Process for preparing...

Details Process for preparing... Process for preparing...

2003-05-22

2004-11-16

Solola, Taofiq (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06818778

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for preparing (−)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and its use for (−)-chiral stationary phases for resolution of racemic compounds. More particularly, the present invention relates to the process for preparing (−)-(18-crown-6)-2,3,11,12-tetracarboxylic acid expressed by the following formula (1) and the use thereof as a stationary phases for resolution of racemic compounds, wherein the use of this stationary phase provides excellent separation of a desired chiral compound from racemic mixture in employing capillary electrophoresis (CE) or liquid chromatography (LC) to elute the desired one first by controlling a flowing order of enantiomers, thus allowing to be consistently separated in an economical due to much less requirement of eluent, quantitative and high purity manner,
wherein the compound of formula (1) is an enantiomer which has not been reported for its preparation processes and uses.
On the other hand, (+)-isomer, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid, of the compound of formula (1) has been synthesized by Hiroyuki Nishi et al. and used for separation of enantiomers from racemic mixtures (
Journal of Chromatography A
, 757, 1997, 225-235). Hiroyuki Nishi et al. have used said enantiomer as a stationary phase of capillary electrophoresis or liquid chromatography to separate out a desired chiral compound from racemic mixture which was unresolvable or difficult to resolve previously. This is particularly useful for the separation of amino compounds.
Further, Yoshio Machida et al. have developed (+)-chiral stationary phase for liquid chromatography by immobilizing (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid on the surface of silica gel to separate enantiomers which was unresolvable or difficult to resolve previously (
Journal of Chromatography A
, 805, 1998, 85-92).
Recently, Myung Ho Hyun et al. have developed a chiral stationary phase for liquid chromatography prepared by a different method immobilizing (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to silica gel to employ in resolving various racemic mixtures (Korea Patent No. 262872
; Journal of Chromatography A
, 822, 1998, 155-161
; Journal of Chromatography A
, 837, 1999, 75-82
; Bull. Korean Chem. Soc.
1998, Vol. 19, No. 8, 819-821).
In addition, it has been reported for resolution of racemic mixtures having amino acid or amine functional groups using (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid in
Journal of Chromatography A
, 680, (1994) 253-261
; Journal of Chromatography A
, 685, (1994) 321-329
; Anal. Chem.
1996, 68, 2361-2365
; Journal of Chromatography A
, 810 (1998) 33-41
; Journal of Chromatography A
, 666 (1994) 367-373;
Electrophoresis
1994, 15, 828-834
; Journal of Chromatography A
, 709 (1995) 81-88;
Chromatographia
Vol. 49, No. 11/12, (1999) 621-627
; Chromatographia
Vol. 33, No. 1/2, (1992) 32-36
; Anal. Chem
. 1992, 64, 2815-2820
; Journal of Chromatography A
, 716 (1995) 371-379
; Journal of Chromatography A
, 715 (1995) 143-149
; Journal of Chromatography A
, 757 (1997) 328-332
; Electrophoresis
1999, 20, 2650-2655
; Electrophoresis
1999, 20, 2605-2613.
Particular examples of amino compounds or drugs which exist in chiral mixtures include tyrosine, phenylglycilne, 2-amino-1-phenylethanol, normetanephrine, norephedrine, alanine-beta-naphthylamide, quinolone derivatives and the like. These optically pure chiral compound separated from the racemic mixture have been possible for quantitative analysis.
However, in these days, technologies such as simulated moving bed (SMB) technology for efficient separation of optically pure compounds directly from racemic mixtures in high yield and large scales are highly increased not only for quantitative analysis but also for the development the pharmaceutical and fine chemical industries (
Chemical
&
Engineering New
, 2000, Jun. 19). Development of novel chiral stationary phases for production chiral drugs becomes significant.
In the process to obtain each enatiomer from racemic mixture in high yield and purity, first fractions are usually pure chiral compound but later fractions are incomplete separation of the components. Thus, it may result poor separation and low purity and yield for especially later flowing chiral compound. Particularly, in the process to determine accurate purity of chiral compound via quantitative analysis, if a major chiral compound elutes first and a minor chiral one does later, it becomes difficult to determine an accurate purity of later flowing compound due to tailing effect of the first fractions. It is general that flowing concentration per unit time is lower and flowing time takes longer for the later flowing compound than the first flowing one.
However, certain pharmaceutical compounds, known to provide effective treatment against disease states or to ameliorate medical conditions, often occur as a chiral mixture where one enantiomeric form has the desired therapeutic activity whereas the other enantiomeric form of the same compound causes undesirable side-effects and may limit drug efficacy. Therefore, it is highly beneficial to be able to separate out and collect the most effective forms of enantiomeric compounds.
Since FDA's (Food and Drug Administration's) Policy Statement revised in 1992 for Development of New Drugs reported that each isomer of the same compound having the same structure is regarded as a different compound and side effects associated with undesired isomer in the human body have often reported, chiral separation with high yield and purity has become more and more important in pharmaceutical and fine chemical fields.
As a result, the demand in the development of capillary electrophoresis, LC chiral column, and simulated moving bed technologies to increase separation efficiency has been rapidly increased in recent years. A separation efficiency may be increased by controlling a flowing order of chiral compounds to be separated. This flowing order in the SMB technology has a significant influence on relative difficulty of the process, purity of the separated compound, cost and the like.
Inventors have applied ASTEC's Cyclobond™, Chirobiotic™ V, T, and R columns which is based on bonding &agr;-, &bgr;- or &ggr;-cyclodextrin, or vancomycin to silica gel to separate various chiral compounds. However, the process is inefficient because it requires too complicate process and much efforts, even though it provides well separation of each enantiomer.
In the process to separate (R) and (S)-isomer and determine accurate purity thereof by employing capillary electrophoresis or LC chiral stationary phase column, if the first flowing fractions are major and the later ones are minor, the first flowing ones can be eluted with some of the later flowing ones due to tailing effect of the first flowing ones, thus it becomes difficult to obtain accurate optical purity. In this case, if the minor compound can be eluted first and major one later, it can avoid tailing effect of the major compound, thus allowing to determine an accurate optical purity of the minor compound. Even though there is tailing effect of the minor compound, the tailing effect associated with the minor compound must be much smaller than that with the major one or can be ignored, thus it does not affect to determine accurate optical purities. In case that the large scale chiral separation is performed by using SMB column or LC chiral stationary phase column, it will be preferable to elute a desired chiral compound first to avoid tailing effect of the later flowing compound, further provides several advantages in reducing amount of eluent, performing process and the processing time. Further, the control of the flowing order allows more accurate optical purity.
SUMMARY OF THE INVENTION
The inventors have completed the present invention by providing a process for preparing (−)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and its use for (−)-chiral stationary phases for resolution of

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