- Development of a Scalable Synthesis of trans-4-Fluorocyclohexylamine via Directed Hydrogenation
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Herein, a scalable and practical process to prepare trans-4-fluorocyclohexylamine hydrochloride (1a) is described. By exploitation of the embedded gem-difluoride motif in the commercially available 4,4-difluorocyclohexanecarboxylic acid, a derived orthoester-masked acid underwent dehydrofluorination to provide the requisite vinyl fluoride for a directed hydrogenation event, enabling selective access to the trans-configuration of 1a.
- Leung, Joyce C.,Nguyen, Thach T.,Krawiec, Mariusz,Gao, Donghong A.,Reeves, Jonathan T.
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p. 632 - 641
(2020/12/22)
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- Eliminative Deoxofluorination Using XtalFluor-E: A One-Step Synthesis of Monofluoroalkenes from Cyclohexanone Derivatives
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The eliminative deoxofluorination of cyclohexanone derivatives using XtalFluor-E is described. The corresponding monofluoroalkenes are obtained in up to 79% yield. Notably, this one-step procedure occurs at room temperature using readily accessible and cost-effective reagents.
- Vandamme, Mathilde,Paquin, Jean-Fran?ois
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supporting information
p. 3604 - 3607
(2017/07/15)
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- Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy
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We designed and synthesized perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl perhexiline analogues 6a-j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroperhexiline analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro) were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated metabolism. In vitro efficacy studies demonstrated that a number of derivatives retained acceptable potency against CPT-1. Having the best balance of properties, 50 was selected for further evaluation. Like perhexiline, it was shown to be selectively concentrated in the myocardium and, using the Langendorff model, to be effective in improving both cardiac contractility and relaxation when challenged with high fat buffer.
- Tseng, Chih-Chung,Noordali, Hannah,Sani, Monica,Madhani, Melanie,Grant, Denis M.,Frenneaux, Michael P.,Zanda, Matteo,Greig, Iain R.
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supporting information
p. 2780 - 2789
(2017/04/21)
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- A 4, 4 - difluoro-cyclohexyl preparation of formic acid method
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The invention relates to a preparation and purification process of a compound 4,4-difluorocyclohexanecarboxylic acid represented in the formula (I). The preparation and purification process is characterized in that a method comprises steps represented in an equation shown in the specification. The processing method has the characteristics of easiness in operation, facilitation of industrial production of 4,4-difluorocyclohexanecarboxylic acid and environmental protection.
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Paragraph 0029; 0030; 0031
(2017/08/25)
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- Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity
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Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compounds have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into molecules. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, 1k), as a crystalline solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogues. The roles of substiuents on 1k in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 1k smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. 1k also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, respectively, in high yields. In addition, 1k effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcohols to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of 1k in addition to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.
- Umemoto, Teruo,Singh, Rajendra P.,Xu, Yong,Saito, Norimichi
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supporting information; scheme or table
p. 18199 - 18205
(2011/03/18)
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- DISUBSTITUTED-AMINODIFLUOROSULFINIUM SALTS, PROCESS FOR PREPARING SAME AND METHOD OF USE AS DEOXOFLUORINATION REAGENTS
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The invention relates to disubstituted-aminodifluorosulfinium salts represented by the formula (I). Processes for preparing same and methods of use as deoxofluorinating reagent is also provided.
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Page/Page column 45-46
(2010/12/31)
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- Aminodifluorosulfinium salts: Selective fluorination reagents with enhanced thermal stability and ease of handling
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Diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M) are crystalline fluorinating agents that are more easily handled and significantly more stable than Deoxo-Fluor, DAST, and their analogues. These reagents can be prepared in a safer and more cost-efficient manner by avoiding the laborious and hazardous distillation of dialkylaminosulfur trifluorides. Unlike DAST, Deoxo-Fluor, and Fluolead, XtalFluor reagents do not generate highly corrosive free-HF and therefore can be used in standard borosilicate vessels. When used in conjunction with promoters such as Et3N3HF, Et3N2HF, or DBU, XtalFluor reagents effectively convert alcohols to alkyl fluorides and carbonyls to gem-difluorides. These reagents are typically more selective than DAST and Deoxo-Fluor and exhibit superior performance by providing significantly less elimination side products.
- Lheureux, Alexandre,Beaulieu, Francis,Bennett, Christopher,Bill, David R.,Clayton, Simon,Laflamme, Franois,Mirmehrabi, Mahmoud,Tadayon, Sam,Tovell, David,Couturier, Michel
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experimental part
p. 3401 - 3411
(2010/07/07)
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- PHENOTHIAZIN DERIVATES, METHOD FOR THE PRODUCTION THEREOF AND USE THEREOF AS PHARMACEUTICALS
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The invention relates to compounds of the formula 1, wherein R1, R2, R3, R4, R5, R6, R7, A and B are as defined herein, the pharmaceutical compositions and the uses as pharmaceuticals.
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Page/Page column 52; 53
(2010/01/31)
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- Initial synthesis of UK-427,857 (Maraviroc)
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The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilizing a polymer supported reagent.
- Price, David A.,Gayton, Simon,Selby, Matthew D.,Ahman, Jens,Haycock-Lewandowski, Sarah,Stammen, Blanda L.,Warren, Andrew
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p. 5005 - 5007
(2007/10/03)
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- Process for producing alpha, alpha-difluorocycloalkane compound
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A method for producing an α,α-difluorocycloalkane at high purity with good efficiency, which comprises a step of treating a fluorocycloalkene with hydrogen fluoride wherein the fluorocycloalkene has one fluorine atom directly bonded to a carbon atom of carbon-carbon unsaturated double bond, more preferably, a step of directly adding the hydrogen fluoride to a reaction mixture obtained by treating the cycloalkanone with the de-oxygen fluorinating agent.
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