- Synthesis of 2-Arylpiperidines via pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids
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The first Pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids is achieved, providing versatile 2-Aryldihydropyridinones for facile synthesis of highly functionalized 2-Arylpiperidines. Key to this arylation is the use of non-phosphine-ligand palladium precatalyst. The substrate scope is demonstrated with >26 examples, and the utility of 2-Aryldihydropyridinones is illustrated by the synthesis of a small collection of 2-Arylpiperidines with substituents or functional groups at any carbon (C2-C6) as well as two NK1 receptor antagonists (+)-CP-999,94 and (+)-L-733,060.
- Zhao, Guodong,Canterbury, Daniel P.,Taylor, Alexandria P.,Cheng, Xiayun,Mikochik, Peter,Bagley, Scott W.,Tong, Rongbiao
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supporting information
p. 458 - 463
(2020/01/21)
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- Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic acid: Application of an organocatalytic direct vinylogous aldol reaction
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The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.
- Pansare, Sunil V.,Paul, Eldho K.
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experimental part
p. 2119 - 2125
(2012/04/17)
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- Concise asymmetric synthesis of (+)-CP-99,994 and (+)-l-733,060 via efficient construction of homochiral syn-1,2-diamines and syn-1,2-amino alcohols
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(Chemical Equation Presented) An efficient asymmetric synthesis of human NK-1 SP receptor antagonists (+)-CP-99,994 and (+)-L-733,060 was achieved starting from a common chiral intermediate (5). Our route featured the SmI 2-induced reductive co
- Liu, Run-Hua,Fang, Kai,Wang, Bing,Xu, Ming-Hua,Lin, Guo-Qiang
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p. 3307 - 3310
(2008/09/20)
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- Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands
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(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.
- Atobe, Masakazu,Yamazaki, Naoki,Kibayashi, Chihiro
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p. 5595 - 5607
(2007/10/03)
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- SUBSTITUTED BENZOLACTAM COMPOUNDS
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This invention relates to compounds of general formula (I): or a pharmaceutically acceptable salt thereof, W, T, Y, X, Q, R, R, and R are defined herein. This invention also relates to compounds of formula (I), depicted above, wherein Y is -NH-; T is (2S,3S)-2-phenylpiperidin-3-yl, where the phenyl group of said (2S, 3S)-2-phenylpiperidine-3-yl may optionally be substituted with fluoro; Q is oxygen and is double bonded to the carbon atom to which it is attached, X is methoxy or ethoxy, R is hydrogen, methyl or halo-C1-C2 alkyl, W is methylene, ethylene or vinylene; R and R are independently hydrogen or methyl, or one of R or R may be hydroxy, when W is ethylene, R and R are both methyl, when W is methylene, and R and R are both hydrogen, when W is vinylene. The invention is further directed to methods of treating various CNS and other disorders using said compounds and pharmaceutical compositions thereof.
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- Substituted benzolactam compounds
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This invention relates to compounds of the general formula (1): or a pharmaceutically acceptable salt thereof, W, T, Y, X, Q, R1, R2, and R3 are defined herein. This invention also relates to compounds of the formula I, depicted above, wherein Y is —NH—; T is (2S,3S)-2-phenylpiperidin-3-yl, where the phenyl group of said (2S, 3S)-2-phenylpiperidine-3-yl may optionally be substituted with fluoro; Q is oxygen and is double bonded to the carbon atom to which it is attached, X is methoxy or ethoxy, R1 is hydrogen, methyl or halo-C1-C2 alkyl, W is methylene, ethylene or vinylene; R2 and R3 are independently hydrogen or methyl, or one of R2 or R3 may be hydroxy, when W is ethylene, R2 and R3 are both methyl, when W is methylene, and R2 and R3 are both hydrogen, when W is vinylene. The invention is further directed to methods of treating various CNS and other disorders using said compounds and pharmaceutical compositions thereof.
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- Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon.
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[reaction: see text] Selective and potent neurokinin substance P receptor antagonists (+)-L-733, 060 (1) and (+)-CP-99, 994 (2) have been synthesized starting from a new (3S)-piperidinol synthon derived from l-glutamic acid. The methods featured a C-2 reg
- Huang, Pei-Qiang,Liu, Liang-Xian,Wei, Bang-Guo,Ruan, Yuan-Ping
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p. 1927 - 1929
(2007/10/03)
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- Enantioselective synthesis of NK-1 receptor antagonists (+)-CP-99,994 and (+)-CP-122,721
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An enantioselective total synthesis of NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721, is described. The key steps are diastereoselective addition of vinyllithium to a chiral benzaldehyde oxime ether and diastereoselective borane reduction of
- Yamazaki, Naoki,Atobe, Masakazu,Kibayashi, Chihiro
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p. 7979 - 7982
(2007/10/03)
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- Substituted benzolactam compounds as substance P antagonists
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Compounds of the formula are effective for the treatment of conditions in mammals which require inhibition of the action of substance P.
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- Stereoselective synthesis of (+)-CP-99,994: A substance P non-peptide antagonist
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A highly stereoflexible total synthesis of (+)-CP-99,994 is achieved starting, from (S)-serine, key steps being a diastereoselective Grignard addition, a one-pot reductive protection of an azide, and one-pot oxidative Wittig olefination.
- Chandrasekhar,Mohanty, Pradyumna K.
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p. 5071 - 5072
(2007/10/03)
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- Pyridinylamino tricyclic compounds as substance P antagonists
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This invention provides a compound of the formula: STR1 and its pharmaceutically acceptable salts, wherein Ar1 is selected from groups of the following formulae: STR2 wherein, R1 and R2 are independently hydrogen or C1 -C6 alkyl; W is (CH2)n wherein n is from 1 to 3, or --CH=CH--; X is C1 -C6 alkoxy or halo C1 -C6 alkoxy; and Ar2 is phenyl optionally substituted by halogen atom. These compounds are useful in the treatment of a gastrointestinal disorder, a central nervous system (CNS) disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine, sunburn, angiogenesis, diseases, disorders and adverse conditions caused by Helicobacter pylori, or the like in a mammalian subject, especially humans.
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- 3-[5-substituted benzyl)amino]-2-phenylpiperidines as substance P antagonists
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This invention provides a compound of the formula: STR1 and its pharmaceutically acceptable salts, wherein R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo C 1 -C 6 alkyl or terahydropyranyl, having one or more substituents selected from cyano, 1,3-thiazolanyl, COOR 2, COR 2, OCOR 2, CONR 3 R 4, NR 3 R 4, NR 5 COR 3 and C.ident.CR 6, wherein R 2 is hydrogen or C 1 -C 4 alkyl, R 3 and R 4 are independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, R 5 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl and R 6 is hydrogen, halo, cyano, C 1 -C 6 alkyl, COOH, COO(C 1 -C 4 alkyl) or phenyl; X is C 1 -C 6 alkoxy or halo C 1 -C 6 alkoxy; and Ar is phenyl optionally substituted with halo.These compounds are useful in the treatment of allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, sunburn, and diseases, disorders and adverse conditions caused by Helicobacter pylori, in a mammalian subject.
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