CN103172659A - L-alpha-glyceryl phosphoryl choline crystal form compound - Google Patents
L-alpha-glyceryl phosphoryl choline crystal form compound Download PDFInfo
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- CN103172659A CN103172659A CN2013101063639A CN201310106363A CN103172659A CN 103172659 A CN103172659 A CN 103172659A CN 2013101063639 A CN2013101063639 A CN 2013101063639A CN 201310106363 A CN201310106363 A CN 201310106363A CN 103172659 A CN103172659 A CN 103172659A
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- crystal formation
- glycerophosphoryl choline
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Abstract
The embodiment of the invention discloses an L-alpha-glyceryl phosphoryl choline crystal form compound, wherein the chemical name is 2-[[[(2R)-2, 3-dihydrozyl propoxyl] hydroxyl phosphoryl] oxyl]-N, N, N-trimethyl ethyl ammonium hydroxide inner salt. The preparation method comprises the following steps of: adding lecithin to methanol liquid, adding an alkali metal alkoxide catalyst, and hydrolyzing to remove acyl; adjusting pH of the liquid by an organic acid or an inorganic acid to 5-6; extracting the liquid with adjusted pH by petroleum ether to remove lipid soluble impurities in the liquid; then, removing inorganic salt and impurities by strong acid, strong base, weak acid and weak base resin to obtain a dope L-alpha-glyceryl phosphoryl choline coarse product; and dissolving the dope L-alpha-glyceryl phosphoryl choline coarse product by methanol liquid, adding acetone to separate out crystals, and then suction filtering and drying to obtain white solid product. The compound provided by the invention has the advantages of simple process, low cost and easy accessibility of raw materials, simpleness in purification, low equipment demand, and easy implementation of industrial conversion.
Description
Technical field
The present invention relates to the glycerophosphoryl choline field, relate in particular to a kind of L-α-glycerophosphoryl choline crystal formation compound.
Background technology
L-α-glycerophosphoryl choline is simple in structure, and bibliographical information is mainly to be obtained by complete synthesis or soybean lecithin hydrolysis, and the preparation method of relevant GPC has more bibliographical information both at home and abroad, as document J.Am.Chem.Soc., 1948,70,1394-1399; Kanu M.Petl, et al., Journal of Lipid Research, 1979, Vol20,674-677; Patent ES2019552A6; Patent US5250719, US5433833A.The disclosed preparation process of above-mentioned document wherein, with complete synthesis method, is generally to utilize the skeleton of glycerine or other compounds to be precursor, and the formation by the phosphatide key after long chain alkylating or acylations comes synthesising target compound.Be characterized in that synthesis step is more, handiness is little, generally uses protecting group, except preparing general basic phosphatide, also will carry out optically active experiment; Become the chlorination chromic salts to prepare GPC after bibliographical information soybean lecithin hydrolysis is also arranged, reacting phase is to complete synthesis simple again, but is difficult for purifying, and aftertreatment relates to the removal of hypertoxic chromium chloride, is not suitable for industrialization.
Summary of the invention
Embodiment of the present invention technical problem to be solved is, provides a kind of technique simple, and raw material is cheap and easy to get, and purifying is simple, and equipment requirements is low, easily realizes the industrial L-α that transforms-glycerophosphoryl choline crystal formation compound.
Described L-α-glycerophosphoryl choline crystal formation compound, molecular structure is as follows:
The preparation method of described L-α-glycerophosphoryl choline crystal formation compound comprises the steps:
(1) Yelkin TTS is added in methanol solution, add alkali metal alkoxide catalyst in solution, acyl group is sloughed in the reaction that is hydrolyzed;
(2) mentioned solution is regulated PH to 5-6 with organic acid or mineral acid;
(3) will regulate solution petroleum ether extraction after PH, remove the oil-soluble impurities in solution;
(4) remove inorganic salt and impurity by strong acid and strong base weak acid and weak base resin again, obtain the L-α of dope shape-glycerophosphoryl choline crude product;
(5) with the L-α of dope shape-glycerophosphoryl choline crude product with dissolve with methanol after, add the acetone crystallize out, then obtain the white solid finished product after crossing suction filtration, drying.
Hydrolysising reacting temperature in described step (1) is 40 ℃-45 ℃, and the reaction times is 24 hours.
Catalyzer alkali metal alcoholates in described step (1) is sodium methylate.
The mol ratio of described Yelkin TTS and catalyzer sodium methylate 1.4: 1.
Organic acid in described step (2) is acetic acid.
As the further improvement of the technical program, in described step (3), with before petroleum ether extraction, first the solution with the methyl alcohol phase concentrates 1/2nd.
Purifying process in described step (4) uses 732 resins, D311 resin, 717 resins, D152 resin column to carry out purifying successively.
In described step (5), the acetone consumption is 40 times of amounts of L-α-glycerophosphoryl choline crude product methanol solution.
Implement the embodiment of the present invention, have following beneficial effect:
Embodiment of the present invention Yelkin TTS is that raw material is processed deacylated tRNA with alkali metal alcoholates in methanol solution, neutralize with organic acid or with mineral acid again, remove inorganic salt and impurity by strong acid and strong base weak acid and weak base resin again, technique is simple, raw material is cheap and easy to get, purifying is simple, and equipment requirements is low, realizes that easily industry transforms.
Embodiment
For making the purpose, technical solutions and advantages of the present invention clearer, below the present invention is described in further detail.
The molecular structure of the present embodiment L-α-glyceryl phosphatide phatidylcholine is as follows:
(L-α-GPC) the preparation of amplification of L-α-glyceryl phosphatide phatidylcholine
The charge ratio table
| Title | Molecular weight | Charging capacity | Mole number | Mol ratio |
| Soybean lecithin (PC) | 788.13 | 231Kg | 293.1 | 1.4 |
| Sodium methylate | 54.02 | 11.1Kg | 205.08 | 1 |
| 732 resins | ? | 180Kg | ? | ? |
| The D311 resin | ? | 180Kg | ? | ? |
| 717 resins | ? | 180Kg | ? | ? |
| The D152 resin | ? | 180Kg | ? | ? |
| Methyl alcohol | ? | 90L+30L | ? | ? |
| Distilled water | / | 390L | ? | ? |
| Sherwood oil | ? | 90L | ? | ? |
Operating procedure
To add in the 100L reactor under PC, sodium methylate, methyl alcohol (90L) room temperature, stir solids is entirely not molten, is heated to 40 ℃, in keeping, 40 ± 5 ℃ of reactions of temperature are 24 hours, and TLC detection reaction system is reacted complete rear cooling room temperature, filter, use the methanol wash filter cake, mother liquor transfers pH to 5-6 with acetic acid (approximately 1024ml), and system is in 40 ℃ of concentrating under reduced pressure to half volume, mother liquor adds sherwood oil (18L * 5) to stir, separatory, methyl alcohol is 40 ℃ of concentrating under reduced pressure mutually, obtain 77.16kg brown color viscous oil thing.4 kinds of resins are respectively charged in resin column respectively use the 30L distilled water flushing, stand-by; Again brown color viscous oil thing is joined in 732 resin columns and rinse this resin column with methyl alcohol (30L), until elutriant is without color, methyl alcohol is given up, and then uses the 360L distilled water flushing, collects elutriant, elutriant added 230 gram gac reflux decolour 30 minutes, destainer is rinsed the D311 resin, collect elutriant, TLC detection elutriant as above goes on foot elutriant not to be had, use the distilled water flushing resin column, stop collecting until TLC detects product-free.Rinse 717 resin columns with the elutriant of collecting again, collect elutriant, TLC detection elutriant as above goes on foot elutriant not to be had, and uses the distilled water flushing resin column, until detecting product-free, TLC stops collecting, use the elutriant collected of step again and rinse the D152 resin column, collect elutriant, TLC detects this elutriant and as above goes on foot elutriant and do not have, use the distilled water flushing resin column, until the TLC testing product is collected without stopping, elutriant is concentrated obtains the faint yellow viscous oil thing of 16.66kg, and molar yield is 22.1%.
(the refining amplification of L-α-GPC) of L-α-glyceryl phosphatide phatidylcholine
The charge ratio table
| Title | Molecular weight | Charging capacity |
| L-α-GPC crude product | 257.2 | 16.62kg |
| Anhydrous methanol | / | 83.1L |
| Acetone | / | 664.8L |
Operating procedure
Add anhydrous methanol under room temperature in L-α-GPC crude product (viscous oil thing) 16.62kg, stirring and dissolving, slowly join mother liquor in acetone again, rapid stirring 15 minutes stops that the teeter column is gentle and quiet put 24 hours, slowly separates out white solid, suction filtration, obtain white solid, 40 ℃ of vacuum-drying 24 hours gets 12.02kg.Yield is 72.2%.
Embodiment of the present invention Yelkin TTS is that raw material is processed deacylated tRNA with alkali metal alcoholates in methanol solution, neutralize with organic acid or with mineral acid again, remove inorganic salt and impurity by strong acid and strong base weak acid and weak base resin again, technique is simple, raw material is cheap and easy to get, purifying is simple, and equipment requirements is low, realizes that easily industry transforms.
Above disclosed is only a kind of preferred embodiment of the present invention, certainly can not limit with this interest field of the present invention, and the equivalent variations of therefore doing according to claim of the present invention still belongs to the scope that the present invention is contained.
Claims (8)
1. L-α-glycerophosphoryl choline crystal formation compound, is characterized in that, molecular structure is as follows:
Described L-α-glycerophosphoryl choline crystal formation compounds process for production thereof comprises the steps:
(1) Yelkin TTS is added in methanol solution, add alkali metal alkoxide catalyst in solution, acyl group is sloughed in the reaction that is hydrolyzed;
(2) mentioned solution is regulated PH to 5-6 with organic acid or mineral acid;
(3) will regulate solution petroleum ether extraction after PH, remove the oil-soluble impurities in solution;
(4) remove inorganic salt and impurity by strong acid and strong base weak acid and weak base resin again, obtain the L-α of dope shape-glycerophosphoryl choline crude product;
(5) with the L-α of dope shape-glycerophosphoryl choline crude product with dissolve with methanol after, add the acetone crystallize out, then obtain the white solid finished product after crossing suction filtration, drying.
2. L-α according to claim 1-glycerophosphoryl choline crystal formation compound, is characterized in that, the hydrolysising reacting temperature in described step (1) is 40 ℃-45 ℃, and the reaction times is 24 hours.
3. L-α according to claim 1 and 2-glycerophosphoryl choline crystal formation compound, is characterized in that, the catalyzer alkali metal alcoholates in described step (1) is sodium methylate.
4. L-α according to claim 3-glycerophosphoryl choline crystal formation compound, is characterized in that, the mol ratio of described Yelkin TTS and catalyzer sodium methylate 1.4: 1.
5. L-α according to claim 1-glycerophosphoryl choline crystal formation compound, is characterized in that, the organic acid in described step (2) is acetic acid.
6. L-α according to claim 1-glycerophosphoryl choline crystal formation compound, is characterized in that, in described step (3), with before petroleum ether extraction, first the solution with the methyl alcohol phase concentrates 1/2nd.
7. L-α according to claim 1-glycerophosphoryl choline crystal formation compound, is characterized in that, the purifying process in described step (4) uses 732 resins, D311 resin, 717 resins, D152 resin column to carry out purifying successively.
8. L-α according to claim 1-glycerophosphoryl choline crystal formation compound, is characterized in that, in described step (5), the acetone consumption is 40 times of amounts of L-α-glycerophosphoryl choline crude product methanol solution.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001256A (en) * | 2015-08-12 | 2015-10-28 | 芜湖福民生物药业有限公司 | Preparation method of choline alfoscerate crystal |
| CN105017307A (en) * | 2015-07-22 | 2015-11-04 | 沈阳天峰生物制药有限公司 | Method for preparing high-purity natural L-alpha-glycerylphosphorylcholine |
| CN106083916A (en) * | 2016-06-08 | 2016-11-09 | 芜湖福民生物药业有限公司 | The preparation method of choline alfoscerate crystal |
| CN106432326A (en) * | 2016-09-07 | 2017-02-22 | 上海现代制药海门有限公司 | Purification method of L-alpha-glycerophosphoryl choline |
| CN107298692A (en) * | 2017-06-12 | 2017-10-27 | 芜湖福民生物药业股份有限公司 | The preparation method of glycerolphosphocholine |
| CN108997412A (en) * | 2018-07-19 | 2018-12-14 | 芜湖福民生物药业股份有限公司 | The method of purification of crude glycerol phosphatidyl choline |
| CN109096326A (en) * | 2018-10-09 | 2018-12-28 | 江苏东南纳米材料有限公司 | A kind of high-purity lysophosphatidyl choline and preparation method thereof |
| US10787469B2 (en) | 2014-06-10 | 2020-09-29 | Chemi S.P.A. | Process for the purification of L-α-glycerophosphorylcholine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990013552A1 (en) * | 1989-05-08 | 1990-11-15 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | PROCESS FOR THE PREPARATION OF L-α-GLYCERYLPHOSPHORYLCHOLINE AND OF L-α-GLYCERYLPHOSPHORYLETHANOLAMINE |
| WO2007145476A1 (en) * | 2006-06-14 | 2007-12-21 | Kim, Hyun Joo | A process for preparation of l-alpha-glycerophosphoryl choline |
| CN102516292A (en) * | 2011-11-08 | 2012-06-27 | 西北大学 | Natural L-alpha-glycerophosphocholine (GPC) and preparation method thereof |
-
2013
- 2013-03-29 CN CN2013101063639A patent/CN103172659A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990013552A1 (en) * | 1989-05-08 | 1990-11-15 | Istituto Chemioterapico Italiano Fine Chemicals S.P.A. | PROCESS FOR THE PREPARATION OF L-α-GLYCERYLPHOSPHORYLCHOLINE AND OF L-α-GLYCERYLPHOSPHORYLETHANOLAMINE |
| WO2007145476A1 (en) * | 2006-06-14 | 2007-12-21 | Kim, Hyun Joo | A process for preparation of l-alpha-glycerophosphoryl choline |
| CN102516292A (en) * | 2011-11-08 | 2012-06-27 | 西北大学 | Natural L-alpha-glycerophosphocholine (GPC) and preparation method thereof |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10787469B2 (en) | 2014-06-10 | 2020-09-29 | Chemi S.P.A. | Process for the purification of L-α-glycerophosphorylcholine |
| CN105017307A (en) * | 2015-07-22 | 2015-11-04 | 沈阳天峰生物制药有限公司 | Method for preparing high-purity natural L-alpha-glycerylphosphorylcholine |
| CN105001256A (en) * | 2015-08-12 | 2015-10-28 | 芜湖福民生物药业有限公司 | Preparation method of choline alfoscerate crystal |
| CN106083916A (en) * | 2016-06-08 | 2016-11-09 | 芜湖福民生物药业有限公司 | The preparation method of choline alfoscerate crystal |
| CN106432326A (en) * | 2016-09-07 | 2017-02-22 | 上海现代制药海门有限公司 | Purification method of L-alpha-glycerophosphoryl choline |
| CN107298692A (en) * | 2017-06-12 | 2017-10-27 | 芜湖福民生物药业股份有限公司 | The preparation method of glycerolphosphocholine |
| CN108997412A (en) * | 2018-07-19 | 2018-12-14 | 芜湖福民生物药业股份有限公司 | The method of purification of crude glycerol phosphatidyl choline |
| CN109096326A (en) * | 2018-10-09 | 2018-12-28 | 江苏东南纳米材料有限公司 | A kind of high-purity lysophosphatidyl choline and preparation method thereof |
| CN109096326B (en) * | 2018-10-09 | 2021-04-30 | 江苏东南纳米材料有限公司 | High-purity lysophosphatidylcholine and preparation method thereof |
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Application publication date: 20130626 |