CN88102709A - 亚叶酸的分离方法 - Google Patents
亚叶酸的分离方法 Download PDFInfo
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- CN88102709A CN88102709A CN88102709.XA CN88102709A CN88102709A CN 88102709 A CN88102709 A CN 88102709A CN 88102709 A CN88102709 A CN 88102709A CN 88102709 A CN88102709 A CN 88102709A
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- folinic acid
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- 239000011672 folinic acid Substances 0.000 title claims abstract description 26
- 229960001691 leucovorin Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 21
- 235000008191 folinic acid Nutrition 0.000 title claims abstract description 18
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- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 title claims abstract description 17
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 title abstract description 4
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 claims abstract description 33
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- 239000011777 magnesium Substances 0.000 abstract description 14
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及制备(6S)-亚叶酸及其盐的方法，其中包括重结晶(6R，S)-亚叶酸的碱土金属盐，而且必要时从所说的亚叶酸碱土金属盐中释放亚叶酸，以及/或者在必要时在碱存在下通过至少一次重结晶将其转化为碱金属盐。本发明还涉及(6S)亚叶酸的钙、镁、钾和钠盐，以及按本发明制备的(6S)-亚叶酸。
Description
本发明涉及制备（6S）-亚叶酸及其盐，特别是亚叶酸钙、镁、钾和钠盐的方法。
亚叶酸是N-[5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰]-L-谷氨酸（5-CHO-（6R，S）-H PteGlu（蝶酰谷氨酸））。N-[5-甲酰基-（6S）-5，6，7，8-四氢-蝶酰]-L-谷氨酸（5-CHO-（6S）-H PteGlu（蝶酰谷氨酸））是嗜橙菌因子（＝柠胶链环球菌的生长促进因子）。
亚叶酸含有二个不对称中心。而且，由于亚叶酸是由叶酸，即N-（蝶酰）-L-谷氨酸合成的，所以在其谷氨酸基团中含有的旋光性碳原子以L形式存在，而由5，6位上双键加氢产生的旋光性碳原子在6位上以外消旋（6R，S）形式存在。因此，合成的亚叶酸（二甲酰四氢叶酸）由两种非对映体1∶1的混合物组成。
在化学治疗中，无论作为一种用于治疗巨成红细胞叶酸缺乏症，即贫血症的药物制剂，还是作为一种具有下述增强作用的解毒药，甲酰四氢叶酸的重要性都日益提高了;在癌症治疗（甲酰四氢叶酸治疗）和诸如牛皮癣及类风湿关节炎一类自体免疫疾病的治疗中，增强叶酸拮抗剂耐受性，特别是增强氨蝶呤和甲氨蝶呤耐受性和增强甲氧苄氨嘧啶-磺胺甲基异恶唑等某些抗寄生物剂的耐受性。
据发现，亚叶酸在例如肝中的天然状态下只以S形式存在。作为叶酸辅助因子的甲酰四氢叶酸的生物化学作用，依赖于其5-CHO（6S）-H4PteGlu的含量。另一方面，其反（R）式，即5-CHO（6S）-H PteGlu却几乎不代谢，而是通过尿慢慢排出，它在生物化学上无活性（J.A.Straw等，《癌研究》，44，3114页，1984年）。
因此，人们做了许多试验，以便分离5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰-L-谷氨酸，不对称地合成5-甲酰基-（6S）-5，6，7，8-四氢-蝶酰-L-谷氨酸和离析出所说的生理活性形式的。在D，Cosulich等人于《美国化学会志》（74，4215-4216页，1952年）中以及在美国专利说明书2688018中，试验了自水溶液中用分步结晶法分离5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰-L-谷氨酸钙或锶等碱土金属盐。但是，在B.Cosulich等人公开的条件下不能实现所需的分离。在PH7～8的水中，例如对5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰-L-谷氨酸钙盐进行结晶时，总是再次获得纯的（6R，S）型物质，利用手性高效液体色谱柱进行色谱分析并且对照旋光度可以定量证明这一点。在这种情况下，结晶时使用的5-CHO（6R，S）-H4PteGlu钙盐是否纯并不是关键，回收得到的总是光学纯的（6R，S）-型物质。（6R、S）-亚叶酸碱土金属盐的过饱和水溶液中如果加入真实的（6S）-亚叶酸碱土金属盐，则既不能分离也不能浓集该（6S）型物质。所以迄今为止，不对称合成法依然仅仅有可能用来制备N-[5-甲酰基-（6S）-5，6，7，8-四氢-蝶酰-L-谷氨酸。
然而，过去已知的合成不对称（6S）-亚叶酸种种方法并不适于在工业规模上制备这种化合物。因此，到目前为止尚未出现制备（6S）-亚叶酸用的切实可行的工业方法。
因此，目交的问题是要开发一种制备（6S）-亚叶酸及其盐的简单、有效、成本低的工业方法。
令人惊奇地发现，在无机或有机碱存在下的碱性环境中，最好自水中使（6R、S）-亚叶酸的碱土金属盐重结晶时，例如使N-[5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰]-L-谷氨酸钙、镁或锶盐（＝（6R、S）-亚叶酸碱土金属盐）重结晶时，（6S）-型物质的结晶开始占优势，而且在得到的结晶中（6S）-型物质含量可达到85%或更高。
在近中性PH下，最好自水中通过进一步重结晶，可以把富含（6S）-型物质并且有高（6S）-型物质含量的亚叶酸碱土金属盐，转化为旋光纯的（6S）-亚叶酸碱土金属盐。
在结晶期间，加入碱土金属离子，例如钙、镁或锶的氯化物，可以提高产率。
因此，本发明目的在于提供一种制备（6S）-亚叶酸及其盐的方法，其中包括使（6R、S）-亚叶酸碱土金属盐重结晶，必要时自所说的亚叶酸碱土金属盐中释放出所说的酸和（或者）在必要时转化为碱金属盐，其特征在于所说的重结晶是在碱存在下进行的。
本发明的目的还在于提供这样一种方法，其中使所得到的结晶在碱存在下或者在近中性PH值下至少再进行一次重结晶。按照本发明的一种优选的具体实施方案，在添加的碱土金属离子存在下进行所说的重结晶。
（6R、S）-亚叶酸碱土金属盐的纯品和粗品，均适于作为本发明的原料物质。
由于此方法，第一次可以在商业上得到N-[5-甲酰基-（6R，S）-5，6，7，8-四氢-蝶酰]-L-谷氨酸的钙盐和镁盐。
亚叶酸钙、镁、锶和钡盐，是适用的亚叶酸碱土金属盐。优选钙盐和镁盐，因为分离后可以直接使用这些盐作为药物药制剂;而锶盐，尤其是钡盐随后在一定程度上被转化为另一种生理上适用的盐。
适用的无机或有机碱有：钠、钾和锂之氢氧化物等碱土金属氢氧化物;尤其是钙和镁之氢氧化物等碱土金属氢氧化物;氨和肼;水溶性有机碱，特别是简单的伯、仲和叔胺：例如甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、丙胺、二丙胺、甲基乙胺、氨基醇类：例如乙醇胺、二乙醇胺、三乙醇胺、丙醇胺、丁醇胺、二羟基丙醇胺（2，3-二羟基丙胺，丝氨醇）、三羟基丁胺[三-（羟甲基）-氨基甲烷]、葡糖胺、N-甲基葡糖胺、杂环胺类：例如吡咯烷、哌啶、吗啉或哌嗪。
在8.5～12间某PH值下，优选在9.0～10.5间某PH值下，按照本发明方法进行第一次重结晶，当PH值更低时，在收获的结晶中不能显著富集（6S）-型物质;当PH值便高时，亚叶酸稳定性明显降低且难于使所说的碱土金属盐结晶。为了从（6S）-亚叶酸碱土金属盐中除去残存的一些（6R）-亚叶酸盐，可以在近中性环境中，例如在6.5～8.5PH下再次进行重结晶。在所说的结晶期间，加入适当的碱土金属离子可以更迅速提高产品的溶解度，因而使产率增加。碱土金属离子，优选Ca、Mg、Sr离子，加入易溶形式盐，例如加入氯化物，硫酸盐或硝酸形式盐。其使用量通常为所说亚叶酸盐量的0.2～4倍。
本发明目的还在于用本发明方法第一次在工业上制成（6S）-亚叶酸盐，特别是亚叶酸钙和（6S）-亚叶酸，以及不论其制备方法如何从现在容易获得的（6S）-亚叶酸碱土金属盐出发，使用例如复分解法易于制得新的（6S）-亚叶酸的镁盐、钠盐和钾盐。
因为（6S）-亚叶酸镁在水中有相当好的溶解度（大于2克/100毫升）和高耐药量，是制备注射溶液的适用原料物质所以它很重要。（6S）-亚叶酸钠和钾盐由于这个原因而更为重要。20℃下（6S）-亚叶酸钙只能形成0.95%的水溶液，它很难被用来制备注射溶液。
详细说明本发明的一些实施例。
实施例1
（6S）-亚叶酸钙
1.结晶：
用12-36克氯化钙（Ca Cl2·2H2O）处理50-60℃约1升温水中的100克（6R、S）-亚叶酸钙粗品，加入氨水（25%）在30℃下调节PH值为10，在18℃下使之结晶。18-20小时后滤出沉淀的产物，依次用稀氯化钙溶液和润湿的乙醇洗涤。制得41克亚叶酸钙，其中含88%（6S）-亚叶酸和12%（6R）-亚叶酸钙，旋光产率为72%。
2.结晶：
将40克从第一次结晶得到的含88%（6S）-亚叶酸盐的（6S）-亚叶酸钙粗品溶解在55-60℃水中，用盐酸水溶液（20%）将其缓缓调节到PH6.1，用40-160克氯化钙处理。55℃下，加入苛性苏打将溶液PH调节到7～7.5。在大约35℃下加入真实的（6S）-亚叶酸钙，使产品在18-20℃下结晶。
大约40小时后，滤出结晶析出的产物，用乙醇水溶液洗涤后干燥。
得到30.4克（S）-亚叶酸钙，其中含98%（S）-亚叶酸盐，旋光的产率为79-81%。
3.结晶：
将（6S）-型物质含量为94-98%的10克（6S）-亚叶酸钙溶解在热水中，用10克氯化钙处理，然后在PH7.0～7.5和18～20℃条件下结晶。3～4天之后滤出产物，用少量水洗涤后，用润湿的乙醇洗涤，干燥。得到8克（6S）-亚叶酸钙纯品，（6S）-亚叶酸钙含量为99-100面积%（by area）。在水中的溶解度：20℃下为0.95克/100毫升，
40℃下为1.5克/100毫升。
比旋光度[α20 D]＝-15°（相对于无水钙盐）。
注解：
亚叶酸钙含量是经高效液体色谱法相对于标准测得的：
（6S）-型物质含量是使用手性柱（Resolvosil-BSA-7）条件下用高效液体色谱法测得的。
实施例2
各种碱存在下用结晶法分离（6R，S）-亚叶酸钙
1.在碱存在下的重结晶
将30克（6R，S）-亚叶酸钙溶解在200-300毫升50℃水中，在30-40℃下对于每摩尔（6R，S）-亚叶酸钙用0.5-0.6当量碱处理。
室温下搅拌溶液5-17小时。通常情况下立即产生自发结晶作用。滤出得到的结晶，顺序用少量5%氯化钙溶液和乙醇洗涤，干燥。试验结果可以从表1中看出。
表 1
2.按1中方法得到的粗品（6S）-亚叶酸钙的重结晶
将按上述方法1得到的粗品（6S）-亚叶酸钙从外加有1-4份氯化钙的PH为6.5～7.5的水中重结晶。在此过程期间，过滤分离溶解度稍小的物质。浓缩和冷却后，自该滤液中结晶纯品（6S）-亚叶酸钙。
（6S）-亚叶酸钙含量等于99.9面积%（by area）。
实施例3
（6S）-亚叶酸镁
1.结晶
把用氯化镁沉淀法自（6R，S）-亚叶酸钠水溶液中制备的30克（6R，S）-亚叶酸镁溶解在热水中，用100克氯化镁处理，加入氢氧化钠水溶液调节PH至10。然后，在搅拌下把此溶液冷却到16-18℃。
几天之后，滤出结晶出的粗品（6S）-亚叶酸镁，用乙醇洗涤后干燥。制得的亚叶酸镁中（6S）-亚叶酸盐含量为80%。
2.重结晶
利用在近中性PH下和外加有氯化镁的少量水中重结晶，从粗品（6S）-亚叶酸镁得到（6S）-亚叶酸盐含量高于理论量95%的纯品（6S）-亚叶酸镁。在水中的溶解度为2.4克/100毫升（20℃下）。
实施例4
（6S）-亚叶酸钠
使（6S）-亚叶酸钙的几乎饱和的水溶液，通过离子交换树脂柱过滤，柱中充填有Na+型阳离子交换树脂，例如Na+型Imberlite IR-120树脂。浓缩洗出液，加入乙醇沉淀亚叶酸钠。（6S）-亚叶酸钠易溶于水中。
利用把（6S）-亚叶酸溶解在等当量氢氧化钠中的方法，也可以制备（6S）-亚叶酸钠。为此目的所需的（6S）-亚叶酸按实施例6制备。
实施例5
（6S）-亚叶酸钾
通过把按实施例6得到的（6S）-亚叶酸溶解在等当量氢氧化钾水溶液中，制得此化合物。
利用乙醇、异丙醇或丙酮处理的方法，可以从（6S）-亚叶酸钾浓缩溶液中沉淀出（6S）-亚叶酸钾。（6S）-亚叶酸钾易溶于水中。
实施例6
（6S）-亚叶酸
用稀盐酸小心处理（6S）-亚叶酸钙水溶液，同时沉淀出（6S）-亚叶酸（即N-（5-甲酰基-（6S）-5，6，7，8-四氢-蝶酰）-L-谷氨酸]，过滤收集。（6S）-亚叶酸几乎不溶于水中。
Claims (5)
1、制备(6S)-亚叶酸碱土金属盐的方法，其中包括在碱存在下使(6R，S)-亚叶酸碱土金属盐重结晶。
2、根据权利要求1的方法，其中包括随后的自所说的碱土金属盐中释放游离的（6S）-亚叶酸和/或将其转化为亚叶酸碱金属的步骤。
3、根据权利要求1或2的方法，其中使得到的亚叶酸碱土金属盐的所说结晶，在碱存在下或者在近中性PH值下，至少进行一次进一步重结晶。
4、根据权利要求1、2或3的方法，其中在涂加的碱土金属离子存在下进行所说的重结晶。
5、按照上述权利要求中任何一项所述的方法制备的（6S）-亚叶酸或其钙盐。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009046581A1 (fr) * | 2007-10-11 | 2009-04-16 | Nanjing Rally Biochemical Inc | Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification |
| CN101792444B (zh) * | 2009-02-02 | 2011-10-12 | 天津康鸿医药科技发展有限公司 | 左亚叶酸钠及其制备方法及药物组合物 |
| CN102101862B (zh) * | 2009-12-21 | 2013-01-09 | 天津康鸿医药科技发展有限公司 | 一种制备左亚叶酸钠或混旋亚叶酸钠的方法 |
| CN105367574A (zh) * | 2015-10-27 | 2016-03-02 | 浙江大为药业有限公司 | 一种高纯度左旋亚叶酸钙的制备工艺 |
| CN111138434A (zh) * | 2019-09-18 | 2020-05-12 | 南京海纳医药科技股份有限公司 | 一种左亚叶酸的制备方法 |
| CN112649524A (zh) * | 2020-12-02 | 2021-04-13 | 重庆华邦胜凯制药有限公司 | 分离检测叶酸中叶酸及叶酸光学异构体的方法 |
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