Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1997-08-21
1998-12-15
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
552104, 560 25, 564 82, 564 92, 564 97, 564 99, 564155, 564158, 564184, 564202, 564211, 564222, C07C23315, C07C23341, C07C23112
Patent
active
058499458
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/00390, field Feb. 21, 1996.
TECHNICAL FIELD
This invention relates to an aminotetralone derivative which is an intermediate for the preparation of a camptothecin derivative (refer to Japanese Patent Application Laid-Open No. 87746/1994), an antitumor agent; and a preparation process thereof.
BACKGROUND ART
(1S, 9S)-1-Amino-9-ethyl-5-fluoro-2,3 -dihydro-9 -hydroxy-4-methyl-1H, 15H)-dione represented by the following formula (6): ##STR2## is a camptothecin derivative which exhibits excellent antitumor activities.
Such a camptothecin derivative can be prepared, for example, by the synthesis route, which will be described below, through the reaction between 8-amino-6-fluoro-5 -methyl-2-(protected amino)-1-tetralone and 10(4H)-trione (refer to Japanese Patent Application Laid-Open No. 87746/1994). ##STR3##
The previous process for the preparation of 8 -amino-6-fluoro-5-methyl-2-amino-1-tetralone which is a synthesis intermediate useful for the preparation of a camptothecin derivative is however accompanied with the drawbacks that in the first place, a multi-stage step including alcohol formation, dehydration and reduction of a double bond is necessary for the reduction of a carbonyl group; and in the second place, although an amino group at the 2 -position is selectively protected after a 2,8-diacetamide derivative is once converted into a 2,8-diamino derivative, the resulting 2,8-diamino derivative is unstable, resulting in a low yield of the target product (refer to Japanese Patent Application Laid-Open No. 87746/1994). There is accordingly a demand for the development of an industrially excellent preparation process.
An object of the present invention is therefore to provide a process for the preparation of an 8-amino-2 -(protected amino)-1-tetralone derivative, which is a synthesis intermediate useful for the industrial preparation of a camptothecin derivative, in a convenient manner and in a high yield.
DISCLOSURE OF THE INVENTION
With the foregoing in view, the present inventors have conducted an extensive investigation. As a result, it has been found that the reduction of a carbonyl group can be conducted efficiently by using a palladium catalyst and an 8-amino-2-(protected amino)-1-tetralone derivative can be obtained by a short step and in a high yield with-out isolating an unstable 2, 8-diamino derivative by subjecting a 2, 8-di(protected amino) derivative to a treatment with an acid to selectively eliminate the protective group from the 8-(protected amino) group, leading to the completion of the present invention.
The preparation process of the 8-amino-2-(protected amino)-1-tetralone derivative (5) according to the present invention can be represented by the following reaction scheme: ##STR4## wherein R.sup.1 and R.sup.2 each independently represents a hydrogen atom, a halogen atom, a hydroxyl group or a C.sub.1-6 alkyl group, X and Y each independently represents an amino group having a protective group and n stands for an integer of 0 to 4.
Described specifically, Compound (5) is prepared by hydrogenating Compound (1) into Compound (2) in the presence of a palladium catalyst, oxidizing the resulting Compound (2) into Compound (3), protecting the amino group of the resulting Compound (3) to obtain Compound (4), and reacting the resulting Compound (4) with an acid to eliminate only the protective group of the amino group at the 8-position. Among the above-described steps, the steps to obtain Compound (4) from Compound (2) are described in Japanese Patent Application Laid-Open No. 87746/1994 or the like. Accordingly, the present invention provides the steps for the preparation of Compound (2) from Compound (1) and Compound (5) from Compound (4).
BEST MODES FOR CARRYING OUT THE INVENTION
In the above reaction scheme, preferred examples of R.sup.1 and R.sup.2 include a methyl group, ethyl group, n-propyl group, isopropyl group, fluorine atom, chlorine atom and bromine atom. Particularly preferred is the case where R.sup.1 and R.sup.2 represent a methyl g
REFERENCES:
patent: 5637770 (1997-06-01), Terasawa et al.
H. Neudeck & K. Schlogl: "Optisch aktive, aromatische Spirane, 8. Mitt." Monatshefte Fur Chemie, vol. 110, No. 3, May/Jun. 1979, pp. 541-565, XP002052910 * p. 554, line 15-line 25; example 1A *.
Kamihara Shinji
Kanai Kazuaki
Noguchi Shigeru
Daiichi Pharmaceutical Co. Ltd.
Kabushikikaisha Yakult Honsha
Raymond Richard L.
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