Process for preparing pyridinecarboxylic esters

Details Process for preparing pyridinecarboxylic esters Process for preparing pyridinecarboxylic esters

1999-01-27

2001-01-02

Fan, Jane (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Utility Patent

active

06169183

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for preparing pyridinecarboxylic esters by reacting halogenated pyridines with carbon monoxide and a C
1-4
-alkanol in the presence of a weak base and a catalyst. The invention further relates to a novel halopyridine as starting material for the preparation according to the invention of a novel pyridinecarboxylic ester. The pyridinecarboxylic esters preparable by the invention process have the general formula:
wherein R
1
is hydrogen, a C
1-6
-alkyl group, a C
1-4
-alkoxycarbonyl group, a C
1-4
-alkoxymethyl group or a fluorinated C
1-6
-alkyl group, R
2
is a C
1-4
-alkyl group and X is chlorine or bromine.
2. Background Art
Pyridinecarboxylic esters are important intermediates, for example, for preparing herbicides (European Published Patent Application No. 0488474) and for preparing drugs against fibrotic diseases (European Published Patent Application No. 0673932).
Processes for preparing pyridinecarboxylic esters by carbonylation reactions starting from mono- and dihalopyridines are known from the literature [European Published Patent Application No. 0282266; International Published Patent Application No. WO 93/18005; U.S. Pat. No. 4,128,554; and
Shokubai
, (Catalysis Society of Japan), 36, (1994), 580]. A disadvantage of these processes is that the pyridinecarboxylic esters are obtained in only moderate yields. A further disadvantage of the processes described in European Published Patent Application No. 0282266 and International Published Patent Application No. WO 93/18005 is that the dihalopyridines employed as starting material are carbonylated with low selectivity. In a further carbonylation process [
J. Mol. Cat.,
66, (1991), 277], high yields of pyridinecarboxylic esters are obtained starting from monohalopyridines, but the reaction requires long reaction times.
BROAD DESCRIPTION OF THE INVENTION
An object of the invention is to provide an economical process for preparing selectively monocarbonylated pyridinecarboxylic esters of the general formula I in high yields starting from dihalopyridines. Other objects and advantages of the invention are set out herein or are obvious herefrom to one skilled in the art.
The objects and advantages of the invention are achieved by the method and compounds of the invention.
The invention involves a process for preparing pyridinecarboxylic esters of the general formula:
wherein R
1
is hydrogen, a C
1-6
-alkyl group, a C
1-4
-alkoxycarbonyl group, a C
1-4
-alkoxymethyl group or a fluorinated C
1-6
-alkyl group, R
2
is a C
1-4
-alkyl group and X is chlorine or bromine. In the process, 2,3-dihalopyridines of the general formula:
wherein R
1
and X are each as defined above, are reacted with carbon monoxide and a C
1-4
-alkanol in the presence of a weak base and a complex of palladium with a bis(diphenylphosphine) of the general formula:
wherein Q is a C
3-6
-alkanediyl group or 1,1′-ferrocenediyl group having optionally C
1-4
-alkyl- or aryl-substituted cyclopentadienyl groups and R
3
to R
6
, independently of one another, are each hydrogen, C
1-4
-alkyl, C
1
-C
4
-alkoxy, fluoromethyl, fluorine, aryl, phenoxy, nitrile or dialkylamino.
R
1
is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or an alkoxycarbonyl group having a straight-chain or branched alkyl group having 1 to 4 carbon atoms, or an alkoxymethyl group having a straight-chain or branched alkyl group having 1 to 4 carbon atoms, or a fluorinated alkyl group having a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Specific examples are methyl, ethyl, n-propyl, i-propyl, n-, i- and t-butyl, pentyl and its isomers, hexyl and its isomers, methoxycarbonyl, ethoxycarbonyl, n- and i-propoxycarbonyl, n-, i- and t-butoxycarbonyl, methoxymethyl, ethoxymethyl, n- and i-propoxymethyl and n-, i- and t-butoxymethyl. Particularly preferably, R
1
is methoxycarbonyl, methoxymethyl or trifluoro. R
2
is a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl and n-, i- and t-butyl. Particularly preferably, R
2
is methyl or ethyl. X is chlorine or bromine; X is particularly preferably chlorine.
A 2,3-dihalopyridine of the general formula II can be prepared in a simple manner starting from 2-chloropyridine 1-oxide (U.S. Pat. No. 5,334,724) or starting from 6-hydroxynicotinic acid [Swiss Patent No. 664,754;
Encyclopedia of Reagents for Organic Synthesis
, Vol. 4, ed. L. A. Paquette, John Wiley & Sons, Chichester, (1995), 2769-2771].
The alkanol used is a straight-chain or branched aliphatic alcohol having 1 to 4 carbon atoms. Specific examples are methanol, ethanol, n- and i-propanol, and n-, i- and t-butanol. Particular preference is given to methanol and ethanol.
The reaction is carried out in the presence of a weak base. Examples of bases which are highly suitable are alkali metal acetates, alkaline earth metal acetates, alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates, alkali metal hydrogen phosphates and alkaline earth metal hydrogen phosphates. Examples include sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate, calcium hydrogen carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium hydrogen phosphate and calcium hydrogen phosphate. Sodium acetate is particularly suitable.
The catalytically active palladium bis(diphenylphosphine) complex is advantageously formed in situ by reacting a Pd(II) salt (for example, the chloride or the acetate, preferably the acetate) or a suitable Pd(II) complex, [for example, bis(triphenylphosphine)palladium(II) chloride] with the diphosphine. The palladium is preferably employed in an amount of from 0.05 to 0.4 mol percent of Pd(II), based on the halogen compound (II). The diphosphine is advantageously employed in excess (based on Pd), preferably in an amount of from 0.2 to 5 mol percent, also based on the halogen compound (II).
Use is advantageously made of bis(diphenylphosphines) (III) where Q is a straight-chain or branched alkanediyl group having 3 to 6 carbon atoms. Examples include propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, pentanediyl and its isomers and hexanediyl and its isomers. Preference is given to those compounds (III) where Q is a straight-chain alkanediyl group having 3 to 6 carbon atoms. Examples include propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl and hexane-1,6-diyl. Particular preference is given to 1,4-bis(diphenylphosphino)butane. Bis(diphenylphosphines) (III) where Q is a 1,1′-ferrocenediyl group having optionally C
1-4
-alkyl- or aryl-substituted cyclopentadienyl groups are likewise employed advantageously. Preferred C
1-4
-alkyl substituents are methyl, ethyl, n-propyl, i-propyl, and n-, i- and t-butyl, particularly preferably methyl and ethyl. Preferred aryl substituents are phenyl and optionally substituted phenyl. Substituted phenyl includes in particular groups such as p-fluorophenyl, p-methoxyphenyl, p-tolyl and p-trifluoromethylphenyl.
R
3
to R
6
of the bis(diphenylphosphines) (III) employed are each, independently of the others, hydrogen, C
1-4
-alkyl, C
1-4
-alkoxy, fluoromethyl, fluorine, aryl, phenoxy, nitrile or dialkylamino.
Methyl, ethyl, n-propyl, i-propyl, and n-, i- and t-butyl are advantageously employed as C
1-4
-alkyl substituents, with particular preference being given to methyl and ethyl. Methoxy, ethoxy, n- and i-propoxy, and n-, i- and t-butoxy are advantageously employed as C
1-4
-alkoxy substituents, with particular preference being given to methoxy and ethoxy. Phenyl and optionally substituted phenyl are advantageously employed as aryl substituents. Substituted phenyl is to be understood as meaning the above-mentioned groups. Phenoxy and optionally substituted phenoxy are advantageously employed as phenoxy substituents. Substituted

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