CN101407518A - Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid - Google Patents
Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid Download PDFInfo
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- CN101407518A CN101407518A CNA2007101330526A CN200710133052A CN101407518A CN 101407518 A CN101407518 A CN 101407518A CN A2007101330526 A CNA2007101330526 A CN A2007101330526A CN 200710133052 A CN200710133052 A CN 200710133052A CN 101407518 A CN101407518 A CN 101407518A
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- Prior art keywords
- formyl
- cho
- salt
- tetrahydrofolic acid
- hexanaphthene
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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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for resolving (6R, S)-5-formyl-tetrahydrofolic acid and for salifying. Optically active organic alkali is used as the resolving agent to form the salt, then after filtration and acidification, the material is extracted and concentrated by organic solvent, then oxide or chloride solution of alkali-earth metal is added, and the material is isolated and crystallized by alcohols after salifying.
Description
Invention field
The present invention relates to the organic medicinal chemistry field, concrete and relate to a kind of organic drug (6R, S)-fractionation and the salifiable method thereof of 5-formyl-tetrahydrofolic acid (THFA).
Background technology
(6S)-and 5-formyl-tetrahydrofolic acid (THFA), chemical name is N-5-formyl radical (6S)-5,6,7, the 8-tetrahydrofolic acid (THFA), promptly (6S)-5-CHO-THF is called for short (6S)-folinic acid, is the configuration of natural existence the (for example in the liver).Its calcium salt structural formula is as follows:
At present, the medicine Calciumlevofolinate of supplying on the market is that (medicine and pharmacology studies show that for 6R, the S) calcium salt of the folinic acid of configuration: the diastereomer (6R of chemosynthesis entirely, S)-Calciumlevofolinate is half of natural (6S)-Calciumlevofolinate in the treatment cancer, and toxicity is two times.(F.M.Sirotanketal.，BioChemical?Pharmacology?28，2993-2997，1979；C.Temple?etal.，CancerTreatment?Reports?65，1117-1119，1981)。
Therefore, synthetic (6R, S)-during 5-CHO-THF-Ca, split and obtain the very necessary of (6S)-5-CHO-THF consistent and salt thereof with natural active substance.
For from (6R, S)-5-CHO-THF splits and to obtain (6S)-5-CHO-THF, people such as Hans.R.Muller (U.S.5,010,194,1991) at (6R, S)-add mineral acid or the organic acid aqueous solution or basic metal in the 5-CHO-THF salt brine solution, behind alkaline earth salt or the ammonium salt, form (6R)-5-CHO-THF salt accordingly by dominant diastereomer (6R)-5-CHO-THF salt, corresponding (6R)-5-CHO-THF salt of separating out is removed by filter, with isolation process (the 6S)-5-CHO-THF salt in the filtrate is obtained solid (6S)-5-CHO-THF salt again.And " ammonium salt " mentioned in this patent only is: tetramethyleneimine, piperidines and alkylbenzyldimethylasaltsum saltsum.
Summary of the invention
The method that the objective of the invention is to establish the simple of a kind of preparation (6S)-5-CHO-THFCa and be suitable for industrial use.
Be surprisingly found out that: to (6R, S)-add organic bases S-(-)-α-Ben Yian in the CHO-THFCa aqueous solution, separate out corresponding (6S)-CHO-THFS-(-)-α-Ben Yian salt precipitation, this salt is dissolved in hexanaphthene, and (concentrated hydrochloric acid: accent pH to 3～4 water=1: 1) add the organic solvent hexanaphthene with hydrochloric acid.Divide and get organic layer (hexanaphthene), the pressure reducing and steaming hexanaphthene adds calcium chloride water, and the ethanol segregation obtains (6S)-5-CHO-THF calcium salt.
Can use also in addition that R-(+)-α-Ben Yian will (6R S)-CHO-THFCa aqueous solution salify, separates out corresponding (6R)-CHO-THFR-(+)-α-Ben Yian salt, removes by filter.(concentrated hydrochloric acid: water=1: 1) transfer pH to 3～4, add hexanaphthene, divide and get organic layer (hexanaphthene), the pressure reducing and steaming hexanaphthene adds calcium chloride water, with the ethanol segregation, obtains (6S)-5-CHO-THF calcium salt with hydrochloric acid to add hexanaphthene in filtrate.
Further, organic bases also has the optical isomer of two of the N-ethyl-2-aminomethylpentazaneands of (+) or (-) as resolving agent.
The organic solvent that extracts (6S)-5-CHO-THF is a toluene, ethyl acetate, or hexanaphthene, preferred hexanaphthene.
The alcohols of segregation (6S)-5-CHO-THF salt also can use methyl alcohol, ethanol, Virahol, or ethylene glycol, preferred alcohol.
Same method is with Ca (OH)
2, Mg
2Cl, dilute NaOH solution also can make corresponding (6S)-5-CHO-THF calcium, magnesium or sodium salt.
The present invention after reduction reaction, can prepare medicine (the 6S)-5-methyl-tetrahydrofolic acid (THFA) calcium (6S-5-MTHFCa) for the treatment of senile dementia with (6S)-5-CHO-THFCa.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, down preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention in advance in design of the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment one
In reaction flask, add (6R, S)-5-CHO-THFCa 102.3g (0.2mol), water 300ml, S-(-)-α-Ben Yian 28.0g (0.2mol) is heated to 70 ℃, makes molten entirely, be chilled to 10 ℃, there is crystallization to separate out, filters and obtain (6S)-5-CHO-THFS-(-)-α-Ben Yian salt crude product, use 50% ethyl alcohol recrystallization.
Above-mentioned 6SS-(-)-α-Ben Yian salt is dissolved in the 300ml water, adds the 200ml hexanaphthene again, transfer pH to 3～4 with 18% hydrochloric acid, divide and get the hexanaphthene layer, the pressure reducing and steaming hexanaphthene adds calcium chloride water with concentrated solution, adds activated carbon filtration, be chilled to 10 ℃, add 200ml ethanol segregation, obtain purer (6S)-5-CHO-THFCa, must measure 45.2g, yield 44.2%, [α]
20 D=-15.0 ° of (C=1, H
2O), purity (HPLC) 〉=98.5%.
Embodiment two
Experimental implementation is with embodiment one, and the aqeous suspension replacement calcium chloride water with calcium hydroxide obtains (6S)-5-CHO-THFCa, must measure 45.5g, yield 44.5%, [α]
20 D=-15.1 ° of (C=1.82, H
2O), purity (HPLC) 〉=98.5%.
Embodiment three
In reaction flask, add (6R, S)-5-CHO-THFCa 102.3g (0.2mol), water 300ml, R-(+)-α-Ben Yian 28.0g (0.2mol) is heated to 70 ℃, makes molten entirely, be chilled to 10 ℃, have crystallization to separate out, remove by filter (6R)-5-CHO-THFR-(+)-α-Ben Yian salt of generation.Filtrate is transferred pH to 3～4 with 18% hydrochloric acid, join in the 300ml hexanaphthene, divide and get the hexanaphthene layer, the pressure reducing and steaming hexanaphthene adds calcium chloride water with concentrated solution, be chilled to 10 ℃, add 200ml ethanol segregation, obtain purer (6S)-5-CHO-THFCa, must measure 43.6g, yield 42.6%, [α]
20 D=-14.9 ° of (C=1, H
2O), purity (HPLC) 〉=98.5%.
Claims (5)
- A 1. fractionation (6R, S)-method of 5-formyl-tetrahydrofolate, wherein use the optical activity organic bases as resolving agent, make it salify, to filter, organic solvent extraction use in acidifying, adding CaCl 2Or Ca (OH) 2, Mg 2Cl, the NaOH aqueous solution concentrates, and generates (6S)-5-formyl-tetrahydrofolate, with the alcohols crystallization of emanating.
- 2. according to the method for claim 1, and preparation (6R, S)-resolving agent of 5-formyl-tetrahydrofolic acid (THFA) organic salt is R-(+)-α-Ben Yian or S-(-)-α-Ben Yian; Or (+) N-ethyl-2-aminomethylpentazaneand or (-) N-ethyl-2-aminomethylpentazaneand.
- 3. according to the method for claim 1, the organic solvent that extracts (6S)-5-formyl-tetrahydrofolic acid (THFA) is: hexanaphthene, toluene, or vinyl acetic monomer.
- 4. according to the method for claim 1, (6S)-5-formyl-tetrahydrofolic acid (THFA) can be respectively and CaCl 2, Ca (OH) 2, Mg 2Cl, or the NaOH aqueous solution becomes corresponding salt.
- 5. according to the method for claim 1, the alcohols of segregation (6S)-5-formyl-tetrahydrofolate can use ethanol, methyl alcohol, Virahol, or ethylene glycol.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101330526A CN101407518A (en) | 2007-10-11 | 2007-10-11 | Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid |
| PCT/CN2007/003074 WO2009046581A1 (en) | 2007-10-11 | 2007-10-29 | A process for resolution of (6r,s)-5-formyltetrahydrofolic acid and its salification |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101330526A CN101407518A (en) | 2007-10-11 | 2007-10-11 | Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101407518A true CN101407518A (en) | 2009-04-15 |
Family
ID=40548935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101330526A Pending CN101407518A (en) | 2007-10-11 | 2007-10-11 | Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid |
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| CN (1) | CN101407518A (en) |
| WO (1) | WO2009046581A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863889A (en) * | 2009-04-20 | 2010-10-20 | 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 |
| CN113666931A (en) * | 2021-09-07 | 2021-11-19 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
Family Cites Families (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 |
| CH673459A5 (en) * | 1987-05-15 | 1990-03-15 | Eprova Ag | |
| DE3821875C1 (en) * | 1988-06-29 | 1990-02-15 | Eprova Ag, Forschungsinstitut, Schaffhausen, Ch | |
| CH681303A5 (en) * | 1991-01-16 | 1993-02-26 | Eprova Ag | |
| DE4136921A1 (en) * | 1991-11-11 | 1993-05-13 | Knoll Ag | METHOD FOR SEPARATING 5-METHYL-TETRAHYDROFOLIC ACID |
| IT1254954B (en) * | 1992-04-30 | 1995-10-11 | Process for preparation of the (6-S) optically active form of folic acid obtained by synthesis |
-
2007
- 2007-10-11 CN CNA2007101330526A patent/CN101407518A/en active Pending
- 2007-10-29 WO PCT/CN2007/003074 patent/WO2009046581A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863889A (en) * | 2009-04-20 | 2010-10-20 | 重庆华邦胜凯制药有限公司 | Method for purifying calcium levofolinate |
| 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 |
| CN113666931A (en) * | 2021-09-07 | 2021-11-19 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
| CN113666931B (en) * | 2021-09-07 | 2023-11-03 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
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| Publication number | Publication date |
|---|---|
| WO2009046581A1 (en) | 2009-04-16 |
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