Chromatographic enantiomer separation of lactones

Details Chromatographic enantiomer separation of lactones Chromatographic enantiomer separation of lactones

1999-09-03

2001-08-14

Fan, Jane (Department: 1612)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C210S656000

Reexamination Certificate

active

06274736

ABSTRACT:

The present invention relates to the use of optically active polymers of N-acryloyl-phenylalanine neomenthylamide as such, in crosslinked form and/or in carrier-bonded form as stationary phases for the chromatographic separation of enantiomers of lactones.
EP 379 917 describes chiral stationary phases which are derived from N-(meth)acryloylamino acid derivatives and which are suitable for the separation of enantiomers, inter alia also of lactone derivatives. Bead polymers are preferably employed as the separating phases.
It is furthermore known from EP 617 019 that (±)-trans-(E)-6-[2-(2,6-diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-5-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (Ii) can be separated into the enantiomers by chromatography on chiral stationary phases. As described in EP 617 019 and 491 226, this lactone is converted into sodium 3R,5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate (A) which inhibits cholesterol biosynthesis and can be employed in medicaments for the treatment of lipoproteinaemia.
EP 617 019 describes that this separation can advantageously be carried out by chromatography on chiral stationary phases, such as are mentioned in EP 379 917. Polymers of S-phenylalanine d-menthyl ester are mentioned there as particularly suitable phases.
However, it has now been found, surprisingly, that the separation of lactone derivatives is particularly efficient if the optically active polymers are derivatives of amino acid amides. Polymers of N-acryloyl-phenylalanine neomenthylamide are particularly suitable.
The invention therefore relates to the use of optically active polymers of N-acryloyl-S-phenylalanine d-neomenthylamide or of the enantiomer thereof as such, in crosslinked form and/or in carrier-bonded form as stationary phases for the chromatographic separation of enantiomers of lactones of the general formula (I)
wherein
R represents an organic radical and
X represents —CH
2
—CH
2
— or —CH═CH—.
The lactones (or the ring-opening products) of the general formula (I) typically act as HMG-CoA reductase inhibitors. Such compounds are suitable, for example, for the treatment of hyperlipoproteinaemia or arteriosclerosis.
Preferred compounds of the formula (I) are HMG-CoA reductase inhibitors in which the radical R is a derivative of an aromatic or partly saturated carbocyclic ring having 6 or 12 carbon atoms, an indole derivative, a pyridine derivative, a pyrrole derivative or an ethene derivative.
Particularly preferred examples for this are the following compounds:
According to an especially preferred embodiment, the invention relates to the use of optically active polymers of N-acryloyl-S-phenylalanine d-neomenthylamide or of the enantiomer thereof as such, in crosslinked form and/or in carrier-bonded form as stationary phases for the chromatographic separation of enantiomers of (±)-trans-(E)-6-[2-(2,6-diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-5-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.
The invention furthermore also relates to a process for the chromatographic separation of enantiomers of lactone compounds of the general formula (I), characterized in that the corresponding enantiomer mixture is separated into the enantiomers by means of an optically active polymer of N-acryloyl-S-phenylalanine d-neomenthylamide or of the enantiomer thereof as the chiral stationary phase, using a suitable mobile phase, the optically active polymer being employed as such, in crosslinked form and/or in carrier-bonded form.
Which lactone compounds of the general formula (I) can preferably be separated into the enantiomers by this process has already been mentioned above.
The chiral stationary phases used according to the invention are derived from N-acryloyl-S-phenylalanine d-neomenthylamide or from its enantiomer N-acryloyl-R-phenylalanine-1-neomenthylamide. The phases derived from N-acryloyl-S-phenylalanine d-neomenthylamide are preferred.
N-Acryloyl-S-phenylalanine d-neomenthylamide or its enantiomer can be prepared by known processes, for example as described in U.S. Pat. No. 5,274,167/EP 379 917.
The optically active N-acryloyl-phenylalanine neomenthylamide polymer used according to the invention is preferably employed in the form of crosslinked insoluble but swellable polymers or in a form bonded to finely divided inorganic carrier materials. It can also be prepared as a linear polymer which is soluble in suitable organic solvents. It is furthermore possible to incorporate 0.1 to 60, preferably 0.1 to 20 mol % of copolymerizable non-chiral monomers into the polymer.
The crosslinked polymers are preferably present in the form of finely divided beads having a particle diameter of 5 to 200 &mgr;m, preferably 10-100 &mgr;m. They can be prepared in a manner known per se by polymerization with the addition of a suitable crosslinking agent, for example as described in U.S. Pat. No. 5,274,167/EP 379 917.
The degree of swelling of the (bead) polymers can be adjusted by the nature and amount of the crosslinking agent (of the crosslinking agents).
For use in practice, (bead) polymers having a degree of swelling (Q) of 1.1 to 10, preferably 2.0 to 7.0, have proved suitable.
Q
=
resin volume (swollen)
resin volume (non-swollen)
The polymer of N-acryloyl-S-phenylalanine d-neomenthylamide or the enantiomer thereof is particularly preferably employed as the stationary phase in a form bonded to finely divided inorganic carrier materials, preferably to silica gel.
Coating of the silica gels with polymerization-active groups by means of free radicals and the polymerization can be carried out by methods known per se.
For example, the optically active polymer can be taken up onto the silica gel by adsorbing it physically or fixing it covalently. The latter can be effected by coating the silica gel surface with polymerizable groups and then carrying out a copolymerization with the optically active monomer. Polymerization of the optically active monomer in the presence of silica gel diol phases, which have been esterified with (meth)acrylic acid, is also widely applicable. Suitable processes are described, for example, in EP 379 917 and EP 282 770.
According to a particularly preferred process, the silica gel is first coated with mercapto groups (SH units) and then reacted with the optically active monomer under polymerization conditions (cf. our European patent application also pending, Application No. 96 119 045.1).
The silica gel modified on the surface with SH units is expediently obtained by reacting the starting material with a compound which contains at least one mercapto group. Suitable derivatizing reagents are known in principle (V. R. Meyer, Praxis der Hochleistungsflüssigchromatographie [High performance liquid chromatography practice], Salle+Sauerlander, 6th Edition 1990, page 79 et seq. and the literature cited therein); they have the general form Q-L-SH, wherein Q represents a reactive group which can react with the OH groups of the silica gel and L represents a spacer group which is inert under the corresponding conditions and ensures the necessary distance between the silica gel and SH group.
Silica gels are preferably coated by reaction of a non-modified silica gel with a silane of the form Z
1
Z
2
Z
3
Si-L-SH, wherein Z
1
, Z
2
and Z
3
independently of one another represent alkyl having up to 4 carbon atoms, halogen, alkoxy having up to 4 carbon atoms or hydroxyl and L represents an optionally substituted alkylene chain having up to 7 carbon atoms.
The reaction can be carried out under base catalysis or in an acid medium. The silica gel is usually reacted in a ratio of the functionalization reagent to silica gel of 1:20 to 1.2:1. Silica gels which comprise 0.1% to 5%, particularly preferably 0.5% to 3% of sulphur in the form of SH groups and in which the optically active polymer is bonded to the mercapto groups of the modified silica gel result.
According to the abovementioned process,

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