Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2003-01-06
2004-02-17
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
06693194
ABSTRACT:
The invention relates to a novel process for preparing by-product-free 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine and to its use as an intermediate in the preparation of herbicidal 7-[(4,6-dimethoxypyrimidin-2-yl)thio]naphthalide derivatives.
Processes for preparing 2-alkylsulfonylpyrimidine derivatives which are disubstituted, in the 4- and 6-position, are already known from EP-A-0 209 779, J. Org. Chem. 26, 792 (1961) and Pestic. Sci. 47, 115 (1996). Some of the processes described proceed in a complicated manner via a plurality of discrete reaction steps, with isolation of the respective intermediates. Thus, for example, the first two documents describe the oxidation to the corresponding 2-alkylsulfonyl-pyrimidine derivatives by introduction of chlorine gas into a two-phase system (Example II-1, page 15) or an absolute alcoholic solution of 2-alkylthiopyrimidine derivatives (example 4,6-dichloro-2-(methylsulfonyl)pyrimidine (compound XXXVII), page 802). Pestic. Sci. describes both the reaction of 4,6-dichloro-2-(alkylthio)-1,3-pyrimidine with sodium alkoxide to the corresponding 4,6-dialkoxy-substituted 2-alkylthio-pyrimidine derivatives and its oxidation to the corresponding 4,6-dialkoxy-2-(alkylsulfonyl)-1,3-pyrimidines with Oxone or hydrogen peroxide and sodium tungstate as catalyst. The pure end product is prepared by recrystallization. However, the observed yields and purities of the products are frequently unsatisfactory for industrial preparation processes. Moreover, the isolation and purification procedures are uneconomical and associated with a high expenditure on apparatus.
It is an object of the present invention to eliminate these disadvantages and to provide a more simple process which is suitable for industrial applications. Surprisingly, it has now been found that 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine can be prepared in a simple manner, in high yield and purity, in an economically and ecologically particularly advantageous manner from 4,6-dichloro-2-(methylthio)-1,3-pyrimidine by reacting the latter compound with an alkali metal methoxide and oxidizing the resulting 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine without isolation directly to the corresponding 2-methylsulfonylpyrimidine derivative and freeing this in a subsequent purification step in the same reaction vessel as a “one-pot reaction” from any by-products formed, allowing direct use, for example, for preparing herbicides according to EP-B-0 447 506.
Accordingly, the present invention provides a process for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine by reacting 4,6-dichloro-2-(methylthio)-1,3-pyrimidine in an inert organic solvent with an alkali metal methoxide, transfer of the resulting 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine into an aqueous-acidic medium and subsequent oxidation of this compound, if appropriate in the presence of a catalyst, wherein the oxidation is followed by a purification step in which the aqueous-acidic reaction mixture is adjusted with aqueous base to a pH in the range of 5-8 and stirred either in the presence or in the absence of an organic solvent.
In the first step (Reaction Scheme 1), the reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with the alkali metal methoxide is expediently carried out in an inert organic solvent such as a hydrocarbon, for example an aromatic hydrocarbon such as benzene, toluene or the isomeric xylenes, preferably in toluene, at reaction temperatures of from 0° C. to the boiling point of the solvent used, preferably at temperatures of from 20° to 60° C.
The alkali metal methoxide used is preferably sodium methoxide or potassium methoxide and particularly preferably a 30% sodium methoxide solution in methanol or solid sodium methoxide (for example 95%), where from 2 to 3 molar equivalents, preferably from 2.05 to 2.50 molar equivalents, of methoxide are used for the substitution reaction, based on 1 mol of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine. Expediently, the methoxide solution or the solid methoxide is added dropwise or added, respectively, in the temperature range stated within a period of 2-6 hours to a solution of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine which has initially been charged, and the reaction mixture is then stirred for from 5 to 10 hours or until no more starting material can be detected, at temperatures of from 50° to 60° C.
After this reaction time, the resulting mixture is prepared for the oxidation in the second step. To optimize the product yield, some of the methanol present in the reaction mixture may first be distilled off under reduced pressure, the distillation being terminated once 50-90% of the total amount of methanol has been distilled off. Water and a water-immiscible azeotrope-forming inert organic solvent, for example toluene, are then added to the resulting reaction mixture, and the entire mixture is heated with stirring to from 30° to 80° C., preferably from 30° to 60° C. After cooling, the aqueous phase is separated off and, to optimize the yield, once more admixed with the inert organic solvent and heated with stirring to from 30° to 80° C., preferably from 30° to 60° C. After cooling, the aqueous phase is separated off and discarded and the two organic phases are combined and substantially evaporated under reduced pressure. Water, heated to from 40° to 80° C., is added to the resulting residue, and the complete remainder of the organic solvent is distilled off azeotropically, until only water can be detected in the distillate.
The oxidation of the resulting and prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in the second step (Reaction Scheme 1) is expediently carried out in a protic solvent or a protic solvent mixture and, depending on the oxidizing agent used, if appropriate in the presence of a catalyst. Thus, expediently, a concentrated acid such as a carboxylic acid, for example 100% acetic acid, is added to the prepared aqueous reaction mixture from the first step, until a 1-80%, preferably 2-10%, aqueous solution of the corresponding carboxylic acid is obtained. To this end, depending on the oxidizing agent used, 0.1-0.2 mol % of a catalyst, based on 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine, such as a tungstate, for example sodium tungstate, is added, and this mixture is heated to from 70° to 90° C., preferably from 75° to 80° C. From 2 to 4 mol, preferably from 2.1 to 3 mol, of an oxidizing agent, such as a peroxide, for example 20-35% hydrogen peroxide solution, based on 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine, are then added dropwise. The exothermic oxidation reaction is maintained at the stated reaction temperature for 1-6 hours or until all of the methylthiopyrimidine or methylsulfoxide pyrimidine has been oxidized to the methylsulfonylpyrimidine.
After the oxidation has ended, excess oxidizing agent present in the reaction mixture is destroyed in a customary manner, known to the person skilled in the art, for example by adding 40% aqueous sodium hydrogen sulfite solution to the reaction mixture until no more oxidizing agent can be detected (potassium iodide/starch test), and the reaction mixture treated in this manner is prepared for the subsequent purification step which is carried out in the same reaction vessel.
One feature of the reaction sequence according to the invention is the purification step which follows as a “one-pot reaction” in the same reaction vessel and which offers great advantages for industrial processes since complicated separation and purification steps can be avoided and the expenditure on apparatus can be reduced.
To this end, the aqueous-acidic reaction mixture obtained in the preceding two-step reaction sequence is first adjusted with an aqueous base at temperatures of from 10° to 90° C. to a pH in the range from 5-8 and then either according to
Variant A) this resulting aqueous phase is stirred in the temperature range of from 10° to 90° C. and at the stated pH for from 0.5 to 5 hours, or
Variant B) is admixed with a water-immiscible inert organic solvent such as an aromatic hydrocarbon, for examp
Jau Beat
Urwyler Bernhard
Ford John M.
Hamilton Thomas
Syngenta Crop Protection Inc.
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