CN108440434A - 一种缬沙坦的新杂质以及合成方法 - Google Patents
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- 239000003513 alkali Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
本发明公开了一种缬沙坦的新杂质以及该杂质的合成方法;该方法以缬沙坦在溶剂中使用强碱高温反应,然后加酸调节pH至1.0‑3.0浓缩得到该杂质。该方法实现了生产中可以通过控制该杂质的生成条件避免生成该杂质,从而降低该杂质以及由该杂质生成的衍生物带到成品的风险。
Description
技术领域:
本发明涉及一种缬沙坦的新杂质以及合成方法,属于医药化工领域。
背景技术:
缬沙坦是由诺华开发的抗血压药,1996年首先在德国上市,缬沙坦是一种血管紧张素Ⅱ受体拮抗剂,主要通过阻断血管紧张素Ⅱ与AT1受体结合,使血管平滑肌舒张而起到降压作用,同时也抑制血管紧张素Ⅱ引起的血管平滑肌增生、内皮功能损害、水钠潴留等作用,具有心、肾、血管保护作用,结构如下所示:
其中式II所示的化合物N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸为缬沙坦化学名,例如专利WO2009125416、US20090203921报道以L-缬氨酸为起始物料经酯化,再与2’-氰基-4-溴甲基联苯进行缩合反应,再经戊酰化、成四氮唑生成缬沙坦:
发明内容:
发明人在研究缬沙坦的制备过程中发现N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸存在一种未曾被报道过的新杂质,该杂质带到成品中去,对成品质量造成影响。该新杂质命名为2-(N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰基)-3-亚甲基-2-烯酸,结构式如式I所示:
本发明还提供了式I所示化合物的制备方法,包括以下步骤:
(a)控制温度60~120℃,使式II的化合物N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸在强碱条件下在水或者有机溶剂中反应,
(b)反应结束后,在步骤(a)的反应液中加酸,调节pH至1.0~3.0,分离得到式I所示化合物,
其中所述碱优选为:碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、甲醇钠。所述碱与式II所示化合物的摩尔比为1:1~10:1。
所述有机溶剂优选为:DMF、甲苯、二甲苯、甲基叔丁基醚或乙酸乙酯。所述水或有机溶剂的体积(毫升)用量相对于式II所示化合物质量(克)用量的1~20倍。
步骤(b)所述酸为盐酸。
步骤(b)加入酸调节pH至1.0~3.0。
综上,该杂质对缬沙坦粗品的质量控制具有重要的影响。目前没有文献报道该杂质的结构以及制备方法,因此定向合成该杂质,建立该杂质的分析方法,对缬沙坦原料药的质量控制有着重要意义。本发明属于首次报道了该杂质。同时合成路线具有反应条件温和,工艺简单,反应时间短,副产物少,收率良好,能得到高纯度产物等优点。
具体实施方式:
实例一:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入水25ml,然后加入氢氧化钠0.46g,于90~100℃下搅拌反应12小时,加入盐酸调节pH至2.0,浓缩得该杂质,称重得4.08g,收率为82%,纯度为87.3%。
实例二:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入水5ml,然后加入氢氧化钠0.46g,于90~100℃下搅拌反应12小时,加入盐酸调节pH至2.0,浓缩得该杂质,称重得4.155g,收率为83.5%,纯度为85.9%。
实例三:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入DMF 5ml,然后加入氢氧化钾0.64g,于90~120℃下搅拌反应12小时,浓缩掉溶剂,加入乙酸乙酯,盐酸调节pH至2.0,水洗、浓缩得该杂质,称重得4.23g,收率为85%,纯度为88.6%。
实例四:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入甲苯50ml,然后加入甲醇钠3.2g,于90~110℃下搅拌反应12小时,盐酸调节pH至2.0,水洗、浓缩得该杂质,称重得4.2g,收率为84.5%,纯度为89.3%。
实例五:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入二甲苯50ml,然后加入7.92g碳酸钾,于100~120℃下搅拌反应12小时,盐酸调节pH至3.0,水洗、浓缩得该杂质,称重得4.37g,收率为88%,纯度为90.3%。
实例六:
取N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸5g于三口瓶中,加入乙酸乙酯100ml,然后加入氢氧化钠0.92g,于60~80℃下搅拌反应12小时,盐酸调节pH至2.0,水洗、浓缩得该杂质,称重得4.17g,收率为84%,纯度为82.6%。
Claims (8)
1.一种化合物,命名为2-(N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰基)-3-亚甲基-2-烯酸,其特征在于结构式如式I所示:
2.一种式I所示化合物的制备方法,其特征在于包括以下步骤:
(a)控制温度60~120℃,使式II的化合物N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸在强碱条件下在水或者有机溶剂中反应,
(b)反应结束后,在步骤(a)的反应液中加酸,调节pH至1.0~3.0,分离得到式I所示化合物,
3.根据权利要求2所述的方法,其特征在于其中所述碱选自:碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、甲醇钠。
4.根据权利要求2所述的方法,其特征在于所述有机溶剂选自:DMF、甲苯、二甲苯、甲基叔丁基醚或乙酸乙酯。
5.根据权利要求2所述的方法,其特征在于所述碱与式II所示化合物的摩尔比为1:1~10:1。
6.根据权利要求2所述的方法,其特征在于所述水或有机溶剂的体积(毫升)用量相对于式II所示化合物质量(克)用量的1~20倍。
7.根据权利要求2所述的方法,其特征在于步骤(b)所述酸为盐酸。
8.根据权利要求2所述的方法,其特征在于步骤(b)加入酸调节pH至1.0~3.0。
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