- Synthesis of some fluorinated acids, ketones and alcohols derived from 3,3,3-trifluoropropionic acid
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The stereoselective synthesis of 3-fluoro-2-alkenoic acids was achieved by the reaction of lithium 3,3,3-trifluoropropionate with Grignard reagents. 2,2,2-Trifluoroethyl alkyl ketones were prepared by the reaction of 3,3,3-trifluoropropionic acid chloride with either lithium dialkylcuprates or magnesium dialkylcuprates. Optically active 1,1,1-trifluoro-3-alkanols were obtained by the enzymatic hydrolysis of the corresponding acetates.
- Xiao, Ling,Kitazume, Tomoya
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- Inhibitors of phenylethanolamine N-methyltransferase that are predicted to penetrate the blood-brain barrier: Design, synthesis, and evaluation of 3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines that possess low affinity toward the α2-adrenoceptor
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(±)-7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline (7) is one of the most potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) reported to date, but a blood-brain barrier (BBB) model indicates that it cannot penetrate the BBB. To increase the lipophilicity of 7 by addition of a nonpolar substituent to the sulfonamide nitrogen, a small library of (±)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4- tetrahydroisoquinolines was synthesized and evaluated as inhibitors of PNMT and for affinity at the α2-adrenoceptor. In addition, this library probed the PNMT active site surrounding the sulfonamide nitrogen of 7. Bulky substituents on the sulfonamide nitrogen are disfavored at the PNMT active site more so than at the α2-adrenoceptor (thus reducing selectivity). On the other hand, alkyl chains on the sulfonamide nitrogen that contain an electron dense atom, such as a fluorine, are favored in the PNMT active site and possess little α2-adrenoceptor affinity, thereby conferring good selectivity (>500). Several members of the library (8, 14, 17, and 18) have excellent PNMT inhibitory potency and selectivity and are predicted, on the basis of their ClogP value (>0.5), to penetrate the BBB to a significant extent. Compounds 17 and 18 are the most potent and selective PNMT inhibitors reported to date.
- Romero, F. Anthony,Vodonick, Steven M.,Criscione, Kevin R.,McLeish, Michael J.,Grunewald, Gary L.
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- Photo-on-Demand Synthesis of Vilsmeier Reagents with Chloroform and Their Applications to One-Pot Organic Syntheses
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The Vilsmeier reagent (VR), first reported a century ago, is a versatile reagent in a variety of organic reactions. It is used extensively in formylation reactions. However, the synthesis of VR generally requires highly toxic and corrosive reagents such as POCl3, SOCl2, or COCl2. In this study, we found that VR is readily obtained from a CHCl3 solution containing N,N-dimethylformamide or N,N-dimethylacetamide upon photo-irradiation under O2 bubbling. The corresponding Vilsmeier reagents were obtained in high yields with the generation of gaseous HCl and CO2 as byproducts to allow their isolations as crystalline solid products amenable to analysis by X-ray crystallography. With the advantage of using CHCl3, which bifunctionally serves as a reactant and a solvent, this photo-on-demand VR synthesis is available for one-pot syntheses of aldehydes, acid chlorides, formates, ketones, esters, and amides.
- Liang, Fengying,Eda, Kazuo,Okazoe, Takashi,Wada, Akihiro,Mori, Nobuaki,Konishi, Katsuhiko,Tsuda, Akihiko
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p. 6504 - 6517
(2021/05/06)
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- Synthesis and [3,3]-sigmatropic rearrangements of 5-(pentafluorosulfanyl)-pent-3-en-2-ol, its homologues, and trifluoromethyl analogues
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The synthesis of aliphatic (pentafluoro-λ6-sulfanyl)(SF5)-substituted compounds is more challenging than that of the related CF3-substituted analogues. Previous investigations of [3,3]-sigmatropic rearrangements of γ-SF5-substituted allylic alcohols failed to yield 3-SF5-substituted carboxylic acid derivatives. Herein, we present the synthesis of a series of 1-SF5-alk-1-en-3-ols and our efforts to apply them in Johnson-Claisen, ester enolate-Claisen, and Ireland-Claisen rearrangements. Unfortunately, these reactions failed to include the 1-SF5-substituted 1,2-double bond, although successful reactions of analogous CF3-allylic alcohols were reported. Further experiments revealed that bulkiness rather than electronic properties of the SF5group prevented [3,3]-sigmatropic rearrangements. Indeed, the introduction of a competing second vinyl group into the system (1-SF5-penta-1,4-dien-3-ol) confirmed that a Johnson-Claisen rearrangement was successful (92% yield of methyl 7-SF5-hepta-4,6-dienoate) with incorporation of the unsubstituted 4,5-double bond while the 1-SF5-substituted 1,2-double bond remained unchanged. Efforts to apply 1-(SF5CF2)-substituted 1,2-double bond systems, which are similar to CF3analogues in steric requirements, in Johnson-Claisen or ester enolate-Claisen rearrangements failed because of the instability of the SF5CF2substituent under various reaction conditions. On the other hand, when the SF5group was separated from the reaction center by a CH2group instead (5-SF5-pent-3-en-2-ol), Johnson-Claisen rearrangements using six orthoesters provided the target 2-substituted 3-(CH2SF5)-hex-4-enoates in 55-76% yields as ～1?:?1 mixtures of diastereomers. As an example to demonstrate the utility of these products, methyl 3-(CH2SF5)-hex-4-enoate was reduced, and the formed alcohol was oxidized to the aldehyde. Finally, initial experiments showed that the synthetic sequence developed for SF5compounds is also applicable for analogous CF3-substituted allylic alcohols (5-CF3-pent-3-en-2-ol) and their Johnson-Claisen rearrangement.
- Haufe, Günter,Husstedt, Wibke S.,dudziński, piotr,matsnev, Andrej V.,thrasher, Joseph S.
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p. 5607 - 5623
(2021/07/02)
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- Method for producing 3, 3, 3 - [...] (by machine translation)
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PROBLEM TO BE SOLVED: To provide a simple, efficient and inexpensive method capable of manufacturing a 3,3,3-trifluoro propionyl compound useful as a pharmaceutical and agricultural synthetic intermediate in an industrial scale.SOLUTION: There is provided a method of manufacturing a compound represented by the formula [1] by reacting a compound represented by the formula [2] with a polar compound after hydrolysis with using sulfuric acid. In the formula [1], X is Cl, OH, ORor NRR, Ris a Cto Calkyl group, a Cto Chalogenated alkyl group or phenyl group, Rand Rmay be same or different and are each independently a hydrogen, a Cto Calkyl group, a Cto Chalogenated alkyl group or phenyl group and each may together form a ring structure.
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Paragraph 0055-0056; 0073
(2019/10/19)
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- Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate and ureas. Anticancer activity evaluation of N-(3,3,3-trifluoroethyl)-N′-substituted ureas
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A new method is described for producing 3,3,3-trifluoroethyl isocyanate from perfluoroisobutene (PFIB). Isocyanate was used for synthesis of carbamates and ureas. A series of trifluoroethyl-substituted ureas has been tested in the National Cancer Institute (NCI, Bethesda, USA) by the NCI-60 DTP Human Tumor Cell Line Screening Program at a single high dose (10-5 M). The moderate anticancer activity was shown against some types of cancer on the individual human cell lines for leukemia, non-small cell lung cancer and renal cancer.
- Luzina, Elena L.,Popov, Anatoliy V.
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- Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry
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Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,β-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.
- McAlpine, Indrawan,Tran-Dubé, Michelle,Wang, Fen,Scales, Stephanie,Matthews, Jean,Collins, Michael R.,Nair, Sajiv K.,Nguyen, Mary,Bian, Jianwei,Alsina, Luis Martinez,Sun, Jianmin,Zhong, Jiaying,Warmus, Joseph S.,O'Neill, Brian T.
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p. 7266 - 7274
(2015/07/28)
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- NOVEL SULFAMIDE PIPERAZINE DERIVATIVES AS PROTEIN TYROSINE KINASE INHIBITORS AND PHARMACEUTICAL USE THEREOF
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The invention relates to compounds of general Formula (I), Wherein R1, R2, R3, R4, R5, m, n are defined herein, and pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, for use - alone or in combination with one or more other pharmaceutically active compounds- in therapy, as JAK kinase and protein tyrosine kinase inhibitors for preventing, treating or ameliorating diseases and complications thereof, including, for example, psoriasis, atopic dermatitis, rosacea, lupus, multiple sclerosis, rheumatoid arthritis, Type I diabetes, asthma, cancer, autoimmune thyroid disorders, ulcerative colitis, Crohn's disesase, Alzheimer's disease, leukaemia, eye diseases such as diabetic retinopathy and macular degeneration as well as other autoimmune diseases and indications where immunosuppression would be desirable for example in organ transplantation.
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Page/Page column 157
(2012/07/27)
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- PROTEOSTASIS REGULATORS
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The present invention is directed to compounds having the Formulae (Ia-Ie), (II), (IIIa-IIId), (IVa-IVc), (Va-Vb), (VIa-VIe), (VII), (VIIIa-VIIIc), and (IX), pharmaceutically acceptable salts, prodrugs and solvates thereof, compositions of any of thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis comprising an effective amount of these compounds.
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Page/Page column 36
(2013/02/27)
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- Chemoselective halogenation of 2-hydroperfluoroalkyl aldehydes
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2-Hydroaldehydes, RfCH(R)CHO, where Rf = CF 3, C2F5, n-C3F7 and R = CF3, C2F5, n-C3F7, Ph, H, were prepared via acid hydrolysis of the corresponding vinyl ethers, R fC(R) = CHOCH3, which can be readily prepared by reaction of Ph3P+C?HOCH3 with the corresponding ketone. The 2-hydroaldehydes can be chemoselectively converted to the acyl halide, RfCH(R)C(O)X (X = Cl, Br), via free-radical halogenation. The perfluoroalkyl group deactivates the 2-position toward radical abstraction of the 2-hydrogen, and halogenation occurs exclusively at the formyl hydrogen. However, halogenations of the 2-hydroaldehydes in glacial acetic acid chemoselectively gives the 2-haloaldehydes, RfCX(R)CHO, X = Cl, Br. Hydrolysis of the 2-hydroperfluoroacyl halides provides a useful route to 2-hydroperfluoroalkyl branched carboxylic acids, useful ketene precursors. This route avoids the use of toxic fluoroolefins, such as perfluoroisobutylene.
- Wiebe, Donald A.,Burton, Donald J.
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experimental part
p. 4 - 11
(2012/07/13)
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- Bis-exo-2-norbornylboron triflate for stereospecific enolization of 3,3,3-trifluoropropionates
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The first boron-mediated enolization - aldolization of 3,3,3- trifluoropropionates has been reported. The preparation and application of bis-exo-bicyclo[2.2.1]heptan-2-ylboron triflate as a superior reagent for diastereospecific enolization has also been described.
- Ramachandran, P. Veeraraghavan,Parthasarathy, Gowrisankar,Gagare, Pravin D.
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supporting information; experimental part
p. 4474 - 4477
(2010/12/24)
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- PYRIMIDYL INDOLINE COMPOUND
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It is intended to provide a pyrimidyl indoline compound which structurally differs from compounds used as active ingredients in conventional oral hypoglycemic agents and has excellent hypoglycemic effect. The present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
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Page/Page column 58
(2010/08/07)
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- Synthesis of nitrogen bicyclic scaffolds: Pyrimido[1,2-a]pyrimidine-2,6- diones
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The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a] pyrimidinediones starting from isothiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of functionalization/ cyclocondensation reactions. [4+2] Cycloaddition reactions took place between diazadienic chains and various acyl chlorides providing sophisticated heterobicycles.
- Grosjean, Sylvain,Triki, Smail,Meslin, Jean-Claude,Julienne, Karine,Deniaud, David
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experimental part
p. 9912 - 9924
(2011/02/22)
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- ANTIOXIDANT INFLAMMATION MODULATORS: OLEANOLIC ACID DERIVATIVES WITH AMINO AND OTHER MODIFICATIONS AT C-17
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This invention provides, but is not limited to, novel oleanolic acid derivatives having the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.
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Page/Page column 109-110
(2009/12/02)
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- Convenient synthesis of 3,3,3-trifluoropropanoic acid by hydrolytic oxidation of 3,3,3-trifluoropropanal dimethyl acetal
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A convenient and efficient method for preparing 3,3,3-trifluoropropanoic acid (1) is reported. The starting material is 1-chloro-3,3,3-trifluoropropene (2) that can be easily transformed into 3,3,3-trifluoropropanal dimethyl acetal (4) on treatment with methanol and KOH followed by acid-catalyzed addition of methanol. Direct transformation of 4 into 1 was efficiently achieved with 30% aqueous hydrogen peroxide (4.0 equiv.) in the presence of FeCl3 (0.025 equiv.) and hydrochloric acid (0.5 equiv.).
- Komata, Takeo,Akiba, Shinya,Hosoi, Kenji,Ogura, Katsuyuki
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- METHOD FOR PRODUCING 3,3,3-TRIFLUOROPROPIONIC ACID CHLORIDE
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There is provided a process for producing 3,3,3-trifluoropropionyl chloride, which is characterized in that 3,3,3-trifluoropropionaldehyde is chlorinated by a chlorinating agent selected from the group consisting of chlorine (Cl2), sulfuryl chloride (SO2Cl2) and organic N-chloro compounds.
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Page/Page column 3; 10
(2009/01/24)
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- Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
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A compound having the general structure of Formula (I): or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: Q is selected from the group consisting of: and L is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, are useful in treating diseases, disorders, or conditions such as metabolic syndrome and dyslipidemia.
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Page/Page column 43
(2008/06/13)
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- COMPOUNDS HAVING AFFINITY FOR DOPAMINE D3 RECEPTOR AND USES THEREOF
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Compounds of formula (I) and salts thereof are disclosed: wherein A, R1, m, R2, n, R3, R4, q, W1, W2, R5 and R6 are as defined in the description. Methods of preparing the compounds and uses thereof in medicine, for example in the treatment of schizophrenia or drug dependency, are also disclosed.
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Page/Page column 27
(2010/02/15)
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- A [2 + 2] cycloaddition route to dimethylaminomethylene vinamidinium salts
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(figure presented) Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).
- Davies, Ian W.,Tellers, David M.,Shultz, C. Scott,Fleitz, Fred J.,Cai, Dongwei,Sun, Yongkui
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p. 2969 - 2972
(2007/10/03)
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- Cyano-substituted dihydropyrimidine compounds and their use to treat diseases
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds induce mitotic arrest thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inducing mitotic arrest.
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- Trifluoromethylation of Aliphatic Halogen Compounds
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Aryl, heteroaryl or vinyl halides can be trifluoromethylated using CF3CO2Na-CuI.With alkyl iodides, however, the method fails, yielding trifluoroacetyl esters instead.Allylic halogens can be substituted with Burton's reagent, obtained from dihalogenodifluoromethane via CF3CdHal and transmetallation with CuI.A new access to trifluoropropionic acid is thereby found.Prop-2-ynyl bromide produces trifluormethylallene.Attempts at trifluoromethylation of bromoacetate with CF3CO2Na-CuI in NMP (N-methyl-2-pyrrolidone) solution led to formation of the trifluoroacetoxy derivative and of a formal adduct of hexafluoroacetone to the α position of NMP.
- Bouillon, Jean-Philippe,Maliverney, Christian,Merenyi, Robert,Viehe, Heinz G.
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p. 2147 - 2149
(2007/10/02)
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