Pyrazoles Knorr synthesis

Hence the investigations made so far were aimed more at showing the capability of an automated micro-reactor system, using the Knorr synthesis as a model reaction however, to a certain extent, information on this synthesis itself was also gained (see Section 4.9.6.5) [20]. The Knorr synthesis of pyrazoles chosen is of industrial interest since by this route compounds with a wide range of biological activity can be produced. 

The standard synthesis for 2,4-dihydro-3//-pyrazol-3-ones is the cyclocondensation of hydrazine, alkyl-or arylhydrazines with y ketocarboxylic esters Knorr synthesis, 1883), e.g. ... 

The first synthetic heterocyclic pharmaceutical seems to be antipyrine. Antipyrine is a pyrazole analgesic and an antipyretic, like aspirin. Ludwig Knorr used Emil Fischer s discoveiy of phenylhy-drazine to synthesize antipyrine, and in 1883, Knorr was granted a patent on the synthesis. In 1885, one year after market introduction, almost 6 metric tons were sold, and in 1899, sales had grown to almost 800 metric tons. More recently, antipyrine has been used in a solution with benzocaine to relieve ear pain and swelling caused by middle ear infections. Knorr s synthesis is shown in Scheme 8.1. Details of the Knorr synthesis are discussed in Chapter 4. 

The Hantzsch synthesis of 2-aminothiazoles [33] and the Knorr synthesis of pyrazoles [34], both of which involve addition-elimination sequences, have also been carried out in microflow reactors. 

The acetoacetyl derivatives are obtained by the reaction of the amine with diketene . In the case of amino acid ester hydrochlorides the presence of one equivalent of sodium methoxide or of a tertiary base is necessary. The group is removed by applying the conditions of the Knorr synthesis of pyrazol derivatives from various /3-keto esters and their derivatives . The protecting group is removed in acetic acid by using an equimolar amount of phenylhydrazine (reaction 3). 

The Knorr pyrazole synthesis has been extensively utilized in the preparation of a number of pyrazoles as metal chelators, photographic dyes, herbicides, and biologically active... 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal-Knorr pyrrole synthesis (page 333). 

Sakya, S. M. Knorr Pyrazole Synthesis In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J. Corey, E. J. Wiley Sons Hoboken, NJ, 2005, 292—300. (Review). 

Reaction between 1,4-ketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 331). 

Condensation of 1,3-diketones with hydrazines or hydroxyamines was conducted in a microflow system to give pyrazoles and isoxazoles in good yields [22]. High-throughput synthesis of pyrrole by the Paal-Knorr condensation of ethanolamine and acetonylacetone was achieved using the CPC CYTOS Lab System [23], The running of the system for 165 min resulted in 714 g of the pyrrole (Scheme 4.14). 

Polshettiwar V, Varma RS (2010) Nano-organocatalyst magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Tetrahedron 66 1091-1097... 

KNORR Pyrazole synlheais 206 KNORR Quinoline synthesis 206 Knorr 209,284 Knowtes 180... 

Only a very few 4,4 -bis(2-pyrazolin-5-ones) linked by a double bond have been prepared. The parent compound of this series, 4-(3-methyl -1 -phenyl - 5 - oxo - 2 - pyrazolin - 4-ylidene)-3-methyl-l-phenyl-2-pyrazolin-5-one (XXII-D), is known as pyrazole blue.323,807,809,816, 1090,1091 was so nameci by Knorr because of its great resemblance to indigo blue. All these compounds are strongly colored. The usual synthesis is by ferric chloride oxidation of monomeric 2-pyrazolin-5-ones (eq. 61)296,809 or by oxidation of the corresponding bis compounds... 

The Knorr pyrazole synthesis with 1,1,3,3-tetraethoxypropane and amin-oguanidine readily gave praxadine (292) which is an anti-inflammatory and analgesic agent [359, 360]. 

Presumably, the Knorr pyrazole synthesis begins with formation of the hydrazone with the more active one of the two carbonyls. In reality, a mixture of the two regioisomers would arise. The hydrazones then cyclize to afford a mixture of regioismeric pyrazoles. 

The Knorr pyrazole synthesis has bestowed a futile ground for medicinal chemists to practice their craft in drug discovery. The most conspicuous example is the synthesis of celecoxib (Celebrex), a selective COX-2 inhibitor prescribed as an analgesic. As shown below, the substrate dione was prepared by the Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of the dione and 4-sulfonamidophenyl-hydrazine hydrochloride then delivered celecoxib. ... 

Another important application of the Knorr pyrazole synthesis is the preparation of rimonabant. 

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