Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-08
2001-08-07
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C528S492000
Reexamination Certificate
active
06271391
ABSTRACT:
This application is a 371 of PCT/JP99/01222 filed Mar. 12, 1999.
1. Field of the Invention
This invention concerns a hydrazide fixed to a resin and derivatives thereof, and a method for synthesizing pyrazolones in a solid phase.
2. Related Art Statement
Solid phase synthesis methods using a resin carrier have been known so far in, for example, peptide synthesis, and the solid phase synthesis method is an effective means for synthesizing a plurality kinds of analogous group of compounds all at once, and it has been considered to apply the solid phase synthesis method also to various kinds of chemical reactions.
However, it has actually been a problem that reactions to which the method is applicable are restricted in the solid phase reaction compared with liquid phase reaction which is predominant in the chemical synthesis. In view of the prior art situation described above for the solid phase synthesis method, the inventors of the present application have studied for improving the effectiveness of the solid phase synthesis method by conducting carbon-carbon bond forming reactions which are most basic and important in the synthesis of organic compounds efficiently on a solid phase.
In particular, the inventors of the present application have found a novel method of conducting a Mannich type reaction starting from an acyl hydrazone using a catalyst and it is an important subject to establish a solid phase synthesis method capable of further improving the effectiveness of this method in view of practical use.
OBJECT AND SUMMARY OF THE INVENTION
Then, it is a subject of this invention in the present application to provide a novel technical means for realizing the Mannich type reaction as described above as a solid phase synthesis method and, more specially, to provide a method of synthesizing pyrazolones by applying the Mannich type reaction utilizing the solid phase synthesis.
For attaining the subject described above, a first invention provides a &bgr;-hydrazino ester fixed to a resin represented by the following formula (III):
where P represents a main chain of a resin polymer, Q represents a hydrocarbon side chain optionally having a substituent which may be boned via a heteroatom, R
1
, R
2
, R
3
and R
4
each represents a hydrocarbon group or a heterocyclic group optionally having a substituent.
A second invention provides a production process for a &bgr;-hydrazino ester fixed to a resin as defined in the first invention, which comprises reacting a hydrazone fixed to a resin represented by the following formula:
P—Q—CO—NH—N═CH—R
1
(II)
where P represents a main chain of a resin, Q represents a hydrocarbon side chain optionally having a substituent which may be boned via a heteroatom and R
1
represents a hydrocarbon group or a heterocyclic group optionally having a substituent, with a ketene silyl acetal represented by the following formula:
where R
2
, R
3
and R
4
each represents a hydrocarbon group or a heterocyclic group which may have a substituent and R
6
represents a hydrocarbon group.
Further, a third invention provides a method of synthesizing pyrazolones which comprises reacting a hydrazone fixed to a resin represented by the following formula:
P—Q—CO—NH—N═CH—R
1
(II)
where P represents a main chain of a resin, Q represents a hydrocarbon side chain optionally having a substituent which may be boned via a heteroatom and R
1
represents a hydrocarbon group or a heterocyclic group optionally having a substituent, with ketene silyl acetals represented by the following formula:
where R
2
, R
3
and R
4
each represents a hydrocarbon group or a heterocyclic group which may have a substituent respectively and R
6
represents a hydrocarbon group, to synthesize a &bgr;-hydrazino ester fixed to a resin represented by the following formula:
where P, Q, R
1
, R
2
, R
3
and R
4
have the same meanings as described above and then conducting cut out from the solid phase and cyclizing reaction, to synthesize pyrazolones represented by at least one of the following formulae (A) and (B)
where R
1
, R
2
and R
3
have the same meanings as described above.
PREFERRED EMBODIMENTS OF THE INVENTION
The present application provides and a hydrazone fixed to a resin which can be derived from a hydrazide fixed to a resin represented by the formula (I) and is represented by a formula (II) as defined in the first invention and the second invention described above, which enables solid phase synthesis method by Mannich type reaction and has not been known at all so far. In any of:
Hydrazide fixed to a resin of the formula (I)
P—Q—CO—NH—NH
2
(I)
Hydrazone fixed to a resin of the formula (II)
P—Q—CO—NH—N═CH—R
1
(II),
P represents a main chain of a resin polymer and Q represents a side chain bonded therewith in which the resin polymer constituting the main chain P may be an addition polymer, polycondensate, crosslinking product thereof, and, for example, addition polymer of alkenes having carbon-carbon doubles bonds or crosslinking polymers therefrom may be considered appropriate. Alkenes can include addition polymer or partial crosslinking product thereof of, for example, aliphatic olefins, aliphatic dienes, as well as &agr;,&bgr;-aliphatic unsaturated carboxylic acids or esters thereof, &agr;,&bgr;-aliphatic unsaturated nitriles, aromatic alkenes such as styrene, &agr;-methylstyrene and divinyl benzene.
Various kinds of polyesters, epoxy resins, polyethers and polyamides as polycondensates may also be considered.
The side chain Q in this invention may include hydrocarbon chains which may have a substituent, or hydrocarbon chains which may have a substituent where an oxygen atom or nitrogen atom may intervene in the hydrocarbon chain as heteroatom, and the side chain Q may be formed together with the main chain: P or may be formed by grafting or pendant addition after forming the main chain P. In any of cases, the hydrocarbon chain may include various aliphatic groups, cycloaliphatic groups, aromatic groups and arylaliphatic groups and, for example, there can be mentioned alkylene chain represent by —(CH
2
)
n
—, a phenylene chain represented by —Ph—, and phenylene alkylene chain represented, for example, by —Ph—(CH
2
)
n
—, —(CH
2
)
n
—Ph—, —Ph—(CH
2
)
n
—Ph—. Alternatively, there can be also mentioned those bonded via heteroatom such as —Ph—O—Ph—, and —Ph—(CH
2
)
n
—O—Ph—.
The hydrocarbons may further contain various kinds of substituents which are not inhibitive to the solid phase synthesis reaction or further activate the reaction. There can be mentioned those substituents, for example, hydrocarbon groups such as alkyl group and aryl group, halogen atom, alkoxy group, acyloxy group, alkoxycarbonyl group, nitro group, cyano group and heterocyclic group.
Further, R
1
in the hydrazone fixed to the resin represented by the formula (II) is a hydrocarbon group or a heterocyclic group which may have a substituent where the hydrocarbon group may be linear or cyclic, saturated or unsaturated and aliphatic or aromatic, arylaliphatic and the heterocyclic group may also be various heterocyclic groups containing oxygen or nitrogen. Then, there can be mentioned various kinds of substituents not inhibitive to the solid phase synthesis reaction or further activating the reaction, for example, hydrocarbons such as alkyl group or aryl group, halogen atom, alkoxy group, acyloxy group, alkoxycarbonyl group, nitro group, cyano group and heterocyclic group.
The hydrazide fixed to the resin represented by the formula (I) can be produced by a method, for example, of carboxylating the resin polymer having the structure:
P—QH
into a carboxylic acid resin:
P—Q—CO—OH
esterifying the same and then reacting the ester with hydrazine.
The carboxylation is conducted, for example, in accordance with the method of Frechet, et al by reaction with BuLi and then reacting with CO
2
. Of course, carboxylation is not restricted to this method. For the production of hydrazide fixed to the resin from the carboxylic acid resin, various m
Kobayashi Shu
Oyamada Hidekazu
Japan Science and Technology Corporation
Ramsuer Robert W.
Wenderoth , Lind & Ponack, L.L.P.
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