Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-25
1999-10-12
Morris, Patricia L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D24912
Patent
active
059657421
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the chlorination of a phenyl ring. In particular it discloses a method by which a chlorine atom is placed in the 4-position of the 1-(2-fluorophenyl) group attached to a 4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, an intermediate in the route to prepare the herbicide ethyl .alpha.-2-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2 ,4-triazol-1-yl]-4-fluorobenzenepropanoate (the "Target Herbicide").
Early attempts to achieve an efficient preparation of the Target Herbicide focused on the method taught in U.S. Pat. No. 4,818,275 in Example 1, in which 1-(5-amino-2-fluoro-4-chlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl- 5-oxo-1H-1,2,4-triazole was prepared in an eight-step route from 2-fluoroaniline. In this process the chlorination of the phenyl ring in the 4-position is accomplished before ring closure to the triazole ring by reacting 2-fluoroacetanilide with sulfuryl chloride in p-dioxane. However, it soon became apparent that this eight step route would not be satisfactory, owing to the excessive number of steps to and poor overall yields.
While the efficiency of a multistep process to prepare a complex molecule can be improved by optimizing the yield of each step, even greater efficiency may be achieved by finding a route with fewer steps. It has now been found that the Target Herbicide may be prepared more efficiently by a new route in which there are only six steps. In the first step 2-fluorohydrazine is cyclized to 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole, which is then chlorinated to 1-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole. In the third step the chlorinated product is difluoromethylated, affording 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H -1,2,4-triazole. In an alternative, less preferred method, 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole may first be difluoromethylated and then chlorinated. The third step intermediate is nitrated, yielding 1-(4-chloro-2-fluoro-5-nitrophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl- 5-oxo-1H-1,2,4-triazole, which is reduced to the corresponding 1-(5-amino-4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl- 5-oxo-1H-1,2,4triazole. In the final step the 5-amino derivative is subjected to diazotization/arylation, yielding the Target Herbicide.
The present invention is directed to the preparation of a key intermediate in this process, the product of the second step, 1-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, which is prepared in surprisingly good yield by the chlorination of 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole by the novel process here disclosed and claimed. In the alternative, but less desirably, the chlorination reaction may be carried out on the potassium salt of the starting material.
When the six-step process outlined above, was first considered, it was thought that the chlorination of 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole in good yield would be difficult to accomplish on a large scale. Attempts to chlorinate 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole with sulfuryl chloride, the chlorinating agent used in the analogous chlorination in the eight-step process, were unsatisfactory, giving very low yields. For example, in one experiment the yield, as determined by gas chromatography (GC), was only about 8 area percent after 18 hours. (In the chlorination reactions reported here, area percent does not represent actual yield of product, since it does not allow for by-products not detectable by GC. However, it is an indication of the extent to which the reaction has progressed, i.e., the percent conversion of starting material.) Early attempts at chlorination with elemental chlorine in the laboratory gave actual yields in the order of seventy percent, even with a substantial molar excess of chlorine. The reaction was not deemed suitable for running in the pilot plant.
Surprisingly, it has now be
REFERENCES:
patent: 5468868 (1995-11-01), Halfon et al.
FMC Corporation
Morris Patricia L.
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