Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-14
2003-05-06
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06559317
ABSTRACT:
The present invention relates to a novel process for preparing 2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazole-5-thiono-1-yl)-propan-2-ol, which is known as an active compound with microbicidal, in particular fungicidal, properties.
It is already known that 2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazole-5-thiono-1-yl)-propan-2-ol can be prepared by initially reacting 3-chloro-2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-propan-2-ol with hydrazine hydrate, if appropriate in the presence of an inert organic solvent, such as alcohol, ether or nitrile, then reacting the resulting 2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine with formaldehyde and alkali metal thiocyanate or ammonium thiocyanate and finally reacting the resulting 2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thiono-1-yl)-propane with oxygen in the presence of sulphur and potassium hydroxide (cf. WO 99-18 087). The reaction sequence can be illustrated by the formula scheme below:
This process has the disadvantage that the hydrazine compound formed in the first step is relatively unstable in the free state. Moreover, it is unfavourable that undesirable by-products are formed in the course of the multi-step synthesis and that the yield is relatively low for a preparation on an industrial scale. Finally, it is likewise detrimental that an interfering overoxidation can take place during the third step, resulting in the elimination of sulphur from the target product.
It has now been found that 2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-3-(4,5-dihydro-1,2,4-triazole-5-thiono-1-yl)-propan-2-ol of the formula
can be prepared when
a) in a first step, 2-(1-chloro-cycloprop-1-yl)-2-(2′-chloro-benzyl)-oxirane of the formula
is initially reacted with hydrazine hydrate in the presence of aromatic hydrocarbon, if appropriate in a mixture with acetonitrile, and hydrogen chloride is then introduced, or the mixture is extracted with aqueous hydrochloric acid
b) in a second step, the resulting 2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine hydrochloride of the formula
is then treated with alkali metal hydroxide in the presence of water and in the presence of aromatic hydrocarbon, if appropriate in a mixture with a lower alcohol, or in the presence of alkyl alkylcarboxylate, and then reacted successively with formaldehyde and thiocyanate of the formula
X—SCN (IV),
in which
x represents sodium, potassium or ammonium,
in the presence of water and in the presence of aromatic hydrocarbon, if appropriate in a mixture with a lower alcohol, or in the presence of alkyl alkylcarboxylate and, if appropriate, in the presence of a catalyst, and
c) in a third step, the resulting 2-(1-chloro-cycloprop-1-yl)-1-(2-chloro-phenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thiono-1-yl)-propane of the formula
is then reacted with iron(III) chloride in the presence of aqueous hydrochloric acid and in the presence of an inert organic diluent.
It is extremely surprising that the triazolinethione derivative of the formula (I) can be prepared by the process according to the invention in higher yields than by the prior-art methods. It is also unexpected that, during the course of the multi-step synthesis, there are virtually no interfering side reactions.
The process according to the invention has a number of advantages. Thus, as already mentioned, it allows the synthesis of the triazolinethione derivative of the formula (I) in high yield. Moreover, it is favourable that the starting materials and reaction components required can be prepared in a simple manner and are available even in relatively large amounts. It is a further advantage that the individual reaction steps and the isolation of the reaction products can be carried out without any difficulties. Finally, it should also be mentioned that the hydrazine hydrochloride derivative of the formula (III), in contrast to the corresponding hydrazine compound, can be handled without any stability problems, and that an overoxidation in the last step can be avoided.
Using sodium hydroxide as neutralizing agent and sodium thiocyanate and Formalin solution as reaction components for carrying out the second step, the course of the process according to the invention can be illustrated by the following formula scheme:
The 2-(1-chloro-cycloprop-1-yl)-2-(2′-chloro-benzyl)-oxirane of the formula (II) required as starting material for carrying out the process according to the invention is know n (cf. EP-A 0 297 345). It can be prepared by reacting the chlorohydrin derivative of the formula
in the presence of an acid binder, such as potassium tert-butoxide, sodium methoxide or potassium carbonate, and in the presence of a diluent, such as dimethylformamide, methanol, n-butanol, tetrahydrofuran, methyl-tert-butyl ether or toluene, at temperatures between 20° C. and 60° C.
When carrying out the first step of the process according to the invention, the oxirane of the formula (II) can be employed both in pure form and in a mixture with the chlorohydrin derivative of the formula (VI).
Aromatic hydrocarbons suitable for carrying out the first step of the process according to the invention are preferably benzene, toluene or xylene. Particular preference is given to using toluene in a mixture with acetonitrile. It is very particularly advantageous to use acetonitrile in an amount which is equimolar to that of the oxirane of the formula (II).
Both the first step and the second and third steps of the process according to the invention are generally carried out under atmospheric pressure. However, it is also possible to work under elevated pressure or, if no gaseous components take part in the reaction, even under reduced pressure.
When carrying out the first step of the process according to the invention, the reaction temperatures can be varied within a certain range. In general, the first step is carried out at temperatures between 20° C. and 150° C., preferably between 60° C. and
For carrying out the first step of the process according to the invention, in general from 3 to 6 mol of hydrazine hydrate are employed per mole of oxirane of the formula (II). Specifically, oxirane of the formula (II), if appropriate in a mixture with chlorohydrin of the formula (VI), is reacted with hydrazine hydrate in the presence of toluene and, if appropriate, in the presence of an amount of acetonitrile which is equivalent to that of the oxirane of the formula (II). Work-up is then carried out by customary methods. In general, the reaction mixture is cooled to room temperature and is mixed with water, the organic phase is separated off and washed with water and an equivalent amount or else an excess of dry hydrogen chloride gas is then introduced with cooling. The resulting solid is separated off, washed with toluene, if appropriate in a mixture with a further hydrocarbon, and dried. However, it is also possible to extract the mixture with aqueous hydrochloric acid. The resulting solid is separated off, washed with toluene, if appropriate in a mixture with a further hydrocarbon, and dried.
In a preferred variant, both the first and the second step of the process according to the invention are carried out under an atmosphere of protective gas. Preferred protective gases are argon and nitrogen.
The alkali metal hydroxide used for carrying out the second step of the process according to the invention is preferably lithium hydroxide, sodium hydroxide or potassium hydroxide. Particular preference is given to using sodium hydroxide.
Preferred aromatic hydrocarbons used as diluents for carrying out the second step of the process according to the invention, both in the treatment of the hydrazine hydrochloride derivative of the formula (III) and in the subsequent reaction with formaldehyde and thiocyanate of the formula (IV), are benzene, toluene and xylene. Preferred lower alcohols are methanol, ethanol or propanol. The preferred alkyl alkylcarbo
Hupperts Achim
Jautelat Manfred
Ruther Michael
Bayer Aktiengesellschaft
Harmuth Raymond J.
Henderson Richard E. L.
Morris Patricia L.
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