Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-09-05
2002-10-08
Rao, Deepak R. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S332000
Reexamination Certificate
active
06462195
ABSTRACT:
FIELD OF INVENTION
The present invention relates to methods for selectively O-alkylating chain or cyclic compounds having CONH groups or enol structures thereof in the molecules. Particularly it relates to methods suitable for preparing pyrimidyloxy or pyridyloxy derivatives, which are compounds useful as intermediates for agrochemicals and medicines, from pyrimidone or pyridone derivatives efficiently and highly selectively in high yields.
BACKGROUND ART
It is known that, when a chain or cyclic compound having one or more CONH groups or enol structures thereof as partial structures in the molecule is alkylated in a basic condition, N-alkyl compounds are produced in preference. Because of this, to obtain O-alkyll compounds selectively, for example, a carbonyl group was halogenated and then a substitution reaction was carried out with a corresponding alcohol in the presence of a base, or in the case of urea structure an isothiourea was synthesized from a corresponding thiourea and a substitution reaction was carried out with a corresponding alcohol. In other words, it was necessary to synthesize a halogenated compound or an isothiourea. There has been a problem that the above methods have applicable limits depending on substrates used.
Meanwhile, pyridyloxy or pyrimidyloxy derivatives are important as intermediates for agrochemicals, medicines and the like. For example, a series of compounds relating to them and their production processes are disclosed in EP 0472 224. However, when pyridyloxy or pyrimidyloxy derivatives are produced by the alkylation reactions of pyridone or pyrimidone compounds, byproducts unusable as target compounds are produced by N-alkylation reactions. Therefore the said processes have not been satisfactory economically.
In addition, J. Org. Chem. 32 4040 (1967) and Japanese Patent Laid-open No. Sho 63-216848 describe examples of preparing pyridyloxy derivatives and pyrimidyloxy derivatives by alkylation reactions of pyridone or pyrimidone with the use of alkali metal salts or silver salts. They have not been satisfactory as industrial production processes because of a large amount of N-alkylated byproducts produced other than target compounds or use of expensive silver salts.
In WO 97/01538 processes for the preparation of pyridyloxy derivatives are disclosed, but are limited to alkylation reactions of pyridones having a substituent at the position of 6.
As described above, in conventional technology, it is necessary to synthesize halogenated compounds or isothioureas, and there have been a problem of applicable limits depending on substrates used. Besides satisfactory results have not been accomplished, due to unnecessary byproducts produced when pyrimidone or pyridone compounds used as starting materials are changed to salts, such as alkali metal salts or silver salts, to react with various alkylating agents.
DISCLOSURE OF THE INVENTION
This invention is to provide economically advantageous methods that a chain or cyclic compound having one or more CONH groups or enol structures thereof as partial structures in the molecule, whose representatives are pyrimidone or pyridone compounds, is O-alkyllated highly selectively by a novel method to give a target compound selectively in high yield or very efficiently.
This invention relates to selective O-alkyllation methods characterized in that, in an O-alkyllation reaction of a chain or cyclic compound having one or more structures represented by Formula (I)
as partial structures, with Compound RL having a leaving group (wherein R is optionally substituted alkyl, optionally substituted allyl or optionally substituted aralkyl, and L is a leaving group), a monovalent copper salt derived from the said chain or cyclic compound is reacted in the presence of a phosphorus compound represented by Formula (II)
(wherein R
1
, R
2
and R
3
are, each same or different, hydrogen, alkyl, aryl, aralkyl, alkoxy, aryloxy or aralkyloxy).
The present invention also relates to methods for selectively O-alkyllating pyrimidone, pyridone or triazine compounds of which the cyclic compounds having one or more structures represented by Formula (I) as partial structures are represented by Formula (III)
(wherein X and Y are each independently CH or N; R
4
is hydrogen, lower alkyl, haloalkyl or lower alkoxy; and R
5
is hydrogen, lower alkyl or trifluoromethyl). This invention also relates to selective O-alkyllation methods characterized in that the compound having a leaving group is represented by Formula (IV)
(wherein L is a leaving group; R
6
is lower alkyl; and W and Z are both hydrogen or become one to form ═O, ═NOCH
3
or ═CHOCH
3
), or by Formula (V)
(wherein R
7
and R
8
are, same or different, chain or branched lower alkyl, haloalkyl, cycloalkyl or aralkyl; and L is as defined above). The present invention also relates to methods for selectively O-alkyllation compounds where Formula (III) is represented by
(wherein R
9
is lower alkyl).
The compounds used as starting materials in the present invention and having one or more structures represented by Formula (I) as partial structures in the molecules, that is, compounds having one or more CONH groups or enol structures thereof as partial structures in the molecules, are not particularly restricted if they have structures able to form copper salts with monovalent copper compounds such as copper (I) oxide. Concrete examples include compounds having basic skeletons such as those shown below:
Compounds shown in brackets are tautomers.
Particularly pyrimidyloxy compounds, pyridyloxy compounds or triazinyloxy compounds, which are useful as intermediates for agrochemicals or medicines, can be produced if the methods of the present invention are applied to pyrimidone, pyridone or triazine compounds represented by Formula (III)
(wherein X and Y are each independently CH or N; R
4
is hydrogen, lower alkyl, haloalkyl or lower alkoxy; and R
5
is hydrogen, lower alkyl or trifluoromethyl),. Concrete examples include compounds shown in the following:
In the present invention, general preparation methods to derive a monovalent copper salt from a chain or cyclic compound having one or more structures represented by Formula (I) as partial structures include, for example, a dehalogenating alkali-metal reaction of an alkali metal salt, such as lithium and potassium, of the aforementioned pyrimidone or pyridone compound with monovalent halogenated copper, such as monovalent copper chloride, or synthesis by reacting monovalent copper cyanide with the aforementioned pyrimidone or pyridone compound. Synthesis by a direct dehydration reaction of the said pyrimidone or pyridone compound with the use of copper(I) oxide (Cu
2
O) is however easiest, and gives a monovalent copper salt with high purity. Besides, it gives extremely good results to the following alkylation reaction.
Compound RL having a leaving group, which is used in the reaction with a copper salt in the present invention, has Leaving Group L. L is preferably halogen or a substituted or unsubstituted arylsulfonic acid residue, and is more preferably selected from the group consisting of chlorine, bromine, iodine and tosyloxy. R is a group corresponding to the structure required for a target compound of pyrimidyloxy or pyridyloxy derivative, and is not particularly restricted. It represents optionally substituted alkyl, allyl or aralkyl depending on the purpose. Concrete examples include methyl, ethyl, isopropyl, allyl and benzyl. Among them, compounds represented by Formulae (IV) and (V) are particularly useful because produced compounds become intermediates for agrochemicals and medicines when selective O-alkyllation reactions are carried out using them. Concrete examples of compounds represented by Formulae (IV) and (V) include those shown in the following:
Ts is a p-toluenesulfonyl group.
Phosphorus compounds used in the present invention, which are added to facilitate reactions and actions to improve reaction selectivity, are preferably those substantially inactive to O-alkyllation reactions and with high aff
Miyazawa Yasuyuki
Takase Mitsuru
Tsubokura Shiro
Jacobson & Holman PLLC
Nippon Soda Co. Ltd.
Rao Deepak R.
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