Asymmetric synthesis of an MMP-3 inhibitor incorporating a 2-alkyl succinate motif
Asymmetric synthesis of an MMP-3 inhibitor incorporating a 2-alkyl succinate motif
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DOI：
10.1021/op034001y
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发表时间：
2003-05-01
影响因子：
3.4
通讯作者：
Thomson, NM
中科院分区：
文献类型：
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作者：
Ashcroft, CP;Challenger, S;Thomson, NM
通过烯化/催化不对称氢化反应合成了具有药用活性的基质金属蛋白酶-3抑制剂UK-370,106(1)。商业上可获得的5-溴-2-碘甲苯分两步转化为联芳基丙醛(11)，它与琥珀酸膦(10)反应，选择性地得到反式-b-取代衣康酸酯(12)。一系列膦修饰的Rh、Ru阳离子络合物催化衣康酸(12)的不对称加氢反应具有良好的转化率和86-96%的对映体过量。由此得到的对映体富集型2-烷基琥珀酸酯(2)分两步精制成所需的药物物质(1)。该合成得益于几种结晶中间体，允许控制工艺杂质，并且可以在容易实现规模化的参数范围内安全操作。对(1)的多晶型的研究表明，该化合物以氢键酰胺和酸性官能团为主干，以平面片状结晶，由联芳丙基形成大的疏水口袋。对这种晶体堆积安排的了解有助于结晶过程的发展，使其能够完全控制固体形态。
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.