## 
The new solid compound has the following characteristics: 
______________________________________ 
IR NMR 
______________________________________ 
C.dbd.O 1730 cm.sup.-1 CH.sub.3 --Si 
0,35 ppm 
singulet 
CH.sub.3 --Si 
780 cm.sup.-1 CH--N 4,52 ppm 
1265 cm.sup.-1 triplet 
NH.sub.2 3200 cm.sup.-1 CH.sub.2 --O 
3,20 ppm 
doublet 
CH-- 2950 cm.sup.-1 Et-O CH.sub.3 
1,25 ppm 
triplet 
CH.sub.2 
3,75 ppm 
quadruplet 
NH.sub.2 
7,40 ppm 
______________________________________ 
EXAMPLE 8 
Condensation of threonine with a silanol 
The mode of operation of Example 1 is used for the reaction: 
##STR17## 
The product obtained with a yield of 95% is solid and has the following 
characteristics: 
______________________________________ 
IR NMR 
______________________________________ 
CO 1720 cm.sup.-1 
CH.sub.3CH 1,5 ppm doublet 
CH.sub.3Si 
800 cm.sup.-1, 1260 cm.sup.-1 
##STR18## 3,10 ppm multiplet (8 beams) 
NH.sub.2 
3200 cm.sup.-1 
CH 2900 cm.sup.-1 
CHN 4,42 ppm doublet 
CH.sub.3CH.sub.2O 
1,25 ppm triplet CH.sub.3 
3,75 ppm quatruplet CH.sub.1 
CH.sub.3Si 0,35 ppm singulet 
______________________________________ 
EXAMPLE 9 
The technique of the preceding examples is applied to the condensation of 
the sodium derivative of threonine with dichloro dimethyl silane. Thus the 
following reaction is carried out: 
##STR19## 
The solid product formed is obtained in a yield of 96%; it has the 
characteristics: 
______________________________________ 
IR NMR 
______________________________________ 
CO 1750 cm.sup.-1 
CH.sub.3CH 1,5 ppm doublet 
CH.sub.3Si 
790 cm.sup.-1, 1250 cm.sup.-1 
##STR20## 3,05 ppm multiplet 
NH.sub.2 
3200 cm.sup.-1 
CH 2900 cm.sup.-1 
CHN 4,42 ppm doublet 
CH.sub.3Si 0,38 ppm singulet 
______________________________________