CN101679391A - (2s-顺式)-2-(溴甲基)-2-(4-氯苯基)-1,3-二氧戊环-4-甲醇甲磺酸酯的改进合成 - Google Patents

(2s-顺式)-2-(溴甲基)-2-(4-氯苯基)-1,3-二氧戊环-4-甲醇甲磺酸酯的改进合成 Download PDF

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CN101679391A
CN101679391A CN200880017239A CN200880017239A CN101679391A CN 101679391 A CN101679391 A CN 101679391A CN 200880017239 A CN200880017239 A CN 200880017239A CN 200880017239 A CN200880017239 A CN 200880017239A CN 101679391 A CN101679391 A CN 101679391A
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acid
dioxolane
solution
methyl alcohol
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W·F·M·菲利尔斯
W·L·A·弗斯塔彭
R·贝林克斯
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Janssen Pharmaceutica NV
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings

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Abstract

本发明涉及制备(2S－顺式)－2－(溴甲基)－2－(4－氯苯基)－1，3－二氧戊环－4－甲醇甲磺酸酯的改进方法，这个化合物是制备apoB分泌/MTP抑制剂米瑞他匹(mitratapide)的一个关键中间体。

Description

(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯的改进合成
本发明涉及制备(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环14-甲醇甲磺酸酯的改进方法，这个化合物是制备apoB分泌/MTP抑制剂米瑞他匹(mitratapide)的一个关键中间体。
米瑞他匹是化合物(-)-[2S-[2α，4α(S*)]]-4-[4-[4-[4-[[2-(4-氯苯基)-2-[[(4-甲基-4H-1，2，4-三唑-3-基)硫代]甲基]-1，3-二氧戊环-4-基]甲氧基]-苯基]-1-哌嗪基]苯基]-2，4-二氢-2-(1-甲基丙基)-3H-1，2，4-三唑-3-酮的INN(国际非专属名称)，具有如下结构：
Figure G2008800172392D00011
米瑞他匹在WO-96/13499中被描述为化合物(40)，具有载脂蛋白B分泌和微粒体甘油三酯转运蛋白抑制性质，因此在肥胖症治疗中用作降脂剂。
WO-00/37463在第20页的操作实施例A.7中公开了米瑞他匹的S-氧化物衍生物和制备中间体(18)(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯的过程。
(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯(以下称为“化合物A”)具有如下结构：
Figure G2008800172392D00012
化合物A
根据Cahn-Ingold-Prelog命名法，其中1，3-二氧戊环上的取代基有(2S，4S)立体化学结构。
由于米瑞他匹的三个手性碳原子中有两个位于1，3-二氧戊环上，有效地合成化合物A因此是高度理想的。
化合物A的制备在WO-00/37463的实施例A.6和A.7中是这样描述的：
Figure G2008800172392D00021
根据WO-00/37463中实施例A.7中的过程，即在溶剂二氯甲烷中，(2S)-2，2-二甲基-1，3-二氧戊环-4-甲醇甲磺酸酯和2-溴-1-(4-氯-苯基)-乙酮反应，得到化合物A，收率为23.7％。
出乎意料是，现在发现在无溶剂的条件下进行同样的反应，同时将氮气鼓泡通过反应混合物或者施加减压以除去所述反应过程中产生的丙酮，可以显著改善所述反应的收率。
Figure G2008800172392D00031
正如实验部分的实施例1进一步证明的那样，改进的用于制备“化合物A”的过程的收率是64.8％，相对于现有技术方法的收率23.7％是几乎3倍增加。
甲磺酸在反应中是作为催化剂使用。其他合适的催化剂是对甲苯磺酸一水合物、氯化氢、硫酸、磷酸、硝酸、甲酸、三氟乙酸、樟脑磺酸、氯化氢的2-丙醇溶液、溴化氢的乙酸溶液或丙酸溶液。
此反应中得到的反应产物可以通过从合适的有机溶剂，如乙醇、2-丙醇、甲基叔丁基醚或乙酸乙酯中结晶来纯化。
进一步纯化可通过如下进行：将结晶后获得的产物溶于二异丙醚直到获得均一的溶液，将所述溶液搅拌7天且向所述溶液中加入甲醇且滤出沉淀物。
试验部分
实施例1
将(2S)-2，2-二甲基-1，3-二氧戊环-4-甲醇甲磺酸酯(1摩尔)和2-溴-1-(4-氯-苯基)-乙酮(0.8摩尔)的混合物在烧瓶中搅拌。加入甲磺酸(0.24摩尔)并且搅拌该反应混合物，同时将氮气鼓泡通过该反应混合物(也可以在真空下搅拌该反应混合物)。6小时后，停止搅拌反应混合物，反应混合物放置过夜。加入乙酸乙酯(1500毫升)，搅拌混合物直至变为均一。然后依次用水(200毫升)，Na2CO3水溶液(150毫升)，和水(150毫升)洗涤反应混合物。将有机层蒸干，残留物从乙醇(1升)中结晶，得到固体残留物。将该残留物溶解于二异丙基醚(DIPE)并搅拌一周，然后加入甲醇，搅拌2小时后，将沉淀物滤出并干燥，获得250.1克(64.8％)的(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯。
通过GC进行色谱分析(HP5-柱，长：25m，ID 320μm；膜厚0.52μm；在柱上；初始温度：50℃；以10℃/分钟加热至300℃)，显示所述(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯的顺式立体异构体纯度大于95％，反式立体异构体纯度低于5％。

Claims (5)

1.一种在催化剂存在的条件下通过(2S)-2，2-二甲基-1，3-二氧戊环-4-甲醇甲磺酸酯和2-溴-1-(4-氯-苯基)-乙酮的反应制备(2S-顺式)-2-(溴甲基)-2-(4-氯苯基)-1，3-二氧戊环-4-甲醇甲磺酸酯的方法，其特征在于该反应是在无溶剂条件下，同时将氮气鼓泡通过反应混合物或施加减压来进行的。
2.根据权利要求1所述的方法，其中该催化剂选自甲磺酸、对甲苯磺酸一水合物、氯化氢、硫酸、磷酸、硝酸、甲酸、三氟乙酸、樟脑磺酸、氯化氢的2-丙醇溶液、和溴化氢的乙酸溶液或丙酸溶液。
3.根据权利要求2所述的方法，其中该催化剂是甲磺酸。
4.一种方法，藉此由权利要求1至3任一项的方法获得的产物通过从选自乙醇、2-丙醇、甲基叔丁基醚或乙酸乙酯的有机溶剂进行结晶来纯化。
5.一种方法，藉此由权利要求4的方法获得的产物通过将其溶于二异丙醚直到获得均一的溶液，将所述溶液搅拌7天且向所述溶液中加入甲醇且滤出沉淀物来纯化。
CN200880017239A 2007-05-25 2008-05-23 (2s-顺式)-2-(溴甲基)-2-(4-氯苯基)-1,3-二氧戊环-4-甲醇甲磺酸酯的改进合成 Pending CN101679391A (zh)

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EP07108944.5 2007-05-25
EP07108944 2007-05-25
PCT/EP2008/056355 WO2008145605A1 (en) 2007-05-25 2008-05-23 Improved synthesis of (2s-cis)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3 dioxolane-4-methanol methanesulfonate(ester)

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JP (1) JP5350367B2 (zh)
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AT (1) ATE474836T1 (zh)
BR (1) BRPI0811902B1 (zh)
CA (1) CA2685797C (zh)
DE (1) DE602008001896D1 (zh)
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IL (1) IL202253A (zh)
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BRPI0811902B1 (pt) 2020-03-24
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US8765979B2 (en) 2014-07-01
ATE474836T1 (de) 2010-08-15
JP5350367B2 (ja) 2013-11-27
IL202253A (en) 2013-07-31
CA2685797A1 (en) 2008-12-04
BRPI0811902A2 (pt) 2014-11-18
US20110196160A1 (en) 2011-08-11
KR101484028B1 (ko) 2015-01-19
WO2008145605A1 (en) 2008-12-04
JP2010527972A (ja) 2010-08-19
EP2152698A1 (en) 2010-02-17

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