CN103087091A - L-alpha-choline glycerophosphate synthesis method - Google Patents
L-alpha-choline glycerophosphate synthesis method Download PDFInfo
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- CN103087091A CN103087091A CN2011103322249A CN201110332224A CN103087091A CN 103087091 A CN103087091 A CN 103087091A CN 2011103322249 A CN2011103322249 A CN 2011103322249A CN 201110332224 A CN201110332224 A CN 201110332224A CN 103087091 A CN103087091 A CN 103087091A
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- glycerophosphorylcholine
- phosphorylcholine
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- tetramethyl ammonium
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Abstract
The present invention relates to a method, which comprises that (R)-(-)-3-chloro-1,2-propanediol and a phosphocholine tetramethyl ammonium salt are subjected to a substitution reaction, and ion exchange resin purification is performed to obtain a L-alpha-choline glycerophosphate pure product. According to the present invention, the used chiral intermediate (R)-(-)-3-chloro-1,2-propanediol is further a key chiral intermediate of an antitussive agent levodropropizine, has characteristics of stable chemical property and convenient and easy obtaining, and is especially for L-alpha-choline glycerophosphate industrial production.
Description
Invention field
The present invention relates to chirality synthetic chemistry and pharmaceutical chemistry field, in particular to the chemical synthesis process of L-α-Glycerophosphorylcholine.
Background technology
(L-α-Glycerophosphoryl Choline, L-α-GPC) are naturally occurring aqueous phospholipid meta-bolites in human body to L-α-Glycerophosphorylcholine.L-α-GPC can pass hemato encephalic barrier, is the synthetic Choline Sources of vagusstoff and phosphoric acid Yelkin TTS, is a kind of important neurotransmitter and phospholipid precursor, has the cognitive ability of improving the elderly and the effect of memory and protection blood vessel.
The structural formula of L-α-GPC is as follows:
The method that obtains at first L-α-GPC is directly to extract (G.Schmidt from Pancreas Bovis seu Bubali, J.Biochem, 1945), also can extract from Ovum Gallus domesticus Flavus lecithin (GB2058792) and soybean lecithin (JP61158990) again and obtain after hydrolysis, shortcoming is complex process, purity is low, and cost is high.
Along with the development of synthetic chemistry, EP0486100 has reported and has utilized the D-acetone glycerol first and 2-chloro-2-oxygen-1,3, the condensation of 2-dioxaphospholane, then can obtain L-α-GPC after occuring to replace ring-opening reaction with Trimethylamine 99:
But the D-acetone glycerol that uses in this route is difficult for preparation, high cost; 2-chloro-2-oxygen-1,3, the complex process of 2-dioxaphospholane, big for environment pollution, and meet water unstable; The replacement ring-opening reaction that Trimethylamine 99 is participated in needs pressurization.
EP0502357 proposes directly to carry out a step condensation with D-acetone glycerol p-toluenesulfonic esters and phosphorylcholine tetramethyl ammonium and obtains L-α-GPC:
(A is alkalimetal ion or tetramethyl ammonium)
The technique of this method is comparatively simple, and the easily detection under ultraviolet lamp of D-acetone glycerol p-toluenesulfonic esters, is convenient to judge reaction end, but still has the expensive problem that causes system-wide line high cost of D-acetone glycerol.
WO2007145476 uses (R)-(+)-condensating glycerine instead and phosphorylcholine carries out the enantiomorph that nucleophilic addition(Adn) obtains L-α-GPC under Isopropylamine exists:
The technique of this method is also comparatively simple, but (R)-(+)-condensating glycerine is difficult for detecting under ultraviolet lamp, be unfavorable for judging reaction end, and unstable under (R)-(+)-condensating glycerine normal temperature, need freezing preservation, generally will carry out purifying again by underpressure distillation before use.
Chinese patent CN101544667 improves on the basis of WO2007145476, they first make (S)-(-)-condensating glycerine p-toluenesulfonic esters with (S)-(-)-condensating glycerine, and then obtain L-α-GPC with the condensation of phosphorylcholine tetraethyl-ammonium salt:
The advantage of this method is convenient to ultraviolet detection after being (S)-(-)-condensating glycerine is made (S)-(-)-condensating glycerine p-toluenesulfonic esters; (S)-(-)-condensating glycerine p-toluenesulfonic esters is solid in addition; be convenient to improve optical purity by recrystallization; but increased upper protection of step step, do not met Atom economy, and the unsettled shortcoming of (S)-(-)-condensating glycerine that still has starting raw material.
Summary of the invention
The purpose of this invention is to provide a kind of new L-α-Glycerophosphorylcholine synthetic method, loaded down with trivial details with the with high costs and unsettled defective of (R)-(+)-condensating glycerine that overcomes the existing existing weak point of synthetic method, especially D-acetone glycerol and purifying thereof.
L-α of the present invention-Glycerophosphorylcholine synthetic method is: under the reflux temperature of solvent, (R)-(-)-3-chlorine-1,2-propylene glycol and phosphorylcholine tetramethyl ammonium are carried out substitution reaction, obtain L-α-Glycerophosphorylcholine crude product; Obtain sterling through ion-exchange resin purification.
(A is alkalimetal ion or tetramethyl ammonium)
The solvent that adopts in the inventive method is selected from one or both in water, methyl alcohol, ethanol, Virahol, acetonitrile, acetone.
After the phosphorylcholine tetramethyl ammonium that adopts in the inventive method ties up in the aqueous solution and to remove calcium ion in phosphoryl chloride choline calcium salt and obtain the chlorination phosphorylcholine with oxalic acid, then with the Tetramethylammonium hydroxide reaction and obtain.
In the inventive method, can to adopt model be the ion exchange resin of Dowex 509H or Amberlite IR-120 or Liwatit S100 to the step of spent ion exchange resin purifying crude product.
A preferred embodiment of the present invention comprises the following steps:
1. remove calcium ion in phosphoryl chloride choline calcium salt with oxalic acid in the aqueous solution, obtain the chlorination phosphorylcholine, add again Tetramethylammonium hydroxide, obtain the phosphorylcholine tetramethyl ammonium, wherein Tetramethylammonium hydroxide is solid, also can be by actual demand and the solution for later use that is made into different concns easy to use;
2. in appropriate solvent, (R)-(-)-3-chlorine-1,2-propylene glycol and phosphorylcholine tetramethyl ammonium are carried out substitution reaction, obtain L-α-Glycerophosphorylcholine crude product;
3. solvent is sloughed in the decompression under heating of the L-α that the upper step was prepared-Glycerophosphorylcholine crude product solution, then is dissolved in deionized water, and removes mineral ion by ion exchange resin, heats at last concentrating under reduced pressure and obtains L-α-Glycerophosphorylcholine sterling.The model of ion exchange resin is: Dowex 509H or Amberlite IR-120 or Liwatit S100.
Method of the present invention directly adopts (R)-(-)-3-chloro-1, the 2-propylene glycol is raw material, with the phosphorylcholine tetramethyl ammonium, one step substitution reaction occuring, namely obtains L-α-Glycerophosphorylcholine crude product, then obtain L-α-Glycerophosphorylcholine sterling through ion-exchange resin purification.The inventive method step is succinct, and productive rate is high; Chiral intermediate (R)-(-) that uses-3-chlorine-1,2-propylene glycol while or crucial chiral intermediate of levodropropizine, its stable chemical nature, suitability for industrialized production, can obtain easily.
Embodiment
The invention will be further described below by embodiment, but these embodiment are not construed as limiting the invention.
The preparation of embodiment one, phosphorylcholine tetramethyl ammonium
100g (0.3mol) phosphoryl chloride choline calcium salt tetrahydrate is dissolved in 350mL water, be heated to 50 ℃, add wherein 27g (0.3mol) oxalic acid, stirring reaction, treat the calcium ion precipitation fully, suction filtration, the filtrate that obtains is evaporated to the dried oily matter that obtains under heating, be the phosphorylcholine muriate.Add wherein 300mL methyl alcohol, stir, then add 54g (0.3mol) Tetramethylammonium hydroxide pentahydrate, be stirred to entirely moltenly, then desolventizing obtains 87.7g phosphorylcholine tetramethyl ammonium under 50 ℃ of vacuum.
The preparation of embodiment two, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in 300mL water, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, and is cooling, remove water under reduced pressure, add 300mL ethanol in residue, making beating removes by filter ammonium salt, filtrate decompression is steamed except ethanol, obtain approximately 70g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment three, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in 300mL methyl alcohol, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, filtrate decompression is steamed except methyl alcohol, obtain approximately 71g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment four, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in 300mL ethanol, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, filtrate decompression is steamed except ethanol, obtain approximately 72g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment five, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in the 300mL Virahol, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, filtrate decompression is steamed except Virahol, obtain approximately 74g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment six, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in the 300mL acetonitrile, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, filtrate decompression is steamed except acetonitrile, obtain approximately 74g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment seven, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in 300mL acetone, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, filtrate decompression is steamed except acetone, obtain approximately 75g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment eight, L-α-Glycerophosphorylcholine crude product
87.7g (0.3mol) phosphorylcholine tetramethyl ammonium is dissolved in the mixed solvent (V/V=1/1) of 300mL ethanol and acetonitrile, add 33g (0.3mol) (R)-(-)-3-chloro-1, the 2-propylene glycol, reflux is spent the night, cooling, remove by filter ammonium salt, the filtrate decompression steaming is desolventized, obtain approximately 74g of L-α-Glycerophosphorylcholine crude product.
The preparation of embodiment nine, L-α-Glycerophosphorylcholine sterling
The 74g L-α that obtains in embodiment five-Glycerophosphorylcholine crude product is dissolved in the 300mL deionized water, adds Dowex 509H ion exchange resin, fully stir, the elimination resin, then with deionized water wash repeatedly, merge the aqueous solution and (use AgNO
3Whether solution chlorine detection ion is divided), except anhydrating, obtain approximately 61.5g of L-α-Glycerophosphorylcholine sterling under 50 ℃ of vacuum, yield is about 83%, and chemical purity is that 99%, ee value is 99%, mp142-143 ℃, [α]
D 25-2.7 (pH 2.5 for c=2.7, water).
The preparation of embodiment ten, L-α-Glycerophosphorylcholine sterling
The 74g L-α that obtains in embodiment six-Glycerophosphorylcholine crude product is dissolved in the 300mL deionized water, adds Amberlite IR-120 ion exchange resin, fully stir, the elimination resin, then with deionized water wash repeatedly, merge the aqueous solution and (use AgNO
3Whether solution chlorine detection ion is divided), except anhydrating, obtain approximately 62.9g of L-α-Glycerophosphorylcholine sterling under 50 ℃ of vacuum, yield is 85%, chemical purity is that 99%, ee value is 99%, mp142-143 ℃, [α]
D 25-2.7 (pH 2.5 for c=2.7, water).
The preparation of embodiment 11, L-α-Glycerophosphorylcholine sterling
The 74g L-α that obtains in embodiment eight-Glycerophosphorylcholine crude product is dissolved in the 300mL deionized water, adds Liwatit S100 ion exchange resin, fully stir, the elimination resin, then with deionized water wash repeatedly, merge the aqueous solution and (use AgNO
3Whether solution chlorine detection ion is divided), except anhydrating, obtain approximately 61.5g of L-α-Glycerophosphorylcholine sterling under 50 ℃ of vacuum, yield is about 83%, and chemical purity is that 99%, ee value is 99%, mp142-143 ℃, [α]
D 25-2.7 (pH 2.5 for c=2.7, water).
Claims (4)
1.L-the synthetic method of α-Glycerophosphorylcholine is characterized in that: under the reflux temperature of solvent, (R)-(-)-3-chlorine-1,2-propylene glycol and phosphorylcholine tetramethyl ammonium are carried out substitution reaction, obtain L-α-Glycerophosphorylcholine crude product; Obtain sterling through ion-exchange resin purification.
2. synthetic method according to claim 1, wherein said solvent is selected from one or both in water, methyl alcohol, ethanol, Virahol, acetonitrile, acetone.
3. after synthetic method according to claim 1, wherein said phosphorylcholine tetramethyl ammonium tie up in the aqueous solution and to remove calcium ion in phosphoryl chloride choline calcium salt and obtain the chlorination phosphorylcholine with oxalic acid, then with the Tetramethylammonium hydroxide reaction and obtain.
4. synthetic method according to claim 1, the ion exchange resin type that wherein said ion-exchange resin purification step adopts number are: Dowex 509H or Amberlite IR-120 or Liwatit S100.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106459106A (en) * | 2014-02-10 | 2017-02-22 | 酶科技株式会社 | Method for preparing racemic or optically active ALPHA-glycerophosphoryl choline |
| CN108101937A (en) * | 2017-11-13 | 2018-06-01 | 湖南华纳大药厂手性药物有限公司 | A kind of method for preparing L- α-glycerolphosphocholine |
| CN109456359A (en) * | 2018-11-13 | 2019-03-12 | 科利生物科技（徐州）有限公司 | A method of isolating and purifying crude product L- ɑ-choline glycerophosphatide |
| CN110028524A (en) * | 2019-05-07 | 2019-07-19 | 天津康巢生物医药股份有限公司 | A kind of process preparing glycerolphosphocholine and its glycerolphosphocholine obtained |
| CN110437275A (en) * | 2019-08-22 | 2019-11-12 | 苏州汉德创宏生化科技有限公司 | A kind of synthetic method promoting brain function compound Choline Glycerophosphate |
| CN110467634A (en) * | 2018-06-16 | 2019-11-19 | 杨凌萃健生物工程技术有限公司 | A kind of glycerolphosphocholine preparation method of high-purity |
| KR20200099021A (en) * | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Method of preparing choline alfoscerate and pharmaceutical composition comprising the same |
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| CN101544667A (en) * | 2008-03-27 | 2009-09-30 | 南京莱尔生物化工有限公司 | Method for synthesizing L-alpha choline glycerophosphatide |
| CN101967160A (en) * | 2010-09-09 | 2011-02-09 | 常熟富士莱医药化工有限公司 | One-step method for preparing raceme DL, D or L-a-glycerin phosphorus acyl choline |
| KR20110106720A (en) * | 2010-03-23 | 2011-09-29 | (주)비씨월드제약 | NOVEL PROCESS FOR THE PREPARATION OF RACEMIC MIXTURE, D-FORM OR L-alpha;-GLYCERYL PHOSPHORYLCHOLINE |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101544667A (en) * | 2008-03-27 | 2009-09-30 | 南京莱尔生物化工有限公司 | Method for synthesizing L-alpha choline glycerophosphatide |
| KR20110106720A (en) * | 2010-03-23 | 2011-09-29 | (주)비씨월드제약 | NOVEL PROCESS FOR THE PREPARATION OF RACEMIC MIXTURE, D-FORM OR L-alpha;-GLYCERYL PHOSPHORYLCHOLINE |
| CN101967160A (en) * | 2010-09-09 | 2011-02-09 | 常熟富士莱医药化工有限公司 | One-step method for preparing raceme DL, D or L-a-glycerin phosphorus acyl choline |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106459106A (en) * | 2014-02-10 | 2017-02-22 | 酶科技株式会社 | Method for preparing racemic or optically active ALPHA-glycerophosphoryl choline |
| EP3106465A4 (en) * | 2014-02-10 | 2017-08-09 | Enzytech, Ltd. | Method for preparing racemic or optically active glycerophosphoryl choline |
| CN108101937A (en) * | 2017-11-13 | 2018-06-01 | 湖南华纳大药厂手性药物有限公司 | A kind of method for preparing L- α-glycerolphosphocholine |
| CN108101937B (en) * | 2017-11-13 | 2020-03-10 | 湖南华纳大药厂手性药物有限公司 | Method for preparing L- α -glycerophosphatidylcholine |
| CN110467634A (en) * | 2018-06-16 | 2019-11-19 | 杨凌萃健生物工程技术有限公司 | A kind of glycerolphosphocholine preparation method of high-purity |
| CN109456359A (en) * | 2018-11-13 | 2019-03-12 | 科利生物科技（徐州）有限公司 | A method of isolating and purifying crude product L- ɑ-choline glycerophosphatide |
| KR20200099021A (en) * | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Method of preparing choline alfoscerate and pharmaceutical composition comprising the same |
| KR102221211B1 (en) * | 2019-02-13 | 2021-03-03 | 한국바이오켐제약 주식회사 | Method of preparing choline alfoscerate and pharmaceutical composition comprising the same |
| CN110028524A (en) * | 2019-05-07 | 2019-07-19 | 天津康巢生物医药股份有限公司 | A kind of process preparing glycerolphosphocholine and its glycerolphosphocholine obtained |
| CN110437275A (en) * | 2019-08-22 | 2019-11-12 | 苏州汉德创宏生化科技有限公司 | A kind of synthetic method promoting brain function compound Choline Glycerophosphate |
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Application publication date: 20130508 |