NO174255B - New oxirane compounds useful for the preparation of fungicidal triazole compounds - Google Patents

Description

This invention relates to new oxirane compounds which are useful as intermediates for the production of certain fungicidal triazole compounds.

Norwegian patent document no. (patent application no. 902561) describes a class of triazole compounds which have been shown to be useful for combating fungal diseases in agriculture. There are compounds with the general formula:

where

E is a bond or an oxygen atom,

A is N(C<H>3)2/ OH, naphthyl,

or phenyl which is optionally

substituted with a total of 1-2 substituents each of which, independently of the others, is selected from halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl and S(0)mR<5>, since at most one substituent can be chosen among

the last two,

B is alkyl with 1-8 carbon atoms, biphenyl, phenyl which is optionally substituted with one or two substituents each of which, independently of the others, is selected from halogen, alkyl with 1-4 carbon atoms, trifluoromethyl and alkoxy with 1-4 carbon atoms; or a heterocyclic group selected from 2-thienyl, 3-thienyl and 4-pyridyl optionally substituted with one or two halogen groups,

Q is hydrogen, halogen, SR<5>, S(0)mR<5>CN or SH,

n is 0 or 1 with the proviso that when A is

N(CH 3 ) 2

or OH, n must be other than 0,

m in each case is 0, 1 or 2,

R and R<1> independently of each other are hydrogen, alkyl of 1-4

carbon atoms or phenyl,

R<2> is hydrogen, allyl, alkyl with 1-4 carbon atoms

R3 and R<4> independently of each other are hydrogen or fluorine,

R<5> is alkyl with 1-4 carbon atoms,

R<7> is alkyl with 1-4 carbon atoms and

R<8> and R<9> independently of each other are hydrogen or CH3,

and salts thereof suitable for agricultural purposes. The compounds can exist in the form of the (S)-isomer or in the form of the racemic mixture.

The same class of triazole compounds is also useful for the treatment of fungal infections in humans and mammals. As far as this medical use of the triazole compounds is concerned, the production of these compounds by an analogous method is protected through Norwegian patent no. 168,174.

A number of the triazole compounds described in the above-mentioned patent application no. 902561 and patent document no. 168,174 can be conveniently prepared from the new oxirane compounds according to the present invention, which have the general formula:

where

A is phenyl which is optionally substituted with 1 or 2

substituents which are each, independently of the others, selected from halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl and S(0)nR<5>, where m is 0, 1 or 2, and R <5> is alkyl with 1-4 carbon atoms, as there can be at most one substituent

selected from the last two,

B has the same meaning as A, except that B cannot

be S(0)mR<5>,

n is 0 or 1,

R and R<1> independently of each other are hydrogen, alkyl of 1-4

carbon atoms or phenyl, and

R<3> and R<4> are hydrogen,

with the proviso that A and B are not both phenyl when R and R<1> are hydrogen and n is 0.

The oxiranes of formula (II) can be prepared using one or the other of the two methods shown in Reaction Core 1 below. According to the first method, vinyl organometallic reagents, e.g. vinyl Grignard reagents, of formula (III) with halogen ketones of formula (IV) in the presence of ether solvents, such as THF or diethyl ether, at a temperature in the range from -90°C to 60°C, preferably in the range from - 10°C to 50°C, for 0.5-24 hours. Depending on the reaction conditions and the significance of X in the halogen ketone starting material (IV), the product can be an oxirane (II), a halohydrin (Ila) or a mixture of (II) and (Ila). The halohydrins (Ila) can be transferred to oxiranes (II) by treatment with a base, e.g. potassium hydride (KH), in a solvent such as THF.

According to the second method, keto-oxiranes of formula (V) are defined by e.g. Wittig reagents, giving epoxyolefins of formula (II).

Unsaturated ketones of formula (VII) can be transferred to epoxyolefins (II) by treatment with dimethylsulfonium methylide. The enones (VII) can be prepared by treating ketones of formula (VI) with carbonyl compounds and suitable catalysts (Reaction Core 2).

Unsaturated ketones of formula (VIII) can be converted to epoxy ketones (V) using basic hydrogen peroxide. definition of (V), as described above, gives epoxyolefins (II) (Reaction Core 3).

The vinyl organometallic compounds of formula (III) are prepared using standard procedures from the corresponding chlorides, bromides or iodides. The haloolefins, the haloketones of formula (IV), the ketooxiranes of formula (V) and the ketones of formula (VI) are known compounds, or they can be prepared using methods that will be known to a person skilled in the art.

As already mentioned, the new oxirane compounds are useful as intermediates for the production of triazole compounds with fungicidal action. More specifically, they can be used for the preparation of such triazole compounds with the general formula (I) indicated above, where E is a bond, R<2> and Q are hydrogen, and A, B, R, R1, R<3>, R <4> and n is as indicated in connection with formula II above, can be prepared by reacting an oxirane compound of formula II with triazole or an alkali metal salt thereof (preferably the Na salt or the K salt) in a suitable solvent (Reaction core 4 ). where M = H or an alkali metal.

When triazole is used, an acid acceptor, such as potassium carbonate, sodium methoxide or sodium hydride, is added to the reaction mixture. Suitable inert solvents include polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and ether solvents such as tetrahydrofuran (THF). Also non-polar solvents, such as toluene, can be used if a phase transfer catalyst, such as tetrabutylammonium bromide, is added. The reaction is carried out at a temperature in the range from 10 to 150°C, preferably in the range from 50 to 120°C, for 0.25-24 hours. It should be noted that varying amounts of the 4H-1,2,4-triazol-4-yl isomers of formula (I) can be formed by the reaction described above. The isomers can, if desired, be separated from each other, using standard separation methods, e.g. chromatograph i.

For a more detailed explanation of the preparation of triazole compounds from the oxirane compounds of formula II, reference is made to Norwegian patent document no. 168,174 and Norwegian patent document no. (patent application no. 902561).

Below is illustrated the preparation of the new oxirane

connections.

Example 1

Preparation of 2-(4-fluorophenyl)-2-[1-(4-fluorophenyl)-ethenyl]-oxirane by Grignard addition to an α-halo ketone.

A dissolved -ation of 5.2 g (0.030 mol) of 2-chloro-4'-fluoroacetophenone in 10 ml of THF. The solution was stirred for 2 hours at 25°C. 10 ml of saturated aqueous NH 4 Cl was added, and the aqueous layer was extracted with Et 2 O/hexane in the ratio of 1:1. The combined organic layers were washed with brine, dried over MgSO 4 and evaporated to give 10.2 g of an amber oil. NMR analysis (CDCl 3 ) showed that the desired oxirane constituted the main product: 6 3.1; 3.3 (two doublets, epoxide protons; 5.5; 5.8 (two singlets, vinyl protons). The material was sufficiently pure to be used as an intermediate in the preparation of triazole compounds.

Example 2

Preparation of 2-(4-fluorophenyl)-2-[1-(4-fluorophenyl)-ethenyl]-oxirane by olefination of 2-(4-fluorophenyl)-2-(4-fluorobenzoyl)-oxirane.

To a solution of 4.3 g (0.012 mol) of methyltriphenylphosphonium bromide in 15 ml of THF cooled to -70°C was added 8.4 ml (0.013 mol) of 1.55 M n-butyllithium over the course of 3 minutes, the temperature was kept lower than -55°C. The resulting yellow slurry was allowed to warm to 0°C over 10 minutes and was then treated with 2.6 g (0.010 mol) of 2-(4-fluorophenyl)-2-(4-fluorobenzoyl)-oxirane in 5 mL of THF. The light brown slurry was stirred for 6 hours at 25°C. After standard work-up, 3.4 g of impure product was obtained, which was flash chromatographed (Et 2 O). 1.7 g of the desired product was thereby obtained, which was sufficiently pure to be used as an intermediate in the preparation of triazo-

Claims (1)

lyl compounds. NMR (CDCl 3 ) δ 3.1 (d); 3.3(d); 5.5 (s); 5.8 (s). Oxirane compounds, characterized in that they have the general formula: where A is phenyl which is optionally substituted with 1 or 2 substituents which are each, independently of the others, selected from halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl and S(0)mR<5>, where m is 0, 1 or 2, and R <5> is alkyl with 1-4 carbon atoms, since at most one substituent can be chosen from the last two, B has the same meaning as A, except that B cannot be S(0)mR<5>, n is 0 or 1, R and R<1> independently of each other are hydrogen, alkyl of 1-4 carbon atoms or phenyl, and R<3> and R<4> are hydrogen, with the proviso that A and B are not both phenyl when R and R<1> are hydrogen and n is 0.