CN116836093A - 一种4-氨基-5-烷基亚磺酰基-2-甲氧基苯甲酸化合物及其制备方法和用途 - Google Patents
一种4-氨基-5-烷基亚磺酰基-2-甲氧基苯甲酸化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明报道了一种4‑氨基‑N‑[(1‑乙基‑2‑吡咯烷基)甲基]‑5‑(乙基磺酰基)‑2‑甲氧基苯甲酰胺中杂质的制备方法和用途,该方法操作简单易行、条件温和、收率高、能耗及污染少,适合实验室级别的标准品制备。
Description
技术领域
本发明属于医药技术领域,涉及一种4-氨基-5-烷基亚磺酰基-2-甲氧基苯甲酸化合物及其制备方法和用途。
背景技术
4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺,其是由法国赛诺菲一圣德拉堡公司开发的一种新型广谱非典型抗精神病药,1997年1月由美国食品药品管理局批准在美国上市。4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺于2011年在国内上市并应用于临床。该药作用机制独特,能选择性与突触前及突触后多巴胺2(dopamine-2,D2)受体、多巴胺3(dopamine-2,D3)受体结合,发挥双重多巴胺受体拮抗作用,临床上主要用于治疗急性进展性或慢性精神分裂症。同时该药还具有较好的抗抑郁效果,且较少引起锥体外系不良反应(extra-pyramidal symptoms,EPS),对体质量、血糖及血脂几乎无影响,是一种安全、有效的新型广谱非典型抗精神病药物。
在新药研究和开发过程中,药物质量是衡量药物品质的重要标准。药物的有关物质(或杂质含量)直接影响到药物的疗效并可能导致毒副作用。为了安全有效的用药,需要严格控制药物有效成分的纯度、杂质的限度,提供高质量标准的药物。因此,在药物的生产、储存以及运输过程中必须严格可控制药物杂质的产生。
经过检索,专利CN113024433A提供了一种4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺亚砜杂质的制备方法:
该合成路线使用了毒性大,环境不友好的双氧水试剂,双氧水适用于医用伤口消毒、环境消毒和食品消毒,但过氧化氢也是世界卫生组织公布的致癌物。
发明人在4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺原料药的研究过程中,意外发现4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺原料药中还存在影响药物使用、存储、运输的其它杂质化合物,并确定了其合成工艺、检测方法,通过将其控制在合理范围内,从而提高了4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺原料药在使用、存储、运输过程中的稳定性。
本发明合成工艺中所使用的间氯过氧苯甲酸稳定性要比双氧水好,双氧水浓度越高,稳定性越差,并且受酸碱性的影响较大,间氯过氧苯甲酸容易形成均相体系,使反应更加平稳的进行,双氧水属于非均相体系,且稳定性不好,
容易失控,反应控制比较难。
发明内容
本发明公开了一种4-氨基-5-烷基亚磺酰基-2-甲氧基苯甲酸化合物及制备方法和用途。
其中R1为C1-6烷基;
步骤一:将化合物1用溶剂溶解,然后加入M-CPBA,搅拌,反应完毕后,分液,萃取,干燥,旋干得化合物2;
步骤二:将化合物2溶于溶剂中,加入NaOH,升温搅拌,反应完毕后,降温调节pH,萃取,分离,干燥,旋干得化合物3。
进一步的,所述步骤1使用的溶剂为二氯甲烷,三氯甲烷,乙酸乙酯,1,2-二氯乙烷,苯、乙醚中的一种或几种,优选二氯甲烷。
进一步的,所述步骤1中化合物1与M-CPBA的摩尔比为1:1~1.5,优选1:1.4。
进一步的,所述步骤1中反应温度为0~15℃,优选0~10℃。
进一步的,所述步骤2使用的溶剂为水溶液,化合物2与氢氧化钠的摩尔比为1:1.5~3,优选1:2。
进一步的,所述步骤2中反应温度为50-70℃,优选60℃,反应液pH调节至3.5~4.5,优选pH为4。
另一方面,本发明涉及一种化合物,其结构如下所示:
另一方面,本发明涉及所述化合物用作标准品或对照品的应用。
另一方面,本发明涉及一种药物组合物,所述药物组合物含有4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺或其药学上可接受的盐和含量不高于0.2%,更优选不高于0.1%,进一步优选不高于500ppm,更进一步优选不高于150ppm,再进一步优选不高于100ppm的式A、式B和/或式C所示化合物。
另一方面,本发明涉及一种检测方法,以辛烷基硅烷基键合硅胶为填充剂(Agilent ZORBAX RX C8,4.6×250mm,5μm或效能相当色谱柱),量取45ml质量浓度5%的稀硫酸溶液,用超纯水定容至1000ml,称量0.7g辛烷磺酸钠,上述溶液溶解后,用稀硫酸调节pH至2.3,作为盐溶液,分别配制流动相A(辛烷磺酸钠缓冲盐(0.7g/1000ml)pH值2.3:甲醇:乙腈体积比为72:16:12),流动相B(辛烷磺酸钠缓冲盐(0.7g/1000ml)pH值2.3:甲醇:乙腈体积比为50:38:12),流速为每分钟1.5ml,检测波长为225nm,柱温40摄氏度,进样体积为10μl,按下表的运行梯度进行洗脱,分别精密称取式A、式B、式C所示化合物,用流动相A溶解并稀释制成每1ml含本品1mg的溶液,作为供试品溶液,精密量取供试品溶液按下表格中的色谱条件注入液相色谱仪,记录色谱图,
时间(分钟) | 流动相A(%体积) | 流动相B(%体积) |
0 | 100 | 0 |
18 | 100 | 0 |
35 | 0 | 100 |
36 | 100 | 0 |
45 | 100 | 0 |
本发明利用式A、式B和/或式C所示化合物作为对照品,还提供了一种用于对4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺成品进行质量控制的方法:利用式A、式B和/或式C化合物作为对照品。优选的质量控制方法,包括以下步骤:称取适量的式A,式B和/或式C化合物,溶于稀释液制备成合适浓度的杂质对照品溶液;接着用LC对4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺成品样品中所含的杂质式A,式B和/或式C化合物作为杂质进行定性或定量研究,在制备过程中对这些杂质化合物进行控制,最终在4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺成品中,未检测到式A、式B或式C所示化合物。
具体实施方式
下面结合实施例对本发明做进一步阐述,但不是对本发明的限定。
实施例1:
控温7℃,将间氯过氧苯甲酸(15.14g,87.74mmol)缓慢分批加入至4-氨基-5-乙硫基-2-甲氧基苯甲酸甲酯(15.00g,62.16mmol)和二氯甲烷(150ml)的混合溶液,加毕后常温下搅拌10分钟,待TLC监测反应完毕后,向反应液缓慢滴加10%质量浓度的亚硫酸钠水溶液至淀粉碘化钾试纸不变蓝,分液,水相用二氯甲烷萃取一次,分离有机层后合并,有机层经干燥后旋干,经柱层析分离后得4-氨基-2-甲氧基-5-乙基亚磺酰基苯甲酸甲酯固体13.10g,产率81.98%。
氢谱归属如下:
1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),6.21(s,1H),5.80(s,2H),3.89(s,3H),3.85(s,3H),3.31–3.06(m,2H),1.24(t,J=7.5Hz,3H)。
实施例2:
将氢氧化钠(1.00g,25.00mmol)加入至4-氨基-2-甲氧基-5-乙基亚磺酰基苯甲酸甲酯(3.21g,12.5mmol)和水(15mL)的混合溶液,升温至60℃搅拌1小时,待TLC监测反应完毕后,移至冰水浴,向反应液中滴加稀盐酸调节pH至4,用二氯甲烷(30mL)萃取5次,分离有机层后合并,有机层经干燥后旋干,用乙酸乙酯(50ml)重结晶得4-氨基-5-乙基亚磺酰基-2-甲氧基苯甲酸2.78g,产率91.50%。
实施例3:
控温7℃,将间氯过氧苯甲酸(15.94g,92.40mmol)缓慢分批加入至4-氨基-2-甲氧基-5-甲硫基苯甲酸甲酯(15.00g,66.00mmol)和二氯甲烷(150ml)的混合溶液,加毕后常温下搅拌10分钟,待TLC监测反应完毕后,向反应液缓慢滴加10%质量浓度的亚硫酸钠水溶液至淀粉碘化钾试纸不变蓝,分液,水相用二氯甲烷萃取一次,分离有机层后合并,有机层经干燥后旋干,经柱层析分离后得4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸甲酯13.22g,产率82.41%。
氢谱归属如下:
1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),6.23(s,1H),5.77(s,2H),3.93–3.85(m,6H),2.96(s,3H)。
实施例4:
将氢氧化钠(1.00g,25.00mmol)加入至4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸甲酯(3.04g,12.5mmol)和水(15mL)的混合溶液,升温至60℃搅拌1小时,待TLC监测反应完毕后,移至冰水浴,向反应液中滴加稀盐酸调节pH至4,用二氯甲烷(30mL)萃取5次,分离有机层后合并,有机层经干燥后旋干,用乙酸乙酯(50ml)重结晶得4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸2.60g,产率为90.81%。
氢谱归属如下:
1H NMR(400MHz,Chloroform-d)δ10.31(s,1H),8.05(s,1H),6.28(s,1H),6.01(s,2H),4.09(s,3H),2.98(s,3H)。
实施例5:
控温20℃,将间氯过氧苯甲酸(15.14g,87.74mmol)缓慢分批加入至4-氨基-5-乙硫基-2-甲氧基苯甲酸甲酯(10.59g,43.89mmol)和二氯甲烷(150ml)的混合溶液,加毕后常温下搅拌10分钟,待TLC监测反应完毕后,向反应液缓慢滴加10%质量浓度的亚硫酸钠水溶液至淀粉碘化钾试纸不变蓝,分液,水相用二氯甲烷萃取一次,分离有机层后合并,有机层经干燥后旋干,经柱层析分离后得4-氨基-2-甲氧基-5-乙基亚磺酰基苯甲酸甲酯固体8.47g,产率75.07%。
实施例6:
将氢氧化钠(1.00g,25.00mmol)加入至4-氨基-2-甲氧基-5-乙基亚磺酰基苯甲酸甲酯(1.61g,6.25mmol)和水(15mL)的混合溶液,升温至40℃搅拌1小时,待TLC监测反应完毕后,移至冰水浴,向反应液中滴加稀盐酸调节pH至3,用二氯甲烷(30mL)萃取5次,分离有机层后合并,有机层经干燥后旋干,用乙酸乙酯(50ml)重结晶得4-氨基-5-乙基亚磺酰基-2-甲氧基苯甲酸1.14g,产率75.04%。
实施例7:
控温25℃,将间氯过氧苯甲酸(15.94g,92.40mmol)缓慢分批加入至4-氨基-5-甲硫基-2-甲氧基苯甲酸甲酯(8.39g,36.96mmol)和二氯甲烷(150ml)的混合溶液,加毕后常温下搅拌10分钟,待TLC监测反应完毕后,向反应液缓慢滴加10%质量浓度的亚硫酸钠水溶液至淀粉碘化钾试纸不变蓝,分液,水相用二氯甲烷萃取一次,分离有机层后合并,有机层经干燥后旋干,经柱层析分离后得4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸甲酯6.81g,产率75.80%。
实施例8:
将氢氧化钠(1.00g,25.00mmol)加入至4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸甲酯(6.08g,25.00mmol)和水(30mL)的混合溶液,升温至80℃搅拌1小时,待TLC监测反应完毕后,移至冰水浴,向反应液中滴加稀盐酸调节pH至5,用二氯甲烷(30mL)萃取5次,分离有机层后合并,有机层经干燥后旋干,用乙酸乙酯(50ml)重结晶得4-氨基-5-甲基亚磺酰基-2-甲氧基苯甲酸4.41g,产率为77.02%。
实施例9:
化合物A、B、C的LC检测方法:
结果:在制备4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺的过程中,分别精密称取各化合物,用流动相A溶解并稀释制成每1ml含本品1mg的溶液,作为供试品溶液,精密量取供试品溶液按上述表格中的色谱条件注入液相色谱仪,记录色谱图,出峰时间分别为约:5.187min、7.867min、2.770min。
尽管以上已经对本发明作了详细描述,但是本领域技术人员理解,在不偏离本发明的精神和范围的前提下,可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作出的详细描述,而应当属于权利要求书。
Claims (10)
1.一种4-氨基-5-烷基亚磺酰基-2-甲氧基苯甲酸化合物的制备方法:
其中R1为C1-6烷基;
步骤一:将化合物1用溶剂溶解,然后加入M-CPBA,搅拌,反应完毕后,分液,萃取,干燥,旋干得化合物2;
步骤二:将化合物2溶于溶剂中,加入NaOH,升温搅拌,反应完毕后,降温调节pH,萃取,分离,干燥,旋干得化合物3。
2.一种如权利要求1所述的制备方法,所述步骤1使用的溶剂为二氯甲烷,三氯甲烷,乙酸乙酯,1,2-二氯乙烷,苯、乙醚中的一种或几种,优选二氯甲烷。
3.一种如权利要求1或2所述的制备方法,所述步骤1中化合物1与M-CPBA的摩尔比为1:1~1.5,优选1:1.4。
4.一种如权利要求1或2所述的制备方法,所述步骤1中反应温度为0~15℃,优选0~10℃。
5.一种如权利要求1所述的制备方法,所述步骤2使用的溶剂为水溶液,化合物2与氢氧化钠的摩尔比为1:1.5~3,优选1:2。
6.一种如权利要求1或5所述的制备方法,所述步骤2中反应温度为50-70℃,优选60℃,反应液pH调节至3.5~4.5,优选pH为4。
7.一种化合物或其可药用盐,其化合物结构如下所示:
8.一种如权利要求7所述化合物用作标准品或对照品的应用。
9.一种药物组合物,所述药物组合物含有4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺或其药学上可接受的盐和含量不高于0.2%,优选不高于0.1%,更优选不高于500ppm,进一步优选不高于150ppm,更进一步优选不高于100ppm的如权利要求7所述的式A、式B和/或式C所示化合物。
10.一种如权利要求7所述化合物的检测方法,以辛烷基硅烷基键合硅胶为填充剂(Agilent ZORBAX RX C8,4.6×250mm,5μm或效能相当色谱柱),量取45ml质量浓度5%的稀硫酸溶液,用超纯水定容至1000ml,称量0.7g辛烷磺酸钠,上述溶液溶解后,用稀硫酸调节pH至2.3,作为辛烷磺酸钠缓冲盐溶液,分别配制流动相A(辛烷磺酸钠缓冲盐(0.7g/1000ml)pH值2.3:甲醇:乙腈体积比为72:16:12),流动相B(辛烷磺酸钠缓冲盐(0.7g/1000ml)pH值2.3:甲醇:乙腈体积比为50:38:12),流速为每分钟1.5ml,检测波长为225nm,柱温40摄氏度,进样体积为10μl,按下表的运行梯度进行洗脱,分别精密称取式A、式B、式C所示化合物,用流动相A溶解并稀释制成每1ml含本品1mg的溶液,作为供试品溶液,精密量取供试品溶液按下表格中的色谱条件注入液相色谱仪,记录色谱图,
。
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