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WO2009046581A1 - Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification - Google Patents

Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
cho
thf
tetrahydrofolate
formyl
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2007/003074
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English (en)
Chinese (zh)
Inventor
Xin Chen
Yicheng Mei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Rally Biochemical Inc
Original Assignee
Nanjing Rally Biochemical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Rally Biochemical Inc filed Critical Nanjing Rally Biochemical Inc
Publication of WO2009046581A1 publication Critical patent/WO2009046581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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. .

Landscapes

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

Abstract

Cette invention concerne un procédé de résolution de (6R,S)-5-formyltetrahydrofolate, lequel procédé consiste à utiliser une base organique ayant une activité optique en tant qu'agent de résolution pour permettre la salification, puis à filtrer, acidifier et extraire au moyen d'un solvant organique, à ajouter une solution aqueuse de CaCl2, Ca (OH)2, MgCl2 ou NaOH pour obtenir (6S)-5-formyltetrahydrofolate, puis à isoler et cristalliser au moyen d'alcool.
PCT/CN2007/003074 2007-10-11 2007-10-29 Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification Ceased WO2009046581A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2007101330526A CN101407518A (zh) 2007-10-11 2007-10-11 (6r,s)-5-甲酰-四氢叶酸的拆分及其成盐的方法
CN200710133052.6 2007-10-11

Publications (1)

Publication Number Publication Date
WO2009046581A1 true WO2009046581A1 (fr) 2009-04-16

Family

ID=40548935

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/003074 Ceased WO2009046581A1 (fr) 2007-10-11 2007-10-29 Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification

Country Status (2)

Country Link
CN (1) CN101407518A (fr)
WO (1) WO2009046581A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101863889B (zh) * 2009-04-20 2013-07-03 重庆华邦胜凯制药有限公司 左亚叶酸钙的纯化方法
CN103102350A (zh) * 2011-11-11 2013-05-15 重庆华邦胜凯制药有限公司 一种左亚叶酸盐的制备方法
CN103214487A (zh) * 2013-04-12 2013-07-24 张家港威胜生物医药有限公司 一种重要医药化工原料(6s)-5-甲基四氢叶酸盐的合成
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
CN111620777A (zh) * 2020-06-10 2020-09-04 成都蓝蜻蜓生物技术有限公司 一种(s)-1，2，3，4-四氢-1-萘甲酸的拆分方法
CN113666931B (zh) * 2021-09-07 2023-11-03 浙江大为药业有限公司 一种高纯左亚叶酸钙的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2688018A (en) * 1952-06-28 1954-08-31 American Cyanamid Co Method of preparing alkaline earth metal salts of 1-leucovorin
CN88102709A (zh) * 1987-05-15 1988-12-28 阿泼洛发公司 亚叶酸的分离方法
CN1038813A (zh) * 1988-06-29 1990-01-17 爱泼洛瓦股份公司 制备四氢叶酸盐的方法
CN1063285A (zh) * 1991-01-16 1992-08-05 埃普罗瓦股份公司 (6s)-和(6r)四氢叶酸的制备方法
US5457202A (en) * 1991-11-11 1995-10-10 Knoll Aktiengesellschaft Resolution of 5-methyltetrahydrofolic acid
IT1254954B (it) * 1992-04-30 1995-10-11 Processo per preparare la forma otticamente attiva (6-s) dell'acido folinico ottenuto per via sintetica

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2688018A (en) * 1952-06-28 1954-08-31 American Cyanamid Co Method of preparing alkaline earth metal salts of 1-leucovorin
CN88102709A (zh) * 1987-05-15 1988-12-28 阿泼洛发公司 亚叶酸的分离方法
CN1038813A (zh) * 1988-06-29 1990-01-17 爱泼洛瓦股份公司 制备四氢叶酸盐的方法
CN1063285A (zh) * 1991-01-16 1992-08-05 埃普罗瓦股份公司 (6s)-和(6r)四氢叶酸的制备方法
US5457202A (en) * 1991-11-11 1995-10-10 Knoll Aktiengesellschaft Resolution of 5-methyltetrahydrofolic acid
IT1254954B (it) * 1992-04-30 1995-10-11 Processo per preparare la forma otticamente attiva (6-s) dell'acido folinico ottenuto per via sintetica

Also Published As

Publication number Publication date
CN101407518A (zh) 2009-04-15

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