Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-13
2002-04-02
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S148000, C564S149000, C564S151000, C560S034000
Reexamination Certificate
active
06365745
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a specific hydrazine derivative useful as a starting material for pharmaceutical products.
BACKGROUND OF THE INVENTION
A hydrazine derivative useful as a starting material for pharmaceutical products, such as tert-butyl 3-[4-(pyridin-2-yl)benzyl]carbazate of the following formula [3] is useful as an intermediate for the anti-AIDS agent described in WO97/40029
and this intermediate is known to be obtained by reducing N-(tert-butoxycarbonyl)-N′-{[4-(pyridin-2-yl)phenyl]methylidene}hydrazone of the following formula [4] in methanol in the presence of 10% Pd/C (WO97/40029, Example 46C). However, there is no detailed explanation or reference to the by-product and the like caused by the reduction.
The present inventors have reduced hydrazone [4] according to Example 46C of WO97/40029 and noted the formation of 4-(pyridin-2-yl)toluene as a by-product resulting from hydrogenolysis of the compound of the formula [3]. They have confirmed that the formation of the by-product lowers the selectivity toward the compound of the formula [3] and that the by-product behaves as a contaminant in the solution and prevents high yield crystallization of the compound of the formula [3]. In view of this, a method for the production of a hydrazine derivative of the formula [3] from a hydrazone derivative of the formula [4] is demanded, by which method the reduction proceeds selectively and a hydrogenolysis reaction (side reaction) can be suppressed.
It is therefore an object of the present invention to provide a method for producing a hydrazine derivative from a hydrazone derivative. According to this method, the reduction proceeds selectively and a hydrogenolysis reaction (side reaction) can be suppressed.
SUMMARY OF THE INVENTION
According to the present invention, there has now been found that the objective reduction proceeds selectively and hydrogenolysis reaction (side reaction) is suppressed by adding, together with a metal hydrogenating catalyst, at least one base selected from the group consisting of an organic base and an inorganic base to the reaction system when producing a hydrazine derivative of the following formula [2] from a hydrazone derivative of the following formula [1].
That is, the present invention relates to a method for producing a hydrazine derivative of the formula [2]:
wherein
R
1
is alkyl group having 1-12 carbon atoms, alkoxy group having 1-6 carbon atoms, halogen atom, hydroxyl group, optionally substituted phenyl group, optionally substituted aralkyl group or optionally substituted aromatic heterocyclic group,
R
2
is alkyl group having 1-12 carbon atoms, alkoxy group having 1-6 carbon atoms, halogen atom, optionally substituted phenyl group, optionally substituted aralkyl group, optionally substituted phenylalkoxy group or optionally substituted aromatic heterocyclic group, and
Ar is phenylene group, naphthylene group or aromatic heterocyclic group (hereinafter to be referred to as hydrazine compound [2]),
which method comprises reducing a hydrazone derivative of the formula [1]
wherein R
1
, R
2
and Ar are as defined above (hereinafter to be referred to as hydrazone compound [1]), in the presence of at least one base selected from the group consisting of an organic base and an inorganic base, and a metal hydrogenating catalyst.
The organic base is preferably a tertiary amine, more preferably triethylamine, and the inorganic base is preferably an alkali metal carbonate, more preferably sodium carbonate. After the reduction reaction, the reaction mixture is cooled as necessary, and filtrated in an atmosphere of an inert gas alone (e.g., nitrogen gas and the like), hydrogen gas alone or a mixed gas of these, whereby the reverse reaction (oxidation reaction) to the hydrazone compound [1] can be suppressed and the hydrazine compound [2] can be obtained in a high yield. For example, after the reduction reaction, the reaction mixture is cooled to not higher than 30° C., and filtrated in an atmosphere of inert gas alone. After the reduction reaction, moreover, a sulfur compound (preferably sodium hydrosulfite) is added to the filtrate obtained by the filtration of the reaction mixture to give a stable hydrazine compound [2] even in a solution state.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following.
The “alkyl group having 1-12 carbon atoms” at R
1
and R
2
is a linear or branched chain, and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like, preferably alkyl group having 1-6 carbon atoms.
The “alkoxy group having 1-6 carbon atoms” at R
1
and R
2
is a linear or branched chain, and is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like, preferably alkoxy group having 1-4 carbon atoms.
The “halogen atom” at R
1
and R
2
is chlorine atom, fluorine atom, bromine atom or iodine atom, which is preferably chlorine atom, fluorine atom or bromine atom.
The substituent of “optionally substituted phenyl group” at R
1
and R
2
is not subject to any particular limitation as long as it does not reduce under the reduction conditions employed in the present invention, and is exemplified by alkyl group having 1-12 carbon atoms (linear or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like), alkoxy group having 1-6 carbon atoms (linear or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like), halogen atom (fluorine atom, bromine atom, iodine atom, chlorine atom) and the like. Phenyl group may be substituted with one or more of these substituents.
The aralkyl group of “optionally substituted aralkyl group” at R
1
and R
2
is that wherein the aryl moiety is phenyl, naphthyl etc., and the alkyl moiety is alkyl group having 1 to 4, preferably 1 or 2, carbon atoms, and is exemplified by benzyl, 1-phenylethyl, 2-phenylethyl and the like. The substituent is not subject to any particular limitation as long as it does not reduce under the reduction conditions employed in the present invention, and is exemplified by alkyl group having 1-12 carbon atoms (linear or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like), alkoxy group having 1-6 carbon atoms (linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like), halogen atom (fluorine atom, bromine atom, iodine atom, chlorine atom) and the like. It may be substituted with one or more of these substituents.
The aromatic heterocyclic group of “optionally-substituted aromatic heterocyclic group” at R
1
and R
2
is exemplified by pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imdazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl and the like, preferably pyridyl. The substituent is not subject to any particular limitation as long as it does not reduce under the reduction conditions employed in the present invention, and is exemplified by alkyl group having 1-12 carbon atoms (linear or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like), alkoxy group having 1-6 carbon atoms (linear or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like), halogen atom (fluorine atom, bromine atom, iodine atom, chlorine atom) and the like.
It may be
Itaya Nobushige
Matsui Kozo
Suga Hiromi
Sugi Kiyoshi
Aulakh Charanjit S.
Sumika Fine Chemicals Co., Ltd.
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