- Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form
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We describe a series of improvements to the synthesis of a 3,8-diazabicyclo[3.2.1]octane derivative that result in a reduced step count and higher overall efficiency compared to previously published syntheses. Our method includes optimization and mechanistic understanding of a key diastereoselective cyclization to achieve a >95:5 diastereomeric ratio, as well as demonstration of a unique enzyme-catalyzed amidation reaction using hexamethyldisilazane as both an ammonia source and scavenger. Finally, we identify a novel cocrystal solid form of the target compound that provides improved purity and material properties. Demonstration of the new chemistry to prepare >100 kg of the target compound serves to illustrate the robustness of the new process.
- Brown, Maria S.,Caporello, Michaella A.,Goetz, Adam E.,Johnson, Amber M.,Jones, Kris N.,Knopf, Kevin M.,Kulkarni, Samir A.,Lee, Taegyo,Li, Bryan,Lu, Cuong V.,Magano, Javier,Puchlopek-Dermenci, Angela L. A.,Reyes, Giselle P.,Ruggeri, Sally Gut,Wei, Lulin,Weisenburger, Gerald A.,Wisdom, Richard A.,Zhang, Mengtan
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- Tetracyclic pyrimidinone compound, preparation method, composition and application thereof
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A tetracyclic pyrimidinone compound represented by a formula (I) or a pharmaceutically acceptable salt thereof has a structure represented by a formula (I), is a brand new Lp-PLA2 inhibitor, and can be used for treating neurodegenerative related diseases such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis and thelike.
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Paragraph 0309-0313
(2021/03/31)
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- Synthesis of bridged bicyclic amino alcohols as compact modules for medicinal chemistry
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The efficient synthetic routes of three bridged bicyclic amino alcohols were reported. It is conceivable that these compounds could be readily used as compact modules in medicinal chemistry to fine-tune physicochemical and pharmacokinetic properties, in order to eventually improve the overall quality of small molecule drug candidates.
- Wu, Guolong,Wang, Di,Zhu, Wei,Shen, Hong,Liu, Haixia,Fu, Lei
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supporting information
p. 12 - 21
(2019/01/04)
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- An improved and scalable process for 3,8-diazabicyclo[3.2.1]octane analogues
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An improved and scalable process for substituted 3,8-diazabicyclo[3.2.1] octane was developed. N-Benzyl-2,5-dicarbethoxy-pyrrolidine 2 was reduced to N-benzyl-2,5-dihydroxymethylpyrrolidine 9 and subsequently debenzylated to afford N-Boc-2,5-dihydroxymeth
- Huang, Long Jiang,Teng, Da Wei
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body text
p. 523 - 526
(2012/01/30)
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- N-benzenesulfonyl L-proline compounds as bradykinin antagonists
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This invention provides a compound of the formula (I): or the pharmaceutically acceptable salts thereof wherein X1 and X2 are halo; R1 andR2 are independently hydrogen or C1-4 alkyl; R3 and R4 are each hydrogen or halo; andR5 is(a) -C3-9 diazacycloalkyl optionally substituted with C5-11 azabicycloalkyl;(b) -C3-9 azacycloalkyl-NH-(C5-11 azabicycloalkyl optionally substituted with C1-4 alkyl);(c) -NH-C1-3 alkyl-C(O)-C5-11 diazabicycloalkyl;(d) -NH-C1-3 alkyl-C(O)-NH-C5-11 azabicycloalkyl, the C5-11 azabicycloalkyl being optionally substituted with C1-4 alkyl;(e) -C3-9 azacycloalkyl optionally substituted with C3-9 azacycloalkyl; or(f) -NH-C1-5 alkyl-NH-C(O)-C4-9 cycloalkyl-NH2. These compounds are useful for the treatment of medical conditions mediated by bradykinin such as inflammation, allergic rhinitis, pain, etc. This invention also provides a pharmaceutical composition comprising the above compound.
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- Base-Catalysed Epimerization Behavior and Unusual Reactivity of N-Substituted Derivatives of 2,5-Dicarbalkoxypyrrolidine. Preparation of a Novel Mixed Carbamic Carbonic Anhydride by a 4-(Dimethylamino)pyridine-Catalyzed Acylation
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The equilibration of cis-trans isomers of 1-substituted 2,5-dicarbalkoxypyrrolidine derivatives (1 = CH2Ph, H, CN, CO2R) results in nearly 1:1 mixtures, contrary to a literature report for 1-benzyl-2,5-dicarbalkoxypyrrolidine.Apparent conversion to the tr
- Kemp, D.S.,Curran, Timothy P.
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p. 5729 - 5731
(2007/10/02)
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