Process for preparing 4,6-dichloro-5-fluoropyrimidine

Details Process for preparing 4,6-dichloro-5-fluoropyrimidine Process for preparing 4,6-dichloro-5-fluoropyrimidine

2000-08-17

2001-07-03

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...

Reexamination Certificate

active

06255486

ABSTRACT:

This application claims priority to German Applications 19939190.4 and 19948933.5 filed on Aug. 18, 1999 and Oct. 11, 1999 respectively.
The invention relates to a novel process for preparing 4,6-dichloro-5-fluoropyrimidine.
BACKGROUND OF THE INVENTION
4,6-dichloro-5-fluoropyrimidine is an intermediate which can be used, for example, for preparing crop protection agents and dyes.
A process for preparing 4,6-dichloro-5-fluoropyrimidine has already been described In DE-A1-197 10609.
In this process, 4,6-dihydroxy-5-fluoropyrimidine is admixed with phosphorus oxychloride and dimethylaniline as base. For work-up, firstly the excess phosphorus oxychloride is distilled off and the residue is subjected to vacuum distillation. This process has the disadvantage that a relatively large amount of base is employed, and that the base can be recovered and re-used only at great cost. Moreover, during the aqueous work-up of the distillation residue, large amounts of wastewater with a high phosphate content are formed. Work-up on an industrial scale is therefore very complicated.
The preparation of 4,6-dichloropyrimidine is described in DE-A1-196 42 533 and DE-A1-195 31 299.
A process for preparing 4,6-dihydroxy-5-fluoropyrimidine is described in JP-A2-61 205 262. In this process, the condensing agent used is formamidine hydrochloride, which is a relatively expensive and highly hygroscopic condensing agent. Accordingly, this process is no alternative for industrial production.
Processes for preparing 4,6-dihydroxypyrimidine derivatives have likewise already been described (cf. WO-A1-94/44327, DE-A1-43 23 180, U.S. Pat. No. 847 139).
BRIEF SUMMARY OF THE INVENTION
Accordingly, it was the object of the present invention to provide a process for preparing 4,6-dichloro-5-fluoropyrimidine which allows the preparation on an industrial scale without addition of bases and where phosphate-containing wastes are avoided or produced in only small amounts.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that 4,6-dichloro-5-fluoropyrimidine (I)
is obtained when
a) compounds of the formula (II),
in which
R represents methyl or ethyl are reacted with formamide in the presence of alkali metal alkoxides, if appropriate in a diluent at elevated temperature, if appropriate under pressure, and the reaction mixture is, if appropriate, acidified with an acid after the reaction, and, if appropriate without intermediate isolation of the compounds of the formula (III),
b) the resulting 4,6-dihydroxy-5-fluoropyrimidine (III) or its alkali metal salt
is reacted with phosphorus oxychloride, and the resulting reaction mixture 1 is subsequently reacted with chlorine in the presence of phosphorus trichloride such that in each case at most 99.9% by weight of the chlorophosphonic acids which are present in the reaction mixture are converted, and the resulting reaction mixture 2 is worked up distillatively, whereby the 4,6-dichloro-5-fluoropyrimidine formed is separated off and the phosphorus oxychloride is recovered.
In a particularly preferred variant, the compounds of the formula (II) are added, if appropriate in a diluent, to a mixture of formamide, alkali metal alkoxides and diluent.
The process according to the invention has the advantages that the condensing agent used in process step a) is formamide.
A further advantage of the novel process is the fact that the chlorination according to process step b) can be carried out without bases. Moreover, the formation of large amounts of phosphate-containing wastewater is avoided, and the phosphorus oxychloride can be recovered.
The process according to the invention for preparing 4,6-dichloro-5-fluoropyrimidine is therefore more environmentally friendly than the processes known to date.
The starting materials of the formula (II) are known substances and can be prepared by simple processes (cf. DE 42 57 882).
All other starting materials are likewise customary commercial products, or they can be prepared from these by simple processes.
In the formula (II), R represents in particular ethyl.
Suitable diluents for carrying out the process step a) are, by way of example and by way of preference, alcohols, in particular alcohols having 1 to 4 carbon atoms, especially methanol.
The preferred diluent for carrying out the process step b) is an excess of phosphorus oxychloride.
For the purpose of the invention, alkali metal alkoxides are potassium alkoxides and in particular sodium alkoxides which are derived from alcohols having 1 to 4 carbon atoms.
For the purpose of the invention, acids are relatively highly concentrated acids, in particular mineral acids, by way of example and by way of preference sulphuric acid, phosphoric acid and in particular hydrochloric acid.
When carrying out the process according to the invention, the reaction temperatures can be varied within a relatively wide range. In general, the process is carried out in a temperature range from 50° C. to the reflux temperature of the mixture in question, in particular at reflux temperature.
The reaction of compounds of the formula (II) according to process step a) is carried out at atmospheric pressure in a temperature range from 50° C. to reflux temperature, preferably in a temperature range from 60° C. to reflux temperature, and under superatmospheric pressure in a temperature range from 60° C. to 120° C., preferably in a temperature range from 80° C. to 110° C.
The reaction of compounds of the formula (III) according to process step b) is preferably carried out in a temperature range from 60° C. to reflux temperature, in particular at from 80° C. to reflux temperature.
The reactions of the process according to the invention are carried out under atmospheric pressure, under elevated or under reduced pressure, preferably under atmospheric pressure.
The reaction of compounds of the formula (II) according to process step a) is carried out under atmospheric pressure or under elevated pressure, in particular under pressures of from 1 to 4 bar, preferably under pressures of from 1.5 to 3 bar.
The reaction of compounds of the formula (III) according to process step b) is preferably carried out under atmospheric pressure.
For carrying out the process according to the invention for preparing the compounds of the formula (III), in process step a), in general from 2 to 10 mol, preferably from 2.5 to 8 mol, of formamide and from 3 to 6 mol, preferably from 3 to 4 mol, of alkali metal alkoxide are employed per mole of the compound of the formula (II).
For carrying out the process according to the invention for preparing the compounds of the formula (I), in process step b), in general from 2.5 to 12 mol, preferably from 3 to 8 mol, of phosphorus oxychloride are employed per mole of the compound of the formula (III).
For carrying out the process according to the invention for preparing compounds of the formula (I), in process step b), in general from 1.7 to 2.1 equivalents, preferably from 1.9 to 2.0 equivalents, of chlorine are employed per mole of the compounds of the formula (III).
For carrying out the process according to the invention for preparing the compounds of the formula (I), in process step b), in general from 1.7 to 2.1 equivalents, preferably from 1.9 to 2.0 equivalents, of phosphorus trichloride are employed per mole of the compounds of the formula (III).
The addition of compounds of the formula (II) according to process step a) or of a mixture of compounds of the formula (II) and formamide is, in particular, carried out by dropwise addition of compounds of the formula (II) which are, if appropriate, dissolved in an alcohol having 1 to 4 carbon atoms, or of a mixture of compounds of the formula (II) and formamide which is, if appropriate, dissolved in an alcohol having 1 to 4 carbon atoms, at temperatures of from 50° C. to reflux temperature, in particular at reflux temperature.
It is a feature of the invention that the addition of the fluoromalonic ester in process step a) is carried out by continuous metered addition of a solution of the fluoromalonic ester, if appropriate in an alcohol having 1 to 4

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