Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2001-07-10
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06258959
ABSTRACT:
The invention relates to a process for the preparation of 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole in which an acetoacetic alkyl ester is nitrosated in the 2-position, reduced to give the amino compound and then condensed to give the 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole.
As well as having other possible uses, this compound is a useful intermediate in the synthesis of 2,4-dimethylpyrrole, which is obtained from the dicarboxylic ester in a known manner by hydrolysis and decarboxylation.
The synthesis of 2,4-dimethyl-3,5-bisethoxycarbonylpyrrole is described in Org. Syntheses, Coll. Vol. II, 202-204 (1943). The reducing agent used for the nitroso group is elemental zinc. The yield is at most 64%. Treibs et al. describe the reduction of the nitroso compound using sodium disulfate (III) (sodium dithionite) in Chem. Ber. 90, 79 (1957) in 85% yield.
Both reducing agents have technological disadvantages. Zinc, being a solid, can only be handled on an industrial scale at relatively high cost. To dispose of the zinc-salt-containing solutions which are produced in an environmentally responsible manner, or to process them further incurs considerable costs. The use of sodium dithionite also produces an increased salt content and is undesired from an environmental point of view.
EP-A 170 214 and 078 545 disclose the hydrogenation of nitrosated 1,3-diketones and of nitrosated &bgr;-ketocarboxylate esters respectively with hydrogen in the presence of a palladium catalyst to give the corresponding amines. Isolating a 2-nitrosoacetoacetic ester and then hydrogenating in this manner gives, essentially by condensation of two molecules of the amino compound to the six-membered ring, the 2,5-dimethyl-3,6-bisalkoxycarbonyl dihydropyrazine or its hydrogenation products. Condensation of the amino compound with an unsubstituted acetoacetic ester to give the pyrrole derivative is therefore no longer possible.
It is an object of the present invention to propose a process for the preparation of 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole which produces the product in high yield and in which the by-products which form can be disposed of without problem.
We have found that this object is achieved by a process for the preparation of 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole, in which an acetoacetic alkyl ester is nitrosated to give the 2-nitrosoacetoacetic alkyl ester, the nitroso compound is reduced to give the amine, and the amine, together with unsubstituted acetoacetic alkyl ester, is condensed with ring closure to give the 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole.
The process according to the invention comprises hydrogenating the nitroso compound with hydrogen in the presence of a noble metal catalyst, and condensing the resulting amino compound without isolation in the presence of the corresponding non-nitrosated acetoacetic alkyl ester to give the 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole.
The synthesis proceeds according to the following equations
R is an alkyl group having from 1 to 4 carbon atoms and is preferably methyl of ethyl.
The noble metal catalyst can be a metal from the platinum group, for example palladium or platinum, on a support having a large surface area, for example activated carbon.
Surprisingly, we have now found that the desired pyrrole derivative is obtained directly without isolation of the nitroso compound by hydrogenation of the nitrosated crude solution in the presence of excess acetoacetic alkyl ester.
It is therefore essential for the synthesis that the nitrosation is carried out with a deficit, i.e. from about 10 to 50%, preferably from 20 to 40% of the stochiometric amount, of sodium nitrite. The nitrosation with sodium nitrite and acetic acid in aqueous solution is usually carried out with cooling to a temperature between 0° C. and room temperature, preferably below 15° C.
The catalytic hydrogenation is normally carried out at slightly elevated temperature, for example in the range from above room temperature to 60° C., and under a hydrogen pressure of from 5 to 20 bar. The resulting 2,4-dimethyl-3,5-bisalkoxycarbonylpyrrole precipitates out of the solution and can be filtered off.
REFERENCES:
patent: 078545 (1983-05-01), None
patent: 170214 (1986-02-01), None
Jones et al. (Pyrrole Studies) A Critical Evaluation of the Knorr Synthesis of trifluoromethylpyrroles Synth. Commun. (1984) 14 (6), pp. 575-578.*
Treibs et al.,Chem. Ber., 90, 1957, 79-90.
Org. Synth. Coll., vol. II, 1943, 202-204.
Ebel Klaus
Frede Markus
Groning Carsten
Kemper Reinhard
BASF - Aktiengesellschaft
Higel Floyd D.
Keil & Weinkauf
Sackey Ebenezer
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