CN110818655A - 1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法 - Google Patents
1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法 Download PDFInfo
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- CN110818655A CN110818655A CN201810913763.3A CN201810913763A CN110818655A CN 110818655 A CN110818655 A CN 110818655A CN 201810913763 A CN201810913763 A CN 201810913763A CN 110818655 A CN110818655 A CN 110818655A
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- piperazine
- mercaptoethoxy
- ethyl
- piperazine hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
1‑[2‑(2‑巯基乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法本发明提供了一种经济实用的制备医药中间体1‑[2‑(2‑巯基乙氧基)乙基]哌嗪盐酸盐的新方法。
Description
技术领域
本发明提供了一种经济实用的制备医药中间体1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的新方法。
背景技术
哌嗪是很多药物的重要组成部分,为分子中含两个氮原子的六元杂环,是富氮杂环化合物的理想结构单元，具有生成焓高、热稳定性好等特点。近年来，哌嗪类化合物在有机合成和医学中的应用已引起了有机化学界和药学界的广泛关注，哌嗪环与传统的有机药物相比，具有更好氮平衡的对称结构。在药物合成中引入哌嗪环,可作为药物增效基团,改善药物的药代动力学性质,提高药物的生物活性；含哌嗪环的化合物可以进一步合成许多类型有机化合物，这些化合物大多具有高效的药理活性,有些已经开发成为临床药物。在2012年公布的全球排名100以内的畅销药物中，我们在约10种畅销药中找到了相应的哌嗪组成部分，如排名比较靠前的Quetiapine (喹硫平)、Aripiprazole （阿立哌唑）、Clozapine(氯氮平)和Olanzapine (奥氮平) 都用于精神疾病治疗，其他如Levofloxacin(左氧氟沙星)用于消炎杀菌、Cetirizine hydrochloride (盐酸西替利嗪)用于抗过敏。
单取代哌嗪的传统工艺是先用Boc/Cbz/Ac等保护即先保护一端的氨基，然后与卤化物反应做另外一端的取代反应，最后去除掉保护基，才得到最终单取代产品。这些传统工艺路线长，耗时，总收率低，在工业化生产中有很大缺陷，很难采用。
发明内容
本发明要所要解决的技术问题是克服上述技术存在的缺陷，提供一种实用、简洁的制备单取代哌嗪的方法。
单取代哌嗪的传统工艺是先用Boc/Cbz/Ac等保护即先保护一端的氨基，然后与卤化物反应做另外一端的取代反应，最后去除掉保护基，才得到最终单取代产品。这些传统工艺路线长，耗时，总收率低，在工业化生产中有很大缺陷，很难采用。本发明的一方面是开发了一种制备高纯1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的新方法：在合适的溶剂或无溶剂条件下，哌嗪盐酸盐和2-(2-氯乙氧基)乙硫醇在100-150摄氏度下搅拌发生反应；不需要保护哌嗪的一个氨基而直接高产率地得到1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐。
所用的溶剂可以使甲苯、二甲苯等高沸点非极性溶剂，优选是无溶剂体系。反应温度可以在100-150摄氏度，最好的温度范围是120-140摄氏度。反应底物可以是无水哌嗪或哌嗪和哌嗪盐酸盐的联合作用，优选是哌嗪和哌嗪盐酸盐的混合物。产品的最终纯化可以用高温减压蒸馏得到其自由碱形式，或形成盐酸盐来低温重结晶得到产品的盐酸盐形式，最佳的高纯产品可以通过重结晶来提纯其盐酸盐，得到含量99.5%以上的高纯产品，避免高温蒸馏纯化过程中产生的哌嗪类杂质，也避免了高温减压蒸馏所需要苛刻的反应设备要求和高成本高能耗。
本发明的工艺条件可以在较宽的范围内进行，而本发明列举的反应条件如溶剂/温度/反应配比/底物选择等不是限制性的，并且仅仅对应于本发明的优选结论。
以下将通过具体实例来阐明本发明的方法。
Claims (2)
1.一种经济实用的制备医药中间体1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的新方法。
2.在合适的溶剂或无溶剂条件下，哌嗪盐酸盐和2-(2-氯乙氧基)乙硫醇在100-150摄氏度下搅拌发生反应；不需要保护哌嗪的一个氨基而直接高产率地得到1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐。
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| CN201810913763.3A CN110818655A (zh) | 2018-08-13 | 2018-08-13 | 1-[2-(2-巯基乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法 |
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