2-Fluorobenzoic acid, synthesis

Amino-3-fluorobenzoic acid is an important intermediate in the synthesis of derivatives of indole, such as the potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist L-670,596 or the anti-inflammatory agent Etodolac. Compounds of this type have therapeutic applications. 2-Amino-3-fluoro-benzoic add is aiso an important precursor for the synthesis of fluoroacridines, which can be converted to interesting tridentate ligands, such as Acriphos. ... 

Another approach to labeling OC with 18F was reported by Hostetler et al. [61]. OC was labeled via an in situ peptide coupling of 4-[18F]fluorobenzoic acid ([18F]FBA) with the N-terminus of OC to provide 4-[18F]fluorobenzoyl-OC ([18F]FB-OC).The process of synthesizing [18F]FB-OC involved a new efficient, one-pot synthesis of [18F]FBA using a microwave cavity and the combination of reagents,1,3-dicyclohexylcarbodiimide and l-hydroxy-7-azabenzo-triazole. Unfortunately, [18F]FB-OC also showed high liver uptake and low uptake in so-... 

The reader is referred to the synthesis of 4,4 -difluorobiphenyl,S8 4-fluorobenzoic acid,59 fluorobenzene,60 and l-bromo-2-fluorobenzene,61 published in Organic Syntheses, and to the syntheses of 3-fluorotoluene, 3-nitrofluorobenzene, 4-fluorobromobenzene, 4-fluoroanisole, 2-fluoronaphthalene, 3-fluoropyridine, and 4,4 -difluorobiphenyl published in Organic Reactions... 

Scheme 18.25. Synthesis of 4-[ F]fluorobenzoic acid and its microwave-enhanced cyclocondensation with 1,2-diamino-benzene.

Among fluorinated LCs, the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles by cyclocondensation of amidoximes with trifluoroacetic anhydride or fluorobenzoic acid derivatives has been reported. In these... 

Conjugate addition of the y-butyrolactam to enals was promoted by diphenyl-prolinol trimethylsilyl ether 12 via the iminium activation process (Scheme 32, second hne) [53]. A satisfactory level of enantioselectivity was generally observed irrespective of the solvent polarity, although the use of aqueous acetonitrile was superior for optimizing the chemical yield and enantioselectivity. In addition, acidic additives had apparent effects on the reaction profile and the highest diastereoselectivity was attained with 2-fluorobenzoic acid. The synthetic utility of this site- and stereoselective transformation was demonstrated in a series of product derivatizations, including the three-step synthesis of a cAMP-specific phosphodiesterase (PDE IV) inhibitor (Scheme 32, third hne). 

For the total synthesis of the phytohormones abamine (75) and abamine SG (77), the amide 70, obtained from 4-fluorobenzoic acid 69, was arylated... 

Once we knew that CP-392,110 was the final candidate, a more efficient bond disconnection was the one across the olefin linker to provide the same quinazolinone nucleus 2 and a novel aldehyde 4 (Scheme 4). The initial starting materials for each of these were meto-fluorobenzoic acid and 2,6-dibromopyridine, which were both available in kilogram quantities at a reasonable price. This disconnection would provide a more efficient synthetic sequence and avoid the potential for "dimer" formation in the aldol addition. The major xmcertainty with this approach was finding an efficient synthesis of the aldehyde 4. 

With the synthesis of the sidechain 4 in hand, we turned our attention to the quinazolinone nucleus 2, which is a known confound. We carried out a reaction sequence which was a modification of the one in the literature (6). As shown in Scheme 12, me/a-fluorobenzoic acid was nitrated to form 24. This reaction will be discussed in more detail vide infra). The nitro group in 24 was reduced with Pd C/Ha to form 25, and the benzoxazinone 26 was formed by treatment of 25 with trimethylorthoaceate (TMOA). Treatment of con5)ound 26 with or Ao-chloroaiiiline provided the quinazolinone 2. This sequence was carried out starting with 10 kg of the we a-fluorobenzoic acid derivative to provide 3.7 kg of final product 2 with the isolation of only two intermediates (25% yield overall). Although this yield has room for considerable optimization, speed was more important than efficiency at this stage of development. 

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