CN102329318A - Preparation method of high-purity tetrahydrofolic acid - Google Patents
Preparation method of high-purity tetrahydrofolic acid Download PDFInfo
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- CN102329318A CN102329318A CN 201110319838 CN201110319838A CN102329318A CN 102329318 A CN102329318 A CN 102329318A CN 201110319838 CN201110319838 CN 201110319838 CN 201110319838 A CN201110319838 A CN 201110319838A CN 102329318 A CN102329318 A CN 102329318A
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Abstract
The invention discloses a preparation method of high-purity tetrahydrofolic acid. The method comprises the following steps: using sodium hydroxide to regulate folic acid in buffer solution under the protection of nitrogen till the folic acid is completely dissolved, dripping NaBH4 reductant in batches, and reducing the folic acid into the tetrahydrofolic acid under the condition of controlling the pH at 6-10. The mixture ratio by weight ratio of the folic acid, the buffer solution, the sodium hydroxide and the reductant is 1:(5-15): (0.18-0.2):(0.5-1.2). By adopting the preparation method of the high-purity tetrahydrofolic acid, the side reactions are few, and the yield of the tetrahydrofolic acid is greatly improved and can achieve 84-90%; and furthermore, the process route of the preparation process is short, the conditions are mild, the operation is simple and easy, platinum dioxide and other precious metals do not need to be used, and the generation of byproducts can be avoided almost.
Description
Technical field
The present invention relates to a kind of preparation method of high purity THFA; Thereby be to use buffered soln specifically as reaction solution control reaction pH value; Adopt the mode of batch charging; Use the reductive agent reduction reaction at normal temperatures and pressures, the folic acid primitive reaction is complete, obtains highly purified THFA with high yield.
Background technology
THFA: Tetrahydrofolic Acid, 5,6,7,8-tetrahydropreroyl-L-glutamicacid, chemical name: N-4-[(2-amino-4-oxo-1,4,5,6,7,8-six hydrogen-6-talk endlessly pyridine) methylamino] benzoyl--L-L-glutamic acid; CAS NO. 135-16-0; Molecular formula: C
19H
23N
7O
6Molecular weight: 445.40; Its structural formula is following:
THFA is as a kind of important medicine intermediate; Be widely used in fields such as biology, chemical industry, pharmacy, Biochemical Research; Has crucial biological physiology effect; It is mainly used in synthetic (5)-formyl radical THFA and salt (LEUCOVORIN ACETATE) or (5)-methyl tetrahydrofolate and salt thereof, is the transhipment and the metabolic coenzyme (enzyme cofactor) of one-carbon unit, participates in the synthetic and metabolism of pyrimidine, purine, Serine, glycocoll etc. in vivo; THFA and verivate thereof are folic acid main action modes in vivo, can be used for treating owing to lack the megaloblastic anemia that folic acid causes; Be used to strengthen the consistency of antifol as toxinicide (antifolate rescue), especially for the ammonia dish purine that strengthens the treatment cancer and the consistency of methylamine dish purine; Be used to strengthen the result of treatment of fluoridizing pyrimidine; Be used to treat the for example autoimmune disease of psoriasis and rheumatic arthritis; Be used to strengthen the for example consistency of three oxygenation benzyls, two Aminometradines-sulfamethoxazole of some antiparasitic agents; Be used for being reduced in the toxicity of chemotherapy two dehydrogenation ammonia THFAs (dideazatetrahydrofolates).Simultaneously, THFA is an important source material of utilizing serine hydroxymethylase Production by Enzymes L-Serine.
(5)-methyl tetrahydrofolate calcium used as a kind of verivate of THFA widely; It is very high that but its quality standard requires; If adopt the not high THFA of purity to synthesize, so synthetic (5) even-purifying that methyl tetrahydrofolate carries out repeatedly also is difficult to obtain satisfactory (5)-methyl tetrahydrofolate.If use purer THFA, so just can synthesize very high (the 5)-methyl tetrahydrofolate of purity at an easy rate.So the higher THFA of purity is the key of synthetic (5)-methyl tetrahydrofolate and salt thereof.Other THFA verivates synthetic also run into same problem.So people are being devoted to seek a kind of method of suitable industrial mass production high purity THFA for a long time always.
THFA is mainly obtained by the folic acid reduction at present, and the method for often using has: chemical reduction method, Tetrahydrofolate dehydrogenase method, shortening method etc.
The shortening method is divided into normal pressure catalytic hydrogenation method and pressurized catalysis hydrogenation method again, be a kind of main method for preparing THFA in early days, but there are a lot of shortcomings in it.1. catalyst levels is bigger: the reduction folic acid of mentioning in the patent (US4665176) need use metal catalyst; Platinum-carbon wherein; The effect of rhodium-carbon catalyst is not very desirable, and needs activation and danger when using platinum oxide to make catalyzer, and all catalyst consumption are all very big.2. the reaction times is longer: patent (US4665176 and US3983118) all needs catalytic hydrogenation 8-24h, also mentions in the patent (US20090198055), and during at 0-5 ℃, the reaction times needs 74h especially at reduction temperature.3. synthetic THFA yield purity is all lower: mention the THFA yield about 75% according to patent (US4665176), the purity of gained THFA is merely 85% (HPLC).Adopt the THFA of this method gained in sum because productive rate is all lower with purity, and the problem of unresolved follow-up purification, make this method be difficult in industry and go up realization scale operation.
Tetrahydrofolate dehydrogenase method (WO2007084738 and US2007190596) is to adopt the biological enzyme reduction; The maximum benefit of enzyme process is a specificity; It can directly be reduced into (the 6S)-THFA with physiologically active with dihydrofolic acid; Synthetic (6S)-THFA can be used for synthetic LFP 754 and reach (6S)-the 5-methyl tetrahydrofolate, is a kind of ideal method.But need to use a large amount of coenzyme NADP 11s in its production process, and need to build the NADPH regeneration system rapidly that matches.Present this method only is adapted at the laboratory carries out, and in the industry, technology and equipment is complicated, and cost is higher, so it is also very difficult this method to be used for scale operation.
Chemical reduction method is the borohydride reduction method, and reductive agent commonly used has NaBH
4(J.Med.Chem., (1979), 22:731, EP0495204 etc.), KBH
4(EP0537842), Na
2S
2O
4+ KBH
4(CN101531661), NaHSO
3(Peking University's journal, (2006), 38:436).Chemical reduction method also is a method the most frequently used in the present industrial production.THFA is unstable, and oxidized and non-refractory will react under nitrogen protection so react easily.Main influence factor has the mass ratio of temperature, reductive agent and folic acid, the pH value of reaction times and reaction solution etc.
Wherein reaction solution pH is bigger to the influence of reaction, NaBH
4, KBH
4, Na
2S
2O
4, NaHSO
3All has strong basicity Deng reductive agent; Thereby the pH value of reaction solution can constantly raise in the process that drips; When reaction solution alkalescence is too strong, a large amount of side reactions will take place, and molecule fracture takes place produces pterin and p-benzoyl base L-glutamic acid (PADGA); Thereby the THFA productive rate that reaction obtains is lower and purity is not high, separation difficulty.The concentration of the buffered soln that uses need be carried out certain change according to the amount of reductive agent.Using buffered soln is exactly to control the pH value of reaction solution to greatest extent as the advantage of reaction solution, thereby significantly reduces the generation of side reaction.
Temperature of reaction also has certain influence to reaction, and speed of reaction was very fast when temperature was higher, but side reaction is a lot, thereby the THFA productive rate that obtains is lower and purity is not high, has increased difficulty for equally follow-up purification.Reaction can more leniently be carried out under the room temperature, but the reaction times is longer, and reaction not exclusively produces a large amount of dihydrofolic acid.So people hope to find a kind of method that can at room temperature rapidly and efficiently reduce folic acid always.
Traditional disposable feed way in the early stage that reaction is carried out, because reductant concentration is too high, causes reaction too violent, causes the generation of side reaction; And,, thereby make its concentration reduce owing to Peng Qinghuana decomposes in the aqueous solution easily in the later stage that reaction is carried out, even prolong the reaction times, still have a large amount of dihydrofolic acid unreacteds complete.And the feeding mode of batch charging is with regard to good two problems of appeal that solved; Because the amount of the reductive agent that begins to drop into is fewer; So avoided the too violent problem of reaction of traditional feed way mid-early stage appearance, when the concentration of reductive agent in the reaction solution reduced, we prepared reductive agent again and drop in the reaction solution; The concentration that keeps reductive agent in the reaction solution improves reduction efficiency.We find in the presence of buffered soln to follow the tracks of reaction through HPLC; Adopt folic acid: Peng Qinghuana=1:10, room temperature reaction 7h still has 24% folic acid unreacted, and promptly the purity of final THFA is lower; Be merely 63～70%, reaction conditions just is not suitable for suitability for industrialized production like this.
Summary of the invention
The objective of the invention is in order to solve above-mentioned folic acid under the highly basic condition, the molecule decomposition of rupturing easily, thus cause a large amount of impurity, influence the problem of quality and yield, and a kind of preparation method of high purity THFA is provided.This preparation method is simple, the purity of THFA, yield height.
Technical scheme of the present invention
A kind of preparation method of high purity THFA, with folic acid in damping fluid, through drip NaBH in batches
4Reductive agent, and control pH is reduced to THFA with folic acid under the condition of 6-10, specifically comprises the steps:
(1), under the nitrogen protection; Is that the ratio of 1:5-15:0.18-0.25:0.5-1.2 drops in the reaction kettle and carries out building-up reactions with folic acid, buffered soln, sodium hydroxide, reductive agent in mass ratio; Wherein reductive agent is in 5-8h; The control identical distance time, divide 3～6 batches and join in the reaction kettle;
The synthetic reaction process controlled temperature is 10-30 ℃, and pH is 6～10, and pH is preferably 7, and mixing speed is 60～120r/min, and the time gets reaction solution after being 5-8h;
Described buffered soln comprises Sodium phosphate, dibasic-citric acid solution, SODIUM PHOSPHATE, MONOBASIC-disodium hydrogen phosphate buffer solution, hydrogen Sodium phosphate, dibasic-potassium dihydrogen phosphate buffer solution, Veronal sodium-hydrochloric acid buffer solution, Tutofusin tris (Tris)-hydrochloric acid buffer solution, boric acid-borax buffer solution, glycocoll-sodium hydroxide buffer solution, borax-sodium hydroxide buffer solution, yellow soda ash-sodium bicarbonate buffer solution or Britton-Robinson buffered soln etc.;
The pH value scope of described buffered soln is 1-14, and suitable pH value scope is 6-10; The concentration of buffered soln is 0.05-2mol/L, and suitable concentration is 0.1mol/L-0.5mol/L;
Described reductive agent is Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, vat powder or sodium sulfite anhy 96, is preferably Peng Qinghuana;
(2), the reaction solution of the gained of step (1) is preferably regulated pH to 3.0-3.5 with 2M hydrochloric acid, separate out the rice white solid, with solid filtering, spend ion-cleaning, vacuum-drying promptly gets THFA in the presence of Vanadium Pentoxide in FLAKES.
The preparation method of above-mentioned a kind of high purity THFA, its reaction equation is following:
Above-mentioned gained THFA can directly be used for preparation (6S)-THFA, (5)-formyl radical THFA or (5)-THFA verivates such as methyl tetrahydrofolate.
Technique effect of the present invention
The preparation method of a kind of high purity THFA of the present invention since with buffered soln as reaction solution, dripping NaBH thereby overcome
4Process in the problem that constantly raises of the pH value of reaction solution, make to drip NaBH
4The pH of reaction solution maintains particular value in the process of reductive agent, thereby reduces the generation of side reaction.
Simultaneously, owing to adopt the mode of batch charging to drip NaBH in the preparation process
4Reductive agent has solved temperature of reaction when low, and the long and reaction of folic acid reductive reaction times not exclusively produces the problem of a large amount of dihydrofolic acid, and reaction can at room temperature react completely fast.And adopt the method that in the reaction times, in batches adds Peng Qinghuana used in the present invention then only needs react 5h, unreacted folic acid is merely 4.91 ~ 6.37% in the reaction solution.Can show thus, only be that the change of feed way just can improve the purity that folic acid is reduced to THFA greatly, reaches 84～90%.
In addition, the operational path of its preparation process is brief, and mild condition is simple to operation, need not use precious metals such as platinum dioxide, and almost no coupling product generates.
Embodiment
Below in conjunction with specific embodiment the present invention is elaborated, but does not limit the present invention.
Analytical procedure adopts the foodstuff additive committee member of Food and Argriculture OrganizationFAO THFA quality standard, 2005 JECFA.25th. FNP.52 Add 13 (2005).
Separator column adopts Hypersil-ODS-C18 (5um; 25 * 04mm), 35 ℃ of column temperatures.Moving phase: 8% methyl alcohol (CH3OH)-50M potassium primary phosphate (pH6.3) damping fluid, flow velocity is 1ml/min.
Folic acid, the used instrument of THFA Determination on content are: Agilent 1100.
The charging capacity of the amount/folic acid of THFA yield=THFA.
Embodiment 1
A kind of preparation method of high purity THFA, step is following:
Under the nitrogen protection, with 10g folic acid be suspended in 100ml buffered soln (in 0.2M boric acid-borax buffer solution, pH=8) in, drip 20%NaOH to pH=7;
Under 25 ℃, slowly drip sodium borohydride aqueous solution (2g is dissolved in the 5ml water), dropwise the back and under this temperature, react 1h; Sodium borohydride aqueous solution is repeated to drip totally 5 times in the identical distance time in the back; Total coreaction Peng Qinghuana 10g, reaction times 6h altogether, reaction solution is light brown;
Above-mentioned reaction process control mixing speed is 60-120r/min;
Regulate pH to 3.0-3.5 with 2M HCl, constantly separate out the rice white solid, filter, with deionized water wash twice, obtain the rice white solid, vacuum-drying gets THFA 8.4g in the presence of Vanadium Pentoxide in FLAKES, and content is 95.4%, and yield is 84.0%.
Above-mentioned behind total reaction time 5h, the reaction solution sampling, the folate content in the assaying reaction liquid, its content are 6.50%, the result accounts for 6.37% of phyllome acid content.
Embodiment 2
A kind of preparation method of high purity THFA, step is following:
Under the nitrogen protection, with 25g folic acid be suspended in 250ml buffered soln (in 0.2M Sodium phosphate, dibasic-sodium dihydrogen phosphate buffer, pH=8) in, drip 20%NaOH to pH=8;
Under 25 ℃, slowly drip sodium borohydride aqueous solution (5g is dissolved in the 10ml water), dropwise the back and under this temperature, react 1h; Sodium borohydride aqueous solution is repeated to drip totally 5 times in the identical distance time in the back; Total coreaction Peng Qinghuana 25g, reaction times 6h altogether, reaction solution is light brown;
Above-mentioned reaction process control mixing speed is 60-120r/min;
The reaction solution of gained is regulated pH to 3.0-3.5 with 2M HCl, constantly separates out the rice white solid, filters; With deionized water wash twice, obtain the rice white solid, vacuum-drying gets THFA 22g in the presence of Vanadium Pentoxide in FLAKES; Content is 97.7%, and yield is 88.0%.
Above-mentioned behind total reaction time 5h, the reaction solution sampling, the folate content in the assaying reaction liquid, its content are 5.86%, the result accounts for 5.63% of phyllome acid content.
Embodiment 3
A kind of preparation method of high purity THFA, step is following:
Under the nitrogen protection, with 100g folic acid be suspended in 1000ml buffered soln (in 0.2M Sodium phosphate, dibasic-sodium dihydrogen phosphate buffer, pH=8) in, drip 20%NaOH to pH=6;
Under 25 ℃, slowly drip sodium borohydride aqueous solution (20g is dissolved in the 50ml water), dropwise the back and under this temperature, react 1h; Sodium borohydride aqueous solution is repeated to drip totally 5 times in the identical distance time in the back; Total coreaction Peng Qinghuana 100g, reaction times 6h altogether, reaction solution is light brown;
Above-mentioned reaction process control mixing speed is 60-120r/min;
The reaction solution of gained is regulated pH to 3.0-3.5 with 2M HCl, constantly separates out the rice white solid, filters; With deionized water wash twice, obtain the rice white solid, vacuum-drying gets THFA 90.2g in the presence of Vanadium Pentoxide in FLAKES; Content is 98.9%, and yield is 90.2%.
Above-mentioned behind total reaction time 5h, the reaction solution sampling, the folate content in the assaying reaction liquid, its content are 4.98%, the result accounts for 4.93% of phyllome acid content.
Embodiment 4
A kind of preparation method of high purity THFA, step is following:
Under the nitrogen protection, with 100g folic acid be suspended in 1000ml buffered soln (in 0.2M Sodium phosphate, dibasic-sodium dihydrogen phosphate buffer, pH=8) in, drip 20%NaOH to pH=6;
Under 25 ℃; Slowly drip sodium borohydride aqueous solution (20g is dissolved in the 50ml water); Dropwise the back and under this temperature, react 1h, the back repeated to drip with the sodium borohydride aqueous solution of amount totally 5 times in the identical distance time, total coreaction Peng Qinghuana 100g; Reaction times 6h altogether, reaction solution is light brown;
Above-mentioned reaction process control mixing speed is 60-120r/min;
The reaction solution of gained is regulated pH to 3.0-3.5 with 2M HCl, constantly separates out the rice white solid, filters; With deionized water wash twice, obtain the rice white solid, vacuum-drying gets THFA 88.7g in the presence of Vanadium Pentoxide in FLAKES; Content is 98.5%, and yield is 88.7%.
Above-mentioned behind total reaction time 5h, the reaction solution sampling, the folate content in the assaying reaction liquid, its content are 5.02%, the result accounts for 4.91% of phyllome acid content.
The above content is merely the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (7)
1. the preparation method of a high purity THFA is a raw material with folic acid, it is characterized in that under nitrogen protection, folic acid in damping fluid, is adjusted to folic acid with sodium hydroxide and dissolves fully, through drip NaBH in batches
4Reductive agent, and control pH is reduced to THFA with folic acid under the condition of 6-10;
The proportioning of described folic acid, buffered soln, sodium hydroxide, reductive agent is a folic acid by mass ratio: buffered soln: sodium hydroxide: reductive agent is 1:5-15:0.18-0.25:0.5-1.2;
Described buffered soln is Sodium phosphate, dibasic-citric acid solution, SODIUM PHOSPHATE, MONOBASIC-disodium hydrogen phosphate buffer solution, hydrogen Sodium phosphate, dibasic-potassium dihydrogen phosphate buffer solution, Veronal sodium-hydrochloric acid buffer solution, Tutofusin tris-hydrochloric acid buffer solution, boric acid-borax buffer solution, glycocoll-sodium hydroxide buffer solution, borax-sodium hydroxide buffer solution, yellow soda ash-sodium bicarbonate buffer solution or Britton-Robinson buffered soln;
The pH value scope of described buffered soln is 4-12, and the concentration of buffered soln is 0.05-2mol/L;
Described reductive agent is Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, vat powder or sodium sulfite anhy 96.
2. the preparation method of a kind of high purity THFA as claimed in claim 1, it is characterized in that the proportioning of described folic acid, buffered soln, sodium hydroxide, reductive agent is a folic acid by mass ratio: buffered soln: sodium hydroxide: reductive agent is preferably 1:10:0.2:1.
3. the preparation method of a kind of high purity THFA as claimed in claim 2 is characterized in that the pH value scope of described buffered soln is preferably 6-10; The concentration of buffered soln is preferably 0.1mol/L-0.5mol/L.
4. the preparation method of a kind of high purity THFA as claimed in claim 3 is characterized in that the pH value scope of described buffered soln is preferably 8; The concentration of buffered soln is preferably 0.2mol/L.
5. like the preparation method of claim 1,2,3 or 4 arbitrary described a kind of high purity THFAs, it is characterized in that specifically comprising the steps:
(1), under the nitrogen protection, folic acid, buffered soln, sodium hydroxide, reductive agent dropped in the reaction kettle than proportioning by quality carry out building-up reactions, wherein reductive agent the control identical distance time, divides 3～6 batches and joins in the reaction kettle in 5-8h;
The synthetic reaction process controlled temperature is 10-30 ℃, and pH is 6-10, and mixing speed is 60-120r/min, and the time gets reaction solution after being 5-8h;
(2), the reaction solution of the gained of step (1) is regulated pH to 3.0-3.5 with hydrochloric acid, separate out the rice white solid, with solid filtering, spend ion-cleaning, vacuum-drying promptly gets THFA in the presence of Vanadium Pentoxide in FLAKES.
6. the preparation method of a kind of high purity THFA as claimed in claim 5 is characterized in that the pH of the described synthetic reaction process control of step (1) is preferably 7, and temperature is preferably 25 ℃.
7. the preparation method of a kind of high purity THFA as claimed in claim 6 is characterized in that the used concentration of hydrochloric acid of step (2) adjusting pH is preferably 2M.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635405A (en) * | 2020-07-02 | 2020-09-08 | 无锡紫杉药业有限公司 | Production process of calcium tetrahydrofolate preparation |
| CN114163439A (en) * | 2021-12-01 | 2022-03-11 | 哈尔滨工业大学（深圳） | Method for preparing tetrahydrofolic acid by catalytic hydrogenation |
| CN114874216A (en) * | 2022-05-19 | 2022-08-09 | 无锡紫杉药业有限公司 | Preparation method of L-5-methyltetrahydrofolic acid |
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| EP0608002A1 (en) * | 1986-09-03 | 1994-07-27 | University Of Strathclyde | Optically active compounds |
| US6162914A (en) * | 1998-04-24 | 2000-12-19 | Cerbios-Pharma S.A. | Process for the reduction of pterins |
| CN101531661A (en) * | 2009-04-15 | 2009-09-16 | 湖北省琴断口监狱 | Preparation method of tetrahydrofolic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124452A (en) * | 1978-07-10 | 1992-06-23 | Bioresearch S.P.A. | Process for producing d,1-5-methyltetrahydrofolic acid and its salts |
| EP0608002A1 (en) * | 1986-09-03 | 1994-07-27 | University Of Strathclyde | Optically active compounds |
| US6162914A (en) * | 1998-04-24 | 2000-12-19 | Cerbios-Pharma S.A. | Process for the reduction of pterins |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635405A (en) * | 2020-07-02 | 2020-09-08 | 无锡紫杉药业有限公司 | Production process of calcium tetrahydrofolate preparation |
| CN114163439A (en) * | 2021-12-01 | 2022-03-11 | 哈尔滨工业大学（深圳） | Method for preparing tetrahydrofolic acid by catalytic hydrogenation |
| CN114874216A (en) * | 2022-05-19 | 2022-08-09 | 无锡紫杉药业有限公司 | Preparation method of L-5-methyltetrahydrofolic acid |
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