- A short enantioselective synthesis of pipecolic acid
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A simple enantioselective route to pipecolic acid is described. The key step involves the Sharpless asymmetric epoxidation of an N-protected aminoheptenol which spontaneously cyclises to a piperidine derivative on deprotection.
- Fernandez-Garcia,McKervey
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Read Online
- TUBULYSIN DERIVATIVES AND METHODS FOR PREPARING THE SAME
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The invention relates to novel means and methods for the synthesis of tubulysin and derivatives thereof, which find their use e.g. as cytotoxic agents in targeted drug delivery. Provided is a method for preparing a tubulysin derivative, comprising reacting compounds A, B and C in a 3- component Passerini reaction, wherein compound A is a carboxylic acid according to the general formula (A); wherein compound B is an aldehyde according to the general formula (B); and wherein compound C is an isocyanide according to the general formula (C).
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Page/Page column 29
(2020/02/16)
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- Pipecolic esters as minimized templates for proteasome inhibition
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Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic “proteolytic machine” such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.
- Giletto, Matthew B.,Osmulski, Pawel A.,Jones, Corey L.,Gaczynska, Maria E.,Tepe, Jetze J.
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p. 2734 - 2746
(2019/03/12)
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- PIPECOLIC ESTERS FOR INHIBITION OF THE PROTEASOME
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The present disclosure relates to chemical compounds that modulate proteasome activity, pharmaceutical compositions containing such compounds, and use of these compounds and compositions for the treatment of disorders of uncontrolled cellular proliferation such as, for example, a cancer. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00274; 00276
(2019/08/26)
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- PROCESS FOR THE PRODUCTION OF COBIMETINIB
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The present invention relates to a novel route of synthesis for the production of enantiomerically pure Cobimetinib, new intermediates in the synthesis of Cobimetinib and an amorphous Cobimetinib hemifumarate salt comprising a high salt content.
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Page/Page column 33
(2019/05/22)
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- Synthesis method of bupivacaine
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The invention belongs to a synthesis method of bupivacaine. The method comprises: adding 2 piperidinecarboxylicacid into aqueous alkali, dropwise adding Cbz and alkaline water, after finishing dropwise adding at normal temperature, reacting for 12 hours, after reaction, extracting with diethyl ether, washing a water layer to be weak-acid with 18% of diluted hydrochloric acid, extracting with the diethyl ether again, combining an diethyl ether layer, drying and filtering, and concentrating to obtain a dried product; adding the dried product into a DMF solvent, then adding a catalyst for reaction for 1 hour at normal temperature, then adding 2,6-dimethylaniline, reacting for 18hours at normal temperature, adding water and ethyl acetate for washing, taking an organic layer, drying and filtering, and concentrating to obtain a dried concentrated product; adding the dried concentrated product into a solvent, then adding a catalyst, pressurizing and introducing hydrogen, filtering after reaction and concentrating to obtain a dried product; adding the product in the above step into a solvent, dropwise adding bromo-n-butane at normal temperature, after dropwise adding, rising temperature to 80 DEG C for reacting for 12 hours, adding diluted hydrochloric acid, slowing cooling to normal temperature, and crystallizing, filtering and drying to obtain the product. The synthesis method has the advantages of higher yield, smaller pollution and low equipment requirement.
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Paragraph 0010; 0015
(2016/10/10)
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- Ring-Strain Effects in Base-Induced Sommelet–Hauser Rearrangement: Application to Successive Stereocontrolled Transformations
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The base-induced Sommelet–Hauser (S–H) rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts into 2-aryl-substituted derivatives was demonstrated. The ring-strain of four-membered N-heterocycles enables efficient generation of the desired ylide intermediate and enhances the rate of the S–H rearrangement. The asymmetric version of the rearrangement was characterized by excellent levels of successive chirality transmissions. The regio- and stereo-controlled nucleophilic ring opening of the rearrangement products produced quaternary α-aryl amino acid esters with excellent enantiopurities.
- Tayama, Eiji,Watanabe, Kazutoshi,Matano, Yoshihiro
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supporting information
p. 3631 - 3641
(2016/07/29)
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- A short enantioselective total synthesis of (R)- and (S)-pipecolic acid
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A convenient and practical total synthesis of (R)- and (S)-pipecolic acid has been achieved by utilizing chiral cis-aziridine-2-carboxylate as the common synthetic precursor. The synthesis involves regioselective reductive cleavage of the aziridine ring and Wittig olefination as key reactions.
- Chavan, Subhash P.,Khairnar, Lalit B.,Chavan, Prakash N.,Kalbhor, Dinesh B.
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p. 1246 - 1251
(2015/02/19)
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- CONDENSED HETEROCYCLIC COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I) wherein R1, A, B, D, E, G, Q, Ar, n, m, and p are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 106
(2010/04/03)
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- Formation of N-acyl-N,N'-dicyclohexylureas from DCC and arenecarboxylic acids in the presence of hydroxybenzotriazole in CH2CI2 at room temperature
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The syntheses of N-acyl-N',N'-dicyclohexylureas from 1,3- dicyclohexylcarbodiimide and arenecarboxylic acids [p-XC6H 4CO2H (X = H or NO2), 2-, 3- or 4-pyridinecarboxylic acid and pyrazinecarboxylic acid] in the
- Kaiser, Carlos R.,Pinheiro, Alessandra C.,De Souza, Marcus V. N.,Wardell, James L.,Wardell, Solange M.S.V.
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experimental part
p. 468 - 472
(2009/08/15)
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- Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors
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Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine- 4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
- Pace, Paola,Di Francesco, M. Emilia,Gardelli, Cristina,Harper, Steven,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Petrocchi, Alessia,Poma, Marco,Rowley, Michael,Scarpelli, Rita,Laufer, Ralph,Paz, Odalys Gonzalez,Monteagudo, Edith,Bonelli, Fabio,Hazuda, Daria,Stillmock, Kara A.,Summa, Vincenzo
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p. 2225 - 2239
(2007/10/03)
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- Discovery and synthesis of HIV integrase inhibitors: Development of potent and orally bioavailable N-methyl pyrimidones
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The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
- Gardelli, Cristina,Nizi, Emanuela,Muraglia, Ester,Crescenzi, Benedetta,Ferrara, Marco,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Poma, Marco,Ferreira, Maria Del Rosario Rico,Scarpelli, Rita,Homnick, Carl F.,Ikemoto, Norihiro,Alfieri, Anna,Verdirame, Maria,Bonelli, Fabio,Paz, Odalys Gonzalez,Taliani, Marina,Monteagudo, Edith,Pesci, Silvia,Laufer, Ralph,Felock, Peter,Stillmock, Kara A.,Hazuda, Daria,Rowley, Michael,Summa, Vincenzo
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p. 4953 - 4975
(2008/03/14)
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- Synthesis of 1,1′-binaphthyl-2,2′-diyl phosphoroselenoic amides and their conversion to optically pure phosphoramidites
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Optically pure phosphoroselenoyl chloride was reacted with racemic amines to give phosphoroselenoic amides as two diastereomeric mixtures in high yields. The diastereomeric mixtures were separated by fractional recrystallization or by chromatography. Extr
- Murai, Toshiaki,Inaji, Shinsuke,Morishita, Ken,Shibahara, Fumitoshi,Tokunaga, Makoto,Obora, Yasushi,Tsuji, Yasushi
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p. 1424 - 1425
(2007/10/03)
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- Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their therapeutic application
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The present invention relates to the use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment or pro
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Page/Page column 19
(2010/02/14)
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- LOCAL ANESTHETIC COMPOUNDS AND USES
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Novel compounds, pharmaceutical compositions and methods are disclosed for producing local anesthesia of long-duration. The compounds of this invention are multibinding compounds that comprise from 2 to 10 ligands covalently attached to a linker or linkers, each ligand being capable of binding to a ligand binding site in a voltage-gated Na + channel to modulate the biological processes/functions thereof.
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- Pyrrolidinic and piperidinic ring fission by conjugate elimination
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Treating N-substituted pyrrolidines and piperidines bearing an allylic chain α to the nitrogen with strong bases leads to the opening of the heterocycle and provides 1,3-dienes disubstituted with an alkoxy and an aminoalkyl chain. The effects of the base and the solvent have been studied, as well as the influence of the ring size and the nitrogen substituent. The results obtained suggest a possible pre-chelation of the base cation before the deprotonation.
- Acquadro, Francesco,Oulyadi, Hassan,Venturello, Paolo,Maddaluno, Jacques
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p. 8759 - 8763
(2007/10/03)
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- Chemical conversion of cyclic α-amino acids to cyclic α-aminophosphonic acids
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The oxidative decarboxylation of cyclic α-amino acids having urethane-type N-protecting groups with lead tetraacetate [Pb(OAc)4] gave 2-hydroxy derivatives, which were transformed into the corresponding α-aminophosphonic acid esters by treatment of trialkyl phosphites in the presence of Lewis acids. Deprotection and ester cleavage of the products in the usual manner afforded cyclic α-aminophosphonic acids. The convenient chemical conversion of five- and six-membered cyclic α-amino acids to the corresponding cyclic α-aminophosphonic acids has been accomplished.
- Kaname,Mashige,Yoshifuji
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p. 531 - 536
(2007/10/03)
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- The Synthesis of 1-Methyl-6,7,8,8a-tetrahydro-5H-indolizin-3-one by the Palladium-Catalyzed Cyclization of N-Bromoacetyl-2-vinylpiperidine
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N-Bromoacetyl-2-vinylpiperidine underwent cyclizalion to give indolizidine derivative in the presence of a base and a catalytic amount of palladium trifluoroacetate.
- Yang, Shyh-Chyun,Shea, Fang-Rong,Chung, Wen-Hung
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p. 293 - 296
(2007/10/03)
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- Aromatic pyrrolidine amide prolyl endopeptidase inhibitors
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A series of aromatic pyrrolidine derivatives and suitable pharmaceutically acceptable salts thereof are disclosed. These compounds are useful as PEP inhibitors in the treatment of Alzheimer's disease, amnesia, dementia, anxiety ischemia, or stroke.
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- ANTITHROMBOTIC AGENTS
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This invention relates to L-arginine aldehyde derivatives, having the formula I STR1 where X and Y have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitor
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- Asymmetric total synthesis of (R)-(-)-cryptopleurine and (R)-(-)-julandine via highly enantioselective amidoalkylations with N-acylhydrazonium salts
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The first enantioselective total syntheses of the phenanthroquinolizidine alkaloid (-)-cryptopleurine (1) and its seco base (-)-julandine [(R)-3] are described. The synthesis of (R)-3 allowed the 9aS configuration to be assigned to natural dextrorotatory julandine as shown by structure (S)-3. Both synthetic approaches are based on the high degree of 1,3-asymmetric induction achieved using an N-acylhydrazonium salt, which belongs to a new structural class of activated azomethines. Upon exposure of methoxylactam 9, with a chiral 2-substituted pyrrolidine auxiliary, to BF3·Et2O and a silyl enol ether the in situ generated N-acylhydrazonium intermediate 10 underwent asymmetric nucleophilic addition to give the (6R)-keto lactams 13 and 14 with complete diastereoselectivity. On the other hand, nucleophilic addition to the N-acylhydrazonium ion 25, with an acyclic chiral auxiliary, showed poor diastereoselectivity. From these results, the high degree of diastereoselection observed for the N-acylhydrazonium ion 10 can be rationalized in terms of the pyramidal stability of the trivalent nitrogen in the chiral pyrrolidine auxiliary. Removal of the chiral auxiliary from 13 and 14 was achieved by reductive N-N bond cleavage using BH3·THF, affording (2S)-piperidine derivatives 15 and 31, respectively, which were transformed into quinolizidinones 30 and 35, respectively, via intramolecular aldol condensation. Reduction of 30 with alane provided (-)julandine [(R)-3]. In addition, 35 was converted to (-)-cryptopleurine (1) in two steps, by radical cyclization with Bu3SnH and AIBN, followed by LiAlH4 reduction.
- Suzuki,Aoyagi,Kibayashi
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p. 6114 - 6122
(2007/10/03)
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- Stereoselective synthesis of (+)-and (-)-lentiginosine
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Simple routes to (1R,2R,8aR)- and (1S,2S,8aS)-lentiginosine have been described, based on Sharpless asymmetric dihydroxylation, starting from (R)- and (S)-pipecolinic acids.
- Gurjar,Ghosh, Lakshmi,Syamala,Jayasree
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p. 8871 - 8872
(2007/10/02)
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- Design, Synthesis, and X-ray Crystallographic Analysis of Two Novel Spirolactam Systems as β-Turn Mimics
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Two novel 5.4-spirolactam systems have been developed as β-turn mimics.The (R)-5.4-spirolactam system of 4 was designed to mimic the type-II β-turn, and the (S)-5.4-spirolactam system of 5 was designed to mimic the type-II' β-turn.The 5.4-spirolactam dipe
- Genin, Michael J.,Gleason, William B.,Johnson, Rodney L.
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p. 860 - 866
(2007/10/02)
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- Piperidinyl carbonyl derivatives
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Novel compounds having the general formula STR1 wherein A and A' are amino acid residues linked by a peptidal bond to the nucleus, are disclosed. These compounds are CNS agents with anxiogenic activity.
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- An Asymmetric Synthesis of 2-Substituted Piperidines through Ozonolysis of Cyclopentenes and Reductive Aminocyclization
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By the action of ozone, sodium cyanoborohydride and the optically active benzylic amines 2, the 1-substituted cyclopentenes 1, 5 and 9 were converted to a diastereometric mixture of 1,2-disubstituted piperidines (3, 6 and 10), respectively.Hydrogenation of these compounds and the following work-up yielded optically active 2-alkylpiperidines (4, up to 68percente.e.), pipecolic acid (7, 84percent e.e.) and 2-(hydroxymethyl)piperidine (11, up to 85percente.e.).Chromatographic separation of the major isomers of 3b and 6 enabled optically pure coniine (4b) and pipecolic acid (7) to be prepared, respectively.
- Kawaguchi, Mamoru,Hayashi, Osamu,Sakai, Noriyuki,Hamada, Masayuki,Yamamoto, Yukio,Oda, Jun'ichi
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p. 3107 - 3112
(2007/10/02)
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- A New Class of Chiral Smectic Liquid Crystals: Substituted Biphenylylcyclohexylideneethanones Having an Axial Chirality
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The introduction of chiral cyclohexylideneethanone unit in a potential mesomorphic structure leads to the first family of optically active liquid crystals having an axial chirality.Racemic compounds 2 were synthesized by a Wittig-type coupling between β-keto phosphonates 6 (R1 = n-C5H11) and substituted cyclohexanone 7 (R2 = H, CH3, t-Bu, OCH3, O-n-C5H11, CO2Et, OCOC6H4CN, OCOC6H4Cl).The optically active molecules 12 were prepared by a new route using the asymmetric coupling of a carbanion α to a chiral sulfoxide 9 (R2 = n-C5H11, CH2OEt) and a substituted biphenyl acid chloride (Ar = R'C6H4C6H4 with R' = n-C5H11, CH3O, n-C8H17O, CN) followed by a stereospecific pyrolytic elimination of the sulfoxide moiety.Derivatives containing only one aromatic ring were not mesomorphic in contrast to those having a biphenyl system.
- Solladie, Guy,Zimmermann, Richard
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p. 4062 - 4068
(2007/10/02)
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- New synthesis of heterocycles by use of palladium catalyzed cycli zation of α-haloamide with internal double bond
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α-Haloamide having internal double bond was allowed to react with a catalytic amount of Pd(PPh3)4 in the presence of base to produce a cyclized product in a fairly good yield possibly through the intermediate of -alkylmetal complex. By use of this method, five and six membered lactams, pyrrolizidine and quinolizidine derivatives were synthesized in fairly good yields.
- Mori, Miwako,Kanda, Nana,Oda, Izumi,Ban, Yoshio
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p. 5465 - 5474
(2007/10/02)
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