Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-15
2002-11-12
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S028000, C549S400000, C549S401000
Reexamination Certificate
active
06479671
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing optically active chromene derivatives useful as a medicament or an intermediate thereof.
BACKGROUND ART
When a compound having some biological activity has an asymmetric center in the molecule, each enantiomer sometimes has a very different property. For example, even if one of enantiomers has a useful biological activity, the other may be inactive or induce side effects. Thus, optical resolution of racemates is very important to the development of medicaments.
The optical resolution methods of racemates are classified into a direct method and an indirect method. In the direct method, a racemate is directly resoluted into optically active compounds and the examples are preferential crystallization, gas chromatography, thin layer chromatography, HPLC and the like. In the indirect method, a racemate is reacted with an optically active reagent (optical resolving agent) to give diastereomers which are separated based on the difference of their physical properties, followed by removing the optically active reagent to give an optically active compound.
For example, a racemate (±)-A reacts with a proper optical resolving agent such as (+)-B to produce diastereomers (+)-A·(+)-B and (−)-A·(+)-B. Each diastereomer has a different physical property based upon which they can be separated by a certain method. When the separation is industrially performed, a recrystallization method is especially preferable, wherein one low-soluble diastereomeric salt only crystallizes while the other remains in a mother liquor owing to difference of their solubilities. Usually a resolution condition may be selected so that the diastereomeric salt containing an desired enantiomer crystallizes with high yield and utmost optical purity. After taking out the crystal, the diastereomeric salt containing an unnecessary enantiomer remains in the mother liquor. Removal of the optical resolving agent (+)-B from the diastereomeric salt separated as crystals and the diastereomeric salt in the mother liquor gives (+)-A and (−)-A, respectively.
However, the known optical resolution is not always effective regardless of the direct or indirect method, because the objective enantiomer can not be obtained with over 50% yield. For improving the yield close to theoretical 100%, the unnecessary enantiomer remaining after the resolution needed to be collected and be converted into the objective enantiomer.
The isolation and racemization of enantiomers of chromene compounds are described in Croatica Chemica Acta Vol. 66, No. 1, pp. 209-216(1993). But in the article, the enantiomer was separated by liquid chromatography and the present invention is not suggested at all.
DISCLOSURE OF INVENTION
The present invention provides a process for producing a compound of the formula (II):
wherein R
1
, R
2
, R
3
and R
4
are each independently hydrogen, hydroxy, halogen, optionally substituted alkyl (wherein the substituent is halogen, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, alkoxy, alkoxyalkyloxy, acyl, alkylenedioxy, amino, alkylamino, aryl or heterocyclyl),
optionally substituted alkenyl wherein the substituent is the same as the above,
optionally substituted alkynyl wherein the substituent is the same as the above,
optionally substituted cycloalkyl wherein the substituent is the same as the above,
optionally substituted alkoxy wherein the substituent is the same as the above,
optionally substituted alkenyloxy wherein the substituent is the same as the above,
optionally substituted alkynyloxy wherein the substituent is the same as the above,
optionally substituted cycloalkoxy (wherein the substituent is alkyl, alkenyl, halogen, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, alkoxy, alkoxyalkyloxy, acyl, amino, alkylamino, alkylenedioxy, aryl or heterocyclyl),
optionally substituted acyloxy (wherein the substituent is halogen, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, alkoxy, alkoxyalkyloxy, acyl, alkylenedioxy, amino, alkylamino, aryl or heterocyclyl),
or optionally substituted amino (wherein the substituent is alkyl, cycloalkyl, aryl or acyl),
R
5
is alkyl or alkoxyalkyl,
A is O or S,
Ar is optionally substituted aryl (wherein the substituent is alkyl, alkenyl, halogen, hydroxy, cycloalkyl, carboxy, alkoxycarbonyl, alkoxy, alkoxyalkyloxy, acyl, alkylenedioxy, amino, alkylamino, aryl or heterocyclyl),
* represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and Q represents an optically active reagent (hereinafter referred to as Compound (II)),
comprising isolating the Compound (II) as crystals from a solution or suspension containing Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer or a mixture thereof and the other symbols are the same as the above).
The present invention provides the above-mentioned process wherein the above Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer or a mixture thereof and the other symbols are the same as the above) is contained in a mother liquor which is left after Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and the other symbols are the same as the above) is isolated as crystals from a solution or suspension containing a compound of the formula (III):
(wherein * represents the position of an asymmetric carbon atom and that the compound is a mixture of the (R) and (S) isomers and the other symbols are the same as the above) (hereinafter referred to as Compound (III)) and an optically active reagent Q.
The present invention provides a process for producing Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and the other symbols are the same as the above) comprising further subjecting Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer or a mixture thereof and the other symbols are the same as the above), which is contained in a mother liquor left after isolating Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and the other symbols are the same as the above) in any of the above processes, to any of the above processes.
The present invention provides a process for producing a compound of the formula
(wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and the other symbols are the same as the above) (hereinafter referred to as Compound (I)) comprising removing an optically active reagent Q from Compound (II) (wherein * represents that the compound is of the same configuration as above Compound (I) and the other symbols are the same as the above) obtained by any one of the above processes.
The present invention provides a process for producing a compound of the formula (&agr;):
(wherein * represents the position of an asymmetric carbon atom and that the compound is the (R) or (S) isomer and the other symbols are the same as the above) (hereinafter referred to as Compound (&agr;)) by the following steps:
1) A step for obtaining a compound of the formula (II):
(wherein * represents the position of an asymmetric carbon atom and that the compound is of the same configuration as above Compound (&agr;) and the other symbols are the same as the above)
and a mother liquor by isolating above Compound (II) as crystals from a solution or suspension containing a compound of the formula (III):
(wherein * represents the position of an asymmetric carbon atom and that the compound is a mixture of the (R) and (S) isomers and the other symbols are the same as the above) and an optically active reagent Q,
2) A step for isomerizing Compound (II) (wherein * represents the position of an asymmetric carbon atom and that the compound i
Ide Yutaka
Konoike Toshiro
Matsumura Ken-ichi
Ohya Takashi
Shinomoto Shoji
Birch & Stewart Kolasch & Birch, LLP
Shionogi & Co. Ltd.
Solola T. A.
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