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首页> 外文期刊>Organic process research & development >Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-clione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1
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Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-clione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1

机译：新型3,5-取代的噻唑烷-2,4-clione化合物作为雌激素相关受体1的强抑制剂的放大工艺开发

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摘要

The development of a reproducible process for multihundred gram production of (Z)-5-((l-(4-chloro-2-(trifluoromethyl)benzyl)-1H-mdazol-S-yl)methylene)-3-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione (26), a potent and selective inhibitor of estrogen-related receptor 1 (ERRl), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9) with thiazolidme-2,4-dione (6, TZD) to form a diastereomeric mixture tert-butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (17), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3R,4R)-21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N-methyl 24, Knoevenagel condensation of 24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde (S) produced the final product 26 in 10% overall yield (99.7% HPLC area% with >99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3R,4R-21 from 3S,4S-22.
机译：（Z）-5-（（1-（4-氯-2-（三氟甲基）苄基）-1H-达唑-S-基）亚甲基）-3-（（3R）的数百克生产可重现方法的开发描述了一种有效和选择性的雌激素相关受体1（ERR1）抑制剂，（4R）-3-氟-1-甲基哌啶-4-基）噻唑烷-2,4-二酮（26）。这种数百克的合成是通过高氯酸镁催化7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸叔丁酯（9）与噻唑烷-2,4-二酮（6）的区域选择性环氧开环而实现的（TZD）形成非对映异构体混合物4-（2,4-dioxothiazolidin-3-yl）-3-羟基哌啶-1-羧酸叔丁酯（17），其中3-羟基被官能团转化为3-氟Deoxo-Fluor处理后的衍生物19。 19的手性分离提供了所需的非对映异构体（3R，4R）-21，其被转化为仲胺23TFA盐。 23的还原胺化反应生成了关键中间体N-甲基24，24的Knoevenagel缩合反应与1-（4-氯-2-（三氟甲基）苄基）-1H-吲唑-5-甲醛（S）的最终产物为10:26聚合八个合成步骤后的总收率％（99.7％HPLC面积％，> 99.5％de），唯一的色谱柱纯化是3R，4R-21与3S，4S-22的手性HPLC分离。

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