CN1063444C - 稳定的结晶(6s)－和(6r)－四氢叶酸 - Google Patents
稳定的结晶(6s)－和(6r)－四氢叶酸 Download PDFInfo
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- CN1063444C CN1063444C CN95106005A CN95106005A CN1063444C CN 1063444 C CN1063444 C CN 1063444C CN 95106005 A CN95106005 A CN 95106005A CN 95106005 A CN95106005 A CN 95106005A CN 1063444 C CN1063444 C CN 1063444C
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- tetrahydrofolate
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- MSTNYGQPCMXVAQ-NEPJUHHUSA-N 6R-Tetrahydrofolic acid Chemical compound C([C@@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-NEPJUHHUSA-N 0.000 title claims abstract description 71
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 title claims abstract description 61
- 238000002425 crystallisation Methods 0.000 claims abstract description 45
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- 238000000034 method Methods 0.000 claims abstract description 30
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
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- 239000005460 tetrahydrofolate Substances 0.000 description 14
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 239000007858 starting material Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 5
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
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- QYNUQALWYRSVHF-STQMWFEESA-N (2s)-2-[[4-[(6as)-3-amino-1-oxo-4,5,6,6a,7,9-hexahydroimidazo[1,5-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid Chemical compound C([C@H]1C2)NC=3NC(N)=NC(=O)C=3N1CN2C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QYNUQALWYRSVHF-STQMWFEESA-N 0.000 description 1
- LPJXPACOXRZCCP-VIFPVBQESA-N (2s)-2-benzamidopentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1 LPJXPACOXRZCCP-VIFPVBQESA-N 0.000 description 1
- KHTQQXJIHRHSRT-UHFFFAOYSA-N 2-amino-4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoic acid Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1CNC1=CC=C(C(O)=O)C(N)=C1 KHTQQXJIHRHSRT-UHFFFAOYSA-N 0.000 description 1
- -1 2-methylpyrrolidone Chemical compound 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-QWHCGFSZSA-N 5-formyl-5,6,7,8-tetrahydrofolate Chemical compound C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-QWHCGFSZSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- 229940125687 antiparasitic agent Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- UOSVKQDEUWYYOT-ACGFUFEJSA-L calcium;(2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioate;(2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound [Ca+2].O=CN1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1.O=CN1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 UOSVKQDEUWYYOT-ACGFUFEJSA-L 0.000 description 1
- JMNIIIQOMSQWJN-ACGFUFEJSA-L calcium;(4s)-4-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca+2].C1NC=2N=C(N)NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1.C1NC=2N=C(N)NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 JMNIIIQOMSQWJN-ACGFUFEJSA-L 0.000 description 1
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- 150000002224 folic acids Chemical class 0.000 description 1
- 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 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003195 pteridines Chemical class 0.000 description 1
- 125000001747 pteroyl group Chemical group [H]C1=C([H])C(C(=O)[*])=C([H])C([H])=C1N([H])C([H])([H])C1=C([H])N=C2N([H])C(N([H])[H])=NC(=O)C2=N1 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- 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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Abstract
本发明涉及稳定的结晶(6S)-和(6R)-四氢叶酸，其用途和其制备方法。结晶(6S)-和(6R)-四氢叶酸既纯又极稳定。这些物质甚至在较高温度下不加稳定剂暴露于空气中时也绝对惰性。在pH≥3.5制备结晶(6S)-四氢叶酸的结晶方法和在pH≥2制备结构(6R)-四氢叶酸的结晶方法都非常简便易行并且收率高。
Description
本发明涉及结晶的N-〔4-〔〔(2-氨基-1，4，5，6，7，8-六氢-4-氧代-(6S)-和-(6R)-蝶啶基)甲基〕氨基〕苯甲酰基-L-谷氨酸(下称结晶(6S)-或(6R)-四氢叶酸)、其用途和制备方法。
四氢叶酸衍生物有两个不对称中心。因为这些衍生物是从叶酸(即N-(蝶酰)-L-谷氨酸)合成而来，所以谷氨酸片断中的光学活性碳原子为L型，而6-位的光学活性碳原子通常由蝶酰基5，6一位双键氢化形成，故以外消旋(即(6R，S))形式存在。因此，形成的四氢叶酸衍生物由两种非对映异物体的1∶1混合物组成。
四氢叶酸盐主要以5-甲酰-5，6，7，8-四氢叶酸钙(leucovorin)或5-甲基-5，6，7，8-四氢叶酸钙的形式使用，作为药物治疗幼巨红细胞性叶酸贫血，作为解毒剂改善肿瘤治疗中叶酸拮抗剂，特别是氨基喋呤和氨甲蝶呤的耐受性(“抗叶酸补救途径”)、增强氟代嘧啶的治疗效果及治疗自身免疫疾病如牛皮癣和风湿性关节炎、改善对某些抗寄生物剂如三甲氧苄二氨嘧啶-磺胺甲基异噁唑的耐受性、及减低化疗中二去氮四氢叶酸盐(dideazatetrahydrofolates)的毒性。四氢叶酸还可用作制备各种叶酸衍生物的起始物。
迄今为止，直接使用四氢叶酸作为药物及作为制备各种四氢叶酸衍生物的起始物是不可能的，因为在制备具有作为药物活性物质可以接受的纯度的四氢叶酸时遇到困难，及四氢叶酸极其不稳定，特别是它对氧化高度敏感〔见本文及A.L.Fitzhugh，Pteridines4(4)，187-191(1993)〕。已发展了各种克服此不稳定性的方法，必须特别提及与本发明有关的DE-OS 2323124。关于与本发明有关的制备四氢叶酸的方法，还必须特别提及EP600460。但是迄今还没有发现在工业上可行的制备超纯的、满足四氢叶酸药物应用的足够稳定性的四氢叶酸的方法。
令人惊异地是，现发现通过结晶光学纯(6S)-或光学纯(6R)-、富集的(6S)-或富集的(6R)-或(6R，S)-四氢叶酸，可得到具有优良稳定性的化学及光学超纯的(6S)-或(6R)-四氢叶酸。生成的结晶(6S)-和/或(6R)-四氢叶酸使得该物质第一次可用作药物或作为工业规模制备其它超纯四氢叶酸衍生物的起始物。
(6S)-四氢叶酸从pH≥3.5的极性介质中结晶，而(6R)-四氢叶酸从pH≥2.0的极性介质中结晶。
适当的极性介质特别为水或水和与水相混溶的有机溶剂的混合物，如水溶性醇，例如甲醇、乙醇、正丙醇、异丙醇、乙二醇；水溶性低级脂肪酸，例如甲酸、乙酸、乳酸；或水溶性酰胺，例如甲酰胺、二甲基甲酰胺、二甲基乙酰胺、1-甲基吡咯烷酮、2-甲基吡咯烷酮、2-哌啶酮。对所用溶剂和混合比例没有特别限制，因为结晶(6S)-四氢叶酸和结晶(6R)-四氢叶酸的溶解性特征一般低于相应的无定形形式。
为了引发(6S)-四氢叶酸结晶，pH在3.5至6.5之间特别适合。为了引发(6R)-四氢叶酸结晶，pH在2至5.5之间特别适合。引发结晶的最佳pH取决于所用物质和目的，并可经简单试验测定。一般的原则是：起始溶液中盐含量越高，要求引发结晶的pH越低，而引发结晶的pH低则要求结晶过程慢，因为不然的话在pH3左右沉淀出无定形四氢叶酸。例如，从用硼氢化物还原叶酸所得反应溶液中直接结晶(6S)-四氢叶酸，引发结晶严格要求pH≤4.8。结晶被引发后，pH可以变化。
在(6S)-四氢叶酸结晶过程中及在(6R)-四氢叶酸结晶过程中，pH升高或通过加入酸或缓冲液保持pH恒定。对于(6S)-四氢叶酸的结晶，如果想得到光学富集的(6S)-四氢叶酸，优选在结晶过程中pH为4.5-5.5；而如果想制备稳定的结晶(6S)-四氢叶酸，则优选结晶过程中pH为3.5-4.5。对于(6R)-四氢叶酸的结晶，独立于所预期结果，优选结晶过程中pH为3.5-4.5。对于每种情况，可在室温、较高温度或较低温度下进行结晶。
一般，结晶时间可为几分钟到数天。结晶时间越长，一般得到的产品纯度越高也更稳定。
从低于适合引发目标异构体结晶的pH开始，或优选从更高pH开始，通过慢慢调节pH自发地结晶(6S)-和(6R)-四氢叶酸。可在适于引发目标异构体结晶的pH范围内通过接种相应的结晶四氢叶酸来引发结晶。
结晶起始物可为外消旋(6R，S)-四氢叶酸、富集的(6S)-或(6R)-四氢叶酸以及无定形或结晶的(6S)-或(6R)-四氢叶酸。适宜的起始物不仅可为已分离的固体物质如(6R，S)-四氢叶酸、如EP495204中所述制得的硫酸和磺酸与(6S)-四氢叶酸的加成盐，而且还可为叶酸通过催化氢化或用硼氢化物还原现场制备的四氢叶酸。(6R)-四氢叶酸可从(6S)-四氢叶酸结晶母液中直接结晶。两种异构体都可从如调pH至＞7或＜2所得溶液、或从悬浮液结晶。
用无定形或部分结晶的光学纯四氢叶酸或其盐作为结晶的起始物，上述方法制得了具有前所未有的纯度(＞98％)及前所未有的稳定性的结晶四氢叶酸。
本发明还涉及结晶(6S)-和/或(6R)-四氢叶酸作为制备药物的成分或用于制备其它四氢叶酸衍生物的用途，因为其优良稳定，固态结晶(6S)-和(6R)-四氢叶酸在实际上无限期的时间内保持高质量。本发明还涉及包含结晶(6S)-和/或(6R)-四氢叶酸的药物制剂。用已知方法如冷冻干燥制备该药物制剂。其施用类似四氢叶酸领域中的已知物质如5-甲酰-5，6，7，8-四氢叶酸的施用。
本发明还涉及通过分步结晶分离(6R，S)-四氢叶酸得到两种非对映异构体(6S)-和(6R)-四氢叶酸的方法。该方法非常简单且收率高。甚至在粗外消旋(6R，S)-四氢叶酸经第一次结晶后，就可得到收率高于70％，且其(6S)组分的量高于75％的结晶(6S)-四氢叶酸，得到收率50％以上，且其(6R)组分的量在80％以上的结晶(6R)-四氢叶酸。在相似条件下进一步结晶，可得到异构体纯度大于95％的结晶(6S)-和(6R)-四氢叶酸。
(6R)-或(6S)-四氢叶酸还可以不经分离直接用于制备其它四氢叶酸衍生物。例如，通过向(6R)-四氢叶酸溶液中加入甲醛可很容易地制备富集的5，10-亚甲基-(6S)-四氢叶酸。
在实施例中所给出的四氢叶酸含量和异构体含量均由HPLC测定。所有四氢叶酸含量均基于无水物质。
实施例1(稳定性)
为了测定结晶(6S)-和(6R)-四氢叶酸的稳定性，这些物质和对比样品一起在60℃空气中压力条件下贮存。在周期性时间间隔内测定剩余的四氢叶酸含量，并与起始值相比示于下表
| 在60℃、空气中的测试时间(天) | ||||||||
| 0 | 2 | 6 | 13 | 21 | 28 | 57 | 360 | |
| 结晶(6S)-四氢叶酸 | 100.0％ | 100.1％ | 102.55％ | 98.7％ | 103.6％ | 103.1％ | 101.2％ | 93.3％ |
| 结晶(6R)-四氢叶酸 | 100.0％ | 96.4％ | 96.1％ | 93.3％ | 92.7％ | 82.0％ | ||
| Yamanollchi′s′结晶(6R,S)-四氢叶酸 | 100.0％ | 83.6％ | 48.6％ | 31.0％ | 13.4％ | |||
| 无定形的(6S)-四氢叶酸 | 100.0％ | 60.4％ | 13.7％ | 7.9％ | ||||
| 无定形的(6R)-四氢叶酸 | 100.0％ | 70.5％ | 29.1％ | 21.6％ | 9.8％ | |||
| 无定形的(6R.S)-四氢叶酸 | 100.0％ | 53.4％ | 17.4％ | 13.2％ | ||||
在60℃空气中甚至在很长测试时间后，结晶(6S)-和(6R)-四氢叶酸还保持很浅的颜色，几乎为白色。相反，为了比较而包括在内的其它产物迅速高度变色。
用于稳定性测试的物质按如下制备：
·结晶(6S)-四氢叶酸
如本专利申请的实施例6
·结晶(6R)-四氢叶酸
如本专利申请的实施例9
·“Yamanouchi’s结晶(6R，S)-四氢叶酸”
如DE-OS 2323124，实施例3
·无定形(6S)-四氢叶酸
将(6S)-四氢叶酸溶解在乙酸中，用乙醚沉淀
·无定形(6R)-四氢叶酸
将(6R)-四氢叶酸溶解在乙酸中，用乙醚沉淀
·无定形(6R，S)-四氢叶酸
将(6R，S)-四氢叶酸溶解在乙酸中，用乙醚沉淀。
实施例2(粉末X射线图)
为了表征结晶(6S)-和(6R)-四氢叶酸的结构特性(结晶性)，在相同条件下测定了这些物质和对比样品的粉末X射线图(衍射谱)。
结晶(6S)-和结晶(6R)-四氢叶酸都产生清晰可分辨的衍射图谱，谱带尖、背景度低。该图谱表明结晶物含量高。相反，“Yamanollchi’s结晶(6R，S)-四氢叶酸”产生分辨度差的图谱，谱带模糊(漫射极大)，且背景度高。该图谱说明无定形(6R，S)-四氢叶酸占优势，仅含低百分数的结晶物。
用于产生粉末X-射线图的物质按如下制备：
·结晶(6S)-四氢叶酸
如本专利申请的实施例6
·结晶(6R)-四氢叶酸
如本专利申请的实施例9
·“Yamanouchi’s结晶(6R，S)-四氢叶酸”
如DE-OS 2323124的实施例3。
实施例3
a)将4g(6R，S)-四氢叶酸悬浮在16ml水中，用25％氨调pH至9。在50℃下，所形成的溶液用盐酸调pH至5，再用氢氧化钠溶液慢慢调至所期望的pH值。取每份2ml在所示pH下的样品，吸滤过滤，用少量水洗涤。
| pH | 量 | (6S)的百分比 |
| pH 5.5 | 0.03 g | 87.8％ |
| pH 6.0 | 0.06 g | 87.8％ |
| pH 6.4 | 0.02 g | 88.6％ |
b)将4g(6R，S)-四氢叶酸悬浮在16ml水中，用25％氨调pH至9。在50℃下，所形成的溶液用盐酸调pH至5，再用盐酸慢慢调至所期望的pH值。取每份2ml在所示pH下的样品，吸滤过滤，用少量水洗。
| pH | 量 | (6S)的百分比 |
| pH 4.8 | 0.09 g | 72.7％ |
| pH 4.5 | 0.15 g | 57.9％ |
| pH 4.2 | 0.27 g | 51.8％ |
c)将4g(6R，S)-四氢叶酸悬浮在16ml水中，用25％氨调pH至9。在50℃下，所形成的溶液用盐酸调pH至5，再用盐酸慢慢调pH至期望的pH值。取每份2ml在所示pH下的样品，吸滤过滤，用少量水洗涤。
| pH | 量 | (6S)的百分比 |
| pH 4.1 | 0.16 g | 56.2％ |
| pH 3.8 | 0.10 g | 52.2％ |
| pH 3.5 | 0.22 g | 51.8％ |
| pH 3.0 | 0.12 g | 51.6％ |
d)将10g(6R，S)-四氢叶酸悬浮在80ml水中，用1N盐酸调pH至1.3。在室温下，用1.8N氨将形成的溶液调至所期望的pH值。取每份2ml在所示pH下的样品，吸滤过滤，用少量水洗涤。
| pH | 量 | (6S)的百分比 |
| pH2.0 | 0.03g | 50.3％ |
| pH2.3 | 0.13g | 50.5％ |
| pH2.5 | 0.12g | 49.3％ |
| pH2.8 | 0.22g | 50.8％ |
| pH3.1 | 0.17g | 49.5％ |
| pH3.5 | 0.21g | 51.5％ |
| pH4.0 | 0.14g | 59.1％ |
| pH4.5 | 0.16g | 56.1％ |
| pH5.1 | 0.22g | 72.7％ |
| pH5.5 | 0.20g | 70.9％ |
表a)至d)中所列数据的方法参数不是最优的，因为按照相同的实验步骤进行了所有的试验，以提高它们的可比性。
实施例4
将5g每份(6R，S)-四氢叶酸悬浮在50ml水中，在室温或40℃静置5天。吸滤过滤(过滤温度=结晶温度)并洗涤后，得到下列结果：
| RT | 40℃ | |||
| 量 | (6S)的百分比 | 量 | (6S)的百分比 | |
| pH 3.11) | 4.2 g | 52.5％ | 4.5 g | 52.2％ |
| pH 4.22) | 3.5 g | 58.9％ | 3.9 g | 59.3％ |
| pH 5.12) | 1.8 g | 82.1％ | 1.5 g | 81.0％ |
1)悬浮(6R，S)-四氢叶酸而无矫正剂时的pH，类似于DE-OS 2323124的实施例3。
2)用氢氧化钠溶液调至所期望pH。
列于该表中的数据的方法参数不是最佳的，因为采用相同的试验步骤进行了所有试验，以提高它们的可比性。
实施例5
将40g(6R，S)-四氢叶酸悬浮在160ml水中，用25％氨调pH至9.3。在50℃下，用盐酸将形成的溶液调至pH5.1，在接下来的结晶过程中保持pH在5.1-5.2之间。当结晶终止后，将混合物冷却至0-5℃，减压过滤并用水洗。
这样就得到19g结晶(6S)-四氢叶酸，其化学含量为95.9％，(6S)百分比为80.5。
一半母液用1.1g乙醇沉淀，得到富集的无定形(6R)-四氢叶酸，其化学含量为63.3％，(6R)百分比为75.9；而另一半母液用6.3g盐酸迅速调pH至3.5，生成富集的无定形(6R)-四氢叶酸，其化学含量为64.8％，(6R)百分比为75.9。
实施例6
将(6S)百分比为99.9的60g(6S)-四氢叶酸与苯磺酸的加成盐(按EP495204中所述方法制备)悬浮在240ml水中，用63ml 1.8N氨或55.2ml 2N氢氧化钠溶液调悬浮液的pH至5.5。保持pH在5.6。然后用30％氢氧化钠溶液将此白色稠悬液的pH调至9.3，将形成的澄清溶液加热至50℃。
然后用盐酸将pH慢慢调至5.2，再接种结晶(6S)-四氢叶酸后，得到43.0g结晶(6S)-四氢叶酸，其化学含量为96.8％，(6S)百分比为99.9。
将生成的结晶(6S)-四氢叶酸溶解在160ml pH9的水中，然后用盐酸慢慢调pH至4.2，再接种结晶(6S)-四氢叶酸后，得到32.5g结晶(6S)-四氢叶酸，其化学含量为98.5％，(6S)百分比为100.0。
在pH4.2下再重结晶，得到化学含量＞99％且(6S)百分比为100.0的结晶(6S)-四氢叶酸。
室温下，生成的结晶(6S)-四氢叶酸在水中的溶解度为0.0022％。
实施例7
将40g(6R，S)-四氢叶酸悬浮在160ml水和40ml甲醇中，用25％氨将悬浮液调至pH9.1，在50℃下，形成的溶液用盐酸慢慢调至pH5.1，在接下来的结晶过程中保持pH5.1-5.2之间。当结晶结束后，将20ml样品在50℃吸滤过滤，用水/甲醇洗涤。得到1.3g结晶(6S)-四氢叶酸，其化学含量为96.1％，(6S)百分比83.0。
将剩余部分冷却至0-5℃，减压过滤，用水/甲醇洗涤。又得到18.6g结晶(6S)-四氢叶酸，其化学含量为90.9％，(6S)百分比为67.1。
实施例8
将60g叶酸悬浮在240ml水中，用30％氢氧化钠溶液调pH至11.5。形成的溶液在70℃下用120ml水中的30g硼氢化钠和12g30％氢氧化钠溶液还原。反应时间约5小时后，反应混合物用180ml水稀释，用盐酸慢慢调pH至4.5。在接下来的结晶过程中，pH升至约5.5。在0-5℃减压过滤此悬液，用少量水洗涤。
得到25.5g结晶(6S)-四氢叶酸，其化学含量为94.4％，(6S)百分比为82.7。干燥后含水量为4.0％。
将20g形成的结晶(6S)-四氢叶酸溶解在pH9的80ml水中，然后用盐酸慢慢调pH至5.1，再接种结晶(6S)-四氢叶酸后，得到4.5g结晶(6S)-四氢叶酸，其化学含量为94.0％，(6S)百分比为94.7，干燥后含水量为1.8％。
实施例9
将(6R)百分比为99.4的50g无定形(6R)-四氢叶酸悬浮在600ml水中，用25％氨调悬液pH到9.0。加热所形成的澄清溶液至50℃。
用盐酸慢慢调节pH为4.4后，保持该pH值，得到42.0g结晶(6R)-四氢叶酸，化学含量为96.2％，(6R)百分比为99.5。
形成的结晶(6R)-四氢叶酸在室温下水中的溶解度为0.014％。
在pH4.4进一步重结晶，得到结晶(6R)-四氢叶酸，其化学含量＞98％，(6R)百分比＞99.5。
实施例10
将40g(6R，S)-四氢叶酸悬浮在160ml水中，用25％氨将悬液调至pH9.3。50℃下，用盐酸慢慢调节所形成溶液的pH至5.1，在结晶过程中保持pH在5.1-5.2之间。结晶结束后，将混合物冷却至室温，减压过滤，用水洗涤。
得到18.2g化学含量为94.0％，且(6R)百分比为77.8的结晶(6S)-四氢叶酸。
将(6S)-四氢叶酸结晶步骤的母液再加热至50℃，用盐酸慢慢调pH至4.4，在接下来的(6R)-四氢叶酸结晶过程中保持pH在4.0-4.5之间。结晶终止后，将混合物冷却至室温，减压过滤，用水洗。
得到12g化学含量为78.0％，(6R)百分比为74.8的结晶(6R)-四氢叶酸。
实施例11
从外消旋四氢叶酸开始，类似于EP600460的实施例2中所述条件，在pH5.2和45℃下重复所述方法。测定所形成产物的化学和光学纯度。同时记录每步的化学总收率。
从这些数据可以清楚地看出，重复施用该方法，使该方法的产物中(6S)的百分比提高而产物含量减低，这是由于重复进行该方法而引起的，必须考虑这一点。这样，即使重复施用该方法也不能制得纯度大于98％的产物。
| 6S的百分比 | 含量g/g | 纯度6S的百分比 | 总收率 | |
| 起始物 | 50％ | 89.6％ | 44.8％ | 100％ |
| 第1次 | 80.5％ | 96.9％ | 78.0％ | 53.5％ |
| 第2次 | 90.0％ | 97.3％ | 87.6％ | 45.4％ |
| 第3次 | 94.4％ | 97.4％ | 91.9％ | 42.0％ |
| 第4次 | 96.4％ | 96.7％ | 93.2％ | 38.9％ |
| 第6次 | 97.7％ | 96.2％ | 94.0％ | 35.2％ |
| 第6次 | 98.4％ | 95.6％ | 94.1％ | 32.2％ |
| 第7次 | 98.9％ | 96.0％ | 94.9％ | 28.6％ |
Claims (13)
1．结晶(6S)-四氢叶酸。
2．结晶(6R)-四氢叶酸。
3．结晶(6S)-和/或(6R)-四氢叶酸的制备方法，其特征在于结晶(6S)-、(6R)-或(6R，S)-四氢叶酸。
4．结晶(6S)-四氢叶酸的制备方法，其特征在于(6S)-或(6R，S)-四氢叶酸在极性介质中pH≥3.5下结晶。
5．结晶(6R)-四氢叶酸的制备方法，其特征在于(6R)-或(6R，S)-四氢叶酸在极性介质中pH≥2下结晶。
6．权利要求4或5的方法，其中水或水与极性水溶性有机溶剂的混合物用作极性介质，结晶在溶液或悬浮液中进行。
7．权利要求4或6的方法，其中为了引发(6S)-四氢叶酸结晶，调节pH至3.5-6.5之间。
8．权利要求5或6的方法，其中为了引发(6R)-四氢叶酸结晶，调节pH至2-5.5之间。
9．权利要求4，5，6，7或8的方法，其特征在于在结晶过程中保持pH恒定。
10．权利要求3，4，5，6，7，8或9的方法，其中通过分步结晶分离出(6S)-四氢叶酸，并从剩余母液中分离(6R)-四氢叶酸。
11．结晶(6S)-和/或(6R)-四氢叶酸作为制备药物或作为制备其它四氢叶酸衍生物的成分的用途。
12．根据权利要求3，4，5，6，7，8，9或10制备的结晶(6S)-和/或(6R)-四氢叶酸作为制备药物或制备其它四氢叶酸衍生物的成分的用途。
13．含有结晶(6S)和/或(6R)-四氢叶酸的药物制剂。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH01442/1994 | 1994-05-09 | ||
| CH01442/94 | 1994-05-09 | ||
| CH144294A CH686369A5 (de) | 1994-05-09 | 1994-05-09 | Stabile kristalline (6S)- und (6R)-Tetrahydrofolseure. |
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| Publication Number | Publication Date |
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| CN1122337A CN1122337A (zh) | 1996-05-15 |
| CN1063444C true CN1063444C (zh) | 2001-03-21 |
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| Country | Link |
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| US (2) | US6271374B1 (zh) |
| EP (1) | EP0682026B2 (zh) |
| JP (2) | JP3419585B2 (zh) |
| KR (1) | KR950032192A (zh) |
| CN (1) | CN1063444C (zh) |
| AT (1) | ATE188699T1 (zh) |
| AU (1) | AU704363B2 (zh) |
| CA (1) | CA2148671C (zh) |
| CH (1) | CH686369A5 (zh) |
| DE (1) | DE59507591D1 (zh) |
| DK (1) | DK0682026T4 (zh) |
| ES (1) | ES2144066T5 (zh) |
| FI (1) | FI120585B (zh) |
| GR (1) | GR3032984T3 (zh) |
| HU (1) | HUT71612A (zh) |
| NO (1) | NO313673B1 (zh) |
| PT (1) | PT682026E (zh) |
| RU (1) | RU2165422C2 (zh) |
| ZA (1) | ZA953673B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH689831A5 (de) * | 1995-11-07 | 1999-12-15 | Eprova Ag | Stabile kristalline Tetrahydrofolsaeure-Salze. |
| CH693905A5 (de) | 1999-04-15 | 2004-04-15 | Eprova Ag | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
| CH694251A5 (de) | 1999-07-14 | 2004-10-15 | Eprova Ag | Herstellung von Tetrahydropterin und Derivaten. |
| CH695217A5 (de) * | 1999-07-14 | 2006-01-31 | Merck Eprova Ag | Verfahren zur Trennung optischer Isomeren von Tetrahydrofolsäureestersalzen und Tetrahydrofolsäure. |
| ITMI20020132A1 (it) | 2002-01-25 | 2003-07-25 | Gmt Fine Chemicals Sa | Processo per l'ottenimento dell'acido (6s)-5,6,7,8-tetraidrofolico |
| WO2005049000A2 (en) | 2003-11-17 | 2005-06-02 | Biomarin Pharmaceutical Inc. | Treatment of phenylketonurias with bh4 |
| CN1748704B (zh) * | 2004-09-15 | 2011-05-04 | 尼普洛株式会社 | 注射用水溶液制剂及其稳定化方法 |
| US20100130500A1 (en) * | 2004-12-08 | 2010-05-27 | Biomarin Pharmaceutical Inc. | Methods and compositions for the treatment of pulmonary hypertension of the newborn |
| SG177613A1 (en) | 2009-07-10 | 2012-03-29 | Linzy O Scott Iii | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
| WO2011100550A2 (en) | 2010-02-12 | 2011-08-18 | Alexander Vuckovic, M.D., Llc | Compositions and methods for treating depression |
| EP2837632B1 (en) | 2012-04-13 | 2016-05-18 | Lianyungang Jinkang Hexin Pharmaceutical Co. Ltd. | Derivatives of triazabicyclo[3.2.1]octane useful for the treatment of proliferative diseases |
| US9629846B1 (en) | 2013-11-14 | 2017-04-25 | Argent Development Group, Llc | Nutritional supplements for women desiring to become pregnant, and pregnant and nursing women |
| US9492421B1 (en) | 2013-11-14 | 2016-11-15 | Argent Development Group, Llc | Nutritional supplements for treatment of iron deficiency anemia |
| WO2016185413A1 (en) | 2015-05-20 | 2016-11-24 | Nestec S.A. | Modified release formulations |
| US10059710B2 (en) | 2016-02-17 | 2018-08-28 | Merck & Cie | Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid |
| WO2018144088A1 (en) | 2016-11-03 | 2018-08-09 | Alexander Vuckovic, M.D., Llc | Compositions and methods for treating depression |
| EP3609895B1 (en) | 2017-03-31 | 2024-10-16 | Merck Patent GmbH | Crystalline sodium salt of 5-methyl-(6s)-tetrahydrofolic acid |
| DK3609894T3 (da) | 2017-03-31 | 2024-09-09 | Merck Patent Gmbh | Krystallinsk natriumsalt af 5-methyl-(6s)-tetrahydrofolsyre |
| EP4501315A1 (en) | 2023-08-04 | 2025-02-05 | Lesaffre et Compagnie | Liquid formulations of folates |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0495204A1 (de) * | 1991-01-16 | 1992-07-22 | EPROVA Aktiengesellschaft | Verfahren zur Herstellung von (6S)- und (6R)-Tetrahydrofolsäure |
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| JPS497416A (zh) * | 1972-05-12 | 1974-01-23 | ||
| US4665176A (en) * | 1984-10-23 | 1987-05-12 | Mitsui Toatsu Chemicals, Incorporated | Process for the preparation of 5,6,7,8-tetrahydrofolic acid |
| GB8621268D0 (en) * | 1986-09-03 | 1986-10-08 | Univ Strathclyde | Separation of substances |
| CH673459A5 (zh) * | 1987-05-15 | 1990-03-15 | Eprova Ag | |
| DE3821875C1 (zh) * | 1988-06-29 | 1990-02-15 | Eprova Ag, Forschungsinstitut, Schaffhausen, Ch | |
| EP0432441B1 (en) * | 1989-12-11 | 1996-06-26 | American Cyanamid Company | Process for the preparation of optically pure diastereoisomers of tetrahydrofolate compounds |
| CH680731A5 (zh) * | 1990-04-12 | 1992-10-30 | Sapec Fine Chemicals | |
| CH683261A5 (it) * | 1991-10-10 | 1994-02-15 | Applied Pharma Res | Procedimento per la preparazione dell'acido metiltetraidrofolico nella forma (6(R,S)(-))N-5 e separazione del diastereoisomero attivo (6(S)(-))N-5) sotto forma di sali. |
| US5198547A (en) * | 1992-03-16 | 1993-03-30 | South Alabama Medical Science Foundation, Usa | Process for N5-formylating tetrahydropteridines |
| US5698693A (en) * | 1992-11-16 | 1997-12-16 | The United States Of America As Represented By The Department Of Health And Human Services | Process of separating the diastereomers of (6R,6S) -5,6,7,8-tetrahydrofolic acid derivatives |
| CH686672A5 (de) * | 1992-12-01 | 1996-05-31 | Cerbios Pharma Sa | Verfahren zur Herstellung von (6S)-5,6,7,8-Tetrahydrofolsaeure. |
| AU2001268035A1 (en) | 2000-03-21 | 2001-10-03 | Bbj Environmental Solutions Inc. | Aqueous cleaning composition with controlled ph |
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| Publication number | Priority date | Publication date | Assignee | Title |
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