Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2002-09-30
2004-05-04
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S354000, C558S443000, C549S369000
Reexamination Certificate
active
06730803
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a &bgr;-keto ester compound, a &bgr;-hydroxy acid compound and an acetonide form of a 1,3-diol derivative, which are useful as a synthetic intermediate for a pharmaceutical or agrichemical agent, and production methods thereof. The &bgr;-keto ester compound, the &bgr;-hydroxy acid compound and the acetonide form of a 1,3-diol derivative obtained by the present invention are useful as a synthetic intermediates for an epothilone derivative being developed as a pharmaceutical agent having antitumor activity.
BACKGROUND OF THE INVENTION
Epothilone is a substance produced by myxobacterium Sorangium cellulosum and is known to have high antitumor activity.
In recent years, energetic studies of synthetic structural conversion in an effort to obtain an epothilone derivative showing higher performance are ongoing (general synthetic methods of epothilone are shown in J. Am. Chem. Soc. 2001, 123, 5407-5413 and publications quoted in this reference). For this purpose, various compounds useful as synthetic intermediates therefore have been studied.
The present inventors have investigated synthetic intermediates useful for the production of the above-mentioned epothilone derivative and noted the idea that the structure of a novel compound, tert-butyl 4-cyano-4-methyl-3-oxopentanoate, represented by the following formula
is useful as the above-mentioned synthetic intermediate. However, this novel compound is difficult to synthesize. That is, as a compound usable as a material for synthesizing the tert-butyl 4-cyano-4-methyl-3-oxopentanoate, a conventionally known 2-cyano-2,2-dimethylacetate represented by the following formula
wherein R
1
is alkyl group having 1 to 6 carbon atoms, is considered, but as is clear from the above-mentioned structural formula, 2-cyano-2,2-dimethylacetate has cyano group and ester residue as reaction sites in a single molecule. Thereby making selective production of the above-mentioned tert-butyl 4-cyano-4-methyl-3-oxopentanoate seems difficult.
However, if the above-mentioned tert-butyl 4-cyano-4-methyl-3-oxopentanoate can be synthesized from the above-mentioned 2-cyano-2,2-dimethylacetate, this compound is a desirable starting material because the compound can be economically prepared on a large-scale and in short steps. Thus, a development of a method for the production of the above-mentioned novel tert-butyl 4-cyano-4-methyl-3-oxopentanoate from 2-cyano-2,2-dimethylacetate has been investigated.
The compounds expected to be usable as synthetic intermediates for an epothilone derivative include a novel compound not published heretofore, which is tert-butyl 4-cyano-4-methyl-3-hydroxypentanoate represented by the following formula
4-cyano-3-hydroxy-4-methylpentanoic acid represented by the following formula
optically active 4-cyano-3-hydroxy-4-methylpentanoic acid represented by the following formula
and optically active 4-cyano-3-hydroxy-4-methylpentanoate of the following formula
wherein R
3
is alkyl group having 1 to 6 carbon atoms. These synthetic intermediates are novel compounds, and convenient and economical production of these synthetic intermediates is expected to afford a large-scale synthesis of the final product, an epothilone derivative.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a novel synthetic intermediate for the synthesis of an epothilone derivative useful as a pharmaceutical or agrichemical agent, particularly as an antitumor agent, and production methods thereof.
[1] A &bgr;-keto ester compound represented by the following formula
wherein R
4
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, or an optically active form thereof.
[2] The compound of the above-mentioned [1], wherein R
4
is hydrogen atom, or an optically active form thereof.
[3] The compound of the above-mentioned [1], wherein R
4
is alkyl group having 1 to 6 carbon atoms, or an optically active form thereof.
[4] A production method of a &bgr;-keto ester compound of the above-mentioned [1], which comprises condensation of a 2-cyano-2,2-dimethylacetate represented by the following formula
wherein R
1
is alkyl group having 1 to 6 carbon atoms, with an alkyl ester represented by the following formula
wherein R
4
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, in the presence of a strong base.
[5] The production method of the above-mentioned [4], wherein R
4
is hydrogen atom.
[6] The production method of the above-mentioned [4], wherein R
4
is alkyl group having 1 to 6 carbon atoms.
[7] The production method of the above-mentioned [4], comprising adding lithium diisopropylamide as a strong base to a mixture of 2-cyano-2,2-dimethylacetate represented by the formula (II) and an alkyl ester represented by the formula (III).
[8] The production method of any of the above-mentioned [4]-[7], which comprises adding cyanoacetate of the following formula
wherein R
1
is alkyl group having 1 to 6 carbon atoms, and dimethyl sulfate continuously or discontinuously to a sodium hydride-containing tetrahydrofuran solution to give 2-cyano-2,2-dimethylacetate of the formula (II), and condensation thereof with an alkyl ester of the formula (III).
[9] A &bgr;-hydroxy acid compound represented by the following formula
wherein R
2
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, and R
4
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, provided that when R
4
is alkyl group having 1 to 6 carbon atoms, R
2
should be tert-butyl group, an optically active form thereof or a salt thereof.
[10] The compound of the above-mentioned [9], wherein R
4
is hydrogen atom, an optically active form thereof or a salt thereof.
[11] The compound of the above-mentioned [9], wherein R
4
is alkyl group having 1 to 6 carbon atoms and R
2
is tert-butyl group, an optically active form thereof or a salt thereof.
[12] A production method of a &bgr;-hydroxy acid compound represented by the formula (V) of the above-mentioned [9], which comprises reducing a &bgr;-keto ester compound represented by the following formula
wherein R
2
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, and R
4
is hydrogen atom or alkyl group having 1 to 6 carbon atoms, provided that when R
4
is alkyl group having 1 to 6 carbon atoms, R
2
should be tert-butyl group, or a salt thereof.
[13] The production method of the above-mentioned [12], wherein R
4
is alkyl group having 1 to 6 carbon atoms and R
2
is tert-butyl group.
[14] The production method of the above-mentioned [13], wherein the reduction is carried out using alkali borohydride and divalent metal chloride.
[15] The production method of the above-mentioned [12], wherein R
4
is hydrogen atom.
[16] The production method of the above-mentioned [15], wherein R
2
is alkyl group having 1 to 6 carbon atoms.
[17] The production method of the above-mentioned [16], wherein the alkyl group having 1 to 6 carbon atoms is tert-butyl group.
[18] The production method of any of the above-mentioned [15]-[17], wherein the reduction is carried out using sodium borohydride.
[19] The production method of the above-mentioned [14], wherein the &bgr;-keto ester compound of the formula (I′), wherein R
2
is alkyl group having 1 to 6 carbon atoms and R
4
is hydrogen atom, is reduced to give a &bgr;-hydroxy acid compound (V-4) represented by the following formula
wherein R
2′
is alkyl group having 1 to 6 carbon atoms, which is a compound of the formula (V) wherein R
2
is alkyl group having 1 to 6 carbon atoms and R
1
is hydrogen atom, and the &bgr;-hydroxy acid comp
Itaya Nobushige
Iwasaki Mitsuhiro
Miyamoto Hideto
Sugi Kiyoshi
Owens Amelia
Sumika Fine Chemicals Co., Ltd.
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