CN103265444B - Crystallization method of 5-aminolevulinic acid phosphate - Google Patents
Crystallization method of 5-aminolevulinic acid phosphate Download PDFInfo
- Publication number
- CN103265444B CN103265444B CN201310144703.7A CN201310144703A CN103265444B CN 103265444 B CN103265444 B CN 103265444B CN 201310144703 A CN201310144703 A CN 201310144703A CN 103265444 B CN103265444 B CN 103265444B
- Authority
- CN
- China
- Prior art keywords
- ala
- phosphatic
- acid phosphate
- salt
- aminolevulinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to a crystallization method of 5-aminolevulinic acid phosphate. The crystallization method comprises the following steps of carrying out ion-exchange of 5-aminolevulinate broth or other solutions containing 5-aminolevulinate to remove anions and a part of impurities, adding phosphoric acid into the treated solution according to a mole ratio of 1: 1 to 1.2: 1 to obtain a 5-aminolevulinic acid phosphate solution, carrying out decoloring and filtration of the 5-aminolevulinic acid phosphate solution, carrying out vacuum condensation of the 5-aminolevulinic acid phosphate solution to obtain 400 to 600g/l of the concentrated solution, gradually cooling the concentrated solution at a cooling rate of 10 to 15 DEG C/h with stirring at a stirring rate of 50 to 200rpm until crystal nucleuses are produced in the concentrated solution, carrying out constant-temperature crystal growing for 1 to 2h, sequentially carrying out stirring cooling until a temperature is in a range of -5 to 0 DEG C, carrying out filtration separation of the crystals, and drying at a temperature of 50 to 70 DEG C to obtain the 5-aminolevulinic acid phosphate crystals. The crystallization method does not adopt an organic solvent, avoids solvent residual and is conducive to use of 5-aminolevulinic acid phosphate in the medicine field.
Description
Technical field
The present invention relates to the phosphatic crystallization method of a kind of 5-ALA.
Background technology
5-ALA (5-amino1evulinic acid, ALA) is that the interior tetrapyrrole compounds of organism is (as protoheme, porphyrin and vitamins B
12deng) common precursor, there is important physiologically active.5-ALA can be used as photosynthesis promoter, adverse-resistant agent, defoliant and weedicide etc. in agricultural, of many uses, environmentally friendly.At medical field, 5-ALA is having great using value as New Generation Optical kinetics medicine aspect the diagnosis of the disease such as brain tumor, skin carcinoma and treatment.
The unstable chemcial property of 5-ALA, commercially available commercial form mostly is its hydrochloride, a kind of crystallization method of 5-ALA hydrochloride is disclosed in CN 200910100980, because hydrochloric acid is volatility strong acid, ALA hydrochloride is in preparation process and mixing, dispersion process, due to the volatilization of hydrochloric acid, equipment is produced to corrosion, and produce irritating smell.
Different with it, phosphoric acid is non-volatile acid, and a little less than acidity than hydrochloric acid is, in the phosphatic preparation process of ALA and mixing, dispersion process, no acidic gaseous volatilization, also significantly reduces the corrosion of equipment.
Meanwhile, because the phosphatic solubleness of 5-ALA is starkly lower than hydrochloride, see accompanying drawing 1.Therefore,, in the time preparing 5-ALA phosphoric acid salt from 5-ALA fermented liquid, can obtain higher crystallization yield.
Relate to the phosphatic crystallization method of ALA, that has reported is solvent-non-solvent precipitator method, crystallization method as disclosed in CN 200780000942 is solvent precipitation, it uses methyl alcohol, ethanol, Virahol is as precipitation solvent, the disclosed crystallization method of CN 200780022901 is the poor solvent precipitator method, it uses methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, gamma-butyrolactone, 1, 4-dioxan, methyl cellosolve, tetraethylene glycol dimethyl ether, triglyme is as poor solvent, because crystallisation process has used organic solvent, inevitably can bring the problem of dissolvent residual, in the time that product is used for field of medicaments, dissolvent residual just becomes the major issue that need keep a close eye on, especially for 1, micro-poison such as 4-dioxan, there is the organic solvent of carinogenicity all the more so.
The present invention, in the situation that not using any organic solvent, prepares highly purified ALA phosphate crystal.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide a kind of 5-ALA phosphatic crystallization method, crystallization purity of the present invention is high, good stability, cost is low and process is environmentally friendly.
The object of the invention is to realize by following scheme: the phosphatic crystallization method of a kind of 5-ALA, comprises the following steps:
(1) preparation quality concentration is the phosphatic thick aqueous solution of 5-ALA of 400 ~ 600 g/L, and this step realizes by following sub-step:
(1.1) fermented liquid of 5-ALA is removed to thalline through microfiltration of ceramic membrane, obtain fermentation clear liquid; Or the concentration of the salt of 5-ALA being dissolved and be diluted to 5-ALA is 0.1M, obtains the dilute solution of 5-ALA salt.
(1.2) dilute solution of fermentation clear liquid step 1.1 being obtained or 5-ALA salt is by hydrogen type strong acid ion exchange resin, 5-ALA is attracted on resin, use deionized water washing resin, remove impurity, use again alkali lye desorb 5-ALA, obtain stripping liquid.
(1.3) in the stripping liquid obtaining, add phosphoric acid acidifying, make stripping liquid pH value reach 2.8 ~ 3.2.
(1.4) in stripping liquid, adding massfraction is 1 ~ 5% Powdered Activated Carbon, and stirring at normal temperature decolouring 30 ~ 60min, filters, and obtains the filtrate of achromaticity and clarification.
(1.5) filtrate vacuum concentration to 5-ALA phosphate concn at 65 ~ 70 DEG C is reached to 400 ~ 600g/L, obtain the phosphatic thick aqueous solution of 5-ALA that 65 ~ 70 DEG C of mass concentrations are 400 ~ 600 g/L.
(2) the phosphatic thick aqueous solution of 5-ALA step 1 being made is cooling gradually under agitation condition, mixing speed is 50 ~ 200 rpm, the rate of temperature fall of crystallisation process is controlled at 10 ~ 15 DEG C/h, stir when 1-3h has nucleus to occur and stop stirring, constant temperature growing the grain 1 ~ 2 h, continues stirring and is cooled to-5 ~ 0 DEG C; By gained crystal separation, solid vacuum-drying 2 ~ 6 h below 65 DEG C obtain the phosphatic crystallization of 5-ALA.
(3) liquid after separating is operated by step 1.2-1.5 and step 2, obtain the phosphatic secondary crystal of 5-ALA;
(4) the phosphatic secondary crystal of 5-ALA that the phosphatic crystallization of 5-ALA that combining step 2 obtains and step 3 obtain, obtains 5-ALA phosphoric acid salt.
The invention has the beneficial effects as follows, the present invention carrys out crystallization by the thick aqueous solution of phosphatic 5-ALA high density by cooling.Adopt aforesaid method, more than the purity of the 5-ALA phosphate crystal obtaining can reach 99 %, secondary crystallization total recovery reaches 91 %.The principal feature of the method is that 5-ALA phosphate crystal directly separates out from the aqueous solution.Compared with prior art, total recovery of the present invention is high, has avoided the use of a large amount of organic solvent, has reduced and has realized the step that crystallization needs, and has saved production time and cost, and production process is environmentally friendly.
Brief description of the drawings
Fig. 1 is ALA hydrochloride and phosphoric acid salt solubility curve figure under differing temps.
Fig. 2 is 5-ALA phosphate crystal photo.
Embodiment
The phosphatic crystallization method of 5-ALA of the present invention, comprises the following steps:
1, preparation quality concentration is the phosphatic thick aqueous solution of 5-ALA of 400 ~ 600 g/L.
This step can be realized by following two kinds of modes:
First kind of way: be the phosphatic thick aqueous solution of 5-ALA of 400 ~ 600 g/L by fermentation method preparation quality concentration.Comprise following sub-step:
The fermented liquid of the 5-ALA 1.1, being obtained by the method described in CN 200710068170.3, removes thalline through microfiltration of ceramic membrane, obtains fermentation clear liquid.
1.2, fermentation clear liquid is passed through to hydrogen type strong acid ion exchange resin, 5-ALA is attracted on resin, uses deionized water washing resin, remove the impurity such as the pigment that is not adsorbed, sugar, negatively charged ion, organic acid, use again alkali lye desorb 5-ALA, obtain stripping liquid.
1.3, in the stripping liquid obtaining, add phosphoric acid acidifying, make stripping liquid pH value reach 2.8 ~ 3.2.
1.4, in stripping liquid, adding massfraction is 1 ~ 5% Powdered Activated Carbon, and stirring at normal temperature decolouring 30 ~ 60min, filters, and obtains the filtrate of achromaticity and clarification.
1.5, filtrate vacuum concentration to 5-ALA phosphate concn at 65 ~ 70 DEG C is reached to 400 ~ 600g/l, obtain the phosphatic thick aqueous solution of 5-ALA that 65 ~ 70 DEG C of mass concentrations are 400 ~ 600 g/L.
The second way: salt (including but not limited to perchlorate, hydriodate, vitriol, hydrobromate, hydrochloride, nitrate, oxalate, sulphite, pyruvate salt, nitrite or their aqueous solution) the preparation quality concentration by 5-ALA is the phosphatic thick aqueous solution of 5-ALA of 400 ~ 600 g/L.Comprise the following steps:
1.1, the salt of 5-ALA (or their aqueous solution) being dissolved and is diluted to 5-ALA concentration is 0.1 M, obtains the dilute solution of 5-ALA salt.
1.2, the dilute solution of the 5-ALA salt obtaining is passed through to hydrogen type strong acid ion exchange resin, 5-ALA is attracted on resin, use deionized water washing resin, remove the impurity such as the negatively charged ion not being adsorbed, use again alkali lye desorb 5-ALA, obtain stripping liquid.
1.3, in the stripping liquid obtaining, add phosphoric acid acidifying, make stripping liquid pH value reach 2.8 ~ 3.2.
1.4, in stripping liquid, adding massfraction is the Powdered Activated Carbon of 1 ~ 5 %, and stirring at normal temperature decolouring 30 ~ 60 min, filter, and obtain the filtrate of achromaticity and clarification.
1.5, filtrate vacuum concentration to 5-ALA phosphate concn at 65 ~ 70 DEG C is reached to 400 ~ 600 g/L, obtain the phosphatic thick aqueous solution of 5-ALA that 65 ~ 70 DEG C of mass concentrations are 400 ~ 600g/L.
2, the phosphatic thick aqueous solution of the 5-ALA that is 400 ~ 600 g/L by 65 ~ 70 DEG C of mass concentrations is cooling gradually under agitation condition, mixing speed is 50 ~ 200 rpm, the rate of temperature fall of crystallisation process is controlled at 10 ~ 15 DEG C/h, stir when 1-3h has nucleus to occur and stop stirring, constant temperature growing the grain 1 ~ 2 h, continues stirring and is cooled to-5 ~ 0 DEG C; By gained crystal separation, solid vacuum-drying 2 ~ 6 h below 65 DEG C obtain the phosphatic crystallization of 5-ALA.
3, the liquid after separation is the phosphatic aqueous solution of 5-ALA, comprises in addition the impurity such as chlorion and sodium ion.Liquid after separation can operate by step 1.2-1.5 and step 2, obtains the phosphatic secondary crystal of 5-ALA, thereby improves the utilization ratio of raw material, reduces production costs.
4, the phosphatic secondary crystal of 5-ALA that the phosphatic crystallization of 5-ALA that combining step 2 obtains and step 3 obtain, obtains 5-ALA phosphoric acid salt.
Method of the present invention is by purifying, the control of phosphoric acid consumption and the control of condensing crystal process to 5-ALA salts solution, successfully realize the phosphatic aqueous solution crystallization of 5-ALA, avoid with an organic solvent, made the finished product stop dissolvent residual.
Further illustrate this invention below in conjunction with embodiment, it is more obvious that object of the present invention and effect will become.
Embodiment 1
The 36 g 5-ALA crystal of hydrochloride deionized water dissolvings that method by described in CN 200910100980.1 is obtained, be diluted to 0.1 M, by hydrogen type strong acid ion exchange resin, with deionized water wash, remove chlorion, use alkali lye desorb, collect stripping liquid 400 ml between pH 3 to pH 7,5-ALA concentration is 0.43 M.In stripping liquid, add phosphoric acid to be adjusted to pH to 2.8; Add 4 g Powdered Activated Carbons, 15 DEG C are stirred decolouring 30 minutes, filter, and obtain the destainer of achromaticity and clarification; Destainer is reached to 430 g/l in 65 DEG C of vacuum concentration to 5-ALA phosphate concn; By concentrated solution cooling gradually under agitation condition, mixing speed is 60 rpm, and rate of temperature fall is controlled at 10 DEG C/h, stops stirring in the time there is nucleus in solution, and constant temperature growing the grain 2 h, continue stirring and be cooled to 0 DEG C; Filtering separation crystal, 65 DEG C dry.Finally obtain 5-ALA phosphate crystal as shown in Figure 2, quality is 28.7 g, and purity is 99.3 %, and crystallization yield is 72.8 %.
Embodiment 2
Remove 5-ALA fermented liquid 18.6 L of thalline through micro-filtration, 5-ALA concentration is 25.1 mM, after separating by ion-exchange, stripping liquid between pH 3 to pH 7 is adjusted to pH 3.2 with 85% phosphoric acid solution, obtain the phosphatic thick aqueous solution of 5-ALA of 1850 ml, wherein 5-ALA phosphate concn is 46.8 g/L, with 37 g powder activity carbon decolorings, after stirring 30 min, filter, with a small amount of deionized water wash gac filter cake, the filtrate obtaining vacuum concentration to 5-ALA phosphate concn at 65 DEG C reaches 570 g/l, by concentrated solution cooling gradually under agitation condition, mixing speed is 100 rpm, rate of temperature fall is controlled at 15 DEG C/h, in the time there is nucleus in solution, stop stirring, constant temperature growing the grain 2 h, continue to stir and be cooled to 0 DEG C, suction filtration isolation of crystalline, 65 DEG C dry.Finally obtain 5-ALA phosphate crystal 63.2 g, purity is 99.4 %, and primary crystallization yield is 73.0 %.To suction filtration residue mother liquor again decolour, filtration, vacuum concentration post crystallization, separate and obtain 5-ALA phosphate crystal 16.4 g, purity is 99.2 %, two-stage crystallization total recovery is 91.9 %.
Embodiment 3
By in embodiment 1 and embodiment 2, the suction filtration residue mother liquor that Crystallization Separation step obtains mixes, being diluted to 5-ALA concentration with deionized water is 0.1 M, liquor capacity is 5.49 L, remove the negatively charged ion in solution by ion-exchange, use alkali lye desorb, collect stripping liquid 1050 ml between pH 3 to pH 7,5-ALA concentration is 0.42 M, in stripping liquid, add phosphoric acid 35.6 ml of 85 % to be adjusted to pH 3.2, add 40 g Powdered Activated Carbons in stripping liquid, 15 DEG C are stirred decolouring 50 minutes, filter, obtain the destainer of achromaticity and clarification.Destainer vacuum concentration to 5-ALA phosphate concn at 70 DEG C is reached to 580 g/l, by concentrated solution cooling gradually under agitation condition, mixing speed is 200 rpm, rate of temperature fall is controlled at 10 DEG C/h, in the time there is nucleus in solution, stop stirring, constant temperature growing the grain 1 h, continues stirring and is cooled to 0 DEG C, isolation of crystalline, 65 DEG C of vacuum-dryings.Finally obtain 5-ALA phosphate crystal 78.1 g, purity is 99.6 %, and crystallization yield is 77.3 %.
Above-described embodiment is used for the present invention that explains, instead of limits the invention, and in the protection domain of spirit of the present invention and claim, any amendment and change that the present invention is made, all fall into protection scope of the present invention.
Claims (2)
1. the phosphatic crystallization method of 5-ALA, is characterized in that, comprises the following steps:
(1) preparation quality concentration is the phosphatic thick aqueous solution of 5-ALA of 400 ~ 600 g/L, and this step realizes by following sub-step:
(1.1) fermented liquid of 5-ALA is removed to thalline through microfiltration of ceramic membrane, obtain fermentation clear liquid; Or the concentration of the salt of 5-ALA being dissolved and be diluted to 5-ALA is 0.1M, obtains the dilute solution of 5-ALA salt;
(1.2) fermentation clear liquid step (1.1) being obtained or the dilute solution of 5-ALA salt are by hydrogen type strong acid ion exchange resin, 5-ALA is attracted on resin, use deionized water washing resin, remove impurity, use again alkali lye desorb 5-ALA, obtain stripping liquid;
(1.3) in the stripping liquid obtaining, add phosphoric acid acidifying, make stripping liquid pH value reach 2.8 ~ 3.2;
(1.4) in stripping liquid, adding massfraction is 1 ~ 5% Powdered Activated Carbon, and stirring at normal temperature decolouring 30 ~ 60min, filters, and obtains the filtrate of achromaticity and clarification;
(1.5) filtrate vacuum concentration to 5-ALA phosphate concn at 65 ~ 70 DEG C is reached to 400 ~ 600g/L, obtain the phosphatic thick aqueous solution of 5-ALA that 65 ~ 70 DEG C of mass concentrations are 400 ~ 600 g/L;
(2) the phosphatic thick aqueous solution of 5-ALA step (1) being made is cooling gradually under agitation condition, mixing speed is 50 ~ 200 rpm, the rate of temperature fall of crystallisation process is controlled at 10 ~ 15 DEG C/h, stir when 1-3h has nucleus to occur and stop stirring, constant temperature growing the grain 1 ~ 2 h, continues stirring and is cooled to-5 ~ 0 DEG C; By gained crystal separation, solid vacuum-drying 2 ~ 6 h below 65 DEG C obtain the phosphatic crystallization of 5-ALA;
(3) liquid after separating is operated by step (1.2)-(1.5) and step (2), obtain the phosphatic secondary crystal of 5-ALA;
(4) the phosphatic secondary crystal of 5-ALA that the phosphatic crystallization of 5-ALA that combining step (2) obtains and step (3) obtain, obtains 5-ALA phosphoric acid salt.
2. the phosphatic crystallization method of 5-ALA according to claim 1, it is characterized in that, in described step (1.1), the salt of described 5-ALA is made up of one or more of perchlorate, hydriodate, vitriol, hydrobromate, hydrochloride, nitrate, oxalate, sulphite, pyruvate salt and the nitrite of 5-ALA.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310144703.7A CN103265444B (en) | 2013-04-24 | 2013-04-24 | Crystallization method of 5-aminolevulinic acid phosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310144703.7A CN103265444B (en) | 2013-04-24 | 2013-04-24 | Crystallization method of 5-aminolevulinic acid phosphate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103265444A CN103265444A (en) | 2013-08-28 |
| CN103265444B true CN103265444B (en) | 2014-11-05 |
Family
ID=49009123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310144703.7A Active CN103265444B (en) | 2013-04-24 | 2013-04-24 | Crystallization method of 5-aminolevulinic acid phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103265444B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187793A (en) | 2016-01-26 | 2016-12-07 | 赵鸣 | 5 aminolevulinic acids and the salt compound of derivant thereof and application |
| CN111517973B (en) * | 2019-02-02 | 2023-08-04 | 中国科学院天津工业生物技术研究所 | Production process for preparing 5-aminolevulinic acid hydrochloride from fermentation broth and application of production process |
| CN111838421B (en) * | 2020-07-27 | 2023-04-21 | 中国科学院天津工业生物技术研究所 | Method for preparing 5-aminolevulinic acid from fermentation broth and application thereof |
| CN113912508A (en) * | 2021-08-31 | 2022-01-11 | 新泰市佳禾生物科技有限公司 | Method for separating and purifying 5-aminolevulinic acid from fermentation liquor |
| CN113862179A (en) * | 2021-09-15 | 2021-12-31 | 上海农乐生物制品股份有限公司 | Rhodopseudomonas palustris, application and method for preparing 5-ALA by using rhodopseudomonas palustris |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2355978T3 (en) * | 2004-03-30 | 2011-04-01 | Cosmo Oil Co., Ltd. | 5-AMINOLEVULINIC ACID PHOSPHATE SALT, PROCESS TO PRODUCE THE SAME AND USE OF THE SAME. |
| JP4989153B2 (en) * | 2006-08-15 | 2012-08-01 | コスモ石油株式会社 | Novel crystals of 5-aminolevulinic acid phosphate and method for producing the same |
| CN101624350B (en) * | 2009-08-06 | 2012-11-07 | 浙江大学 | Crystallization method of 5-aminolevulinic propionic hydrochloride |
-
2013
- 2013-04-24 CN CN201310144703.7A patent/CN103265444B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103265444A (en) | 2013-08-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103265444B (en) | Crystallization method of 5-aminolevulinic acid phosphate | |
| JP5814946B2 (en) | Method for producing succinic acid | |
| CN103880625A (en) | Method for preparing D, L-mandelic acid and derivative of D, L-mandelic acid | |
| WO2011047634A1 (en) | Method for preparing citric acid | |
| CN103420826A (en) | Method for extracting succinic acid from fermentation broth | |
| CN103804173B (en) | A kind of process for purification of fermentation organic acid | |
| CN108690050B (en) | A kind of purification process of sulbactam | |
| CN101624350B (en) | Crystallization method of 5-aminolevulinic propionic hydrochloride | |
| CN108516568B (en) | Production method of potassium nitrate | |
| CN110938713A (en) | Refining process of crystalline glucose | |
| CN108707158B (en) | Method for purifying cefpirome sulfate | |
| CN105669511B (en) | A kind of hydroxyproline refining methd | |
| CN114149477A (en) | Crystallization method of high-purity vitamin B12 crystal and product thereof | |
| CN103408638B (en) | A kind of preparation technology of vancomycin crystallization | |
| CN110885357B (en) | Method for separating and purifying glutamine dipeptide by nanofiltration membrane | |
| CN105315300B (en) | A kind of cefoxitin sodium, preparation method and the usage | |
| CN103224505A (en) | Preparation method of cefpirome sulfate | |
| CN109369501B (en) | Process for purifying tryptophan by directly flocculating fermentation liquor | |
| CN103772415B (en) | A kind of preparation method being prepared Cephalonium by 7-amino-cephalosporanic acid single stage method | |
| CN103772224B (en) | Preparation method of D-threonine | |
| CN115232002B (en) | Method for extracting shikimic acid from whole water phase | |
| KR102284843B1 (en) | Method of producing 5'-guanylic acid disodium 7 hydrate crystals | |
| CN108047252B (en) | Preparation method of CPC sodium salt | |
| CN114478676A (en) | Preparation method of high-purity sodium deoxycholate | |
| CN107098935B (en) | A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20130828 Assignee: Jiangsu Good Harvest-Weien Agrochemical Co., Ltd. Assignor: Zhejiang University Contract record no.: 2015990000776 Denomination of invention: Crystallization method of 5-aminolevulinic acid phosphate Granted publication date: 20141105 License type: Common License Record date: 20150906 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |