Synthèse de la 6‐ et de la 8‐trifluorométhyl‐quinoléine

Abstract

La synthbse de la 5-et de la 7-trifluorom6thyl-quinol6ine (11 et 111) a partir de la m-trifluorotoluidine (I) ayant deja 6t6 r6alis8e1), nous exposons ici celle de la 6-et de la 8-trifluorom6thyl-quinoleine (IV et V). Celle-ci est beaucoup plus laborieuse en raison de la difficult6 de la preparation des produits de depart, 1'0-et la p-trifluorot oluidine .Rouche2) avait deja prepare 1'0-et le p-nitro-trifluorotolubne, en nitrant le m-ac6tamino-trifluorotolubne, et en d6saminant ensuite les produits de nitration. Au eours du m6me travail il a obtenu 1'0 -trif luorot oluidine.Cette m6thode &ant assez longue et le rendenient mddiocre, nous avons essay6 d'autres m6thodes dans l'espoir d'arriver plus facilement aux produits diisirds.La nitration du trifluorotol~bne~) donne presque exclusivement le dbriv6 mbta, c'est pourquoi nous avons essay6 de preparer le trichloro-p-nitrotolubne en chlorurant le p-nitrotolubne; sa fluoruration aurait dii nous donner directement 1s trifluoro-p-nitrotolubne.Nous n'avons pas reussi h introduire les trois atomes de ehlore dans le groupement m6thyle. Jusqu'h 145O, il n'y a substitution que d'un atome d'hydrogbne. Si on augmente la tempi.rature, on constate la formation, dans la phase gazeuse, d'un peu de dichloro-p-nitrotolubne. Si on diipasse M O O , l'absorption de chlore devient plus rapide, mais en meme temps on constate la formation d'eau, et dans le produit final de la reaction, on trouve un melange des chlorures de l'acide p-chlorobenzoique et de l'acide p-nitrobenzofque. Suivant les conditions de l'opiiration, la quantit6 de chlorure de l'acide p-chlorobenzo'ique peut atteindre 40 yo de la masse totale du produit de la r6action.La substitution du groupe nitro par le chlore, lors d'une chloruration, n'a pas encore 6tB signalee. Cette curieuse riiaction se produit probablement suivant le schema VI-X.A noter que les melanges de diverses proportions des acides p-chlorobenzoiques fondent a des temperatures comprises entre les temperatures de fusion de ces acides4).

New Fluoro Derivatives of the Pyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide System: Evaluation of Fluorine Binding Properties in the Benzodiazepine Site on γ-Aminobutyrric Acid Type A (GABAA) Receptor. Design, Synthesis, Biological, and Molecular Modeling Investigation

“…The Bz site/GABA A -R binding affinity of newly synthesized compounds was evaluated by their ability to displace [ 3 H]flumazenil (Ro15-1788) from its specific binding in bovine brain membrane and was expressed as K i value only for those compounds inhibiting radioligand binding by more than 80% at fixed concentrations of 10 μM. The binding data (Table 3, compounds 7-13, [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][38][39][40][41][42] show that all compounds were able to bind to Bz site/GABA A -R with good affinity, with only a few exceptions.…”

“…Compounds having the CF 3 group in position 8 (19,21,(23)(24)(25)(27)(28)(29)(30)(31)(32) show all pharmacophoric groups correctly set to form efficient hydrogen bonds and lipophilic interactions, thus explaining the good/fair affinity of the 8-CF 3 derivatives compared to the 7-CF 3 (18,20,22, and 26). The The position of a trifluoromethyl group at the pyrazolobenzotriazine core is important even when a halogen atom (26)(27)(28)(29) is present in position 3.…”

“…For synthesis of the trifluoromethyl derivatives (Scheme ), the intermediates ethyl 5-aminopyrazole-4-carboxylate 1 − 3 were synthesized from the corresponding 3-, 4-, 5-trifluoromethyl-2-nitro-phenylhydrazine − and 2-cyano-3-ethoxypropenate, following a previously reported procedure . The next cyclization to the pyrazolobenzotriazine system was obtained in standard conditions of 10% sodium hydroxide solution and then were acidified with concentrated HCl.…”

“…General Procedure for the Synthesis of 5-Aminopyrazoles 1-3, 6. A suspension of the suitable 3-, 4-, 5-trifluoromethyl-2-nitrophenylhydrazine [23][24][25] or 2-nitro-5-trifluoromethoxy phenylhydrazine, 5 (1 mmol), and 2-cyano-3-ethoxypropenate (1 mmol) in ethanol (50 mL) with HCl as acid catalyst, were refluxed until the starting material disappeared in TLC (toluene/ethyl acetate/acetic acid 8:2:1 v/v/v). The workup of the final solution gave the ethyl 1-(2-nitro-3-, 4-, 5-trifluoromethylphenyl)-5-aminopyrazol-4-carboxylate, 1-3, and the ethyl 1-(2-nitro-5-trifluoromethoxyphenyl)-5-aminopyrazol-4-carboxylate 6, that were recrystallized by suitable solvent.…”

Catalytic Trifluoromethylation of Aryl- and Vinylboronic Acids by 2-Cyclopropyl-1-(trifluoromethyl)benzo[b]thiophenium Triflate

“…In particular, trifluoromethylated aromatic (CF 3 Ar) compounds are widely used in a key component of drugs on the market such as cinacalcet and fipronil. , More recently, they have been sought after as key functional units of asymmetric catalysts and ligands for organic reactions . Since simple CF 3 Ar derivatives are popular as raw materials, an efficient and scaleable synthesis of CF 3 Ar compounds using inexpensive reagents is required . On the other hand, direct introduction of a CF 3 group into aromatic compounds is suitable in a late stage of the synthetic sequence. , Late-stage direct trifluoromethylation using a shelf-stable trifluoromethylation reagent appears to be highly advantageous for drug discovery strategies by allowing novel pharmacophores to be devised, synthesized, and screened.…”