CN101544667A - Method for synthesizing L-alpha choline glycerophosphatide - Google Patents
Method for synthesizing L-alpha choline glycerophosphatide Download PDFInfo
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- CN101544667A CN101544667A CN200810024585A CN200810024585A CN101544667A CN 101544667 A CN101544667 A CN 101544667A CN 200810024585 A CN200810024585 A CN 200810024585A CN 200810024585 A CN200810024585 A CN 200810024585A CN 101544667 A CN101544667 A CN 101544667A
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- glycerophosphorylcholine
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Abstract
The invention provides a method for synthesizing L-alpha GPC. The method uses a chiral raw material (S)-(-)-epihydric alcohol to prepare (2R)-(-)-glycidyl tosylate to be condensed with tetraethylammonium phosphocholine to synthesize the L-alpha-GPC through ion exchange resin purification. A chiral intermediate substance, namely the (2R)-(-)-glycidyl tosylate used by the method has the characteristics of good stability, high purity of ee percent, high yield of the product L-alpha-GPC (75.6 percent) and the like.
Description
Invention field
The present invention relates to chirality organic 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) is a naturally occurring aqueous phospholipid meta-bolites in the body to L-α-Glycerophosphorylcholine.L-α-GPC can pass hemato encephalic barrier, is vagusstoff and phosphoric acid Yelkin TTS synthetic choline source, is a kind of important neurotransmitter and phospholipid precursor, and cognitive ability and the memory of improving the elderly are arranged, and the protection blood vessel function.
L-α-GPC and chemical structural formula thereof are as follows:
Previously in order to obtain L-α-GPC, directly method is from Pancreas Bovis seu Bubali (G.Schmidt, J.Biochem, 1945,161,523) extract, also can extract through hydrolysis from Ovum Gallus domesticus Flavus lecithin (GB2058792) or from soybean lecithin (JP61158990), for obtaining the high L-α-GPC of purity, complex process, cost is high.Along with the progress of chemical technology, EP0486100 proposes with D-acetone glycerol and 2-oxygen-2-chloro-1.3.2-epoxy phosphorus pentane, again with Trimethylamine 99 open loop condensation:
Yet prepare D-acetone glycerol and 2-oxygen-2-chloro-1.3.2-epoxy phosphorus pentane, through polystep reaction, complex process, environmental pollution, and the latter is very unstable, is very easily decomposed by airborne moisture content, preserves difficulty, and using Trimethylamine 99 needs compressive reaction.
EP0502357 proposes to carry out condensation prepared L-α-GPC with D-acetone glycerol p-toluenesulfonic esters and phosphorylcholine tetramethyl ammonium, and (A can be Li, Na
+, K
+, or N
+(CH
3)
4):
Its advantage is the easily separated purifying of D-acetone glycerol p-toluenesulfonic esters, and one step of condensation, yield was up to 75%.But, starting raw material D-acetone glycerol (D-glyceryl alcohol contract acetone) be with D-N.F,USP MANNITOL through and condensation of acetone, NaIO
4Oxidative cleavage is again through NaBH
4The reduction and make, cost value is higher.
WO2007/145476 uses Shapless epoxy addition reaction principle, proposes to carry out nucleophilic addition(Adn) with (R)-(+) condensating glycerine (glycidol of (R)-(+)) and phosphorylcholine in the presence of Isopropylamine, prepares L-GPC through ion-exchange resin purification again.
This processing method is succinct, but total recovery is lower than 50%.Need freezing preservation to avoid self condensation in view of Racemic glycidol (2) instability, necessary detection purity before using is also wanted the underpressure distillation purifying usually.
Content of the present invention
The present invention is directed to the synthetic route of existing synthetic L-α-GPC and the defective that technology exists, the unstable of particularly (R) or (S)-Racemic glycidol and be difficult to the defective of purifying, our inventive method has been proposed: (S)-Racemic glycidol is made (2R)-Racemic glycidol p-toluenesulfonic esters, then with the condensation of phosphorylcholine tetraethyl-ammonium salt, purified again L-α-GPC.
B: tetraethyl ammonium hydroxide, PC: phosphorylcholine
2 (Racemic glycidol) is formula (2R) or (2S) type no matter since on C (1) position the O-p-toluenesulfonic esters of the derivative, particularly Racemic glycidol of replacement, make C (1) to activate, can be with nucleophilic reagent generation substitution reaction.The present invention utilizes this chemical property just, uses (2R)-Racemic glycidol p-toluenesulfonic esters and phosphorylcholine tetraethyl-ammonium salt to carry out condensation reaction.
Because 2 has been introduced p-toluenesulfonic esters on C (1) position, make it to become solid-state (mp45-48 ℃) by liquid state, character is more stable, can carry out recrystallization, improves ee% purity (〉=90%); And the existence of phenyl ring, help the HPLC ultraviolet detection, at room temperature handle and store.More advantageously the yield of chiral intermediate (2R)-Racemic glycidol p-toluenesulfonic esters and phosphorylcholine tetraethyl-ammonium salt condensation reaction L-α-GPC can reach 75.6%.
Though step preparation (2R)-Racemic glycidol p-toluenesulfonic esters that the present invention is many, its characteristics: improve ee% purity, be convenient to operation, store, α-GPC total recovery (53.1%) is significant to improve L-.
Content of the present invention can be divided four steps:
One. preparation (2R)-2 p-toluenesulfonic esters
With commercially available (S)-condensating glycerine (gold for a long time strange chemical company in Shenyang produces) or press Sharpless (J.Am.Chem.Soc., 1987,109,5765-5780) (the S)-Racemic glycidol of method preparation is made (2R)-Racemic glycidol p-toluenesulfonic esters with Tosyl chloride under alkalescence (acid binding agent) condition.Wherein acid binding agent is triethylamine or pyridine or piperidines or 4-Dimethylamino pyridine; Tosyl chloride is excessive.
Two. preparation phosphorylcholine tetraethyl-ammonium salt
In acidic aqueous solution, remove calcium ion with commercially available choline chloride 60 calcium salt four hydrates (production of Shanghai Yi Yao fine chemistry industry company), obtain the chlorination phosphorylcholine, add quaternary ammonium hydroxide again, make it salify with oxalic acid.Wherein quaternary ammonium hydroxide can be Tetramethylammonium hydroxide or tetraethyl ammonium hydroxide, or TBAH.
Three. preparation L-α-Glycerophosphorylcholine muriate
In dehydrated alcohol, carry out condensation reaction with (the 2R)-2 of the first step preparation and the phosphorylcholine tetraethyl-ammonium salt of second step preparation, remove tosic acid tetraethyl-ammonium salt, use the dilute hydrochloric acid hydrolysis again, obtain the Glycerophosphorylcholine muriate.
Four. preparation L-α-GPC
Whether the L-α-GPC chloride soln of the 3rd step preparation is removed the evaporate to dryness that desolvates, be dissolved in deionized water, and spent ion exchange resin carries out the dechlorination ion manipulation, and go to use up with silver nitrate solution chlorine detection ion, concentrating under reduced pressure obtains L-α-GPC.Wherein ion exchange resin is Dowex 509H or Amberlite IR-120 or Liwatit S100.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
The preparation of embodiment one, (2R)-(-)-Racemic glycidol p-toluenesulfonic esters
Taking by weighing (S)-(-)-Racemic glycidol 74.1g (1.0mol) is dissolved in the 100ml anhydrous pyridine, be chilled to 0 ℃, dropping is dissolved in the solution that the 150ml anhydrous pyridine is formed by 209.8g (1.1mol) Tosyl chloride, mixing solutions was stirred 18 hours in 0 ℃, pour into then to frozen water, make it the pyridine hydrochloride that solubilizing reaction generates.With chloroform extraction (200ml * 3), extract washs with 3% dilute hydrochloric acid, uses NaHCO again
3Washing washes organic layer at last with water, uses anhydrous Na
2SO
4Dry chloroform extracted solution, decompression steam gets chloroform, gets solids.
With above-mentioned solids Virahol (200ml) and toluene (200ml) crystallization, get (2R)-(-)-Racemic glycidol p-toluenesulfonic esters 85.1g, measure chemical purity 96.5% with chiral column HPLC, optical purity (ee) 96.6%, get 160.5g, yield 70.3%, secondary recrystallization, mp45-48 ℃, [α]
D 20=-18 ° of (c=2.5CHCl
3).
The preparation of embodiment two, intermediate phosphorylcholine tetraethyl ammonium
21.9g (0.1mol) phosphorylcholine muriate is dissolved in the 100ml methyl alcohol, adds 9.1g (0.1mol) tetraethyl ammonium hydroxide again, boil off solvent in 40 ℃ of vacuum and get the 29.2g ammonium salt.
Embodiment three, L-α-1, the muriatic preparation of 2-Racemic glycidol phosphorylcholine
29.2g (0.1mol) phosphorylcholine tetraethyl-ammonium salt is dissolved in the 300ml dehydrated alcohol, add 22.8g (0.1mol) (2R)-(-)-the Racemic glycidol p-toluenesulfonic esters, reflux 18 hours, cooling removes by filter ammonium salt, removes methyl alcohol under reduced pressure.
The above-mentioned product 24g that obtains is dissolved in the 100ml95% ethanol, and in 35-45 ℃ of following heating hydrolysis 1-2 hour, solvent removed in vacuo obtained the muriate 24g of L-α-GPC with 5ml1mol/L hydrochloric acid.
Embodiment four
The above-mentioned 24gL-α-GPC muriate that obtains is dissolved in the 100ml deionized water, adds Dowex 509H ion exchange resin, stir, elimination resin (recyclable, regeneration) repeatedly washs with deionized water, merges the aqueous solution, uses AgNO
3Detect whether eliminate chlorion, remove in 35-40 ℃ of vacuum and anhydrate, get elaboration L-α-GPC 19.5g, yield 75.6%, chemical purity 98.6%, optical purity ee:99.0%, mp142-143 ℃, [α]
D 20=-2.8 ° of (c=2.6, H
2O, pH5.8).
Claims (1)
1, a kind of synthetic method of L-α-Glycerophosphorylcholine the steps include:
The first step: preparation (2R)-2 p-toluenesulfonic esters
Earlier (S)-condensating glycerine and Tosyl chloride are made (2R)-Racemic glycidol p-toluenesulfonic esters with acid binding agent under alkaline condition, wherein acid binding agent is triethylamine or pyridine or piperidines or 4-Dimethylamino pyridine; Tosyl chloride is excessive.
Second step: preparation phosphorylcholine tetraethyl-ammonium salt
Remove calcium ion with oxalic acid with choline chloride 60 calcium salt four hydrates in acidic aqueous solution, obtain the chlorination phosphorylcholine, add quaternary ammonium hydroxide again, make it salify, wherein quaternary ammonium hydroxide is Tetramethylammonium hydroxide or tetraethyl ammonium hydroxide, or TBAH.
The 3rd step: preparation L-α-Glycerophosphorylcholine muriate
(2R)-2 with the first step preparation, the phosphorylcholine tetraethyl-ammonium salt of 3-epoxy-1-propyl alcohol p-toluenesulfonic esters and the preparation of second step carries out condensation reaction in dehydrated alcohol, remove tosic acid tetraethyl-ammonium salt, use the dilute hydrochloric acid hydrolysis again, obtain L-α-Glycerophosphorylcholine muriate.
The 4th step: preparation L-α-Glycerophosphorylcholine
L-α-Glycerophosphorylcholine the chloride soln of the 3rd step preparation is removed the evaporate to dryness that desolvates, be dissolved in deionized water, whether and spent ion exchange resin carries out the dechlorination ion manipulation, and go to the greatest extent with silver nitrate solution chlorine detection ion, and concentrating under reduced pressure obtains L-α-Glycerophosphorylcholine.Wherein ion exchange resin is Dowex 509H or Amberlite IR-120 or Liwatit S100.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102260286A (en) * | 2011-05-27 | 2011-11-30 | 合肥工业大学 | Method for separating and purifying crude product L-alpha-glycerophosphocholine |
| CN102516292A (en) * | 2011-11-08 | 2012-06-27 | 西北大学 | Natural L-alpha-glycerophosphocholine (GPC) and preparation method thereof |
| CN102617633A (en) * | 2012-03-01 | 2012-08-01 | 济南康和医药科技有限公司 | Synthesis method of L-alpha-glycerophosphoryl choline |
| CN102964377A (en) * | 2012-11-30 | 2013-03-13 | 西北大学 | Method for preparing natural L-alpha-glycerol phosphatidylcholine |
| CN103087091A (en) * | 2011-10-27 | 2013-05-08 | 上海秀新臣邦医药科技有限公司 | L-alpha-choline glycerophosphate synthesis method |
| CN103304594A (en) * | 2013-06-18 | 2013-09-18 | 上海科利生物医药有限公司 | Preparation method of L-alpha-glycerophosphoryl choline |
| CN108191908A (en) * | 2017-12-28 | 2018-06-22 | 上海科生物医药有限公司 | A kind of preparation method of L- α-choline glycerophosphatide |
| CN109021010A (en) * | 2018-06-25 | 2018-12-18 | 抚顺大恒化工有限公司 | A kind of preparation method of L- α-Choline Glycerophosphate |
| CN109265477A (en) * | 2018-11-13 | 2019-01-25 | 科利生物科技（徐州）有限公司 | L- ɑ-choline glycerophosphatide preparation method |
| 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 |
| CN113481249A (en) * | 2021-08-13 | 2021-10-08 | 陕西科技大学 | Method for preparing lecithin type n-3PUFA by enzyme method |
-
2008
- 2008-03-27 CN CN200810024585A patent/CN101544667A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101967160B (en) * | 2010-09-09 | 2013-04-10 | 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 |
| CN102260286B (en) * | 2011-05-27 | 2014-01-15 | 合肥工业大学 | Method for separating and purifying crude product L-alpha-glycerophosphocholine |
| CN102260286A (en) * | 2011-05-27 | 2011-11-30 | 合肥工业大学 | Method for separating and purifying crude product L-alpha-glycerophosphocholine |
| CN103087091A (en) * | 2011-10-27 | 2013-05-08 | 上海秀新臣邦医药科技有限公司 | L-alpha-choline glycerophosphate synthesis method |
| CN102516292A (en) * | 2011-11-08 | 2012-06-27 | 西北大学 | Natural L-alpha-glycerophosphocholine (GPC) and preparation method thereof |
| CN102516292B (en) * | 2011-11-08 | 2014-09-10 | 西北大学 | Natural L-alpha-glycerophosphocholine (GPC) and preparation method thereof |
| CN102617633A (en) * | 2012-03-01 | 2012-08-01 | 济南康和医药科技有限公司 | Synthesis method of L-alpha-glycerophosphoryl choline |
| CN102964377A (en) * | 2012-11-30 | 2013-03-13 | 西北大学 | Method for preparing natural L-alpha-glycerol phosphatidylcholine |
| CN102964377B (en) * | 2012-11-30 | 2015-05-27 | 西北大学 | Method for preparing natural L-alpha-glycerol phosphatidylcholine |
| CN103304594A (en) * | 2013-06-18 | 2013-09-18 | 上海科利生物医药有限公司 | Preparation method of L-alpha-glycerophosphoryl choline |
| CN103304594B (en) * | 2013-06-18 | 2015-07-08 | 上海科利生物医药有限公司 | Preparation method of L-alpha-glycerophosphoryl choline |
| CN108191908A (en) * | 2017-12-28 | 2018-06-22 | 上海科生物医药有限公司 | A kind of preparation method of L- α-choline glycerophosphatide |
| CN109021010A (en) * | 2018-06-25 | 2018-12-18 | 抚顺大恒化工有限公司 | A kind of preparation method of L- α-Choline Glycerophosphate |
| CN109021010B (en) * | 2018-06-25 | 2020-08-07 | 金久奇(抚顺)药业有限公司 | Preparation method of L- α -choline alfoscerate |
| CN109265477A (en) * | 2018-11-13 | 2019-01-25 | 科利生物科技（徐州）有限公司 | L- ɑ-choline glycerophosphatide preparation method |
| 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 |
| CN113481249A (en) * | 2021-08-13 | 2021-10-08 | 陕西科技大学 | Method for preparing lecithin type n-3PUFA by enzyme method |
| CN113481249B (en) * | 2021-08-13 | 2022-06-03 | 陕西科技大学 | Method for preparing lecithin type n-3PUFA by enzyme method |
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