CN113563377A - Novel phosphorylcholine synthesis process technical method - Google Patents
Novel phosphorylcholine synthesis process technical method Download PDFInfo
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- CN113563377A CN113563377A CN202110800649.1A CN202110800649A CN113563377A CN 113563377 A CN113563377 A CN 113563377A CN 202110800649 A CN202110800649 A CN 202110800649A CN 113563377 A CN113563377 A CN 113563377A
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- phosphorylcholine
- choline
- choline hydroxide
- reaction
- temperature
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- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 title claims abstract description 50
- 229950004354 phosphorylcholine Drugs 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 13
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012528 membrane Substances 0.000 claims abstract description 19
- 229940075419 choline hydroxide Drugs 0.000 claims abstract description 18
- 238000000909 electrodialysis Methods 0.000 claims abstract description 16
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims abstract description 10
- 235000019743 Choline chloride Nutrition 0.000 claims abstract description 10
- 229960003178 choline chloride Drugs 0.000 claims abstract description 10
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000006366 phosphorylation reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 7
- 239000006227 byproduct Substances 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012668 chain scission Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011090 industrial biotechnology method and process Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- 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)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The invention relates to a novel Phosphorylcholine (PC) synthesis process method, which not only can improve the synthesis yield of phosphorylcholine, but also fundamentally solves the problems of low synthesis efficiency and more byproducts of the conventional process of phosphorylcholine; the new process directly obtains choline hydroxide by performing electrodialysis treatment on choline chloride through a bipolar membrane, and then phosphorylates the choline hydroxide to obtain phosphorylcholine, wherein the comprehensive product yield reaches 95%, and compared with the traditional process, the product yield is improved by 70%; the invention can not only improve the product yield of phosphorylcholine, but also avoid the generation of byproducts, and the process has the advantages of simple flow, convenient operation, low investment and operation cost, no generation of three wastes and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a novel bipolar membrane electrodialysis technical synthesis method.
Background
Phosphorylcholine is an important component of organisms and widely exists in cell membranes and exocrine bodies of cells. The phosphorylcholine-containing polymer has good biocompatibility and biological safety, and is widely applied to the fields of medical instruments and tissue engineering. Recent research proves that the nanoparticles containing phosphorylcholine have unique in vivo circulation performance, and the development of the phosphorylcholine-based nano drug carrier has important application prospect.
The common Phosphorylcholine (PC) is extracted and synthesized from animal and plant bodies, and is synthesized by a process (choline chloride: polyphosphoric acid =3:1 is added in proportion, the reaction condition temperature is controlled at 140-145 ℃, the pressure is controlled at-0.09 to-0.1 MPA, the phosphorylcholine is obtained by direct phosphorylation reaction, a large amount of byproducts exist in the obtained product, the yield of the phosphorylcholine is 55 percent, the phosphorylcholine is one of indispensable components when being applied to nerve medicines, and the research in the field is increasingly concerned by people in recent years.
No report is found on a method for directly preparing the choline hydroxide by a bipolar membrane electrodialysis method. The process of the invention is applied to the synthesis of phosphorylcholine and becomes an important means, and the bipolar membrane electrodialysis technology is utilized to convert choline chloride into choline hydroxide, thereby realizing the production of phosphorylcholine, reducing the byproducts of phosphorylcholine and improving the yield of phosphorylcholine.
Disclosure of Invention
The invention aims to provide a novel process technology, the synthesis yield of phosphorylcholine is improved by a bipolar membrane electrodialysis technology, and the technology is simple to operate, environment-friendly, economical and suitable for an industrial synthesis process. The invention improves the yield of phosphorylcholine and reduces by-products in the reaction.
The technical scheme of the invention is as follows: the phosphorylcholine synthesis process mainly comprises the following steps:
(1) and (3) generation of choline hydroxide: performing bipolar membrane electrodialysis treatment on choline chloride to obtain choline hydroxide and hydrochloric acid;
(2) the reaction conditions of the phosphorylcholine are as follows: dropwise adding 85% phosphoric acid into a choline hydroxide reaction kettle, adjusting the pH to 5-7, controlling the reaction temperature to 0-5 ℃, and reacting for 4-8 h to obtain choline phosphate; after the reaction is finished, obtaining the phosphorylcholine by reduced pressure distillation, wherein the pressure is-0.095 to-0.1 MPA, and the temperature is controlled at 80-95 ℃;
(3) the reaction conditions for generating the phosphorylcholine are as follows: adding phosphorylcholine and polyphosphoric acid into a reaction kettle according to the proportion of 1:1, controlling the pressure at-0.1 MPA, the temperature at 140-; and extracting the obtained product with ethanol to obtain Phosphorylcholine (PC).
The invention has the advantages and positive effects that:
(1) according to the invention, the choline chloride is generated into choline hydroxide by adopting a bipolar membrane electrodialysis technology through an ion conversion function of electric energy, no by-product is generated in the process, and pure choline hydroxide is obtained;
(2) the invention adopts phosphate radical to replace chloride ion, avoids the interference of chloride ion in phosphorylation reaction, aggravates the chain scission recombination of polyphosphoric acid and choline hydroxide, makes the reaction condition milder and facilitates the process generation;
(3) the bipolar membrane electrodialysis technology is adopted to change the traditional synthesis process route, greatly improve the product yield and reduce the environmental pollution.
Drawings
FIG. 1 is a schematic route diagram of the chemical reaction for the synthesis of phosphorylcholine according to the novel industrial technique of the present invention.
Detailed Description
Example 1
1000 mL of 75% choline chloride solution is added into a bipolar membrane electrodialysis device, and the membrane stack area of the bipolar membrane electrodialysis is 0.1m2After 135 min of treatment, 950 mL of 65% choline hydroxide is obtained; 480 g of 85 percent phosphoric acid is dripped to adjust the pH value to 3.2 to 3.8, so as to generate a phosphorylcholine solution; then, carrying out reduced pressure distillation under the following control conditions: pulling the rod to constant weight under the pressure of-0.1 MPA and the temperature of 80-90 ℃; 600 g of polyphosphoric acid is added, the pressure is controlled to be minus 0.1MPA, the temperature is 140-150 ℃, and after the reaction time is 4-8 h, 932.6g of phosphorylcholine is obtained, and the comprehensive yield of the product is 95.7%.
Example 2
500 mL of 75% choline chloride solution is added into a bipolar membrane electrodialysis device, and the membrane stack area of the bipolar membrane electrodialysis is 0.1m2After 76 min of treatment, 480 mL of 65% choline hydroxide is obtained; adding 250 g of 85% phosphoric acid dropwise to adjust the pH value to 3.2-3.8 to generate a phosphorylcholine solution; then, carrying out reduced pressure distillation under the following control conditions: pulling the rod to constant weight under the pressure of-0.1 MPA and the temperature of 80-90 ℃; adding 301 g of polyphosphoric acid, controlling the pressure at-0.1 MPA, the temperature at 140-150 ℃ and the reaction time at 3-8 h to obtain 438.4 g of phosphorylcholine, wherein the reaction yield is 91.2%.
Example 3
1000 mL of 50% choline chloride solution was charged to a bipolar membrane electrodialysis apparatus, doubleThe membrane stack area of the polar membrane electrodialysis is 0.1m2After 110 min of treatment, 950 mL of 39% choline hydroxide is obtained; 260 g of 85 percent phosphoric acid is dripped to adjust the pH value to 3.2-3.8, and a phosphorylcholine solution is generated; then, carrying out reduced pressure distillation under the following control conditions: the pressure is controlled at-0.1 MPA, the temperature is 80-90 ℃, and the pull rod is pulled to constant weight; adding 302 g of polyphosphoric acid, controlling the pressure at-0.1 MPA, the temperature at 140-150 ℃ and the reaction time at 4-8 h to obtain 443.8 g of phosphorylcholine, wherein the reaction yield is 94.7%.
The above three technical formulations show and describe the basic principles, main features and advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents.
Claims (4)
1. A novel phosphorylcholine synthesis process method mainly comprises the following steps:
(1) production of choline hydroxide: choline chloride is used as a raw material, and choline hydroxide and hydrochloric acid are prepared by bipolar membrane electrodialysis;
production of phosphorylcholine: dripping phosphoric acid into choline hydroxide to generate phosphorylcholine;
phosphorylcholine: phosphorylcholine is obtained by the phosphorylation reaction of phosphorylcholine and polyphosphoric acid.
2. The method according to claim 1, wherein said choline hydroxide forms: treating 20-75% choline chloride by bipolar membrane electrodialysis equipment to obtain choline hydroxide and hydrochloric acid.
3. The method as set forth in claim 1, wherein the reaction conditions for preparing phosphorylcholine are: dropwise adding 85% phosphoric acid into a choline hydroxide reaction kettle, adjusting the pH to 5-7, controlling the reaction temperature to 0-5 ℃, and reacting for 4-8 h to obtain choline phosphate; after the reaction is finished, obtaining the phosphorylcholine by reduced pressure distillation, wherein the pressure is-0.095 to-0.1 MPA, and the temperature is controlled at 80-95 ℃.
4. The method according to claim 1, wherein the phosphorylcholine-forming reaction conditions are: adding 75% of phosphorylcholine and polyphosphoric acid into a reaction kettle according to the proportion of 1:1, controlling the pressure at-0.1 MPA, the temperature at 140-; and extracting the obtained product with ethanol to obtain Phosphorylcholine (PC).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110800649.1A CN113563377A (en) | 2021-07-15 | 2021-07-15 | Novel phosphorylcholine synthesis process technical method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110800649.1A CN113563377A (en) | 2021-07-15 | 2021-07-15 | Novel phosphorylcholine synthesis process technical method |
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| CN113563377A true CN113563377A (en) | 2021-10-29 |
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|---|---|---|---|
| CN202110800649.1A Pending CN113563377A (en) | 2021-07-15 | 2021-07-15 | Novel phosphorylcholine synthesis process technical method |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006144057A (en) * | 2004-11-18 | 2006-06-08 | Toho Earthtech Inc | Method for producing choline salt |
| 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 |
| WO2013128393A1 (en) * | 2012-02-28 | 2013-09-06 | Frichem Private Limited | A process for preparing pure citicoline (cdp-choline) |
| 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 |
| CN104066711A (en) * | 2011-12-29 | 2014-09-24 | 塔明克公司 | Process for the production of choline hydroxide |
| CN104844647A (en) * | 2015-05-07 | 2015-08-19 | 芜湖福民生物药业有限公司 | Preparation method of glycerinum phosphatidylcholine |
| 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 |
| CN113548973A (en) * | 2021-07-28 | 2021-10-26 | 上海德迈世欧化工有限公司 | Preparation method of electronic-grade choline hydroxide solution |
-
2021
- 2021-07-15 CN CN202110800649.1A patent/CN113563377A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006144057A (en) * | 2004-11-18 | 2006-06-08 | Toho Earthtech Inc | Method for producing choline salt |
| CN104066711A (en) * | 2011-12-29 | 2014-09-24 | 塔明克公司 | Process for the production of choline hydroxide |
| 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 |
| WO2013128393A1 (en) * | 2012-02-28 | 2013-09-06 | Frichem Private Limited | A process for preparing pure citicoline (cdp-choline) |
| 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 |
| CN104844647A (en) * | 2015-05-07 | 2015-08-19 | 芜湖福民生物药业有限公司 | Preparation method of glycerinum phosphatidylcholine |
| 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 |
| CN113548973A (en) * | 2021-07-28 | 2021-10-26 | 上海德迈世欧化工有限公司 | Preparation method of electronic-grade choline hydroxide solution |
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