CN1456561A - Preparations of leucovorin and its carbonates - Google Patents
Preparations of leucovorin and its carbonates Download PDFInfo
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- CN1456561A CN1456561A CN 03121531 CN03121531A CN1456561A CN 1456561 A CN1456561 A CN 1456561A CN 03121531 CN03121531 CN 03121531 CN 03121531 A CN03121531 A CN 03121531A CN 1456561 A CN1456561 A CN 1456561A
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- calcium salt
- folinic acid
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- leucovorin
- salt
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Abstract
A process for preparing levo-folinic acid and its calcium salt includes such steps as dissolving (6RS)-folinic acid and its calcium salt, chromatography with the adsorption column of neutral or alkaline adsorbent, eluting, collecting solution, regulating pH to 7.0, adding alcohol to educe out (6S)-folinic acid and its calcium salt, and recrystallizing in water 1-3 times. Its advantages are high purity (99% or more), high output and low cost.
Description
Technical field
That the present invention relates to is the direct preparation method of the preparation method of a kind of (6S)-folinic acid and calcium salt thereof, especially (6S)-Calciumlevofolinate, and it is mainly used in detoxifcation antagonist of anti-anaemia and tumour medicine etc.
Background technology
Disclose two preparation method's patents of invention about levoleucovorin calcium in the Chinese patent communique, the patent No. is respectively 88102709.X and 89109727.9.Also have similarly open on other the correlation technique professional technique magazine abroad.But all at present technology openly all can reduce the preparation were established of two kinds of (6S)-Calciumlevofolinates, route＜one〉be the intermediate Split Method: split by (6RS)-tetrahydrofolic acid (THFA) and can get (6S)-tetrahydrofolic acid (THFA), get (6R)-5 through cyclization, the 10-methylene tetrahydrofolate, or directly by (6RS)-5, the 10-methylene tetrahydrofolate splits and obtains (6R)-5, the 10-methylene tetrahydrofolate
2., promptly get (6S)-Calciumlevofolinate through hydrolysis again.Route＜two〉the same with Chinese patent 88102709, directly be alkalescence by regulating PH with the racemize Calciumlevofolinate, utilize (6S)-Calciumlevofolinate solubleness than (6R) thereby-the little way of separating out earlier of Calciumlevofolinate, split and obtain (6S)-Calciumlevofolinate.Through experiment confirm, two kinds of methods all can obtain (the 6S)-Calciumlevofolinate of specific optical rotation-10～-15.Route＜one 〉:
Or directly by (6RS)-5, the 10-methylene tetrahydrofolate splits and obtains (6R)-5, and the 10-methylene tetrahydrofolate promptly gets (6S)-Calciumlevofolinate through hydrolysis again:
Route＜two 〉:
But above-mentioned two kinds of preparation methods, relative complex process, suitability for industrialized production are difficult to guarantee, and manufacturing cost is higher, the efficient of pharmacy is lower.
Summary of the invention
The object of the present invention is to provide a kind of method of utilizing adsorpting column chromatography from (6RS)-folinic acid and calcium salt thereof, to isolate the preparation method of the l-leucovorin and the calcium salt thereof of (6S)-folinic acid and calcium salt thereof.It is to select for use neutrality or meta-alkalescence sorbent material upper prop to constitute adsorption column, with (6RS)-folinic acid and calcium salt dissolving back upper prop thereof, the buffered soln of water, organic solvent or PH6.0-11.0 and mixing solutions thereof wash as eluent again, collect (6S)-folinic acid and calcium salt content thereof greater than 80% o'clock solution, regulate PH7.0, add ethanol separate out (6S)-folinic acid and calcium salt thereof, (6S) folinic acid and the calcium salt thereof that water recrystallization 1-3 time must be more than 99% again.
Described sorbent material is selected for use as silica types such as silica gel, albumen silica gel; Or select for use as alumina type such as activated alumina, alkali aluminas; Or select for use as cellulose families such as Microcrystalline Cellulose, DEAE Mierocrystalline celluloses; Or activated carbon, Magnesium Silicate q-agent, silicon magnesium type sorbent material.
Described by at least a 5cm of the formation * 120cm in the above sorbent material adsorption column and carry out column chromatography method, (6RS)-folinic acid and calcium salt thereof are separated.
Described (6RS)-folinic acid and the calcium salt thereof that carries out the adsorption column upper prop cools off the solution that forms again after being dissolved in hot water earlier.
At least a for as in edta salt, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, carbonate, supercarbonate, ammonium salt and composition thereof of buffered soln in the eluent that described adsorption column is selected for use;
The method of the present invention's preparation (6S)-folinic acid and calcium salt thereof is simply effective, and easy suitability for industrialized production, and it is also high to produce effects,
Embodiment
Below be described in detail with the example.
Example 1: get the suitable DEAE Mierocrystalline cellulose upper prop of granular size (5cm * 120cm), rinse well with the EDTA-2Na buffered soln of PH8.5; Getting 30g (6RS)-Calciumlevofolinate is dissolved in the 200ml hot water, cooling back upper prop, EDTA-2Na buffered soln flushing with PH8.5, HPLC with the albumen silicagel column detects, collect (6S)-folinate content greater than 80% o'clock solution, regulate PH7.0, add ethanol separate out (6S)-Calciumlevofolinate, again water recrystallization 1～3 time (the 6S)-Calciumlevofolinate more than 99%.
Example 2: get the suitable Magnesium Silicate q-agent sorbent material upper prop of granular size (5cm * 120cm), rinse well with the ammonium salt buffered soln of PH8.5～9.0; Getting 30g (6RS)-Calciumlevofolinate is dissolved in the 200ml hot water, cooling back upper prop, ammonium salt buffered soln flushing with PH9.0, HPLC with the albumen silicagel column detects, collect (6S)-folinate content greater than 80% o'clock solution, regulate PH7.0, add ethanol separate out (6S)-Calciumlevofolinate, again water recrystallization 1～3 time (the 6S)-Calciumlevofolinate more than 99%.
Example 3 is got the suitable alkali alumina sorbent material upper prop (5cm * 120cm), rinse well with the aqueous solution of granular size; Getting 30g (6RS)-Calciumlevofolinate is dissolved in the 200ml hot water, cooling back upper prop, wash with the aqueous solution, HPLC with the albumen silicagel column detects, collect (6S)-folinate content greater than 80% o'clock solution, regulate PH7.0, add ethanol separate out (6S)-Calciumlevofolinate, again water recrystallization 1～3 time (the 6S)-Calciumlevofolinate more than 99%.
Claims (6)
1, the preparation method of a kind of l-leucovorin and calcium salt thereof, it is characterized in that it is to select for use neutrality or meta-alkalescence sorbent material upper prop to constitute adsorption column, with (6RS)-folinic acid and calcium salt dissolving back upper prop thereof, the buffered soln of water, organic solvent or PH6.0-11.0 and mixing solutions thereof wash as eluent again, collect (6S)-folinic acid and calcium salt content thereof greater than 80% o'clock solution, regulate PH7.0, add ethanol separate out (6S)-folinic acid and calcium salt thereof, (6S) folinic acid and the calcium salt thereof that water recrystallization 1-3 time must be more than 99% again.
2, the preparation method of l-leucovorin according to claim 1 and calcium salt thereof is characterized in that described sorbent material selects for use as silica types such as silica gel, albumen silica gel; Or select for use as alumina type such as activated alumina, alkali aluminas; Or select for use as cellulose families such as Microcrystalline Cellulose, DEAE Mierocrystalline celluloses; Or activated carbon, Magnesium Silicate q-agent, silicon magnesium type sorbent material.
3, the preparation method of l-leucovorin according to claim 2 and calcium salt thereof, it is characterized in that described by at least a 5cm of the formation * 120cm in the above sorbent material adsorption column and carry out column chromatography separation method, (6RS)-folinic acid and calcium salt thereof are separated.
4,, it is characterized in that (the 6RS)-folinic acid of described adsorption column upper prop and calcium salt thereof cool off the solution that forms again after being dissolved in hot water earlier according to the preparation method of claim 1 or 2 or 3 described l-leucovorins and calcium salt thereof.
5, the preparation method of l-leucovorin according to claim 4 and calcium salt thereof is characterized in that at least a for as in edta salt, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, carbonate, supercarbonate, ammonium salt and composition thereof of buffered soln in the eluent that described adsorption column selects for use;
6, l-leucovorin according to claim 1 and calcium salt thereof are used for anti-anaemia and tumour medicine and detoxifcation antagonist.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03121531 CN1456561A (en) | 2003-04-01 | 2003-04-01 | Preparations of leucovorin and its carbonates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03121531 CN1456561A (en) | 2003-04-01 | 2003-04-01 | Preparations of leucovorin and its carbonates |
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| CN1456561A true CN1456561A (en) | 2003-11-19 |
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| CN 03121531 Pending CN1456561A (en) | 2003-04-01 | 2003-04-01 | Preparations of leucovorin and its carbonates |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102101862B (en) * | 2009-12-21 | 2013-01-09 | 天津康鸿医药科技发展有限公司 | Method for preparing L-sodium folinate or DL-sodium folinate |
| CN103102350A (en) * | 2011-11-11 | 2013-05-15 | 重庆华邦胜凯制药有限公司 | Preparation method of levofolinate |
| CN113336757A (en) * | 2021-04-27 | 2021-09-03 | 南京海纳医药科技股份有限公司 | Preparation method of levofolinic acid crystal |
| 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 |
-
2003
- 2003-04-01 CN CN 03121531 patent/CN1456561A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102101862B (en) * | 2009-12-21 | 2013-01-09 | 天津康鸿医药科技发展有限公司 | Method for preparing L-sodium folinate or DL-sodium folinate |
| CN103102350A (en) * | 2011-11-11 | 2013-05-15 | 重庆华邦胜凯制药有限公司 | Preparation method of levofolinate |
| CN113336757A (en) * | 2021-04-27 | 2021-09-03 | 南京海纳医药科技股份有限公司 | Preparation method of levofolinic acid crystal |
| CN113336757B (en) * | 2021-04-27 | 2022-05-13 | 南京海纳医药科技股份有限公司 | Preparation method of levofolinic acid crystal |
| 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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