3-Oxo carboxylic acid derivatives

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the (3-hydroxy carboxylic acid derivative. If one starts with an activated add derivative, the fonnation of a (3-lactone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138], Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to (3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139],... 

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

Derivatives of 1 -ethy l-7-alkylamino-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 137 have been reduced to corresponding diamines 138 and afterwards converted exclusively to linearly annelated imidazo[4,5-g]quinoline-7-carboxylic acid derivatives 139 (Scheme 43) (88KFZ33). 

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

Reaction of 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l, 2,3- e]-1,4-ben-zothiazine-6-carboxylic acid and its ethyl ester with B(OH)3 in AC2O in the presence of ZnCl2 afforded 6-[(diacetoxyboryl)oxycarbonyl] derivative 323 (R = OAc)], which was reacted with primary and cyclic amines to give 10-amino-9-fluoro-7-carboxylic acid derivatives 324 (97MI41, 98MI30). 6-[(Difluoroboryl)oxycarbonyl derivative 323 (R = F) was obtained from ethyl 9,10-difluoro-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazine-6-carboxylate with BF3-THF complex. Reaction of 323 (R = F) and 1-methylpiperazine in DMF at 50-60 °C and subsequent acidic hydrolysis afforded 7 (97MI1). 

An improved method for the synthesis of 4-hydroxy-1-oxo-l,2-dihydroisoquinoline-3-carboxylic acid derivatives 130 was presented <06S1971>. This improved three-step method efficiently converts phthalic anhydride 131 to the desired dihydroisoquinolines 130 in high yields over three steps with only one purification. 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

Due to the pharmaceutical importance of their reaction products, a number of fluorinated 4-oxo-l,4-dihydroquinoline-3-carboxylic acid derivatives have been treated with various thiols (Table 8). The displacement of fluorine proceeds under moderate conditions regiosclcctively at C-7 or C5 giving 2 or 3, respectively in the ease of the 5,6,7,8-tetrafluoro derivative, fluorine is replaced at C5 in a nonpolar solvent, e.g. toluene, and at C7 in polar solvents, e.g. ethanol.18... 

Table 8. Selected Examples of Sulfanyl-Substituted 4-Oxo-l,4-dihydroquinoline-3-carboxylic Acid Derivatives by Thiolation of the Respective Fluoro Derivatives3...

Peptide a-oxo esters 1 (R4= alkyl, substituted alkyl) and a-oxoamides 2 can be prepared by treatment of a-substituted carboxylic acid derivatives (X1 = H, X2=OH X1, X2=CH2, N2) with an oxidizing agent (Scheme 3).Pa6,s,9] The final peptidyl products can contain either a mixture of enantiomers at C2 in PI of the peptide or be optically pure depending on the method employed for the preparation of the key intermediates or peptide a-substituted carboxylic acid derivatives, or the choice of the oxidizing agent in the final step. 

Zinc- and silver-ion coordination equilibria of 15 4-oxo-4//-pyrido[ 1,2-a]pyrimidines-3-carboxylic acid derivatives with different degrees of saturation were investigated by polarographic, potentiometric, and spectro-photometric method (87MI14). 

Tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-one was prepared by the decarboxylation of 6,7,8,9-tetrahydro-4-oxo-47/-pyrido[ 1,2-a]pyrimi-dine-3-carboxylic acid in 85% phosphoric acid at 160-170°C for 6 hours (85ACH305). Decarboxylation of 9-anilino-4-oxotetrahydropyridopy-rimidine-3-carboxylic acid derivatives 422 occurred in refluxing 2% aqueous sodium hydroxide under argon to give 3-unsubstituted derivatives 423 [85JCS(P1)1015],... 

Heating 10-(4-methyl-l-piperazinyl) and 10-fluoro-substituted derivatives of ethyl 9-fluoro-3-methylene-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate in a 1 1 mixture of cone. HC1 and AcOH afforded 3-hydroxy-3-methyl-6-carboxylic acid derivatives (92CCC216). 

Condensation of 1- and /V(6)-alkyl and unsubstituted 6-aminoindazoles with diethyl ethoxy-methylenemalonate in Dowtherm A at elevated temperature gave the ethyl 6,9-dihydro-9-oxo-pyrazolo[3,4 /]quinoline-8-carboxylates (88) (Equation (49)) <83JHC1351>. The 6-ethyl-8-carboxylic acid derivative is a potent antibacterial agent. 

The design and s)mthesis of the new oxime-functionalized pyrrolidine derivative of gemifloxacin, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, was first described in Scheme 4.1 starting from step (a) to step (i) in the scheme. Then, the new pyrrolidine derivative moiety was coupled with a certain quinoline carboxylic acid derivative (7-chloro (or fluoro)-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid) to form the new fluoroquinolone drug, gemifloxacin as described in Scheme 4.1. 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

Knoll, Meszaros and others studied the structure-activity relationship of analgetic 4-oxo-4H-pyrido[l,2-u]pyrimidine-3-carboxylic acid derivatives.Following detailed investigations, derivatives... 

Synthesis of (+)-Eurylene. The reaction of a-sulfonyl anions with carboxylic acid derivatives is used as the key step in the construction of various natural products. The resulting (3-oxo sulfone intermediate is then further elaborated and/or desulfonylated to afford the desired product. A variety of carboxylic acid derivatives has been used, esters being most often employed, as depicted in Eq. 149 for the synthesis of the triterpene polyether (+)-eurylene.149... 

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