- Concise and Additive-Free Click Reactions between Amines and CF3SO3CF3
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Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3SO3CF3 will be increasingly as important as SO2F2 as a click agent in future drug design and development.
- Song, Hai-Xia,Han, Zhou-Zhou,Zhang, Cheng-Pan
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supporting information
p. 10907 - 10912
(2019/08/02)
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- STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
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The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.
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- Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release
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Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
- Smith, Chris D.,Wang, Aixia,Vembaiyan, Kannan,Zhang, Jingqun,Xie, Cuihong,Zhou, Qiang,Wu, Guogen,Chen, S. R. Wayne,Back, Thomas G.
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p. 8626 - 8655
(2013/12/04)
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- Convenient synthesis of Carvedilol utilizing 3-(9H-carbazol-4-yloxy)-1- chloropropan-2-yl phenyl carbonate as a key intermediate
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Convenient synthesis of pharmaceutically important moiety Carvedilol, 1 (β-adrenergic blocking agent) has been reported utilizing 3-(9H-carbazol-4-yloxy)-1-chloropropan-2-yl phenyl carbonate 8 as a key intermediate. The synthetic scheme involves the reaction of intermediate 8 with 2-(2-methoxy phenoxy)- ethanamine 5 by using N,N-Dimethyl-4-aminopyridine (DMAP) in N,N-dimethylformamide (DMF) which yield 3-(2-(2- methoxyphenoxy)ethyl)-5- ((9H-carbazol-4-yloxy)methyl)oxazolidin- 2-one 7 via 1-(9H-carbazol-4-yloxy)-3- chloropropan-2-yl 2- (2-methoxyphenoxy)ethylcarbamate 6. The resulted compound 7 has further been converted to the required Carvedilol and this approach could be useful for the preparation of many β-amino alcohols without formation of Impurity B.
- Kumar, B. Anand,Ashrafuddin,Rajesh,Parveen, Sadhika,Madhusudhan
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p. 780 - 784
(2012/06/30)
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- Lewis acid mediated nucleophilic ring-opening of 1-Benzhydryl Azetidine-3-ol with aryl alcohols: A formal synthesis of carvedilol
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Lewis acid mediated nucleophilic azetidine ring opening of 1-benzhydrylazetidine-3-ol with phenolic oxygen as nucleophile is reported. This approach was also utilized successfully to synthesize, carvedilol a β-adrenergic blocking agent.
- Krishna Reddy,Ramamohan,Ganesh,Srinivas,Mukkanti,Madhusudhan
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p. 3468 - 3472
(2012/07/30)
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- Synthesis of racemic and chiral Carvedilol starting from corresponding 5-(chloromethyl)oxazolidin-2-one
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The synthesis of racemic Carvedilol ((±)-1) has been achieved starting from 2-(chloromethyl) oxirane ((±)-2) in a four-step sequence. 5-(Chloromethyl) oxazolidin-2-one ((±)-3) and 5-((9Hcarbazol-4-yloxy) methyl) oxazolidin-2-one ((±)-4) are intermediates. A similar sequence starting from (R)- or (S)-2-(chloromethyl)oxirane 2 give corresponding chiral 5-((9Hcarbazol-4-yloxy)methyl) oxazolidin-2-one 4 followed by chiral Carvedilol 1. The synthetic sequence followed avoids the formation of impurity B (bis impurity). This approach can be useful for the preparation of pharmaceutically important moieties containingβ-amino alcohols without formation of bis impurity.
- Anand Kumar,Veera Babu,Rao, Rama Koteshwar,Srinivas, Kumbam,Madhusudhan,Mukkanti
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p. 1430 - 1435
(2012/11/06)
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- A facile synthesis of carvedilol, β-adrenergic blocking agent, via a key 5-substituted-.-oxazolidinone intermediate
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A facile synthesis of Carvedilol via a key 5-substituted-.-oxazolidinone intermediate is described and this approach avoids the formation of bis side product (impurity B). This approach could be useful for the preparation of many β-amino alcohols without formation of bis impurity.
- Madhusudhan,Kumar, B. Anand,Chintamani,Rao, M. Narasimha,Udaykiran,Suresh,Kumar, V. Kiran,Mukkanti
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experimental part
p. 606 - 610
(2010/12/25)
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- Ryanodine receptor inhibitors and methods relating thereto
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The present invention provides novel ryanodine receptor type 2 (RyR2) inhibitors and methods of their use in the treatment of cardiac conditions. In general, the RyR2 inhibitors of the present invention assist in the normalization of intracellular calcium homeostasis. In certain embodiments, the RyR2 inhibitors are store-overload-induced Ca2+ release (SOICR) inhibitors that minimally inhibit or do not inhibit Ca2+-induced Ca2+ release (CICR), thereby providing beneficial effects in cardiac therapy.
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Page/Page column 17
(2010/11/28)
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- Intermediate for the preparation of carvedilol
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A new intermediate having the formula (V) ???wherein X and Y are leaving groups; and R is phenyl optionally substituted with one or more electrophilic substituents; is disclosed. The new intermediate is useful for the preparation of carvedilol in a synthesis that avoids the use of any oxirane or similar hazardous reagents.
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