CN1093128C - 制备依普沙坦的方法 - Google Patents
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Abstract
本发明涉及制备依普沙坦的方法。
Description
本发明的技术领域
本发明涉及制备依普沙坦(eprosartan)的方法。此化合物作为血管紧张素II受体拮抗剂描述在美国专利5185351中，其能用于治疗高血压、充血性心力衰竭和肾衰竭。
本发明的背景技术
美国专利5185351描述了制备咪唑化合物、尤其是制备依普沙坦的方法。虽然用在此专利中描述的方法制得了其中所要求保护的咪唑化合物，但是当以工业规模制备咪唑化合物例如依普沙坦时，此制备方法仍需要改进。
现在已经发现，依普沙坦可通过三步反应制备。这三步是：(步骤1)区域选择性地保护2-正丁基-4-甲酰基咪唑；(步骤2)步骤1产物与(2-噻吩基甲基)丙二酸单C1-4烷基酯之间的反应；和(步骤3)生成季盐，然后进行碱处理和酸化。当大规模制备应用于医疗事业的依普沙坦时，此合成路线的效率以及依普沙坦的质量和产率就显得特别重要。
本发明的描述
本发明提供了制备依普沙坦，即式(I)所示的化合物(E)-α-[[2-丁基-1-[(4-羧基苯基)甲基]-1H-咪唑-5-基]亚甲基]-2-噻吩丙酸或其可药用盐的方法，
其中包括以下步骤：(i)用碱处理式(II)化合物，
然后与区域选择性氮保护剂例如丙烯酸的C1-4烷基酯衍生物反应；
(ii)在催化剂存在下，用式(III)化合物与式(IV)化合物反应，
其中R1是氮保护基团，是由(1)连接所述氮原子与吸电子基团例如酯(COOR″，其中R″＝C1-4烷基)、酸、羰基、腈、砜或亚砜的亚乙基桥或(2)连接所述氮原子与新戊酸酯、2-(三甲基甲硅烷基)乙氧基、甲氧基、叔丁氧基或苄氧基的亚甲基桥组成，
其中R′是C1-4烷基；
(iii)在升高的温度下，用式(V)化合物与式(VI)化合物反应，
其中R′和R1的定义同上
其中R是C1-4烷基，且X是卤素或OR*，其中R*是CH3SO2-或p-CH3C6H4SO2-，然后除去N-3保护基，水解掉R′和R酯基，并且任选地形成可药用盐。
式(I)化合物的酸加成盐是通过本领域已知方法用适当的无机酸或有机酸形成的。合适的酸的代表性实例是马来酸、富马酸、乙酸、琥珀酸、盐酸、氢溴酸、硫酸、磷酸或甲磺酸。式(I)化合物的可药用酸加成盐优选其甲磺酸加成盐。
式(I)化合物的碱加成盐是通过本领域已知方法用适当的无机碱或有机碱形成的。阳离子盐是通过将母化合物用过量的含有合适阳离子的碱性试剂如氢氧化物、碳酸盐或醇盐处理得到的；或者是用合适的有机胺处理而得到的。阳离子的代表性实例是Li+、Na+、K+、Ca++、Mg++和NH4 +。
如本说明书所使用的那样，C1-4烷基表示有1-4个碳原子的支链或非支链烷基。C1-4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。R′代表的C1-4烷基优选为乙基，R″代表的C1-4烷基优选为乙基或甲基，R代表的C1-4烷基优选为乙基或甲基。
下面的反应式I概述了制备依普沙坦的新的合成路线的三个步骤。
反应式1
根据反应式I，用碱例如1，8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)或1，1，3，3-四甲基胍处理2-正丁基-4-甲酰基咪唑，然后与区域选择性氮保护剂例如丙烯酸甲酯、丙烯酸乙酯、乙酰溴、新戊酸氯甲酯(POM-Cl)或二碳酸二叔丁酯反应，以在咪唑环中位阻最小的氮原子上生成衍生物。此反应可在乙酸乙酯、乙腈、甲苯、DMF、THF或1-甲基-2-吡咯烷酮(NMP)中进行。优选在50-60℃、在乙酸乙酯中使用DBU和丙烯酸甲酯或乙酸乙酯来进行此反应。一般情况下，然后是将反应式I-1化合物与(2-噻吩基甲基)丙二酸单乙酯在合适的溶剂如甲苯、乙腈、DMF、THF、NMP或DMSO中，在催化剂如哌啶或过量丙酸中的哌啶鎓丙酸盐的存在下，在合适的温度如约70℃-约100℃下反应。优选在甲苯中使用哌啶在65℃-70℃的回流温度下进行此反应；此回流温度是通过将反应混合物置于减压条件下而获得的。然后将反应式I-2化合物与苄基卤如4-(溴甲基)苯甲酸甲酯或乙酯或甲磺酸苯甲酯或甲苯磺酸苯甲酯在升高的温度例如100-120℃，优选105-110℃下反应来制备反应式I-2化合物的季盐。水解掉酯基，用例如碱如氢氧化钠或氢氧化钾水溶液除去N-保护基，以得到依普沙坦(反应式I-3化合物)。然后，可按照上述方法制备其可药用盐。
或者，也可以用下面反应式II所概述的反应路线来制备依普沙坦。
反应式II
依据反应式II，将在反应式I中所述的第一步反应和第二步反应的次序倒过来。在此合成顺序中，2-正丁基-4-甲酰基咪唑与(2-噻吩基甲基)丙二酸单乙酯在催化剂存在下反应，然后将此反应的产物区域选择性地进行氮保护。按照反应式I所述方法进行季化作用和碱性后处理以得到依普沙坦。
在制备依普沙坦过程中所用的新的中间体也包括在本发明的范围内。这些中间体在上文中已描述过。
通过下面的实施例来举例说明本发明。这些实施例不是为了限制如上文所定义并且如下文权利要求书所要求保护的本发明的范围。
实施例
实施例1制备(E)-α-[[2-丁基-1-[(4-羧基苯基)甲基]-1H-咪唑-5-基]亚甲基]-2-噻吩丙酸(依普沙坦)步骤1：制备下式化合物
在室温下，依次用丙烯酸甲酯(131.5kg，1527mol)、1，8-二氮杂二环[5.4.0]十一碳-7-烯(DBU，7.75kg，50.9mol)处理2-正丁基-4-甲酰基咪唑(155.0kg，1018mol)在乙酸乙酯(775.0L)中的均匀溶液。然后将反应混合物加热到50-60℃(加热时，混合物变得完全均匀)，在此温度下搅拌直到反应完全(约2小时)。在真空下将过量的丙烯酸甲酯和乙酸乙酯蒸馏掉，同时基础温度保持在60℃以下。用甲苯(1033L)稀释含有上述步骤1产物的残留青铜色油状物，不用进一步纯化，直接用于下一步反应。步骤2：制备下式化合物
用(2-噻吩基甲基)丙二酸单乙酯(267.3kg @100％，1171mol)和哌啶(21.7kg，255mol)处理得自上面步骤1的粗产物。在减压条件下将得到的溶液加热至回流(65-70℃)；通过迪安-斯达克分水法除去反应中生成的水。继续回流直至反应完全(约2-3小时)。将反应混合物冷却至55-60℃，依次用20％重量比的盐水(485.3L)和软化水(485.3L)洗涤，以除去大量的哌啶催化剂。然后在真空下蒸馏除去甲苯，同时基础温度保持在60℃以下。含有步骤2产物的残留青铜色油状物不用进一步纯化，直接用于下一步反应。步骤3：制备下式化合物
用甲苯(583.0L)稀释含有步骤2粗产物的残留油状物。用4-(溴甲基)苯甲酸甲酯固体(291.6kg @100％，1273mol)处理得到的溶液，然后在70-75℃搅拌30分钟以确保溶液均匀。在真空下蒸馏除去甲苯，蒸馏温度保持在60-75℃。将得到的粘稠油状物在95-100℃加热直到反应显示完全(约6-10小时)。将反应混合物冷却至75-80℃，用IMS(含有1％体积比甲醇的乙醇，1534.0L)稀释。制备氢氧化钠水溶液[203.7kg(5093mol)氢氧化钠溶在软化水(936.0L)中]，将其加到季盐中间体的乙醇溶液中。将混合物加热至回流(约80℃)，继续回流直到季盐完全水解成标题化合物(约2小时)。将反应混合物冷却至50-60℃，用6 N的盐酸处理(约479.0L，2874mol)直至pH达到5.1-5.3。将得到的浆液冷却至10-15℃，，在此温度下放置约2小时直至沉淀完全。过滤浆液，将此湿的饼状产物依次用50％体积比的含水IMS(约520L)和水(约1790L)洗涤，得到了344.9kg淡棕色标题化合物，为潮湿固体(三步反应的估计产率为66.9％)。
应当知道，上述具体实施方案不是对本发明的限制，并且本发明保留保护所列举的具体实施方案以及在后面权利要求的范围内所作的所有改进的权利。
Claims (4)
1.制备依普沙坦，即式(I)化合物或其可药用盐的方法，
其中包括以下步骤：(i)用碱处理式(II)化合物，
然后与区域选择性氮保护剂丙烯酸甲酯、丙烯酸乙酯、乙酰溴、新戊酸氯甲酯或二碳酸二叔丁酯反应；
(ii)在催化剂哌啶或过量丙酸中的哌啶鎓丙酸盐存在下，用式(III)化合物与式(IV)化合物反应，
其中R1是氮保护基团，是由(1)连接所述氮原子与吸电子基团C1-4烷基酯、酸、羰基、腈、砜或亚砜的亚乙基桥或(2)连接所述氮原子与新戊酸酯、2-(三甲基甲硅烷基)乙氧基、甲氧基、叔丁氧基或苄氧基的亚甲基桥组成，
其中R′是C1-4烷基；
(iii)在升高的温度下，用式(V)化合物与式(VI)化合物反应，
其中R′和R1的定义同上
其中R是C1-4烷基，且X是卤素或OR*，其中R*是CH3SO2-或p-CH3C6H4SO2-；然后水解掉R′和R 酯基，除去N-3保护基，并且任选地形成可药用盐。
2.根据权利要求1的制备依普沙坦即式(I)化合物或其可药用盐的方法，其中包括以下步骤：(i)用碱处理式(II)化合物，
然后与丙烯酸的C1-4烷基酯衍生物反应；
(ii)在催化剂哌啶或过量丙酸中的哌啶鎓丙酸盐存在下，用式(IIIb)化合物与式(IV)化合物反应，
其中R″是C1-4烷基，
其中R′是C1-4烷基；以及
(iii)在升高的温度下，用式(Vb)化合物与式(VI)化合物反应，
其中R′和R″的定义同上
其中R是C1-4烷基，且X是卤素，
然后水解掉R′和R酯基，除去N-3保护基，并且任选地形成可药用盐。
3.根据权利要求1的制备依普沙坦即式(I)化合物或其可药用盐的方法，其中包括以下步骤：(i)用1，8-二氮杂二环[5.4.0]十一碳-7-烯处理式(II)化合物，然后与丙烯酸甲酯反应；(ii)在哌啶存在下，用式(IIIa)化合物
与式(IVa)化合物反应，
(iii)在升高的温度下，用式(Va)化合物与式(VIa)化合物反应，然后水解掉酯基，除去N-3保护基，并且任选地形成可药用盐。
4.制备依普沙坦，即式(I)化合物或其可药用盐的方法，
其中包括以下步骤：
(i)在催化剂哌啶或过量丙酸中的哌啶鎓丙酸盐存在下，用式(II)化合物
与式(IV)化合物反应，
其中R′是C1-4烷基；(ii)用碱处理式(VII)化合物，
然后与区域选择性氮保护剂丙烯酸甲酯、丙烯酸乙酯、乙酰溴、新戊酸氯甲酯或二碳酸二叔丁酯反应；
(iii)在升高的温度下，用式(V)化合物与式(VI)化合物反应，
其中R′的定义同上，R1是氮保护基团，是由(1)连接所述氮原子与吸电子基团C1-4烷基酯、酸、羰基、腈、砜或亚砜的亚乙基桥或(2)连接所述氮原子与新戊酸酯、2-(三甲基甲硅烷基)乙氧基、甲氧基、叔丁氧基或苄氧基的亚甲基桥组成，其中R是C1-4烷基，且X是卤素或OR*，其中R*是CH3SO2-或p-CH3C6H4SO2-；
然后水解掉R′和R酯基，除去N-3保护基，并且任选地形成可药用盐。
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| Application Number | Priority Date | Filing Date | Title |
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| US3819697P | 1997-02-14 | 1997-02-14 | |
| US60/038,196 | 1997-02-14 |
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| CN1247538A CN1247538A (zh) | 2000-03-15 |
| CN1093128C true CN1093128C (zh) | 2002-10-23 |
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| IL (4) | IL131310A (zh) |
| IN (1) | IN188000B (zh) |
| MA (1) | MA24472A1 (zh) |
| MY (1) | MY120024A (zh) |
| NO (1) | NO317761B1 (zh) |
| NZ (1) | NZ337182A (zh) |
| OA (1) | OA11086A (zh) |
| PE (1) | PE59799A1 (zh) |
| PL (1) | PL192837B1 (zh) |
| PT (1) | PT973769E (zh) |
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| SI (1) | SI0973769T1 (zh) |
| SK (1) | SK285125B6 (zh) |
| TR (1) | TR199901935T2 (zh) |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR011126A1 (es) * | 1997-02-14 | 2000-08-02 | Smithkline Beecham Corp | Procedimiento para preparar eprosartano y compuestos intermediarios. |
| US6630498B2 (en) * | 1997-08-06 | 2003-10-07 | Smithkline Beecham Corporation | Eprosartan arginyl charge-neutralization-complex and a process for its preparation and formulation |
| WO2000004862A2 (en) * | 1998-07-20 | 2000-02-03 | Smithkline Beecham Corporation | Bioenhanced formulations comprising eprosartan in oral solid dosage form |
| US20060099230A1 (en) * | 2004-11-10 | 2006-05-11 | Chin-Chih Chiang | Novel formulations of eprosartan with enhanced bioavailability |
| WO2008078330A1 (en) * | 2006-12-27 | 2008-07-03 | Hetero Drugs Limited | Improved process for eprosartan |
| CA2703231A1 (en) * | 2007-10-22 | 2009-04-30 | Orchid Research Laboratories Limited | Histone deacetylase inhibitors |
| CN101215284B (zh) * | 2007-12-31 | 2010-10-13 | 浙江华海药业股份有限公司 | 一种改进的依普罗沙坦的制备方法 |
| WO2011004384A2 (en) | 2009-06-05 | 2011-01-13 | Glochem Industries Limited | Process for the preparation of eprosartan |
| CN102584709B (zh) * | 2011-12-19 | 2016-08-17 | 浙江华海药业股份有限公司 | 一种改进的依普罗沙坦中间体芳基咪唑醛的制备工艺 |
| CN103288742A (zh) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | 一种高纯度英加韦林原料的制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5418250A (en) * | 1989-06-14 | 1995-05-23 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists |
| US5185351A (en) * | 1989-06-14 | 1993-02-09 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists |
| ES2142789T3 (es) * | 1989-06-14 | 2000-05-01 | Smithkline Beecham Corp | Acidos imidazolil-alquenoicos. |
| NZ239161A (en) * | 1990-07-31 | 1994-01-26 | Smithkline Beecham Corp | Substituted [1h-imidazol-5-yl] alkanoic acid derivatives; medicaments, |
| WO1992010189A1 (en) | 1990-12-14 | 1992-06-25 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
| AR011126A1 (es) * | 1997-02-14 | 2000-08-02 | Smithkline Beecham Corp | Procedimiento para preparar eprosartano y compuestos intermediarios. |
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