Carboxamides fluoro

Treatment of ethyl 10-methylthio-9-fluoro-3-methyl-2,3-dihydro-7-oxo-7//-pyrido[l,2,3- 7e]-l,4-benzoxazine-6-carboxylate with oxone in aqueous MeOH at 0°C afforded 10-methylsulfonyl derivative (99H(51)1563). Methylthio group in a 7-(4-methylthiophenyl)-5-oxo-2,3-dihydro-5//-pyrido[l,2,3- 7e]-l,4-benzoxazine-3-carboxamide was oxidized to a sulfoxide and a sulfone group (OOMIPl). 

Reaction of ethyl 7-bromo-8-fluoro-l-(2-bromo-l-methylethyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate with MeNH2 yielded 10-bromo-A, 1, 3-trimethyl-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-<7e]quinoxaline-3-carboxamide (OOMIPIO). 

The fluoro substituents proved to induce changes in the reactivities of the methyl- (X = H) and trifluoromethyl-substituted (X = F) pyrido[3, 2 4,5]furo[3,2- [l,3]oxazin-4(47r)-ones 105 with nucleophiles. When methyl-substituted compounds 105 (X = H) were reacted with piperidine in toluene, Wacetylamino carboxamides 106 were formed by nucleophilic attack at the carbonyl group of the l,3-oxazin-4-one ring (Scheme 16). However, the similar reactions of the trifluoromethyl-substituted analogs 105 (X = F) resulted in formation of amidino carboxylic acids 107 by attack at electron-poor position 2 <1995JFC(74)1>. 

The most important applications of the in situ photochemical fluorodediazoniation start from heterocyclic amines for which the diazonium tetrafluoroborates are impossible to isolate. In this way, fluorinated imidazoles,123-253,254-257 261 benzimidazoles,262 pyrazoles,254-256,262 indazoles,158 thiazoles,259 and triazoles259-262 have been prepared (Table 4). Some of these are the precursors of biologically active compounds such as fluoro-substituted histidines or histamines,123,253-257,258 or 5-fluoro-l/ -D-ribofuranosylimidazole-4-carboxamide.261... 

Reduction of 8-nitro-9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2, 3-cfe][l,4]benzoxazine-6-carboxamides with Na2S204 in aqueous MeOH under reflux for 5 h gave 8-amino derivatives in 51-74% yields (09WOP2009/035634). 8-Amino derivative was obtained from (S)-8-nitro-9-fluoro-10-(l-aminocyclopropyl)-7-oxo-2,3-dihydro-7/T-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid by catalytic hydrogenation over Pd/C catalyst in AcOH (06MIP1). 

Aminopyrrolidin-1 -yl)-6-fluoro-4-oxo-1 -(thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (13, R = OH) gave the corresponding 3-carboxamide (13, R = NH2) via the unisolated acid chloride (13, R = Cl) (ClC02Et, Et3N then NH3/EtOH 54%).352... 

Af-Methyl-jV-(l-methylpropyl)-l(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide, 323, possessing high affinity and selectivity for PBBS (peripheral-type benzodiazepine binding sites)312 in living man, has been labelled313 with n.c.a. fluorine-18, obtained via lsO(p, n)18F nuclear reaction, by an aromatic nucleophilic substitution process (equation 139). (n.c.a. = no carrier added)... 

Fluoro-l-phenylpyrazole-4-carboxamides 304 have been formed by condensation of the 5-fluoro-l-phenylpyrazole-4-carboxylic acid 303 with amines (Equation 58) <2000EJ0823>. 4-Benzoyl-l-(4-nitrophenyl)-5-phenyl-l//-pyrazole-3-carboxylic acid 305 was converted via reactions of its acid chloride with alcohols or N-nucleophiles, into the corresponding ester or amide derivatives 306 (Equation 59) <2004CHE1039>. Resin-bound pyrazole-4-carboxylic... 

Electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxamide 724 gives good yields of diastereoisomers 725, which were further transformed into a series of 3-fluoro-3-deazaguanosine analogues 726 (Scheme 178) <2005SL1586>. 

N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1 H-indol-3-ylidene)methyl]-2,4-dimethyl-1 H-pyrrole-3-carboxamide (25)-2-hydroxybutanedioic acid... 

Mutlib, A. et al., Formation of unusual glutamate conjugates of l-[3-(aminomethyl) phenyl]-/V-[3-fluoro-2 -(methylsulfonyl)-[l,l -biphenyl]-4-yl]-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (DPC 423) and its analogs the role of gamma-glutamyltrans-peptidase in the biotransformation of benzylamines, Drug Metab. Dispos., 29 (10), 1296, 2001. 

The course of the cyclization of amino (or acylamino) ketones to pyrido[2,3-phenyl group is replaced by 2-fluorophenyl. Under mildly alkaline conditions, the amino and fluoro functions react to form a sandwiched 4-pyridinone ring. This compound is methylated (Mel-NaH-DMF) at N-2. A side-chain amino group which may be regarded as a vinylogous carboxamide displaces a bz-fluorine atom on heating with sodium hydride. 

Lithiation of diazines with directing groups (methoxy, methylthio, chloro, fluoro, even iodo, and various carboxamides) is straightforward and such derivatives are used widely. In contrast to the useful... 

Pipamperone, I. [4.(4-Fluorophenyl)-4-oxobut-< - 1,4 -bipiperidineJ-4 -carboxamide 1 -[3-(p-fluoro-benzoyl)propyl]-[I,4 -bipiperidine]-4 -carboxamide l -ip-fluorophenyl)-4-(4 -piperidino-4 -carbamoylpiperidino)-l butanone l [7-(4-fluorobenzoyl)propyl] -4-piperidinopiper-idine-4-carboxamide 4 -fluoro-4-(/V-[4-(lV-piperidino)-4-carbamido]piperidino]butyrophenone floropipamide R 3345 Dipiperon Piperonyl Prop tan C1,H30FNjOj mol wt 375,49. C 67.17%, H 8.05%, F 5.06%, N 11.19%, 6 8.52%. Prepn of the dihydrochloride by reaction of y-chloro-4-fluorobutyrophenone and 4-piperidinopiperidine-4-carbox-... 

Upon treatment of y-hydroxy-a-fluoro-a-trifluoromethyl carboxamides 99 by an organoaluminum reagent a single diastereomer of a-trifluoromethyl lactones 100 forms. 

Ogu, K. Matsumoto, S. Akazome, M. Ogura, K. Novel Synthesis of a-Trifluoromethy-lated a-Amino Acid Derivatives from y-Hydroxy-a-fluoro-a-trifluoromethyl Carboxamides. Org. Lett. 2005, 7,589-592. 

Bixafen is another pyrazole carboxamide recently developed by Bayer CropScience. These active ingredients illustrate the fluoro-substituted pyrazole, thiazole, and pyrrole carboxamides as left part of the molecules that are being developed by several companies. 

A most dramatic difference is the case of fluoride [4,129]. In a competition between carboxamide and fluoro substituents arranged ortho on a benzene ligand, LDA rapidly removes the proton ortho to F with complete selectivity [4]. In another example, amide dominates over a m-methoxide but with low selectivity [24]. The collective results suggest that conformational effects are signiflcant (best conformation of the Cr(CO)3 tripod), and that inductive effects are relatively more important than speciflc coordination of the base to a ring ortho substituent (compared to the uncomplexed arene). The high inductive effect of F is critical in directing deprotonation of the fluorobenzene complexes. 

Quan, M.L., et al. Discovery ofl-(3 -Aminobenzisoxazol-5 -yl)-3-trifluoromethyl-A-[2-fluoro-4-[(2 -dimethy-laminomethyl)imidazol-l-yl]phenyl-lF7-pyrazole-5-carboxamide Hydrochloride (Razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor. J. Med. Chem. 2005, 48, 1729-1744. 

Amino- (27, X = H2) gave 4-benzylideneamino-7-chlQro-6-fluoro-3-cinnoline-carboxamide (27, X = CHPh) (PhCHO, trace AcOH, EtOH, reflux, 3 h 60% ... 

Lysine salt of 6- Chloro - 5- fluoro-3 (2-thienyl)-2 oxindole -1- carboxamide... 

Some V-alkyl 3-(4 -deoxy-4 -fluoro-a-L-arabinopyranosyl)-l, 2,4-oxadiazole-5-carboxamides have been made by fluorination of the corresponding 3-P-d-xylofuranosyl compounds using DAST. ... 

Several aminofluoropyridines are prepared either by the Hofmann reaction or the Curtius degradation. Thus, 2-amino-6-fluoropyridine is easily obtained from either 6-fluoropicolinamide or 6-fluoropicolinic hydrazide. 3-Amino-2-fluoro-pyridine and S-amino-2-fluoropyridine are prepared best from the appropriate 2-fluoropyridine carboxamide rather than from the hydrazide because the a-fluorine atom is easily replaced by hydrazine. 

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