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WO2009046581A1 - A process for resolution of (6r,s)-5-formyltetrahydrofolic acid and its salification - Google Patents

A process for resolution of (6r,s)-5-formyltetrahydrofolic acid and its salification Download PDF

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WO2009046581A1
WO2009046581A1 PCT/CN2007/003074 CN2007003074W WO2009046581A1 WO 2009046581 A1 WO2009046581 A1 WO 2009046581A1 CN 2007003074 W CN2007003074 W CN 2007003074W WO 2009046581 A1 WO2009046581 A1 WO 2009046581A1
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cho
thf
tetrahydrofolate
formyl
salt
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Chinese (zh)
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Xin Chen
Yicheng Mei
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Nanjing Rally Biochemical Inc
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    • 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

Definitions

  • the present invention relates to the field of organic pharmaceutical chemistry, and in particular to a method for the resolution of an organic drug (6R,S)-5-formyl-tetrahydrofolate and its salt formation.
  • (6S)-5-formyl-tetrahydrofolate chemical name N-5-formyl (6S)-5,6,7,8-tetrahydrofolate, ie (6S)-5-CHO-THF, abbreviation (6S)-leucovorin, a configuration that occurs naturally (eg, in the liver).
  • 6S calcium salt structure is as follows -
  • the commercially available drug leucovorin is a calcium salt of folinic acid in the (6R, S) configuration
  • medical research has shown that: chemically synthesized diastereomer (6R, S)-colate is used in the treatment of cancer. It is half of natural (6S)-folate, but the toxicity is twice.
  • 6R, S chemically synthesized diastereomer
  • the object of the present invention is to establish a simple and industrially suitable process for the preparation of (6S 5-CHO-THF ⁇ Ca).
  • the (6R,S)-CHO-THF ⁇ Ca aqueous solution can be salted with R-(+)-a-phenethylamine to precipitate the corresponding (6R)-CHO-THF ⁇ ⁇ -(+)- ⁇ - Phenylethylamine salt, removed by filtration.
  • Add cyclohexane to the filtrate and adjust the pH to 3 ⁇ 4 with hydrochloric acid (concentrated hydrochloric acid: water 1: 1), add cyclohexane, separate the organic layer (cyclohexane), and distill off the cyclohexane after vacuum distillation.
  • An aqueous calcium chloride solution was isolated by ethanol to obtain a (6S)-5-CHO-THF calcium salt.
  • organic base is used as a resolving agent as an optical isomer of (+) or N-ethyl-2-aminomethylpyrrole.
  • the organic solvent for extracting (6S)-5-CHO-THF is toluene, ethyl acetate, or cyclohexane, preferably cyclohexane.
  • the alcohol which is isolated from the (6S)-5-CHO-THF salt may also be methanol, ethanol, isopropanol or ethylene glycol, preferably ethanol.
  • (6S)-5-CHO-THF calcium, magnesium or sodium salt can also be prepared by using Ca(OH) 2 , Mg 2 Cl, dilute NaOH solution.
  • the drug for treating Alzheimer's disease (6S)-5-methyl-tetrahydrofolate (6S-5-MTHF ⁇ Ca) can be prepared. .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for resolution of (6R,S)-5-formyltetrahydrofolate, which comprises using optically active organic base as resolving agent to salify, and filtering, acidizing, extracting by organic solvent, adding CaCl2, Ca (OH)2, MgCl2 or NaOH aqueous solution to obtain (6S)-5-formyltetrahydrofolate, isolating and crystalizing by alcohol.

Description

(6R，S)-5-甲酰 -四氢叶酸的拆分及其成盐的方法  Resolution of (6R,S)-5-formyl-tetrahydrofolate and method for forming salt thereof

发明领域  Field of invention

本发明涉及有机药物化学领域， 具体而涉及到一种有机药物 (6R,S)-5-甲酰-四氢叶酸的拆分及其成盐的方法。  The present invention relates to the field of organic pharmaceutical chemistry, and in particular to a method for the resolution of an organic drug (6R,S)-5-formyl-tetrahydrofolate and its salt formation.

背景技术 Background technique

(6S)-5-甲酰 -四氢叶酸， 化学名称为 N-5-甲酰基 (6S)-5，6，7，8-四氢 叶酸， 即 (6S)-5-CHO-THF， 简称 (6S)-亚叶酸， 是天然存在 (例如肝中) 的构型。 其钙盐结构式如下-  (6S)-5-formyl-tetrahydrofolate, chemical name N-5-formyl (6S)-5,6,7,8-tetrahydrofolate, ie (6S)-5-CHO-THF, abbreviation (6S)-leucovorin, a configuration that occurs naturally (eg, in the liver). Its calcium salt structure is as follows -

Figure imgf000002_0001
目前， 市场上供应的药物亚叶酸钙全是 (6R,S)构型的亚叶酸的钙 盐， 医药学研究表明： 化学合成的非对映体 (6R，S)-亚叶酸钙在治疗癌 症中是天然 (6S)-亚叶酸钙的一半,而毒性却是二倍。（RM.Sirotanketal., Biochemical Pharmacology 28,2993-2997, 1979;C.Temple etal.,Cancer Treatment Reports 65， 1117- 1119, 1981 )。
Figure imgf000002_0001
At present, the commercially available drug leucovorin is a calcium salt of folinic acid in the (6R, S) configuration, and medical research has shown that: chemically synthesized diastereomer (6R, S)-colate is used in the treatment of cancer. It is half of natural (6S)-folate, but the toxicity is twice. (RM. Sirotanketal., Biochemical Pharmacology 28, 2993-2997, 1979; C. Temple et al., Cancer Treatment Reports 65, 1117-1119, 1981).

因此， 在合成 (6R,S)-5-CHO-THF-Ca时， 拆分获得与天然的活性 物质一致的 (6S)-5-CHO-THF及其盐的十分必要的。  Therefore, in the synthesis of (6R,S)-5-CHO-THF-Ca, it is necessary to obtain (6S)-5-CHO-THF and its salt in agreement with the natural active substance.

为 了 从（6R，S)-5-CHO-THF 拆分得 到 (6S)-5-CHO-THF ， Hans.R.Muller等人 (U.S. 5,010,194,1991)在 (6R，S)-5-CHO-THF盐水溶 液中加入无机酸或有机酸的水溶液或碱金属， 碱土金属盐或铵盐后， 由 占优势 的 非对 映 体（6R)-5-CHO-THF 盐组 成相 应 的 (6R)-5-CHO-THF盐， 将析出的相应的 (6R)-5-CHO-THF盐过滤除去， 再用离析方法将滤液中 的（6S 5-CHO-THF 盐得到固体 (6S)-5-CHO-THF盐。 而该专利中提到的 "铵盐"仅为： 吡咯垸鐺， 哌啶鎗和吗啉鎿盐。 In order to obtain (6S)-5-CHO-THF from (6R,S)-5-CHO-THF, Hans. R. Muller et al. (US 5,010,194,1991) adding an aqueous solution of an inorganic or organic acid or an alkali metal, alkaline earth metal or ammonium salt to an aqueous solution of (6R,S)-5-CHO-THF salt, The advantageous diastereomer (6R)-5-CHO-THF salt constitutes the corresponding (6R)-5-CHO-THF salt, and the corresponding (6R)-5-CHO-THF salt precipitated is removed by filtration and reused. Separation method The 6S 5-CHO-THF salt in the filtrate gave a solid (6S)-5-CHO-THF salt. The "ammonium salt" mentioned in the patent is only: pyrrole oxime, piperidine gun and鎿 鎿 salt.

发明内容 Summary of the invention

本发明的目的是确立一种制备 (6S 5-CHO-THF · Ca 的简单的和 适于工业上使用的方法。  The object of the present invention is to establish a simple and industrially suitable process for the preparation of (6S 5-CHO-THF · Ca).

令人惊奇地发现： 向 (6R，S) -CHO-THF · Ca水溶液中加入有机碱 S-(-)-a-苯乙胺，. 析出相应的 (6S)-CHO-THF · S-(-)-a-苯乙胺盐沉淀， 将该盐溶于环己烷用盐酸 (浓盐酸:水 = 1 :1)调 pH到 3〜4,加入有机 溶剂环己垸。 分取有机层 (环己垸）， 减压蒸去环己垸， 加入氯化钙水 溶液，乙醇离析,得到 (6S)-5-CHO-THF钙盐。  Surprisingly, it was found that the organic base S-(-)-a-phenethylamine was added to the aqueous solution of (6R,S)-CHO-THF·Ca, and the corresponding (6S)-CHO-THF·S-( Precipitation of -)-a-phenethylamine salt, dissolving the salt in cyclohexane, adjusting the pH to 3 to 4 with hydrochloric acid (concentrated hydrochloric acid: water = 1:1), and adding an organic solvent to cyclohexanone. The organic layer (cyclohexane) was separated, the cyclohexane was distilled off under reduced pressure, and aqueous calcium chloride solution was added thereto, and ethanol was isolated to obtain (6S)-5-CHO-THF calcium salt.

另外也可以用 R-(+)-a-苯乙胺将 (6R,S) -CHO-THF · Ca水溶液成 盐， 析出相应的 (6R)-CHO-THF · Ε -(+)-α-苯乙胺盐， 过滤除去。 在滤 液中加入环己垸用盐酸 (浓盐酸：水 = 1： 1 )调 pH到 3〜4，加入环己垸， 分取有机层 (环己烷)， 减压蒸去环己垸， 加入氯化钙水溶液， 用乙醇 离析， 得到 (6S)-5-CHO-THF钙盐。  Alternatively, the (6R,S)-CHO-THF·Ca aqueous solution can be salted with R-(+)-a-phenethylamine to precipitate the corresponding (6R)-CHO-THF · Ε -(+)-α- Phenylethylamine salt, removed by filtration. Add cyclohexane to the filtrate and adjust the pH to 3~4 with hydrochloric acid (concentrated hydrochloric acid: water = 1: 1), add cyclohexane, separate the organic layer (cyclohexane), and distill off the cyclohexane after vacuum distillation. An aqueous calcium chloride solution was isolated by ethanol to obtain a (6S)-5-CHO-THF calcium salt.

进一步地， 有机碱作为拆分剂还有 (+)或 的 N-乙基- 2-氨甲基吡 咯垸二个的光学异构体。 提取 (6S)-5-CHO-THF的有机溶剂是甲苯， 乙酸乙酯， 或环己烷， 优选环己烷。 Further, the organic base is used as a resolving agent as an optical isomer of (+) or N-ethyl-2-aminomethylpyrrole. The organic solvent for extracting (6S)-5-CHO-THF is toluene, ethyl acetate, or cyclohexane, preferably cyclohexane.

离析 (6S)-5-CHO-THF盐的醇类也可以使用甲醇， 乙醇， 异丙醇， 或乙二醇， 优选乙醇。  The alcohol which is isolated from the (6S)-5-CHO-THF salt may also be methanol, ethanol, isopropanol or ethylene glycol, preferably ethanol.

同样的方法， 用 Ca(OH)2，Mg2Cl,稀 NaOH溶液也可以制成相应的 (6S)-5-CHO-THF钙， 镁或钠盐。 In the same manner, the corresponding (6S)-5-CHO-THF calcium, magnesium or sodium salt can also be prepared by using Ca(OH) 2 , Mg 2 Cl, dilute NaOH solution.

本发明以 (6S)-5-CHO-THF * Ca经还原反应后， 即可制备治疗老 年痴呆症的药物 (6S)-5-甲基 -四氢叶酸钙 (6S-5-MTHF · Ca)。  In the present invention, after the reduction reaction of (6S)-5-CHO-THF*Ca, the drug for treating Alzheimer's disease (6S)-5-methyl-tetrahydrofolate (6S-5-MTHF·Ca) can be prepared. .

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 of 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. . The percentages in the present invention are percentages by weight unless otherwise stated. Embodiment 1

在反应瓶中加入（6R，S)-5-CHO-THF · Ca 102.3g(0.2mol) , 水 300ml, S-(-)-a-苯乙胺 28.0g(0.2mol)，加热至 70°C， 使全溶， 冷至 10°C， 有结晶析出， 过滤得到 (6S)-5-CHO-THF · S-(-)-a-苯乙胺盐粗 品， 用 50%乙醇重结晶。  (6R,S)-5-CHO-THF·Ca 102.3g (0.2mol), 300ml of water, S-(-)-a-phenylethylamine 28.0g (0.2mol), heated to 70° C, completely dissolved, cooled to 10 ° C, crystallized, and filtered to give (6S)-5-CHO-THF · S-(-)-a-phenylethylamine salt, which was recrystallized from 50% ethanol.

将上述 6S · S- (-) -a-苯乙胺盐溶于 300ml水中， 再加入 200ml环 己烷， 用 18%盐酸调 pH至 3〜4， 分取环己垸层， 减压蒸去环己烷， 将浓缩液加入氯化钙水溶液，加入活性炭过滤，冷至 10°C，加入 200ml 乙醇离析，得到较纯的 (6S)-5-CHO-THF -Ca,得量 45.2g，收率 44.2%， [a]20 D=-15.0。(C=l，H2O)，纯度 (HPLC) 98.5%。 实施例二 The above 6S · S-(-)-a-phenethylamine salt was dissolved in 300 ml of water, 200 ml of cyclohexane was added, and the pH was adjusted to 3 to 4 with 18% hydrochloric acid, and the cyclohexyl layer was separated and evaporated under reduced pressure. Cyclohexane, the concentrate was added to the aqueous solution of calcium chloride, added to the activated carbon for filtration, cooled to 10 ° C, and added to 200 ml of ethanol to isolate, to obtain a relatively pure (6S)-5-CHO-THF-Ca, the amount of 45.2 g, received The rate is 44.2%, [a] 20 D = -15.0. (C=l, H 2 O), purity (HPLC) 98.5%. Embodiment 2

实验操作同实施例一， 以氢氧化钙的水悬浮液代替氯化钙水溶 液， 得到（6S)-5-CHO-THF · Ca， 得量 45.5g， 收率 44.5 %， [a]20 D=-15.1°(C=1.82,H2O)，纯度 (HPLC) 98.5%。 The experimental operation was the same as in the first embodiment. An aqueous suspension of calcium hydroxide was used instead of the aqueous calcium chloride solution to obtain (6S)-5-CHO-THF·Ca, and the yield was 45.5 g, and the yield was 44.5 %. [a] 20 D = -15.1 ° (C = 1.82, H 2 O), purity (HPLC) 98.5%.

实施例三 Embodiment 3

在反应瓶中加入 (6R,S)-5-CHO-THF · Ca 102.3g(0.2mol) , 水 300ml, R-(+)-a-苯乙胺 28.0g(0.2mol)，加热至 70 °C，使全溶，冷至 10°C， 有结晶析出， 过滤除去生成的 (6R)-5-CHO-THF · R-(+)-a-苯乙胺盐。 将滤液用用 18%盐酸调 pH至 3〜4， 加入到 300ml环己烷中， 分取 环己烷层，减压蒸去环己垸，将浓缩液加入氯化钙水溶液，冷至 10°C， 加入 200ml乙醇离析，得到较纯的 (6S)-5-CHO-THF -Ca,得量 43.6g， 收率 42.6%， [a]2。D=-14.9。(01，H20)，纯度 (HPLC) 98.5%。 (6R,S)-5-CHO-THF · Ca 102.3g (0.2mol), 300ml of water, R-(+)-a-phenylethylamine 28.0g (0.2mol), heated to 70 ° C, completely dissolved, cooled to 10 ° C, crystallized, and the resulting (6R)-5-CHO-THF · R-(+)-a-phenethylamine salt was removed by filtration. The filtrate was adjusted to pH 3 to 4 with 18% hydrochloric acid, added to 300 ml of cyclohexane, and the cyclohexane layer was separated, and the cyclohexane was distilled off under reduced pressure. The concentrate was added to a calcium chloride aqueous solution and cooled to 10 °. C, by adding 200 ml of ethanol to isolate, to obtain relatively pure (6S)-5-CHO-THF-Ca, the yield was 43.6 g, the yield was 42.6%, [a] 2 . D = -14.9. (01, H 2 0), purity (HPLC) 98.5%.

Claims

权 利 要 求 书 Claim 1 . 一种拆分 (6R,S)-5-甲酰-四氢叶酸盐的方法， 其中使用光学活性有 机碱作为拆分剂， 使之成盐，过滤，酸化，用有机溶剂提取，加入 CaCl2 或 Ca(OH)2，Mg2Cl，NaOH水溶液浓縮，生成 (6S)-5-甲酰-四氢叶酸盐，用 醇类离析结晶。 What is claimed is: 1. A method for dissolving (6R,S)-5-formyl-tetrahydrofolate, wherein an optically active organic base is used as a resolving agent, which is salted, filtered, acidified, and extracted with an organic solvent. CaCl 2 or Ca(OH) 2 , Mg 2 Cl, and an aqueous NaOH solution were added to concentrate to give (6S)-5-formyl-tetrahydrofolate, which was crystallized from an alcohol. 2. 根据权利要求 1的方法， 制备 (6R，S)-5-甲酰-四氢叶酸有机盐的拆 分剂是 R-(+)-a-苯乙胺或 S-(-)-a-苯乙胺； 或 (+)N-乙基 -2-氨甲基吡咯 烷或 (-) N-乙基 -2-氨甲基吡咯垸。  2. The method according to claim 1, wherein the resolving agent for preparing the (6R,S)-5-formyl-tetrahydrofolate organic salt is R-(+)-a-phenethylamine or S-(-)-a - phenethylamine; or (+) N-ethyl-2-aminomethylpyrrolidine or (-) N-ethyl-2-aminomethylpyrrole. 3.根据权利要求 1的方法， 提取 (6S)-5-甲酰 -四氢叶酸的有机溶剂是： 环己垸， 甲苯， 或醋酸乙酯。  The method according to claim 1, wherein the organic solvent for extracting (6S)-5-formyl-tetrahydrofolate is: cyclohexane, toluene, or ethyl acetate. 4. 根据权利要求 1的方法， （6S)-5-甲酰-四氢叶酸可以分别与 CaCl2， Ca(OH)2,Mg2Cl,或 NaOH水溶液成相应的盐。 4. The method according to claim 1, wherein (6S)-5-formyl-tetrahydrofolate is separately formed into a corresponding salt with CaCl 2 , Ca(OH) 2 , Mg 2 Cl, or aqueous NaOH. 5. 根据权利要求 1的方法， 离析 (6S)-5-甲酰-四氢叶酸盐的醇类可以 使用乙醇， 甲醇， 异丙醇， 或乙二醇。  The method of claim 1, wherein the alcohol of (6S)-5-formyl-tetrahydrofolate can be used as ethanol, methanol, isopropanol or ethylene glycol.
PCT/CN2007/003074 2007-10-11 2007-10-29 A process for resolution of (6r,s)-5-formyltetrahydrofolic acid and its salification Ceased WO2009046581A1 (en)

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CN101863889B (en) * 2009-04-20 2013-07-03 重庆华邦胜凯制药有限公司 Method for purifying calcium levofolinate
CN103102350A (en) * 2011-11-11 2013-05-15 重庆华邦胜凯制药有限公司 Preparation method of levofolinate
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
CN105367574A (en) * 2015-10-27 2016-03-02 浙江大为药业有限公司 Process for preparing high purity sinistral leucovorin calcium
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
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