Process for the preparation of strobilurin intermediates

Details Process for the preparation of strobilurin intermediates Process for the preparation of strobilurin intermediates

2001-08-13

2003-12-16

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S248000, C564S256000, C564S259000, C564S265000

Reexamination Certificate

active

06664422

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel improved process of preparing certain intermediates for highly active fungicides from the class of the strobilurins. Another aspect of the invention are the novel intermediates per se which have been prepared for the process of this invention.
SUMMARY OF THE INVENTION
The fungicidal strobilurins have previously been described in e.g. WO-A-95/18789 or the later WO-A-95/21153 and WO-A-95/21154. The processes disclosed therein are typical laboratory routes which for large scale production are not in all steps suitable. The present invention now provides a new improved process designed for large scale industrial production which allows the production of strobilurins and its key intermediates in an industrial production process.
DETAILED DESCRIPTION
The fungicidal strobilurins have the general formula I
wherein
R
1
is hydrogen, fluoro or chloro,
R
2
is methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro or bromo, and
X is NH or oxygen.
The known individual strobilurins of formula I are listed in the following table
TABLE 1
Comp. No.
R
1
R
2
X
01
H
Cl
O
02
H
Cl
NH
03
H
F
O
04
H
F
NH
05
F
H
O
06
F
H
NH
07
Cl
H
O
08
Cl
H
NH
09
Cl
Cl
O
10
Cl
Cl
NH
11
F
F
O
12
F
F
NH
13
Cl
F
O
14
Cl
F
NH
15
F
Cl
O
16
F
Cl
NH
17
H
Br
O
18
H
Br
NH
19
H
CN
O
20
H
CN
NH
21
H
CH
3
O
22
H
CH
3
NH
23
H
OCH
3
O
24
H
OCH
3
NH
25
H
C
2
H
5
O
26
H
C
2
H
5
NH
27
H
CF
3
O
28
H
CF
3
NH
29
H
OC
2
H
5
O
30
H
OC
2
H
5
NH
The fungicidal strobilurins of formula I are synthesized by a conventional etherification step from the oxime compound of formula II
wherein R
1
and R
2
are as defined for formula I in the presence of a base with the coupling component III
wherein X is as defined for formula I and Hal is halogen, preferably chlorine or bromine.
The coupling components III and most of the members of the oximes of formula II are known.
According to the process of this invention the oximes of formula II are obtained by the process comprising reacting a propiophenone of formula IV
wherein R
1
and R
2
are as defined for the compounds of formula I in the presence of hydrogen chloride with an organic nitrite, e.g. alkyl nitrite such as iso- or n-pentyl nitrite, and converting the resulting ketooxime of formula V
wherein R
1
and R
2
are as defined for the compounds of formula I into the compound of formula II by reacting it with an aqueous solution of O-methyl-hydroxylamine-hydrochloride, and subsequent isomerisation of the (E,E/E,Z)-mixture of compound II into predominantly the (E/E)-form thereof.
The two-step process of the invention (IV→V→II) may be carried out in large industrial scale vessels. The first step (IV→V) is advantageously conducted in an inert organic solvent, e.g. tetrahydrofurane, dioxane, toluene, xylenes or a cyclic hydrocarbon like cyclohexane, methylcyclohexane, or iso or n-pentanol, etc. at temperatures between −20° C. and +60° C., with −5° C. to +40° C., and especially +25° C. to +40° C., and even more +10° C. to +40° C. being preferred. In the second step the keto group is replaced by the methoximino function in a single step reaction. The resulting intermediate may be isomerised in situ in the work-up solution and it may be isolated therefrom, if desired. However, for the large scale production process it is even more advantageous to use the work-up solution directly for the coupling of intermediate II with the intermediate III.
The product of formula II is preferably used in the from of the (E,E)-isomer for further coupling with the compound of formula III for producing the fungicidal stobilurins.
Alternatively, the compounds of formula II may be obtained by diazotizing an aniline of formula VI
and reacting the resulting diazonium salt with methylglyoxal-1-oxime of formula VII
and methylating the resulting ketooxime of formula VIII
with an methylating agent and reacting the resulting O-methyl ketooxime of formula IX
with hydroxylamine.
Alternatively, in a variant the compounds of formula VII may be obtained by diazotizing an aniline of the formula VI and reacting the resulting diazonium salt with isopropenylacetate of formula X
and reacting the resulting ketone of formula XI
with an organic nitrite in the presence of hydrogene chloride.
The diazotization reaction is carried out in an organic solvent with an organic nitrite, e.g. an alkyl nitrite as isoamyl nitrite, or an aryl nitrite, as phenyl nitrte; or, more preferably, in aqueous solution with nitrous acid or a salt thereof, in presence of an acid. Preferred nitrites are sodium nitrite, potassium nitrite, magnesium nitrite, particularly preferred is sodium nitrite. Preferred acids are hydrochloric acid, sulfuric acid and nitrosulfuric acid.
Advantageous is a temperature of −10° C. to +30° C. and a pH 0-3.
The diazonium compound is preferably reacted in the presence of CuCl
2
or CuSO
4
at −10° C. to +40° C., more preferably −10° C. to +15° C., and at pH 2-7, more preferably at pH 3-5. The amount of the copper salt is 1 to 20 mol %, more preferably 3 to 6 mol %, in relation to the aniline of formula VI.
Methylation of the ketooxime of formula VII is carried out with a methylating agent such as methyl iodide, dimethylsulfate or diazomethane in presence of a base, e.g. potassium carbonate or sodium hydride in a suitable solvent at suitable reaction temperatures as described by H. S. Anker and H. T. Clarke in Organic Synthesis, Coll. Vol. 3,172.
The introduction of the oxime function into the intermediate of formula XI is preferably carried out in an inert organic solvent, e.g. tetrahydrofurane, dioxane, toluene, xylenes or a cyclic hydrocarbon like cyclohexane, methylcyclohexane, or iso- or n-pentanol, etc. at temperatures between −20° C. and +60° C., with −5° C. to +40° C., and especially +25° C. to 40° C. and even more +10° C. to +40° C. in the presence of e.g. hydrogen chloride by treatment with an organic nitrite, e.g. an alkyl nitrite as iso- or n-pentyl nitrite, or an aryl nitrite, as phenyl nitrite
According to the process of the invention the following intermediates of formula II may be obtained with high yields. Novel intermediates of formula II constitute another feature of the present invention.
TABLE 2
Intermediates of formula II
Comp. No.
R
1
R
2
01
H
Cl
02
H
F
03
F
H
04
Cl
H
05
Cl
Cl
06
F
F
07
Cl
F
08
F
Cl
09
H
Br
10
H
CN
11
F
CH
3
12
H
OCH
3
13
H
C
2
H
5
14
H
CF
3
15
H
OC
2
H
5


REFERENCES:
patent: 5889059 (1999-03-01), Bayer et al.
patent: 5981581 (1999-11-01), Bayer et al.
patent: 6100263 (2000-08-01), Bayer et al.
patent: 6187812 (2001-02-01), Bayer et al.
patent: 19 719 054 (1998-11-01), None
patent: 95/18789 (1995-07-01), None
patent: 95/21153 (1995-08-01), None
patent: 96/11183 (1996-04-01), None
patent: 97/20808 (1997-06-01), None
Organic Syntheses Coll., vol. 3, pp. 172-174, (date unavailable) submitted by H.S. Anker & H.T. Clarke, Carboxymethoxylamine Hemihydrochloride.

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