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 PDFInfo
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 11
- VVIAGPKUTFNRDU-OLZOCXBDSA-N (2s)-2-[[4-[[(6r)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid 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-OLZOCXBDSA-N 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 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 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 150000007530 organic bases Chemical class 0.000 claims abstract description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 3
- FFFHBHWCZONDKN-UHFFFAOYSA-N (1-ethylpyrrol-2-yl)methanamine Chemical compound CCN1C=CC=C1CN FFFHBHWCZONDKN-UHFFFAOYSA-N 0.000 claims description 2
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 claims 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Natural products NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims 1
- 229940117803 phenethylamine Drugs 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 abstract description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract description 5
- 239000001110 calcium chloride Substances 0.000 abstract description 3
- 229910001628 calcium chloride Inorganic materials 0.000 abstract description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 abstract 2
- 235000011148 calcium chloride Nutrition 0.000 abstract 1
- 229910001629 magnesium chloride Inorganic materials 0.000 abstract 1
- 239000011575 calcium Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 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 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].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 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 2
- 159000000007 calcium salts Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 239000011578 levomefolic acid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 description 1
- 235000007635 levomefolic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- -1 pyrrole oxime Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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.
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 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)
| 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)
| 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 |
-
2007
- 2007-10-11 CN CNA2007101330526A patent/CN101407518A/zh active Pending
- 2007-10-29 WO PCT/CN2007/003074 patent/WO2009046581A1/fr active Application Filing
Patent Citations (6)
| 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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