CN108610359B - Preparation method of phosphorylcholine chloride calcium salt - Google Patents
Preparation method of phosphorylcholine chloride calcium salt Download PDFInfo
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- ICVPTJCCKTXCDT-UHFFFAOYSA-L calcium;2-(trimethylazaniumyl)ethyl phosphate;chloride Chemical compound [Cl-].[Ca+2].C[N+](C)(C)CCOP([O-])([O-])=O ICVPTJCCKTXCDT-UHFFFAOYSA-L 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 238000003756 stirring Methods 0.000 claims abstract description 36
- 239000013078 crystal Substances 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 13
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960001231 choline Drugs 0.000 claims abstract description 10
- 229920000137 polyphosphoric acid Polymers 0.000 claims abstract description 10
- 238000007789 sealing Methods 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims description 30
- 238000001914 filtration Methods 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000006386 neutralization reaction Methods 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 14
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 13
- 239000000920 calcium hydroxide Substances 0.000 claims description 13
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 13
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 12
- 239000001110 calcium chloride Substances 0.000 claims description 12
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 12
- ALESPATZLNIRQR-UHFFFAOYSA-M calcium;2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium;chloride Chemical compound [Cl-].[Ca].OCC[N+](C)(C)C#P=O ALESPATZLNIRQR-UHFFFAOYSA-M 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 238000003860 storage Methods 0.000 claims description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005259 measurement Methods 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 2
- 239000011574 phosphorus Substances 0.000 abstract description 2
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 15
- 235000019743 Choline chloride Nutrition 0.000 description 15
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 15
- 229960003178 choline chloride Drugs 0.000 description 15
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 6
- 239000012024 dehydrating agents Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 230000000865 phosphorylative effect Effects 0.000 description 3
- -1 phosphorylcholine chloride tetrahydrate Chemical compound 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000011229 interlayer Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- RZZPDXZPRHQOCG-UHFFFAOYSA-N [[5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound OC1C(O)C(COP([O-])(=O)OP(O)(=O)OCC[N+](C)(C)C)OC1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-UHFFFAOYSA-N 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention belongs to the technical field of preparation of phosphorus-containing organic compound intermediates, and particularly relates to a preparation method of phosphorylcholine chloride calcium salt. Firstly, heating a reaction kettle to 80 ℃, then adding 100kg of phosphoric acid, starting stirring and vacuum, continuously heating to 160 ℃, starting timing when the temperature is raised to 150 ℃, and stirring for 2-3 hours until no water is evaporated; after anhydrous is evaporated, cooling to 100-105 ℃, opening a manhole, slowly adding 100kg of choline crystals, adjusting the vacuum state to about 0.03MPa, sealing the manhole after adding, and starting timing reaction; and (3) when the time reaches 2h, opening a manhole, slowly adding 133kg of polyphosphoric acid, sealing the manhole after the adding is finished, and continuing stirring until the time reaches 10 h. The invention provides a preparation method of phosphorylcholine calcium chloride, which can be used for adjusting the reaction temperature, time and pressure by optimizing process steps so as to achieve the purpose of improving the yield, and the yield of the phosphorylcholine calcium chloride prepared by the method provided by the invention can reach 200% according to the calculation of measurement, so that the benefit of enterprises is effectively improved.
Description
Technical Field
The invention belongs to the technical field of preparation of phosphorus-containing organic compound intermediates, and particularly relates to a preparation method of phosphorylcholine chloride calcium salt.
Background
Phosphorylcholine chloride calcium salt (phosphorylcholine chloride tetrahydrate), formula: c5H13CaClNO4And P. It is an important component for forming phospholipid and lecithin in vivo, is an indispensable raw material for preparing cytosine nucleoside diphosphocholine (CDP choline for short), is an important intermediate for synthesizing phospholipid compounds with biological activity, and especially is an important raw material for preparing lecithin PC, LPC and GPC with biological activity. Meanwhile, the phosphorylcholine group is the head of main phospholipid of a red blood cell membrane, and can be connected to various biological materials due to the good biocompatibility, and the phosphorylcholine chloride calcium salt can be used as a novel active intermediate for synthesizing a phosphorylcholine-containing medicament, can also be used for synthesizing a medical material with good biocompatibility or for surface modification of the biomedical material, and has great research and application values in the fields of biomimetic synthesis and modification. Since it is a choline drug, and is used for treating diseases such as fatty liver, it is widely used in the fields of medicine and biology.
Before the synthesis of phosphorylcholine chloride, a great deal of research is available in foreign countries, and the main synthesis process route comprises the following steps:
1) the synthesis method takes choline chloride as a raw material and takes phosphoryl chloride, phosphorus pentoxide and ethyl metaphosphate as a phosphorylating agent of the choline chloride;
2) using chloroethanol as raw material, phosphorylating chloroethanol with phosphoryl chloride and ethyl metaphosphate, then using trimethylamine to convert intermediate into phosphoryl choline chloride;
3) the synthesis method comprises the steps of taking choline chloride as a raw material, taking diphenyl phosphoryl chloride as a phosphorylating agent of the choline chloride, and separating an intermediate product by using chloroauric acid salt.
Most of the process routes have the defects of complex reaction components, difficult raw material obtaining (some of which even use noble metal), long reaction period, difficult separation and purification, poor product purity, low yield and the like, and the whole process is complex, has higher cost and is not suitable for industrial production.
The Chinese patent publication No. CN102584891B discloses a method for preparing phosphorylcholine chloride calcium salt, which comprises the following steps: reacting choline chloride with polyphosphoric acid at a temperature to generate phosphorylcholine chloride; performing neutralization reaction on phosphorylcholine chloride, excessive calcium carbonate and calcium hydroxide in water to generate phosphorylcholine chloride calcium salt, and after the reaction is finished, performing filter pressing to obtain an aqueous solution of the phosphorylcholine chloride calcium salt; and (3) carrying out ultrafiltration on the water solution of the phosphorylcholine chloride calcium salt by using a 0.45-micron microporous ultrafiltration membrane, and concentrating and dehydrating the obtained filtrate to obtain the phosphorylcholine chloride calcium salt.
Although the technical problems of complex reaction components and difficult raw material acquisition in the prior art are solved to a certain extent, the yield can only reach 98-102%, and the rapid development of enterprises is seriously restricted due to low capacity and high energy consumption.
Disclosure of Invention
Aiming at the technical problems of low productivity and high energy consumption in the preparation method of the phosphorylcholine chloride calcium salt, the invention provides the preparation method of the phosphorylcholine chloride calcium salt, which has the advantages of reasonable design, simple structure, low cost, high productivity and low energy consumption.
In order to achieve the purpose, the invention adopts the technical scheme that the preparation method of the phosphorylcholine chloride calcium salt comprises the following effective steps:
a. firstly, heating a reaction kettle to 80 ℃, then adding 100kg of phosphoric acid, starting stirring and vacuum, continuously heating to 160 ℃, starting timing when the temperature is raised to 150 ℃, and stirring for 2-3 hours until no water is evaporated;
b. after anhydrous is evaporated, cooling to 100-105 ℃, opening a manhole, slowly adding 100kg of choline crystals, adjusting the vacuum state to about 0.03MPa, sealing the manhole after adding, and starting timing reaction;
c. when the time is 2 hours, opening a manhole, slowly adding 133kg of polyphosphoric acid, sealing the manhole after the adding is finished, and continuously stirring until the time is 10 hours;
d. then, cooling the reaction kettle to 80 ℃, adding 250kg of water, uniformly stirring to obtain a reaction solution, and putting the reaction solution into a barrel for metering and temporary storage for later use;
e. adding 125kg of pure water into the neutralization kettle, adding 1/20 of reaction liquid into the neutralization kettle, starting stirring, slowly adding calcium hydroxide solid after uniformly stirring, adjusting the pH value to 5-5.5 within 30-40min, and stabilizing for 20min to obtain a mixed solution;
f. filtering the mixed solution by adopting a plate-and-frame filtering mode, returning the filtrate to the neutralization kettle, stopping filtering when the precipitation in the kettle is basically filtered completely, and storing a filter cake in the plate-and-frame;
g. continuously slowly adding calcium hydroxide solid into the neutralization kettle until the pH value reaches about 7.5, starting a diaphragm pump, then filtering by using the original filter cake, and collecting filtrate to a ton barrel after the filtration is finished;
h. repeating the step e to the step g until the reaction solution is completely used, taking 3 to 4 batches of filtrate obtained in the step e to the step g to a concentration kettle, adding calcium chloride solid, stirring and dissolving completely, starting vacuum, introducing steam into a jacket, heating to 80 ℃, and concentrating;
i. concentrating until a large amount of crystals are separated out, stopping steam, vacuum-pumping, cooling to 40-50 deg.C, adding ethanol, stirring, and cooling to room temperature. Obtaining crystal mixed liquid;
j. and filtering the crystal mixed solution by adopting a plate-and-frame filtering mode to obtain crystals, and drying the crystals at 70 ℃ to obtain the phosphorylcholine chloride calcium salt.
Preferably, the g step further comprises collecting the filtrate in a ton bucket, collecting the filter cake, adding 125kg of water into the neutralization kettle, adding the filter cake into the neutralization kettle again, stirring for 20min, filtering, collecting the filtrate in a ton bucket, mixing with the previously collected filtrate to obtain a batch.
Preferably, in the h step, the calcium chloride solid is added in an amount of 2Kg per batch of the filtrate.
Preferably, in step i, the amount of ethanol added is 5Kg 8 batches of filtrate.
Compared with the prior art, the invention has the advantages and positive effects that,
1. the invention provides a preparation method of phosphorylcholine calcium chloride, which can be used for adjusting the reaction temperature, time and pressure by optimizing process steps so as to achieve the purpose of improving the yield, and the yield of the phosphorylcholine calcium chloride prepared by the method provided by the invention can reach 200% according to the calculation of measurement, so that the benefit of enterprises is effectively improved.
Detailed Description
In order that the above objects, features and advantages of the present invention can be more clearly understood, the present invention will be further described with reference to the following examples. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced in other ways than those specifically described herein, and thus the present invention is not limited to the specific embodiments of the present disclosure.
Example 1, this example provides a preparation method of phosphorylcholine chloride calcium salt, which aims to solve the existing calculation problem of low yield, and for this reason, this example improves from esterification reaction, neutralization reaction to concentration, and further achieves the object of the present invention, and the preparation method of phosphorylcholine chloride calcium salt provided in this example includes the following effective steps:
firstly, the temperature of the reaction kettle is raised to 80 ℃, in the embodiment, the reaction kettle is a steam heating reaction kettle, namely, hydrogen is introduced into an interlayer of the reaction kettle, so that the purpose of heating and raising the temperature is achieved, after the temperature is raised to 80 ℃, 100kg of phosphoric acid is added into the reaction kettle, stirring and vacuum are started, the temperature is continuously raised to 160 ℃, timing is started when the temperature is raised to 150 ℃, stirring is carried out for 2 hours until no water is evaporated, and the main purpose of the step is to discharge the moisture in the phosphoric acid, so that the phosphoric acid can better react with choline chloride.
After no water is evaporated, cooling to 100 ℃, opening a manhole, slowly adding 100kg of choline crystals, simultaneously adjusting the vacuum state to about 0.03MPa, sealing the manhole after adding, and starting timing reaction. The addition amount of the choline crystals (choline chloride) of 100kg is more than or equal to 2 percent of the normal complete reaction amount, so as to reduce moisture and ensure the normal reaction, thereby achieving the purpose of improving the yield.
When the time reaches 2 hours, a manhole is opened, 133kg of polyphosphoric acid is slowly added, the manhole is sealed after the adding is finished, the stirring is continued until the time reaches 10 hours, in the step, the reaction is kept for 2 hours, the polyphosphoric acid is added as a dehydrating agent, after choline chloride is added into the dehydrated phosphoric acid, the system is thick, water in the system cannot be drawn out in time, the polyphosphoric acid is used as a good dehydrating agent and can be decomposed into phosphoric acid by water to participate in the reaction again, on one hand, the inhibition of the existence of water in the system on the reaction is reduced, the reaction is continued to be carried out in the positive direction, on the other hand, the proportion of the phosphoric acid and the choline chloride is increased, the proportion of the choline chloride participating in the reaction is greatly increased, and the yield of the calcium salt of.
And then, cooling the reaction kettle to 80 ℃, adding 250kg of water, uniformly stirring to obtain a reaction solution, putting the reaction solution into a barrel for metering and temporary storage for later use, wherein in the step, the main purpose of adding water is to conveniently perform the next reaction on the obtained reaction solution, and the obtained reaction solution is a phosphorylcholine chloride solution. The above reaction is an esterification reaction.
In order to obtain the phosphorylcholine calcium chloride salt, firstly, 125kg of pure water is added into a neutralization kettle, 1/20 of reaction liquid is added into the neutralization kettle, stirring is started, calcium hydroxide solid is slowly added after stirring is uniformly carried out, the pH value of the calcium hydroxide solid is adjusted to 5 within 30-40min and is stabilized for 20min, a mixed solution is obtained, in the step, the phosphorylcholine chloride and the calcium hydroxide are subjected to neutralization reaction, the phosphorylcholine calcium chloride salt is further obtained, in order to ensure the completeness of the reaction and further achieve the purpose of increasing the yield, in the embodiment, the obtained reaction liquid is firstly divided into 20 batches for reaction, and meanwhile, the corresponding pH value is controlled within effective reaction time so as to achieve the purpose of full reaction.
Then, the mixed liquid is filtered by adopting a plate-and-frame filtering mode, the filtrate returns to the neutralization kettle, the filtering is stopped after the precipitation in the kettle is basically filtered completely, the filter cake is stored in the plate-and-frame, the calcium hydroxide solid is continuously and slowly added into the neutralization kettle until the pH value is about 7.5, the diaphragm pump is started, then the original filter cake is utilized for filtering, after the filtering is finished, the filtrate is collected to a ton bucket, and a certain amount of filtrate is also contained in the filter cake.
Taking 3-4 batches of the obtained filtrate to a concentration kettle, adding calcium chloride solids, wherein the addition amount of the calcium chloride solids is 2Kg of the batches of the filtrate, and in the embodiment, taking 3 batches, the actual addition amount of the calcium chloride solids is 6 Kg. Stirring and dissolving completely, starting vacuum, introducing steam into a jacket, heating to 80 ℃, concentrating, stopping steam and vacuum when a large number of crystals are separated out, cooling to 40 ℃, adding ethanol, wherein the adding amount of the ethanol is 5Kg 8 times of the batch of the filtrate, and the main purpose of multiplying 8 is to ensure that the ethanol corresponds to 8 times of the mass of choline, so that 120Kg is actually stirred and cooled to normal temperature. Obtaining crystal mixed liquid; and filtering the crystal mixed solution by adopting a plate-and-frame filtering mode to obtain crystals, and drying the crystals at 70 ℃ to obtain the phosphorylcholine chloride calcium salt.
In this example, the purpose of adding calcium chloride solid and ethanol is well known in the art, and therefore, in this example, the reaction is controlled by means of batch reaction, adjustment of PH, temperature, addition amount of raw material, and the like, and the purpose of improving the yield is achieved, without detailed description.
By metering and calculating the yield of the dried calcium phosphorylcholine chloride salt, the yield of the calcium phosphorylcholine chloride salt prepared by the method provided by the embodiment is 200%.
The yield of the calcium phosphorylcholine chloride reaches the expected requirement, and various indexes of the calcium phosphorylcholine chloride are detected:
table 1: calcium phosphorylcholine chloride
| Item | Standard of merit | Example 1 |
| Chlorine content | 13-14.5％ | 13.6％ |
| Calcium content | 15-16.1％ | 15.7％ |
| Moisture content | 19-23％ | 19％ |
| pH | 7-8.5 | 7.6 |
| Choline residue | ≤0.1％ | ≤0.1％ |
Example 2, this example provides a method for preparing phosphorylcholine chloride calcium salt,
firstly, the temperature of the reaction kettle is raised to 80 ℃, in the embodiment, the reaction kettle is a steam heating reaction kettle, namely, hydrogen is introduced into an interlayer of the reaction kettle, so that the purpose of heating and raising the temperature is achieved, after the temperature is raised to 80 ℃, 100kg of phosphoric acid is added into the reaction kettle, stirring and vacuum are started, the temperature is continuously raised to 160 ℃, timing is started when the temperature is raised to 150 ℃, stirring is carried out for 3 hours until no water is evaporated, and the main purpose of the step is to discharge the moisture in the phosphoric acid, so that the phosphoric acid can better react with choline chloride.
After no water is evaporated, cooling to 105 ℃, opening a manhole, slowly adding 100kg of choline crystals, adjusting the vacuum state to about 0.03MPa, sealing the manhole after adding, and starting timing reaction. The addition amount of the choline crystals (choline chloride) of 100kg is more than or equal to 2 percent of the normal complete reaction amount, so as to reduce moisture and ensure the normal reaction, thereby achieving the purpose of improving the yield.
When the time reaches 2 hours, a manhole is opened, 133kg of polyphosphoric acid is slowly added, the manhole is sealed after the adding is finished, the stirring is continued until the time reaches 10 hours, in the step, the reaction is kept for 2 hours, the polyphosphoric acid is added as a dehydrating agent, after choline chloride is added into the dehydrated phosphoric acid, the system is thick, water in the system cannot be drawn out in time, the polyphosphoric acid is used as a good dehydrating agent and can be decomposed into phosphoric acid by water to participate in the reaction again, on one hand, the inhibition of the existence of water in the system on the reaction is reduced, the reaction is continued to be carried out in the positive direction, on the other hand, the proportion of the phosphoric acid and the choline chloride is increased, the proportion of the choline chloride participating in the reaction is greatly increased, and the yield of the calcium salt of.
And then, cooling the reaction kettle to 80 ℃, adding 250kg of water, uniformly stirring to obtain a reaction solution, putting the reaction solution into a barrel for metering and temporary storage for later use, wherein in the step, the main purpose of adding water is to conveniently perform the next reaction on the obtained reaction solution, and the obtained reaction solution is a phosphorylcholine chloride solution. The above reaction is an esterification reaction.
In order to obtain the phosphorylcholine calcium chloride salt, firstly, 125kg of pure water is added into a neutralization kettle, 1/20 of reaction liquid is added into the neutralization kettle, stirring is started, calcium hydroxide solid is slowly added after stirring is uniformly carried out, the pH value of the calcium hydroxide solid is adjusted to 5-5.5 within 30-40min and is stabilized for 20min, mixed liquid is obtained, in the step, the phosphorylcholine chloride and the calcium hydroxide are subjected to neutralization reaction, and then the phosphorylcholine calcium chloride salt is obtained.
Then, the mixed liquid is filtered by adopting a plate-and-frame filtering mode, the filtrate returns to the neutralization kettle, the filtering is stopped after the precipitation in the kettle is basically filtered completely, the filter cake is stored in the plate-and-frame, the calcium hydroxide solid is continuously and slowly added into the neutralization kettle until the pH value is about 7.5, the diaphragm pump is started, then the original filter cake is utilized for filtering, after the filtering is finished, the filtrate is collected to a ton bucket, and a certain amount of filtrate is also contained in the filter cake.
Taking 3-4 batches of the obtained filtrate to a concentration kettle, adding calcium chloride solids, wherein the addition amount of the calcium chloride solids is 2Kg of the batches of the filtrate, and in the embodiment, taking 3 batches, the actual addition amount of the calcium chloride solids is 6 Kg. Stirring and dissolving completely, starting vacuum, introducing steam into a jacket, heating to 80 ℃, concentrating, stopping steam and vacuum when a large number of crystals are separated out, cooling to 40-50 ℃, adding ethanol, wherein the adding amount of the ethanol is 5Kg 8 times of the batch of the filtrate, and the main purpose of multiplying 8 is to ensure that the ethanol corresponds to 8 times of the mass of choline, so that 120Kg is actually obtained, and stirring and cooling to normal temperature. Obtaining crystal mixed liquid; and filtering the crystal mixed solution by adopting a plate-and-frame filtering mode to obtain crystals, and drying the crystals at 70 ℃ to obtain the phosphorylcholine chloride calcium salt.
In this example, the purpose of adding calcium chloride solid and ethanol is well known in the art, and therefore, in this example, the reaction is controlled by means of batch reaction, adjustment of PH, temperature, addition amount of raw material, and the like, and the purpose of improving the yield is achieved, without detailed description.
By metering and calculating the yield of the dried calcium phosphorylcholine chloride salt, the yield of the calcium phosphorylcholine chloride salt prepared by the method provided by the embodiment is 200%.
The yield of the calcium phosphorylcholine chloride reaches the expected requirement, and various indexes of the calcium phosphorylcholine chloride are detected:
table 2: calcium phosphorylcholine chloride
| Item | Standard of merit | Example 1 |
| Chlorine content | 13-14.5％ | 14.2％ |
| Calcium content | 15-16.1％ | 16.0％ |
| Moisture content | 19-23％ | 19％ |
| pH | 7-8.5 | 7.7 |
| Choline residue | ≤0.1％ | ≤0.1％ |
The above description is only a preferred embodiment of the present invention, and not intended to limit the present invention in other forms, and any person skilled in the art may apply the above modifications or changes to the equivalent embodiments with equivalent changes, without departing from the technical spirit of the present invention, and any simple modification, equivalent change and change made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the technical spirit of the present invention.
Claims (4)
1. A preparation method of phosphorylcholine chloride calcium salt is characterized by comprising the following steps:
a. firstly, heating a reaction kettle to 80 ℃, then adding 100kg of phosphoric acid, starting stirring and vacuum, continuously heating to 160 ℃, starting timing when the temperature is raised to 150 ℃, and stirring for 2-3 hours until no water is evaporated;
b. after anhydrous is evaporated, cooling to 100-105 ℃, opening a manhole, slowly adding 100kg of choline crystals, adjusting the vacuum state to 0.03MPa, sealing the manhole after adding, and starting timing reaction;
c. when the time is 2 hours, opening a manhole, slowly adding 133kg of polyphosphoric acid, sealing the manhole after the adding is finished, and continuously stirring until the time is 10 hours;
d. then, cooling the reaction kettle to 80 ℃, adding 250kg of water, uniformly stirring to obtain a reaction solution, and putting the reaction solution into a barrel for metering and temporary storage for later use;
e. adding 125kg of pure water into the neutralization kettle, adding 1/20 of reaction liquid into the neutralization kettle, starting stirring, slowly adding calcium hydroxide solid after uniformly stirring, adjusting the pH value to 5-5.5 within 30-40min, and stabilizing for 20min to obtain a mixed solution;
f. filtering the mixed solution by adopting a plate-and-frame filtering mode, returning the filtrate to the neutralization kettle, stopping filtering after the precipitation and filtration in the kettle are completed, and storing a filter cake in the plate-and-frame filtering mode;
g. continuously and slowly adding calcium hydroxide solid into the neutralization kettle until the pH value reaches 7.5, starting a diaphragm pump, then filtering by using the original filter cake, and collecting filtrate to a ton barrel after the filtration is finished;
h. repeating the step e-g until the reaction solution is completely used, taking 3-4 batches of filtrate obtained in the step e-g to a concentration kettle, adding calcium chloride solid, stirring and dissolving completely, starting vacuum, introducing steam into a jacket, heating to 80 ℃, and concentrating;
i. concentrating until a large amount of crystals are separated out, stopping steam, vacuumizing, cooling to 40-50 ℃, adding ethanol, stirring, and cooling to normal temperature to obtain a crystal mixed solution;
j. and filtering the crystal mixed solution by adopting a plate-and-frame filtering mode to obtain crystals, and drying the crystals at 70 ℃ to obtain the phosphorylcholine chloride calcium salt.
2. The method of claim 1, wherein the step g further comprises collecting the filtrate in a ton tank, collecting the filter cake, adding 125kg of water into the neutralization kettle, adding the filter cake into the neutralization kettle again, stirring for 20min, filtering, collecting the filtrate in a ton tank, mixing with the previously collected filtrate, and collecting the filtrate as a batch.
3. The process for the preparation of calcium phosphorylcholine chloride salt according to claim 2, characterized in that in the h step, the amount of calcium chloride solid added is 2Kg per batch of the filtrate.
4. The process for the preparation of calcium phosphorylcholine chloride salt according to claim 3, characterized in that in step i, ethanol is added in an amount of 5Kg by 8 batches of the filtrate.
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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 |
| CN103936785A (en) * | 2014-05-04 | 2014-07-23 | 苏州天马精细化学品股份有限公司 | Method for preparing phosphorylcholine chloride calcium salt tetrahydrate |
| 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 |
| CN105198761A (en) * | 2015-10-20 | 2015-12-30 | 山东恩贝科技有限公司 | Crystal with high content of choline chloride and preparation method of crystal |
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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 |
| CN103936785A (en) * | 2014-05-04 | 2014-07-23 | 苏州天马精细化学品股份有限公司 | Method for preparing phosphorylcholine chloride calcium salt tetrahydrate |
| 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 |
| CN105198761A (en) * | 2015-10-20 | 2015-12-30 | 山东恩贝科技有限公司 | Crystal with high content of choline chloride and preparation method of crystal |
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Denomination of invention: Preparation method of calcium phosphate choline chloride Effective date of registration: 20230311 Granted publication date: 20200529 Pledgee: Bank of China Limited Gaotang Sub-branch Pledgor: SHANDONG AOBO BIOTECHNOLOGY CO.,LTD. Registration number: Y2023980034501 |