WO2008031284A1 - A process for resolution of 5-methyltetrahydrofolic acid and its salification - Google Patents
A process for resolution of 5-methyltetrahydrofolic acid and its salification Download PDFInfo
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- WO2008031284A1 WO2008031284A1 PCT/CN2006/002615 CN2006002615W WO2008031284A1 WO 2008031284 A1 WO2008031284 A1 WO 2008031284A1 CN 2006002615 W CN2006002615 W CN 2006002615W WO 2008031284 A1 WO2008031284 A1 WO 2008031284A1
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- methyltetrahydrofolate
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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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- the present invention relates to the field of organic chemistry, and in particular to a method for the resolution and salt formation of an organic drug (6S)-5-methyltetrahydrofolate from (6R,S)-5-methyltetrahydrofolate.
- (6S)-5-methyltetrahydrofolate N-(5-methyl)-6(S)-5,6,7,8,-tetrahydropteroyl-L-glutamic acid, abbreviated (6S)-5-MTHF, the structural formula is as follows:
- (6S)-5-methyltetrahydrofolate is the predominant form of tissue and blood folic acid. Participate in many important biochemical reactions in the body (such as biosynthesis of sputum and thymine).
- the naturally occurring 5-MTHF is only S-type, while the synthetic R-form is biochemically inactive and excreted through the kidneys.
- (6S)-5-MTHF does not require a cumbersome enzymatic metabolic step in the human body and can be directly utilized. (Zhang Yue et al, Fine and Chemical, 13, (22), 13, 2005).
- (6S)-5-MTHF has two important roles as a drug: in oncology treatment, combined with methotrexate (Methotrexate) and 5-fluorouracil (5-Fluorouracil) for treatment of tumor; treatment by folic acid Caused by anemia.
- Methotrexate methotrexate
- 5-fluorouracil 5-fluorouracil
- 6S-5-MTHF is the only drug in folic acid that can pass through the blood-brain barrier and has the effect of preventing Alzheimer's disease (Alzheimer's disease).
- Synthetic (6S)-5-MTHF is the main active ingredient of pharmaceuticals and food additives, preventing fetal neural tube defects, arteriosclerosis, treating megaloblastic anemia And so on.
- (6S)-5-MTHF is difficult and expensive.
- the synthesis method is a hydrogenation and methylation reaction of folic acid to prepare a (6R,S) racemate (Federico.G et al, GB 1572 138, 1977; U.S. 5,124,452, 1978). It has been suggested that chemical resolution of the corresponding enantiomer 6R-acid or 6S-acid is not possible. (Clinical Science and Molecular Medicine 45, 625-631, 1973).
- the present invention proposes an organic base ⁇ -phenethylamine and its pair which are readily available in the market.
- a method for the preparation of (6S)-5-methyltetrahydrofolate by resolution of a racemate (6R,S)-5-methyltetrahydrofolate, characterized by a resolving agent, followed by alkaline earth metal hydroxide A (6S)-5-methyltetrahydrofolate calcium salt or a magnesium or zinc salt is prepared from an object or an oxide such as calcium hydroxide or magnesium hydroxide or zinc oxide.
- the present invention is further precipitated and crystallized with 95% ethanol or anhydrous ethanol, preferably 95% ethanol.
- the present invention relates to a process for the preparation of (6S)-5-methyltetrahydrofolate, which is obtained by resolution from a racemate by the use of an organic base, wherein the organic base is alpha-phenethylamine or (+) or (- Enantiomer of ⁇ ; phenethylamine is dissolved in water, heated to 20-80 ° C, stirred a small amount of (6R, S)-5-MTHF aqueous suspension, stirred and gradually dissolved completely Salt formation, the salt is cooled to 20 ° C, and the salt formed by the 6S-acid is filtered and separated; the salt formed by the 6S-acid is suspended in water, and the sodium hydroxide solution is added to dissolve the sodium salt; 20-60 ⁇ , then add calcium hydroxide, a small amount of stirring to complete the addition until dissolved; then add 95% ethanol to produce a precipitate, that is, the (6S)-5-methyltetrahydrofolate calcium salt is prepared.
- the organic base is al
- ⁇ -phenethylamine may be a racemate or a single optical isomer, and (-)- ⁇ -phenethylamine is preferred.
- the racemate (6R, S 5-MTHF is prepared by Calcium Falinate from Suzhou Surui Pharmaceutical Co., Ltd., Jiangsuzhou, and is prepared by neutralization reduction; ⁇ -phenylethylamine and enantiomer are Provided by Jiangsu Changzhou Kerunda Chemical Co., Ltd.
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Abstract
A process for preparation of calcium (6S)-5- methyltetrahydrofolate, including the following steps: resolution of racemic (6R,S)-5-methyltetrahydrofolic acid using α-phenethylamine to obtain (6S)-5- methyltetrahydrofolic acid and salification of (6S)-5- methyltetrahydrofolic acid with alkaline earth metal hydroxide especially calcium hydroxide to get calcium (6S)-5- methyltetrahydrofolate.
Description
5-甲基四氢叶酸的拆分及其成盐方法 技术领域 Resolution of 5-methyltetrahydrofolate and its salt formation method
本发明涉及有机化学领域， 具体而言涉及到有机药物 (6S)-5- 甲基四氢叶酸从 (6R,S)-5-甲基四氢叶酸的拆分及成盐的方法。 The present invention relates to the field of organic chemistry, and in particular to a method for the resolution and salt formation of an organic drug (6S)-5-methyltetrahydrofolate from (6R,S)-5-methyltetrahydrofolate.
背景技术 ' Background technique '
(6S)-5-甲基四氢叶酸的化学名称为 N-(5-甲基) -6(S)-5，6,7，8，-四氢 蝶酰基 -L-谷氨酸， 简称 (6S)-5-MTHF， 结构式如下： The chemical name of (6S)-5-methyltetrahydrofolate is N-(5-methyl)-6(S)-5,6,7,8,-tetrahydropteroyl-L-glutamic acid, abbreviated (6S)-5-MTHF, the structural formula is as follows:
(6S)-5-甲基四氢叶酸是组织和血液叶酸的主要形式。参与体内多 种重要的生化反应（如嘌呤和胸腺嘧啶的生物合成等）。 天然存在的 5-MTHF仅为 S型，而合成的 R型在生物化学上无活性的，通过肾脏 排出体外。 （6S)-5-MTHF在人体内不需要经过繁琐的酶促代谢步骤， 可以直接被利用。 （张越等， 精细和化学品， 13,(22),13，2005)。 (6S)-5-methyltetrahydrofolate is the predominant form of tissue and blood folic acid. Participate in many important biochemical reactions in the body (such as biosynthesis of sputum and thymine). The naturally occurring 5-MTHF is only S-type, while the synthetic R-form is biochemically inactive and excreted through the kidneys. (6S)-5-MTHF does not require a cumbersome enzymatic metabolic step in the human body and can be directly utilized. (Zhang Yue et al, Fine and Chemical, 13, (22), 13, 2005).
较先， （6S)-5-MTHF作为药物具有两个方面的重要作用： 在肿瘤 学治疗上，联合用甲氨蝶呤 (Methotrexate)和 5-氟尿嘧啶 (5-Fluorouracil) 治疗肿瘤； 治疗由叶酸引起的贫血。 最近的研究表明： （6S)-5-MTHF 是叶酸类药物中唯一可以透过血脑屏障， 具有防治阿尔茨海默（老年 痴呆症）的作用的药物。合成的 (6S)-5-MTHF是主要药物活性成份和 食品添加剂， 有预防胎儿神经管缺陷，动脉硬化， 治疗巨幼细胞贫血
等作用。 First, (6S)-5-MTHF has two important roles as a drug: in oncology treatment, combined with methotrexate (Methotrexate) and 5-fluorouracil (5-Fluorouracil) for treatment of tumor; treatment by folic acid Caused by anemia. Recent studies have shown that: (6S)-5-MTHF is the only drug in folic acid that can pass through the blood-brain barrier and has the effect of preventing Alzheimer's disease (Alzheimer's disease). Synthetic (6S)-5-MTHF is the main active ingredient of pharmaceuticals and food additives, preventing fetal neural tube defects, arteriosclerosis, treating megaloblastic anemia And so on.
一般而言， 要从人体或动物组织和血液中提取， 分离和纯化 In general, it is extracted, isolated and purified from human or animal tissues and blood.
(6S)-5-MTHF是有难度的， 且成本昂贵。而应用合成方法是由叶酸进 行氢化和甲基化反应而制备得到 (6R，S)外消旋体（Federico.G etal,GB 1572 138,1977； U.S 5,124,452,1978)。 曾经有人认为用化学方法拆分 成相应的对映体 6R-酸或 6S-酸是不可能的。 （Clinical Science and Molecular Medicine 45,625-631,1973) . (6S)-5-MTHF is difficult and expensive. The synthesis method is a hydrogenation and methylation reaction of folic acid to prepare a (6R,S) racemate (Federico.G et al, GB 1572 138, 1977; U.S. 5,124,452, 1978). It has been suggested that chemical resolution of the corresponding enantiomer 6R-acid or 6S-acid is not possible. (Clinical Science and Molecular Medicine 45, 625-631, 1973).
而 Klaus.S等提出了以有机碱 N-乙基 -2-氨甲基吡咯垸或它的对 映体为拆分剂为特征的从外消旋体 (6R,S)-5-甲基四氢叶酸制备 (6S)-5-甲基四氢叶酸的方法 （U.S 5,457,202,1992 ) , 为拆分 (6R,S)-5-MTHF开创了先例， 但由于 N-乙基 -2-氨甲基吡咯尤其是 (+) 或 (-)的对映体市场价格较贵， 限制了它的应用；有的文献在生成钙盐 时用的是氯化钙 （Fedrico Qetal,U.S 5,124,452,1992) , 最终在产品 (6S)-5-MTHF-Ca 中易残留大量的氯离子而造成不符合药品或食品添 加剂的氯离子限量检査。 Klaus.S et al. proposed a racemic (6R,S)-5-methyl group characterized by the organic base N-ethyl-2-aminomethylpyrrole or its enantiomer as a resolving agent. Method for preparing (6S)-5-methyltetrahydrofolate by tetrahydrofolate (US 5,457,202,1992), setting a precedent for resolution of (6R,S)-5-MTHF, but due to N-ethyl-2-ammonia The enantiomers of methylpyrrole, especially (+) or (-), are more expensive in the market and limit its use; some literatures use calcium chloride in the formation of calcium salts (Fedrico Qetal, US 5,124,452, 1992). Finally, a large amount of chloride ions are easily left in the product (6S)-5-MTHF-Ca, resulting in a chloride ion limit inspection that does not comply with drugs or food additives.
发明内容 Summary of the invention
为了避免现有拆分 (6R,S)-5-MTHF和成盐的工艺过程中存在的 缺陷和不足之处，本发明提出了以市场易得的有机碱 α-苯乙胺和它的 对映体为拆分剂为特征的从外消旋体 (6R,S)-5-甲基四氢叶酸拆分制 备 (6S)-5-甲基四氢叶酸的方法， 进而以碱土金属氢氧化物或氧化物， 例如氢氧化钙或氢氧化镁或氧化锌制成 (6S)-5-甲基四氢叶酸钙盐或 镁盐或锌盐。
针对上述现有文献 (6S)-5-MTHF和其盐制备方法的缺陷和不足 之处， 我们发现了一个能拆分 (6R，S 5-MTHF的有机碱及其光学对映 体，进而发现用碱土金属的氢氧化物或氧化物例如氢氧化钙或氢氧化 镁或氧化锌 盐的制备 (6S)-5-MTHF盐的方法。 In order to avoid the defects and deficiencies existing in the prior process of splitting (6R,S)-5-MTHF and salt formation, the present invention proposes an organic base α-phenethylamine and its pair which are readily available in the market. A method for the preparation of (6S)-5-methyltetrahydrofolate by resolution of a racemate (6R,S)-5-methyltetrahydrofolate, characterized by a resolving agent, followed by alkaline earth metal hydroxide A (6S)-5-methyltetrahydrofolate calcium salt or a magnesium or zinc salt is prepared from an object or an oxide such as calcium hydroxide or magnesium hydroxide or zinc oxide. In view of the defects and deficiencies of the above-mentioned existing literature (6S)-5-MTHF and its salt preparation method, we have found that an organic base and its optical enantiomers capable of being resolved (6R, S 5-MTHF) can be found A method of preparing a (6S)-5-MTHF salt using an alkaline earth metal hydroxide or an oxide such as calcium hydroxide or magnesium hydroxide or a zinc oxide salt.
鉴于 (6S)-5-MTHF-Ca在水中不易结晶沉淀， 本发明进一步用 95 %乙醇， 也可以用无水乙醇使之沉淀结晶， 优选 95%乙醇。 In view of the fact that (6S)-5-MTHF-Ca is not easily crystallized in water, the present invention is further precipitated and crystallized with 95% ethanol or anhydrous ethanol, preferably 95% ethanol.
本发明涉及制备 (6S)-5-甲基四氢叶酸的工艺过程， 通过应用有机 碱从外消旋体中拆分得到产物， 其中有机碱是 α-苯乙胺或 (+)或 (-)的对 映体； 将 α-苯乙胺溶于水， 加热至 20-80°C， 搅拌下， 少量多次加入 (6R,S)-5-MTHF水悬浮液， 搅拌逐步使之溶解完全成盐， 将盐冷却至 20 °C , 将 6S-酸生成的盐结晶过滤而分离出来； 再将 6S-酸生成的盐悬 浮于水中， 加入氢氧化钠溶液， 使之成钠盐溶解； 在 20-60Ό下， 再加 入氢氧化钙， 少量多次搅拌加完，直至溶解为止； 然后加入 95%乙醇， 使产生沉淀， 即制备得 (6S)-5-甲基四氢叶酸钙盐。 The present invention relates to a process for the preparation of (6S)-5-methyltetrahydrofolate, which is obtained by resolution from a racemate by the use of an organic base, wherein the organic base is alpha-phenethylamine or (+) or (- Enantiomer of α; phenethylamine is dissolved in water, heated to 20-80 ° C, stirred a small amount of (6R, S)-5-MTHF aqueous suspension, stirred and gradually dissolved completely Salt formation, the salt is cooled to 20 ° C, and the salt formed by the 6S-acid is filtered and separated; the salt formed by the 6S-acid is suspended in water, and the sodium hydroxide solution is added to dissolve the sodium salt; 20-60 Ό, then add calcium hydroxide, a small amount of stirring to complete the addition until dissolved; then add 95% ethanol to produce a precipitate, that is, the (6S)-5-methyltetrahydrofolate calcium salt is prepared.
上述已经提到的 α-苯乙胺可以是外消旋体， 也可以是单一光学异 构体， 而 (-)-α-苯乙胺为首选。 The above-mentioned α-phenethylamine may be a racemate or a single optical isomer, and (-)-α-phenethylamine is preferred.
外消旋体 (6R,S 5-MTHF是由江苏省苏州市苏瑞医药化工有限公 司提供亚叶酸钙（Calcium Falinate), 经中和还原而制备； α-苯乙胺及 对映体是由江苏省常州科润达化工有限公司提供。 The racemate (6R, S 5-MTHF is prepared by Calcium Falinate from Suzhou Surui Pharmaceutical Co., Ltd., Jiangsu Province, and is prepared by neutralization reduction; α-phenylethylamine and enantiomer are Provided by Jiangsu Changzhou Kerunda Chemical Co., Ltd.
具体实施方式 detailed description
下面通过实施例对本发明作进一步说明。 应该理解的是，本 发明实施例所述制备方法仅仅是用于说明本发明,而不是对本发 明的限制,在本发明的构思提前下对本发明制备方法的简单改进 都属于对本发明要求保护的范围。 除非另有说明，本发明中的百
分数是重量百分数 实施例一、 The invention is further illustrated by the following examples. It should be understood that the preparation methods described in the embodiments of the present invention are only for explaining the present invention, and are not intended to limit the present invention. The simple improvement of the preparation method of the present invention in advance of the concept of the present invention belongs to the scope claimed by the present invention. . Unless otherwise stated, the hundred in the present invention The score is the weight percentage of the first embodiment.
在 1000ml三颈瓶中加入 56.0g(0.4mol) (±)-α-苯乙胺和 300ml 水， 再加入含有 107.1g(0.2mol) (6R，S)-5-MTHF的 300ml水溶液， 搅 拌， 加热反应至 80°C， 冷却至 60°C， 过滤除去微溶的 6R-酸盐。 将 滤液加入活性炭脱色， 过滤， 冷却至 20° (， 有结晶产生， 真空过滤， 得 6S-酸盐结晶 42.8g， 收率 36.9%， [α]20 ο: +22.1。 (C=l , 乙醇)。 56.0 g (0.4 mol) of (±)-α-phenethylamine and 300 ml of water were added to a 1000 ml three-necked flask, and then a solution of 107.1 g (0.2 mol) of (6R,S)-5-MTHF in 300 ml of water was added and stirred. The reaction was heated to 80 ° C, cooled to 60 ° C, and the sparingly soluble 6R-acid salt was removed by filtration. The filtrate was decolorized by adding activated carbon, filtered, and cooled to 20° (crystallized, vacuum filtered to obtain 42.8 g of 6S-acid salt crystals, yield 36.9%, [α] 20 ο : +22.1. (C=l, ethanol ).
将上述得到得 6S-酸盐悬浮于 200ml水中，分次加入 5.9g(0.08mol) 氢氧化钙粉末， 边搅拌， 边加热至 40°C， 至全部溶解； 边冷却边加 入 95 %乙醇， 逐步有白色或淡黄色沉淀产生， 过滤干燥， 得 (6S)-5-MTHF · Ca · 5H20 39.1g,—次结晶收率 95.1%， [a]20 D:+34.5° (01,H20)光学纯度 98.5%。 实施例二、 ， The 6S-acid salt obtained above was suspended in 200 ml of water, and 5.9 g (0.08 mol) of calcium hydroxide powder was added in portions, and the mixture was heated to 40 ° C while stirring to dissolve all; while adding 95% ethanol while cooling, stepwise A white or light yellow precipitate was obtained, which was filtered and dried to give (6S)-5-MTHF · Ca · 5H 2 0 39.1 g, - crystallization yield 95.1%, [a] 20 D : +34.5 ° (01, H 2 0) Optical purity 98.5%. Embodiment 2,
在 1000ml 的三颈瓶中加入 28.0g(0.2mol) (-)-a-苯乙胺和水 150ml,再加入含有 107.1g(0.2mol)的 (6R,S)-5-MTHF的 300ml水溶液， 加热至 75Ό , 冷却至 55°C， 过滤除去未溶解的 6R-酸盐， 将母液加 入活性炭， 过滤， 冷却至 18-20°C， 有结晶产生， 真空过滤， 得结晶 6S-酸盐 47.4g， 收率 40.8%， [a]20 D: +22.5° (C=l， 乙醇)。 28.0 g (0.2 mol) of (-)-a-phenylethylamine and 150 ml of water were added to a 1000 ml three-necked flask, and then a solution of 107.1 g (0.2 mol) of (6R,S)-5-MTHF in 300 ml of water was added. Heat to 75 ° C, cool to 55 ° C, remove undissolved 6R-acid salt by filtration, add the mother liquor to activated carbon, filter, cool to 18-20 ° C, crystallize, vacuum filter, give crystal 6S-acid salt 47.4g , yield 40.8%, [a] 20 D : +22.5° (C=l, ethanol).
将上述得到的 6S-酸盐悬浮于水中， 加入 10%氢氧化钠溶液， 使 PH值为 8-9，. 使温度不超过 30° (：， 然后分次加入 7.4g(0.1mol)氢氧化
钙粉末， 边搅拌边温热， 温度不超过 40°C， 应全部溶解， 搅拌下加 入 95 %乙醇， 有白色沉淀或淡黄色沉淀产生， 过滤干燥， 得 46.4g (6S)-5-MTHF · Ca · 5H20， 一次结晶收率 96.2%， [a]20 D: +35.Γ (C=1,H20)光学纯度 99.0%。 实施例三、 The 6S-acid salt obtained above was suspended in water, and a 10% sodium hydroxide solution was added to make a pH of 8-9. The temperature was not more than 30° (:, and then 7.4 g (0.1 mol) of hydroxide was added in portions. Calcium powder, warm while stirring, the temperature does not exceed 40 ° C, should be completely dissolved, add 95% ethanol with stirring, a white precipitate or a pale yellow precipitate, filtered and dried to give 46.4g (6S)-5-MTHF · Ca · 5H 2 0, primary crystallization yield 96.2%, [a] 20 D : +35. Γ (C = 1, H 2 0) optical purity 99.0%. Embodiment 3
在 1000ml 的三颈瓶中加入 28.0g(0.2mol) (+)-a-苯乙胺和水 150ml,再加入含有 107.1g(0.2mol)的 (6R，S)-5-MTHF的 300ml水溶液， 操作同实施例一，得 44.4g6S-酸盐，收率 38.2%， [a]20 D: +21.8。 (C=l , 乙醇)。 28.0 g (0.2 mol) of (+)-a-phenethylamine and 150 ml of water were added to a 1000 ml three-necked flask, and then a solution of 107.1 g (0.2 mol) of (6R,S)-5-MTHF in 300 ml of water was added. The operation was the same as in Example 1 to obtain 44.4 g of 6S-acid salt, yield: 38.2%, [a] 20 D : +21.8. (C=l, ethanol).
将上述得到的 6S-酸盐悬浮于 200ml水中， 加入到碳酸钠水溶液 中， 使溶液的 PH值为 7.5-8.5，然后分次加入 O.lmol氢氧化钙粉末， 边搅拌边温热， 温度不超过 40'C， 应全部溶解， 搅拌下， 加入 95% 乙醇， 有白色沉淀或淡黄色沉淀产生， 过滤干燥， 得 45.2g (6S)-5-MTHF - Ca · 5¾0, 一次结晶收率 96.1 %， [a]20 D: +34.5° (C=1,H20) 光学纯度 99.0%。
The 6S-acid salt obtained above was suspended in 200 ml of water, added to an aqueous solution of sodium carbonate, and the pH of the solution was 7.5-8.5, and then 0.1 mol of calcium hydroxide powder was added in portions, and the mixture was warmed while stirring, and the temperature was not More than 40'C, should be dissolved completely, add 95% ethanol, add white precipitate or light yellow precipitate, and filter to dry, get 45.2g (6S)-5-MTHF - Ca · 53⁄40, primary crystallization yield 96.1% , [a] 20 D : +34.5° (C=1, H 2 0) Optical purity 99.0%.
Claims
1. 一种应用有机碱拆分外消旋体 (6R,S 5-甲基四氢叶酸制备 (6S)-5-甲基四氢叶酸， 再用碱土金属氢氧化物或氧化物成盐制备 (6S)-5-甲基四氢叶酸钙的方法。 1. Preparation of (6S)-5-methyltetrahydrofolate by using an organic base to separate a racemate (6R, S 5-methyltetrahydrofolate, and then preparing with an alkaline earth metal hydroxide or oxide) Method for (6S)-5-methyltetrahydrofolate.
2. 根据权利要求 1 的方法， 其中有机碱是 (± α-苯乙胺、 （+)-α- 苯乙胺或 (-)-α-苯乙胺。 2. A process according to claim 1 wherein the organic base is (± alpha-phenethylamine, (+)-α-phenethylamine or (-)-α-phenethylamine.
3. 根据权利要求 1的方法， 其中碱土金属的氢氧化物或氧化物 是氢氧化钙或氢氧化镁或氧化锌。 3. A method according to claim 1 wherein the hydroxide or oxide of the alkaline earth metal is calcium hydroxide or magnesium hydroxide or zinc oxide.
4. 根据权利要求 1的方法， 其中 (6S)-5-甲基四氢叶酸成盐的过 程中先溶解于水， 后用 95%乙醇或无水乙醇沉淀的方法。
The method according to claim 1, wherein the (6S)-5-methyltetrahydrofolate is first dissolved in water in the form of a salt, followed by precipitation with 95% ethanol or absolute ethanol.
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| CN2006100415414A CN101143863B (en) | 2006-09-13 | 2006-09-13 | Resolution for 5-methyltetrahydrofolic acid and salifying method thereof |
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| WO2008031284A1 true WO2008031284A1 (en) | 2008-03-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/CN2006/002615 WO2008031284A1 (en) | 2006-09-13 | 2006-10-08 | A process for resolution of 5-methyltetrahydrofolic acid and its salification |
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| Country | Link |
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| CN (1) | CN101143863B (en) |
| WO (1) | WO2008031284A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103333A1 (en) * | 2008-02-20 | 2009-08-27 | Gnosis S.P.A. | Process for the diastereoisomeric resolution of 5-methyltetrahydrofolic acid |
| WO2015193778A1 (en) * | 2014-06-16 | 2015-12-23 | Mylan Laboratories Ltd. | Crystalline form of levomefolate calcium |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516247A (en) * | 2010-12-15 | 2012-06-27 | 连云港金康医药科技有限公司 | A-type calcium L-5-methyltetrahydrofolate polymorphism and preparation method thereof |
| CN104557937B (en) * | 2012-01-20 | 2017-03-08 | 连云港金康和信药业有限公司 | (6S) 5 methyl tetrahydrofolate salt crystal formations and preparation method thereof |
| CN102702200B (en) * | 2012-04-25 | 2014-11-12 | 连云港金康和信药业有限公司 | (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof |
| CN102584826B (en) * | 2012-01-20 | 2015-04-29 | 连云港金康医药科技有限公司 | (6S)-5-methyl tetrahydrofolate crystal form and preparation method thereof |
| KR101673979B1 (en) * | 2012-04-13 | 2016-11-08 | 리안윤강 진강 해신 파머수티컬 코. 엘티디. | Compound jk12a and preparation thereof |
| CN103664945B (en) * | 2012-09-07 | 2016-01-20 | 南京莱因医药科技有限公司 | The preparation method of L-5-methyl tetrahydrofolate amino acid salts |
| CN103214487A (en) * | 2013-04-12 | 2013-07-24 | 张家港威胜生物医药有限公司 | Synthesis of important medical chemical raw material (6S)-5-methyl tetrahydrofolate |
| CN109164182B (en) * | 2018-09-19 | 2021-06-11 | 无锡紫杉药业有限公司 | Method for analyzing and detecting optical purity of L-tetrahydrofolic acid p-toluenesulfonate (6S) |
| CN111620777A (en) * | 2020-06-10 | 2020-09-04 | 成都蓝蜻蜓生物技术有限公司 | Resolution method of (S) -1,2,3, 4-tetrahydro-1-naphthoic acid |
| CN111635405A (en) * | 2020-07-02 | 2020-09-08 | 无锡紫杉药业有限公司 | Production process of calcium tetrahydrofolate preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5457202A (en) * | 1991-11-11 | 1995-10-10 | Knoll Aktiengesellschaft | Resolution of 5-methyltetrahydrofolic acid |
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2006
- 2006-09-13 CN CN2006100415414A patent/CN101143863B/en not_active Expired - Fee Related
- 2006-10-08 WO PCT/CN2006/002615 patent/WO2008031284A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5457202A (en) * | 1991-11-11 | 1995-10-10 | Knoll Aktiengesellschaft | Resolution of 5-methyltetrahydrofolic acid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103333A1 (en) * | 2008-02-20 | 2009-08-27 | Gnosis S.P.A. | Process for the diastereoisomeric resolution of 5-methyltetrahydrofolic acid |
| WO2015193778A1 (en) * | 2014-06-16 | 2015-12-23 | Mylan Laboratories Ltd. | Crystalline form of levomefolate calcium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101143863A (en) | 2008-03-19 |
| CN101143863B (en) | 2010-08-11 |
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