关键词： Salts   Crystallization   Crystal structure   Hydrophobicity   Hydrogenation  

摘要： An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent (11), which was reacted with the phosphonosuccinate (10) to selectively afford the trans-b-substituted itaconate (12). Catalytic asymmetric hydrogenation of the itaconate (12) was achieved in good conversion and with 86-96% enantiomeric excess with a range of phosphine-modified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate (2) was elaborated to the desired drug substance (1) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of (1) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.

关键词： SUCCINIC acid   ALDEHYDES   PYRROLIDINE   ALIPHATIC compounds  

摘要： The nucleophilic Michael addition of 2-(diphenylmethoxymethyl)-1-methyleneamino pyrrolidine 1D to prochiral aliphatic and aromatic alkylidene malonates 2 takes place in the presence of MgI2 to afford the corresponding Michael adducts 3 in excellent yields and good selectivities. In the aromatic series, optically pure (de > 98%) major diastereomers (S,S)-3 were isolated in good yields (77-93%) after chromatographic separation. Direct, racemization-free ***2-catalyzed thiolysis of compounds 3 afforded dithioacetals 7. These compounds were transformed into malonates 8 and succinic semialdehyde derivatives 9 by Raney Nickel mediated desulfuration or decarboxylation, respectively.

关键词： ENANTIOSELECTIVE catalysis   AZEPINES  

摘要： A simple and versatile method for the enantio- and diastereoselective synthesis of mono- or disubstituted 3-aminoazepanes is described. The key step involves a highly regio- and diastereoselective tandem ring-enlargement/alkylation or reduction process. This novel synthetic route provides enantiomerically pure constrained diamines interesting as scaffolds for medicinal chemistry.

关键词： KETENES   CHROMATOGRAPHIC analysis   BROMIDES  

摘要： A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthesis of 1 was completed via Suzuki coupling of aryl bromide 7a with unprotected aryl piperazine boronic acid 13. Residual palladium and iron generated in the Suzuki coupling were efficiently removed from crude 1 via a simple extractive workup using lactic acid.

关键词： 双手性   噁唑硼烷   催化还原反应   不对称合成   催化剂   1,3,2-噁唑硼烷  

摘要： 第一次成功设计、合成了新型的双手性口恶唑硼烷还原体系 ,并将其应用于前手性酮的不对称还原。实验结果表明 ,双手性口恶唑硼烷体系在手性相匹配的情况下 ,对前手性酮还原的对映选择性明显地优于单手性的口恶唑硼烷的还原体系。

关键词： 制药行业   手性药物   手性技术   不对称合成   手性源合成   消旋体  

摘要： 综述了工业上的手性技术和各种方法及其在制药行业的应用及手性技术的最新发展.

关键词： 联萘类化合物   制备   应用   不对称合成   手性配体   2,2'-位置取代基   手性拆分  

摘要： 概述了 2 ,2’位置上带有不同取代基的 1,1’联萘化合物 ,如 2氨基 2’羟基 1,1’联萘、2羟基 2’巯基 1,1’联萘和 2氨基 2’巯基 1,1’联萘的制备及在不对称合成中的应用研究进展 .

关键词： 手性双噁唑啉配体   合成   金属配合物   不对称合成   结构   C2-对称性   β-氨基醇  

摘要： 介绍了手性双口恶唑啉配体的各种结构类型、合成方法及其金属配合物在不对称反应中的研究近况。参考文献 2

关键词： 手性药物   不对称合成   药物研究   手性化合物  

摘要： 本文论述了发展手性及手性药物研究的意义以及国内外的研究现状,提出了该领域存在的关键科学问题以及多学科交叉研究的实施措施。

关键词： amino acids   asymmetric synthesis   carboxylic acids   glycine equivalent   alpha-hydroxy acids  

摘要： The chiral oxazinone 2 has been developed as a new chiral glycine equivalent for the asymmetric synthesis of mono- and disubstituted a-amino acids. It is derived from the alpha-hydroxy-carboxylic acid 1, which serves as a chiral auxiliary, and is easily accessible in enantiomerically pure form by optical resolution of the racemic compound (RS)-1. For alkylation reactions, 2 was deprotonated with sBuLi or phosphazenic base. Subsequent treatment with alkyl halides yielded the monosubstituted compounds 13/14a-c, e, f, (ent)-13d, (ent)14d, while a second alkylation step, via the corresponding enolates, provided the disubstituted compounds 17/18a-d. Both alkylation steps proceeded with good yields and excellent diastereoselectivities (up to 99% de) and even less reactive electrophiles such as isopropyl iodide could be used. The results obtained in this reaction supported the assumption that the enolate of 2, as well as those of the monosubstituted derivatives of 2, have less tendency to form the aggregates that hamper alkylation reactions with other systems with higher oxygen content. From the major diastereomers of both the mono- and the disubstituted derivatives of 2 the corresponding a-amino acids 33a-c and 34a-d were obtained in high enantiomeric purity by hydrolytic cleavage of the oxazinone ring, accomplished either in two steps with aqueous TFA and aqueous NaOH or in one with either aqueous NaOH or 3 N HBr. Alkylation of the enolate ions of (S)-2 or (R)-2 with epichlorohydrins as bifunctional electrophiles provided the hydroxymethylenecyclopropyl derivatives 21 and 22. Hydrolysis of 21 and 22 afforded the free amino acids 35 and (ent)-35. Reductive animation with aniline after oxidation of 21 and 22 to the corresponding aldehydes 24 and 26 provided the compounds 25 and 27, whereas Mitsunobu treatment of 21 and 22 with 1-phenyl-3-(trifluoroacetyl)urea (28) afforded the urea derivatives 29 and 31. Hydrolysis of these compounds yielded the corresponding 1-aminocylopr