CN110229155A - A kind of preparation method of l-leucovorin calcium impurities and impurity calcium salt - Google Patents
A kind of preparation method of l-leucovorin calcium impurities and impurity calcium salt Download PDFInfo
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- CN110229155A CN110229155A CN201910555291.3A CN201910555291A CN110229155A CN 110229155 A CN110229155 A CN 110229155A CN 201910555291 A CN201910555291 A CN 201910555291A CN 110229155 A CN110229155 A CN 110229155A
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- 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
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Abstract
The invention belongs to chemical pharmacy fields, are related to a kind of preparation method of impurity of the drug standard items, and in particular to the preparation method of l-leucovorin calcium impurities and impurity calcium salt.Firstly, the present invention provides a kind of preparation methods of l-leucovorin calcium impurities to react in aqueous solution with reducing agent using compound of formula I folic acid as raw material, reacting liquid pH value is adjusted with aqueous alkali and inorganic acid respectively, obtains Formula II compound dihydrofoilic acid；The Formula II compound is reacted with formic acid, and purified water agitation and filtration is added, and obtains formula III compound 10- formoxyl dihydrofoilic acid.The present invention also provides a kind of preparation methods of 10- formoxyl dihydrofoilic acid calcium, and using folic acid as raw material, dihydrofoilic acid is first made, and then dihydrofoilic acid reacts to obtain 10- formoxyl dihydrofoilic acid with formic acid, add calcium salt, and reaction obtains 10- formoxyl dihydrofoilic acid calcium.
Description
Technical field
The invention belongs to chemical pharmacy fields, are related to a kind of preparation method of impurity of the drug standard items, and in particular to Zuo Ya
The preparation method of folic acid calcium impurities and impurity calcium salt.
Background technique
Calcium Levofolinate be one kind be mainly used for treat osteosarcoma through large dosage of Methylaminopterin treatment after with folic acid antagonist phase
The drug for closing symptom may further be used to macrocytic caused by treatment folic acid deficiency, can also be used in combination with fluorouracil to prolong
The life cycle of long progressive stage colorectal cancer patients alleviates symptom.
, it is specified that impurity to Calcium Levofolinate, i.e. 10- formoxyl dihydrofoilic acid carry out quantitative study in European Pharmacopoeia,
And it is incorporated into quality standard.The prior art respectively has advantage and disadvantage to the preparation method of 10- formoxyl dihydrofoilic acid, for example, patent
In US4148999, using Calcium Levofolinate intermediate 5,10- methine -6 (R)-tetrahydrofolic acid hydrochloride is in the water-soluble of pH=11
Reaction is stirred at room temperature in opening in liquid, in this way, it is low to obtain 10- formoxyl dihydrofoilic acid purity, contains impurity 10- formoxyl
The impurity such as tetrahydrofolic acid, dihydrofoilic acid, 10- formoxyl folic acid, 5- formoxyl tetrahydrofolic acid.
Therefore, the present invention provides a kind of preparation method of 10- formoxyl dihydrofoilic acid, the present invention have concise in technology,
Product that is not high to equipment requirement, the obtaining advantage high through calibration content.Further, since 10- formoxyl dihydrofoilic acid itself is no
Stablize, the present invention also provides a kind of preparation methods of 10- formoxyl dihydrofoilic acid calcium salt, obtain a kind of chemical combination that property is stable
Object has guiding significance for the control of drug quality.
Summary of the invention
In view of this, an object of the present invention, is to provide a kind of preparation method of 10- formoxyl dihydrofoilic acid.
A kind of preparation method of l-leucovorin calcium impurities, the impurity are 10- formoxyl dihydrofoilic acid；The preparation side
Method is reacted with reducing agent in aqueous solution using compound of formula I folic acid as raw material, adjusts reaction with aqueous alkali and inorganic acid respectively
Liquid pH value obtains Formula II compound dihydrofoilic acid；It is reacted with the dihydrofoilic acid with formic acid, and purified water agitation and filtration is added,
Obtain formula III compound 10- formoxyl dihydrofoilic acid.Reaction process is as follows:
Further, the reducing agent includes one of sodium hydrogensulfite, sodium pyrosulfite or a variety of；The folic acid with also
Former agent molar ratio is 1:4~6.
Sodium hydrogensulfite and sodium pyrosulfite make reducing agent, and relatively using sodium dithionite safety, being added to the water will not be produced
Raw risk of explosion, and reduction process is relatively mild.
Further, the aqueous alkali includes sodium hydrate aqueous solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, carbon
One of sour aqueous solutions of potassium, ammonia spirit are a variety of；Reacting liquid pH value is adjusted to 8~9 with the aqueous alkali；It is described inorganic
Acid includes one of hydrochloric acid, sulfuric acid or a variety of；Reaction solution pH to 0.5~1.0 is adjusted with the inorganic acid.
Folic acid is added in reaction flask, with water as solvent, reaction solution pH to 8~9 is adjusted with buck, reducing agent is added,
Be warming up to 20 DEG C~60 DEG C reaction 2h~3h, be cooled to 0 DEG C~5 DEG C, be added dropwise to inorganic acid, adjust reaction solution pH to 0.5~
1.0, keep the temperature 0 DEG C~5 DEG C reactions for 24 hours, filtering obtains dihydrofoilic acid.
Further, the mass ratio of the Formula II compound and formic acid is 1g:12g~36g.
Dihydrofoilic acid salt and formic acid are added in reaction flask, 20 DEG C~40 DEG C reaction for 24 hours~36h are kept the temperature, after fully reacting,
50 DEG C of vacuum distillations remove formic acid removal, and purified water stirring and crystallizing is added, and filtering obtains 10- formoxyl dihydrofoilic acid.
The two of the object of the invention are to provide a kind of preparation method of 10- formoxyl dihydrofoilic acid calcium salt.
A kind of preparation method of l-leucovorin calcium impurities, the impurity are 10- formoxyl dihydrofoilic acid；The preparation side
Method is reacted with reducing agent in aqueous solution using compound of formula I folic acid as raw material, adjusts reaction with aqueous alkali and inorganic acid respectively
Liquid pH value obtains Formula II compound dihydrofoilic acid；It is reacted with the dihydrofoilic acid with formic acid, and purified water agitation and filtration is added,
Obtain formula III compound 10- formoxyl dihydrofoilic acid.
Further, the formula III compound is reacted with calcium salt in aqueous solution, and is adjusted and reacted with sodium hydrate aqueous solution
Liquid pH to 6~7.5 obtains formula IV compound 10- formoxyl dihydrofoilic acid calcium.Reaction process is as follows:
Further, the reducing agent includes one of sodium hydrogensulfite, sodium pyrosulfite or a variety of；The folic acid with also
Former agent molar ratio is 1:4~6.
Further, the aqueous alkali includes sodium hydrate aqueous solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, carbon
One of sour aqueous solutions of potassium, ammonia spirit are a variety of；Reacting liquid pH value is adjusted to 8~9 with the aqueous alkali；It is described inorganic
Acid includes one of hydrochloric acid, sulfuric acid or a variety of；Reaction solution pH to 0.5~1.0 is adjusted with the inorganic acid.
Folic acid is added in reaction flask, with water as solvent, reaction solution pH to 8~9 is adjusted with buck, reducing agent is added,
Be warming up to 20 DEG C~60 DEG C reaction 2h~3h, be cooled to 0 DEG C~5 DEG C, be added dropwise to inorganic acid, adjust reaction solution pH to 0.5~
1.0, keep the temperature 0 DEG C~5 DEG C reactions for 24 hours, filtering obtains dihydrofoilic acid.
Further, the mass ratio of the Formula II compound and formic acid is 1:12~36.
Further, the calcium salt includes one of calcium chloride, calcium acetate or a variety of；The formula III compound and calcium salt
Molar ratio is 1:0.5~1.0.
Dihydrofoilic acid salt and formic acid are added in reaction flask, 20 DEG C~40 DEG C reaction for 24 hours~36h are kept the temperature, after fully reacting,
50 DEG C of vacuum distillations remove formic acid removal, and purified water stirring and crystallizing is added, and filter to get 10- formoxyl dihydrofoilic acid.By 10- formyl
Base dihydrofoilic acid is added in purified water, adjusts reaction solution pH to 6~7.5 with sodium hydrate aqueous solution, and calcium salt, room temperature reaction is added
1h, filtering, 50 DEG C of decompression dryings obtain 10- formoxyl dihydrofoilic acid calcium.
The utility model has the advantages that
1) the present invention provides a kind of preparation method of 10- formoxyl dihydrofoilic acid, this method concise in technology wants equipment
Ask product that is not high, obtaining high through calibration content.
2) the present invention also provides a kind of preparation method of 10- formoxyl dihydrofoilic acid calcium, 10- formoxyl dihydrofoilic acid calcium
It is a kind of compound that property is stable, there is guiding significance for the control of drug quality.
Detailed description of the invention
Fig. 1 10- formoxyl dihydrofoilic acid calcium synthesis flow.
Fig. 2 10- formoxyl dihydrofoilic acid synthesis flow.
Fig. 3 10- formoxyl Calcium leucovorin HPLC figure.
Fig. 4 10- formoxyl Calcium leucovorin mass spectrogram.
Specific embodiment
The preferred embodiment of the present invention is described in detail below.Illustrated embodiment is in order to preferably to of the invention
Content is illustrated, but is not that the contents of the present invention are only limitted to illustrated embodiment.So those skilled in the art's root
Nonessential modifications and adaptations are carried out to embodiment according to foregoing invention content, still fall within protection scope of the present invention.
Embodiment 1
It takes 10g (22.7mmol) folic acid to be dissolved in 200ml water, with sodium hydrate aqueous solution tune reaction solution pH to 8.5, stirs
Dissolved clarification is mixed, 17.2g (90.7mmol) sodium pyrosulfite is added, is warming up to 30 DEG C of insulation reaction 2h, is cooled to 0 DEG C~5 DEG C, is added dropwise
Entering hydrochloric acid, adjust reaction solution pH=0.5, keeps the temperature 0 DEG C~5 DEG C reactions for 24 hours, filtering, 50 DEG C are dried under reduced pressure to obtain 8.6g dihydrofoilic acid,
Yield 79.6%.
It takes 8.6g (19.4mmol) dihydrofoilic acid salt to be dissolved in 104g formic acid, keeps the temperature 25 DEG C of reaction 30h, fully reacting
Afterwards, 50 DEG C of vacuum distillations remove formic acid removal, and 86ml purified water stirring and crystallizing, filtering is added, and 50 DEG C of drying obtain 7.0g 10- formoxyl
Dihydrofoilic acid, yield 83.1%.
Embodiment 2
It takes 8.6g (19.4mmol) dihydrofoilic acid salt to be dissolved in 104g formic acid, keeps the temperature 25 DEG C of reaction 30h, fully reacting
Afterwards, 50 DEG C of vacuum distillations remove formic acid removal, and 86ml purified water stirring and crystallizing is added, and filter to get 10- formoxyl dihydrofoilic acid.It will
10- formoxyl dihydrofoilic acid is dissolved in 86ml purified water, adjusts pH value of solution=7.0 with sodium hydrate aqueous solution, 1.1g is added
(9.7mmol) calcium chloride, reacts at room temperature 1h, filtering, and 50 DEG C of pressing and stovings obtain 6.3g 10- formoxyl dihydrofoilic acid calcium, yield
67.7%.
Embodiment 3
It takes 15g (34.0mmol) folic acid to be dissolved in 300ml water, with potassium hydroxide aqueous solution tune reaction solution pH to 8.0, stirs
Dissolved clarification is mixed, 21.2g (204mmol) sodium hydrogensulfite is added, is warming up to 40 DEG C of insulation reaction 2h, is cooled to 0 DEG C~5 DEG C, is added dropwise
Enter hydrochloric acid, adjust reaction solution pH=0.8, keeps the temperature 0 DEG C~5 DEG C reactions for 24 hours, filtering, 50 DEG C are dried under reduced pressure to obtain 10.7g dihydro leaf
Acid, yield 71.0%.
It takes 10.7g (24.2mmol) dihydrofoilic acid salt to be dissolved in 257g formic acid, keeps the temperature 40 DEG C of reactions for 24 hours, fully reacting
Afterwards, 50 DEG C of vacuum distillations remove formic acid removal, and 107ml purified water stirring and crystallizing, filtering is added, and 50 DEG C of decompression dryings obtain 8.6g 10-
Formoxyl dihydrofoilic acid, yield 81.6%.
Embodiment 4
It takes 15g (34.0mmol) folic acid to be dissolved in 300ml water, with potassium hydroxide aqueous solution tune reaction solution pH to 8.0, stirs
Dissolved clarification is mixed, 21.2g (204mmol) sodium hydrogensulfite is added, is warming up to 40 DEG C of insulation reaction 2h, is cooled to 0 DEG C~5 DEG C, is added dropwise
Enter hydrochloric acid, adjust reaction solution pH=0.8, keeps the temperature 0 DEG C~5 DEG C reactions for 24 hours, filtering, 50 DEG C are dried under reduced pressure to obtain 10.7g dihydro leaf
Acid, yield 71.0%.
It takes 10.7g (24.2mmol) dihydrofoilic acid salt to be dissolved in 257g formic acid, keeps the temperature 40 DEG C of reactions for 24 hours, fully reacting
Afterwards, 50 DEG C of vacuum distillations remove formic acid removal, and 107ml purified water stirring and crystallizing is added, and filter to get 10- formoxyl dihydrofoilic acid.
10- formoxyl dihydrofoilic acid is dissolved in 107ml purified water, adjusts pH value of solution=6.8 with sodium hydrate aqueous solution,
1.6g (14.5mmol) calcium chloride is added, reacts at room temperature 1h, filtering, 50 DEG C of pressing and stovings obtain 6.5g 10- formoxyl dihydro leaf
Sour calcium, yield 56.0%.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (10)
1. a kind of preparation method of l-leucovorin calcium impurities, which is characterized in that the impurity is 10- formoxyl dihydrofoilic acid；Institute
The preparation method stated is reacted with reducing agent in aqueous solution using compound of formula I folic acid as raw material, respectively with aqueous alkali and inorganic
Acid adjusts reacting liquid pH value, obtains Formula II compound dihydrofoilic acid；It is reacted with the dihydrofoilic acid with formic acid, and purified water is added
Agitation and filtration obtains formula III compound 10- formoxyl dihydrofoilic acid:
2. preparation method according to claim 1, which is characterized in that the reducing agent includes sodium hydrogensulfite, burnt sulfurous
One of sour sodium is a variety of；The folic acid and reducing agent molar ratio are 1:4~6.
3. preparation method according to claim 1, which is characterized in that the aqueous alkali include sodium hydrate aqueous solution,
One of potassium hydroxide aqueous solution, aqueous sodium carbonate, wet chemical, ammonia spirit are a variety of；It is molten with the buck
Liquid adjusts reacting liquid pH value to 8~9；The inorganic acid includes one of hydrochloric acid, sulfuric acid or a variety of；It is adjusted with the inorganic acid
Reaction solution pH to 0.5~1.0.
4. preparation method according to claim 1, which is characterized in that the mass ratio of the Formula II compound and formic acid is 1:
12~36.
5. a kind of preparation method of l-leucovorin calcium impurities calcium salt, which is characterized in that the preparation method is with compound of formula I leaf
Acid is raw material, is reacted in aqueous solution with reducing agent, adjusts reacting liquid pH value with buck and inorganic acid respectively, obtains Formula II chemical combination
Object dihydrofoilic acid；It is reacted with the dihydrofoilic acid with methanol, and purified water agitation and filtration is added, obtain formula III compound 10- first
Acyl group dihydrofoilic acid:
6. preparation method according to claim 5, which is characterized in that the formula III compound in aqueous solution with calcium salt
Reaction, and reaction solution pH to 6~7.5 is adjusted with sodium hydrate aqueous solution, obtain formula IV compound 10- formoxyl dihydrofoilic acid
Calcium:
7. preparation method according to claim 5, which is characterized in that the reducing agent includes sodium hydrogensulfite, burnt sulfurous
One of sour sodium is a variety of；The folic acid and reducing agent molar ratio are 1:4~6.
8. preparation method according to claim 5, which is characterized in that the aqueous alkali include sodium hydrate aqueous solution,
One of potassium hydroxide aqueous solution, aqueous sodium carbonate, wet chemical, ammonia spirit are a variety of；It is molten with the buck
Liquid adjusts reacting liquid pH value to 8~9；The inorganic acid includes one of hydrochloric acid, sulfuric acid or a variety of；It is adjusted with the inorganic acid
Reaction solution pH to 0.5~1.0.
9. preparation method according to claim 5, which is characterized in that the mass ratio of the Formula II compound and formic acid is 1:
12~36.
10. preparation method according to claim 6, which is characterized in that the calcium salt includes calcium chloride, one in calcium acetate
Kind is a variety of；The formula III compound and calcium salt molar ratio are 1:0.5~1.0.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387953A (en) * | 2021-06-16 | 2021-09-14 | 海南通用康力制药有限公司 | Synthesis method and application of calcium folinate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4148999A (en) * | 1977-08-22 | 1979-04-10 | The Government Of The United States Of America | Preparation and purification of citrovorum factor |
| WO2018009664A1 (en) * | 2016-07-06 | 2018-01-11 | Cornell University | Stable pro-vitamin derivative compounds, pharmaceutical and dietary compositions, and methods of their use |
| CN108164531A (en) * | 2018-02-12 | 2018-06-15 | 江苏红豆杉药业有限公司 | A kind of preparation method of L-5- methyl tetrahydrofolates calcium |
| CN109627244A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | Enzyme process prepares L-5- methyl tetrahydrofolate calcium |
-
2019
- 2019-06-25 CN CN201910555291.3A patent/CN110229155B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4148999A (en) * | 1977-08-22 | 1979-04-10 | The Government Of The United States Of America | Preparation and purification of citrovorum factor |
| WO2018009664A1 (en) * | 2016-07-06 | 2018-01-11 | Cornell University | Stable pro-vitamin derivative compounds, pharmaceutical and dietary compositions, and methods of their use |
| CN108164531A (en) * | 2018-02-12 | 2018-06-15 | 江苏红豆杉药业有限公司 | A kind of preparation method of L-5- methyl tetrahydrofolates calcium |
| CN109627244A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | Enzyme process prepares L-5- methyl tetrahydrofolate calcium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387953A (en) * | 2021-06-16 | 2021-09-14 | 海南通用康力制药有限公司 | Synthesis method and application of calcium folinate |
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