CN117586166A - 一种用于制备艾莎利酮的化合物及其制备方法 - Google Patents
一种用于制备艾莎利酮的化合物及其制备方法 Download PDFInfo
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- CN117586166A CN117586166A CN202311592450.XA CN202311592450A CN117586166A CN 117586166 A CN117586166 A CN 117586166A CN 202311592450 A CN202311592450 A CN 202311592450A CN 117586166 A CN117586166 A CN 117586166A
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- 150000002576 ketones Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
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- 239000002904 solvent Substances 0.000 claims abstract description 23
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- 238000000034 method Methods 0.000 claims abstract description 10
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- 230000008569 process Effects 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种用于制备艾莎利酮的化合物,结构式[Ⅱ]如下:制备方法包括以下步骤:化合物[Ⅱ]通过化合物[Ⅲ]与4‑甲磺酰基苯胺在溶剂中酰胺缩合剂催化反应得到,反应式如下;本发明提供的化合物及制备方法,反应条件更加温和,工艺更加稳定,产量更高,提供了一种有利于艾沙利酮国产化的有效合成途径。
Description
技术领域
本发明涉及医药化工技术领域,特别是涉及一种用于制备艾莎利酮的化合物及其制备方法。
背景技术
艾沙利酮是一种用于治疗高血压症的口服、非甾体类、选择性、新型盐皮质激素受体(MR)阻断剂,其消旋的艾沙利酮最早由Exelixis公司于2005年07月30日提出名为“作为药用制剂的吡咯衍生物”的WO2006/012642专利报道。其阻转异构体由第一三共株式会社于2008年04月08日提出名为“吡咯衍生物的阻转异构体”的WO2008/126831专利提出。完整的合成路线如下:
其中,化合物1与艾沙利酮[Ⅰ]为同一化合物。
该路线主要缺陷在于4-甲基-5-(2-三氟甲基-苯基)-2,3-二氢-1H-吡咯-3-羧酸甲酯制备需要通过柱层析纯化,成品需要过液相制备拆分,总收率仅有3.69%,难以实现产业化。
WO2014168103A1用氰基乙酸乙酯代替了氰基乙酸甲酯,用氯化亚砜/氯化氢/硫酸催化关环代替了雷尼镍催化关环,吡咯烷的亚胺在关环后就进行羟乙基化,在中间步骤用活性胺拆分代替WO2008/126831的最后一步液相拆分,具体路线如下:
该路线涉及的反应均为常规反应,涉及后处理方式均为常规操作,可产业化程度较高。不足之处在于,由化合物8制备化合物18使用了氯化亚砜和硫酸,硫化物残留非常容易造成由化合物18制备化合物17时催化剂中毒。此外,WO2014168103A1在中国的专利CN106916092B对拆分试剂辛可宁、奎宁、辛可尼丁、奎尼丁和中间体1631030-72-2及其S构型的奎宁盐进行了保护,2034年4月6日才到期,不利于药品国产化。
WO2015030010A1用溴乙酸乙酯代替的碳酸乙烯酯,水解后得到1665283-34-0,再用辛可宁等活性胺进行拆分,然后硼氢化钠-三氟化硼还原得到1665290-31-2,乙基溴化镁催化与4-(甲磺酰基)苯胺反应,用盐酸淬灭后再用乙酸异丁酯提取、浓缩,用甲基环己烷精制得到艾沙利酮,具体合成路线如下:
该路线主要不足是羧酸还原使用了硼氢化钠+三氟乙醚还原体系,反应过程产生剧毒硼乙烷气体,也使用了高活性的格式试剂,容易增加副反应。
印度专利IN202121024569报道在吡咯环2位氯还原前拆分,具体合成路线如下:
该路线拆分后再进行吡咯环2位氯还原,增加了羧酸的活性与空间位阻,更有利于拆分,不足在于羧酸酸性较强,直接钯碳还原容易造成催化剂失活。
发明内容
针对上述现有技术的不足,本专利申请所要解决的技术问题是如何提供一种反应条件温和,工艺稳定,产量高的用于制备艾莎利酮的化合物及其制备方法。
为了解决上述技术问题,本发明采用了如下的技术方案:
一种用于制备艾莎利酮的化合物,结构式[Ⅱ]如下:
一种用于制备艾莎利酮的化合物的制备方法,包括以下步骤:
化合物[Ⅱ]通过化合物[Ⅲ]与4-甲磺酰基苯胺在溶剂中酰胺缩合剂和缚酸剂催化反应得到,反应式如下;
其中,所述溶剂为四氢呋喃、乙腈、1,4-二氧六环、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、1,2-二氯乙烷、氯仿、甲基叔丁基醚或甲苯中的一种或几种溶剂混合。
其中,所述酰胺缩合剂为CDI、DCC、DMAP、EDCI、DIC、HOBt、HOAt、草酰氯或氯化亚砜等中的一种或两种,优选草酰氯、CDI和DCC。
其中,所述缚酸剂为三乙胺、N,N-二异丙基乙胺、吡啶、N-甲基吗啉、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾等,优选三乙胺、N,N-二异丙基乙胺或吡啶。
反应后用酯类、醚类、氯代烃类或芳香类溶剂提取,并浓缩得到化合物[Ⅱ]。化合物[Ⅱ]可通过柱层析分离纯化。
其中,所述酯类溶剂为乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸异丙酯、甲酸乙酯、甲酸丙酯等,优选乙酸乙酯。
其中,所述醚类溶剂为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃等,优选甲基叔丁基醚。
其中,所述氯代烃类溶剂为二氯甲烷、氯仿、1,2-二氯乙烷等,优选二氯甲烷。
其中,所述芳香类溶剂为苯、甲苯、氯苯、二甲苯等,优选甲苯。
如酰胺缩合剂选择草酰氯,产生化合物[Ⅱa]中间态,结构式如下:
化合物[Ⅱa]在水解溶剂中加入碱溶液中合适温度下水解成化合物[Ⅱ],用酯类、醚类、氯代烃类或芳香类溶剂提取,并浓缩得到较纯的化合物[Ⅱ]。
其中,所述水解溶剂为甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮等,优选四氢呋喃。
其中,所述碱溶液为氢氧化钠水溶液、氢氧化钾水溶液、碳酸钾水溶液、碳酸钠水溶液、氢氧化锂水溶液等,优选氢氧化钠水溶液和氢氧化钾水溶液。
其中,化合物[Ⅱ]通过催化还原制备艾沙利酮[Ⅰ],反应式如下:
其中,催化还原所用的催化剂为钯碳或雷尼镍金属催化剂。
其中,催化还原所用的还原剂为氢气、甲酸或甲酸盐。
其中,催化还原所用的溶剂为水、甲醇、乙醇、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
综上,本发明提供的化合物及制备方法,反应条件更加温和,工艺更加稳定,产量更高,提供了一种有利于艾沙利酮国产化的有效合成途径。
附图说明
图1为化合物[Ⅲ]的1H-NMR谱图。
图2为化合物[Ⅱ]的1H-NMR谱图。
图3为化合物[Ⅱ]的MS谱图。
图4为化合物[Ⅰ]的1H-NMR谱图。
具体实施方式
下面结合附图对本发明作进一步的详细说明。在本发明的描述中,需要理解的是,方位词如“上、下”和“顶、底”等所指示的方位或位置关系通常是基于附图所示的方位或位置关系,仅是为了便于描述本发明和简化描述,在未作相反说明的情况下,这些方位词并不指示和暗示所指的装置或元件必须具有特定的方位或者以特定的方位构造和操作,因此不能理解为对本发明保护范围的限制;方位词“内、外”是指相对于各部件本身的轮廓的内外。
一种用于制备艾莎利酮的化合物,(5S)-2-氯-1-(2-羟乙基)-4-甲基-N-[4-(甲磺酰基)苯基]-5-[2-(三氟甲基)苯基]-1H-吡咯-3-甲酰胺,结构式[Ⅱ]如下:
一种用于制备艾莎利酮的化合物的制备方法,包括以下步骤:
化合物[Ⅱ]通过化合物[Ⅲ]与4-甲磺酰基苯胺在溶剂中酰胺缩合剂和缚酸剂催化反应得到,反应式如下;
实施时,所述溶剂为四氢呋喃、乙腈、1,4-二氧六环、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、1,2-二氯乙烷、氯仿、甲基叔丁基醚或甲苯中的一种或几种溶剂混合。
实施时,所述酰胺缩合剂为CDI、DCC、DMAP、EDCI、DIC、HOBt、HOAt、草酰氯或氯化亚砜等中的一种或两种,优选草酰氯、CDI和DCC。
实施时,所述缚酸剂为三乙胺、N,N-二异丙基乙胺、吡啶、N-甲基吗啉、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾等,优选三乙胺、N,N-二异丙基乙胺或吡啶。
反应后用酯类、醚类、氯代烃类或芳香类溶剂提取,并浓缩得到化合物[Ⅱ]。化合物[Ⅱ]可通过柱层析分离纯化。
实施时,所述酯类溶剂为乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸异丙酯、甲酸乙酯、甲酸丙酯等,优选乙酸乙酯。
实施时,所述醚类溶剂为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃等,优选甲基叔丁基醚。
实施时,所述氯代烃类溶剂为二氯甲烷、氯仿、1,2-二氯乙烷等,优选二氯甲烷。
实施时,所述芳香类溶剂为苯、甲苯、氯苯、二甲苯等,优选甲苯。
如酰胺缩合剂选择草酰氯,产生化合物[Ⅱa]中间态,结构式如下:
化合物[Ⅱa]在水解溶剂中加入碱溶液中合适温度下水解成化合物[Ⅱ],用酯类、醚类、氯代烃类或芳香类溶剂提取,并浓缩得到较纯的化合物[Ⅱ]。
实施时,所述水解溶剂为甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮等,优选四氢呋喃。
实施时,所述碱溶液为氢氧化钠水溶液、氢氧化钾水溶液、碳酸钾水溶液、碳酸钠水溶液、氢氧化锂水溶液等,优选氢氧化钠水溶液和氢氧化钾水溶液。
实施时,化合物[Ⅱ]通过催化还原制备艾沙利酮[Ⅰ],反应式如下:
其中,催化还原所用的催化剂为钯碳或雷尼镍金属催化剂。优选5%至10%的钯碳。
实施时,催化还原所用的还原剂为氢气、甲酸或甲酸盐。优选甲酸钠和氢气。
实施时,催化还原所用的溶剂为水、甲醇、乙醇、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。优选水、甲醇、乙醇、四氢呋喃。
其中,缩写名称解释:
CDI:N,N'-羰基二咪唑;
DCC:N,N'-二环己基碳二亚胺;
DMAP:4-二甲氨基吡啶;
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
DIC:N,N'-二异丙基碳二亚胺;
HOBt:1-羟基苯并三唑;
HOAt:N-羟基-7-氮杂苯并三氮唑。
化合物[Ⅲ]的制备:
化合物[Ⅲ]参考印度专利IN202121024569的实施例1至实施例6制备,异构体含量小于2%。1HNMR(600MHz,DMSO):δ12.21(s,1H),7.89(d,J=7.7Hz,1H),7.79(t,J=7.4Hz,1H),7.73(t,J=7.7Hz,1H),7.54(d,J=7.5Hz,1H),4.98(br,1H),3.86(m,1H),3.42(m,3H),1.85(s,3H),具体见附图1。
化合物[Ⅱ]的制备(用草酰氯制备):
在5L三口反应瓶中加入化合物[Ⅲ]400g(1.15mol)、二氯甲烷3.6L和草酰氯0.4L(4.73mol),室温反应2小时。反应液减压蒸馏至断流得到浓缩物。在浓缩物中加入3.6L四氢呋喃和4-甲磺酰基苯胺360g(1.83mol),室温滴加N,N-二异丙基乙胺1L,然后升温回流反应至TLC检测反应完全(展开剂:石油醚-乙酸乙酯(3:1),反应液用甲醇稀释)。降温至室温,减压浓缩至断流,得到N-{[4-(甲基磺酰基)苯基]氨基}草氨酸2-((S)-2-氯-3-甲基-4-[4-(甲基磺酰基)苯基]氨基甲酰基}-2-[2-(三氟甲基)苯基]-1H-吡咯-1-基)乙酯湿品。
向装有N-{[4-(甲基磺酰基)苯基]氨基}草氨酸2-((S)-2-氯-3-甲基-4-[4-(甲基磺酰基)苯基]氨基甲酰基}-2-[2-(三氟甲基)苯基]-1H-吡咯-1-基)乙酯湿品的反应瓶中加入四氢呋喃4.5L、48%氢氧化钾水溶液300g(3.6mol)和水3.6L,升温至35-45℃反应至TLC检测反应完全(展开剂:石油醚-乙酸乙酯(3:1),反应液用甲醇稀释)。反应完毕后降温至室温,加入乙酸乙酯2L搅拌均匀,分液,有机相40℃减压浓缩至干。向浓缩物中加入乙醇600ml,于35-45℃滴加水7.5L搅拌结晶,降温至0-10℃后过滤,滤饼干燥得到式(Ⅱ),可无需纯化直接进行下一步反应。也可以柱层析纯化(洗脱剂:正己烷-乙酸乙酯(10~1:1),收集馏分,浓缩后得到较纯的化合物[Ⅱ]。1HNMR(600MHz,DMSO):δ10.30(s,1H),7.97(d,J=8.8Hz,2H),7.92(d,J=7.8Hz,1H),7.88(d,J=8.8Hz,2H),7.81(d,J=7.4Hz,1H),7.76(d,J=7.7Hz,1H),7.53(d,J=7.5Hz,1H),4.90(s,1H),3.87(m,1H),3.46(s,3H),3.17(s,3H),1.83(s,3H),具体见附图2。MS(+ESI):501.09(M+H,同位素:502.09和503.09),1001.17(2M+H,1003.17),具体见附图3。
化合物[Ⅱ]的制备(用CDI催化制备):
在1L三口反应瓶中加入化合物[Ⅲ]40g(0.12mol)、4-甲磺酰基苯胺20.5g
(0.12mol)、二氯甲烷400ml和CDI 20.0g(1.2mol),室温过夜。加入400ml水搅拌分液,有机层浓缩至干,可无需纯化直接进行下一步反应。也可以柱层析纯化(洗脱剂:正己烷-乙酸乙酯(10~1:1),收集馏分,浓缩后得到较纯的化合物[Ⅱ]。
艾沙利酮[Ⅰ]的制备(钯碳催化甲酸钠还原):
将化合物[Ⅱ]260g、乙醇2L、甲酸钠140g、5%钯碳30g加入5L三口圆底烧瓶中,升温至55-65℃搅拌反应至TLC检测反应完全(展开剂:乙酸乙酯-石油醚(1:1))。冷却至室温,过滤,滤液减压浓缩至干,得到艾沙利酮[Ⅰ]。1HNMR(600MHz,CDCl3):δ8.11(s,1H),7.80(m,5H),7.62(t,J=7.4Hz,1H),7.58(t,J=7.6Hz,1H),7.53(s,1H),7.33(d,J=7.4Hz,1H),3.71(m,2H),3.64(m,2H),3.03(s,3H),2.05(s,3H),具体见附图4。
艾沙利酮[Ⅰ]可用乙醇水混合液精制,或乙酸乙酯与正己烷精制,异构体含量小于0.1%。
艾沙利酮[Ⅰ]的制备(钯碳催化氢化):
将化合物[Ⅱ]260g、乙醇2L、5%钯碳30g加入5L三口圆底烧瓶中,氮气置换空气,氢气置换氮气,常压升温至55-65℃搅拌反应至TLC检测反应完全(展开剂:乙酸乙酯-石油醚(1:1))。冷却至室温,过滤,滤液减压浓缩至干,得到艾沙利酮[Ⅰ]。
最后应说明的是:本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等统计数的范围之内,则本发明也意图包含这些改动和变型。
Claims (9)
1.一种用于制备艾莎利酮的化合物,其特征在于,结构式[Ⅱ]如下:
2.一种用于制备艾莎利酮的化合物的制备方法,其特征在于,包括以下步骤:
化合物[Ⅱ]通过化合物[Ⅲ]与4-甲磺酰基苯胺在溶剂中酰胺缩合剂和缚酸剂催化反应得到,反应式如下;
3.根据权利要求2所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,所述溶剂为四氢呋喃、乙腈、1,4-二氧六环、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、1,2-二氯乙烷、氯仿、甲基叔丁基醚或甲苯中的一种或几种溶剂混合。
4.根据权利要求2所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,所述酰胺缩合剂为CDI、DCC、DMAP、EDCI、DIC、HOBt、HOAt、草酰氯或氯化亚砜中的一种或两种。
5.根据权利要求2所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,所述缚酸剂为三乙胺、N,N-二异丙基乙胺、吡啶、N-甲基吗啉、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾等,优选三乙胺、N,N-二异丙基乙胺或吡啶。
6.根据权利要求1所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,化合物[Ⅱ]通过催化还原制备艾沙利酮[Ⅰ],反应式如下:
7.根据权利要求6所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,催化还原所用的催化剂为钯碳或雷尼镍金属催化剂。
8.根据权利要求6所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,催化还原所用的还原剂为氢气、甲酸或甲酸盐。
9.根据权利要求6所述的一种用于制备艾莎利酮的化合物的制备方法,其特征在于,催化还原所用的溶剂为水、甲醇、乙醇、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
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