Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-18
2002-01-08
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06337400
ABSTRACT:
TECHNICAL FIELD
This invention relates to a process for the preparation of an intermediate for the preparation of a camptothecin derivative (refer to Japanese Patent Laid-Open No. HEI 6-87746) useful as an antitumor agent.
BACKGROUND ART
The compound represented by the below-described formula (a) (which will hereinafter be abbreviated as Compound (a). Similar abbreviation will be applied to the compounds represented by other numbers), that is, (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione exhibits excellent antitumor activity and is therefore useful as an antitumor agent (refer to Japanese Patent Laid-open No. HEI 6-87746).
The above compound can be obtained, for example, by the below-described synthesis route through the reaction between 8-amino-6-fluoro-5-methyl-2-trifluoroacetylamino-1-tetralone and (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10-(4H)trione (refer to Japanese Patent Laid-Open No. HEI 6-87746).
(4S)-4-Alkyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10-(4H)-trione (Compound (10)), which is one of the important intermediates for the preparation of the above compound, is known to be prepared, for example, in accordance with the following reaction scheme (J. Med. Chem., 554(1980)).
wherein R
1
represents a C
1-6
alkyl group, R
2
, R
3
, R
4
and R
6
each independently represents a C
1-6
alkyl, aryl or aralkyl group, R
5
represents a hydrogen atom or a C
1-5
alkyl group, R
5a
represents a C
1-5
alkyl group; and the reaction in the parentheses is that for obtaining Compound (7a) by alkylating Compound (7) when R
5
is a hydrogen atom.
In the above reaction scheme, the reaction for obtaining 6-cyano-1,1-(ethylenedioxy)-7-[(alkoxycarbonyl)-alkyl]-5-oxo-&Dgr;6(8)-tetrahydroindolizine (7) from Compound (1) is reported by Wani et al. (J. Med. Chem., 554(1980)).
The method reported by Wani et al. is however accompanied with the problems such as prolonged reaction time, inferior operability and use of a dangerous reagent. Accordingly, there has been a demand for the development of an industrially superior preparation process.
Described specifically, the enol-etherification reaction for preparing Compound (2) from Compound (1) is effected in the presence of ammonium chloride as a catalyst and it takes even 7 days to complete the reaction. The subsequent cyclization reaction for preparing Compound (3) from Compound (2) is effected using acetone as a solvent, and it takes about 14 hours to complete this reaction. In the next cyclization reaction step for obtaining Compound (4) from Compound (3), dimethylformamide is used as a solvent and it takes as long as 40 hours for the reaction.
The ketalization reaction of Compound (5) is effected in the presence of p-toluenesulfonic acid as a catalyst in a solvent of toluene under azeotropic dehydration with ethylene glycol. This reaction is however accompanied with the problems that the solvent about 80 times the amount of the ketone (5) should be used twice, it takes 20 hours for the completion of the reaction, and the reaction needs cumbersome operation.
In the carbonylation reaction of Compound (6), toluene is used as a solvent and a metal hydride regarded as a dangerous reagent is used as a base. In addition, this step is accompanied with the problems that it includes a dropwise addition step and precipitation of crystals occurs during the reaction, which disturbs stirring.
Accordingly, an object of the present invention is to provide a process for preparing 6-cyano-1,1-(ethylene-dioxy)-7-[(alkoxycarbonyl)-alkyl]-5-oxo-&Dgr;6(8)-tetrahydro-indolizine (7), which is a synthesis intermediate for the industrial preparation process of a camptothecin derivative (a), within a short time in a convenient manner.
DISCLOSURE OF THE INVENTION
Under such situations, the present inventors have carried out an extensive investigation. As a result, it has been found that Compound (4) can be prepared within a short time in a convenient manner by effecting the reaction from Compound (1) to Compound (4) under specified conditions.
Described specifically, the present inventors have investigated the use of an acid catalyst except ammonium chloride for the enol-etherification reaction. As a result, it has been found that the use of the acid catalyst enables to complete the reaction within about one hour, thereby bringing about a drastic reduction in the reaction time. It has also been found that a change of the solvent for the cyclization reaction to a polar solvent such as dimethyl sulfoxide makes it possible to obtain target Compound (4) from Compound (2) in the same solvent within a short time without isolating Compound (3) or a salt thereof, thereby bringing about a drastic reduction in the reaction time.
It has also been found that by the use of a Lewis acid as a catalyst for the ketalization reaction of Compound (5), the using amount of the solvent can be decreased and the reaction can be completed within about one hour; and that the dropwise addition step can be omitted by using a metal alkoxide having a higher safety as a base for the carbonylation reaction subsequent to the ketalization reaction, thereby bringing about a substantial improvement in the safety and operability, leading to the completion of the present invention.
The process according to the present invention is represented by the following reaction scheme:
wherein R
1
, R
2
, R
3
, R
4
, R
5
and R
6
have the same meanings as defined above.
In the present invention, there is thus provided a process for the preparation of a compound represented by the formula (4), which comprises reacting a compound represented by the formula (1) with an orthoformate ester in the presence of an acid catalyst to obtain a compound represented by the formula (2), reacting the resulting compound (2) with &agr;-cyanoacetamide in a polar solvent in the presence of a base to obtain a compound represented by the formula (3) or salt thereof, then reacting the resulting compound (3) with an acrylic ester.
In the present invention, there is also provided a process for the preparation of a compound represented by the formula (7), which comprise reacting a compound represented by the formula (5) with ethylene glycol in a solvent in the presence of a Lewis acid to obtain a compound represented by the formula (6) and then reacting the resulting compound with a carbonate diester in a solvent in the presence of a metal alkoxide.
BEST MODES FOR CARRYING OUT THE INVENTION
Compound (5) used as a raw material in the present invention may be prepared by the above process, but preparation in accordance with the below-described reaction scheme is industrially advantageous, because the reaction time can be shortened drastically and at the same time, it is possible to effect most of the reaction in one pot.
In the above reaction scheme, R
1
represents a C
1-6
alkyl group and examples of it include methyl, ethyl, n-propyl, isopropyl and n-butyl. R
2
, R
3
, R
4
and R
6
each independently represents a C
1-6
alkyl group, aryl group or aralkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of the aryl group include a phenyl group which may contain one or more than one substituents selected from the group consisting of halogen atoms, C
1-6
alkyl groups and nitro group. As the aralkyl group, the above-exemplified alkyl group substituted by the above phenyl group can be used and examples include benzyl, substituted benzyl, phenetyl and substituted phenetyl.
Among them, a methyl or n-propyl group is more preferred as R
1
, with a methyl group being particularly preferred. As R
2
, R
3
, R
4
or R
6
, a methyl or ethyl group is more preferred.
Here, Compound (1) can be prepared by the process described in O. S., Coll. Vol. 1, 238(1958), for example, by reacting a ketone such as acetone with an oxalate diester.
First, Compound (1) is subjected to enol-
Kamihara Shinji
Kanai Kazuaki
Noguchi Shigeru
Daiichi Pharmaceutical Co. Ltd.
Seaman D. Margaret
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