CN113024407A - 一种沙芬酰胺亚硝杂质化合物及其制备方法 - Google Patents
一种沙芬酰胺亚硝杂质化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种式I化合物,同时公开了式I化合物制备方法及其在沙酚酰胺成品质量检查时作为基因毒性杂质对照品的用途,本发明的实施有效的控制了沙酚酰胺或甲磺酸沙芬酰胺的质量,从而保证甲磺酸沙芬酰胺临床使用的安全性和有效性。
Description
技术领域
本发明属于药物化学技术领域,具体涉及沙芬酰胺亚硝杂质化合物以及其制备方法。
背景技术
甲磺酸沙芬酰胺(Safinamide methanesulfonate),化学结构式2所示,化学名称为(S)-2-[4-(3-氟苄氧基)苄氨基]丙酰胺甲磺酸盐
沙芬酰胺(safinamide)是一种电压敏感的钠通道和钙通道阻断剂、谷氨酸释放的抑制剂、选择性MAO-BI以及多巴胺和去甲肾上腺素的摄取抑制剂。它能选择性影响放电不正常的神经元而不改变正常神经元的活动。II期临床研究表明,它与多巴胺受体激动剂联用可明显减轻PD的运动症状,如震颤、运动困难等。
沙芬酰胺在2015年2月24在欧洲被批准上市。美国也已递交NDA,处于预注册阶段。作为一个“me-too”的药物,它和Teva公司的Azilect(雷沙吉兰)和司来吉兰(selegiline)一样是单胺氧化酶B(MAO-B)抑制剂。MAO-B抑制剂通常作为单药治疗早期PD患者,或者被添加到晚期PD患者的治疗方案中以能更好地控制症状并减少所需的其他帕金森病药物的剂量。2012年5月完成了针对早期和晚期病人的四个关键性III期临床试验,从超过2000位PD患者中得到长期和短期数据,证明沙芬酰胺具有很好的安全谱以及类似于同类其他药物的疗效。
杂质研究是药物研发过程中的一项重要内容,直接关系到药物的质量控制以及用药安全性,通过控制药物产品中的杂质可以保证产品的质量以及安全性。药物的杂质主要源于合成过程中副产物以及药物的降解。目前很少有报道其亚硝类基因毒性杂质,而本发明是针对沙芬酰胺在合成工艺、存储和使用过程中产生的,而且会对产品质量产生影响的杂质,对控制产品质量有着重要的意义。
发明内容
本发明提供沙芬酰胺亚硝杂质化合物以及其制备方法,所述杂质化合物为式I化合物,化学名为(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,其中式I化合物中为顺式结构(syn),反式结构(anti)中的一种或混合物。
本发明提供以下技术方案用于该杂质化合物的制备,该方法包括将沙芬酰胺或甲磺酸沙芬酰胺与亚硝酸钠在溶剂中,在酸性条件下反应得到沙芬酰胺亚硝杂质式I化合物。
其中式I结构为沙芬酰胺或甲磺酸沙芬酰胺。所用的反应溶剂优选自水,乙腈、四氢呋喃,甲醇,乙醇,N,N-二甲基亚酰胺,二甲亚砜、N-甲基吡咯烷酮、或1,4-二氧六环,或上述溶剂和水的混合溶剂。酸优选为:盐酸,硫酸,乙酸,对甲苯磺酸,一水对甲苯磺酸,苯磺酸。
本发明还提供一种用于对沙芬酰胺成品的质量进行控制的方法,其特征在于:利用式I化合物作为基因毒性杂质对照品。优选的质量控制方法,包括以下步骤:称取适量的式I化合物,溶于稀释液制备成合适浓度的杂质对照品溶液;接着用反相液质联用(LC-MS)色谱方法对沙芬酰胺中间体和成品样品中所含的式I化合物进行定性或定量基因毒性杂质研究。另外,根据本发明的杂质I化合物的制备方法工艺成本低,容易控制,原料易得;且所得到的产品质量稳定,收率高。
本发明的有益效果在于:本发明发现了新的杂质化合物I,并提供了该杂质化合物的制备方法和作为检测沙芬酰胺成品质量时作为对照品的用途,可有效的控制了沙芬酰胺的质量,从而保证沙芬酰胺临床使用的安全性和有效性。
附图说明
图1为式I化合物的1H-NMR谱图。
图2为式I化合物的ESI-MS谱图。
式I所示化合物通过核磁共振(1H NMR)、质谱(ESI-MS)进行结构表征,检测结果分别如图1和图2所示。对核磁共振氢谱进行解析,归属如下:
1H NMR(400MHz,CDCl3))显示:δ1.28(d,J=3.2Hz,3H,CH3),1.67(d,J=3.2Hz,3H,CH3),式I化合物手性碳相连的甲基氢,顺式结构(syn)和反式结构(anti)均有存在,所以在高场显示有两组氢。δ4.50-6.00间峰归属苄基位的四个氢,手性碳相连的亚甲基氢。δ6.50-7.50间峰归属于芳香环氢和酰胺氢。
质谱(ESI-MS)显示:[M+Na]+=354.10,[M+Na]+=370.10的偶合峰,[M-NO]+=301.15,[M-N(NO)CH(CH3)CONH2]+=215.1碎片峰,式I化合物的理论分子量为331.13。
具体实施方式
以下实施例用于说明本发明,应注意,以下描述只是为进一步说明本发明的特征和优点而列举,并不对本发明的权利要求范围进行限制。
实施例1:控制温度为15~30℃,将20.0g的甲磺酸沙芬酰胺加入200mL乙腈和400mL水中,未溶解,滴加24.8g浓盐酸至反应中,固体全部溶解,加入12.0g亚硝酸钠,搅拌10-15分钟,有白色固体析出,控制温度为15~30℃,搅拌12-16小时。加入乙酸乙酯萃取两次,每次用量为400mL,分液,收集乙酸乙酯有机相,减压浓缩乙酸乙酯有机相至无液体流出,然后再加入400mL乙酸乙酯和200mL水洗涤,分液,减压浓缩乙酸乙酯有机相至无液体流出,加入400mL异丙醇,加热至77-82℃,搅拌溶解,降温至室温15~30℃,搅拌1-2小时,过滤得到湿品于60℃真空烘干后得到白色固体,14.0g(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,收率83%。
实施例2:控制温度为15~30℃,将15.0g的沙芬酰胺加入150mL四氢呋喃中,滴加24.5g浓盐酸至反应中,固体全部溶解,加入12.0g亚硝酸钠,搅拌10-15分钟,有白色固体析出,控制温度为15~30℃,搅拌12-16小时。加入乙酸乙酯萃取两次,每次用量为300mL,分液,收集乙酸乙酯有机相,减压浓缩乙酸乙酯有机相至无液体流出,然后再加入300mL乙酸乙酯和150mL水洗涤,分液,减压浓缩乙酸乙酯有机相至无液体流出,加入300mL异丙醇,加热至77-82℃,搅拌溶解,降温至室温15~30℃,搅拌1-2小时,过滤得到湿品于60℃真空烘干后得到白色固体,13.5g(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,收率80%。
实施例3:控制温度为15~30℃,将5.0g的沙芬酰胺加入50mL甲醇中,加入3.5g对甲苯磺酸一水物至反应中,固体全部溶解,加入3.0g亚硝酸钠,搅拌10-15分钟,有白色固体析出,控制温度为15~30℃,搅拌12-16小时。加入乙酸乙酯萃取两次,每次用量为100mL,分液,收集乙酸乙酯有机相,减压浓缩乙酸乙酯有机相至无液体流出,然后再加入100mL乙酸乙酯和50mL水洗涤,分液,减压浓缩乙酸乙酯有机相至无液体流出,加入100mL异丙醇,加热至77-82℃,搅拌溶解,降温至室温15~30℃,搅拌1-2小时,过滤得到湿品于60℃真空烘干后得到白色固体,12.7g(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,收率75%。
实施例4:控制温度为15~30℃,将5.0g的沙芬酰胺加入50mL异丙醇中,加入1.0g硫酸至反应中,固体全部溶解,加入3.0g亚硝酸钠,搅拌10-15分钟,有白色固体析出,控制温度为15~30℃,搅拌12-16小时。加入乙酸乙酯萃取两次,每次用量为100mL,分液,收集乙酸乙酯有机相,减压浓缩乙酸乙酯有机相至无液体流出,然后再加入100mL乙酸乙酯和50mL水洗涤,分液,减压浓缩乙酸乙酯有机相至无液体流出,加入100mL异丙醇,加热至77-82℃,搅拌溶解,降温至室温15~30℃,搅拌1-2小时,过滤得到湿品于60℃真空烘干后得到白色固体,12.7g(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,收率75%。
实施例5:控制温度为15~30℃,将5.0g的沙芬酰胺加入50mLN,N-二甲基甲酰胺中,溶解,滴加1.8g甲磺酸至反应中,加入3.0g亚硝酸钠,搅拌10-15分钟,控制温度为15~30℃,搅拌12-24小时。加入乙酸乙酯萃取两次,每次用量为100mL,分液,收集乙酸乙酯有机相,减压浓缩乙酸乙酯有机相至无液体流出,然后再加入100mL乙酸乙酯和50mL水洗涤,分液,减压浓缩乙酸乙酯有机相至无液体流出,加入100mL异丙醇,加热至77-82℃,搅拌溶解,降温至室温15~30℃,搅拌1-2小时,过滤得到湿品于60℃真空烘干后得到白色固体,12.7g(S)-2-[4-(3-氟苄氧基)苄亚硝氨基]丙酰胺,收率75%。
实施例6:本实施例举例说明对式I化合物在沙芬酰胺成品质量检测时作为基因毒性杂质对照品的用途。沙芬酰胺成品为仲胺,产生亚硝类杂质的风险较高,需要进行控制沙芬酰胺成品中基因毒性亚硝类杂质,提高沙芬酰胺成品安全性。
色谱条件:
仪器:高效液相质谱色谱仪,配备紫外检测器,ESI/MS检测器
色谱柱:Agilent Poroshell 120EC-C18 2.7um,50*3.0mm
流动相A:1mL的三氟乙酸和5mmol的醋酸钾溶于1000mL水中
流动相B:乙腈
稀释液:乙睛:纯化水=1:1(V/V)
HPLC/MS条件
式I化合物对照品储备溶液的配制:准确称式I化合物标准品45mg,加入100ml容量瓶中,先用纯乙睛溶解、超声,后用稀释液溶解稀释至刻度,混匀后再移取1.0mL到100mL容量瓶中,用稀释液稀释到刻度,混匀。(4.5μg/mL)
式I化合物对照品溶液的配制:准确移取式I化合物杂质对照品储备溶液1.0mL到100mL容量瓶中用稀释液稀释到刻度,混匀。(45ng/mL)
沙芬酰胺供试品溶液的配制:准确称取沙芬酰胺样品30mg到10mL容量瓶中,用稀释液稀释到刻度,混匀。(3mg/mL)
式I化合物作为基因毒性杂质对照品测定沙芬酰胺成品的质量检查结果如下:
Claims (6)
2.根据权利要求1所述的式I化合物在沙芬酰胺成品质量检测时作为基因毒性杂质对照品的用途。
3.一种式I所示化合物的制备方法,包括以下步骤:
根据权利要求2所述的一种沙芬酰胺杂质化合物的制备方法,该方法包括将沙芬酰胺或甲磺酸沙芬酰胺与亚硝酸钠置于溶剂中,在酸性条件下反应得到沙芬酰胺亚硝杂质式I化合物。
4.根据权利要求3的方法所述,其特征在于反应溶剂优选自水,乙腈、四氢呋喃,甲醇,乙醇,N,N-二甲基亚酰胺,二甲亚砜、N-甲基吡咯烷酮或1,4-二氧六环,或上述溶剂和水的混合溶剂。
5.根据权利要求3任一项所述的方法所述,其特征在于酸优选为:盐酸,硫酸,对甲苯磺酸,甲磺酸。
6.根据权利要求3所述的方法,包括以下步骤:称取适量的式I的所示化合物,溶于稀释液制备成合适浓度的杂质对照品溶液;接着用反相液质联用(LC-MS)色谱方法对沙芬酰胺中间体和成品样品中所含的式I化合物进行亚硝类基因毒性杂质的定性或定量研究。
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