CN116262713A - 一种二甲磺酸赖右苯丙胺的杂质及其制备方法和用途 - Google Patents
一种二甲磺酸赖右苯丙胺的杂质及其制备方法和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于有机合成领域,具体涉及一种二甲磺酸赖右苯丙胺的杂质及其制备方法和用途。
背景技术
二甲磺酸赖右苯丙胺,化学名(2S)-2,6-氨基-N-[(1S)-1-甲基-2-苯乙基]己酸胺二甲磺酸盐,分子式C17H33N3O7S2,分子量455.58982,CAS登记号608137-33-3,是由英国希雷(Shire)生物制药公司与New River Pharma公司合作开发的苯丙胺衍生物。该药于2007年2月首次在美国上市,用于治疗儿童注意力缺陷和多动障碍(attention-deficit/hyperactivity disorder ADHD),目前二甲磺酸赖右苯丙胺是唯一一种被批准用于所有年龄大于6岁的ADHD患者维持治疗的兴奋药。而在2015年1月FDA又批准该药作为首例和唯一一例成人中度至重度暴食症治疗药物,其应用前景广泛,所述二甲磺酸赖右苯丙胺的结构如下所示:
药品杂质含量是衡量药品质量的重要指标,杂质的含量影响了用药的安全性,成品药中杂质越多,可能出现的用药风险越大。因此,对二甲磺酸赖右苯丙胺中的杂质进行分析研究,进一步研究合成杂质化合物的对照品,将对二甲磺酸赖右苯丙胺的生产、质量控制有重要意义。
发明内容
本发明的目的在于提供一种新的二甲磺酸赖右苯丙胺的杂质及其制备方法,以及其作为二甲磺酸赖右苯丙胺原料药质量控制或研究过程中的标准品或对照品的用途。
本发明提供了式I所示化合物或其盐;
进一步地,上述式I所示化合物的盐是式I所示化合物与酸形成的盐,所述酸为有机酸或无机酸,优选的,所述有机酸为甲酸、乙酸、枸橼酸、富马酸、马来酸、琥珀酸、甲磺酸中的任一种或其组合;所述无机酸为盐酸、硫酸、硝酸、氢溴酸中的任一种或其组合;
更优选地,所述式I所示化合物的盐为式I所示化合物的二甲磺酸盐。
本发明还提供了上述化合物或其盐的制备方法,包括如下步骤:
(1)右旋苯丙胺硫酸盐和BOC-D-LYS(BOC)-OH(中文名为(R)-2,6-二叔丁氧羰基氨基己酸)在溶剂a中,羧基活化剂和有机碱的作用下发生缩合反应,得反应液;
(2)将步骤(1)的反应液加入溶剂b中与酸反应脱除保护基,得式I所示化合物的盐;
或,(3)将步骤(2)得到的盐溶于水中,用有机溶剂洗涤,加碱调节pH至8~14后,再加有机溶剂萃取,萃取液干燥,析晶所得的晶体即为式I所示化合物;
反应式如下:
其中,X为0~2的整数。
进一步地,步骤(1)所述溶剂a为二氯甲烷、三氯甲烷、乙酸乙酯、甲苯中的一种或多种,优选为二氯甲烷和DMF中的至少一种,更优选为二氯甲烷和DMF的混合物,所述二氯甲烷和DMF的混合物中二氯甲烷和DMF的体积比为(1~3):1;
所述羧基活化剂为EDCI、HOBT、DCC中的一种或多种,优选为EDCI和HOBT的混合物,所述EDCI和HOBT的混合物中,EDCI和HOBT的摩尔比为(1~3):1;
所述有机碱为N-甲基吗啉、三乙胺、吡啶中的一种或多种,优选为N-甲基吗啉;
和/或,步骤(2)所述溶剂b为异丙醇、四氢呋喃、二氯甲烷、乙腈中的一种或多种,优选为四氢呋喃;
所述酸为甲酸、乙酸、枸橼酸、富马酸、马来酸、琥珀酸、甲磺酸、盐酸、硫酸、硝酸、氢溴酸中的至少一种,X为1~2;优选为甲磺酸,X为2;
和/或,步骤(3)所述有机溶剂是二氯甲烷、二氯乙烷、三氯甲烷、甲苯、二甲苯、庚烷、辛烷和磺化煤油中的一种或多种,优选为二氯甲烷;
所述碱是氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙的一种或多种,优选为氢氧化钠、氢氧化钾中的一种或多种。
进一步地,上述右旋苯丙胺硫酸盐、R-2,6-二叔丁氧羰基氨基己酸、羧基活化剂、有机碱和酸的摩尔比为1:(1-3):(1~4):(4~10):(4~10),优选为1:(1~2):(2~3):(4~8):(4~8),更优选为1:(1.2~1.3):(1.5~2):(4~6):(4~6)。
进一步地,步骤(1)所述缩合反应的条件为:0~40℃反应2~6h,优选为25~35℃反应4h;
步骤(2)所述反应的条件为:40~70℃反应4~8h;优选为50~65℃反应6h;
步骤(3)所述析晶为25~35℃自然静置析晶;所述萃取液的干燥方式为加入无水硫酸钠或无水硫酸镁的一种或多种进行干燥,干燥后过滤。
进一步地,步骤(1)还包括如下对反应液进行处理的步骤:
依次用水、酸溶液和饱和氯化钠水溶液洗涤反应液,取有机层加干燥剂干燥后取滤液,浓缩;优选地,所述干燥剂为无水硫酸钠或无水硫酸镁,所述酸溶液的pH值为2~5,优选为3~4。
进一步地,步骤(2)还包括除去溶剂b的步骤,优选为减压浓缩除去溶剂b。
本发明还提供了上述的化合物或其盐在二甲磺酸赖右苯丙胺原料药质量研究的标准品或对照品中的用途;
优选地,所述标准品或对照品中,式I所示化合物或其盐的含量大于96%,更优选为大于98%。
本发明还提供了一种二甲磺酸赖右苯丙胺原料药,所述原料药中式I所示化合物或其盐的含量不超过0.2%,优选为不超过0.15%;
本发还提供了检测上述的二甲磺酸赖右苯丙胺原料药中式I所示化合物和/或其手性异构体的方法,即采用高效液相色谱法检测,所述高效液相色谱的色谱条件如下:
色谱柱:以十八烷基硅烷键合硅胶为填充剂;柱温:45~55℃;检测波长:215nm;进样体积:3~7μL;流速:0.8~1.2ml/min;稀释剂:乙腈和水的混合物,乙腈与水的体积比为(25~35):(65~75);
流动相由A相和B相组成,A相为6~7g/L的无水辛烷磺酸钠水溶液,pH值为2~3;流动相B为乙腈;
优选地,色谱柱:以十八烷基硅烷键合硅胶为填充剂;柱温:50℃;检测波长:215nm;进样体积:5μL;流速:1.0ml/min;稀释剂:乙腈和水的混合物,乙腈与水的体积比为30:70;
流动相由A相和B相组成,A相为6.49g/L的无水辛烷磺酸钠水溶液,pH值为2.49;B相为乙腈;
梯度洗脱条件如下:
时间(分钟) | A相占流动相的体积(%) | B相占流动相的体积(%) |
0 | 70 | 30 |
15 | 70 | 30 |
22 | 63 | 37 |
30 | 63 | 37 |
50 | 30 | 70 |
55 | 30 | 70 |
55.1 | 70 | 30 |
60 | 70 | 30 |
主峰保留时间为23~23.5min的物质即本发明式I化合物和/或其手性异构体。
本发明的有益效果:发明人在研究二甲磺酸赖右苯丙胺原料药的合成工艺时,得到了一种新的化合物,即本发明式I所示化合物或其盐,该化合物是二甲磺酸赖右苯丙胺原料药或制剂产品中的一种杂质,其含量不应超过0.2%,优选为不超过0.15%。若该杂质或其盐在成品药中的含量过高,会导致药品质量不合格而无法上市销售,因此,本发明在提供该新杂质的同时提供了其制备方法,制得的产品中式I化合物或其盐的含量大于98%,可以作为二甲磺酸赖右苯丙胺原料药或制剂生产过程中检测该杂质或其盐的标准品,有效进行质量控制,保证药品安全。
本发明所述EDCI是:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,HOBT是:1-羟基苯并三唑,DCC是二环己基碳二亚胺。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明实施例1中式I所示化合物的二甲磺酸盐的核磁共振氢谱图。
图2为本发明实施例1中式I所示化合物的二甲磺酸盐的核磁共振碳谱图。
图3为本发明实施例1中式I所示化合物的二甲磺酸盐的红外谱图。
图4为本发明实施例1中式I所示化合物的二甲磺酸盐的紫外光谱图。
图5为二甲磺酸赖右苯丙胺样品的高效液相色谱图。
图6为本发明式I所示化合物的高效液相色谱图。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。本说明书中室温表示为25-35℃。
实施例1、本发明化合物的制备
称取23.07g右旋苯丙胺硫酸盐、45.54g BOC-D-Lys(BOC)-OH、28.76g EDCI和8.51g HOBT,加入125ml二氯甲烷和75ml DMF搅拌均匀。滴加50.58g NMM,滴加完毕后,室温下搅拌反应4h得反应液。反应液用水、PH值为3-4的盐酸溶液和饱和氯化钠水溶液分别洗涤一次,有机相用无水硫酸钠搅拌干燥;抽滤后减压浓缩得浅黄色固体。该固体加入200ml四氢呋喃,60℃搅拌溶解后,再加入48.10g甲磺酸,保持在60℃搅拌反应6h;反应液减压浓缩除去四氢呋喃后,固体加水溶解,溶解后用二氯甲烷洗涤,静置分液,水层用氢氧化钠水溶液调节pH至14后用二氯甲烷萃取,静置分液,有机层用无水硫酸钠干燥后抽滤,滤液室温下自然挥发析出白色固体,抽滤,滤饼于45±5℃下减压干燥后即得5.19g杂质,收率为18.19%,含量为98.0%。制得的产物的核磁共振氢谱图、核磁共振碳谱图、红外谱图和紫外光谱图如图1~4所示,可确定本发明式I化合物成功合成。
实施例2、本发明化合物的制备
称取36.80g右旋苯丙胺硫酸盐、55.20g BOC-D-Lys(BOC)-OH、39.24g EDCI和15.10g HOBT,加入200ml三氯甲烷和120ml DMF,室温搅拌。滴加80.25g NMM,滴加完毕后,室温下搅拌反应4h得反应液。反应液用水、PH值为3-4的盐酸溶液和饱和氯化钠水溶液分别洗涤一次,有机相用无水硫酸钠搅拌干燥;抽滤后减压浓缩得浅黄色固体。该固体加入400ml四氢呋喃,60℃搅拌溶解后,再加入76.56g甲磺酸,保持在60℃搅拌反应6h;反应液减压浓缩除去四氢呋喃后,固体加水溶解,溶解后用二氯甲烷洗涤,静置分液,水层用氢氧化钠水溶液调节pH至13后用二氯甲烷萃取,静置分液,有机层用无水硫酸钠干燥后抽滤,滤液室温下自然挥发析出白色固体,抽滤,滤饼于45±5℃下减压干燥后即得8.21g杂质;收率为18.04%,含量为98.3%。
实施例3、本发明化合物的制备
称取30.20g右旋苯丙胺硫酸盐、49.25g BOC-D-Lys(BOC)-OH、40.00g DCC和11.12g HOBT,加入300ml甲苯,室温搅拌。滴加65.10g NMM,滴加完毕后,室温下搅拌反应4h得反应液。反应液用水、PH值为3-4的盐酸溶液和饱和氯化钠水溶液分别洗涤一次,有机相用无水硫酸钠搅拌干燥;抽滤后减压浓缩得浅黄色固体。该固体加入300ml四氢呋喃,60℃搅拌溶解后,再加入63.98g甲磺酸,保持在60℃搅拌反应6h;反应液减压浓缩除去四氢呋喃后,固体加水溶解,溶解后用二氯甲烷洗涤,静置分液,水层用氢氧化钠水溶液调节pH至12后用二氯甲烷萃取,静置分液,有机层用无水硫酸钠干燥后抽滤,滤液室温下自然挥发析出白色固体,抽滤,滤饼于45±5℃下减压干燥后即得6.77g杂质,收率为18.13%,含量为98.1%。
实施例4、本发明化合物的来源
二甲磺酸赖右苯丙胺原料药的合成路线如下:
由于起始物料BOC-L-Lys(BOC)-OH(SM-2)中存在手性异构体BOC-D-Lys(BOC)-OH(R-2,6-二叔丁氧羰基氨基己酸)杂质,因此,本发明杂质即在制备路线中,中间体3(LDAA-3)与SM-2反应时,同时与其手性异构体BOC-D-Lys(BOC)-OH反应产生的衍生杂质。
取该工艺合成路线中得到的二甲磺酸赖右苯丙胺用进行有关物质的检测。
检测方法如下:
主要实验仪器:
仪器:Agilent高效液相色谱仪-1260
色谱条件:
色谱柱:十八烷基硅烷键合硅胶(Inertsil ODS-3,4.6×150mm,5μm);
柱温:50℃;
检测波长:215nm;
进样体积:5μl;
流速:1.0ml/min;
稀释剂:乙腈-水(30:70,v/v);
流动相A:取无水辛烷磺酸钠6.49g,加1000ml水使溶解,用磷酸调节pH值至2.5,过滤,脱气,即得;
流动相B:取乙腈过滤,脱气,即得;
梯度洗脱条件:
时间(分钟) | 流动相A(%) | 流动相B(%) |
0 | 70 | 30 |
15 | 70 | 30 |
22 | 63 | 37 |
30 | 63 | 37 |
50 | 30 | 70 |
55 | 30 | 70 |
55.1 | 70 | 30 |
60 | 70 | 30 |
供试品溶液:称取二甲磺酸赖右苯丙胺样品60.50mg,精密称定,置10ml容量瓶中,加入稀释剂使溶解并稀释至刻度,摇匀,即得。
对照品溶液:取式I杂质对照品,加稀释剂配置浓度为0.03mg/ml的溶液。
用上述检测方法对供试品溶液进行检测,得检测图谱(图5),用上述检测方法对供试品溶液进行检测,得式I化合物的定位图谱(图6)。并用外标法计算可得检测结果。需要特别说明的是,式I化合物为手性化合物,如果存在式I的手性异构体杂质,则该异构体与式I化合物的出峰时间一致,因此,检测出的23.211min处的峰代表式I化合物与其可能存在的手性异构体杂质的总和,即以本发明化合物作为对照品,可以实现对二甲磺酸赖右苯丙胺样品中式I化合物和/或其手性异构体杂质的检测。
检测结果如下:
综上,本发明提供了一种二甲磺酸赖右苯丙胺的新杂质,并且提供了该杂质的制备方法,制得的产物中该杂质的含量高于98%,可以作为二甲磺酸赖右苯丙胺原料药或制剂生产过程中检测该杂质或其盐的标准品,有效进行质量控制,保证药品安全,具有良好的应用前景。
Claims (10)
2.如权利要求1所述化合物或其盐,其特征在于,所述式I所示化合物的盐是式I所示化合物与酸形成的盐,所述酸为有机酸或无机酸;
优选的,所述有机酸为甲酸、乙酸、枸橼酸、富马酸、马来酸、琥珀酸、甲磺酸中的任一种或其组合;所述无机酸为盐酸、硫酸、硝酸、氢溴酸中的任一种或其组合。
4.如权利要求3所述的制备方法,其特征在于,步骤(1)所述溶剂a为二氯甲烷、三氯甲烷、乙酸乙酯、甲苯中的一种或多种;
所述羧基活化剂为EDCI、HOBT、DCC中的一种或多种;
所述有机碱为N-甲基吗啉、三乙胺、吡啶中的一种或多种;
和/或,步骤(2)所述溶剂b为异丙醇、四氢呋喃、二氯甲烷、乙腈中的一种或多种;
所述酸为甲酸、乙酸、枸橼酸、富马酸、马来酸、琥珀酸、甲磺酸、盐酸、硫酸、硝酸、氢溴酸中的至少一种,X为1~2;
和/或,步骤(3)所述有机溶剂是二氯甲烷、二氯乙烷、三氯甲烷、甲苯、二甲苯、庚烷、辛烷和磺化煤油中的一种或多种;
所述碱是氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙的一种或多种。
5.如权利要求3所述的制备方法,其特征在于,所述右旋苯丙胺硫酸盐、R-2,6-二叔丁氧羰基氨基己酸、羧基活化剂、有机碱和酸的摩尔比为1:(1-3):(1~4):(4~10):(4~10)。
6.如权利要求3所述的制备方法,其特征在于,步骤(1)所述缩合反应的条件为:0~40℃反应2~6h;
步骤(2)所述反应的条件为:40~70℃反应4~8h;
步骤(3)所述析晶为25~35℃自然静置析晶;所述萃取液的干燥方式为加入无水硫酸钠或无水硫酸镁的一种或多种进行干燥,干燥后过滤。
7.如权利要求3所述的制备方法,其特征在于,步骤(1)还包括如下对反应液进行处理的步骤:
依次用水、酸溶液和饱和氯化钠水溶液洗涤反应液,取有机层加干燥剂干燥后取滤液,浓缩;所述酸溶液的pH值为2~5;
和/或步骤(2)还包括除去溶剂b的步骤。
8.权利要求1或2所述的化合物或其盐在二甲磺酸赖右苯丙胺原料药质量研究的标准品或对照品中的用途。
10.检测权利要求9所述的二甲磺酸赖右苯丙胺原料药中式I所示化合物或其手性异构体的方法,其特征在于,采用高效液相色谱法检测,所述高效液相色谱的色谱条件如下:
色谱柱:以十八烷基硅烷键合硅胶为填充剂;柱温:45~55℃;检测波长:215nm;进样体积:3~7μL;流速:0.8~1.2ml/min;稀释剂:乙腈和水的混合物,乙腈与水的体积比为(25~35):(65~75);
流动相由A相和B相组成,A相为6~7g/L的无水辛烷磺酸钠水溶液,pH值为2~3;B相为乙腈;
梯度洗脱条件:
主峰保留时间为23~23.5min的物质即本发明式I所示化合物或其手性异构体。
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