Method for the production of 1-substituted 5-hydroxypyrazoles

Details Method for the production of 1-substituted 5-hydroxypyrazoles Method for the production of 1-substituted 5-hydroxypyrazoles

2001-05-03

2001-12-11

Ramsuer, Robert W. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S370400

Reexamination Certificate

active

06329530

ABSTRACT:

This application is a 371 of PCT/EP 99/08515 filed November 1999.
The present invention relates to a process for preparing 1-substituted 5-hydroxypyrazoles of the formula I
in which R
1
is C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
3
-C
6
-cycloalkyl or C
1
-C
4
-alkoxy, where these groups may be substituted by halogen, C
1
-C
4
-alkoxy, phenoxy, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylthiocarbonyl or by a cyclic ring system having 3-14 ring atoms.
1-Substituted 5-hydroxypyrazoles are used as intermediates for preparing pharmaceutics and crop protection agents, in particular herbicides, and are disclosed, for example, in WO 96/26206, WO 97/23135, WO 97/19087, U.S. Pat. No. 5,631,210, WO 97/12885, WO 97/08164, ZA 9510980, WO 97/01550, WO 96/31507, WO 96/30368 and WO 96/25412.
Processes for their preparation are therefore of interest.
To date, the following syntheses are known as processes for preparing lower 1-alkyl-5-hydroxypyrazoles:
1. a preparation where 2-methyl-1-(p-toluenesulfonyl)-3-pyrazolidone or 2-methyl-1-acetylpyrazolidone is hydrolyzed (J. Prakt. Chem. 313 (1971), 115-128 and J. Prakt. Chem. 313 (1971), 1118-1124).
2. a variant in which alkyl 5-hydroxy-1-alkylpyrazole-4-carboxylate is synthesized by cyclization of a dialkyl alkoxymethylenemalonate with lower alkylhydrazines, an aqueous solution of mineral acid is subsequently added to this reaction product and hydrolysis and decarboxylation are carried out simultaneously (see JP 61257974, JP 60051175, JP 58174369, JP 58140073 and JP 58140074 and also U.S. Pat. No. 4,643,757).
3. a synthesis in which ethyl propiolate is reacted with methylhydrazine to give 5-hydroxy-1-methylpyrazole (Annalen 686 (1965), 134-144).
4. a synthesis route in which 3-hydrazinopropionic esters, which are formed by addition of hydrazine to acrylic esters, are reacted with aldehydes to give the corresponding hydrazones, which are subsequently cyclized (see JP 06166666, JP 61229852 and JP 61268659 and also EP 240001).
5. a synthesis variant in which a 5-hydroxy-1-methylpyrazole-3-carboxylic acid is cleaved thermally (Chem. Ber. 109 (1976), 261).
6. a process in which 3-alkoxyacrylic esters are reacted with methylhydrazine and ethylhydrazine to give 1-methyl-5-hydroxypyrazole and 1-ethyl-5-hydroxypyrazole, respectively (see JP 189 271/86, EP-A-837 058).
The process of the 1st synthesis route mentioned above entails several steps and is complicated. Introduction and removal of a protecting group is awkward, means an additional number of steps and reduces the yield.
The 2nd preparation possibility entails several steps; moreover, in addition to the 1-alkyl-5-hydroxypyrazoles, the regioisomers of the target compound are formed at the same time, and they have to be separated off from the target compounds in a complicated procedure. Furthermore, the synthesis is associated with a poor C yield since a C4 building block is employed from which, at the end of the process, a carbon atom has to be cleaved off again.
In the 3rd synthesis variant, which describes only the preparation of 1-methyl-5-hydroxypyrazole, it is unavoidable to employ highly hyperstoichiometric amounts of methylhydrazine, thus rendering the process uneconomical. In addition, the isomer 3-hydroxy-1-methylpyrazole, which is also formed, has to be separated off from 1-methyl-5-hydroxypyrazole in a complicated procedure during purification. Furthermore, owing to the high cost of propiolic ester, this process is uneconomical.
The process of the 4th alternative entails several steps and is complicated. The last step of the complex process affords only poor yields and a large number of byproducts.
The thermal cleavage of the 5th synthesis route requires a high temperature, and the yield of 6% is very low.
The 6th synthesis route, which describes only the preparation of 1-methyl-5-hydroxypyrazole, uses 3-alkoxyacrylic esters which are difficult to prepare and are expensive. The preparation of 3-alkoxyacrylic esters is carried out by reaction of methanol with expensive propiolic esters (Tetrahedron Lett. 24 (1983), 5209, J. Org. Chem. 45 (1980), 48, Chem. Ber. 99 (1966), 450, Chem. Lett. 9 (1996), 727-728), by reacting &agr;,&agr;-dichlorodiethyl ether, which is expensive and difficult to synthesize, with bromoacetic esters (Zh. Org. Khim. 22 (1986), 738), by reaction of bromoacetic esters with trialkyl formates (Bull. Soc. Chim. France N 1-2 (1983), 41-45) and by elimination of methanol from 3,3-dialkoxypropionic esters (DE 3701113) (obtainable by reacting the expensive methyl propiolate with methanol (J. Org. Chem. 41 (1976), 3765)), by reacting 3-N-acetyl-N-alkyl-3-methoxypropionic esters with methanol (J. Org. Chem. 50 (1985), 4157-4160, JP
60-156643
), by reacting acrylic esters with alkylamines and acetic anhydride (J. Org. Chem. 50 (1985), 4157-4160), by reacting ketene with trialkyl orthoformate (DK 158462), by palladium- and simultaneously copper-catalyzed reaction of acrylic esters with methanol (DE 4100178.8), by reaction of trichloroacetyl chloride with vinyl ethyl ether (Synthesis 4 (1988), 274), by reacting &agr;,&agr;,&agr;-trichloro-&bgr;-methoxybuten-2-one with methanol (Synthesis 4 (1988), 274) and by reacting the sodium salts of 3-hydroxyacrylic esters with alcohols (DB 3641605). The fact that the 3-alkoxyacrylic esters are difficult to obtain thus renders the synthesis according to 6. uneconomical. Moreover, JP 189 271/86 only describes the isolation of the 5-hydroxy-1-methylpyrazole as the hydrochloride, but no details are given for the isolation and purification of the free base. Efforts to apply the reaction conditions described in JP 189 271/86 and to isolate the free base result in only very 35 poor yields which are uneconomical for a preparation of hydroxypyrazoles on an industrial scale. EP-A 837 058 only discloses the preparation of 5-hydroxy-1-ethylpyrazole.
Consequently, these synthesis routes are not satisfactory as economical and efficient processes for preparing 1-substituted-5-hydroxypyrazoles. This is particularly true for the industrial preparation of the 1-substituted 5-hydroxypyrazoles in large amounts.
It is an object of the present invention to provide an alternative preparation process for preparing 1-substituted 5-hydroxypyrazoles which does not have the abovementioned disadvantages of the prior art processes.
We have found that this object is achieved by the process according to the invention for preparing 1-substituted 5-hydroxypyrazoles of the formula I
in which R
1
is C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
3
-C
6
-cycloalkyl or C
1
-C
4
-alkoxy, where these groups may be substituted by halogen, C
1
-C
4
-alkoxy, phenoxy, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylthiocarbonyl or by a cyclic ring system having 3-14 ring atoms, by
a) reacting an alkyl vinyl ether of the formula III
 in which R
2
is C
1
-C
6
-alkyl or C
3
-C
6
-cycloalkyl with phosgene IVa, “diphosgene” IVb or “triphosgene” IVc
 to give acyl chlorides of the formula V
b) converting these by elimination of hydrogen chloride into the corresponding 3-alkoxyacryloyl chloride of the formula VI
 and
c) reacting this with hydrazines of the formula VII
 in which R
1
is as defined above to give 5-hydroxypyrazoles of the formula I.
Preferred embodiments of the process according to the invention are shown in the subclaims and in the description below.
Step a):
The process according to the invention starts with alkyl vinyl ethers of the formula III which are initially reacted at from −78° C. to 100° C., preferably from −10° C. to 80° C., in particular from 20° C. to 60° C., with an acyl chloride of the formula IVa, IVb or IVc, to give the corresponding acyl chloride of the formula V.
The reaction can be carried out without using solvents or diluents if the reaction partners are liquid at the reaction temperature. However, it is also possible to carry out the reaction in an aprotic solvent or diluent.
Suitable solvents or diluents are, for example, aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petrole

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