Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-09-17
2004-05-11
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S002000, C544S065000, C544S066000
Reexamination Certificate
active
06734304
ABSTRACT:
The present patent application is filed under 35 U.S.C. 371 for International Application PCT/EPO1/02731, filed Mar. 12, 2001, which was published in German as International Patent Publication WO 01/72719 on Oct. 4, 2001, which is entitled to the right of priority of German Patent Application DE 100 14 607.4, filed Mar. 24, 2000.
The invention relates to a novel process for preparing known asymmetric 4,6-bis(aryloxy)pyrimidine derivatives.
Asymmetric 4,6-bis(aryloxy)pyrimidine derivatives are known and are used, for example, as pesticides in crop protection (cf. WO 94/02470, WO 97/27189, WO 98/21189, WO 99/57116).
The preparation of asymmetric 4,6-bis(aryloxy)pyrimidine derivatives is more difficult than the preparation of symmetric 4,6-bis(aryloxy)pyrimidine compounds since the different aryloxy groups have to be introduced in separate reactions.
A plurality of processes for preparing asymmetric 4,6-bis(aryloxy)pyrimidine derivatives has already been disclosed.
WO 94/02470 describes the preparation of asymmetric 4,6-bis(aryloxy)pyrimidine derivatives by a two-step process. Reaction of 4,6-dichloropyrimidine (A) with one equivalent of a phenol derivative (B) under basic reaction conditions and subsequent reaction with a second phenol derivative (D) gives asymmetric 4,6-bis(aryloxy)pyrimidine derivatives (E) (cf. Scheme 1).
This process has the disadvantage that an exchange of the aryloxy groups takes place in the second reaction step, giving a product mixture of asymmetric 4,6-bis(aryloxy)pyrimidine derivatives (E) and the symmetric 4,6-bis(aryloxy)pyrimidine derivatives (F) and (G).
As a consequence, the asymmetric 4,6-bis(aryloxy)pyrimidine derivatives (E) are obtained in poor yield and can only be isolated by complicated separation methods.
To avoid the problem of the exchange of the aryloxy groups to the second reaction step, it is possible to use the starting material 4,6-difluoropyrimidine (cf. Scheme 2 and WO 94/02470, EP-A1-794 177).
However, this process has the disadvantage that 4,6-difluoropyrimidine has to be prepared by a chlorine/fluorine exchange, starting from 4,6-dichloro-pyrimidine. The preparation of asymmetric 4,6-bis(aryloxy)pyrimidine derivatives therefore requires an additional reaction step. Preferred starting materials are therefore 4,6-dichloropyrimidine or 4,6-dichloropyrimidine derivatives.
The preparation of asymmetric 4,6-bis(aryloxy)pyrimidine derivatives starting from 4,6-dichloro-5-halogeno-pyrimidine analogously, to the process described in WO 94/02470 is described in WO 98/41513.
EP-A1-794 177, U.S. Pat. Nos. 5,849,910 and 5,977,363 describe a further process for preparing asymmetric 4,6-bis(aryloxy)pyrimidine derivatives (E) starting from 4,6-dichloropyrimidine (A) (cf. Scheme 3).
In this process, the aryloxy-chloropyrimidine derivative (C) obtained after the first reaction step is treated with at least one molar equivalent of a tertiary amine.
The intermediates formed are pyrimidinyl-ammonium derivatives (J), which are reacted with phenol derivatives (D) to give asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives (E).
This process has the disadvantage that at least equivalent molar amounts of the tertiary amine are required, which can only be recovered using complicated procedures. Moreover, the asymmetric 4,6-bis(aryloxy)pyrimidine derivatives are only obtained in moderate yields. This process is therefore unsuitable for the large-scale industrial preparation, especially if expensive amines are used.
It has now been found that asymmetric 4,6-bis(aryloxy)pyrimidine derivatives of the general formula (I),
in which
Ar
1
represents in each case substituted or unsubstituted aryl or heterocyclyl,
X represents hydrogen, fluorine, chlorine or bromine,
L
1
, L
2
, L
3
, L
4
and L
5
are identical or different and independently of one another each represents hydrogen, halogen, cyano, nitro, alkylcarbonyl formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, in each case optionally halogen-substituted alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl, or
L
1
, L
2
, L
3
and L
4
are identical or different and independently of one another each represents hydrogen, halogen, cyano, nitro, alkylcarbonyl, formyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, in each case optionally halogen-substituted alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl, and
L
5
represents one of the groups below:
where * denotes the point of attachment to the phenyl radical, and where the radicals
are different,
are obtained when
4,6-dichloropyrimidine derivatives of the general formula (II),
in which
X is as defined above,
a) are initially, in a first step, reacted with compounds of the general formula (III),
Ar
1
—OH, (III)
in which
Ar
1
is as defined above,
if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor,
and the resulting compounds of formula (IV),
in which
Ar
1
and X are each as defined above
are then, in a second step, reacted with compounds of the general formula (V),
in which
L
1
, L
2
, L
3
, L
4
and L
5
are each as defined above,
if appropriate in the presence of a solvent, if appropriate in the presence of a base and with addition of from 2 to 40 mol % of 1,4-diazabicyclo[2.2.2]octane (DABCO), or
b) are initially, in a first step, reacted with compounds of the general formula (V),
in which
L
1
, L
2
, L
3
, L
4
and L
5
are each as defined above,
if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor,
and the resulting compounds of the formula (VI),
in which
X, L
1
, L
2
, L
3
, L
4
and L
5
are each as defined above,
are then, in a second step, reacted with compounds of general formula (III),
Ar
1
—OH, (III)
in which
Ar
1
is as defined above,
if appropriate in the presence of a solvent, if appropriate in the presence of a base and with addition of from 2 to 40 mol % of 1,4-diazabicyclo[2.2.2]octane (DABCO).
In the definitions, the saturated or unsaturated hydrocarbon chains, such as alkyl, alkanediyl, alkenyl or alkinyl, are in each case straight-chain or branched, including in combination with heteroatoms, such as, for example, in alkoxy, alkylthio or alkylamino. Unless indicated otherwise, preference is given to hydrocarbon chains having 1 to 6 carbon atoms. Unless indicated otherwise, hydrocarbon chains having 2 to 6 carbon atoms are preferred for alkenyl or alkinyl.
Halogen generally represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.
Aryl represents aromatic, mono- or polycyclic hydrocarbon rings, such as, for example, phenyl, naphthyl, anthranyl, phenanthryl, preferably phenyl or naphthyl, in particular phenyl.
Heterocyclyl represents saturated or unsaturated, and also aromatic, cyclic compounds where at least one ring member is a heteroatom, i.e. an atom different from carbon. If the ring contains a plurality of heteroatoms, this can be identical or different. Preferred heteroatoms are oxygen, nitrogen or sulphur. If the ring contains a plurality of oxygen atoms, these are adjacent. If appropriate, the cyclic compounds form a polycyclic ring system together with other carbocyclic or heterocyclic, fused-on or bridged rings. Preference is given to mono- or bicyclic ring systems, in particular to mono- or bicyclic aromatic ring systems.
Cycloalkyl represents saturated carbocyclic compounds which, if appropriate, form a polycyclic ring system together with other carbocyclic fused-on or bridged rings.
A polycyclic ring system can be attached to a heterocyclic ring or a fused-on carbocyclic ring. This heterocyclyl group can also be mono- or polysubstituted, preferably by methyl, ethyl or halogen. Preference is given to mono- or bicyclic ring systems, in particular mono- or bicyclic aromatic ring systems.
Halogenoalkoxy represents partially or fully halogenated alkoxy. In the case of polyhalogenated halogenoalkoxy, the halogen atoms can be identical or d
Gayer Herbert
Hübsch Walter
Stelzer Uwe
Weintritt Holger
Bayer Aktiengesellschaft
Ford John M.
Henderson Richard E. L.
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