CN1993355A - 奥美沙坦酯的纯化方法 - Google Patents
奥美沙坦酯的纯化方法 Download PDFInfo
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- CN1993355A CN1993355A CNA2005800262573A CN200580026257A CN1993355A CN 1993355 A CN1993355 A CN 1993355A CN A2005800262573 A CNA2005800262573 A CN A2005800262573A CN 200580026257 A CN200580026257 A CN 200580026257A CN 1993355 A CN1993355 A CN 1993355A
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- Prior art keywords
- olmesartan medoxomill
- solution
- acid
- olmesartan
- water
- Prior art date
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- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 10
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 10
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- 239000005480 Olmesartan Substances 0.000 claims description 92
- 229960005117 olmesartan Drugs 0.000 claims description 92
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims description 91
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种奥美沙坦酯的纯化方法。
Description
本申请要求提交于2004年9月2日的美国临时专利申请60/606,437和提交于2004年12月22日的60/638,736的优先权。
技术领域
本发明涉及纯化奥美沙坦酯的方法。
背景技术
奥美沙坦酯的化学名称是4-(1-羟基-1-甲基乙基)-2-丙基-1-[[2’-(1H-四唑-5-基)[1,1’-联苯基]-4-基]甲基]-1H-咪唑-5-甲酸(5-甲基-2-氧基-1,3-间二氧杂环戊烯-4-基)甲基酯(Merck Index,第13版)。
奥美沙坦酯的化学结构是:
实验式为C29H30N6O6。
分子量为558.58。
奥美沙坦酯是一种药物前体,其在吸收过程中被水解,并且它是一种选择性AT1亚型血管紧张素II受体拮抗体。奥美沙坦酯由Yanagisawa等人在US专利5,616,599中公开。其作为BENICAR以5mg、20mg和40mg的薄膜包衣片进行销售,用于人类的高血压治疗。
奥美沙坦酯(OLM-Mod)自身的合成如下所示(另参见Annu.Rep.Sankyo Res.Lab 2003,55,1-91):
现有技术的合成方法集中在被取代的咪唑和被取代的溴化甲基联苯的偶联上。这些奥美沙坦酯中间体的其它合成方法描述于:JP11302260,JP11292851,JP07053489,JP06298683,US5621134,EP838458,DE19757995,US6111114和US6214999。
现有技术合成方法的步骤(vi)(解保护步骤)如下所示:
’599专利的实施例61(b)公开了一种由三苯甲基奥美沙坦酯(MTT)和含水醋酸制备粗奥美沙坦酯的方法,见第176栏,第24-37行。除去三苯基甲醇(TPC),并通过蒸发分离出奥美沙坦酯。
由于酸性条件和水的存在,在通过酯键水解所进行的反应过程中还形成了杂质OLM-酸。OLM-酸的化学结构是:
OLM-酸的实验式为C24H26N6O3,其分子量为446.50。现有技术方法得到每面积百分比HPLC中含2.2%OLM-酸的粗奥美沙坦酯。’599专利还公开了该化合物可以通过常规方法包括再结晶作进一步纯化,见第64栏,第43-45行。BENICAR每面积百分比HPLC中含0.3%OLM-酸。
需要这样一种方法,其使奥美沙坦酯中酯键的水解最小化,并由此提供更纯的产品。此外,从工业和实用性的观点考虑,希望避免对色谱纯化步骤的需要。本发明提供了改进的用于纯化奥美沙坦酯的方法以及具有低OLM-酸水平的奥美沙坦酯。
附图说明
图1描述了一种纯化的奥美沙坦酯样品的典型色谱。
发明内容
一方面,本发明提供了一种纯化奥美沙坦酯的方法,其包括下列步骤:提供奥美沙坦酯在C3-6酮,优选丙酮中的溶液;加水至溶液中;以及回收纯化的奥美沙坦酯。该方法可进一步包括加热溶液的步骤。该方法还可进一步包括在加水后冷却溶液以沉淀纯化的奥美沙坦酯的步骤。
另一方面,本发明提供了一种制备奥美沙坦酯的方法,其包括下列步骤:使三苯甲基奥美沙坦酯与酸在水可混溶有机溶剂(有或没有水,优选丙酮和水)中接触以得到奥美沙坦酯第一溶液和三苯基甲醇沉淀物;从第一溶液中分离三苯基甲醇沉淀物;使第一溶液和碱接触以得到奥美沙坦酯沉淀物;回收奥美沙坦酯沉淀物;将奥美沙坦酯沉淀物溶于C3-6酮,优选丙酮中,以形成第二溶液;加水至第二溶液中;以及回收纯化的奥美沙坦酯。
再一方面,本发明提供了一种奥美沙坦酯,其含有少于约0.3%的OLM-酸,更优选少于约0.05%,并最优选少于约0.03%。本发明还提供了含有这种奥美沙坦酯的药物组合物。
具体实施方式
在一个实施方案中,本发明提供了一种纯化奥美沙坦酯的方法,其包括下列步骤:提供奥美沙坦酯在C3-6酮中的溶液;加水至溶液中;以及回收纯化的奥美沙坦酯。
优选地,C3-6酮是丙酮、甲乙酮、二乙酮或叔丁基甲基酮。最优选地,C3-6酮是丙酮。
为了提供奥美沙坦酯在C3-6酮中的溶液,酮的优选量相对于约1g固体奥美沙坦酯为至少约7体积(volume)的酮,更优选的是相对于约1g固体奥美沙坦酯为至少约10体积的酮。酮可以含有水,如约4体积%-约14体积%的水,优选约4体积%的水。
该方法可进一步包括加热奥美沙坦酯在C3-6酮中的溶液的步骤。在这种实施方案中,奥美沙坦酯在C3-6酮中的溶液优选被加热至约30℃到约回流温度,更优选被加热至约40℃到约回流温度。
加水以沉淀纯化的奥美沙坦酯。所加水量优选相对于约1体积的C3-6酮为约0.5-约2体积,更优选为至少约1∶1,按体积计。
加水之后,该方法可进一步包括冷却溶液以导致沉淀的步骤。溶液可以被冷却至低于约30℃的温度,更优选至约室温。如本文中所用的,术语“室温”是指约20℃-约30℃的温度,优选为约20℃-约25℃的温度。
回收纯化的奥美沙坦酯可以通过本领域公知的任何方法进行,如过滤或离心分离。该方法可进一步包括干燥已沉淀的纯化奥美沙坦酯的步骤。干燥可以通过例如加热至约30℃-约60℃的温度而进行。可以降低压力以加速干燥过程,例如至低于1个大气压,更优选至低于约100mmHg。
在另一个实施方案中,本发明提供了一种制备奥美沙坦酯的方法,其包括下列步骤:使三苯甲基奥美沙坦酯与酸在水可混溶有机溶剂中接触以得到奥美沙坦酯第一溶液和三苯基甲醇沉淀物;从第一溶液中分离三苯基甲醇沉淀物;使第一溶液和碱接触以得到奥美沙坦酯沉淀物;回收奥美沙坦酯沉淀物;将奥美沙坦酯沉淀物溶于C3-6酮中以形成第二溶液;加水至第二溶液中;以及回收纯化的奥美沙坦酯。
优选的水可混溶有机溶剂包括但不限于,丙酮、乙腈和叔丁醇。特别优选丙酮。优选使三苯甲基奥美沙坦酯与水可混溶有机溶剂和水的混合物接触。最优选使三苯甲基奥美沙坦酯与丙酮和水的混合物接触。优选地,水和水可混溶有机溶剂例如丙酮的比率以体积计优选为约1∶3-约3∶1。
与第一溶液接触的酸除去了三苯基甲醇以形成奥美沙坦酯的酸式盐。该酸优选是pH为约0-约4的强酸。合适的酸包括但不限于,有机酸如甲酸、乙酸、苯甲酸和草酸;含氧酸如高氯酸、氯酸、亚氯酸、次氯酸、硫酸、亚硫酸、对甲苯磺酸、硝酸、亚硝酸、磷酸和碳酸;和二元酸如氢氟酸、氢氯酸、氢溴酸、氢氰酸、氢硫酸。氢氯酸和对甲苯磺酸,尤其硫酸是优选的。酸的量优选为约2-约8当量,更优选为约3-约4当量,并最优选为约3当量。
当使三苯甲基奥美沙坦酯与酸接触时,温度优选为约10℃-约60℃,更优选为约40℃。在一个优选的实施方案中,使三苯甲基奥美沙坦酯、水可混溶有机溶剂和酸的结合物保持约3-约15小时。优选地,使该结合物保持约4-约6小时,最优选保持约4小时。
在一个优选的实施方案中,在分离三苯基甲醇之前,加水以避免形成不希望的副产物。所加的水量优选为约2体积每克三苯甲基奥美沙坦酯。沉淀可以目测为溶液的浑浊或悬浮于溶液中或在含有溶液的容器底部收集到的沉淀物明显颗粒的形成。
从溶液中分离三苯基甲醇可以通过本领域公知的任何方法进行,如过滤或离心分离。
分离三苯基甲醇之后,使奥美沙坦酯溶液与碱接触。合适的碱包括但不限于,碱金属和碱土金属的氢氧化物、碳酸盐和碳酸氢盐。特例的碱包括但不限于,氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾和碳酸钙。碳酸钾,尤其碳酸氢钠是优选的。所用碱的当量优选约等于所用酸的当量,也就是所用碱的量与所用酸的量相比优选约为0.8-1.5当量。该碱优选提高了溶液的pH值,但是溶液不需要达到碱性pH值。在使溶液与碱接触后,优选将溶液保持在约2℃-约25℃的温度下,并优选保持在大约室温下。如本文中所用,术语“室温”是指约20℃-30℃的温度,优选为20℃-25℃的温度。保持溶液直至奥美沙坦酯沉淀。
然后可以通过本领域公知的任何方法回收沉淀物即粗奥美沙坦酯,如过滤或离心分离。奥美沙坦酯以其游离碱形式回收,即四唑上的氮是游离的。
反应进展可以通过本领域公知的任何方法进行检测,例如,HPLC、GC、TLC、NMR和质谱分析。
本发明方法制备出具有低水平OLM-酸的奥美沙坦酯。本文中描述的杂质的所有百分比按220nm下的HPLC的面积百分比提供。根据US5,616,599所制备的粗奥美沙坦酯含有2.2%的OLM-酸。相比之下,根据本发明所制备的粗奥美沙坦酯含有少于约1%的OLM-酸,例如仅约0.89%的OLM-酸。
对于纯化产物来说,BENICAR含有0.3%的OLM-酸。因而,现有方法将粗奥美沙坦酯中的OLM-酸从2.2%减少至0.3%。然而,当根据本发明方法纯化这种粗奥美沙坦酯时,OLM-酸的量被减少至0.26%。通过使用本发明所制备的粗奥美沙坦酯可以进一步减少OLM-酸的量。当粗奥美沙坦酯含有少于约1%的OLM-酸时,本发明的纯化方法可以将OLM-酸水平减少到少于约0.3%。
本发明进一步提供了一种含有少于约0.3%的OLM-酸的奥美沙坦酯,更优选为少于约0.05%,并且最优选少于约0.03%。本发明还提供了含有这种奥美沙坦酯的药物组合物。
含有上述奥美沙坦酯的药物组合物可以制备为经口、肠胃外、直肠、皮肤、向颊或鼻给药的药物。适于口服给药的形式包括固体形式,如片剂、粉末、颗粒、胶囊、栓剂、囊剂、锭剂和糖锭,以及液体形式,如糖浆、悬浮液和酏剂。肠胃外给药的合适形式包括含水或不含水的溶液或乳液,而对于直肠给药,合适的给药形式包括含亲水性或疏水性载体的栓剂。对于局部给药,本发明提供了本领域公知的合适透皮递药系统,并且对于经鼻递药,提供了本领域公知的合适的气雾剂递药体系。
除了活性成分外,本发明组合物可以含有一种或多种赋形剂或辅剂。赋形剂是惰性成分,其被加至药物组合物中以进行稀释或赋予形状或稠度。辅剂促进了活性成分的作用。制剂科学家根据经验以及对本领域中标准过程和参考资料的考虑可以很容易地确定赋形剂和辅剂的选择和用量。
稀释剂增加了固体药物组合物的体积(bulk),并且可以制备患者和护理者易于操作的含有该组合物的药物剂型。用于固体组合物的稀释剂包括例如,微晶纤维素(例如Avicel)、微细纤维素、乳糖、淀粉、预胶凝淀粉、碳酸钙、硫酸钙、糖、葡萄糖结合剂、糊精、葡萄糖、磷酸氢钙二水合物、三代磷酸钙、高岭土、碳酸镁、氧化镁、麦芽糖糊精、甘露糖醇、聚甲基丙烯酸酯(例如Eudragit)、氯化钾、粉状纤维素、氯化钠、山梨糖醇和滑石。
被压紧为剂型如片剂的固体药物组合物可以包括赋形剂,所述赋形剂的功能包括有助于在压制之后将活性成分和其它赋形剂结合在一起。用于固体药物组合物的结合剂包括阿拉伯胶、藻酸、卡波姆(例如卡波姆)、羧甲基纤维素钠、糊精、乙基纤维素、明胶、瓜耳胶、氢化植物油、羟乙基纤维素、羟丙基纤维素(例如Klucel)、羟丙基甲基纤维素(例如Methocel)、液体葡萄糖、硅酸镁铝、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚乙烯吡咯酮(例如Kollidon和Plasdone)、预胶凝淀粉、藻酸钠和淀粉。
被压紧的固体药物组合物在患者胃中的溶解速率可以通过向组合物中加入崩解剂而提高。崩解剂包括藻酸、羧甲基纤维素钙、羧甲基纤维素钠(例如Ac-Di-Sol和Primellose)、胶体二氧化硅、交联羧甲纤维素钠、交联聚维酮(例如Kollidon和Polyplasdone)、瓜耳胶、硅酸镁铝、甲基纤维素、微晶纤维素、波拉克林钾、粉状纤维素、预胶凝淀粉、藻酸钠、淀粉羟基乙酸钠(例如Explotab)和淀粉。
可以加入助流剂以改善非被压紧的固体组合物的流动性并且提高剂量的准确度。可用作助流剂的赋形剂包括胶体二氧化硅、三硅酸镁、粉状纤维素、淀粉、滑石和三代磷酸钙。
当通过压紧粉状组合物而制造剂型如片剂时,该组合物经受例如来自冲床和冲模的压力。一些赋形剂和活性成分具有粘附于冲床和冲模表面的趋势,这能够导致产品具有凹点以及其它的表面不平整性。可以将润滑剂加至组合物中以降低粘附并使产品易于从冲模中脱离出来。润滑剂包括硬脂酸镁、硬脂酸钙、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、氢化蓖麻油、氢化植物油、矿物油、聚乙二醇、苯甲酸钠、十二烷基硫酸钠、十八烷基富马酸钠、硬脂酸、滑石和硬脂酸锌。
芳香剂和香味增强剂使剂型对于患者来说更可口。能够包含于本发明组合物中的用于药物产品的常规芳香剂和香味增强剂包括麦芽酚、香草醛、乙基香草醛、薄荷醇、柠檬酸、富马酸、乙基麦芽酚和酒石酸。
固体和液体组合物也可以用任何药学上可接受的着色剂染色以改善它们的外观和/或有利于患者识别产品或单位剂量水平。
在本发明液体药物组合物中,活性成分和任何其它固体赋形剂悬浮于液体载体中,所述载体例如水、植物油、乙醇、聚乙二醇、丙二醇或甘油。
液体药物组合物可以包含乳化剂以使活性成分和/或不溶的赋形剂均匀分散在整个组合物中。可用于本发明液体组合物的乳化剂包括例如,明胶、蛋黄、酪蛋白、胆固醇、阿拉伯胶、黄蓍胶、角叉菜、果胶、甲基纤维素、卡波姆、十八醇十六醇混合物和鲸蜡醇。
本发明液体药用组合物还可以包含粘性增强剂以改善产品的口感和/或覆盖胃肠道内壁。这样的试剂包括阿拉伯胶、藻酸膨润土、卡波姆、羧甲基纤维素钙或钠、十八醇十六醇混合物、甲基纤维素、乙基纤维素、明胶瓜耳胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、麦芽糖糊精、聚乙烯醇、聚乙烯吡咯酮、碳酸异丙烯酯、藻酸丙二酯、藻酸钠、淀粉羟基乙酸钠、淀粉黄蓍胶和黄原胶。
可以加入甜味剂改善味道,例如山梨糖醇、糖精、糖精钠、蔗糖、天冬甜素、果糖、甘露糖醇和转化糖。
可以加入摄入安全量的防腐剂和螫合剂以改善储存稳定性,例如醇、苯甲酸钠、丁化羟基甲苯、丁化羟基茴香醚和乙二胺四乙酸。
根据本发明,液体组合物还可包含缓冲剂例如葡糖酸、乳酸、柠檬酸或乙酸、葡糖酸钠、乳酸钠、柠檬酸钠或醋酸钠。
本发明的剂型可以是胶囊,它在硬的或软的外壳内含有所述组合物,优选粉状或颗粒状的本发明固体组合物。所述外壳可由明胶制备,并任选含有增塑剂例如甘油和山梨糖醇,和遮光剂或着色剂。
虽然在任何给定的情况下最合适的给药将取决于所治疗的症状的性质和严重程度,但本发明最优选的途径是口服。剂量可适当地以单位剂量形式表示,并能够通过制药领域中公知的任何方法制备。
用于制片或胶囊填充的组合物可以通过湿式制粒法制备。在湿式制粒法中,使粉状形式的部分或全部活性成分和赋形剂混合,然后进一步在液体(通常为水)的存在下混合,这使所述粉末结块成颗粒。筛选和/或研碎所述颗粒,干燥,然后再筛选和/或研碎为预期粒度。然后可以将所述颗粒制片,或者可以在制片前加入其它赋形剂例如助流剂和/或润滑剂。
通常可以通过干混来制备制片组合物。例如,可以将混合的活性成分和赋形剂组合物压紧成棒状或片状,然后再粉碎成被压紧的颗粒。接着可以将所述被压紧的颗粒压制成片剂。
作为干法制粒的替代,可以使用直接压制技术将混合的组合物直接压制为被压紧的剂型。直接压制法生产出更均匀的无颗粒的片剂。特别适于直接压制制片的赋形剂包括微晶纤维素、喷雾干燥乳糖、磷酸二钙二水合物和胶体二氧化硅。
本发明的胶囊填充物可包括根据制片所描述的任何一种前述的混合物和颗粒,但是它们并不经过最后的制片步骤。
实施例
实施例1:奥美沙坦酯的制备
将MTT(10g)、丙酮/水(2/2体积)和3当量的H2SO4加入250的圆底烧瓶中。在室温下搅拌所述混合物约4-6小时。通过加水使三苯基甲醇(TPC)沉淀并滤出。向滤液中加入NaHCO3,将混合物冷却至5℃并搅拌1小时。粗奥美沙坦酯作为白色晶体得到(收率为90%,OLM-酸:0.89%面积,由HPLC测定)。
实施例2:奥美沙坦酯的纯化(结晶)
将丙酮加入1L烧瓶中。加入粗奥美沙坦酯,加热混合物并回流1小时,浓缩至10体积。冷却溶液至室温,加水(10体积)。在室温下搅拌混合物1小时,过滤沉淀并在45℃,10mmHg下干燥(收率为87%)。OLM-酸含量为0.04%,由HPLC测定。
实施例3:奥美沙坦酯的纯化(结晶)
将含有4体积%水的丙酮加入1L烧瓶中。加入粗奥美沙坦酯(10g),加热混合物并回流1小时。冷却溶液至室温,加水(10体积)。搅拌混合物1小时,过滤沉淀并在45℃,10mmHg下干燥(收率为90%)。OLM-酸含量为0.04%,由HPLC测定。
实施例4:奥美沙坦酯的纯化(结晶)
将含有4体积%水的丙酮加入1L烧瓶中。加入粗奥美沙坦酯(10g),加热混合物并回流1小时。冷却溶液至室温,加水(10体积)。在2℃下搅拌混合物1小时,过滤沉淀。并在45℃,10mmHg下干燥固体白色粉末(收率为95%)。OLM-酸含量为0.07%,由HPLC测定。
实施例5:奥美沙坦酯的纯化(结晶)
加热奥美沙坦酯在丙酮(7.5体积)中的浆液并回流1.5小时。冷却混合物至室温,加水(10体积)。在室温下搅拌混合物1小时,过滤沉淀并在45℃,10mmHg下干燥(收率为91%)。OLM-酸含量为0.06%,由HPLC测定。
实施例6:奥美沙坦酯的杂质分布图测定
用稀释剂在50ml容量瓶中按体积稀释15mg奥美沙坦酯标准物,由此制备0.1%的奥美沙坦酯标准溶液。用稀释剂将此溶液稀释1/50,然后稀释1/20。
用稀释剂在50ml容量瓶中按体积稀释15mg奥美沙坦酯样品,由此制备奥美沙坦酯样品溶液。
用20分钟的停机时间(stop time)注射标准溶液。
注射样品溶液,并使色谱继续直至梯度末端。
HPLC
柱填充物 Discovery HS C1850*4.6mm,3μC.N 269250-U
洗脱液A: 用HClO4调整至pH=2.5的0.025M NaClO4
洗脱液B: 乙腈
洗脱液梯度: 时间(分钟) 洗脱液A(%) 洗脱液B
(%)
0 75 25
15 55 45
25 35 65
30 35 65
停机时间: 30分钟
平衡时间: 5分钟
流速: 1.5ml/分钟
检测器: 220nm
注射体积: 10μl
稀释剂: 50%洗脱液A;50%洗脱液B
柱温: 25℃
自动取样器温度:5℃
用合适的积分器测定每种杂质的面积。在HPLC法中OLM-酸的检测极限是0.01%。
计算
色谱分析(参见图1)的相对保留时间如下:
物质 | RT | RRT |
OLM-酸 | 1.67 | 0.23 |
OLM | 7.20 | 1.00 |
OLM-甲基 | 8.66 | 1.20 |
OLM-Cl | 9.05 | 1.26 |
OLM-除去 | 9.41 | 1.31 |
TPC | 18.61 | 2.58 |
MTT | 25.37 | 3.52 |
通过参考具体的优选实施方案和说明性实施例来描述本发明,本领域技术人员能够理解,不背离本说明书所公开的发明的精神和范围的对所描述和说明的发明的修改。提出实施例以帮助理解本发明,但这些实施例既不意味也不应该被认为是以任何方式限制其范围。所述实施例未包括常规方法的详细描述。
Claims (29)
1.一种纯化奥美沙坦酯的方法,其包括:
a)提供奥美沙坦酯在C3-6酮中的溶液;
b)加水至溶液中;以及
c)回收纯化的奥美沙坦酯。
2.根据权利要求1的方法,其中C3-6酮选自丙酮、甲乙酮、二乙酮和叔丁基甲基酮。
3.根据权利要求2的方法,其中C3-6酮是丙酮。
4.根据权利要求1的方法,其中C3-6酮的量相对于约1g固体奥美沙坦酯为至少约7体积。
5.根据权利要求4的方法,其中C3-6酮的量相对于约1g固体奥美沙坦酯为至少约10体积。
6.根据权利要求1的方法,其中奥美沙坦酯在C3-6酮中的溶液进一步含有约4体积%-约14体积%的水。
7.根据权利要求6的方法,其中奥美沙坦酯在C3-6酮中的溶液进一步含有约4体积%的水。
8.根据权利要求1的方法,其进一步包括加热奥美沙坦酯在丙酮中的溶液至约30℃到约回流温度。
9.根据权利要求8的方法,其中奥美沙坦酯在丙酮中的溶液被加热至约40℃到约回流温度。
10.根据权利要求1的方法,其中所加水量相对于约1体积的C3-6酮为约0.5-约2体积的水。
11.根据权利要求10的方法,其中所加水量相对于约1体积的C3-6酮为至少约1体积的水。
12.根据权利要求1的方法,其进一步包括在步骤b)后冷却溶液至低于约30℃的温度。
13.根据权利要求12的方法,其中溶液被冷却至约室温。
14.根据权利要求1的方法,其进一步包括干燥已纯化的奥美沙坦酯。
15.根据权利要求1的方法,其中纯化的奥美沙坦酯含有少于约0.3%的OLM-酸。
16.根据权利要求15的方法,其中纯化的奥美沙坦酯含有少于约0.05%的OLM-酸。
17.根据权利要求16的方法,其中纯化的奥美沙坦酯含有少于约0.03%的OLM-酸。
18.一种纯化奥美沙坦酯的方法,其包括:
a)使三苯甲基奥美沙坦酯与酸在水可混溶有机溶剂中接触以得到奥美沙坦酯第一溶液和三苯基甲醇沉淀物;
b)从第一溶液中分离三苯基甲醇沉淀物;
c)使第一溶液和碱接触以得到奥美沙坦酯沉淀物;
d)回收奥美沙坦酯沉淀物;
e)将奥美沙坦酯沉淀物溶于C3-6酮中以形成第二溶液;
f)加水至第二溶液中;以及
g)回收纯化的奥美沙坦酯。
19.根据权利要求18的方法,其中第一溶液进一步含有水。
20.根据权利要求18的方法,其中水可混溶有机溶剂选自丙酮、乙腈和叔丁醇。
21.根据权利要求20的方法,其中水可混溶有机溶剂是丙酮。
22.根据权利要求21的方法,其中第一溶液进一步含有水,并且在第一溶液中水和丙酮的比率以体积计为约1∶3-约3∶1。
23.根据权利要求18的方法,其中纯化的奥美沙坦酯含有少于约0.3%的OLM-酸。
24.根据权利要求23的方法,其中纯化的奥美沙坦酯含有少于约0.05%的OLM-酸。
25.根据权利要求24的方法,其中纯化的奥美沙坦酯含有少于约0.03%的OLM-酸。
26.一种奥美沙坦酯,其含有少于约0.3%的OLM-酸。
27.根据权利要求26的奥美沙坦酯,其含有少于约0.05%的OLM-酸。
28.根据权利要求27的奥美沙坦酯,其含有少于约0.03%的OLM-酸。
29.一种药物组合物,其包含权利要求26的奥美沙坦酯和一种药学上可接受的赋形剂。
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Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060281800A1 (en) * | 2005-04-12 | 2006-12-14 | Glenmark Pharmaceuticals Limited | Polymorphic form of olmesartan and process for its preparation |
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AR083523A1 (es) | 2010-10-29 | 2013-03-06 | Interquim Sa | Procedimiento de obtencion del olmesartan medoxomilo |
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WO2013021312A1 (en) | 2011-08-05 | 2013-02-14 | Lupin Limited | Process for the preparation of olmesartan medoxomil |
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Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5138069A (en) * | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
DE3634717A1 (de) * | 1986-10-11 | 1988-04-14 | Dynamit Nobel Ag | Verfahren zur herstellung von 5-methyltetrazol |
US4870188A (en) | 1987-04-16 | 1989-09-26 | Neorx Corporation | Vinyl substituted radiohalogen conjugates for protein labeling |
US4870186A (en) * | 1987-05-22 | 1989-09-26 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
DE4036706A1 (de) * | 1990-11-17 | 1992-05-21 | Hoechst Ag | Verfahren zur behandlung der cardialen sowie der vasculaeren hypertrophie und hyperplasie |
US5656650A (en) * | 1990-12-14 | 1997-08-12 | Smithkline Beecham Corp. | Angiotensin II receptor blocking compositions |
IE914572A1 (en) * | 1991-01-17 | 1992-07-29 | Zeneca Ltd | Chemical process |
US5591762A (en) * | 1991-02-06 | 1997-01-07 | Dr. Karl Thomae Gmbh | Benzimidazoles useful as angiotensin-11 antagonists |
US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
IS1756B (is) * | 1991-02-21 | 2000-12-28 | Sankyo Company Limited | Hliðstæðuaðferð til framleiðslu 1-Biphenylmethylimidazole afleiða |
US5252753A (en) * | 1991-11-01 | 1993-10-12 | Ortho Pharmaceutical Corporation | Process for the preparation of certain substituted biphenyl tetrazoles and compounds thereof |
US5310928A (en) * | 1991-11-18 | 1994-05-10 | E. I. Du Pont De Nemours And Company | Process for preparing biphenyltetrazole compounds |
US5264447A (en) * | 1992-09-01 | 1993-11-23 | Merck & Co., Inc. | Angiotensin II antagonist |
JPH06298683A (ja) | 1993-04-15 | 1994-10-25 | Sankyo Co Ltd | 光反応による4−(2−置換)フェニルベンジルブロミド類の製造法 |
US5721263A (en) * | 1993-06-07 | 1998-02-24 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition for angiotensin II-mediated diseases |
JPH0753489A (ja) | 1993-06-11 | 1995-02-28 | Sankyo Co Ltd | ビフェニルカルボキサミド誘導体の製造法 |
US5412102A (en) | 1994-05-27 | 1995-05-02 | Syntex (U.S.A.) Inc. | Processes for preparing 1-butyl-2-[2'-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid |
JP2928982B2 (ja) * | 1994-10-27 | 1999-08-03 | 住化ファインケム株式会社 | 4’−ブロモメチル−2−シアノビフェニルの製造法 |
JPH08325248A (ja) | 1995-05-26 | 1996-12-10 | Chugoku Kayaku Kk | テトラゾール類の新規な合成試薬及びそれを用いたテトラゾール類の製造方法 |
US5994348A (en) * | 1995-06-07 | 1999-11-30 | Sanofi | Pharmaceutical compositions containing irbesartan |
JP3671266B2 (ja) * | 1996-03-21 | 2005-07-13 | 東洋化成工業株式会社 | 5−置換テトラゾール類の製造方法 |
GB9613470D0 (en) | 1996-06-27 | 1996-08-28 | Ciba Geigy Ag | Small solid oral dosage form |
IT1291551B1 (it) * | 1997-04-11 | 1999-01-11 | Luso Farmaco Inst | Processo per la preparazione di composti 4-bromometil bifenilici |
FR2771090B1 (fr) * | 1997-11-17 | 2000-02-04 | Sanofi Sa | Procede de preparation de derives de bromomethyl-biphenyle |
DE19757995A1 (de) | 1997-12-29 | 1999-07-08 | Great Lakes Chem Konstanz Gmbh | Verfahren zur Herstellung von aromatischen Brommethyl-Verbindungen |
JP4185182B2 (ja) | 1998-04-08 | 2008-11-26 | 第一三共株式会社 | イミダゾール誘導体の製造方法 |
JP4260241B2 (ja) | 1998-04-21 | 2009-04-30 | 第一三共株式会社 | イミダゾール誘導体の製造法 |
US6271418B1 (en) * | 2000-02-22 | 2001-08-07 | Nippon Kayaku Co., Ltd. | Process for preparing (hetero) aromatic substituted benzene derivatives |
HUP0400553A3 (en) * | 2000-11-21 | 2010-03-29 | Daiichi Sankyo Company | Pharmaceutical compositions |
EP1535901B8 (en) * | 2002-06-12 | 2008-09-24 | Sumitomo Chemical Company, Limited | Process for producing 4'-bromomethyl-2-cyanobiphenyl |
CN1271068C (zh) | 2003-03-25 | 2006-08-23 | 上海医药工业研究院 | 一种奥美沙坦酯的制备方法 |
ITMI20032338A1 (it) * | 2003-11-28 | 2005-05-29 | Dinamite Dipharma S P A In Forma A Bbreviata Diph | Composti feniltetrazolici. |
-
2005
- 2005-09-02 CA CA002573800A patent/CA2573800A1/en not_active Abandoned
- 2005-09-02 US US11/217,472 patent/US7528258B2/en not_active Expired - Fee Related
- 2005-09-02 CN CNA2005800262573A patent/CN1993355A/zh active Pending
- 2005-09-02 CN CNA2005800219037A patent/CN1976926A/zh active Pending
- 2005-09-02 WO PCT/US2005/031481 patent/WO2006029056A1/en active Application Filing
- 2005-09-02 EP EP05797758A patent/EP1706401A1/en not_active Withdrawn
- 2005-09-02 JP JP2006538570A patent/JP4511550B2/ja not_active Expired - Fee Related
-
2007
- 2007-02-26 IL IL181549A patent/IL181549A0/en unknown
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CN102584804B (zh) * | 2011-12-13 | 2016-05-18 | 浙江华海药业股份有限公司 | 一种三苯甲基奥美沙坦酯脱保护基制备奥美沙坦酯的工艺 |
US9273026B2 (en) | 2012-07-20 | 2016-03-01 | Novartis Ag | Carbamate/urea derivatives |
US9034874B2 (en) | 2012-07-20 | 2015-05-19 | Novartis Ag | Carbamate/urea derivatives |
US9624192B2 (en) | 2012-07-20 | 2017-04-18 | Novartis Ag | Carbamate/urea derivatives |
CN108658954A (zh) * | 2018-06-12 | 2018-10-16 | 广州小桔生物科技有限公司 | 一种高纯度奥美沙坦酯的精制方法 |
CN109761966A (zh) * | 2019-01-30 | 2019-05-17 | 浙江省食品药品检验研究院 | 一种奥美沙坦酯晶体及其制备方法 |
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WO2006029056A1 (en) | 2006-03-16 |
JP2007509992A (ja) | 2007-04-19 |
EP1706401A1 (en) | 2006-10-04 |
IL181549A0 (en) | 2007-07-04 |
CN1976926A (zh) | 2007-06-06 |
JP4511550B2 (ja) | 2010-07-28 |
CA2573800A1 (en) | 2006-03-16 |
US20060069141A1 (en) | 2006-03-30 |
US7528258B2 (en) | 2009-05-05 |
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