Catalyst – solid sorbent – or support therefor: product or process – Solid sorbent – Organic
Reexamination Certificate
1995-06-26
2001-08-21
Griffin, Walter D. (Department: 1764)
Catalyst, solid sorbent, or support therefor: product or process
Solid sorbent
Organic
C502S401000, C502S407000, C210S198200, C210S656000, C210S660000
Reexamination Certificate
active
06277782
ABSTRACT:
The present invention relates to new chiral adsorbents and to methods for preparing them. The invention also relates to certain new compounds on which the chiral adsorbents are based and to the preparation of these new compounds.
Optical isomers can be separated by the formation of diastereomers using chiral reagents, followed by separation using liquid or gas chromatography or crystallisation, or by direct chromatographic separation using chiral phase systems. The growing interest in resolving pharmaceutical substances and determining their enantiomeric purity has entailed an increased need of direct chromatographic separation OF ENANTIOMERS. This separation technique uses either a chiral selective substance in the mobile phase or a chiral stationary phase. In recent years, great attention has been paid to direct chromatographic separation of enantiomers using chiral stationary phases. A number of different chiral adsorbents have been suggested, but only a few of them, such as those based on cellulose derivatives or derivatised amino acids, have met with any appreciable commercial success in preparative chromatography. This largely depends on the stringent demands that are placed on chiral stationary phases to be suitable for preparative, i.e. large-scale, separations, primarily by HPLC (High Performance Liquid Chromatography). For such separations, the columns must have high enantioselectivity, high capacity, i.e. allowing the addition of relatively large amounts of racemate, high efficiency, i.e. giving small band broadening in the chromatogram, as well as high universality, i.e. allowing separation of as many structurally different types of chemical compounds as possible.
According to the present invention, chiral stationary phases based on network polymerised derivatives of dicarboxylic acids, diamines, dioles or hydroxy acids which are chemically bonded to a solid carrier have been found to thoroughly satisfy the demands placed on such phases for use in both analytical and preparative separations. One example of such an derivative is tartaric acid as such which is one of the less expensive optically active organic starting materials available on the market today, which makes the present invention in its different aspects economically attractive.
The optically active adsorbent according to the invention is characterized in an optically active network polymer covalently bound to a carrier.
The optically active network polymer comprises optically active derivatives of dicarboxylic acids, diamines, dioles or hydroxy acids.
Each functional group of the optically active derivatives of dicarboxylic acids, diamines or dioles comprises at least one aliphatic carbon residue with up to 15 carbon atoms and at least one terminal unsaturation.
Derivatives of diols are aliphatic esters, carbonates or carbamates having up to 15 carbon atoms in the carbon chain and a terminal unsaturation.
Derivatives of diamines are amides, carbamates and urea having up to 15 carbon atoms in the carbon chain and a terminal unsaturation.
Derivatives of the dicarboxylic acids are esters and amides having up to 15 carbon atoms in the carbon chain and a terminal unsaturation.
The most preferred derivative of the hydroxy acids is tartaric acid.
Examples of compounds of interest are:
D- or L-tartaric acid
(1R,2R)-(−)-1,2 diamino cyclohexan
(+)-2.2′-diamino binaphthyl -(1,1′)
(1R,2R)-(−)-1,2-cyclohexan diol
(+)-(2R,3R)-1,45-dimethoxy-2,3-butandiol
D-(−)-citramalic acid
D-(+)-malic acid.
The invention is defined in more detail in the appended claims.
The adsorbents are according to one preferred embodiment of the present invention based on network polymerised tartaric acid derivatives which are bonded to a carrier, such as a silica gel (SiO
2
gel). As is known in the art, certain tartaric acid derivatives bonded to silica gel can be used as chiral stationary phases. Such phases with non-polymeric derivatives bonded to silica (so-called brush type) as well as a number of chiral applications for such tartaric acid derivatives, are described by W. Lindner and I. Hirschböck in J. Pharm. Biomed. Anal. 1984, 2, 2, 183-189. Chiral stationary phases based on a simple, non-polymeric tartaric acid derivative are also disclosed by Y. Dobashi and S. Hara in J. Org. Chem. 1987, 52, 2490-2496. The advantages of the tartaric acid derivative being part of a network polymer phase, as in the present invention, are that several chiral centres are obtained on the carrier, which results in increased capacity, and that a more protected carrier surface is obtained. For a silica carrier, this results in a reduced number of accessible free silanol groups, which means a decrease of achiral polar interactions, which impair the enantioselectivity. Enhanced enantioselectivity is also obtained with a polymer phase as compared with a monomer one, probably because the polymer can form a three-dimensional structure that can have chiral cavities.
The tartaric acid derivatives that are polymerised are in themselves optically homochiral derivatives and contain at least two stereogenic centres. The derivatives can be characterised by the general formula:
wherein R
1
is a group RNH—, RO—, RR′N— or HO— and R
2
is a group RNHCO—, RCO—, ROCO—, H— or R—, R being an aliphatic hydrocarbon residue having up to 15 carbon atoms, an aryl group, an aralkyl group, naphthyl group or an anthryl group and R′ being hydrogen or an alkyl group having up to 7 carbon atoms, the derivatives containing at least two groups R
1
or R
2
containing an aliphatic unsaturation. R
1
and R
2
may contain one or more chiral centres. When R is an aliphatic hydrocarbon residue, this may be an alkyl, a cycloalkyl, an alkenyl or an alkynyl group. R then suitably contains up to 10 carbon atoms and suitably is an alkyl or alkenyl group and preferably an alkenyl group. R may be an aryl group or an aralkyl group. These groups may contain 1, 2 or 3 rings and be unsubstituted or substituted with one or more substituents on the ring or rings. Examples of such substituents are alkyl groups, hydroxy groups, halogens, nitro groups and alkenyl groups. R′ suitably is hydrogen or an alkyl group having 1 or 2 carbon atoms. Suitably, R
1
is a group RNH—, RO— or RR′N—, and preferably a group RNH—. R then suitably is an allyl group, an alpha-phenylethyl group or a naphthyl group and most preferred any of the two first-mentioned ones. R
2
suitably is a group RNHCO—, RCO— or H— and preferably a group RNHCO— or RCO—. R then suitably is a phenyl, an allyl, a 3,5-dinitrophenyl, an naphthyl, a methacryl, an alpha-phenylethyl, a 3,5-dimethylphenyl, a tertiary-butyl, or an isopropyl group. Preferably, R is a phenyl, an allyl, a 3,5-dinitrophenyl, an naphthyl, a methacryl or an alpha-phenylethyl group. The two groups R
1
in the derivatives should be equal, and the two groups R
2
should also be equal.
Especially suitable are tartaric acid derivatives of formula I which can be characterised by the formulae
In compounds of formula Ia, R
1
thus is an allyl amine residue, and in compounds of formula Ib, R
1
is a phenylethyl amine residue and R
2
is as defined above.
Compounds of formula Ia include diallyl tartaric diamide (R,R or S,S) which is commercially available, and derivatives thereof. In compounds of formula Ia, R
2
suitably is a group RNHCO—, RCO— or H, R being as defined above. R may, for example, be a bulky alkyl group, such as isopropyl or tertiary butyl, a benzyl group, a phenyl group, a naphthyl group or an anthryl group, and any substituents on the aromatic ring may be any of those indicated above. Most preferred, R
2
is a group RNHCO— or RCO—, where R contains an aryl group, which optionally is substituted. Advantageously, the compounds contain an aromatic nucleus, since &pgr;,&pgr;-interactions are then obtained with aromatic racemates, which may confer advantages in separation. Examples of some specific, suitable groups R
2
for compounds of formula Ia are: phenyl carbamoyl, &agr;-phenylethyl carbamoyl, 3,5-dimet
Allenmark Stig
Andersson Shalini
Moller Per
Sanchez Domingo
Bullock In Suk
Burns Doane Swecker & Mathis L.L.P.
Eka Nobel AB
Griffin Walter D.
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