Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-12-20
2003-05-13
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...
C544S319000
Reexamination Certificate
active
06562970
ABSTRACT:
The present invention relates to a process for preparing 4-chloro-6-hydroxypyrimidine from 4-chloro-6-methoxypyrimidine. 4-Chloro-6-hydroxypyrimidine is a valuable intermediate for preparing crop protection agents, with the first stage of further processing frequently comprising a conversion of 4-chloro-6-hydroxypyrimidine into 4,6-dichloropyrimidine.
Various methods for synthesizing 4-chloro-6-hydroxypyrimidine have been disclosed. For example, J. Chem. Soc. (1961), 1298 describes the hydrolysis of 4,6-dichloropyrimidine with aqueous hydrochloric acid.
According to J. Med. Chem. 7, 5 (1964) a methylthio group is eliminated from 4-chloro-6-hydroxy-2-methylthiopyrimidine or a diazotizing hydroxylation of 4-amino-6-chloropyrimidine is carried out.
Furthermore, J. Org. Chem. USSR (English translation) 2, 230 (1966) describes the alkaline hydrolysis of a compound of the type Het-O—NH—CO—O—C
2
H
5
to the compound Het-OH where Het-OH is said to represent 4-chloro-6-hydroxypyrimidine.
The disadvantages of these processes are that they start from the desired product of further processing, that they require starting materials which are difficult to obtain, that they can be carried out only in a time-consuming and complicated manner and/or that they produce sulfur-containing waste products which can be disposed of only in a complicated manner.
Furthermore, Helv. Chim. Acta 42, 1317 (1959) describes the hydrolysis of 4-chloro-6-methoxypyrimidine to 4-chloro-6-hydroxypyrimidine using aqueous hydrochloric acid as reagent.
The disadvantage of this process is that the product can be isolated only by a time-consuming workup and, for the desired further processing to 4,6-dichloropyrimidine, it must be carefully dried.
A process for preparing 4-chloro-6-hydroxypyrimidine which is characterized in that 4-chloro-6-methoxypyrimidine is reacted with hydrogen halide has now been found.
Examples of a suitable hydrogen halide are HCl, HBr and HI. HCl and HBr are preferred, and HCl is particularly preferred. The use of mixtures of hydrogen halides is also possible. The hydrogen halides can be employed for example as such or mixed with a solvent, for example mixed with one of the solvents described below. The hydrogen halide is generally substantially anhydrous, that is to say it contains, for example, less than 1 mol %, preferably less than 0.1 mol %, of water.
A further possibility is to generate the hydrogen halides to be employed in situ from a halogen compound, for example an inorganic or organic acid halide, and a protic compound, for example water, an alcohol or an inorganic or organic acid. In this case, preferably only as much of the protic compound, in particular water, is employed as is used to form hydrogen halide.
It is possible to employ per mole of 4-chloro-6-methoxypyrimidine for example 1 to 30 mol, preferably 2 to 15 mol, of hydrogen halide. An excess of hydrogen halide is advantageous especially when unreacted hydrogen halide escapes during the reaction.
Solvents suitable in principle are those which do not interfere with the reaction of the invention, for example aliphatic solvents such as alkanes, cycloalkanes, halogenoalkanes and aliphatic ethers, aromatic solvents such as benzene, toluene, xylenes, halogenobenzenes, halogenotoluenes and benzotrifluorides, alcohols with 1-4 C atoms such as ethanol and isopropanol, nitriles such as acetonitrile and benzonitrile, nitrogen-containing solvents such as dimethylformamide, dimethylacetamide, cyclic ureas and lactams and ethers such as alkyl ethers, aryl ethers, alkyl aryl ethers and polyethers. Toluene, xylenes, dimethylformamide, acetonitrile, dichlorobenzenes or chlorotoluenes are preferably employed.
Special drying of the solvents is unnecessary. They can be employed with the water content normally present in technical grades. It is possible where appropriate to add small amounts of water or alcohols as catalysts to the process of the invention, for example 0.1 to 1.0 mol % based on 4-chloro-6-methoxypyrimidine employed. However, such an addition of catalyst can also be dispensed with.
The process of the invention can be carried out, for example, at temperatures in the range 0 to 200° C. 40 to 180° C. are preferred, and 60 to 160° C. are particularly preferred.
The pressure in the process of the invention is not critical, possible examples being 0.1 to 20 bar. 0.5 to 3 bar are preferred. Atmospheric pressure is particularly preferred.
A further possibility is not to isolate 4-chloro-6-hydroxypyrimidine but to meter a chlorinating agent, for example phosphorus oxychloride or phosgene, directly into the reaction mixture after the end of the reaction of the invention and thus convert it into 4,6-dichloropyrimidine. The precondition for this procedure is that the process of the invention is carried out in solvents which do not react in an unwanted manner with the chlorinating agent.
The process of the invention can be carried out in various embodiments, for example batchwise, semicontinuously, continuously or semibatchwise. Examples of possible procedures are as follows: dry hydrogen halide is passed at the desired reaction temperature into 4-chloro-6-methoxypyrimidine in a solvent.
With suitable choice of the solvent, for example of the preferred solvents indicated above, it is possible after the reaction of 4-chloro-6-methoxypyrimidine is substantial or complete for the reaction mixture to be brought to a temperature for example in the range 5 to 30° C., and for the precipitated product to be filtered off with suction.
Another possibility is to meter in hydrogen halide which is dissolved in one of the abovementioned solvents.
A further possibility is to meter 4-chloro-6-methoxypyrimidine into hydrogen halide in one of the abovementioned solvents and to stir at room temperature.
Working up is also possible by distillation. Besides these, other reaction procedures and workups are also possible.
The process of the invention makes it possible to prepare 4-chloro-6-hydroxypyrimidine in an exceptionally simple manner. For example, the conversion can be brought about by simply passing hydrogen halide into a solution of 4-chloro-6-methoxypyrimidine. It is particularly advantageous that the eliminated methyl group results in the form of methyl halide which escapes in the form of a gas from the system. This is particularly the case when hydrogen chloride is used. A further great advantage is that, if the solvent is suitably chosen, the 4-chloro-6-hydroxypyrimidine which is formed precipitates and can be isolated in a simple manner, for example by filtration.
REFERENCES:
J. Med. Chem. 7, 5, Jan. 8, 1964, pp. 1-10, Charles Heidelberger, David G. Parsons and David C. Remy, Syntheses of 5-Trifluoromethyluracil and 5-Trifluoromethyl-2′-decoxyuridine .
*Desmond J. Brown: “Pyrimidine Reactions. XSVII.” Australian Journal of Chemistry, vol. 31, No. 2, Feb. 1978, pp. 1391-1395, XP000960999 Australia.
Cramm Günther
Klausener Alexander
Mais Franz-Josef
Steffan Guido
Bayer Aktiengesellschaft
Eyl Diderico van
Ford John M.
Gil Joseph C.
Mrozinski John E.
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