- Method for pipeline continuous fluorination with fluorine salt as fluorine source
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The method comprises the following steps: dissolving a fluorine salt in an aqueous polar aprotic solvent as reaction liquid A, dissolving an aryl (heterocyclic) chloride in a polar aprotic solvent as reaction liquid B, and reacting a polar aprotic solvent in the reaction liquid A with a polar aprotic solvent of the reaction liquid B. The reaction medium consisting of the preheated reaction liquid A and the preheated reaction liquid B enters the reaction coil for a fluorination reaction, and the resulting product from the reaction coil is subjected to post-treatment to obtain the product. The method has the characteristics of no need of adding a phase transfer catalyst, continuous production, low production cost and the like.
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Paragraph 0056-0061; 0094-0096
(2021/10/27)
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- Nucleophilic Fluorination of Heteroaryl Chlorides and Aryl Triflates Enabled by Cooperative Catalysis
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Aryl and heteroaryl fluorides are growing to be dominant motifs in pharmaceuticals and agrochemicals, yet they are rare in both nature and commodity chemicals. As a consequence, there is an increasingly urgent need to develop mild, cost-effective, and scalable methods for fluorination. The most straightforward route to synthesize aryl fluorides is through the halide exchange "halex"reaction, but conditions, cost, and atom economy preclude most available methods from large-scale manufacturing processes. We report a new approach that leverages the cooperative action of 18-crown-6 ether and tetramethylammonium chloride to catalytically access the reactivity of tetramethylammonium fluoride and achieve halex fluorinations under mild conditions with operational ease. The described methodology readily converts both heteroaryl chlorides and aryl triflates to their corresponding (hetero)aryl fluorides in high yields and purities.
- Hong, Cynthia M.,Whittaker, Aaron M.,Schultz, Danielle M.
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p. 3999 - 4006
(2021/03/09)
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- Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination
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Nucleophilic aromatic fluorination (SNAr) is among the most common methods for the formation of C(sp2)-F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me4NF·ROH) as fluoride sources for SNAr fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me4NF·t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for SNAr fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated.
- Bland, Douglas C.,Lee, So Jeong,Morales-Colón, Mariá T.,Sanford, Melanie S.,Scott, Peter J. H.,See, Yi Yang
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supporting information
p. 4493 - 4498
(2021/06/28)
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- PROCESS FOR FLUORINATING COMPOUNDS
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Disclosed are mild temperature (e.g., from 0 to 80°C) SNAr fluorinations of a variety of halide and sulfonate substituted aryl and heteroaryl substrates using NMe4F.
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Page/Page column 29; 33; 35
(2017/02/28)
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- Synthesis and characterization of 2-pyridylsulfur pentafluorides
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Current approaches to prepare SF5-substituted heterocycles during the synthesis of targeted heterocyclic compounds require the use of SF5-functionalized aryl or alkyne reagents or SF5Cl as a source of the SF5 functional group. Herein we report that excess oxidative fluorination of 2,2' -dipyridyl disulfide with a KF/Cl2 /MeCN system leads to the formation of thirteen new 2-pyridylsulfur chlorotetrafluorides (2-SF4Cl-pyridines). These molecules are found to undergo further chlorine-fluorine exchange reactions by treatment with silver(I) fluoride enabling ready access to a series of ten new substituted 2-pyridylsulfur pentafluorides (2-SF5-pyridines). This is the first preparatively simple and readily scalable example of the transformation of an existing heterocyclic sulfur functionality to prepare SF5-substituted heterocycles.
- Kanishchev, Oleksandr S.,Dolbier, William R.
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supporting information
p. 280 - 284
(2015/04/21)
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- Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination
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This paper describes the room-temperature SNAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-effective than fluorination with CsF.
- Schimler, Sydonie D.,Ryan, Sarah J.,Bland, Douglas C.,Anderson, John E.,Sanford, Melanie S.
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p. 12137 - 12145
(2016/01/09)
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- Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents
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Dihydrolevoglucosenone (Cyrene) is a bio-based molecule, derived in two simple steps from cellulose, which demonstrates significant promise as a dipolar aprotic solvent. The dipolarity of dihydrolevoglucosenone is similar to NMP, DMF and sulpholane. Dihydrolevoglucosenone demonstrates similar performance to NMP in a fluorination reaction and the Menschutkin reaction. This journal is the Partner Organisations 2014.
- Sherwood, James,De Bruyn, Mario,Constantinou, Andri,Moity, Laurianne,McElroy, C. Rob,Farmer, Thomas J.,Duncan, Tony,Raverty, Warwick,Hunt, Andrew J.,Clark, James H.
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supporting information
p. 9650 - 9652
(2014/08/18)
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- Preparation of nitropyridines by nitration of pyridines with nitric acid
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Preparation of nitropyridines by nitration of pyridines with nitric acid was discussed. Trifluoroacetic anhydride was chilled in an ice bath and the pyridine or substituted pyridines were slowly added and stirred at chilled conditions for 2 h. Relative amounts of the reactants were required for the nitration of pyridine were characterized by 1H and Nuclear magnetic resonance (NMR) spectroscopy and elemental analysis. It was observed that the yields of β-nitropyridines obtained using the standard protocol were generally higher than those obtained using N2O3.
- Katritzky, Alan R.,Scriven, Eric F. V.,Majumder, Suman,Akhmedova, Rena G.,Vakulenko, Anatoliy V.,Akhmedov, Novraz G.,Murugan, Ramiah,Abboud, Khalil A.
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p. 538 - 541
(2007/10/03)
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- Syntheses and EGFR kinase inhibitory activity of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles
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The syntheses and EGFR kinase inhibitory activity of a series of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles are described. Both reversible and irreversible binding inhibitors were prepared. These series were compared with each other and with the corresponding 4-anilinoquinoline-3-carbonitriles. Compounds having a 1,7-naphthyridine core structure can retain high potency while those with a 1,8-naphthyridine core are significantly less active. These results are consistent with molecular modeling observations.
- Wissner, Allan,Hamann, Philip R.,Nilakantan, Ramaswamy,Greenberger, Lee M.,Ye, Fei,Rapuano, Timothy A.,Loganzo, Frank
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p. 1411 - 1416
(2007/10/03)
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- SUBSTITUTED-3-CYANO-[1.7],[1.5], AND [1.8]-NAPHTHYRIDINE INHIBITORS OF TYROSINE KINASES
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This invention provides compounds of formula (I) having structure (a) wherein A'' is a diavalent moiety selected from the group (a, b, c) which are useful as inhibitors of protein tyrosine kinase.
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- Bisarylamines as potassium channel openers
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Compounds, compositions and methods are provided which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides bisarylamines, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases) and as neuroprotective agents (e.g., to prevent stroke and the like) by opening potassium channels associated with the onset or recurrence of the indicated conditions.
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- Pyridine-substituted benzanilides as potassium ion channel openers
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The present invention provides a genus of pyridine-substituted benzanilides that are useful as openers of potassium ion channels. The compounds of the invention are of use in both therapeutic and diagnostic methods.
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- Pyridine-substituted benzanilides as potassium ion channel openers
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The present invention provides a genus of pyridine-substituted benzanilides that are useful as openers of potassium ion channels. The compounds of the invention are of use in both therapeutic and diagnostic methods.
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- Process for preparing 4,6-disubstituted pyrido[3,4-d]pyrimidines
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An improved process for the preparation of 4,6-disubstituted pyrido[3,4-d]pyrimidines is described where 5-amino-2-fluoropyridine is converted in seven operations to the desired products, as well as other valuable intermediates used in the process.
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- 3-Pyridyl enantiomers and their use as analgesics
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The present invention relates to a method of controlling pain in mammals, including humans, comprising administering to a mammal or patient in need of treatment thereof selected compounds of formula I: STR1 or a pharmaceutically acceptable salt thereof. The invention further relates to selected (R) and (S) compounds of formula I above which are useful as analgesics as well as neuronal cell death preventors and anti-inflammatories.
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- Synthesis of 6-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones via directed lithiation of 2-substituted 5-aminopyridine derivatives
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Directed lithiation of Boc or pivaloyl derivatives of 2-substituted 5-aminopyridines with BuLi-TMEDA in diethyl ether at -10°C gave 4-lithio derivatives which were quenched with CO2 to give the analogous C-4 carboxylic acids. Hydrolysis of the protecting groups with either TFA or aqueous KOH gave 2-substituted 5-aminopyridine-4-carboxylic acids which were converted to 6-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones by reaction with formamide or, more optimally, formamidine acetate. Boc protected aminopyridines provided the best overall results, with synthesis of these derivatives best achieved by direct reaction of the aminopyridine with di-tert-butyl dicarbonate in the absence of added base.
- Rewcastle, Gordon W.,Denny, William A.,Winters, R. Thomas,Colbry, Norman L.,Showalter, H. D. Hollis
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p. 2221 - 2226
(2007/10/03)
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- Halogen-Exchange Fluorination of Aromatic Halides with HF or HF-Base
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Heteroatomic halides such as 2-chloropyrimidines and 2-chloropyridines, and 2,4-dinitrochlorobenzene underwent halogen-exchange fluorination with the treatment of HF or HF-base solutions to afford the corresponding fluorides in good yields.
- Fukuhara, Tsuyoshi,Yoneda, Norihiko
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p. 509 - 512
(2007/10/02)
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- NUCLEOPHILIC FLUORINATION OF CHLORINATED N-HETEROCYCLES WITH TETRABUTYLPHOSPHONIUM HYDROGENDIFLUORIDE AND DIHYDROGENTRIFLUORIDE
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Fluorination of various chlorinated N-heterocycles with tetrabutylphosphonium hydrogendifluoride (1) or dihydrogentrifluoride (2) readilly proceeded in high yields under mild conditions.
- Uchibori, Yukitaka,Umeno, Masayuki,Yoshioka, Hirosuke
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p. 1507 - 1510
(2007/10/02)
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- Aprotic Nitration (NO2+BF4-) of 2-Halo- and 2,6-Dihalopyridines and Transfer-Nitration Chemistry of Their N-Nitropyridinium Cations
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NO2+BF4- nitration of 2,6-dibromo-1 and 2,6-dichloropyridine 2 in CH3CN results in predominant C-nitration, whereas in CH2Cl2, N-nitration is predominant.With 2,6-difluoropyridine 3 only C-nitration was observed.Dehalogenation of the C-nitrated 1 and 2 affords 3-nitropyridine (3-NP) in moderate but greatly improved yields over conventional protic nitration of pyridine.Despite favorable presence of steric inhibition to resonance and the I-effect of halogens, N-nitrated pyridinium salts 1b and 2b do not transfer-nitrate to aromatics even under forcing conditions.The lack of transfer-nitration reactivity is not due to in situ rearrangement of the nitro onium to nitrito oniums ions.A mechanism involving neighboring group participation by the 2,6-halogens is proposed.The monohalo-N-nitropyridinium cations transfer-nitrate toluene and benzene.Transfer nitration selectivity of the 2-bromo-N-nitro- and 2-chloro-N-nitropyridinium cations are comparable (KT/KB = 41-44), but the 2-fluoro-N-nitro cation is much less selective (more reactive) (KT/KB = 15.4), indicative of a stronger -I effect, weakening the N+-N+ bond.
- Duffy, Joseph L.,Laali, Kenneth Khosrow
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p. 3006 - 3009
(2007/10/02)
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- THE SYNTHESIS OF ORGANOFLUORINE COMPOUNDS USING POTASSIUM FLUORIDE-TETRAPHENYLPHOSPHONIUM BROMIDE SYSTEMS.
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The reactivity of potassium fluoride in nucleophilic fluorine transfer reactions can appreciably enhanced by the presence of tetraphenyl phosphonium bromide.Rate accelerations are especially large in non dipolar aprotic solvents.
- Clark, James H.,Macquarrie, Duncan J.
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p. 111 - 114
(2007/10/02)
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- ACTION DU METHYLTRI(N-BUTYL)FLUOROPHOSPHORANE SUR LES HALOGENURES ET LES SULFONATES D'ALKYLE
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Monofluorophosphoranes R3MePF are used in exchange reactions to prepare monofluorinated organic compounds.Tri(n-butyl)methylfluorophosphorane (n-Bu3MePF), easily available, is the most reactive.In solvents of low polarity or even in non-polar solvents, it reacts at -70 deg C with alkyl sulphonates and halides activated by ester, ketone, or ether functions.Thus, fluorinated epoxides can be obtained directly by exchange from their chlorinated or brominated homologues.
- Leroy, J.,Bensoam, J.,Humiliere, M.,Wakselman, C.,Mathey, F.
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p. 1931 - 1936
(2007/10/02)
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