- Total Synthesis of Glipizide and Glibenclamide in Continuous Flow
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Glipizide and glibenclamide remain some of the widely prescribed antidiabetic sulfonylurea drugs for the treatment of type 2 diabetes mellitus. Herein the authors report on an isocyanate-free synthetic procedure towards the preparation of these on demand drugs at multigram scale using continuous flow technology. The safety concern over the use of isocyanates in most of the existing synthetic routes was dealt with in this present work by using N-carbamates synthesised in situ from activation of amines with chloroformates as safer alternatives. An overall yield of 80–85 % was obtained for the semi-telescoped steps within 10 min total residence time.
- Sagandira, Cloudius R.,Khasipo, Agnes Z.,Watts, Paul
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supporting information
p. 16028 - 16035
(2021/10/14)
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- Dehydrogenative Synthesis of Carbamates from Formamides and Alcohols Using a Pincer-Supported Iron Catalyst
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We report that the pincer-ligated iron complex (iPrPNP)Fe(H)(CO) [1, iPrPNP- = N(CH2CH2PiPr2)2-] is an active catalyst for the dehydrogenative synthesis of N-alkyl- and N-aryl-substituted carbamates from formamides and alcohols. The reaction is compatible with industrially relevant N-alkyl formamides, as well as N-aryl formamides, and 1°, 2°, and benzylic alcohols. Mechanistic studies indicate that the first step in the reaction is the dehydrogenation of the formamide to a transient isocyanate by 1. The isocyanate then reacts with the alcohol to generate the carbamate. However, in a competing reaction, the isocyanate undergoes a reversible cycloaddition with 1 to generate an off-cycle species, which is the resting state in catalysis. Stoichiometric experiments indicate that high temperatures are required in catalysis to facilitate the release of the isocyanate from the cycloaddition product. We also identified several other off-cycle processes that occur in catalysis, such as the 1,2-addition of the formamide or alcohol substrate across the Fe-N bond of 1. It has already been demonstrated that the transient isocyanate generated from dehydrogenation of the formamide can be trapped with amines to form ureas and, in principle, the isocyanate could also be trapped with thiols to form thiocarbamates. Competition experiments indicate that trapping of the transient isocyanate with amines to produce ureas is faster than trapping with an alcohol to produce carbamates and thus ureas can be formed selectively in the presence of alcohols. In contrast, thiols bind irreversibly to the iron catalyst through 1,2 addition across the Fe-N bond of 1, and it is not possible to produce thiocarbamates. Overall, our mechanistic studies provide general guidelines for facilitating dehydrogenative coupling reactions using 1 and related catalysts.
- Bernskoetter, Wesley H.,Hazari, Nilay,Mercado, Brandon Q.,Townsend, Tanya M.
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p. 10614 - 10624
(2021/09/02)
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- Highly Regioselective Carbamoylation of Electron-Deficient Nitrogen Heteroarenes with Hydrazinecarboxamides
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The use of hydrazinecarboxamides as a new class of carbamoylating agents has been established through the dehydrazinative Minisci reaction of electron-deficient nitrogen heteroarenes. A wide range of electron-deficient nitrogen heteroarenes, including isoquinoline, quinoline, pyridine, phenanthridine, quinoxaline, and phthalazine, underwent copper/acid-catalyzed oxidative carbamoylation with hydrazinecarboxamide hydrochlorides to afford structurally diverse nitrogen-heteroaryl carboxamides as single regioisomers in moderate to excellent yields. The functional group tolerance was substantially demonstrated in the direct carbamoylation of quinine obviating multistep sequences involving protecting groups and prefunctionalization of the heterocycle.
- He, Zeng-Yang,Huang, Chao-Fan,Tian, Shi-Kai
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supporting information
p. 4850 - 4853
(2017/09/23)
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- One-pot synthesis of carbamates and thiocarbamates from Boc-protected amines
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A highly efficient one-pot procedure for the synthesis of carbamates and thiocarbamates has been described. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, the isocyanate intermediates were generated in situ for further reactions with alcohols and thiols to afford the desired carbamates and thiocarbamates in high yields.
- Kim, Hee-Kwon,Lee, Anna
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p. 4890 - 4892
(2016/10/21)
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- Facile one-pot synthesis of unsymmetrical ureas, carbamates, and thiocarbamates from Cbz-protected amines
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A novel one-pot synthesis of unsymmetrical ureas, carbamates and thiocarbamates from Cbz-protected amines has been developed. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, isocyanates are generated in situ, which facilitate rapid reaction with amines, alcohols, and thiols to afford the corresponding ureas, carbamates and thiocarbamates in high yields.
- Kim, Hee-Kwon,Lee, Anna
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supporting information
p. 7345 - 7353
(2016/08/05)
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- Synthesis and application of isocyanates radiolabeled with carbon-11
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Carbon-11 labeled isocyanates are efficiently prepared by dehydration of [11C]carbamate salts, which in turn are easily formed from cyclotron-produced [11C]CO2 and amines in the presence of a CO2 fixation agent. The [11C]isocyanates are useful radiosynthons for the synthesis of a variety of [carbonyl-11C]- labeled asymmetrical ureas and carbamate esters. The method is well suited to incorporate any isotope of carbon, and is especially useful for positron emission tomography (PET) radiotracers for in vivo imaging. This is demonstrated by using the method to make [carbonyl-11C]-6-hydroxy-[1,1′- biphenyl]-3-yl cyclohexylcarbamate which is a novel radiotracer for PET imaging of fatty acid amide hydrolase.
- Wilson, Alan A.,Garcia, Armando,Houle, Sylvain,Sadovski, Oleg,Vasdev, Neil
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supporting information; experimental part
p. 259 - 264
(2011/03/19)
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- Phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as carbonyl source: Facile and selective synthesis of carbamates and ureas under mild conditions
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The selective syntheses of carbamates, symmetric -ureas, and unsymmetrical ureas have been accomplished by the -reaction of amines with phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as a carbonyl source under mild conditions. It is noteworthy that this process is mild, economic, and convenient.
- Lee, Hyung-Geun,Kim, Min-Jung,Park, Song-Eun,Kim, Jeum-Jong,Kim, Bo Ram,Lee, Sang-Gyeong,Yoon, Yong-Jin
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experimental part
p. 2809 - 2814
(2010/03/03)
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- Design, synthesis, and structure - Activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors
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Fatty acid amide hydrolase (FAAH), an intracellular serine hydrolase enzyme, participates in the deactivation of fatty acid ethanolamides such as the endogenous cannabinoid anandamide, the intestinal satiety factor oleoylethanolamide, and the peripheral analgesic and anti-inflammatory factor palmitoylethanolamide. In the present study, we report on the design, synthesis, and structure-activity relationships (SAR) of a novel class of potent, selective, and systemically active inhibitors of FAAH activity, which we have recently shown to exert potent anxiolytic-like effects in rats. These compounds are characterized by a carbamic template substituted with alkyl or aryl groups at their O- and N-termini. Most compounds inhibit FAAH, but not several other serine hydrolases, with potencies that depend on the size and shape of the substituents. Initial SAR investigations suggested that the requirements for optimal potency are a lipophilic N-alkyl substituent (such as n-butyl or cyclohexyl) and a bent O-aryl substituent. Furthermore, the carbamic group is essential for activity. A 3D-QSAR analysis on the alkylcarbamic acid aryl esters showed that the size and shape of the O-aryl moiety are correlated with FAAH inhibitory potency. A CoMSIA model was constructed, indicating that whereas the steric occupation of an area corresponding to the meta position of an O-phenyl ring improves potency, a region of low steric tolerance on the enzyme active site exists corresponding to the para position of the same ring. The bent shape of the O-aryl moieties that best fit the enzyme surface closely resembles the folded conformations observed in the complexes of unsaturated fatty acids with different proteins. URB524 (N-cyclohexylcarbamic acid biphenyl-3-yl ester, 9g) is the most potent compound of the series (IC50 = 63 nM) and was therefore selected for further optimization.
- Tarzia, Giorgio,Duranti, Andrea,Tontini, Andrea,Piersanti, Giovanni,Mor, Marco,Rivara, Silvia,Plazzi, Pier Vincenzo,Park, Chris,Kathuria, Satish,Piomelli, Daniele
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p. 2352 - 2360
(2007/10/03)
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- A highly-efficient synthesis of benzoxazine-2,4-diones
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Base-promoted reaction of salicylate esters with isocyanates provides a highly efficient route to benzoxazine-2,4-diones.
- Boontheung, Pinmanee,Perlmutter, Patrick
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p. 2629 - 2630
(2007/10/03)
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- α-Haloalkyl haloformates and related compounds. 2. Synthesis of dichloromethyl carbonates and their transformation to carbamates
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Dichloromethyl carbonates, easily available upon treatment alcohols with dichloromethyl chloroformate, react with various amines to give carbamates in high yield under mild conditions. Extension of the reaction for the synthesis of oxazolones from 2-aminoalcohols is also demonstrated.
- Patonay,Hegedus,Mogyorodi,Zolnai
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p. 2507 - 2513
(2007/10/02)
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- α-Haloalkyl Haloformates and Related Compounds 1. A Convenient Synthesis of Carbamates via Chloromethyl Carbamates
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The preparation of carbamates under mild conditions utilizing a new class of activated carbonates (containing chloromethyl function) is described.
- Patonay, Tamas,Patonay-Peli, Erzsebet,Mogyorodi, Ferenc
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p. 2865 - 2885
(2007/10/02)
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