CN103936785A - Method for preparing phosphorylcholine chloride calcium salt tetrahydrate - Google Patents
Method for preparing phosphorylcholine chloride calcium salt tetrahydrate Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 18
- JGULOZKZZMBGFX-UHFFFAOYSA-L calcium;2-(trimethylazaniumyl)ethyl phosphate;chloride;tetrahydrate Chemical compound O.O.O.O.[Cl-].[Ca+2].C[N+](C)(C)CCOP([O-])([O-])=O JGULOZKZZMBGFX-UHFFFAOYSA-L 0.000 title abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000007788 liquid Substances 0.000 claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 30
- 235000011007 phosphoric acid Nutrition 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 18
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000000920 calcium hydroxide Substances 0.000 claims abstract description 18
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims abstract description 18
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 15
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 claims abstract description 14
- 239000001506 calcium phosphate Substances 0.000 claims abstract description 14
- 235000019691 monocalcium phosphate Nutrition 0.000 claims abstract description 14
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 11
- 239000001110 calcium chloride Substances 0.000 claims abstract description 11
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 11
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 46
- 229960001231 choline Drugs 0.000 claims description 31
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- MMFBVFWEERQGJK-UHFFFAOYSA-N calcium;tetrahydrate Chemical compound O.O.O.O.[Ca] MMFBVFWEERQGJK-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000000108 ultra-filtration Methods 0.000 claims description 14
- 229910000150 monocalcium phosphate Inorganic materials 0.000 claims description 13
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 11
- 230000008020 evaporation Effects 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 239000010409 thin film Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 150000001805 chlorine compounds Chemical class 0.000 claims description 6
- 239000008247 solid mixture Substances 0.000 claims description 5
- DZNXQEJLVYZVSK-UHFFFAOYSA-N C(C)(=O)OCC[N+](C)(C)C.P(=O)(Cl)(Cl)Cl Chemical compound C(C)(=O)OCC[N+](C)(C)C.P(=O)(Cl)(Cl)Cl DZNXQEJLVYZVSK-UHFFFAOYSA-N 0.000 claims description 4
- 230000004044 response Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 20
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 abstract description 12
- 235000019743 Choline chloride Nutrition 0.000 abstract description 12
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 abstract description 12
- 229960003178 choline chloride Drugs 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000012065 filter cake Substances 0.000 abstract description 4
- 239000000706 filtrate Substances 0.000 abstract description 4
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000002912 waste gas Substances 0.000 abstract description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 abstract 1
- 229940062672 calcium dihydrogen phosphate Drugs 0.000 abstract 1
- 229910000389 calcium phosphate Inorganic materials 0.000 abstract 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 abstract 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 abstract 1
- 229940038472 dicalcium phosphate Drugs 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 239000008213 purified water Substances 0.000 description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 8
- 239000011574 phosphorus Substances 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- -1 Phosphoryl chloride choline calcium salt Chemical class 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 102000011759 adducin Human genes 0.000 description 6
- 108010076723 adducin Proteins 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000237502 Ostreidae Species 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 235000020636 oyster Nutrition 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 229950004354 phosphorylcholine Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002910 solid waste Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- AZRZBCASYOBNKQ-UHFFFAOYSA-N 6-chloro-3,5-diaminopyrazine-3-carboxamide Chemical compound CN(C)C(N)=NC(=O)C1=NC(Cl)=C(N)N=C1N AZRZBCASYOBNKQ-UHFFFAOYSA-N 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-M CDP-choline(1-) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-M 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001284 citicoline Drugs 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000011162 core material Substances 0.000 description 1
- SWRNIYAQKATHDJ-UHFFFAOYSA-N dichloro(dichlorophosphanyl)phosphane Chemical compound ClP(Cl)P(Cl)Cl SWRNIYAQKATHDJ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000011172 small scale experimental method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
Abstract
The invention relates to a method for preparing phosphorylcholine chloride calcium salt tetrahydrate. The method is characterized by consisting of the following steps: (1) dropwise adding a phosphoric acid solution of anhydrous choline chloride into orthophosphoric acid, and reacting at the temperature of 130-180 DEG C, so as to produce phosphorylcholine chloride; (2) enabling a reaction solution to be subjected to neutralization reaction with a proper amount of calcium chloride, calcium carbonate and calcium hydroxide in water; (3) after neutralization reaction, carrying out solid-liquid separation, and refining filter cakes, so as to obtain calcium dihydrogen phosphate or dicalcium phosphate; (4) filtrating a filtrate, obtained through filtrating, with a filter, and then, concentrating and dehydrating; (5) crystallizing a concentrated solution by adding an alcohol solvent, thereby obtaining the product. The method has the advantages that the process flow is simple, waste gases, waste water and waste residues are not generated, and the product quality meets the requirements of crude drug production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate.
Background technology
Phosphoryl chloride choline calcium salt (English full name: Phosphoryl Choline Chloride Calcicam Salt) be the important composition that forms the interior phosphatide of organism and Yelkin TTS, be the core material of preparation Cytidine Diphosphate Choline (the English CDPC of abbreviation), its structural formula is as follows:
, there are three kinds of structures in different according to crystal water, a kind of containing crystal water, a kind of containing a part crystal water, a kind of four molecular crystal water that contain; Generally, for medical material medicine and intermediate purposes, be the phosphoryl chloride choline calcium salt containing four molecular crystal water.The specification of quality of phosphoryl chloride choline calcium salt tetrahydrate product is conventionally as follows:
| Outward appearance | White crystalline powder |
| Water content | 19.0~23.0% |
| PH(1 gram is dissolved in 100ml water) | 7.0~8.5 |
| Titration content (butt) | 97.0%~102.0% |
| Chlorinity | 10.0%~11.5% |
| Calcium content | 11.5%~13.0% |
| Phosphorus content | 8.6~10.0% |
Synthesizing of phosphoryl chloride choline calcium salt; many documents are to be all starting raw material from choline chloride 60; obtain phosphoryl chloride choline from different phosphorus esterification reagent reactions; and then react and change into phosphoryl chloride choline calcium salt with inorganic calcium salt; according to different crystallization processes and drying temperature, can obtain a kind of in three kinds of different crystal water structures.
Document JP 113924 (A) is used primary ammonium phosphate to do phosphorus esterification reagent, uses acetic acid and make condensing agent in synthesizing, and causes raw materials cost higher, and waste water is difficult to process.Document JP 026893 is used phosphorus oxychloride as phosphorus esterification reagent, but in reaction process, has the acid gas of a large amount of hydrogenchloride to emit, and need to add extra measure, and be unfavorable for environmental protection aspect equipment and control.Document CN 102584891 is used polyphosphoric acid to do phosphorus esterification reagent and uses the choline chloride 60 aqueous solution to do starting raw material, and reaction process can exist the problem of high energy consumption and the high three wastes.The use phosphoric acid such as document Japanese kokai publication sho JP62-113924 are done reaction reagent, but material ratio, temperature of reaction, time and aftertreatment technology used have a lot of local needs to improve and reform, also exist the three wastes and energy consumption large, the quality product large problem that fluctuates simultaneously.
Summary of the invention
The invention provides a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate, its object is to solve the problem that impurity in the product existing in the preparation method of current phosphoryl chloride choline calcium salt is more and produce a large amount of waste water, waste gas, solid waste etc.
For achieving the above object, the technical solution used in the present invention is: a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate, is characterized in that: described preparation method is comprised of following steps:
The first step, anhydrous chlorides of rase choline and ortho-phosphoric acid are made into dropping solution, again described dropping solution is added drop-wise to 130 ℃ ~ 180 ℃ contain in ortho-phosphoric reactor, stir and react, dropping finishes rear continuation and controls temperature of reaction between 130 ℃ ~ 180 ℃, reaction end is as the criterion with anhydrous steaming, and after reaction finishes, obtains phosphoryl chloride acetylcholine response liquid;
Wherein, in described dropping solution, anhydrous chlorides of rase choline and ortho-phosphoric mass ratio are 2:1 ~ 1:2; Ortho-phosphoric mass ratio in described dropping solution and reactor is 1:2 ~ 2:1;
Second step, the temperature of described phosphoryl chloride acetylcholine response liquid is down to 10 ℃ ~ 50 ℃, then to it, add water, after mixing, add again calcium chloride, calcium carbonate, calcium hydroxide, neutralization is arrived the pH of the aqueous solution 5 ~ 10, produces secondary calcium phosphate and monocalcium phosphate solid mixture after neutralization reaction, filters; Wherein, the mass ratio of described calcium chloride, calcium carbonate, calcium hydroxide and described anhydrous chlorides of rase choline is 0.3 ~ 0.8:1.0 ~ 2.0:0.4 ~ 2.0:1;
The 3rd step, the secondary calcium phosphate that described second step is filtered out and monocalcium phosphate solid mixture are added in water, then add calcium hydroxide, make pH be controlled at 9 ~ 13, obtain secondary calcium phosphate solid after filtration drying; Or add again appropriate phosphoric acid, pH is controlled between 4 ~ 7, after filtration drying, obtain monocalcium phosphate solid;
The 4th step, the first cleaner liquid obtaining after described second step is filtered filters and obtains the second cleaner liquid through 0.1 ~ 10 μ m strainer; Again that described the second cleaner liquid is concentrated through thin film evaporation or ultra-filtration membrane, be concentrated to volume and be described the first cleaner liquid volume 10% ~ 60% till, obtain concentrated solution; Wherein, the temperature of described thin film evaporation is 70 ~ 140 ℃, and the concentrated pressure of described ultra-filtration membrane is at 0.5 ~ 2.0MPa, and the temperature of ultrafiltration and concentration is at 15 ℃ ~ 50 ℃;
The 5th step, to described concentrated solution, adding volumetric concentration is that 95% ethanol carries out crystallization, described volumetric concentration is that the volume of 95% ethanol is 1 ~ 20 times of described concentrated liquid accumulated amount, cools to after 0 ~ 10 ℃, filters to obtain solids; Described solids obtains phosphoryl chloride choline calcium salt tetrahydrate after drying.
Related content in technique scheme is explained as follows:
1, in such scheme, in described the 4th step, be concentrated to volume and be described the first cleaner liquid volume 30% ~ 50% till, obtain concentrated solution.
2,, in such scheme, preferably scheme is that in described the 5th step, volumetric concentration is that the volume of 95% ethanol is 5 ~ 15 times of described concentrated liquid accumulated amount.
Principle of the present invention and beneficial effect: reaction process of the present invention is that the de-a part water of choline chloride 60 and phosphoric acid carries out the main structure that condensation reaction obtains phosphoryl chloride choline calcium salt tetrahydrate product.But in reaction process in the past, the condensation by-product that has more a part phosphoric acid and two molecule choline chloride 60s produces, and is called for short dibasic acid esters impurity.In order to suppress the generation of this by product, choline chloride 60 must with excessive phosphatase reaction, add thermal condensation.But if phosphoric acid is too much, in last handling process, can produce a large amount of phosphoric acid salt three wastes, be unfavorable for environmental protection.After deliberation, the present invention has carried out ratio optimization, and when the consumption of phosphoric acid is 2.0 ~ 3.0 times of choline chloride 60 consumption (in mass), dibasic acid esters side reaction is inhibited, and the phosphoric acid salt solid waste generating is also fewer.
Except ratio optimization, the optimization of feed way, also can suppress the generation of dibasic acid esters, improves product yield; For this reason, the present invention makes part phosphoric acid and raw material choline chloride 60 after solution, is progressively added drop-wise in the phosphoric acid of high temperature, like this, dripping the choline chloride 60 going down will fall with phosphatase reaction rapidly, and now phosphoric acid, in remarkable excessive state, can significantly suppress the generation of dibasic acid esters impurity; While drip finishing, reaction conversion ratio has reached 60% left and right, then continues insulation reaction, and when the water outlet of condenser, while not having obvious water to flow out, reaction can stop, can not time expand, otherwise yield can reduce.
After condensation reaction finishes, in reaction solution, except acid Phosphorylcholine intermediate, also has the phosphoric acid of a great deal of surplus; For wanting separated product, generally add inorganic calcium salt, the secondary calcium phosphate that utilization generates and monocalcium phosphate, in the extremely low solubleness in water the inside, make excessive phosphoric acid precipitates out, phosphorus dichloride phatidylcholine calcium salt is water miscible, and product and inorganic phosphate just can be accomplished solid-liquid separation like this.
Because calcium chloride is water-soluble better, add calcium chloride can improve the amount of calcium ion and chlorion in the aqueous solution, keep appropriate chlorine ion concentration in the aqueous solution, the quaternary ammonium root with Phosphorylcholine is kept to ionic equilibrium; Calcium hydroxide mainly plays neutralizing effect, regulate the pH meta-alkalescence of the aqueous solution, but calcium hydroxide belongs to middle highly basic, as only used calcium hydroxide, can make N-process pH fluctuation large, is unfavorable for like this quality of product; Add appropriate calcium carbonate, it also has neutralizing effect with phosphoric acid on the one hand, its alkalescence a little less than, as added calcium carbonate, neutralize, the pH fluctuation of N-process can be less, calcium carbonate is under neutral and meta-alkalescence condition in addition, solubleness is very low, and unnecessary calcium carbonate solid particulate plays filtrating aid function, if do not added calcium carbonate, N-process very easily produces the gelatinous precipitate of monocalcium phosphate and secondary calcium phosphate, causes follow-up filtration difficulty.That is to say, compatibility of the present invention is used calcium chloride, calcium carbonate, three kinds of calcons of calcium hydroxide can make N-process there will not be pH fluctuation, the pH of solution is neutralized to 5 ~ 10 gradually, also can not produce the colloidal solid of sad filter, and neutralization and filtration are just than being easier to operation.In addition, calcium carbonate and calcium hydroxide must be granuliform solids, can not use blocks of solid, otherwise owing to consolidating inclusion, do not reach good result.
For the solid of filtering in the present invention, be mainly secondary calcium phosphate, monocalcium phosphate solid mixture, these solids filtering out, are added in suitable quantity of water, add appropriate calcium hydroxide, make pH be controlled at 9 ~ 13, after filtration drying, obtain secondary calcium phosphate solid; Or add appropriate phosphoric acid, pH is controlled between 4 ~ 7, after filtration drying, obtain monocalcium phosphate solid.The cleaner liquid filtering out, with after appropriate phosphoric acid or calcium hydroxide polyphony pH, then after 0.2 μ m accurate filter filters, is obtained to the dilute solution of phosphoryl chloride choline calcium salt, and adding alcohol after concentrated could crystallization.
Concentration process, for general autoclave concentrating under reduced pressure, thickening efficiency is very low, and energy consumption is high, and feed liquid is for a long time in the condition of high temperature, and feed liquid can be degraded, and this kind of method is only applicable to small-scale experiment; And the present invention uses thin film evaporation or ultra-filtration membrane to concentrate, for thin film evaporation, efficiency is high, and temperature is at 70 ~ 140 ℃, and feed liquid can be concentrated to rapidly required concentration, and is that material is very short in the high temperature state also residence time, does not have feed liquid degraded; Be concentrated to volume and be initial cleaner liquid volume 10% ~ 60% till; It is also very suitable that ultra-filtration membrane is concentrated in process of the present invention, at ambient temperature, concentrates fast most moisture, and feed concentration is improved rapidly.The filter membrane of every square metre, the moisture of the concentrated 20kg of energy per hour.The pressure of ultrafiltration and concentration process is at 0.5 ~ 2.0MPa, and the temperature of ultrafiltration and concentration is at 15 ℃ ~ 50 ℃, be concentrated to initial cleaner liquid volume 10% ~ 60% till.
The invention has the advantages that in phosphoryl chloride choline calcium salt tetrahydrate product, foreign matter content is few, product purity is high, and quality product reaches the requirement of production of raw medicine; The secondary calcium phosphate producing in preparation method of the present invention, that monocalcium phosphate can be used as by product is for sale, and preparation process environmental protection, produces without the three wastes; Concentrated mode of the present invention is that thin film evaporation or ultra-filtration membrane are concentrated, just concentrates and puts in place at short notice, and technological process is simple, for industrialized production saving of work and time, has also kept the stability of product simultaneously.
Embodiment
The invention will be further described for embodiment below:
Embodiment mono-: a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate
In 2L four-hole boiling flask, add 1032g ortho-phosphoric acid, be heated to 160 ~ 165 ℃, drip by 1032g ortho-phosphoric acid the clear liquor that mixes with 852g choline chloride 60, after dropping finishes, continue, at 160 ~ 165 ℃ of reaction 2h, until anhydrous, to steam.Collect approximately altogether water 520g.
Feed liquid proceeds to 50 liters of glass reaction stills, and temperature is down to after 30 ℃, adds 15kg purified water, is stirred to solution achromaticity and clarification transparent, and pH, between 1 ~ 2, adds calcium chloride 520g, and stirring at room is to CL; Slowly add calcium carbonate 900g, have a large amount of foams to produce, feed liquid off-white color emulsus, stirring at room 30min, adding calcium hydroxide 540g, stirring at room 30min, keeps pH 8.0, and feed liquid off-white color emulsus, adds 2kg purified water, and repetition measurement pH is 8.0 constant.
Centrifuging, filter cake rinses by purified water, adds calcium hydroxide, makes pH be controlled at 9 ~ 13, centrifugal, dry, obtains secondary calcium phosphate solid 2.3kg.
Cleaner liquid obtains colourless transparent liquid 21kg through the PP micro-filtrate membrane filtration in 0.2 μ m aperture; With test-type ultra-filtration membrane, be concentrated into 4L and finish to concentrate, wherein, ultrafiltration pressure is 1.5MPa, and the temperature of ultrafiltration and concentration is between 20 ~ 30 ℃.
Under stirring at room, add 95% ethanol 10L, feed liquid is muddy to oyster white gradually, stirs 1h, add 95% ethanol 1.5L, stir 30min, 0 ~ 5 ℃ of crystallization 3h, decompress filter, by 2150ml 75% ethanol/purified water, embathe once, drain, wet product, at 60 ℃ of vacuum-drying 3h, obtains phosphoryl chloride choline calcium salt tetrahydrate dry product 1052g.After testing, infrared discriminating meets reference substance standard infared spectrum; PH 7.1, water-content 21.0%, chlorinity 10.7%, phosphorus content 9.5%, calcium content 12.4%, titration content 98.8%.
Embodiment bis-: a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate
In 2L four-hole boiling flask, add 1032g ortho-phosphoric acid, be heated to 160 ~ 165 ℃, drip by 1032g ortho-phosphoric acid the clear liquor that mixes with 852g choline chloride 60, after dropping finishes, continue, at 160 ~ 165 ℃ of reaction 2h, until anhydrous, to steam.Collect approximately altogether water 520g.
Feed liquid proceeds to 50 liters of glass reaction stills, and temperature is down to after 30 ℃, adds 15kg purified water, is stirred to solution achromaticity and clarification transparent, and pH, between 1 ~ 2, adds calcium chloride 520g, and stirring at room is to CL; Slowly add calcium carbonate 900g, have a large amount of foams to produce, feed liquid off-white color emulsus, stirring at room 30min, adding calcium hydroxide 540g, stirring at room 30min, keeps pH 8.0, and feed liquid off-white color emulsus, adds 2kg purified water, and repetition measurement pH is 8.0 constant.
Centrifuging, filter cake rinses by purified water, then adds appropriate phosphoric acid, and pH is controlled between 4 ~ 7, centrifugal, dry, obtains monocalcium phosphate solid 2.2kg.
Cleaner liquid obtains colourless transparent liquid 21kg through the PP micro-filtrate membrane filtration in 0.2 μ m aperture; By test-type thin film evaporation, be concentrated into 4.5L, the material temperature of thin film evaporation, lower than 70 ℃, finishes concentrated.
Under stirring at room, add 95% ethanol 12L, feed liquid is muddy to oyster white gradually, stirs 1h, add 95% ethanol 2L, stir 30min, 0～5 ℃ of crystallization 3h, decompress filter, 75% ethanol/purified water 2150ml embathes once, drain, wet product, at 60 ℃ of vacuum-drying 3h, obtains phosphoryl chloride choline calcium salt tetrahydrate dry product 1024g.After testing, infrared discriminating meets reference substance standard infared spectrum; PH 7.3, water-content 21.5%, chlorinity 10.4%, phosphorus content 9.6%, calcium content 12.3%, titration content 99.1%.
Embodiment tri-: a kind of preparation method of phosphoryl chloride choline calcium salt tetrahydrate
In 2L four-hole boiling flask, add 1988g ortho-phosphoric acid, be heated to 160 ~ 165 ℃, drip by 639g ortho-phosphoric acid the clear liquor that mixes with 852g choline chloride 60, after dropping finishes, continue, at 160 ~ 165 ℃ of reaction 2h, until anhydrous, to steam.Collect approximately altogether water 503g.
Feed liquid proceeds to 50 liters of glass reaction stills, and temperature is down to after 30 ℃, adds 15kg purified water, is stirred to solution achromaticity and clarification transparent, and pH, between 1 ~ 2, adds calcium chloride 298g, and stirring at room is to CL; Slowly add calcium carbonate 1278g, have a large amount of foams to produce, feed liquid off-white color emulsus, stirring at room 30min, adding calcium hydroxide 670g, stirring at room 30min, keeps pH 8.0, and feed liquid off-white color emulsus, adds 2kg purified water, and repetition measurement pH is 8.0 constant.
Centrifuging, filter cake rinses by purified water, then adds appropriate phosphoric acid, and pH is controlled between 4 ~ 7, centrifugal, dry, obtains monocalcium phosphate solid 2.6kg.
Cleaner liquid obtains colourless transparent liquid 21kg through the PP micro-filtrate membrane filtration in 0.2 μ m aperture; By test-type thin film evaporation, be concentrated into 5L, the material temperature of thin film evaporation, lower than 70 ℃, finishes concentrated.
Under stirring at room, add 95% ethanol 12L, feed liquid is muddy to oyster white gradually, stirs 1h, add 95% ethanol 2L, stir 30min, 0～5 ℃ of crystallization 3h, decompress filter, 75% ethanol/purified water 2150ml embathes once, drain, wet product, at 60 ℃ of vacuum-drying 3h, obtains phosphoryl chloride choline calcium salt tetrahydrate dry product 785g.After testing, infrared discriminating meets reference substance standard infared spectrum; PH 7.3, water-content 21.5%, chlorinity 10.4%, phosphorus content 9.6%, calcium content 12.3%, titration content 99.1%.
Above-described embodiment is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (3)
1. a preparation method for phosphoryl chloride choline calcium salt tetrahydrate, is characterized in that: described preparation method is comprised of following steps:
The first step, anhydrous chlorides of rase choline and ortho-phosphoric acid are made into dropping solution, again described dropping solution is added drop-wise to 130 ℃ ~ 180 ℃ contain in ortho-phosphoric reactor, stir and react, dropping finishes rear continuation and controls temperature of reaction between 130 ℃ ~ 180 ℃, reaction end is as the criterion with anhydrous steaming, and after reaction finishes, obtains phosphoryl chloride acetylcholine response liquid;
Wherein, in described dropping solution, anhydrous chlorides of rase choline and ortho-phosphoric mass ratio are 2:1 ~ 1:2; Ortho-phosphoric mass ratio in described dropping solution and reactor is 1:2 ~ 2:1;
Second step, the temperature of described phosphoryl chloride acetylcholine response liquid is down to 10 ℃ ~ 50 ℃, then to it, add water, after mixing, add again calcium chloride, calcium carbonate, calcium hydroxide, neutralization is arrived the pH of the aqueous solution 5 ~ 10, produces secondary calcium phosphate and monocalcium phosphate solid mixture after neutralization reaction, filters; Wherein, the mass ratio of described calcium chloride, calcium carbonate, calcium hydroxide and described anhydrous chlorides of rase choline is 0.3 ~ 0.8:1.0 ~ 2.0:0.4 ~ 2.0:1;
The 3rd step, the secondary calcium phosphate that described second step is filtered out and monocalcium phosphate solid mixture are added in water, then add calcium hydroxide, make pH be controlled at 9 ~ 13, obtain secondary calcium phosphate solid after filtration drying; Or add again appropriate phosphoric acid, pH is controlled between 4 ~ 7, after filtration drying, obtain monocalcium phosphate solid;
The 4th step, the first cleaner liquid obtaining after described second step is filtered filters and obtains the second cleaner liquid through 0.1 ~ 10 μ m strainer; Again that described the second cleaner liquid is concentrated through thin film evaporation or ultra-filtration membrane, be concentrated to volume and be described the first cleaner liquid volume 10% ~ 60% till, obtain concentrated solution; Wherein, the temperature of described thin film evaporation is 70 ~ 140 ℃, and the concentrated pressure of described ultra-filtration membrane is at 0.5 ~ 2.0MPa, and the temperature of ultrafiltration and concentration is at 15 ℃ ~ 50 ℃;
The 5th step, to described concentrated solution, adding volumetric concentration is that 95% ethanol carries out crystallization, described volumetric concentration is that the volume of 95% ethanol is 1 ~ 20 times of described concentrated liquid accumulated amount, cools to after 0 ~ 10 ℃, filters to obtain solids; Described solids obtains phosphoryl chloride choline calcium salt tetrahydrate after drying.
2. the preparation method of phosphoryl chloride choline calcium salt tetrahydrate according to claim 1, is characterized in that: in described the 4th step, be concentrated to volume and be described the first cleaner liquid volume 30% ~ 50% till, obtain concentrated solution.
3. the preparation method of phosphoryl chloride choline calcium salt tetrahydrate according to claim 1, is characterized in that: in described the 5th step, volumetric concentration is that the volume of 95% ethanol is 5 ~ 15 times of described concentrated liquid accumulated amount.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892664A (en) * | 2015-05-07 | 2015-09-09 | 芜湖福民生物药业有限公司 | Method for preparing phosphocholine chloride calcium salt tetrahydrate |
| CN106083918A (en) * | 2016-06-08 | 2016-11-09 | 芜湖福民生物药业有限公司 | The preparation method of phosphoryl chloride choline calcium salt four hydrate |
| CN108546273A (en) * | 2018-02-05 | 2018-09-18 | 浙江云涛生物技术股份有限公司 | A kind of new process preparing phosphoryl chloride choline calcium salt |
| CN108610359A (en) * | 2018-04-21 | 2018-10-02 | 山东奥博生物科技有限公司 | The preparation method of phosphoryl chloride choline calcium salt |
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| CN102584891A (en) * | 2012-01-13 | 2012-07-18 | 太仓市茜泾化工有限公司 | Preparation method of phosphoryl chloride choline calcium salt |
| CN103694271A (en) * | 2013-12-02 | 2014-04-02 | 常熟富士莱医药化工有限公司 | Preparation method of calcium phosphorylcholine chloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102584891A (en) * | 2012-01-13 | 2012-07-18 | 太仓市茜泾化工有限公司 | Preparation method of phosphoryl chloride choline calcium salt |
| CN103694271A (en) * | 2013-12-02 | 2014-04-02 | 常熟富士莱医药化工有限公司 | Preparation method of calcium phosphorylcholine chloride |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892664A (en) * | 2015-05-07 | 2015-09-09 | 芜湖福民生物药业有限公司 | Method for preparing phosphocholine chloride calcium salt tetrahydrate |
| CN106083918A (en) * | 2016-06-08 | 2016-11-09 | 芜湖福民生物药业有限公司 | The preparation method of phosphoryl chloride choline calcium salt four hydrate |
| CN106083918B (en) * | 2016-06-08 | 2018-07-06 | 芜湖福民生物药业有限公司 | The preparation method of four hydrate of phosphoryl chloride choline calcium salt |
| CN108546273A (en) * | 2018-02-05 | 2018-09-18 | 浙江云涛生物技术股份有限公司 | A kind of new process preparing phosphoryl chloride choline calcium salt |
| CN108610359A (en) * | 2018-04-21 | 2018-10-02 | 山东奥博生物科技有限公司 | The preparation method of phosphoryl chloride choline calcium salt |
| CN108610359B (en) * | 2018-04-21 | 2020-05-29 | 山东奥博生物科技有限公司 | Preparation method of phosphorylcholine chloride calcium salt |
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