CN102329318B - Preparation method of high-purity tetrahydrofolic acid - Google Patents
Preparation method of high-purity tetrahydrofolic acid Download PDFInfo
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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 tetrahydrofolic acid (THFA), thereby be to use buffered soln as reaction solution control reaction pH value specifically, 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 tetrahydrofolic acid (THFA) with high yield.
Background technology
Tetrahydrofolic acid (THFA): Tetrahydrofolic Acid, 5,6,7,8-tetrahydropreroyl-L-glutamicacid, chemical name: the pyridine of talking endlessly of N-4-[(2-amino-4-oxo-1,4,5,6,7,8-six hydrogen-6-) 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 as follows:
Tetrahydrofolic acid (THFA) is as a kind of important medicine intermediate, be widely used in fields such as biology, chemical industry, pharmacy, Biochemical Research, has very important biological physiology effect, it is mainly used in synthesizing (5)-formyl radical tetrahydrofolic acid (THFA) and salt (formyl tetrahydrofolic acid) or (5)-methyl tetrahydrofolate and salt thereof, be the coenzyme (enzyme cofactor) of transhipment and the metabolism of one-carbon unit, participate in the synthetic and metabolism of pyrimidine, purine, Serine, glycine etc. in vivo; Tetrahydrofolic acid (THFA) and derivative thereof are folic acid main action modes in vivo, can be used for treating owing to lack the megaloblastic anemia that folic acid causes; For the consistency that strengthens antifol, treat the ammonia dish purine of cancer and the consistency of methylamine dish purine especially for enhancing as toxinicide (antifolate rescue); Be used for strengthening the result for the treatment of of fluoridizing pyrimidine; Be used for the treatment of for example autoimmune disease of psoriasis and rheumatic arthritis; Be used for strengthening for example consistency of three oxygenation benzyls, two Aminometradines-sulfamethoxazole of some antiparasitic agents; Toxicity for reducing two dehydrogenation ammonia tetrahydrofolic acid (THFA)s (dideazatetrahydrofolates) in chemotherapy.Simultaneously, tetrahydrofolic acid (THFA) is the important source material of utilizing serine hydroxymethylase Production by Enzymes L-Serine.
(5)-methyl tetrahydrofolate calcium is widely used as a kind of derivative of tetrahydrofolic acid (THFA), it is very high that but its quality standard requires, if adopt the not high tetrahydrofolic acid (THFA) of purity to synthesize, so He Cheng (5) even-purifying that methyl tetrahydrofolate carries out repeatedly also is difficult to obtain satisfactory (5)-methyl tetrahydrofolate.If use purer tetrahydrofolic acid (THFA), so just can synthesize very high (the 5)-methyl tetrahydrofolate of purity at an easy rate.So the higher tetrahydrofolic acid (THFA) of purity is the key of synthetic (5)-methyl tetrahydrofolate and salt thereof.Other tetrahydrofolic acid (THFA) derivatives synthetic also run into same problem.So people are being devoted to seek a kind of method of suitable industrial mass production high purity tetrahydrofolic acid (THFA) for a long time always.
Tetrahydrofolic acid (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 tetrahydrofolic acid (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 need activate when using platinum oxide to make catalyzer and dangerous, 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. He Cheng tetrahydrofolic acid (THFA) yield purity is all lower: mention the tetrahydrofolic acid (THFA) yield about 75% according to patent (US4665176), the purity of gained tetrahydrofolic acid (THFA) only is 85% (HPLC).Adopt the tetrahydrofolic acid (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 industrial realization scale operation.
Tetrahydrofolate dehydrogenase method (WO2007084738 and US2007190596) is to adopt the biological enzyme reduction, the benefit of enzyme process maximum is specificity, it can directly be reduced into dihydrofolic acid (the 6S)-tetrahydrofolic acid (THFA) with physiologically active, (the 6S)-tetrahydrofolic acid (THFA) that synthesizes can reach (6S)-the 5-methyl tetrahydrofolate for the synthesis of l-leucovorin, is a kind of desirable 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, industrial, the technology and equipment complexity, 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 method the most frequently used in the present industrial production.The tetrahydrofolic acid (THFA) instability, 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; fracture takes place and produces pterin and p-benzoyl base L-glutamic acid (PADGA) in molecule; thereby the tetrahydrofolic acid (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 tetrahydrofolic acid (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 wish 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 in the later stage that reaction is carried out, owing to sodium borohydride decomposes in the aqueous solution easily, thereby make its concentration reduce, 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 reduces, we prepare 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: sodium borohydride=1:10, room temperature reaction 7h still has 24% folic acid unreacted, and namely the purity of final tetrahydrofolic acid (THFA) is lower, only be 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 tetrahydrofolic acid (THFA) is provided.This preparation method is simple, the purity of tetrahydrofolic acid (THFA), yield height.
Technical scheme of the present invention
A kind of preparation method of high purity tetrahydrofolic acid (THFA), with folic acid in damping fluid, by drip NaBH in batches
4Reductive agent, and control pH is reduced to tetrahydrofolic acid (THFA) with folic acid under the condition of 6-10, specifically comprises the steps:
(1), under the nitrogen protection, be that the ratio of 1:5-15:0.18-0.25:0.5-1.2 drops in the reactor 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 reactor;
Synthetic reaction process control temperature is 10-30 ℃, and pH is that 6～10, 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, glycine-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 sodium borohydride, POTASSIUM BOROHYDRIDE, vat powder or sodium bisulfite, is preferably sodium borohydride;
(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 namely gets tetrahydrofolic acid (THFA) in the presence of Vanadium Pentoxide in FLAKES.
The preparation method of above-mentioned a kind of high purity tetrahydrofolic acid (THFA), its reaction equation is as follows:
Above-mentioned gained tetrahydrofolic acid (THFA) can be directly used in preparation (6S)-tetrahydrofolic acid (THFA), (5)-formyl radical tetrahydrofolic acid (THFA) or (5)-tetrahydrofolic acid (THFA) derivatives such as methyl tetrahydrofolate.
Technique effect of the present invention
The preparation method of a kind of high purity tetrahydrofolic acid (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 the reaction times of folic acid reduction 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 sodium borohydride used in the present invention then only needs react 5h, unreacted folic acid only is 4.91 ~ 6.37% in the reaction solution.Can show thus, only be that the purity that the change of feed way just can be reduced to folic acid tetrahydrofolic acid (THFA) improves greatly, reaches 84～90%.
In addition, the operational path of its preparation process is brief, and mild condition is simple to operation, does not need to use precious metals such as platinum dioxide, and almost no coupling product generates.
Embodiment
The present invention is described in detail below in conjunction with specific embodiment, but do not limit the present invention.
Analytical procedure adopts the foodstuff additive committee member of Food and Argriculture OrganizationFAO tetrahydrofolic acid (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 tetrahydrofolic acid (THFA) Determination on content are: Agilent 1100.
The charging capacity of the amount/folic acid of tetrahydrofolic acid (THFA) yield=tetrahydrofolic acid (THFA).
Embodiment 1
A kind of preparation method of high purity tetrahydrofolic acid (THFA), step is as follows:
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 sodium borohydride 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 tetrahydrofolic acid (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 tetrahydrofolic acid (THFA), step is as follows:
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 sodium borohydride 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 tetrahydrofolic acid (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 tetrahydrofolic acid (THFA), step is as follows:
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 sodium borohydride 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 tetrahydrofolic acid (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 tetrahydrofolic acid (THFA), step is as follows:
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, afterwards repeat to drip the same sodium borohydride aqueous solution of measuring totally 5 times in the identical distance time, total coreaction sodium borohydride 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 tetrahydrofolic acid (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.
Above said content only is 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 tetrahydrofolic acid (THFA); be raw material with folic acid; it is characterized in that under nitrogen protection; with folic acid in damping fluid; being adjusted to folic acid with sodium hydroxide dissolves fully; by dripping the reductive agent for sodium borohydride, POTASSIUM BOROHYDRIDE, vat powder or sodium bisulfite in batches, and control pH is at 6-
Under 10 the condition folic acid is reduced to tetrahydrofolic acid (THFA);
The proportioning of described folic acid, buffered soln, sodium hydroxide, reductive agent is 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, 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, glycine-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.
2. the preparation method of a kind of high purity tetrahydrofolic acid (THFA) as claimed in claim 1, it is characterized in that the proportioning of described folic acid, buffered soln, sodium hydroxide, reductive agent is 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 tetrahydrofolic acid (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 tetrahydrofolic acid (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. as the preparation method of claim 1,2,3 or 4 arbitrary described a kind of high purity tetrahydrofolic acid (THFA)s, 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 reactor 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 reactor in 5-8h;
Synthetic reaction process control 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, use deionized water wash, vacuum-drying namely gets tetrahydrofolic acid (THFA) in the presence of Vanadium Pentoxide in FLAKES.
6. the preparation method of a kind of high purity tetrahydrofolic acid (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 tetrahydrofolic acid (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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| 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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|---|---|---|---|---|
| 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 |
| 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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2011
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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 |
| 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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| CP03 | Change of name, title or address |
Address after: 317200 No. 789, Renmin East Road, Chicheng street, Tiantai County, Zhejiang Patentee after: ZHEJIANG SHENGDA BIO-PHARM CO., LTD. Patentee after: Shanghai Institute of Technology Address before: 317200, Zhejiang City, Taizhou province Tiantai Road East Road Extension Patentee before: Zhejiang Shengda Pharmaceutical Co., Ltd. Patentee before: Shanghai Institute of Technology |