cas 203866-16-4, N-Boc-cis-4-Fluoro-L-proline methyl ester

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Synthesis, Ni(II) Schiff base complexation and structural analysis of fluorinated analogs of the ligand (S)-2-[N-(N′-benzylprolyl)amino]benzophenone (BPB)
Herein we report the first X-ray crystal structure of the well-known (S)-l-ala-Ni-BPB complex (1) and compare this with the X-ray crystal structures obtained for two novel fluorinated (S)-l-ala-Ni-BPB complexes (8 and 12) that contain either an S- or R-fluorine atom on the proline ring of the BPB ligand. The preparation of complexes 8 and 12 has been enabled by the synthesis of two new fluorinated BPB ligands (7 and 11). In this work we looked to observe the structural effects that the introduction of a single fluorine atom had on the known complex 1. Arising from this, we highlight a novel fluorine-nickel interaction that on the basis of DFT calculations appears to provide additional stabilization to one of the complexes prepared ((S)-l-ala-Ni-BPB complex 8).
Tatum, Natalie J.,Yufit, Dmitry S.,Cobb, Steven L.,Coxon, Christopher R.
p. 77 - 83
(2015)
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COMPOUNDS TARGETING RNA-BINDING PROTEINS OR RNA-MODIFYING PROTEINS
The invention relates to a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, compositions comprising the same and methods of preparing and using the same. The variables are described herein.
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Page/Page column 271

(2021/09/11)

Large-Scale Practical Synthesis of Boc-Protected 4-Fluoro-l-Proline
A large-scale synthesis process of N-Boc-4-fluoro-l-proline (1) from N-Boc-4-hydroxy-l-proline methyl ester (2) using nosyl fluoride (13) as a deoxyfluorinating agent has been developed. An eco-friendly and large-scale feasible process using a single solvent was developed to afford moderate yields of products with excellent purity >99% by high-performance liquid chromatography. The key feature of the optimization involving chromatography-free purification and isolation on a kilogram-scale at a pilot plant scale is described.
Kashid, Bharat,Merwade, Arvind Y,Rafeeq, Mohammad,Tamboli, Yasinalli,Yadav, Ram Prasad
p. 1609 - 1613
(2020/10/26)

Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
Liu, Qingjie,Batt, Douglas G.,Weigelt, Carolyn A.,Yip, Shiuhang,Wu, Dauh-Rurng,Ruzanov, Max,Sack, John S.,Wang, Jinhong,Yarde, Melissa,Li, Sha,Shuster, David J.,Xie, Jenny H.,Sherry, Tara,Obermeier, Mary T.,Fura, Aberra,Stefanski, Kevin,Cornelius, Georgia,Khandelwal, Purnima,Tino, Joseph A.,Macor, John E.,Salter-Cid, Luisa,Denton, Rex,Zhao, Qihong,Dhar, T. G. Murali
supporting information
p. 2510 - 2518
(2020/12/03)

Photoredox-catalyzed deoxyfluorination of activated alcohols with Selectfluor
Herein we disclose a deoxyfluorination of alcohols with an electrophilic fluorine source via visible-light photoredox catalysis. This radical-mediated C–F coupling is capable of fluorinating secondary and tertiary alcohols efficiently, complementing previously reported nucleophilic deoxyfluorination protocols.
González-Esguevillas, María,Miró, Javier,Jeffrey, Jenna L.,MacMillan, David W.C.
p. 4222 - 4227
(2019/06/13)

Rapid Deoxyfluorination of Alcohols with N-Tosyl-4-chlorobenzenesulfonimidoyl Fluoride (SulfoxFluor) at Room Temperature
The deoxyfluorination of alcohols is a fundamentally important approach to access alkyl fluorides, and thus the development of shelf-stable, easy-to-handle, fluorine-economical, and highly selective deoxyfluorination reagents is highly desired. This work describes the development of a crystalline compound, N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor), as a novel deoxyfluorination reagent that possesses all of the aforementioned merits, which is rare in the arena of deoxyfluorination. Endowed by the multi-dimensional modulating ability of the sulfonimidoyl group, SulfoxFluor is superior to 2-pyridinesulfonyl fluoride (PyFluor) in fluorination rate, and is also superior to perfluorobutanesulfonyl fluoride (PBSF) in fluorine-economy. Its reaction with alcohols not only tolerates a wide range of functionalities including the more sterically hindered alcoholic hydroxyl groups, but also exhibits high fluorination/elimination selectivity. Because SulfoxFluor can be easily prepared from inexpensive materials and can be safely handled without special techniques, it promises to serve as a practical deoxyfluorination reagent for the synthesis of various alkyl fluorides.
Guo, Junkai,Kuang, Cuiwen,Rong, Jian,Li, Lingchun,Ni, Chuanfa,Hu, Jinbo
supporting information
p. 7259 - 7264
(2019/05/10)

BENZIMIDAZOLE-LINKED INDOLE COMPOUND ACTING AS NOVEL DIVALENT IAP ANTAGONIST
The present invention discloses a benzimidazole-linked indole compound acting as novel divalent IAP antagonist, specifically disclosing the compound shown in fomulas (I) or a pharmaceutically acceptable salt thereof.
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Paragraph 0161; 0162

(2019/03/14)

Design and synthesis of galactose-conjugated fluorinated and non-fluorinated proline oligomers: Towards antifreeze molecules
Galactose-conjugated fluorinated and non-fluorinated proline oligomers that exhibit an α-helical structure with hydrophilic and lipophilic parts were designed as potential antifreeze molecules. These galactose-proline oligomers were synthesized and their physical properties were evaluated. Interestingly, the non-fluorinated galactose-proline oligomers showed in contrast to the fluorinated analogues weak antifreeze activity. The difference in antifreeze activity should be attributed to the fluorine gauche effect, which should induce a conformation in fluorinated prolines that is different from that of natural proline. The results obtained in this study thus suggest that the 3D conformation of the galactose-conjugated fluorinated and non-fluorinated proline oligomers is very important for their anti-freezing properties.
Sumii, Yuji,Hibino, Hayata,Saidalimu, Ibrayim,Kawahara, Hidehisa,Shibata, Norio
supporting information
p. 9749 - 9752
(2018/09/10)

Synthesis and antibacterial activity of 6(R)- and 6(S)-fluoropenibruguieramine As: Fluorine as a probe for testing the powerfulness of memory of chirality (MOC)
The synthesis of 6(R)- and 6(S)- fluoropenibruguieramine As has been achieved, employing the elegant strategy developed by Kim and co-workers. Single diastereomers were formed via the key intramolecular aldol reaction, and both of the products were unambiguously confirmed by X-ray diffraction crystallography. This reaction shows that the fluorine amide effect could not compete with the memory of chirality (MOC) effect, thus further demonstrating the powerfulness of MOC effect in asymmetric synthesis. The biological testing carried out in this work indicates that the principal of antibacterial activity of the natural extract is probably not penibruguieramine A.
Liu, Ting,Yan, Nan,Zhao, Hui,Wang, Zhen-Xing,Hu, Xiang-Guo
p. 18 - 23
(2018/01/10)

HETEROCYCLIC DERIVATIVES AS ANTIBACTERIAL COMPOUNDS
Compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, their preparation, pharmaceutical compositions comprising such compounds and their use in treating and/or preventing bacterial infections are disclosed.
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Page/Page column 17

(2018/09/21)

As hepatitis c inhibitor spiro compound and its use in medicine
The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
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Paragraph 1003-1005

(2017/12/28)

AlkylFluor: Deoxyfluorination of Alcohols
A practical, high-yielding method for the deoxyfluorination of alcohols is presented using AlkylFluor, a novel salt analogue of PhenoFluor. AlkylFluor is readily prepared on multigram scale and is stable to long-term storage in air and exposure to water. The practicality and applicability of this method is demonstrated with a variety of primary and secondary alcohol substrates.
Goldberg, Nathaniel W.,Shen, Xiao,Li, Jiakun,Ritter, Tobias
supporting information
p. 6102 - 6104
(2016/12/09)

METAL OXIDE CATALYZED RADIOFLUORINATION
Inter alia, the first titania-catalyzed [18F]-radiofluorination in highly aqueous medium is provided. In embodiments, the method utilizes titanium dioxide, 1 : 1 acetonitrile- thexyl alcohol solvent mixture and tetrabutylammonium bicarbonate as a base. Radiolabeling may be directly performed with aqueous [18F]fluoride without the need for drying/azeotroping step, which reduces radiosynthesis time while keeping high fluoride conversion. The general applicability of the synthetic strategy to the synthesis of the wide range of PET probes from tosylated precursors is demonstrated.
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Paragraph 0111; 0113

(2016/02/28)

4-Fluoro and 4-hydroxy pyrrolidine-thioxotetrahydropyrimidinones: Organocatalysts for green asymmetric transformations in brine
The synthesis of both trans- and cis-diastereomers of pyrrolidinine-thioxotetrahydropyrimidinone bearing either a fluorine or a hydroxyl group was accomplished. The new compounds were tested for their catalytic properties in a variety of asymmetric organic transformations and compared with the first generation catalyst. It was found that the new catalysts could efficiently catalyze the reactions in brine, without the use of organic solvent, and by employing an almost stoichiometric amount of reagents. Thus, the products were isolated by simple extractions, avoiding the use of chromatography in excellent yields, diastereoselectivities, and enantioselectivities.
Kaplaneris, Nikolaos,Koutoulogenis, Giorgos,Raftopoulou, Marianna,Kokotos, Christoforos G.
p. 5464 - 5473
(2015/06/16)

PyFluor: A low-cost, stable, and selective deoxyfluorination reagent
We report an inexpensive, thermally stable deoxyfluorination reagent that fluorinates a broad range of alcohols without substantial formation of elimination side products. This combination of selectivity, safety, and economic viability enables deoxyfluorination on preparatory scale. We employ the [18F]-labeled reagent in the first example of a no-carrier-added deoxy-radiofluorination.
Nielsen, Matthew K.,Ugaz, Christian R.,Li, Wenping,Doyle, Abigail G.
supporting information
p. 9571 - 9574
(2015/08/18)

1 -(CYCLOPENT-2-EN-1 -YL)-3-(2-HYDROXY-3-(ARYLSULFONYL)PHENYL)UREA DERIVATIVES AS CXCR2 INHIBITORS
The invention relates to 1-(3-sulfonylphenyl)-3-(cyclopent-2-en-1-yl)urea derivatives, and their use in treating or preventing diseases and conditions mediated by the CXCR2 receptor. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
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Page/Page column 121

(2015/12/18)

Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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Paragraph 1061; 1062; 1063; 1064; 1065

(2015/03/28)

Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors
A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).
Ji, Xun,Su, Mingbo,Wang, Jiang,Deng, Guanghui,Deng, Sisi,Li, Zeng,Tang, Chunlan,Li, Jingya,Li, Jia,Zhao, Linxiang,Jiang, Hualiang,Liu, Hong
p. 111 - 122
(2014/03/21)

Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2- carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors
Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.
Li, Jia,Ji, Xun,Xia, Chunmei,Wang, Jiang,Su, Mingbo,Zhang, Lei,Dong, Tiancheng,Li, Zeng,Wan, Xia,Li, Jingya,Zhao, Linxiang,Gao, Zhaobing,Jiang, Hualiang,Liu, Hong
p. 242 - 256
(2014/09/29)

Enantioselective Michael addition of cyclic ketones to nitroolefins catalyzed by a novel fluorine-insertion organocatalyst
A novel fluorine-insertion organocatalyst, which was designed based on the fluorine-ammonium ion gauche effect, was synthesized and used successfully to catalyze the asymmetric Michael addition of cyclic ketones to nitroolefins. High yields and excellent diastereo- and enantioselectivities were achieved under mild conditions. A possible stereochemical model is also proposed.
Wang, Yanan,Jiang, Min,Liu, Jin-Tao
p. 212 - 218
(2014/03/21)

BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.
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Page/Page column 143; 144

(2014/09/16)

BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND PHARMACEUTICAL APPLICATIONS THEREOF
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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Paragraph 00434

(2014/02/16)

FUSED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
Provided are fused tricyclic compounds effective to inhibit the function of the NS5A protein of formula (I), wherein X, X', Y, Y', A, A',Q1, Q2, R1-R4, X4, R5a, f and W are defined as in the description. Also provided herein are pharmaceutical compositions thereof, and uses in the manufacture of a medicament for treating HCV infection or a HCV disorder thereof.
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Paragraph 00403; 00404

(2014/06/23)

SPIRO RING COMPOUND AS HEPATITIS C VIRUS (HCV) INHIBITOR AND USES THEREOF FIELD OF THE INVENTION
A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.
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Page/Page column 144; 145

(2014/06/23)

Efficient SN2 fluorination of primary and secondary alkyl bromides by copper(I) fluoride complexes
Copper(I) fluoride complexes ligated by phenanthroline derivatives have been synthesized and structurally characterized by X-ray crystallography. These complexes adopt as either ionic or neutral forms in the solid state, depending on the steric bulkiness of the substituent groups on the phenanthroline ligands. These complexes react with primary and secondary alkyl bromides to produce the corresponding alkyl fluorides in modest to good yields. This new method is compatible with a variety of important functional groups such as ether, thioether, amide, nitrile, methoxyl, hydroxyl, ketone, ester, and heterocycle moieties.
Liu, Yanpin,Chen, Chaohuang,Li, Huaifeng,Huang, Kuo-Wei,Tan, Jianwei,Weng, Zhiqiang
p. 6587 - 6592
(2013/12/04)

Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes
A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2- carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC50 = 0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4 = 1324; DPP-9/DPP-4 = 1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.
Wang, Jiang,Feng, Ying,Ji, Xun,Deng, Guanghui,Leng, Ying,Liu, Hong
p. 7418 - 7429
(2013/11/19)

Late-stage deoxyfluorination of alcohols with phenofluor
An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting the selectivity in substrates with multiple alcohols is given.
Sladojevich, Filippo,Arlow, Sophie I.,Tang, Pingping,Ritter, Tobias
supporting information
p. 2470 - 2473
(2013/03/28)

Modulating NHC catalysis with fluorine
Fluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts. By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was possible to modulate the behaviour of the corresponding N-heterocyclic carbene (NHC) with minimal steric alterations to the catalyst core. In this study, the effect of hydrogen to fluorine substitution was evaluated as part of a molecular editing study. X-ray crystallographic analyses of a number of derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglich rearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0:13.0).
Rey, Yannick P.,Gilmour, Ryan
p. 2812 - 2820
(2014/01/06)

OXADIAZOLE COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
The invention provides novel beta-secretase inhibitors and methods for their including methods of treating Alzheimer's disease.
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Page/Page column 94

(2012/05/05)

Method for Manufacturing Hydroxyl Group Substitution Product
In the present invention, a hydroxyl group substitution product is manufactured by reaction of an alcohol with sulfuryl fluoride (SO2F2) in the presence of an organic base and a nucleophile (X?). The present invention is thus effective as an industrial manufacturing method that uses a relatively cheap reagent suitable for large-scale applications and can be accomplished in a simple process with easy purification operation and less waste generation and is suitably applicable for manufacturing of optically active hydroxyl group substitution products, notably optically active α-hydroxyl group substitution ester and optically active 4-hydroxyl group substitution proline. The manufacturing method of the present invention solves all of the prior art problems and can be applied for industrial uses.
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Page/Page column 12

(2011/10/19)

Methods for Production of Optically Active Fluoropyrrolidine Derivatives
Useful industrial methods for producing optically active fluoropyrrolidine derivatives as useful fluorinated intermediates are disclosed.
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Page/Page column 8

(2010/07/10)

Fluorous synthesis of 18F radiotracers with the [ 18F]fluoride ion: Nucleophilic fluorination as the detagging process
Tag team: The flouro-detagging of flourous sulfonates by the [ 18F]fluoride ion was found to be an advantageous strategy for the preparation of various 18F-labeled prosthetic groups and known radiotracers (see picture). Fluorous solid phase extraction (FSPE) was used to separate the excess fluorous precursor from the labeled material, which suggests that traditional purification protocols such as distillation or tedious separation can be avoided. (Chemical Equation Presented).
Bejot, Romain,Fowler, Thomas,Carroll, Laurence,Boldon, Sophie,Moore, Jane E.,Declerck, Jerome,Gouverneur, Veronique
supporting information; experimental part
p. 586 - 589
(2009/04/14)

DEHYDROXYLATED FLUORINATING AGENT
There is provided a novel, useful dehydroxyfluorination agent containing sulfuryl fluoride (SO2F2) and an organic base that is free from a free hydroxyl group in the molecule. According to the present dehydroxyfluorination agent, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is not preferable in large-scale use, and it is possible to advantageously produce optically-active fluoro derivatives, which are important intermediates of medicines, agricultural chemicals and optical materials, for example, 4-fluoroproline derivatives, 2'-deoxy-2'-fluorouridine derivatives, optically-active α-fluorocarboxylate derivatives, and monofluoromethyl derivatives, even in large scale.
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Page/Page column 15

(2009/03/07)

Nucleophilic fluorination of triflates by tetrabutylammonium bifluoride
(Chemical Equation Presented) Careful examination of nucleophilicity, basicity, and leaving group ability led us to discover the nucleophilic fluorination of triflates by weakly basic tetrabutylammonium bifluoride, which provides excellent yields with minimal formation of elimination-derived side products. Primary hydroxyl groups as well as secondary hydroxyl groups in acyclic chains or in five-membered rings are excellent substrates, whereas benzylic and aldol-type secondary hydroxyl groups give poor yields as a result of the instability of their triflates.
Kim, Kyu-Young,Bong, Chan Kim,Hee, Bong Lee,Shin, Hyunik
p. 8106 - 8108
(2008/12/22)

Practical syntheses of 4-fluoroprolines
4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.
Chorghade, Mukund S.,Mohapatra, Debendra K.,Sahoo, Gokarneswar,Gurjar, Mukund K.,Mandlecha, Manish V.,Bhoite, Nitin,Moghe, Santosh,Raines, Ronald T.
experimental part
p. 781 - 784
(2009/04/04)

Development of a kilogram-scale synthesis of cis-LC15-0133 tartrate, a potent dipeptidyl peptidase IV inhibitor
(45)-N-Boc-4-fluoro-L-proline methyl ester (4) was prepared from the following sequence of reactions: esterification of trans-4-hydroxy-L-proline (2), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7. Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9. Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17. Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis- and trans-17 at this stage. After the deprotection of the N,O-methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis- and Awns-mixture of LC15-0133 (1) in the course of tartrate salt formation provided cis-LC15-0133 (1a) tartrate salt in 83% yield (>98% de).
Kim, Bong Chan,Kim, Kyu-Young,Lee, Hee Bong,Shin, Hyunik
p. 626 - 631
(2013/01/03)

1,3-Dihydro-2H-Indole-2-One Compound and Pyrrolidine-2-One Compound Fused With Aromatic Heterocycle
It is intended to provide a drug which is efficacious against pathological conditions relating to arginine-vasopressin V1b receptor. More particularly speaking, it is intended to provide a drug which has a therapeutic or preventive effect on depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug addiction, epilepsy, brain infarction, brain ischemia, brain edema, head injury, inflammation, immune diseases, alopecia and so on. As the results of intensive studies, a novel 1,3-dihydro-2H-indol-2-one compound and a pyrrolidin-2-one compound fused with a heteroaromatic ring, which are highly selective antagonists of arginine-vasopressin V1b receptor, have high metabolic stabilities and show favorable brain penetration and high plasma concentrations, are found, thereby achieving the above objective.
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Page/Page column 59

(2009/01/24)

NOVEL DIPEPTIDYL PEPTIDASE INHIBITORS AND PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to novel compounds representated by formula (I), where R, R1, R2, R3, X, Y, m, n are as defined.The present invention relates to compounds of the general formula I their derivatives, their analogs, their tautomeric forms, their stereoisomers, their diastereomers, their bioisosteres, their polymorphs, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them which are predominantly dipeptidyl peptidase IV inhibitors. The present invention also relates to the processes for the preparation of novel compounds of formula (I) and their use in treating type II diabetes and diabetic complications thereof and also for treating dislipidemia, hypercholesterolemia, obesity and hyperglycemia.
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Page/Page column 61

(2008/06/13)

Synthesis, SAR, and X-ray structure of novel potent DPPIV inhibitors: Oxadiazolyl ketones
Synthesis of a novel series of DPPIV inhibitors with 1,2,4- and 1,3,4-oxadiazolyl ketone derivatives and its structure-activity relationships are discussed. Compound 18h showed good inhibitory activity against DPPIV and favorable pharmacokinetic properties. In vivo pharmacodynamic efficacy and co-crystal structure of compound 18h with DPPIV is also described.
Koo, Ki Dong,Kim, Min Jung,Kim, Sungsub,Kim, Kyoung-Hee,Hong, Sang Yong,Hur, Gwong-Cheung,Yim, Hyeon Joo,Kim, Geun Tae,Han, Hee Oon,Kwon, O Hwan,Kwon, Tae Sik,Koh, Jong Sung,Lee, Chang-Seok
p. 4167 - 4172
(2008/02/09)

VLA-4 INHIBITOR
An object of the present invention is to provide a compound which selectively inhibits binding of a ligand and ±421 integrin (VLA-4), a process for producing the compound, and a medicament containing the compound. A compound represented by the formula (I) etc. orasaltthereof, a process for producing the compound or a salt thereof, a medicament containing the compound or a salt thereof, as well as a preventive and/or a therapeutic agent for a disease caused by cell adhesion, for example, inflammatory reaction, autoimmune disease, cancer metastasis, bronchial asthma, nasal obstruction, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and rejection reaction at transplantation, containing the compound or a salt thereof as a primary component. [wherein Y 1 represents a divalent aryl group etc. , V 1 represents an aryl group etc., and R 11 to R 14 represent H, OH or a halogen atom etc.]
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(2008/06/13)

A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules
Aprotic solvents are usually preferred for the SN2 reactions, because nucleophilicity and hence SN2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with [18F]fluorine (t1/2 = 110 min) for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [ 18F]fluoride-radiolabeled molecular imaging probes-[ 18F]FDG, [18F]FLT, [18F]FP-CIT, and [ 18F]FMISO-in high yield and purity and in shorter times compared to conventional syntheses.
Kim, Dong Wook,Ahn, Doo-Sik,Oh, Young-Ho,Lee, Sungyul,Kil, Hee Seup,Oh, Seung Jun,Lee, Sang Ju,Kim, Jae Seung,Ryu, Jin Sook,Moon, Dae Hyuk,Chi, Dae Yoon
p. 16394 - 16397
(2007/10/03)

PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE FLUOROPROLINE DERIVATIVE
A process for producing an optically active fluoroproline derivative represented by the general formula (2) by fluorinating an optically active hydroxyproline derivative represented by the general formula (1). The process comprises adding N-(2-chloro-1,1,2-trifluoroethyl) diethylamine or N-(1,1,2,3,3,3-hexafluoropropyl) diethylamine which is inexpensive and easy to handle to an aprotic nonpolar organic solvent at a temperature of 10?C or lower and then fluorinating the compound at a temperature ranging from 10 to 50?C. This process enables to produce an optically active fluoroproline derivative represented by the general formula (2) in which the configuration at position-4 of a compound represented by the general formula (1) is inverted, in a high purity with reduced by-product production. (1) (2) wherein R1 represents a substituted or unsubstituted alkyl or aryl group; R2 represents a substituted or unsubstituted alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl or aryloxycarbonyl group; and an asterisk (*) denotes an asymmetric carbon.
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(2008/06/13)

PROCESS FOR PRODUCTION OF CIS-4-FLUORO-L-PROLINE DERIVATIVES
The present invention provides a safer method for production of a cis-4-fluoro-L-proline derivative under milder conditions and in good yield to give a product of high purity on an industrial scale at low cost. Namely, the present invention provides a method for producing a cis-4-fluoro-L-proline derivative, which comprises reacting a trans-4-hydroxy-L-proline derivative of the following Formula [I]: (wherein R1 represents a protecting group for an α-amino group, and R2 represents a protecting group for a carboxyl group) with N,N-diethyl-N-(1,1,2,3,3,3-hexafluoropropyl)amine in the presence of a hydrogen fluoride-scavenger.
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Page/Page column 5-6

(2008/06/13)

Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
Chiba, Jun,Takayama, Gensuke,Takashi, Tohru,Yokoyama, Mika,Nakayama, Atsushi,Baldwin, John J.,McDonald, Edward,Moriarty, Kevin J.,Sarko, Christopher R.,Saionz, Kurt W.,Swanson, Robert,Hussain, Zahid,Wong, Angela,MacHinaga, Nobuo
p. 2725 - 2746
(2007/10/03)

An efficient solid-phase synthesis of biologically important DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine dimers (DSB-120) and their C2-fluorinated analogues
A facile method for the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepine dimers has been developed. p-Nitrophenyl carbonate Wang resin attached to 2-amino-5-methoxy-methyl benzoate has been utilized as the resin-bound starting material and these reactions are monitored by FT-IR spectroscopy of resin beads.
Kamal, Ahmed,Shankaraiah,Devaiah,Reddy, K. Laxma
p. 6553 - 6556
(2007/10/03)

Diastereoselectivity in the alkylation of 4-fluoroproline methyl esters
The reaction of alkylation of cis- and trans-4-fluoro-N-Boc-l-proline methyl esters has been examined by exposing their lithium enolates to a range of alkylating agents. The process showed a high degree of facial diastereoselectivity (except when methyl iodide was used as alkylating agent), invariably giving rise to products bearing the alkyl group in anti with respect to the fluorine atom. A tentative model to account for the observed stereoselectivity is also proposed.
Filosa, Rosanna,Holder, Claude,Auberson, Yves P.
p. 8929 - 8932
(2007/10/03)

1,3-DIHYDRO-2H-INDOL-2-ONE DERIVATIVE
A 1,3-dihydro-2H-indol-2-one derivative expressed by Formula 1 (wherein R1 is a halogen atom, a C1 to C4 alkyl group, etc., and R2 is a hydrogen atom, a halogen atom, etc., or R2 is in the 6-position of the indol-2-one and R1 and R2 join together to form a C3 to C6 alkylene group, R3 is a halogen atom, a hydroxyl group, etc., and R4 is a hydrogen atom, a halogen atom, a C1 to C4 alkyl group, etc., or R4 is in the 3-position of the phenyl and R3 and R4 join together to form a methylenedioxy group, R5 is a hydrogen atom or a fluorine atom, R6 is an ethylamino group, a dimethylamino group, etc., R7 is a C1 to C4 alkoxy group, and R8 is a C1 to C4 alkoxy group), or a pharmaceutically acceptable salt of this derivative. This is a novel compound that has antagonistic activity against an aruginine-vasopressin V1b receptor.
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(2008/06/13)

PROCESS FOR PRODUCTION OF FLUORO DERIVATIVE
A fluoro derivative can be produced by reacting a hydroxy derivative with sulfuryl fluoride (SO2F2) in the presence of an organic base or in the presence of an organic base and a salt or complex composed of an organic base and hydrogen fluoride. This process enables to advantageously produce an optically active fluoro derivative (e.g., a 4-fluoroproline derivative, a 2'-deoxy-2'-fluorouridine derivative and an optically active α-fluorocarboxylate ester derivative) which is an important intermediate for the production of a pharmaceutical or agricultural agent or an optical material, even in large quantity without using a perfluoroalkanesulfonyl fluoride which is undesirable for industrial applications.
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(2008/06/13)

BICYCLIC PYRAZOLE DERIVATIVE
A compound represented by the following formula (I), a prodrug thereof, or a pharmaceutically acceptable salt of either. These are compounds having high DPP-IV inhibitory activity and improved in safety, nontoxicity, etc. (I) [In the formula, R1 represents hydrogen, optionally substituted alkyl, etc.; the solid line and dotted line between A1 and A2 indicate a double bond (A1=A2), etc.; A1 represents a group represented by the formula C(R2), etc.; A2 represents a group represented by the formula C(R4), etc.; R2 represents hydrogen, optionally substituted alkyl, etc.; R4 represents hydrogen, optionally substituted alkyl, etc.; R6 represents hydrogen, optionally substituted aryl, etc.; and -Y represents, e.g.; a group represented by the formula (A): (A) (wherein ml is 0, 1, 2, or 3; and R7 is absent, or one or two R7's are present and each independently represents optionally substituted alkyl, etc.).]
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Page/Page column 179-180

(2010/11/30)

METHOD FOR PRODUCING FLUORINATED PROLINE DERIVATIVE
Disclosed is a method for efficiently producing a high-purity fluorinated proline derivative with high yield. Specifically disclosed is a method for producing a compound represented by the general formula (2) below wherein a compound represented by the formula (1) below is reacted with a fluorination agent, and then chlorine, bromine, iodine, hypochlorous acid, hypochlorite, hypobromous acid, hypobromite or N-halogenosuccinimide is caused to act on the reaction product obtained by the preceding reaction and containing the compound represented by the general formula (2) below and a by-product for chemically changing the by-product. (1) (In the formula (1), R1 represents an unsubstituted or substituted alkyl group having 1-6 carbon atoms or the like; R2 represents an unsubstituted or substituted alkyl group having 1-6 carbon atoms or the like; and R3 represents a hydroxyl group or the like.) (2) (In the formula (2), R1 and R2 are as defined above.)
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(2008/06/13)