CN1318415C - 分离4－(2－氯－4－氟苯基)－2－(3,5－二氟－2－吡啶基)－6－甲基－1,4－二氢－5－嘧啶羧酸甲酯外消旋体的方法 - Google Patents

分离4－(2－氯－4－氟苯基)－2－(3,5－二氟－2－吡啶基)－6－甲基－1,4－二氢－5－嘧啶羧酸甲酯外消旋体的方法 Download PDF

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CN1318415C
CN1318415C CNB028104544A CN02810454A CN1318415C CN 1318415 C CN1318415 C CN 1318415C CN B028104544 A CNB028104544 A CN B028104544A CN 02810454 A CN02810454 A CN 02810454A CN 1318415 C CN1318415 C CN 1318415C
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fluorophenyl
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CN1531532A (zh
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S·戈德曼
P·费
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Bayer Pharma AG
Bayer Intellectual Property GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的对映异构体可借助(-)-莰烷酸分离。

Description

分离4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯外消旋体的方法
技术领域
本发明涉及用(-)-莰烷酸分离对映异构的4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的方法。
化合物4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯对应于下式
它能起到HBV核心蛋白抑制剂的作用，适合用于肝炎，尤其是乙型肝炎的预防和治疗。用于制备它的化合物和各种各样的方法公开在EP-A1080 086(实例61)中。优选的任选活性形式是(-)-对映异构体。各种对映异构体可在手性柱上进行分离。虽然该方法可获得良好结果，但它不适合工业生产。
现已发现，两种对映异构的4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯可通过其非对映异构的(-)-莰烷盐实现分离；这是由于其(R)-对映异构体的(-)-莰烷盐在许多溶剂中的溶解度小于(S)-对映异构体的(-)-莰烷盐。术语“盐”，就本发明目的而言，还包括共结晶的产物；按照NMR谱，该碱主要以非质子化形式存在。
因此，本发明涉及借助(-)-莰烷酸分离对映异构的4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的方法。
该非对映异构盐的溶解度之间的差异原则上可用于其两种不同类型的分离：第一，通过将溶解度较小的非对映异构体从溶液中(分级)结晶出来，或者第二，通过将溶解度较大的非对映异构体从固体非对映异构体的混合物中溶解出来。
于是，程序将是这样的，(-)莰烷酸与待分离外消旋体起反应给出对应非对映异构盐，然后 或者a)将反应产物溶解并通过冷却该溶液和/或部分地赶出溶剂诱导溶解度较小的产物沉淀，并将沉淀的产物从溶液中分离， 或者b)该固体反应产物以溶剂处理，以便使溶解度较大的产物溶解并将该溶液与溶解度较小的残余物分离。
术语“溶剂”包括，就本发明目的而言，所有传统溶剂，例如，烃类如苯、二甲苯、甲苯、己烷、环己烷或石油馏分，卤代烃如二氯甲烷、三氯甲烷、四氯甲烷、三氯乙烷、四氯乙烷、1，2-二氯乙烷或三氯乙烯，醇如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇，醚如二乙基醚、甲基异丙基醚、二异丙基醚、乙二醇单甲醚、乙二醇二甲醚、二甘醇二甲醚、四氢呋喃，二烷、酮如丙酮、丁酮，羧酸如冰醋酸，酯如乙酸乙酯和乙酸丁酯，杂环如吡啶，或非质子溶剂如硝基甲烷、乙腈、二甲基甲酰胺、二甲基亚砜和六甲基磷酰三胺以及所述化合物的混合物。任选，也可以在水-可混溶有机溶剂中加入水。待分离外消旋体与(-)-莰烷酸之间的反应优选的溶剂是醇，尤其是乙醇；非对映异构盐分离优选的溶剂是醚、酯和酮，尤其是二异丙基醚。
非对映异构体的溶解可在一定温度范围内进行；优选地，在溶剂沸点直至20℃的范围。溶解度较小的非对映异构纯盐的结晶期间或者溶解度较大的非对映异构纯盐洗出期间的温度也可在宽范围内选择；优选该温度在-40～20℃，优选约0℃。
游离对映异构体从非对映异构纯盐中的释放可借助各种传统碱如氨、碱金属氢氧化物如氢氧化钠或钾、碱金属碳酸盐或碳酸氢盐如碳酸钠或碳酸钾或碳酸氢钠或钾来实现。纯对映异构体随后可用有机溶剂直接从碱性水溶液中萃取出来。
(-)-莰烷酸可通过将其水溶液酸化而沉淀，随后可重复使用。
本发明还涉及R-和S-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的(-)-莰烷酸盐。
实例：用(-)-莰烷酸的外消旋体的拆分
(-)(4R)-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶甲酸甲酯
37.68g(95.21mmol)4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶甲酸甲酯和18.87g(95.21mmol)(-)-莰烷酸溶解在沸腾乙醇中。冷却后，乙醇蒸发至干；残余物经粉碎后与二异丙基醚混合，加热至回流温度。冷却至0℃并静置过夜之后，抽滤出晶体，并用冷二异丙基醚洗涤。滤饼悬浮在乙酸乙酯中，用10wt％碳酸钠水溶液调节至碱性，并用乙酸乙酯萃取两次。有机相以硫酸钠干燥并蒸发。残余物中加少量冷乙醇进行结晶。获得17.7g(93.7％)(-)-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶甲酸甲酯(ee97％，HPLC)。
绝对构型(R)用x-射线研究确定。

Claims (4)

1.一种用(-)-莰烷酸拆分4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的对映异构体的方法，其特征在于：
a)该拆分方法是在温度范围在溶剂沸点直至0℃的范围进行的；和
b)(-)莰烷酸与待分离外消旋体起反应给出对应非对映异构盐，并且然后；
c)或者将反应产物溶解于传统溶剂例如烃类、醇、醚、酮、酯、非质子溶剂或所述溶剂的混合物或者所述溶剂与水的混合物中，并通过冷却该溶液和/或部分地赶出溶剂诱导溶解度较小的产物沉淀，并将沉淀的产物从溶液中分离，或者该固体反应产物以传统溶剂例如烃类、醇、醚、酮、酯、非质子溶剂或所述溶剂的混合物或者所述溶剂与水的混合物处理，以便使溶解度较大的产物溶解并将该溶液与溶解度较小的残余物分离。
2.权利要求1的方法，其中(R/S)-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的(-)莰烷酸盐通过结晶达到分离，然后对映异构体用碱释放，并且任选，从移出的固体(-)-莰烷酸盐和/或从移出的溶液中离析出来。
3.权利要求1的方法，其中溶解度较大的非对映异构体被从(R/S)-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的(-)莰烷酸盐的混合物中溶解出来，所形成的溶液与溶解度较小的非对映异构体分离，用碱释放出对映异构体，以及任选，从移出的固体(-)-莰烷酸盐和/或从移出的溶液中离析出来。
4.R-4-(2-氯-4-氟苯基)-2-(3，5-二氟-2-吡啶基)-6-甲基-1，4-二氢-5-嘧啶羧酸甲酯的(-)莰烷酸盐。
CNB028104544A 2001-05-23 2002-05-15 分离4－(2－氯－4－氟苯基)－2－(3,5－二氟－2－吡啶基)－6－甲基－1,4－二氢－5－嘧啶羧酸甲酯外消旋体的方法 Expired - Fee Related CN1318415C (zh)

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DE10125131A DE10125131A1 (de) 2001-05-23 2001-05-23 Verfahren zur Spaltung des Methyl 4-(2-chlor-4-fluorphenyl)-2-(3,5-difluor-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrmidincarboxylat-Racemats
DE10125131.9 2001-05-23

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US20040138176A1 (en) * 2002-05-31 2004-07-15 Cjb Industries, Inc. Adjuvant for pesticides
FR2853650B1 (fr) * 2003-04-10 2006-07-07 Merck Sante Sas Procede de dedoublement d'amines utiles pour le traitement de desordres associes au syndrome d'insulino-resistance
CN101468986B (zh) * 2007-12-26 2010-12-29 香港南北兄弟国际投资有限公司 一种二氢嘧啶消旋化合物的拆分方法
RU2688193C1 (ru) * 2013-11-27 2019-05-21 Саншайн Лейк Фарма Ко., Лтд. Процессы приготовления производных дигидропиримидина и их промежуточных соединений
AR101319A1 (es) * 2014-07-31 2016-12-07 Hoffmann La Roche Resolución quiral de los ésteres del ácido 4-aril-2-tiazol-2-il-1,4-dihidropirimidin-5-carboxílico
AR107633A1 (es) 2016-02-19 2018-05-16 Hoffmann La Roche Procedimiento para la preparación del ácido 4-fenil-5-alcoxicarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il-[metil]-3-oxo-5,6,8,8a-tetrahidro-1h-imidazo[1,5a]pirazin-2-il-carboxílico
CN113614088A (zh) 2019-03-25 2021-11-05 豪夫迈·罗氏有限公司 Hbv核心蛋白变构修饰剂化合物的固体形式

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WO2000058302A1 (de) * 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b

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WO2000058302A1 (de) * 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b

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ES2249591T3 (es) 2006-04-01
DE50204325D1 (de) 2006-02-02
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CN1531532A (zh) 2004-09-22
HK1069823A1 (en) 2005-06-03
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