Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-04-15
2002-11-12
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S308000
Reexamination Certificate
active
06479702
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 3-amino-1-indanol which is a novel compound and a process for synthesizing it, further to an enantiomerically active compound of 3-amino-1-indanol and a process for enantiomerically resolving it, and to a separating agent for enantiomeric isomers comprising the enantiomerically active compound as an effective ingredient.
PRIOR ART
Aminoindanols are important intermediates for various fine chemical derivatives including physiologically active substances such as medicines and pesticides. For example, it is disclosed in J. Med. Chem., 35, 2525 (1992), J. Med. Chem., 35, 1702 (1992), J. Med. Chem., 35, 1685 (1992) etc. that cis-1-amino-2-indanol is an effective intermediate for production of anti-HMV drugs.
Moreover, enantiomerically active aminoindanols are effective as separating agents for enantiomerically active carboxylic acids (chiral acids), and JP-A 11-511742 discloses a process for separating chiral acids with 1-aminoindan-2-ol.
3-Amino-1-indanol is a compound also expected to be a synthetic intermediate for medicines and pesticides or a separating agent for chromatography or an enantiomeric resolving agent for racemic bodies, but no body has succeeded in the synthesis thereof and thus it is highly desired to establish the synthetic process.
DISCLOSURE OF THE INVENTION
As a result of the extensive studies for solving the above problems, the present inventors have found out 3-amino-1-indanol which is a novel compound and a convenient process for synthesizing 3-amino-1-indanol using an easily available starting material, further a process for an effective enantiomeric resolution of 3-amino-1-indanol obtained, and a separating agent for enantiomeric isomers comprising an enantiomerically active compound of 3-amino-1-indanol as an effective ingredient. Thus, they have accomplished the present invention.
That is, the present invention provides 3-amino-1-indanol represented by the formula (I):
wherein the configuration between OH group and NH
2
group are cis-configuration or trans-configuration and the compound may be a racemic body or an enantiomerically active compound.
Moreover, the present invention provides a process for synthesizing the 3-amino-1-indanol represented by the above formula (I), which comprises the steps of protecting the amino group of &bgr;-phenyl-&bgr;-alanine represented by the formula (II):
with a protective group to give a compound represented by the formula (III):
(wherein A represents RCO- or ROCO- group (wherein R is an alkyl group having 1 to 30 carbon atoms or an aryl group)); subjecting the compound to Friedel-Crafts acylation to give a compound represented by the formula (IV):
(wherein A has the same meaning as above); and then removing the protective group of the compound, followed by reduction. Further, it provides an enantiomerically active compound of 3-amino-1-indanol, and a process for enantiomerically resolving 3-amino-1-indanol, which comprises the steps of treating a mixture of enantiomerically active compounds of 3-amino-1-indanol represented by the above formula (I) with an enantiomerically active carboxylic acid; and then separating formed diastereomer salts from each other, and a separating agent for enantiomeric isomers comprising 3-amino-1-indanol represented by the above formula (I) as the effective ingredient. Furthermore, the present invention provides use of the enantiomerically active compound of the 3-amino-1-indanol represented by the above formula (I) as a separating agent for enantiomeric isomers. In addition, the present invention provides a process for enantiomerically separating a racemic body of the target compound to be separated with 3-amino-1-indanol represented by the above formula (I).
3-Amino-1-indanol of the present invention represented by the formula (I) may be cis-isomer or trans-isomer, or a racemic body or an enantiomerically active compound.
&bgr;-Phenyl-&bgr;-alanine (II) used as a starting material can be synthesized from benzaldehyde, malonic acid, and ammonium acetate according to a known method. The amino group of the resulting &bgr;-Phenyl-&bgr;-alanine (II) is protected with a protective group using a compound having a group usable as an amino-protecting group, such as acetic anhydride, benzoyl chloride, 9-fluorenylmethyl chloroformate, benzyloxycarbonyl chloride, or di-t-butyl dicarbonate, to give the compound (III). As the amino-protecting group, preferred is acetyl group or benzoyl group, and more preferred is acetyl group. Then, by subjecting the compound (III) to Friedel-Crafts acylation, an indan skeleton-having compound represented by the formula (IV) can be obtained. Friedel-Crafts acylation is effected by first adding PCl
5
to the compound (III), reacting them in a solvent such as ethyl ether or THF, and further reacting the product in a solvent such as methylene chloride at a temperature of 0 to 5° C. with adding AlCl
3
. A summary of the above reactions is illustrated in the following reaction scheme.
wherein A has the same meaning as above; Ac represents acetyl group and Ph represents phenyl group.
Then, by removing the protective group from the resulting compound (IV) and reduction, 3-amino-1-indanol can be obtained. Depending-on the methods for removal of the protective group from the resulting compound (IV) and reduction, the ratio of the trans-isomer and the cis-isomer can be changed, and thereby the trans-isomer or the cis-isomer can be selectively synthesized. The following will describe the process for synthesizing the trans-isomer and the cis-isomer in detail.
First, the following illustrates a summary of the process for synthesizing (±)-trans-3-amino-1-indanol (racemic body) (I-1) from the compound (IV).
wherein A has the same meaning as above.
Namely, the trans-isomer of 3-amino-1-indanol represented by the formula (I) can be predominantly obtained in a ratio of trans:cis=3:1 by heating the compound (IV) obtained in the above under reflux under an acidic condition, to give a hydrochloride salt (V) through removal of the protective group, and further reducing the carbonyl group. The reduction of the carbonyl group to hydroxyl group is conducted by means of a metal hydride reagent such as sodium borohydride.
By purifying the mixture (I) of the trans- and cis-isomers, (±)-trans-3-amino-1-indanol (racemic body) (I-1) can be obtained. As the purifying method, used is preferably made of a method of forming a salt of the mixture (I) with a 2-arylcarboxylic acid such as 2-naphthylacetic acid, heating the salt under reflux, and then allowing to stand at room temperature. By this method, only the salt of the trans-isomer can be selectively crystallized. Subsequently, the above trans-isomer (I-1) can be obtained by treating the salt with an aqueous solution of an alkali selected from sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide potassium hydroxide etc, and then extracting with a suitable organic solvent.
Next, the following illustrates a summary of the process for synthesizing (±)-cis-3-amino-1-indanol (racemic body) (I-2) from the compound (IV).
wherein A has the same meaning as above; Ac represents acetyl group; and Et represents ethyl group.
Namely, by dissolving the compound (IV) in a suitable solvent and subjecting it to reduction with, for example, sodium borohydride, cis-isomer of (±)-N-acyl-3-aminoindan-1-ol (VI) can be predominantly obtained in a ratio of cis:trans=3:1. At that time, the reaction solvent is preferably tetrahydrofuran (THF). Moreover, the reaction temperature is preferably from −100 to −50° C. Then, the resulting mixture (VI) of the cis- and trans-isomers are purified by a chromatography, recrystallization or the like, to give (±)-cis-N-acyl-3-aminoindan-1-ol (VII).
(±)-cis-3-Amino-1-indanol (racemic body) (I-2) can be obtained by heating the resulting (±)-cis-N-acyl-3-aminoindan-1-ol (VII) in a suitable basic organic solvent under reflux and then extracting with a su
Katsumata Yoshiyuki
Kinbara Kazushi
Saigo Kazuhiko
Barts Samuel
Daicel Chemical Industries Ltd.
Flynn ,Thiel, Boutell & Tanis, P.C.
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