Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-08-27
2003-07-29
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C548S366100
Reexamination Certificate
active
06600071
ABSTRACT:
The present invention relates to a process for preparing substituted hydroxypyrazoles, and also to novel intermediates.
Lower 1-alkyl-5-hydroxypyrazoles are known compounds which are used as intermediates for active compounds in agrochemicals, in particular for preparing herbicides (see WO 97/23135, WO 97/19087, U.S. Pat. No. 5,631,210, WO 97/12885, WO 97/08164, ZA 9510980A, WO 97/01550, WO 96/31507, WO 96/30368, WO 96/25412).
As processes for preparing lower 1-alkyl-5-hydroxypyrazoles the following syntheses are known:
1. A preparation in which 2-methyl-1-(p-toluenesulfonyl)-3-pyrazolidone or 2-methyl-1-acetylpyrazolidone is hydrolyzed (J. Prakt. Chem. 1971, 313, 115-128 and J. Prakt. Chem. 1971, 313, 1118-1124);
2. A variant in which an alkyl ester of 5-hydroxy-l-alkylpyrazole-4-carboxylic acid is built up by cyclizing a dialkyl alkoxymethylenemalonate using lower alkylhydrazines, subsequently adding an aqueous mineral acid solution to this reaction product and carrying out the hydrolysis and decarboxylation simultaneously (see JP 61257974, JP 60051175, JP 58174369, JP 58140073 and JP 58140074 and also U.S. Pat. No. 4643757);
3. A synthesis in which ethyl propiolate is reacted with methylhydrazine to form 5-hydroxy-l-methylpyrazole (Annalen 1965, 686, 134-144);
4. A synthetic route in which,3-hydrazinopropionic esters formed by addition of hydrazine onto acrylic esters are reacted with aldehydes to give the corresponding hydrazones and are subsequently cyclized (see JP 06166666, JP 61229852 and JP 61268659 and also EP 240001);
5. A synthetic variant in which 5-hydroxy-l-methylpyrazole-3-carboxylic acid is dissociated thermally (Chem. Ber. 1976, 109, p. 261).;
6. A process in which 3-alkoxyacrylic esters are reacted with methylhydrazine to give 1-methyl-5-hydroxypyrazole (see JP 189 271/86).
The above-described syntheses have various disadvantages:
In the 1st synthetic route mentioned above, the process has a plurality of stages and is complicated. The insertion and removal of a protective group is cumbersome, results in additional steps and reduces the yield.
The 2nd method of preparation has a plurality of stages and, in addition, forms not only the l-alkyl-5-hydroxypyrazoles but at the same time also the regioisomeric l-alkyl-3-hydroxypyrazoles which have to be separated from the target compounds at some cost. Furthermore, the synthesis gives a poor C yield since use is made of a C4 building block from which a C atom has to be removed again at the end of the process.
In the 3rd synthetic variant, which describes only the preparation of l-methyl-5-hydroxypyrazole, the use of amounts of methylhydrazine far above the stoichiometric amount is indispensable, thus making the process uneconomical. In addition, the 3-hydroxy-l-methylpyrazole which is likewise formed has to be removed at some cost from the l-methyl-5-hydroxypyrazole during the purification. Furthermore, this process is uneconomical because of the high price of the propiolic ester.
In the 4th alternative, the process has a plurality of stages and is complicated. The last step of the complicated process gives only poor yields and many by-products.
In the 5th synthetic route, a high temperature is necessary for the thermal dissociation and the yield of 6% is very low.
In the 6th method of synthesis, which describes only the preparation of l-methyl-5-hydroxypyrazole, use is made of 3-alkoxyacrylic esters which are cumbersome to prepare and expensive. 3-alkoxyacrylic esters are prepared by reaction of methanol with expensive propiolic esters (Tetrahedron Lett. 1983, 24, 5209, J. Org. Chem. 1980, 45, 48, Chem. Ber. 1966, 99, 450, Chem. Lett. 1996, 9, 727-728), by reaction of expensive and difficult-to-synthesize &agr;,&agr;-dichloro(diethyl ether) with bromoacetic esters (Zh. Org. Khim. 1986, 22, 738), by reaction of bromoacetic esters with trialkyl formates (Bull. Soc. Chim. France 1983, N 1-2, 41-45) and by elimination of methanol from 3,3-dialkoxypropionic esters (DE 3701113) (obtainable by reaction of the expensive methyl propiolate with methanol (J. Org. Chem. 1976, 41, 3765), by reaction of 3-N-acetyl-N-alkyl-3-methoxypropionic esters with methanol (J. Org. Chem. 1985, 50, 4157-4160, JP 60-156643), by reaction of acrylic esters with alkylamines and acetic anhydride (J. Org. Chem. 1985, 50, 4157-4160), by reaction of 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 1988, 4, 274), by reaction of &agr;,&agr;,&agr;-trichloro-B-methoxybuten-2-one with methanol (Synthesis 1988,4, 274) and by reaction of the sodium salts of 3-hydroxyacrylic esters with alcohols (DE 3641605)). The poor accessibility of the 3-alkoxyacrylic esters therefore makes the synthesis by the 6th route uneconomical. Furthermore, JP 189 271/86 describes the isolation of 5-hydroxy-1-methylpyrazole as hydrochloride but gives no information on the isolation and purification of the free base. If an attempt is made to employ the reaction conditions described in JP 189 271/86 and to isolate the free base, only very small yields which are uneconomical for an industrial-scale preparation of hydroxypyrazoles are obtained.
Consequently, these synthetic routes cannot be considered to be economical and efficient processes for preparing 1-alkyl-5-hydroxypyrazoles. This applies particularly to the industrial preparation of 1-alkyl-5-hydroxypyrazoles in large quantities.
It is an object of the present invention to provide an alternative process for preparing 1-alkyl-5-hydroxypyrazoles which does not have the abovementioned disadvantages of the previously known preparative methods.
We have found that this object is achieved by the process of the present invention.
The present invention provides a process for preparing compounds of the formula I
in which R
1
is hydrogen, an aliphatic group having 1-8 carbon atoms, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylthiocarbonyl or a cyclic ring system having 3-14 ring atoms, and R
2
is hydrogen, an aliphatic group having 1-8 carbon atoms, or R
1
and R
2
together with the carbon atom to which they are bound form a cyclic or bicyclic ring system having 3-14 ring atoms, comprising the preparation of compounds of the formula II
in which R
3
and R
4
are readily detachable groups and R
1
and R
2
are as defined above, as starting materials or intermediates and cyclization of these under suitable reaction conditions to give compounds of the formula I.
The process of the present invention makes it possible to prepare compounds of the formula I in a high yield. The cyclization proceeds in yields of at least 80%, in the case of less bulky radicals R at least 90%. Less bulky radicals are, in particular, those in which the group —CHR
1
R
2
is a group having 1-6 carbon atoms. Another advantage is that diacylhydrazines of the formula II can be converted into the 1-substituted 5-hydroxypyrazoles of the formula I under particularly convenient conditions, for example short reaction times. The cyclization is preferably catalyzed by acids or bases. A further advantage is that the starting compounds required for the synthesis are readily available and inexpensive. Additional advantages are that the compounds of the formula II are obtained in high purity and that the hydroxypyrazoles of the formula I can be obtained in free form, i.e. essentially free of acid addition salts. In the previously known syntheses, the hydroxypyrazoles were virtually always formed as their acid addition salts, e.g. hydrochlorides, which had to be converted into the free hydroxypyrazoles in an additional work-up step. In the synthesis according to the present invention, on the other hand, the hydroxypyrazoles are obtained directly in the form of the free base which is essentially free of acid addition salts. A further advantage of the process of the present invention is that the 3-hydroxypyrazoles are obtained regioselectively. The proportion of 3-hydroxypyrazoles is low. The yield of 5-
Götz Norbert
Götz Roland
Rack Michael
BASF - Aktiengesellschaft
Ramsuer Robert W.
LandOfFree
Method for producing 1-substituted 5-hydroxpyrazoles does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing 1-substituted 5-hydroxpyrazoles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing 1-substituted 5-hydroxpyrazoles will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3068992