- Efficient synthesis of 2-(trifluoromethyl)nicotinic acid derivatives from simple fluorinated precursors
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Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed Involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy
- Kiss, Laszlo E.,Ferreira, Humberto S.,Learmonth, David A.
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- Trifluoromethylation of aryl and heteroaryl halides with fluoroform-derived CuCF3: Scope, limitations, and mechanistic features
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Fluoroform-derived CuCF3 recently discovered in our group exhibits remarkably high reactivity toward aryl and heteroaryl halides, performing best in the absence of extra ligands. A broad variety of iodoarenes undergo smooth trifluoromethylation with the ligandless CuCF3 at 23-50 C to give the corresponding benzotrifluorides in nearly quantitative yield. A number of much less reactive aromatic bromides also have been trifluoromethylated, including pyridine, pyrimidine, pyrazine, and thiazole derivatives as well as aryl bromides bearing electron-withdrawing groups and/or ortho substituents. Only the most electrophilic chloroarenes can be trifluoromethylated, e.g., 2-chloronicotinic acid. Exceptionally high chemoselectivity of the reactions (no side-formation of arenes, biaryls, and C2F5 derivatives) has allowed for the isolation of a large number of trifluoromethylated products in high yield on a gram scale (up to 20 mmol). The CuCF3 reagent is destabilized by CuX coproduced in the reaction, the magnitude of the effect paralleling the Lewis acidity of CuX: CuCl > CuBr > CuI. While SNAr and SRN1 mechanisms are not operational, there is a well-pronounced ortho effect, i.e., the enhanced reactivity of ortho-substituted aryl halides 2-RC6H4X toward CuCF3. Intriguingly, this ortho-effect is observed for R = NO2, COOH, CHO, COOEt, COCH3, OCH3, and even CH3, but not for R = CN. The fluoroform-derived CuCF3 reagent and its reactions with haloarenes provide an unmatched combination of reactivity, selectivity, and low cost.
- Lishchynskyi, Anton,Novikov, Maxim A.,Martin, Eddy,Escudero-Adan, Eduardo C.,Novak, Petr,Grushin, Vladimir V.
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p. 11126 - 11146
(2013/12/04)
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- NOVEL PRECURSORS
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The present invention relates to a Compound of the formula (I), wherein X represents CN, COOR, wherein R represents hydrogen or a carboxyl protecting group, CONR'2, wherein R' represents hydrogen or a carboxyl protecting group, or nitro; R1, R2, R3, R4, R5 independently of each other represent hydrogen, C1-C6 alkyl, halogen, trifluoromethyl, cyano, nitro, substituted aryl or substituted heteroaryl group; Y represents hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C7-C13 alkaryl, trifluoromethyl, cyano, nitro, substituted aryl or substituted heteroaryl group; and wherein the stereochemically unspecified double bonds in the above formula (I) represent either the E,E; E,Z; Z,E or Z,Z configuration.
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Page/Page column 13-14
(2009/05/30)
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- The Hemetsberger-Knittel synthesis of substituted 5-, 6-, and 7-azaindoles
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A series of substituted 5-, 6-, and 7-azaindoles were prepared via the Hemetsberger-Knittel reaction. In general, better yields were obtained at higher temperatures and shorter reaction times than required for the formation of the analogous indoles, and in some cases, only decomposition occurred below a minimum temperature. The resulting templates offer up to five sites for subsequent functionalization to allow a wide range of chemical diversity. Georg Thieme Verlag Stuttgart.
- Roy, Patrick J.,Dufresne, Claude,Lachance, Nicolas,Leclerc, Jean-Philippe,Boisvert, Michel,Wang, Zhaoyin,Leblanc, Yves
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p. 2751 - 2757
(2007/10/03)
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- Process for preparing 2-haloalkylnicotinic acids
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The present invention relates to a process for preparing 2-haloalkylnicotinic acids and haloalkylnicotinic acid derivatives starting from halomethyl-substituted enones and 3-dialkylaminoacrylic esters and also to intermediates of the process according to the invention.
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- Development of orally active oxytocin antagonists: Studies on 1-(1-{4- [1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy].2methoxybenzoyl}- 4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines
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The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N- oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.
- Bell, Ian M.,Erb, Jill M.,Freidinger, Roger M.,Gallicchio, Steven N.,Guare, James P.,Guidotti, Maribeth T.,Halpin, Rita A.,Hobbs, Doug W.,Homnick, Carl F.,Kuo, Michelle S.,Lis, Edward V.,Mathre, David J.,Michelson, Stuart R.,Pawluczy, Joseph M.,Pettibone, Douglas J.,Reiss, Duane R.,Vickers, Stanley,Williams, Peter D.,Woyden, Carla J.
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p. 2146 - 2163
(2007/10/03)
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