- ALTERNATE PROCESSES FOR THE PREPARATION OF OMECAMTIV MECARBIL
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Aspects of the present application relate to process for the preparation of Omecamtiv mecarbil and salts thereof. Specific aspects relate to novel urea intermediate, preparative process thereof and its use in the preparation of Omecamtiv mecarbil and salts thereof. The improved process for the preparation of Omecamtiv mecarbil are industrially viable.
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- SYNTHESIS OF OMECAMTIV MECARBIL
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Provided herein is a synthesis for omecamtiv mecarbil dihydrochloride hydrate and various intermediates. (I)
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- Development of a Factory Process for Omecamtiv Mecarbil, a Novel Cardiac Myosin Activator
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The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5-phosphate. Overall, the longest linear sequence consists of six steps, including a final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modified-release formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturability.
- Caille, Seb,Allgeier, Alan M.,Bernard, Charles,Correll, Tiffany L.,Cosbie, Andrew,Crockett, Richard D.,Cui, Sheng,Faul, Margaret M.,Hansen, Karl B.,Huggins, Seth,Langille, Neil,Mennen, Steven M.,Morgan, Bradley P.,Morrison, Henry,Muci, Alexander,Nagapudi, Karthik,Quasdorf, Kyle,Ranganathan, Krishnakumar,Roosen, Philipp,Shi, Xianqing,Thiel, Oliver R.,Wang, Fang,Tvetan, Justin T.,Woo, Jacqueline C. S.,Wu, Steven,Walker, Shawn D.
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p. 1558 - 1567
(2019/09/04)
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- Palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate: A practical synthesis of unsymmetrical ureas
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An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate is reported. The protocol allows for the synthesis of unsymmetrical N,N'-di- and N,N,N'-trisubstituted ureas in one pot and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive elimination steps of the reaction, including the first demonstration of reductive elimination from an arylpalladium isocyanate complex to produce an aryl isocyanate.
- Vinogradova, Ekaterina V.,Fors, Brett P.,Buchwald, Stephen L.
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p. 11132 - 11135
(2012/08/28)
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- Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions
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A facile synthesis of unsymmetrical N,N′-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation-deprotection protocol, followed by a second arylation.
- Breitler, Simon,Oldenhuis, Nathan J.,Fors, Brett P.,Buchwald, Stephen L.
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supporting information; experimental part
p. 3262 - 3265
(2011/08/07)
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- Compounds, Compositions and Methods
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Certain substituted urea derivatives modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 20-21
(2009/08/14)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 90-91
(2010/11/27)
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- COMPOUNDS, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 48
(2010/11/28)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives modulate diskeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T, and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere, and are useful in the treatment of obesity, sarcopenia, wasting syndrome, frailty, muscle spasm, cachexia, neuromuscular diseases (e.g., amyotrophic lateral sclerosis, spinal muscular atrophy, familial or acquired myopathies or muscular dystrophies), post-surgical and post-traumatic muscle weakness, and other conditions.
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Page/Page column 60-61
(2008/06/13)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 47-48
(2010/11/27)
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- Compounds, compositions and methods
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 33-34
(2008/06/13)
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