Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-03-19
2004-11-16
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S469000, C548S494000, C546S152000, C546S156000, C564S092000, C564S099000, C514S311000, C514S312000, C514S415000, C514S419000, C514S605000
Reexamination Certificate
active
06818777
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a compound represented by general formula A, which is useful as intermediate at the total synthesis of vindoline,
(in the formula, R
1
is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzenesulfonyloxy group, and alkylsulfonyloxy group, R
2
is 1,1-dimethylethoxycarbonyl [(1,1-Dimethylethoxy)carbonyl, Boc] group or acetyl group, R
3
is alkyl group, R
4
is benzyl or substituted benzyl group. R
5
is H, tetrahydropyranyl (THP) group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.), alkyl acrylates represented by general formula B, which is important an intermediate at the total synthesis of vindoline,
[in the formula, R
1
is one selected from the group consisting of H, OH, alkoxy group, substituted or non-substituted benzene sulfonyloxy group, and alkyl sulfonyloxy group, R
2
is 1,1-dimethylethoxycarbonyl (indicated as Boc in a constitutional formula) group or acetyl group and, R
3
is alkyl group. R
5
is H, tetrahydropiranyl (THP) group, ethoxyethyl group, methoxymethyl group, acetyl group, benzoyl group, trialkylsilyl group or alkyldiarylsilyl group.], especially relates to an effective method for synthesis of indole derivatives possessing a methyl acrylate group having good reproducibility and suited to mass production, and an effective method for production of substituted quinolines represented by general formula C, which is useful for the synthesis of said general formula A, and whose regioselectivity and yield are improved.
(R
1
, R
2
and R
3
are independently selected from the group consisting of H, OH, alkoxy group, alkyl, amino, amide and halogen.)
BACKGROUND OF THE INVENTION
Natural vinblastine (1) extracted from a plant belonging to Apocynaciae is an antitumor agent which is currently used as a clinical medicine. However, since this agent shows a strong side effects, the developments for a new congeners are broadly carried out in Japan or outside of Japan.
The inventors of the present invention has already reported the art referring to the total synthesis of vindoline which consists a half (lower side) of vinblastine (1) used for the synthesis of above mentioned vinblastine and its congeners. However, for the total synthesis of vindoline, syntheses of various intermediates are necessary, the improvements of the reproducibility of each processes and yield are needed, and the further improvement for process suited to the production concerning the commercial scale is needed.
Usually, the compound represented by said general formula B, which is the important intermediate for the synthesis of vindoline, was synthesized using the derivatives of above mentioned general formula A, whose substituent at 2-position is replaced with iodine, as the starting material by palladium-catalyzed coupling reaction with tin compound as shown in the following Schema 1 [S. Kobayashi, T. Ueda, T. Fukuyama, Synlett., 883-886 (2000)].
However, by above mentioned reaction, it is difficult to accomplish the reaction in good yield and with good reproducibility, and further, in above mentioned reaction, there is a problem that the uses of agents such as toxic arsenic compound or carcinogeic hexamethyltriamidephosphate (HMPA) are necessary. Therefore, the establishment of the method for synthesis of above mentioned intermediate B characterizing not including above mentioned technical problems was desired. Further, as one intermediate for the synthesis of above mentioned intermediate A, quinolines represented by general formula C, namely, substituted quinoline which has a substituted group on benzene ring and does not have a substituted group on pyridine ring is used. As the typical well-known method for synthesis for a substituted quinoline which has a substituted group on benzene ring, a method for synthesis named Skraup quinoline synthesis which obtains quinoline by heating anilines, glycerin and oxidant under the presence of strong acid such as sulfuric acid can be mentioned [R. H. F. Manske, M. Kulka, Org. React. 28, 59-98 (1953)]. However, since said method needs a process to react by high temperature using strong acid, many byproducts are generated besides the aimed compound. Therefore, very complicated separation and purification process is necessary to obtain the aimed product and the yield by said method is not always good. Further, in a synthetic reaction of substituted quinoline which uses meta substituted aniline or 2,3-disubstituted aniline as a starting material, mixture of 5-substituted quinoline and 7-substituted quinoline, or mixture of 6,7-substituted quinoline and 5,6-substituted quinoline, which are regioisomers are generated. In the case of said mixture, sometimes one isomer has predominant over another isomer at the generation by maximum four times amount according to the substitution effect, however, in general, the regioselectivity of the reaction is not so high, and this point is pointed out as a problem [M. H. Palmer, J. Chem. Soc., 3645-3652 (1962)]. Still more, the yield is also not so good.
Furthermore, the compound represented by above mentioned general formula C is the compound used as the synthetic intermediate of general formula A, which are the intermediate at the total synthesis of vindoline. And, for the establishment of effective synthetic process for the total synthesis of vindoline, the improvement of the intermediate processes composing total synthesis is very important. Especially, the establishment of the method producing substituted quinolines, which have a substituted group on benzene ring alone and do not have a substituted group on pyridine ring, with improved regioselectivity has been strongly desired.
Therefore, the first object of the present invention is to provide a method for production of the intermediate B represented by general formula B, which dissolves the problem of above mentioned conventional art has, having good yield and reproducibility, and further, said method should be applicable to the production process of commercial scale. The inventors of the present invention have conducted an eager study to investigate the method for production of the compound represented by general formula B not by way of 2-iodoindole shown in the conventional art, and to establish the method for production by way of compound represented by general formula A. Thus the first object of the present invention is accomplished.
The second object of the present invention is to provide a method for the production of substituted quinolines by which the problems in conventional method for production of substituted quinolines have are improved. The inventors of the present invention have investigated the case to obtain the aimed compound represented by general formula C from substituted aniline by way of cyclization reaction, and have found out that the regioselectivity and the yield can be remarkably improved by using following process. Namely, as the first, sulfonamide derivative of above mentioned substituted aniline is prepared, then acrolein is added and a precursor for cyclization reaction is prepared and the precursor is used. The second object of the present invention is accomplished by use of the compound represented by general formula D at the cyclization reaction.
DISCLOSURE OF THE INVENTION
The first one of the present invention is the compound represented by general formula A which is useful as the intermediate at the total synthesis of vindoline.
The second one of the present invention is a method for synthesis of indole derivatives which are useful for the synthesis of vindoline represented by general formula B comprising, hydrogenation of the compound represented by general formula A, transforming benzyl ester to carboxylic acid, then formation of an acrylic acid alkyl ester unit by Mannich reaction accompanied by decarboxylation under the condition of Mannich reaction. Desirably, the second one of the present invention is
Fukuyama Tohru
Tokuyama Hidetoshi
Chang Ceila
Coppins Janet L.
Japan Science and Technology Agency
Sherman & Shalloway
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