CN103788068B - 高熔点的手性苯并咪唑类化合物钠盐、制备方法及其用途 - Google Patents
高熔点的手性苯并咪唑类化合物钠盐、制备方法及其用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及一种高熔点的右旋兰索拉唑的钠盐，及其制备方法，以及该种钠盐在制药领域的用途。该钠盐为无定形粉末，在水中的溶解度大，稳定性好，适于制备注射剂型。
Description
技术领域
本发明涉及一种高熔点的手性苯并咪唑类化合物的钠盐，及其制备方法，以及该种钠盐在制药领域的用途。
背景技术
苯并咪唑类系列衍生物作为质子泵抑制剂已经开发上市多年，其代表性的奥美拉唑、兰索拉唑、泮托拉唑和雷贝拉唑等在临床中得到应用广泛。由于其分子结构中的硫具有手性，一些手性的拉唑类药物如埃索美拉唑、右兰索拉唑、左泮托拉唑、右雷贝拉唑等在世界各国陆续上市。
兰索拉唑为全球第二个上市的苯并咪唑类质子泵抑制剂，由日本武田公司开发，1993年在法国首次上市。其手性右旋体右兰索拉唑于2009年1月30日由美国FDA批准上市，剂型为口服胶囊剂。
对于注射剂的制备，希望化合物具有较高的水溶性。右旋兰索拉唑不溶于水，在制备冻干粉针的工艺过程中需要添加大量的氢氧化钠将其溶解在水中，氢氧化钠溶解时大量放热，而右旋兰索拉唑对热高度不稳定，采用这种方法制备右旋兰索拉唑冻干粉针存在着工艺及产品质量可控性不强的缺点。
苯并咪唑类质子泵抑制剂化合物结构中的硫原子具有手性，因此含有左右旋的一对对映异构体。咪唑环上氮氢显示一定的酸性，能够与强碱成盐。中国专利CN200610045936公开了一种制备兰索拉唑钠的方法，该方法简单采用兰索拉唑与氢氧化钠以1∶1-1∶1.2(W／W)的比例反应后将水浓缩至干获得，但其中未提及兰索拉唑右旋体钠盐的制备及其熔点等数据。中国专利CN200810024534公开了A、B两种晶型的兰索拉唑钠的制备方法及其X-衍射数据，该专利也未提及右兰索拉唑钠的制备方法及其晶型数据。中国专利CN201101243031、CN200910262068、CN01819816、CN00809063、CN20110199215公开的均为右兰索拉唑的结晶方法及晶型，未涉及右兰索拉唑钠的制备及晶型。
中国专利CN200510017379公开了兰索拉唑钠的制备方法，采用含醇的溶剂将兰索拉唑与带有金属钠离子的碱性化合物如氢氧化钠、钠氢、烷基胺钠、烷基醇钠反应，于-20～20℃下结晶获得，并提及该方法适用于兰索拉唑及其手性右旋、左旋体。发明人曾尝试采用该专利方法制备右旋兰索拉唑钠，并未获得成功。该专利实施例中制得的兰索拉唑钠盐熔点在160-163℃之间。
众所周知，消旋化合物与手性的酸或碱成盐后，利用其手性盐在某种溶剂中溶解度的差异达到分离单一异构体的目的。但通常不采用无机酸碱与消旋体成盐分离单一异构体，其主要原因是，通常消旋体与无机酸碱成盐之后左右旋异构体溶解度并无差异。
但是在右旋兰索拉唑钠盐的研究中，我们意外的发现，右旋兰索拉唑钠与其消旋体兰索拉唑钠在某些有机溶剂中的溶解度存在很大差异。例如以四氢呋喃或乙酸乙酯为溶剂时，兰索拉唑能够与金属钠或氢氧化钠顺利成盐后析出，获得高纯度的兰索拉唑钠盐，而右旋兰索拉唑与强碱成盐后无法从溶剂中析出，导致所得右旋兰索拉唑钠盐纯度不高，熔点降低。因此，不能将制备兰索拉唑钠盐的方法直接应用于右旋兰索拉唑钠盐的合成。
发明内容
本发明为了克服上述现有技术存在的缺点，提供了一种高熔点的右旋兰索拉唑钠盐，该钠盐不含有结晶水及其他结晶溶剂，具有高于199℃的熔点。该钠盐具有极好的水溶性，易于制备注射剂型。
此外，本发明提供了一种制备高熔点右旋兰索拉唑钠的方法：将右旋兰索拉唑溶解于干燥的有机溶剂中，可以选择醚类(例如乙醚、甲基乙基醚、甲基叔丁基醚或四氢呋喃)，或选择C1-C4的醇类溶剂；之后加入金属钠或含有钠离子的强碱(例如钠氢、甲醇钠、乙醇钠或氢氧化钠)，10～30℃搅拌2h，过滤，滤液中加入溶剂量0.2％～1％(V／V)的水(如果加入的含有钠离子的强碱为氢氧化钠则不加水)，减压蒸去全部溶剂，得到残余物为粗品。粗品精制时，加入酮类溶剂(例如丙酮、丁酮、2-戊酮或3-戊酮)，再加入无水硫酸钠，室温搅拌15分钟，过滤，减压蒸去部分溶剂后，加入石油醚或C6-C7烷烃(例如正己烷、环己烷或正庚烷)，固体析出后过滤，将过滤所得固体于30℃以下真空干燥即得右旋兰索拉唑钠(I)固体。附图1为高熔点的右旋兰索拉唑钠(I)DSC分析图谱，附图2为高熔点的右旋兰索拉唑钠(I)的粉末X-衍射图，显示该固体为无定形物。
本发明还提供了另一种精制右旋兰索拉唑钠的方法，即粗品加入异丙醇与水的混合物，30～40℃搅拌溶解后，降温至-10～5℃静置析晶，过滤后可得。附图3为右旋兰索拉唑钠(II)DSC分析图谱，附图4为右旋兰索拉唑钠(II)的粉末X-衍射图，显示该固体为无定形物。
本发明还公开了一种使用高熔点右旋拉索拉唑钠制备的用于治疗伴有出血的胃溃疡、十二指肠溃疡、急性应激性溃疡及急性胃粘膜病变的注射剂，该注射剂在工业生产过程中仅需使用注射用水溶解，加少量氢氧化钠调节pH值后冷冻干燥即可制得。
附图说明
图1为高熔点的右旋兰索拉唑钠(I)的DSC分析图谱。
图2为高熔点的右旋兰索拉唑钠(I)的粉末X-衍射图谱。
图3为高熔点右旋兰索拉唑钠(II)的DSC分析图谱。
图4为高熔点右旋兰索拉唑钠(II)的粉末X-衍射图。
具体实施方式
以下对比例试验方法参考公开文献中兰索拉唑钠盐的制备方法，对右旋兰索拉唑钠的制备进行研究。
对比例1(参考专利CN200510017379实施例1兰索拉唑钠盐的制备方法)
右旋兰索拉唑10g加至0.1mol／L当量的氢氧化钠水溶液27ml，搅拌5分钟，加入二氯甲烷27ml，搅拌10分钟，分液，水相用27ml二氯甲烷洗涤，合并有机相，过滤澄清，减压浓缩至12ml。加入乙醇60ml，蒸干，加乙酸乙酯70ml搅拌回流30分钟，然后冷却放置过夜，无固体析出。
将上述乙酸乙酯溶液减压蒸馏至剩余20ml左右，静置2h，仍无固体析出，将乙酸乙酯蒸干，固体用乙醚洗涤，40℃真空干燥，得白色粉末状固体7.6g。
对比例2(参考专利CN200810024534的A晶型兰索拉唑钠盐的制备方法)
右旋兰索拉唑10g，投入溶解有2.16g氢氧化钠的40ml水中，搅拌至全部溶解，用二氯甲烷洗涤反应液4次，过滤，滤液用乙醇带水，减压蒸馏近干，加入30ml乙酸乙酯，搅拌回流0.5小时后冷却析晶，无固体析出，将乙酸乙酯溶液减压蒸馏至5ml，冷却析晶，有少量结晶析出，过滤，40℃以下减压干燥4小时，得白色固体3.2g。
可以发现右旋兰索拉唑钠在有机溶剂中的溶解度与兰索拉唑钠不同，成盐后难于从四氢呋喃，乙酸乙酯等有机溶剂中析出。
实施例1
将右旋兰索拉唑10g溶解于30ml甲醇中，加入1.1g氢氧化钠，10～30℃搅拌2h，过滤，减压蒸去全部溶剂，向残余固体粉末中加入丙酮20ml，再加入无水硫酸钠0.5g，室温搅拌15分钟，过滤，减压浓缩至剩余丙酮溶液5ml，加入正己烷25ml，固体析出后过滤，40℃以下真空干燥即得右旋兰索拉唑钠9.1g。水份：0.2％，mp：199～202℃，元素分析：C，48.94％；H，3.52％；F，14.41％；N，10.90％；Na，5.76％；S，8.22％。
实施例2
将右旋兰索拉唑10g溶解于40ml干燥的四氢呋喃中，加入1g金属钠块，10～30℃搅拌2h，过滤除去未反应的金属钠，向滤液中滴加入0.2ml水，减压蒸去全部溶剂，向残余固体粉末中加入丁酮20ml，再加入无水硫酸钠0.5g，室温搅拌15分钟，过滤，减压浓缩至干，加入异丙醇与水9∶1(V／V)的混合液20ml，加热至30～40℃搅拌溶解，-10～5℃静置析晶4小时，过滤，40℃以下真空干燥即得右旋兰索拉唑钠7.6g。水份4.9％，mp：214～219℃，元素分析：C，48.87％；H，3.92％；F，14.62％；N，11.14％；Na，5.68％；S，8.19％。
实施例3
将右旋兰索拉唑5g溶解于50ml乙醇中，加入0.9g乙醇钠，10～30℃搅拌2h，过滤，向滤液中加入0.25ml水，减压蒸去全部溶剂，向残余固体粉末中加入2-戊酮30ml，再加入无水硫酸钠0.5g，室温搅拌15分钟，过滤，减压浓缩至剩余2-戊酮溶液5ml，加入环己烷25ml，固体析出后过滤，40℃以下真空干燥即得右旋兰索拉唑钠4.3g。水份：0.2％，mp：202～205℃，Na含量：5.82％。
实施例4
将右旋兰索拉唑5g溶解于60ml干燥的甲基叔丁基醚中，加入0.9g钠氢，10～30℃搅拌2h，过滤，向滤液中加入0.3ml水，减压蒸去全部溶剂，向残余固体粉末中加入正丁醇与水19∶1(V／V)的混合液30ml，加热至30～40℃搅拌溶解，-10～5℃静置析晶4小时，过滤，40℃以下真空干燥即得右旋兰索拉唑钠7.6g。水份4.0％，mp：215～220℃，Na含量：5.71％。
实施例5
含有右旋兰索拉唑钠的冻干粉针剂的制备方法
(1)处方：
(2)溶液配制称取处方量的右旋兰索拉唑钠、甘露醇及EDTA二钠，加入处方量70％的注射用水，搅拌溶解后，使用0.1mol／L氢氧化钠溶液调节pH=10.5-11.5，加水至全量，经0.45微米，0.22微米滤膜过滤，以2ml／瓶灌装于西林瓶中，半加塞，送入冻干机中。
(3)冷冻干燥将制品冻至-40℃预冻，保温3小时。将导热油温度升至-20℃，保持10小时；将导热油温度升至0℃，保持5小时；将导热油温度升至10℃，保持3小时；将导热油温度升至25℃，终点判断合格后关机，出箱轧盖。
右旋兰索拉唑、对比例1、对比例2、实施例1、实施例2样品的理化性质及影响因素对比研究数据如下表。
仪器熔点仪：YRT-3熔点仪
元素分析仪：ElementaVarioELIII型元素分析仪
高效液相色谱仪：Agilent1260
表1：右旋兰索拉唑与几种方法制备的右旋兰索拉唑钠理化性质对比试验
由上表对比试验数据可知：右旋兰索拉唑成钠盐后极大的增强了其稳定性，对比例1和2方法制备的右旋兰索拉唑钠盐为混合物，熔点低，钠含量偏低，稳定性较差。实施例1和2样品成盐完全，熔点及钠含量测定显示为高纯度的右旋兰索拉唑钠盐，成盐后性质稳定，能够在60℃下10天保持稳定。
需要说明的是，以上所述仅为本发明的部分实施例，并不用于限定本发明的范围，凡在本发明的精神和原则之内所作出的任何修改、等同的替换和改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种制备无定形的右旋兰索拉唑钠的方法，其特征在于，包含如下步骤：将右旋兰索拉唑5g溶解于50mL乙醇中，加入0.9g乙醇钠，10-30℃搅拌2h，过滤，向滤液中加入0.25mL水，减压蒸去全部溶剂，向残余固体粉末中加入2-戊酮30mL，再加入无水硫酸钠0.5g，室温搅拌15分钟，过滤，减压浓缩至剩余2-戊酮溶液5mL，加入环己烷25mL，固体析出后过滤，40℃以下真空干燥即得右旋兰索拉唑钠4.3g；其中，所得右旋兰索拉唑钠为无定形物，水份0.2％，熔点202-205℃，Na含量5.82％。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1329003A (zh) * | 2000-06-19 | 2002-01-02 | 中国科学院成都有机化学研究所 | 光学纯兰索拉唑的制备方法 |
| US7271182B2 (en) * | 2000-08-04 | 2007-09-18 | Takeda Pharmaceutical Company Limited | Salts of benzimidazole compound and use thereof |
| WO2011121546A1 (en) * | 2010-03-31 | 2011-10-06 | Ranbaxy Laboratories Limited | Salts of dexlansoprazole and their preparation |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
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| US7271182B2 (en) * | 2000-08-04 | 2007-09-18 | Takeda Pharmaceutical Company Limited | Salts of benzimidazole compound and use thereof |
| WO2011121546A1 (en) * | 2010-03-31 | 2011-10-06 | Ranbaxy Laboratories Limited | Salts of dexlansoprazole and their preparation |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
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