Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

Hansen Marvin M.; Jarmer Daniel J.; Arslantas Enver; DeBaillie Amy C.; Frederick Andrea L.; Harding Molly; Hoard David W.; Hollister Adrienne; Huber Dominique; Kolis Stanley P.; Kuehne-Willmore Jennifer E.; Kull Thomas; Laurila Michael E.; Linder Ryan J.; Martin Thomas J.; Martinelli Joseph R.; McCulley Michael J.; Richey Rachel N.; Starkey Derek R.; Ward Jeffrey A.; Zaborenko Nikolay; Zweifel Theo

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Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

机译：BACE抑制剂LY2886721。的合成第二部分异恶唑烷作为手性氨基噻嗪的前体，选择性肽偶联和可控的反应结晶

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An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by "pH cycles" to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided desirable API bulk density and powder flow properties.

机译：提出了五个步骤的高效合成LY2886721（1），手性硝酮环加合物2的总收率为46％。关键挑战是在氢解过程中最大限度地减少去氟杂质的形成，以裂解异恶唑烷环并去除苄基手性助剂。氨基噻嗪部分的安装要求对试剂BzNCS和CDI进行仔细的化学计量控制，包括原位转化监测，以最大程度地减少副产物的形成。显着的区域选择性肽偶联提供了1，而没有在氨基噻嗪氮上的竞争性酰化或双酰化。综合考虑化学和结晶过程，确定了肽偶联和反应性结晶的最佳溶剂体系，可提供1的高纯度并具有物理性质控制。在结晶接近结束时进行浆料研磨操作，然后进行“ pH循环”以消化研磨过程中形成的细粉，显着降低了晶体的长径比，并提供了所需的API堆积密度和粉末流动性。

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《Organic process research & development》 |2015年第9期|共17页
作者
Hansen Marvin M.; Jarmer Daniel J.; Arslantas Enver; DeBaillie Amy C.; Frederick Andrea L.; Harding Molly; Hoard David W.; Hollister Adrienne; Huber Dominique; Kolis Stanley P.; Kuehne-Willmore Jennifer E.; Kull Thomas; Laurila Michael E.; Linder Ryan J.; Martin Thomas J.; Martinelli Joseph R.; McCulley Michael J.; Richey Rachel N.; Starkey Derek R.; Ward Jeffrey A.; Zaborenko Nikolay; Zweifel Theo;
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1. Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization [J] . Hansen Marvin M., Jarmer Daniel J., Arslantas Enver, Organic process research & development . 2015,第9期

机译：BACE抑制剂LY2886721。的合成第二部分异恶唑烷作为手性氨基噻嗪的前体，选择性肽偶联和可控的反应结晶
2. Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2 [J] . Fujimoto Kazuki, Matsuoka Eriko, Asada Naoya, Journal of Medicinal Chemistry . 2019,第10期

机译：基于结构的选择性β-位点淀粉样蛋白前体蛋白质切割酶1（BACE1）抑制剂：靶向翼片以获得对BACE2的选择性
3. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides [J] . Berg S., Swahn B.-M., Kolmodin K., Journal of Medicinal Chemistry . 2012,第21期

机译：具有β-淀粉样蛋白肽体内脑还原功能的β-位淀粉样蛋白前体蛋白裂解酶（BACE1）抑制剂的设计与合成
4. Design, Synthesis, and Pharmacological Evaluation of Novel Tasiamide B Derivatives: Selective Inhibitors of BACE1 [C] . Jian Liu, SimingYang, Wei Zhang, Chinese International Peptide Symposium . 2013

机译：新型三胺B衍生物的设计，合成和药理评价：BACE1的选择性抑制剂
5. Asymmetric synthesis of stereochemically-defined and conformationally-constrained novel amino acids via direct alkylation of chiral nickel(II)-coordinated Schiff bases of glycine and alanine, and design and synthesis of selective peptide and non-peptide ligands for the delta-opioid receptor. [D] . Tang, Xue-jun. 2002

机译：通过手性镍（II）配位的甘氨酸和丙氨酸的席夫碱直接烷基化的立体化学定义和构象约束的新型氨基酸的不对称合成，以及δ阿片受体的选择性肽和非肽配体的设计和合成。
6. β-site amyloid precursor protein-cleavingenzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloidprecursor protein cleavage [O] . Erik Portelius, Robert A Dean, Ulf Andreasson, 2014

机译：β位淀粉样蛋白前体蛋白裂解酶1（BACE1）抑制剂治疗通过替代淀粉样蛋白诱导Aβ5-X肽前体蛋白裂解
7. β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage [O] . Erik Portelius, Robert A Dean, Ulf Andreasson, 2014

机译：β位淀粉样蛋白前体蛋白裂解酶1（BACE1）抑制剂处理通过替代性淀粉样蛋白前体蛋白裂解诱导Aβ5-X肽

Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

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