Polymers chromatographic separation of enantiomers

Details Polymers chromatographic separation of enantiomers Polymers chromatographic separation of enantiomers

1994-08-12

2003-05-06

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C548S495000, C560S041000, C560S125000, C560S145000, C560S153000, C560S169000, C564S153000

Reexamination Certificate

active

06559334

ABSTRACT:

The invention relates to novel optically active polymerisable dipeptides, to the process for the preparation thereof, to the polymerisation thereof and to the use of the polymers as adsorbents for the chromatographic separation of enantiomers.
The separation of enantiomers of active substances represents an important task because the individual enantiomers often have different biological effects and side effects. The fractionation can advantageously take place by chromatography on chiral stationary phases or adsorbents.
A number of adsorbents suitable for the chromatographic separation of enantiomers of active substances have already been disclosed (G. Gübitz, Chromatographia 30 (1990), 555-564; EP 249 078; EP 379 917). Nevertheless it is repeatedly found that the fractionation of an active substance racemate is impossible or only poor on the known adsorbents.
It has been found, surprisingly, that for a number of active substance racemates the novel adsorbents according to the invention have a very high selectivity which makes fractionation distinctly more efficient than on adsorbents hitherto disclosed. This means that either higher space-time yields are possible in preparative separations, or an improved analysis of enantiomers, for example of biological analytes, is possible.
The invention therefore relates to polymerisable optically active dipeptides of the formula (I)
in which
R
1
and R
3
are identical or different and represent C
1
-C
5
-alkyl, A—O—CH
2
, A—S—CH
2
, CH
3
—S—(CH
2
)
2
, cyclohexyl-CH
2
, cyclohexyl, phenyl, benzyl, 4-A—O-benzyl, benzyl-(CH
2
), indolyl, naphthyl-CH
2
or naphthyl, where A is hydrogen, methyl, t-butyl or benzyl,
R
2
denotes hydrogen, methyl or fluorine,
X represents oxygen or NR
5
,
where R
5
is hydrogen, methyl, ethyl or, together with R
4
, forms a C
5
-C
6
-cycloalkyl radical, and
R
4
represents a straight-chain or branched C
3
-C
18
-alkyl radical or a mono- to tetra-C
1
-C
4
-alkyl-substituted C
3
-C
12
-cycloalkyl radical, benzyl, 1-phenylethyl or represents a phenyl which is mono- to disubstituted by fluorine, chlorine, trifluoromethyl, methoxy or C
1
-C
4
-alkyl.
Preferred compounds of the formula (I) are those in which R
1
, R
3
and R
5
have the stated meaning, R
2
denotes hydrogen or methyl, and R
4
represents C
3
-C
8
-alkyl (such as, for example, 2-propyl, 3-pentyl, t-butyl, neopentyl), C
5
-C
7
-cycloalkyl (cyclopentyl, cyclohexyl, cycloheptyl), up to tetra-C
1
-C
4
-alkyl-substituted C
6
-cycloalkyl (such as menthyl, bornyl, fenchyl), benzyl, 1-phenylethyl, phenyl, 4-t-butylphenyl, 3,5-dichlorophenyl or 3,5-dimethylphenyl.
If X denotes not O but NR
5
, it is then possible for R
4
also to represent methyl and ethyl or to form with R
5
a C
5
-C
6
ring.
If R
4
is a chiral radical, it is advantageously used in optically active form.
Particularly preferred dipeptides of the formula (I) are those derived from the amino acids alanine, aminobutyric acid, valine, norvaline, leucine, isoleucine, terleucine, norleucine, neopentylglycine, serine, cysteine, methionine, hexahydrophenylalanine, hexahydrophenylglycine, phenylglycine, phenylalanine, tyrosine, homophenylalanine, tryptophan, naphthylalanine or naphthylglycine.
Examples of particularly preferred compounds which may be mentioned are:
N-methacryloyl-S-Leu-S-Ile O-t-butyl ester, N-methacryloyl-S-Leu-S-Phe-d-menthylester, N-methacryloyl-S-Leu-S-Leu-3-pentylamide, N-methacryloyl-S-Val-S-Val-t-butylamide, N-acryloyl-S-Phe-S-Phe-2-propylester, N-methacryloyl-S-Val-S-Ala-1-bornylester, N-methacryloyl-S-Ala-S-Met-3-pentylamide, N-methacryloyl-R-Phg-S-Val-t-butylester, N-methacryloyl-S-Leu-R-Phe-1-menthylester, N-methacryloyl-S-Ala-R-(S)-methyl-Cys-diethylamide, N-methacryloyl-S-Ala-S-Leu-d-menthylester, N-methacryloyl-S-Phg-S-Val-t-butyl ester, N-methacryloyl-S-Leu-S-Ile-3-pentylester, N-methacryloyl-S-Phg-S-Met-diethylamide, N-methacryloyl-S-Leu-R-hexahydrophenylglycine diethylamide, N-methacryloyl-S-Nle-S-Ile-t-butyl-ester.
The compounds of the formula (I) according to the invention are prepared by
A) linking dipeptide derivatives of the formula (II)
 in which
R
1
and R
3
have the abovementioned meaning, and
B represents a group which is customary in peptide chemistry and is easy to eliminate,
using the linkage reactions customary in peptide chemistry to the radical XR
4
where X and R
4
have the abovementioned meaning,
 and subsequently eliminating the radical B using methods customary in peptide chemistry, and reacting the compounds, which are then obtained, of the general formula (III)
 where appropriate in the form of their acid addition products, with acryloyl derivatives of the formula (IV)
 in which
R
2
has the abovementioned meaning, and
Y represents fluorine, chlorine, bromine or represents the radical —OCO—CR
2
═CH
2
,
 in the presence of an acid-binding agent in inert organic solvents to give compounds of the formula (I), or
B) linking amino acid derivatives of the formula (V)
 in which
R
1
and R
2
have the abovementioned meaning,
 to a second amino acid derivative of the formula (VI),
 in which
R
3
, Y and R
4
have the abovementioned meaning, by customary methods to give dipeptides of the formula (I).
Preferred embodiments of process variant A comprise the use of compounds of the formula (II) in which B represents groups which are easy to eliminate such as t-butoxycarbonyl (BOC) or carbobenzoxycarbonyl (CBZ).
The introduction of the radical XR
4
represents a linkage reaction which is customary in peptide chemistry. For example, amines react either after activation of the carboxylic acid functionality with bases such as triethylamine or N-methylmorpholine and chloroformic esters, with active esters via N-hydroxysuccinimide (HOSU) and dicyclohexylcarbodiimide (DCC) or by addition of EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline). Alcohol residues can be introduced, for example, by acid catalysis (HCl) or with water-eliminating reagents such as, for example, thionyl chloride or DCC; this is carried out in inert organic solvents such as, for example, tetrahydrofuran, dichloromethane, toluene or t-butyl methyl ether.
The radical B is eliminated in the case of BOC preferably with HCl or trifluoroacetic acid and in the case of CBZ preferably by hydrogenolysis.
The reaction of III with IV preferably takes place in the presence of an acid-binding agent such as, for example, triethylamine or sodium hydroxide solution. Examples of inert solvents which are employed are dichloromethane, toluene or t-butyl methyl ether.
In the reaction according to process variant B, the coupling of V with VI preferably takes place by activation with bases such as triethylamine or N-methylmorpholine and chloroformic ester, by preparing an active ester with HOSU and DCC, or by addition of EEDQ in an inert organic solvent such as, for example, tetrahydrofuran, dichloromethane or t-butyl methyl ether.
The invention also relates to the optically active polymers and copolymers which can be obtained by, respectively, polymerisation and copolymerisation of the optically active dipeptides of the formula (I) and which contain at least 40 mol %, preferably at least 50 mol %, of structural units of the formula (VII),
in which
R
1
to R
4
and X have the meanings stated for formula (I).
The optically active polymers of the formula (VII) according to the invention are preferably in the form of crosslinked insoluble but swellable bead polymers or in a form bound to finely divided inorganic support materials such as, for example, silica gel. They can also be prepared as linear polymers which are soluble in suitable organic solvents. It is furthermore possible to copolymerise various dipeptides of the formula (I) according to the invention, as well as to incorporate 0.1 to 60, preferably 0.1 to 20, mol % of other copolymerisable monomers into the polymers.
The mechanical properties of the optically active bead polymers, especially the pressure stability in the swollen state, can be improved by incorporating 2 to 60% by weight (based on the

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