Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-03-16
2002-01-29
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S042000, C536S053000, C562S471000, C562S473000
Reexamination Certificate
active
06342592
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a method which comprises synthesising bifunctional compounds then chiral compounds from the bifunctional compounds, also to synthesising supports comprising these chiral compounds, normally in the form of a cross-linked three-dimensional chiral network and generally with a modifiable degree of cross-linking depending on the desired degree of swelling, and the use of these supports for preparing and separating enantiomers, or for asymmetric synthesis. The invention also relates to bifunctional compounds, their use as a source of functionalised polymers, and to the chiral compounds, also to the use of these chiral compounds in a chiral support for separating and preparing enantiomers, principally for analytical or preparative chromatography, and for asymmetric synthesis.
BACKGROUND OF THE INVENTION
Enantiomer separation is a field which has been expanding for about twenty years both on the preparative and on the analytical levels. This is particularly true in the pharmaceutical field, where the law requires the separate study of optical isomers of any chiral component of a medication composition. Substituted polysaccharides have been the subject of a number of studies, and celluloses physically deposited on a silica gel support are commercially available. Such compounds have the disadvantage, however, of usually being soluble in polar organic solvents, which drastically limits their applications.
Recent solutions to the problem of solubility have been found by forming covalent bonds between the substituted polysaccharide and the support. Kimata et al. have published their results (“Analytical methods and instrumentation”, vol. 1, 23-29 (1993)) on a stationary chiral phase based on -tris-2,3,6(4-vinylbenzoate) cellulose deposited on silica gel, then polymerised on the support.
Chromatographic data obtained with two racemic test mixtures were as follows:
Deposited and polymerised
Deposited support
support
Stilbene
1-(1-naphthyl)
Stilbene
1-(1-naphthyl
oxide
ethanol)
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 partition ratios, i.e., if i=1 or 2,
k
i
′
=
t
Ri
-
t
0
t
o
where t
Ri
is the retention time of compound i;
and t
0
is the non-retained solute transit time;
&agr; is the relative retention ratio:
α
=
t
R2
-
t
0
t
R1
-
t
0
=
k
′
2
k
′
1
R
S
is the peak resolution:
R
S
=
1
4
(
α
-
1
α
)
(
k
′
2
1
+
k
′
2
)
(
N
)
1
2
where N is the plate number
N
=
a
(
t
R
ω
)
2
where &ohgr; is the peak width at a given ordinate, related to the square of the standard deviation or variance &sgr;
2
by the relationship &ohgr;
2
=a&sgr;
2
, giving
N
=
16
(
t
R
ω
)
2
=
5.54
(
t
R
σ
)
2
A systematic reduction in the relative retention ratios obtained can be seen between the deposited support and the deposited and polymerised support: 10% less on the trans-stilbene oxide (&agr; varies between 1.54 and 1.39) and 25% less for the 1-(1-naphthyl)ethanol.
This phenomenon can be explained by partial solubility of the polymerised support due to incomplete polymerisation because of weak reactivity of the vinyl benzoate group under the reaction conditions used.
Kimata et al. did not describe any examples of separation in a pure polar solvent.
Okamoto et al. (in European patent EP-B-0 155 637) described polymers which are chemically bonded to a silica gel. In particular, they described grafting tris-2,3,6-phenylcarbamate cellulose onto silica gel via a tritylated intermediate, then forming a covalent bond between the silica gel and the partially derived polysaccharide carbamate, by the action of a diisocyanate.
The results of elemental analyses carried out during the different stages of synthesis were as follows (EP-B-0 155 637, page 8 to page 9, line 33).
C%
H%
N%
1. Trityl cellulose deposited on silica
15.40
1.23
0.09
2. Detritylated cellulose deposited on silica
3.61
0.60
—
3. Cellulose bonded to silica by toluene-2,4-
—
—
—
diisocyanate
4. Cellulose phenyl carbamate bonded to
3.23
0.27
0.45
silica and washed with THF/chloroform
The drop in the degree of grafting between the cellulose deposited on silica (2) and cellulose phenylcarbamate bonded to silica (4) is important knowing that the degree of (4) calculated after (2) is of the order of 14% of carbon. The loss of hydrocarbon moieties can thus be estimated to be 80% from formation of the covalent bond between the cellulose and the silica by the diisocyanate arm, followed by derivative formation by reacting the OH groups with phenyl isocyanate and final washing with chloroform.
No example of separation in polar solvents was given for the support obtained.
Okamoto et al (Japanese patent JP 06-206-893) have described an oligosaccharide chemically bonded to silica gel by means of an imine function reduced to an amine. Amylose is then chemicoenzymatically regenerated from this oligosaccharide. The available hydroxyl functions are then reacted with carbamate functions to form derivatives. No example of separation in a polar solvent was given.
It is important to use a large column excess for preparative applications. The possibility of using 100% of chiral material in the form of pure polymer beads of substituted polysaccharides instead of physically depositing them on a support has proved effective in increasing mass yields in preparative chiral chromatographic processes. Thus patents EP-B-0 348 352, EP-B-0 316 270 and International patent application WO 96/27639 relate to the production of cellulose beads for separating optical isomers.
However, pure polymer beads are soluble in polar solvents such as halogenated solvents—tetrahydrofuran, dioxane, etc. It is thus impossible to use these solvents either pure or in mixtures with high proportions of these solvents, to carry out isomer separation.
In order to overcome this disadvantage, Francotte et al. recommended irradiation polymerisation of polysaccharide derivatives. (WO 96/27615).
However, the degree of polymerisation appears to be difficult to control in such a process. No example of separation in a pure polar solvent is given.
Minguillon et al. described the synthesis of cellulose carbamates with partial derivatives formed by reaction with an undecenoyl chloride. However, the structure of the support was not explained (J. of Chromatog. A 728 (1996), 407-414 and 415-422).
Lange (U.S. Pat. No. 5,274,167) described the polymerisation of optically active methacrylic acid derivatives, but the structure of the support was not explained. No example of separation in a pure polar solvent was given.
The present invention concerns the preparation of novel chiral compounds and their use in preparing or separating enantiomers, in particular on a support or in polymer beads.
SUMMARY OF THE INVENTION
The chiral supports are obtained in the form of pure polymer beads of the chiral compound which is normally polymerised and cross-linked, preferably into a three-dimensional glycosidic network or obtained in the form of a chiral compound attached to a support via a covalent bond, then polymerised and cross-linked, preferably into a three-dimensional glycosidic network.
The chiral supports of the invention have remarkable stability in polar solvents such as TIF (tetrahydrofuran), chloroform, methylene chloride, acetonitrile, toluene, acetone or ethyl acetate.
For the first time, separation of a racemic molecule on a support based on a polysaccharide has been carried out in pure chloroform (see Examples IA, IB, IC and ID).
This exceptional stability towards polar solvents of the novel chiral supports is associated with the extremely fast mass transfer kinetics between the solutes and the three-dimensional glycosidic network. Again for the first time, separations have been carried out in the normal or inverse mode using an elution gradient on stationary chiral phases (see Examples IIA and IIB).
Further,
Duval Raphaël
Leveque Hubert
Institut Francais du Petrole and Chiralsep
Kumar Shailendra
Millen White Zelano & Branigan P.C.
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