CN102060769B - 一种托伐普坦的制备方法 - Google Patents
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- 229960001256 tolvaptan Drugs 0.000 title claims abstract description 20
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Abstract
本发明涉及一种精氨酸血管加压素V2受体拮抗剂托伐普坦的制备方法。此制备方法可以高纯度、高收率的得到托伐普坦及其中间体,可以作为工业化方法加以大规模的生产。同时,减少了废液排放,有利于劳动保护,降低了生产成本,提高了经济效益。
Description
技术领域
本发明属于化学制药技术领域,涉及用于治疗由充血性心力衰竭、肝硬化和抗利尿激素分泌不足综合征导致低钠血症的托伐普坦制备方法。
背景技术
托伐普坦(Tolvaptan商品名:Samsca),化学名为N-[4-[(7-氯-2,3,4,5-四氢-5-羟基-1H-1-苯并氮杂卓-1-基)羰基]-3-甲基苯基]-2-甲基苯甲酰胺,系日本大冢制药公司(Otsuka Pharm)研发的-种可口服的选择性非肽类新型V2受体拮抗剂。美国FDA于2009年5月批准其用于治疗由充血性心力衰竭(CHF)、肝硬化以及抗利尿激素分泌不足综合征所导致的高容性或等容性低钠血症。口服托伐普坦片能明显减轻患者体重和水肿,且不破坏血电解质平衡,并能有效升高CHF患者并发的低钠血症。临床研究表明,托伐普坦与其它抗心衰药物相比耐受性好,治疗中不必限制水的摄入,不良反应轻,应用前景广阔。
该产品的制备国内外已有文献报道,如文献Kondo K,Ogawa H,YamashitaH,et al.
7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine(OPC-41061):a potent,orally activenonpeptide arginine vasopressin V2 receptor antagonist[J].Bioorg MedChem,1999,7(8):1743-1754.中提供了以下合成方法:
流程1:将II和三乙胺溶于二氯甲烷中,缓慢滴入2-甲基-4-硝基苯甲酰氯,室温搅拌反应2小时,将反应液倒入水中,用二氯甲烷萃取。有机层用无水硫酸钠干燥,浓缩,残留物通过硅胶色谱柱分离,得中间体III。
流程2:将III加入到乙醇溶液中,加入浓盐酸,向混合液中逐滴加入氯化亚锡的乙醇溶液。室温搅拌过夜,然后将反应液倒入冰水,用氢氧化钠溶液将PH调至8-9,然后用二氯甲烷萃取。有机层用无水硫酸钠干燥,浓缩,残留物通过硅胶色谱柱分离,得中间体IV。
流程3:按照流程1操作,得到中间体V。
流程4:将中间体V加入甲醇中,室温下分批加入硼氢化钠,反应1小时,混合液浓缩,残留物用三氯甲烷提取,水洗,干燥,浓缩,用无水甲醇-无水乙醚重结晶,得到产品托伐普坦。
本制备方法的缺点有:
(1)各步反应流程均需经过柱色谱分离,产品收率低,操作繁琐,溶媒的回收处理困难,生产成本高,不适合工业大规模制备。
(2)流程2后处理时,将反应液直接倒入水中,用氢氧化钠溶液调pH至8-9,然后用二氯甲烷萃取,消耗大量碱液,产生大量废水,环境污染严重。
(3)流程2后处理时,后续处理用二氯甲烷萃取,乳化严重,萃取困难,制约产品收率。
(4)流程4用氯仿提取反应液,无水甲醇-无水乙醚重结晶。氯仿有长期肝毒性,工人劳动保护要求高。无水乙醚易燃易爆,不利于车间安全操作。
发明内容
本发明的目的在于,克服现有技术的缺点与不足,提供一种适合大规模生产托伐普坦的制备方法。它可以高收率、高纯度的得到托伐普坦及其中间体,可作为工业化方法加以大规模的生产。即对各步流程后处理采用重结晶的方法,减少或杜绝易燃易爆及有毒试剂,经工艺改进,减少废液排放,有利于劳动保护,降低了生产成本,提高了经济效益。
本发明提供的技术方案如下:
反应流程1:用N-甲基吗啉为缚酸剂,反应产品采用无水甲醇、无水乙醇、异丙醇重结晶。
反应流程2:反应完全后,减压回收溶剂,将反应液冷却,冷却温度为-25-5℃,析出中间体3的盐酸盐。过滤,将盐酸盐转移至水中,用碱性氢氧化钠溶液调PH至8-9,所用氢氧化钠的浓度为5-85%,充分搅拌,过滤即可得中间体IV。
反应流程3:反应完全后,残留物用醇类和有机烷基烃类混合溶剂重结晶,所用醇类优选无水甲醇、无水乙醇、异丙醇,所用有机烷基烃类优选石油醚、正己烷,醇类和烷基烃类的混合比例为(6-4)∶(4-6)。
反应流程4:残留物提取试剂优选二氯甲烷,重结晶溶剂优选醇类和有机烷基烃类混合溶剂,所用醇类优选无水甲醇、无水乙醇、异丙醇,所用有机烷基烃类优选石油醚、正己烷,醇类和烷基烃类的混合比例为(3-7)∶(7-3)。
本发明与现有技术相比,其显著特点是:
(1)各步反应均采用单一溶媒或混合溶媒重结晶,操作简单,产品收率高,重结晶母液可以反复利用,节约生产成本,适合工业大规模制备。
(2)流程2后处理时,减少碱液的消耗,避免产生大量工业废水,有利于环境保护。
(3)流程2后处理时,直接调盐酸盐,节约生产成本,操作简单。
(4)流程4避免使用氯仿、无水乙醚等有毒和易燃易爆试剂,降低了工人劳动保护要求,有利于车间安全生产。
(5)降低生产成本,经济效益显著。
具体实施方式
为了更充分的解释本发明的实施,提供托伐普坦的制备方法实施实例。这些实施例仅仅是解释、而不是限制本发明的范围。其中的化合物II是由上海诺特生物科技有限公司生产,纯度98.0%,所用试剂均有市售。
实施例1:中间体III的合成
2-甲基-4-硝基苯甲酸(购自天津阿法埃莎化学有限公司,纯度>99%,25g,0.14mol)加至250ml反应瓶中,与二氯亚砜回流条件下反应3h,减压蒸出二氯亚砜,得2-甲基-4-硝基苯甲酰氯(26.8g,淡黄色油状液体),不用纯化,直接用于下步反应。
中间体II(20g,0.1mol)和2-甲基-4-硝基苯甲酰氯(22.4g,0.11mol)加至250ml反应瓶中。加入二氯甲烷(50ml),冰浴冷却至0~5℃搅拌至溶,缓慢滴加N-甲基吗啉(11.2g,0.11mol),滴毕搅拌片刻,室温反应4h。TLC[展开剂:乙酸乙酯-石油醚(1∶1),下同]显示反应完全后,加入饱和碳酸氢钠水溶液(20ml),搅拌10min,过滤,滤饼用二氯甲烷(15ml×2)洗涤。合并滤液和洗液,用饱和氯化钠溶液(30ml×3)洗涤,无水硫酸钠干燥后过滤。滤液减压回收溶剂,剩余物用无水甲醇重结晶,得白色粉末状固体III(27.5g,75.2%),mp 154.8~155.6℃。纯度97.9%(HPLC归一化法)。
实施例2:中间体IV的合成
中间体III(10g,28mmol)加至250ml反应瓶中,加入浓盐酸(40ml)和乙醇(50ml),搅拌,缓慢滴加氯化亚锡(20g,88mmol)的乙醇溶液(40ml)。滴毕室温反应5h。TLC显示反应完全后,减压蒸出乙醇约70ml,剩余物-10℃-0℃冷却静置过夜。过滤,滤饼用水洗涤后倒入水(40ml)中。加20%氢氧化钠水溶液(约60ml)调至pH 9。过滤,用无水乙醇重结晶,得淡黄色粉末状固体IV(6.3g,68.7%),mp 190.4~191.1℃。纯度97.2%(HPLC归一化法)。
实施例3:中间体V的合成
中间体IV(5g,15mmol)和三乙胺(2.3g,23mmol)依次加到100ml反应瓶中,加入二氯甲烷(30ml),搅拌至全部溶解。滴加邻甲基苯甲酰氯(2.8g,18mmol),滴毕室温反应1h。TLC显示反应完全后倒入冰水(约40ml)中,用二氯甲烷(20ml×3)萃取,合并有机相,依次用5%盐酸(25ml×3)和饱和氯化钠溶液(25ml×3)洗涤,无水硫酸钠干燥后过滤。滤液减压回收溶剂(约50ml),剩余物用无水甲醇-石油醚(2∶1)重结晶,得白色晶体中间体V(6.2g,90.9%),mp 121.1~123.6℃。纯度98.6%(HPLC归一化法)。
实施例4:托伐普坦的合成
中间体V(5g,11mmol)加至100ml反应瓶中,加入无水甲醇(25ml),搅拌,然后向反应液中分批加入硼氢化钠(0.65g,17mmol),加毕室温反应1h。TLC显示反应完全后,减压回收甲醇(约20ml),剩余物中加入二氯甲烷(25ml),用饱和氯化钠溶液(25ml×3)洗涤。无水硫酸钠干燥后过滤,滤液减压回收溶剂,剩余物用无水甲醇-石油醚(2∶1)重结晶,得白色晶体托伐普坦(4.85g,96.6%),mp 220.1~221.5℃。纯度99.2%(HPLC归一化法)。ESI-HRMS(C26H25ClN2O3,m/z)实测值(计算值):447.1476(447.1481)[M-H]-。
Claims (4)
1.一种托伐普坦的制备方法,其特征在于:
(1)在N-甲基吗啉存在下,中间体Ⅱ与2-甲基-4-硝基苯甲酰氯在二氯甲烷中发生酰化反应,得到中间体Ⅲ,并用醇类溶媒重结晶;
(2)中间体Ⅲ与氯化亚锡完全反应后的处理方法,先蒸出反应溶剂,然后冷却,析出固体产物,溶于水中,用碱性水溶液调节pH8-9,得到中间体Ⅳ;
(3)中间体Ⅳ在二氯甲烷中,与邻甲基苯甲酰氯反应,得到的中间体Ⅴ用单一或混合的醇类和有机烷基烃类溶媒重结晶,所述重结晶溶媒中,醇类溶媒为无水甲醇、无水乙醇、异丙醇,有机烷基烃类溶媒为石油醚、正己烷,两者比例为(6-4):(4-6);
(4)中间体Ⅴ与硼氢化钠反应完全后的后处理方法,用二氯甲烷提取,再用单一或混合的醇类和有机烷基烃类溶媒重结晶,所述重结晶溶媒中,醇类溶媒为无水甲醇、无水乙醇、异丙醇,有机烷基烃类溶媒为石油醚、正己烷,两者比例为(3-7):(7-3)。
2.权利要求1所述的托伐普坦的制备方法,其特征在于所述流程(1)的醇类溶媒为无水甲醇、无水乙醇或异丙醇。
3.权利要求1所述的托伐普坦的制备方法,其特征在于所述流程(2)的后处理过程中冷却温度为-25-5℃。
4.权利要求1所述的托伐普坦的制备方法,其特征在于所述流程(2)的后处理过程中所用碱性水溶液为氢氧化钠或氢氧化钾的水溶液,浓度为5-85%。
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