CN112047881B - 一种坦帕诺的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种坦帕诺的制备方法,属于医药领域。该方法以(S)‑4‑(3‑溴苯基)‑6,8‑二氯‑2‑甲基=1,2,3,4‑四氢异喹啉为原料,制成格氏试剂后直接与二氧化硫反应得到亚磺酸盐中间体,不经分离纯化直接与化合物2在次氯酸钠和醋酸的作用下得到坦帕诺;操作简便,反应周期短,大大减少了人工成本;此路线避免了使用剧毒试剂苄硫醇和氯气,减少了人员伤害,更为环保;避免了使用昂贵的钯催化剂,降低了生产成本;更适合工业化生产。
Description
技术领域
本发明属于医药领域,具体涉及一种坦帕诺的制备方法。
背景技术
坦帕诺(tenapanor)是一种治疗便秘型肠易激综合征(IBS-C)的新药,由美国Ardelyx生物制药公司研制,于2019年9月获FDA批准上市。肠易激综合征(IBS)是一种常见的功能性胃肠道障碍综合征,以腹痛或腹部不适,伴有便秘或腹泻等排便习惯及形态改变,症状多为反复发作或慢性迁延。发病年龄多数于20~50岁之间。欧美发达国家的发病率为10%~15%,我国普通人群发病率约10%,以中青年居多,女性患病率高于男性。此外,近半数IBS患者也出现上胃肠道症状,如胃烧灼感、恶心、呕吐等及肠外症状如背痛、头痛、心悸、尿频、尿急、性功能障碍及心肾疾病等。尚有不同程度的心理精神异常表现,如焦虑、抑郁、紧张等。IBS的便秘或腹泻等排便习惯及形态改变,按Bristol分型法,主要分为腹泻型(IBS-D)、便秘型(IBS-C)、混合型(IBS-M)和不定型(IBS-U)。便秘型肠易激综合征(IBS-C)是一种以反复腹痛和胃肠道转运延长为特征的常见胃肠道疾病。IBS-C的发病机制尚未完全阐明,目前治疗IBS-C的药物以缓解症状为主,迫切需要新的靶点。坦帕诺(tenapanor)是IBS钠氢离子交换体-3(NHE 3)抑制剂,通过抑制钠/氢交换蛋白3(NHE3)分子,减少小肠和结肠对钠的吸收,促进水分分泌进入肠道,从而促进肠道蠕动、软化粪便,并能缓解腹痛,达到治疗便秘型肠易激综合征的作用。此外我国复星医药控股子公司正在扩大其适应证,进行用于治疗心肾疾病透析患者的高磷血症的临床试验研究。
坦帕诺(tenapanor,代号RDX5791,AZD1722)化学名为3-((S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-N-(26-(3-((S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基)磺酰胺基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂六碳酰基)苯磺酰胺;分子式为C50H66Cl4N8O10S2,分子量为1145.049,结构式如下:
坦帕诺(tenapanor)的合成最早在美国ardelyx公司申请的专利WO2010078449中公开了一种方法:
以3-溴苯乙酮为起始原料,经溴代、胺烷基化、还原和环合四步反应得到中间体4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉(3),用D-(+)-二苯甲酰基酒石酸进行拆分得到S-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉(1),再经钯催化的偶联反应和氯化反应得到中间体S-3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰氯(4);它与过量的1,8-二氨基-3,6-二氧杂辛烷反应得到中间体(5)的三氟醋酸盐,再与1,4-二异氰酸基丁烷反应得到坦帕诺(tenapanor)盐酸盐。此专利公开的中间体(5)的三氟醋酸盐和坦帕诺(tenapanor)盐酸盐制备步骤均采用制备液相得到,不适合工业化生产。在钯催化的偶联步骤中用到苄硫醇,气味较大,空气污染严重,随后的氯化反应中用到有强烈刺激性气味的剧毒气体氯气,都不适合工业化生产。
另一项专利WO2019091503中公开的合成方法如下:
拆分后的S-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉(2),经钯催化的偶联反应和氯化反应得到中间体S-3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰氯(4),再与单Boc保护的1,8-二氨基-3,6-二氧杂辛烷反应后脱Boc得到中间体(5),最后与1,4-二异氰酸基丁烷反应得到坦帕诺(tenapanor),此路线与先前的专利WO2010078449相比,没有太大的变化,仅仅是最后两步反应采用了Boc保护的中间体做反应物,提高了反应收率,同时产品纯化不再依靠制备液相分离。
此专利还公开了一种汇聚式合成方法,如下:
此方法是先合成化学结构中间的胺基物,单Boc保护的1,8-二氨基-3,6-二氧杂辛烷与1,4-二异氰酸基丁烷反应得到中间体(2)的盐酸盐,然后与中间体(4)反应得到坦帕诺(tenapanor),此改进提高了反应收率。
专利WO2020051014公开了另外两种合成方法:
中间体(5)与羰基二咪唑(CDI)反应得到氨基活化的中间体(6),再与1,4-丁二胺反应得到坦帕诺(tenapanor);或者1,4-丁二胺先与羰基二咪唑(CDI)反应得到两个氨基都氨基活化的中间体(7*),再与中间体(5)反应得到坦帕诺(tenapanor);此路线采用CDI活化的方法得到脲结构,与WO2019091503的方法(异氰酸酯的方法)相比,改进不大。它们都没有涉及中间体(4)的合成方法改进,都是按照WO2010078449的报道的钯催化偶联后氯化反应来制备磺酰氯中间体(4)。
发明内容
为了克服现有技术中坦帕诺合成过程需要使用高危险高毒性试剂、操作步骤繁琐和产品质量不高等缺陷,本发明的目的在于提供一种坦帕诺的制备方法。
本发明解决其技术问题所采用的技术方案是:一种坦帕诺的制备方法,包括以下步骤:
以化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉为原料,溶解到有机溶剂中,与异丙基氯化镁-氯化锂络合物进行第一阶段反应制备其格式试剂的溶液;再与二氧化硫的有机溶剂溶液进行第二阶段的反应制备其亚磺酸氯化镁盐的溶液;最后与化合物2在次氯酸钠和冰醋酸的作用下进行第三阶段反应得到坦帕诺;
进一步地,所述有机溶剂为四氢呋喃或2-甲基四氢呋喃。
反应路线如下:
进一步地,所述(S)-4-(3-溴苯基)-6,8-二氯-2-甲基=1,2,3,4-四氢异喹啉、异丙基氯化镁-氯化锂络合物、二氧化硫、化合物2、次氯酸钠和冰醋酸的摩尔比为:1.0:1.0-1.2:2.0-2.5:0.4-0.5:1.6-2.5:0.8-1.2。
进一步地,所述第一阶段反应制备(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉格式试剂溶液的反应温度为-20-0℃,反应时间为0.5-4小时。
进一步地,所述第二阶段的反应制备(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉亚磺酸氯化镁盐溶液的反应温度为-20-35℃,反应时间为0.5-4小时。
进一步地,所述第三阶段反应温度为-5-35℃,反应时间为1-8小时。
本发明的物料化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉和化合物2可以通过WO2019091503和WO2020051014公开的制备方法得到。在反应的第一阶段采用交换法制备Turbo型格氏试剂,反应选择型和产物稳定型都得到较大提高;在第二阶段与干燥的二氧化硫反应得到亚磺酸盐后立即进行第三阶段的氧化酰胺化反应,对反应温度和投料比例进行了优化,使得反应收率得到较大提高。
本发明具有以下有益效果:本发明以(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉为原料,制成格氏试剂后直接与二氧化硫反应得到亚磺酸盐中间体,不经分离纯化直接与化合物2在次氯酸钠和醋酸的作用下得到坦帕诺(tenapanor);反应条件温和,一锅法合成,操作简便,反应周期短,大大减少了人工成本;此路线避免了使用剧毒试剂苄硫醇和氯气,减少了人员伤害,更为环保;避免了使用昂贵的钯催化剂,降低了生产成本;产品纯度高,更适合工业化生产。
具体实施方式
以下是本发明的具体实施例,对本发明的技术方案做进一步描述,但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1
氮气保护下,化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基=1,2,3,4-四氢异喹啉0.1mol溶解到150ml四氢呋喃中,降温至-10℃,慢慢滴加异丙基氯化镁-氯化锂络合物的四氢呋喃溶液(0.11mol,1.3M in THF),滴加完成后继续在-5-0℃左右搅拌1小时,得到化合物1的格式试剂的四氢呋喃溶液。
反应瓶中加入500ml四氢呋喃,降温至-10℃,通入二氧化硫气体0.23mol,将上述新制备的格式试剂滴加到溶液中,滴加完成后慢慢升到室温搅拌1小时,通入氮气除去过量的二氧化硫气体,得到化合物1的亚磺酸氯化镁盐的溶液。
上述溶液降温到0℃,依次加入化合物20.045mol、次氯酸钠水溶液(0.21mol,1.4mol/L)和冰醋酸0.1mol慢慢升到室温搅拌反应5小时。反应液减压浓缩除掉大部分四氢呋喃,用二氯甲烷提取两次,合并有机相,依次用碳酸氢钠水溶液和饱和食盐水洗涤,分液干燥,减压浓缩,残留物用甲醇重结晶得到白色固体产品,收率78.6%。
实施例2
氮气保护下,化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基=1,2,3,4-四氢异喹啉0.1mol溶解到150ml2-甲基四氢呋喃中,降温至-20℃,慢慢滴加异丙基氯化镁-氯化锂络合物的2-甲基四氢呋喃溶液(0.12mol,1.4M in THF),滴加完成后继续在-10-0℃左右搅拌0.5小时,得到化合物1的格式试剂的2-甲基四氢呋喃溶液。
反应瓶中加入500ml2-甲基四氢呋喃,降温至-20℃,通入二氧化硫气体0.21mol,将上述新制备的格式试剂滴加到溶液中,滴加完成后慢慢升到室温搅拌3小时,通入氮气除去过量的二氧化硫气体,得到化合物1的亚磺酸氯化镁盐的溶液。
上述溶液降温到-5℃,依次加入化合物20.042mol、次氯酸钠水溶液(0.16mol,1.4mol/L)和冰醋酸0.08mol慢慢升到室温搅拌反应1小时。反应液减压浓缩除掉大部分2-甲基四氢呋喃,用二氯甲烷提取两次,合并有机相,依次用碳酸氢钠水溶液和饱和食盐水洗涤,分液干燥,减压浓缩,残留物用甲醇重结晶得到白色固体产品,收率78.9%。
实施例3
氮气保护下,化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基=1,2,3,4-四氢异喹啉0.1mol溶解到150ml四氢呋喃中,降温至-15℃,慢慢滴加异丙基氯化镁-氯化锂络合物的四氢呋喃溶液(0.1mol,1.1M in THF),滴加完成后继续在-5-0℃左右搅拌4小时,得到化合物1的格式试剂的四氢呋喃溶液。
反应瓶中加入500ml四氢呋喃,15℃通入二氧化硫气体0.25mol,将上述新制备的格式试剂滴加到溶液中,滴加完成后慢慢升到室温搅拌0.5小时,通入氮气除去过量的二氧化硫气体,得到化合物1的亚磺酸氯化镁盐的溶液。
上述溶液15℃依次加入化合物20.04mol、次氯酸钠水溶液(0.25mol,1.4mol/L)和冰醋酸0.12mol慢慢升到室温搅拌反应3小时。反应液减压浓缩除掉大部分四氢呋喃,用二氯甲烷提取两次,合并有机相,依次用碳酸氢钠水溶液和饱和食盐水洗涤,分液干燥,减压浓缩,残留物用甲醇重结晶得到白色固体产品,收率79.2%。
实施例4
氮气保护下,化合物1(S)-4-(3-溴苯基)-6,8-二氯-2-甲基=1,2,3,4-四氢异喹啉0.1mol溶解到150ml2-甲基四氢呋喃中,降温至0℃,慢慢滴加异丙基氯化镁-氯化锂络合物的四氢呋喃溶液(0.105mol,1.3M in THF),滴加完成后继续在-5-0℃左右搅拌2小时,得到化合物1的格式试剂的四氢呋喃与2-甲基四氢呋喃混合溶液。
反应瓶中加入500ml2-甲基四氢呋喃,35℃通入二氧化硫气体至反应瓶增重12.8g(0.2mol),将上述新制备的格式试剂滴加到溶液中,滴加完成后室温搅拌4小时,通入氮气除去过量的二氧化硫气体,得到化合物1的亚磺酸氯化镁盐的溶液。
上述溶液35℃依次加入化合物20.05mol、次氯酸钠水溶液(0.23mol,1.4mol/L)和冰醋酸0.11mol慢慢降到室温搅拌反应8小时。反应液减压浓缩除掉大部分有机溶剂,用二氯甲烷提取两次,合并有机相,依次用碳酸氢钠水溶液和饱和食盐水洗涤,分液干燥,减压浓缩,残留物用甲醇重结晶得到白色固体产品,收率80.7%。
Claims (5)
2.如权利要求1所述的坦帕诺的制备方法,其特征在于,所述(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉、异丙基氯化镁-氯化锂络合物、二氧化硫、化合物2、次氯酸钠和冰醋酸的摩尔比为:1.0 : 1.0-1.2 : 2.0-2.5 : 0.4-0.5 : 1.6-2.5 : 0.8-1.2。
3.如权利要求1所述的坦帕诺的制备方法,其特征在于,所述第一阶段反应制备(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉格氏试剂溶液的反应温度为-20-0℃,反应时间为0.5-4小时。
4.如权利要求1所述的坦帕诺的制备方法,其特征在于,所述第二阶段的反应制备(S)-4-(3-溴苯基)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉亚磺酸氯化镁盐溶液的反应温度为-20-35℃,反应时间为0.5-4小时。
5.如权利要求1所述的坦帕诺的制备方法,其特征在于,所述第三阶段反应温度为-5-35℃,反应时间为1-8小时。
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