CN103265444B - Crystallization method of 5-aminolevulinic acid phosphate - Google Patents
Crystallization method of 5-aminolevulinic acid phosphate Download PDFInfo
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- 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
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- aminolevulinic acid
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 37
- XWNWBYZHOAIHTK-UHFFFAOYSA-N 5-amino-4-oxopentanoic acid;phosphoric acid Chemical compound OP(O)(O)=O.NCC(=O)CCC(O)=O XWNWBYZHOAIHTK-UHFFFAOYSA-N 0.000 title abstract 7
- 239000013078 crystal Substances 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 239000012535 impurity Substances 0.000 claims abstract description 6
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims abstract 21
- 239000007788 liquid Substances 0.000 claims description 37
- 239000007864 aqueous solution Substances 0.000 claims description 19
- 230000008025 crystallization Effects 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 229910019142 PO4 Inorganic materials 0.000 claims description 15
- 239000010452 phosphate Substances 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 8
- 229910021641 deionized water Inorganic materials 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000855 fermentation Methods 0.000 claims description 7
- 230000004151 fermentation Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000005352 clarification Methods 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000003456 ion exchange resin Substances 0.000 claims description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 5
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001471 micro-filtration Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000000919 ceramic Substances 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004728 pyruvic acid derivatives Chemical class 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 2
- -1 5-ALA phosphoric acid salt Chemical class 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000005342 ion exchange Methods 0.000 abstract description 3
- 150000001450 anions Chemical class 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 210000004940 nucleus Anatomy 0.000 abstract 1
- 238000002207 thermal evaporation Methods 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000003016 phosphoric acids Chemical class 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- ZLHFONARZHCSET-UHFFFAOYSA-N 5-aminolevulinic acid hydrochloride Chemical compound Cl.NCC(=O)CCC(O)=O ZLHFONARZHCSET-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000370738 Chlorion Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012716 precipitator Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- HNBPGMZUKDCQEE-UWTATZPHSA-N D-alanyl phosphate Chemical compound C[C@@H](N)C(=O)OP(O)(O)=O HNBPGMZUKDCQEE-UWTATZPHSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002837 defoliant Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000029553 photosynthesis Effects 0.000 description 1
- 238000010672 photosynthesis Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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.
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