Quinolinecarboxylates, synthesis

Fluorine is used for the fluorination of sites x to sulfoxides with simultaneous oxidation of the sulfoxide moiety to a sulfone. The electrophilic fluorine attacks the electron lone pairs of the sulfur atom with a consequent loss of hydrogen fluoride forming an S-fluorosulfoxy alkene. A second molecule of fluorine adds across the newly formed double bond resulting, after hydrolysis, in an a-fluoro sulfone 12.88 This reaction is used for the construction of a fluorocy-clopropane derivative 13 which is essential in the synthesis of one of the most promising members of the quinolinecarboxylic acid antibiotics.89... 

Synthesis of intermidate l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ... 

Another Ru(BINAP)-catalyzed asymmetric hydrogenation that has been performed at manufacturing scale involves the reduction of a functionalized ketone. The reduction of hydroxyacetone catalyzed by [NH2Et2]+[ RuCl(p-tol-BINAP) 2 (li-CI)3 (39) proceeds in 94% ee (Scheme 12.11).46 The chiral diol (40) is incorporated into the synthesis of levofloxacin (41), a quinolinecarboxylic acid that exhibits marked antibacterial activity. Current production of 40 is 40 tons per year by Takasago International Corp.46... 

The present review covers all the available published data on the Pfitzinger reaction beginning from the time of its discovery. The investigated material has been classified on the basis of the structure of the initial ketones separate sections cover the reactions of isatins with dialkyl ketones, keto acids, alkyl aryl ketones, and alkyl hetaryl ketones and also with cyclic ketones. Papers describing the synthesis of 4-quinolinecarboxylic acids by methods related to the Pfitzinger reaction are discussed in a separated section. 

Pfitzinger first reported the synthesis of 2-methyl-4-quinolinecarboxylic acid (6) as a result of the reaction of isatin (7) with acetone in the presence of an aqueous solution of alkali in a paper published in 1886 [ 1 ]. 

In [88] it was shown that the ketones 81 and 82 react with the isatins 10 and 32 only if the Ar does not contain substituents at the o-position to the carbonyl group the products 87 and 88 here are obtained with almost quantitative yields. By replacing the methyl group in the acetophenones by RCH2 [in ketones of type 89] it is possible to obtain 2,3-disubstituted quinolinecarboxylic acids with structure 90, many examples of the synthesis of which are summarized in Table 6 [24, 80, 82, 89, 90-97],... 

The schemes below give the available data on the synthesis of derivatives of 4-quinolinecarboxylic acid 121-123 with substituted indole [110], pyridine [13, 104, 111, 113], or substituted quinoxaline [113] residues at position 2. It should be noted that compounds 122 with a pyridyl substituent were synthesized in the search for substances having antimalarial activity. 

This section reviews the results of investigations on other methods for the synthesis of 4-quinolinecarboxylic acid derivatives, including various 2-quinolone-4-carboxylic acids. The transformations were mostly based on various substituted hydroxyindoles or isatins. 

A well-known method for the synthesis of 4-quinolinecarboxylic acid derivatives involves the aldol condensation of isatins with ketones having an activated CH2 group in the presence of bases, followed by recyclization of the condensation products (or some of their subsequent transformations) to the desired compounds. Thus, the ketols 164 are formed with good yields from the ketones 163 and isatin 7 in the presence of ammonia and are transformed into 2-substituted quinolinecarboxylic acids 165 when heated in an acidic medium [23, 76],... 

One method of preparation is carried out analogously to the synthesis of BAY X 8843 by the regioselective reaction of l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 87 [143,144] with S,S-2,8-diazabicy-clo[4.3.0]nonane 84 to give the betaine 9, which is then converted into the hydrochloride with dilute hydrochloric acid 47 [34,103,139]. In this reaction, the hydrochloride crystallizes out in the form of the monohydrate in an acicular form the monohydrate can, however, also be isolated in the form of prisms under special conditions [145]. 

He, X. C. Wang, B. Bai, D. L. Studies on asymmetric synthesis of huperzine A-1. Palladium-catalyzed asymmetric bicycloannulation of 5,6,7,8-tetrahydro-2-methoxy-6-oxo-5-quinolinecarboxylic esters. Tetrahedron Lett., 1998, 39(5-6) 411 14. 

An example is the synthesis of ethyl a-ethoxalylpropionate (R = CH,) in 70% yield. Ethyl oxalate and ethyl succinate form ethyl a-ethoxalyl-succinate (83%). In a mixed ester condensation, the use of a more reactive ester, such as the phenyl or biphenyl ester, helps to prevent side reactions. Simple heterocyclic esters, namely, ethyl nicotinate and ethyl 8-quinolinecarboxylate, undergo the mixed ester condensation in good yields. The internal condensation of ethyl adipate to give 2-carbethoxycyclopentanone (Dieckmann reaction) is an example of cyclization (81%). ... 

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