Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-07-21
2002-04-02
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S321000, C544S330000, C544S331000, C544S182000
Reexamination Certificate
active
06365739
ABSTRACT:
DESCRIPTION
Process for the preparation of 4,6-disubstituted 2-isocyanatopyrimidines and their use as intermediates for active compound syntheses.
The invention relates to the technical field of the chemical synthesis of biologically active compounds, preferably the processes for the preparation of plant protection agents and of intermediates for these processes.
It is known that 4,6-disubstituted 2-isocyanatopyrimidines can be employed in principle as intermediates for the production of pharmaceuticals, plant protection agents, polymers or dyes from the chemical classes of the carbamates, ureas and sulfonylureas; cf. e.g. EP-A-232067, BR-A8602648 and chemical handbooks. Only a few processes are published for the preparation of the reactive isocyanate group on the pyrimidine radical.
According to J. Mass Spec. 30 (1995) p. 338, 4,6-dimethoxy-2-isocyanato-pyrimidine was produced in the high temperature pyrolysis (400-900° C.) of certain sulfonylurea derivatives and characterized by mass spectroscopy. The pyrolysis process, however, has only minor industrial importance, because the product cannot be obtained therewith in appreciable preparative amounts.
EP-A-232067 describes the phosgenation of 2-amino-4,6-dimethoxy-pyrimidine in the presence of an amine base (triethylamine), where the intermediate, however, has not been isolated or characterized, but has been directly further processed with a sulfonamide to give a sulfonylurea. According to a general scheme, 4,6-dimethoxy-2-isocyanatopyrimidine and/or N-(4,6-dimethoxypyrimidin-2-yl)carbamoyl chloride is postulated as an intermediate in EP-A-232067. The process for the preparation of the intermediate and the overall process to the herbicidal sulfonylurea, however, has some disadvantages, which stand against its implementation on the industrial scale. Firstly, a large excess of amine base (especially 4 equivalents of triethylamine) and a large excess of phosgene (especially 8 equivalents) are employed. Such an excess cannot be used on the industrial scale for reasons of process safety, product quality and reasons of cost. The product quality is particularly adversely affected, because under the conditions of the reaction and on distilling off the excess phosgene, which is carried out at 90° C. according to EP-A-232067, the base triethylamine and phosgene can react with one another (cf. also J.-P-Senet, “The Recent Advance in Phosgene Chemistry”, Société des Poudres et Explosives (Ed.) 1997, pp. 105-106). This leads on the one hand, depending on the secondary reactions which are difficult to control in detail from reaction batch to reaction batch, to poorly reproducible reaction courses and yields and partly to toxicologically harmful by-products. In the known process, decomposition products and salts are produced which contribute to the increased contamination of the product. Moreover, the triethylamine can react with the phosgene in the gas phase during the reaction as a result of its relatively high vapor pressure and form a white precipitate at various sites of the apparatus used for the reaction and thus make the conduct of the reaction difficult and further impair the purity of the product.
Many isocyanates are very reactive and are therefore not isolated as a rule from the reaction mixture or a prepurified solution after the preparation, but further processed directly with nucleophilic compounds to give addition products. For the further processing of isocyanates of the abovementioned type, solvents or solvent mixtures are suitable to a differing extent. For example, the solvent mixture employed in EP-A-232067 for the further processing of the intermediate can only be separated off with difficulty after the reaction and can therefore not be used on the industrial scale. Because of the mentioned disadvantages of the known process, its yield for the preparation of the intermediate and its total yield for the preparation of the further processing products are not acceptable.
It was therefore the object to make available a modified process which in comparison with the abovementioned process represents an improved or industrially realizable preparation of 4,6-disubstituted 2-isocyanatopyrimidines and preferably also allows a further processing to give carbamates, ureas and sulfonylureas with advantages such as improved total yield and/or product purity, decreased use of starting materials or a simplified process course.
One subject of the invention is a process for the preparation of compounds of the formula (I)
in which each of the radicals X and Y independently of one another is hydrogen, halogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy or (C
1
-C
4
)alkylthio, where each of the last-mentioned 3 radicals is unsubstituted or substituted by one or more radicals from the group consisting of halogen, (C
1
-C
4
)alkoxy and (C
1
-C
4
)alkylthio, or di[(C
1
-C
4
)alkyl]amino, (C
3
-C
6
)cycloalkyl, (C
3
-C
5
)alkenyl, (C
3
-C
5
)alkynyl, (C
3
-C
5
)alkenyloxy or (C
3
-C
5
)alkynyloxy,
which comprises reacting a compound of the formula (II) or its salts
in which X and Y are defined as in formula (I),
with 1 to 6 mol of phosgene per mole of compound of the formula (II), in the presence of 2 to 3.5 molar equivalents of a base per mole of compound of the formula (II) and in the presence of an aprotic organic solvent at a reaction temperature in the range from −30 to +60° C., preferably in the range from −30 to +40° C., in particular in the range from −10 to +30° C., to give the compound of the formula (I).
Preferred processes for the preparation of compounds of the formula (I) are those in which each of the radicals X and Y independently of one another is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, methylthio, trifluoromethyl, trichloromethyl, difluoromethoxy, dimethylamino, diethylamino, allyl, propargyl, allyloxy or propargyloxy;
particularly preferred in this case are those processes in which one of the radicals X and Y is halogen, preferably chlorine, methyl, ethyl, methoxy, ethoxy, methylthio, trifluoromethyl, trichloromethyl, difluoromethoxy, dimethylamino, diethylamino, allyl, propargyl, allyloxy or propargyloxy and the other of the radicals X and Y is methyl, ethyl, methoxy, ethoxy, methylthio or difluoromethoxy;
very particularly preferred processes are those in which X and Y in pairs are methyl/methyl, methyl/methoxy, chlorine/methyl, chlorine/methoxy or methoxy/methoxy.
In connection with the chemical terms used in this description, the definitions customary for the person skilled in the art apply, if not specifically defined otherwise. The radicals alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio and the corresponding unsaturated and/or substituted radicals in the carbon structure are in each case straight-chain or branched. If not specially indicated, in these radicals the lower carbon structures, e.g. having 1 to 6 carbon atoms or in the case of unsaturated groups having 2 to 6 carbon atoms, are preferred.
Alkyl radicals, also in the combined meanings such as alkoxy, haloalkyl etc. are, for example, methyl, ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls, such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls, such as n-heptyl, 1-methylhexyl and 1,4-dimethylpentyl; alkenyl and alkynyl radicals have the meaning of the possible unsaturated radicals corresponding to the alkyl radicals; alkeryl is, for example, allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl and 1-methylbut-2-en-1-yl; alkynyl is, for example, propargyl, but-2-yn-1-yl, but-3-yn-1-yl, 1-methylbut-3-yn-1-yl.
Cycloalkyl is a carbocyclic, saturated ring system preferably having 3-8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine. Haloalkyl, -alkenyl and -alkynyl are alkyl, alkenyl or alkynyl which is partly or completely substituted by halogen, preferably by fluorine, chlorine and/or bromine, in particular by fluorine and/or chlorine, e.g. monohal
Ford Mark James
Lachhein Stephen
Balasubramanian Venkataraman
Frommer & Lawrence & Haug LLP
Hoechst Schering AgrEvo GmbH
Raymond Richard L.
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