Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-09-13
2002-02-12
Moore, Margaret G. (Department: 1712)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S056000, C210S635000, C210S730000
Reexamination Certificate
active
06346616
ABSTRACT:
The invention relates to chloro-, hydroxy- and alkoxysilane derivatives of polysaccharides or oligosaccharides as novel compounds which are polymerizable and cross-linkable, and a method for obtaining them.
The invention also relates to novel material supports obtained from said derivatives and containing said silane derivatives of polysaccharides or oligosaccharides chemically grafted by a covalent bond with the support and polymerizable and cross-linkable in a three-dimensional network. The invention also relates to a method for obtaining said support materials.
The invention also relates to the use of said support materials in separation or in preparation of enantiomers, through employment in gaseous, liquid or supercritical chromatography, by electrophoresis, electrochromatography or by percolation processes through membranes containing said support materials.
The separation of enantiomers has been an expanding field for some twenty years, at both the preparation and analysis level. This is true in particular of pharmacy applications, where legislation requires a separate study of the optical isomers of any compound included in the composition of a medicament. Substituted polysaccharides have the subject of numerous studies, and celluloses deposited physically on a silica gel support are marketed. However, such compounds have the disadvantage of being most often soluble in organic polar solvents, which singularly limits their use.
Recent solutions have been provided to the problem of solubilization, by establishing covalent bonds between the substituted polysaccharide and the support. Kimata et al. published their results (Analytical Methods and Instrumentation, Vol. 1, 23-29 (1993)) on a chiral stationary phase based on cellulose-tris-2,3,6-(4-vinyl benzoate) deposited on silica gel then polymerized on the support.
The chromatographic data obtained with two racemic test mixtures are as follows:
Deposited and polymerized
Deposited support
support
1-(1-naphthyl
1-(1-naphthyl
Stilbene oxide
ethanol)
Stilbene oxide
ethanol)
k′1
1.08
2.15
1.04
1.47
k′2
1.66
2.84
1.44
1.80
&agr;
1.54
1.32
1.39
1.22
R
s
3.63
2.34
3.82
1.44
where
k′1 and k′2 are the capacity factors, that is to say if i=1 or 2, k′
i
=(t
Ri
−t
o
/t
o
, t
Ri
being the retention time of the compound i and t
o
the dead time;
&agr; is the selectivity factor: &agr;=(t
R2
−t
o
)/(t
R1
−t
o
)=k′2/k′1
R
s
is the resolution factor:
R
s
=
1
4
(
(
α
-
1
)
(
α
)
)
(
(
k
′
2
)
(
1
+
k
′
2
)
)
(
N
)
1
/
2
N being the number of plates determined on the basis of chromatographic values measured on chromatogram.
A systematic decline in the obtained selectivity factors can be seen between the deposited support and the deposited and polymerized support: 10% less on trans-stilbene oxide (&agr; changes from 1.54 to 1.39) and 7.5% less for 1-(1-naphthyl)ethanol (&agr; changes from 1.32 to 1.22).
This phenomenon could be explained by a partial solubility of the polymerized support because of an incomplete polymerization due to a low reactivity of the vinyl benzoate group in the reaction conditions employed.
On the other hand, Kimata et al. offer no example of separation in a pure polar solvent (patent or publication).
Okamoto et al. have described (EP-B-0 155 637) polymers chemically bound to silica gel. They describe in particular the grafting of cellulose tris-2,3,6-phenyl carbamate onto silica gel via a tritylated intermediate then the realization of the covalent bond, between the silica gel and the partially derived polysaccharide carbamate, by action of a diisocyanate.
The results of the elemental analyses carried out at various synthesis stages are as follows (EP-B-0 155 637, page 8 to page 9, line 33).
C %
H %
N %
1.
Cellulose trityl deposited on silica
15.40
1.23
0.09
2.
Detriylated cellulose deposited on
3.61
0.60
—
silica
3.
Cellulose bound to the silica by toluene
—
—
—
2,4 diisocyanate
4.
Phenyl carbamate cellulose bound to the
3.23
0.27
0.45
silica and washed with THF/chloroform
The drop in the rate of grafting between the cellulose deposited on silica (2) and the cellulose phenyl carbamate bound to the silica (4) is substantial knowing that the rate of (4) calculated according to (2) is of the order of 14% carbon. The loss of hydrocarbon groups can thus be estimated at 80% from the realization of the covalent bond, between the cellulose and the silica, by the diisocyanate arm followed by the derivation of the OHs with phenyl isocyanate and the final washing with chloroform. No example of separation in polar solvents is given for the support obtained.
Okamoto et al. have described (JP-A-06-206 893) an oligosaccharide chemically bound to silica gel via an amine-reduced imine function. The amylose is then regenerated by the chemoenzymatic route from this oligosaccharide. The available hydroxyl functions are then derived as carbamate functions. No example of separation in a pure polar solvent is given.
On the other hand, it is beneficial to work with a substantial column overload for preparatory applications. The possibility of using 100% of the chiral material in the form of balls of pure polymer of substituted polysaccharides, instead of depositing them physically on a support, has proved effective in increasing the mass yields of preparatory chiral chromatography processes. Thus patents EP-B-348 352, and EP-B-316 270 and WO-A-96/27 639 relate to the realization of cellulose balls for the separation of optical isomers.
However, the pure polymer balls are soluble in polar solvents such as halogenated solvents, tetrahydrofuran, dioxan, etc. It is thus impossible to use these pure solvents or mixtures with high proportions of the latter to realize separations of isomers.
In order to overcome this drawback, Francotte et al. described the polymerization by is radiation of derived polysaccharides (WO-A-96/27 615).
However, the rate of polymerization seems difficult to control in such a process, cross-linking by photochemical process preferentially occurring at the surface of the polymer ball, the rays being unable to penetrate inside the ball. No example of separation is given in a pure polymer.
Francotte et al. have also described in international application WO-A-97/04 011 the chemical cross-linking of carbamates and esters of polysaccharides not containing a polymerizable group. According to the author, crosslinking took place in the presence of a radical polymerization initiator. The reaction mechanism and the structure of the products obtained are not described. No example of separation in a pure polar solvent is given.
Lange at al. have described (U.S. Pat. No. 5,274,167) the polymerization of optically active derivatives of methacrylic acid, the structure of the support not being explained. No example of separation in a pure polar solvent is given.
Minguillon et al. have described the synthesis of partially derived cellulose carbamates with an undecenoyl chloride. However, the structure of the support is not explained (J. of Chromatog. A 728 (1996), 407-414 and 415-422).
Oliveros et al. (WO-A-95/18 833) describe polysaccharide derivatives containing an ethylene radical and deposited on a silica gel support containing vinyl groups then polymerized. No example of separation is given with a pure polar solvent.
The present invention relates to the preparation of novel silane derivatives of polysaccharides or oligosaccharides containing chlorosilane, hydroxysilane or alkoxysilane functions which are easily polymerizable and cross-linkable in a three-dimensional network. Said derivatives are used for obtaining novel support materials containing them and characterized in that that are bound by a chemical covalent bond to the support and concomitantly polymerized and cross-linked in a three-dimensional network. Said support materials are used for the separation of enantiomers by chromatography, in particular in pure polar solvents such as chloroform, dichloromethane, tetrahydrofuran, acetone,
Institut Francais du Pe'trole
Millen White Zelano & Branigan P.C.
Moore Margaret G.
Zimmer Marc S.
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