CN103665028A - Preparation method of L-alpha-choline glycerophosphate - Google Patents
Preparation method of L-alpha-choline glycerophosphate Download PDFInfo
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Abstract
The invention discloses a preparation method of L-alpha-choline glycerophosphate. According to the method, (2S)-3-halogenated-1,2-propylene oxide and phosphoryl choline salt are used as the raw materials, and are subjected to esterification and hydrolysis reaction in a solvent to obtain the L-alpha-choline glycerophosphate crude product, and the crude product is subjected to silica gelcolumn chromatography and purification through ion exchange resin to obtain the L-alpha-choline glycerophosphate pure product. Compared with the prior art, the preparation method disclosed by the invention has the advantages that the operation is simpler; the adopted chiral material (2S)-3-halogenated-1,2-propylene oxide is cheap and easy to obtain; the prepared crude product is subjected to silica gelcolumn chromatography and purification through ion exchange resin to obtain the L-alpha-choline glycerophosphate product with higher quality, and the L-alpha-choline glycerophosphate content is more than 99%; the technical process is more suitable for large scale production.
Description
Technical field
The invention belongs to chirality organic chemistry and field of medicine preparing technology, be specifically related to a kind of chemical synthesis process of the L-of preparation α-Choline Glycerophosphate.
Background technology
L-α-Choline Glycerophosphate (L-α-Glycerophosphoryl Choline, L-α-GPC) is the natural a kind of aqueous phospholipid meta-bolites being present in human body.According to patent GB2058792 report, in body, it belongs to anticholinesterase, can pass hemato encephalic barrier, is the necessary choline source of synthesis of acetyl choline and phosphatidylcholine.L-α-Choline Glycerophosphate can improve different ages stage crowd's cognition and memory capability, has the release that promotes teenager's tumor growth hormone, its effect of growing tall of indirect help.Japanese Patent JP2009155337 report, L-α-Choline Glycerophosphate has lipidemia to the elderly, and protection blood vessel especially has remarkable effect to prevention and treatment senile dementia (AD), can effectively improve this neurone degenerative disease of senile dementia.Modern society's average life span, the whole world entered the aging epoch in continuous prolongation, and the number of old dementia patients increases gradually, was badly in need of the medicine of this treatment persistence neural function moving obstacle on market.Present stage L-α-Choline Glycerophosphate has been widely used in the industries such as medicine, healthcare products.
The structural formula of L-α-Choline Glycerophosphate (I) is as follows:
The preparation method of earliest documents report L-α-Choline Glycerophosphate is natural product extraction method, mainly first from the Yelkin TTS of ox pancreas liver and yolk (GB2058792), soybean (JP61158990), to extract the separated Phosphorylcholine that obtains, through hydrolysis, obtain L-α-Choline Glycerophosphate again, but this method complex process, extract purity is lower.
The enzyme process of CN102757989 report is prepared L-α-Choline Glycerophosphate, mainly to take Yelkin TTS as raw material, with extraction using alcohol, evaporate to dryness ethanol obtains extract, then extract is soluble in water, with Phospholipid hydrolase, is hydrolyzed, through decolouring, decompression, steam water, dissolve with methanol, ion exchange resin separation and purification, obtains L-α-Choline Glycerophosphate.The problems such as this technique exists low conversion rate, and the purity of product is not high.
Along with the synthetic development of medicine, the route of more chemosynthesis L-α-Choline Glycerophosphates occurs in succession, EP0486100; EP0502357; the method of the reports such as JP2007269657 is first 1,2 hydroxyl protection of glycerine to be got up, and carries out condensation after making D-propylidene glycerine again; the reactions such as open loop make L-α-Choline Glycerophosphate; the shortcoming of this technique is that propylidene glycerine is difficult for preparation, and cost is higher, operates more complicated; be unsuitable for suitability for industrialized production, reaction formula is as follows:
There is condensation reaction through chirality R-Racemic glycidol and PC in the employing of WO2007145476 report, obtain L-α-Choline Glycerophosphate in Virahol.But this method exists Racemic glycidol unstable, the problem of self easy polymerization, causes that whole technique is unstable and ultimate yield is lower, and reaction formula is as follows:
Korean Patent KR2009128631; KR200939132; Chinese patent CN101544667; CN101544667; CN102617633 etc. improve on the basis of above-mentioned technique; with different blocking groups as toluene sulfo group, benzyl, ethanoyl etc. are first got up the hydroxyl protection of Racemic glycidol, then with PC condensation reaction, last hydrolysis obtains L-α-Choline Glycerophosphate.But this technological reaction time is longer, operation is comparatively complicated, is unsuitable for suitability for industrialized production.Reaction formula is as follows:
CN101967160 has reported, through PC salt, obtains L-α-Choline Glycerophosphate with reacting of 3-chlorine-1,2-propylene glycol; but the 3-chlorine-1,2-propylene glycol of this technique has the characteristic of high poison, is suspicious carcinogens; be unfavorable for the labour protection in large production, its reaction formula is as follows:
Summary of the invention
The shortcoming that the object of the invention is to overcome prior art, with not enough, provides the simple L-α-Choline Glycerophosphate of a kind of processing step new preparation method.
The invention discloses a kind of preparation method of L-α-Choline Glycerophosphate; adopted new synthetic route; it is characterized in that with PC salt (III) and (2S)-3-halo-1; 2-propylene oxide (IV) is raw material, in solvent through esterification obtain carboxylate (V), again after hydrolysis reaction L-α-Choline Glycerophosphate (I) crude product.Crude product obtains L-α-Choline Glycerophosphate (I) sterling through silica gel column chromatography, ion-exchange resin purification.
The synthetic route of the synthetic L-α-Choline Glycerophosphate (I) of the present invention is as follows:
The invention discloses the novel method of the different preparation L-α-Choline Glycerophosphate (I) of a kind of and existing bibliographical information, in research process, the raw material of reaction, proportioning, solvent, temperature etc. have been carried out to comprehensive investigation, through repetition test, determined optimum reaction condition.By the screening to silica gel column chromatography eluent, investigation to strong acid type and strong base ion exchange resin type number and ratio of weight and number, finally determined first through silica gel column chromatography decon, then through the purification process (seeing the following form) of the deionized L-α-Choline Glycerophosphate of ion exchange resin (I).
The preparation technology of L-α-Choline Glycerophosphate (I) investigates
(2S)-3-of the present invention halo-1,2-propylene oxide (IV) comprises (2S)-3-chloro-1,2-propylene oxide, (2S)-3-bromo-1,2-propylene oxide, (2S)-3-iodo-1,2 epoxy prapane, these (2S)-3-halo-1,2-propylene oxide has been used widely preparing resin, glycerine, rubber, Mierocrystalline cellulose etc., cheaply be easy to get, preferably (2S)-3-chloro-1,2 epoxy prapane.
PC salt of the present invention (III) is PC metal-salt or PC ammonium salt.PC metal-salt comprises sodium salt, sylvite etc., and PC ammonium salt comprises tetramethyl ammonium, tetraethyl-ammonium salt etc., preferably PC sodium salt, sylvite.These PC salt (III) are reference reports, by PC calcium salt (II) decalcification salify, are made.
PC salt of the present invention (III) is 1:1 ~ 2 with mole proportioning of (2S)-3-halo-1,2 epoxy prapane (IV), and preferred mole of proportioning is 1:1 ~ 1.5.
Esterification reaction temperature of the present invention is 20 ℃ to 100 ℃, and preferable reaction temperature is 60 ~ 85 ℃.
Solvent of the present invention is one or both solvent in methyl alcohol, ethanol, Virahol, acetone, acetonitrile, water.Preferred single solvent methyl alcohol, ethanol, Virahol.
Hydrolysis reaction of the present invention is the method for reference report, with the reaction that is hydrolyzed of the hydrochloric acid of 1M.
Purification process of the present invention is first to use silica gel column chromatography, and then through ion-exchange resin purification.
The eluent of silica gel column chromatography of the present invention is the mixed solvent of acetone, methyl alcohol, water and Glacial acetic acid, and preferably acetone, methyl alcohol, water and Glacial acetic acid volume ratio are 3:3:2:2.
Ion exchange resin of the present invention is the resin that strong acid type and strong base are mixed, comprise that 001 * 7 type mixes with 201 * 7 types, 001 * 2 type mixes with 201 * 2 types, and 001 * 8 type mixes with 201 * 8 types etc., and preferably 001 * 7 type mixes with 201 * 7 types.The ratio of weight and number of strong acid type and strong base ion exchange resin is 1:1 ~ 6.Preferably 001 * 7 type and 201 * 7 type mixture iron exchange resins, ratio of weight and number is 1:2.
A preferred embodiment of the present invention comprises the following steps:
1. the preparation of PC salt (III).
2. there is esterification with 2S-3-halo-1,2 epoxy prapane (IV) in PC salt (III), obtains carboxylate (V).
3. the hydrochloric acid hydrolysis of 1M for carboxylate (V), obtains L-α-Choline Glycerophosphate (I) crude product.
4. L-α-Choline Glycerophosphate (I) crude product is removed impurity through silica gel column chromatography.
5. through ion exchange resin, remove mineral ion, obtain L-α-Choline Glycerophosphate (I) sterling.
The positively effect that L-α-Choline Glycerophosphate preparation method disclosed by the invention compared with prior art had is:
Raw material (2S)-3-halo-1,2 epoxy prapane is cheaply easy to get, easy and simple to handle, the crude product of preparation after silica gel column chromatography and ion-exchange resin purification, products obtained therefrom L-α-Choline Glycerophosphate (I) better quality, content is all more than 99%.Through pharmacodynamic experiment, prove: L-α-Choline Glycerophosphate prepared by the present invention is the same with commercially available L-α-Choline Glycerophosphate that senile dementia is had to treatment improvement effect.
Embodiment
Below in conjunction with embodiment, the present invention is described, the scheme of embodiment described here, do not limit the present invention, one of skill in the art can make improvements and change according to content of the present invention, these described improvement and variation all should be considered as within the scope of the invention, and scope of the present invention and essence are limited by claim.Wherein said main raw material PC calcium salt (four water things), (2S)-3-halo-1,2 epoxy prapane all have commercially available.
reference example 1
The preparation of PC sodium salt
In reaction flask; add PC calcium salt (II) 15.00g(0.046mol) and water 75ml; be stirred to molten clear; the sodium carbonate solution that dropping is made into by anhydrous sodium carbonate 9.65g and water 30ml, drips and finishes, stirring at room 2 hours; filter; evaporated under reduced pressure obtains PC sodium salt 11.00g, yield 91.70%, HPLC purity 96.50%.
reference example 2
The preparation of PC sylvite
With reference example 1 operation, with Anhydrous potassium carbonate, replace anhydrous sodium carbonate, make PC sylvite 12.60g, yield 93.69%, HPLC purity 92.81%.
reference example 3
The preparation of PC tetramethyl ammonium
In reaction flask, add PC calcium salt (II) 15.00g(0.046mol) and water 75ml, be stirred to molten clear; add oxalic acid 4.05g; be warming up to 40 ℃ of reaction 4h, filter, filtrate decompression evaporate to dryness obtains oily matter; methyl alcohol 60ml dissolves; add Tetramethylammonium hydroxide pentahydrate 8.10g, reaction 3h, evaporated under reduced pressure obtains PC tetramethyl ammonium 11.25g; yield 84.68%, HPLC purity 90.85%.
embodiment 1
The preparation of L-α-Choline Glycerophosphate (I) crude product
In reaction flask, the PC sodium salt 8.19g(0.03mol that adds reference example 1 method to prepare) methyl alcohol 100ml solution, agitation and dropping (2S)-3-chloro-1; 2-propylene oxide 3.06g(0.033mol), be warming up to 60 ~ 65 ℃, thin layer tracks to and has reacted; filter, filtrate decompression evaporate to dryness, obtains carboxylate (V); with ethanol 50ml, dissolve; the hydrochloric acid 3.7ml that adds 1M, 35～40 ℃ are stirred 4h, filter; evaporated under reduced pressure, obtains L-α-Choline Glycerophosphate (I) crude product 9.10g.
embodiment 2
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with PC sylvite 9.56g(0.03mol) (reference example 2 preparations) replacement PC sodium salt 8.19g, obtain L-α-Choline Glycerophosphate (I) crude product 8.92g.
embodiment 3
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with PC tetramethyl ammonium 9.65g(0.03mol) (reference example 3 preparations) replacement PC sodium salt 8.19g, obtain L-α-Choline Glycerophosphate (I) crude product 8.86g.
embodiment 4
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with (2S)-3-bromo-1,2 epoxy prapane 4.52g(0.033mol) replace (2S)-3-chloro-1,2 epoxy prapane 2.78g, obtain L-α-Choline Glycerophosphate (I) crude product 8.73g.
embodiment 5
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with (2S)-3-iodo-1,2 epoxy prapane 6.07g(0.033mol) replace (2S)-3-chloro-1,2 epoxy prapane 2.78g, obtain L-α-Choline Glycerophosphate (I) crude product 8.55g.
embodiment 6
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, (2S)-3-chloro-1,2 epoxy prapane is increased to 4.17g(0.045mol), obtain L-α-Choline Glycerophosphate (I) crude product 8.93g.
embodiment 7
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, (2S)-3-chloro-1,2 epoxy prapane is increased to 5.56g(0.06mol), obtain L-α-Choline Glycerophosphate (I) crude product 8.85g.
embodiment 8
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, in room temperature (20～25 ℃) reaction, obtain L-α-Choline Glycerophosphate (I) crude product 8.18g.
embodiment 9
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, 80 ℃ of reactions, with acetonitrile 100ml, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.37g.
embodiment 10
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with ethanol 100ml, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.57g.
embodiment 11
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with Virahol 100ml, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.63g.
embodiment 12
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with mixed solvent (V/V=1:1) 100ml of second alcohol and water, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.31g.
embodiment 13
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with mixed solvent (V/V=1:2) 100ml of methyl alcohol and acetonitrile, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.42g.
embodiment 14
The preparation of L-α-Choline Glycerophosphate (I) crude product
With embodiment 1 operation, with mixed solvent (V/V=1:2) 100ml of ethanol and acetonitrile, replace methyl alcohol 100ml, obtain L-α-Choline Glycerophosphate (I) crude product 8.19g.
embodiment 15
The preparation of L-α-Choline Glycerophosphate (I) sterling
By L-α-Choline Glycerophosphate (I) crude product obtaining in embodiment 1 appropriate eluent (acetone, methyl alcohol, water and Glacial acetic acid volume ratio are 3:3:2:2) dissolving for 9.10g, add to 80g silicagel column, wash-out, flaggy is followed the tracks of and is collected, and concentrating under reduced pressure, obtains oily 8.97g.Again this oil is dissolved with deionized water 15ml, add to (ratio of weight and number strong acid type: strong base=1:2) in the ion exchange resin 225g that strong acid type (001 * 7) and strong base (201 * 7) mix, deionized water wash-out, with silver nitrate solution chlorine detection ion, whether eliminate simultaneously, collect elutriant, concentrating under reduced pressure, vacuum-drying obtains L-α-Choline Glycerophosphate (I) sterling 7.20g, it is 142.3 ~ 143.3 ℃ of 99.78%, mp that HPLC method is surveyed purity, [α]
20 d=-2.73 ° of (c=2.6, H
2o).
1H?NMR?(D
2O,300MHz)：3.22(s,9H)，3.62?(m,?4H)，3.91(m,?4H)，4.28?(m,?2H)。
embodiment 16
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.92g purifying by obtaining in embodiment 2, obtains L-α-Choline Glycerophosphate (I) sterling 6.89g, and it is 141.1 ~ 142.2 ℃ of 99.28%, mp that HPLC method is surveyed purity, [α]
20 d=-2.68 ° of (c=2.6, H
2o).
embodiment 17
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.86g purifying by obtaining in embodiment 3, obtains L-α-Choline Glycerophosphate (I) sterling 6.91g, and it is 141.7 ~ 142.8 ℃ of 99.32%, mp that HPLC method is surveyed purity, [α]
20 d=-2.65 ° of (c=2.6, H
2o).
embodiment 18
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.73g purifying by obtaining in embodiment 4, obtains L-α-Choline Glycerophosphate (I) sterling 6.92g, and it is 141.8 ~ 142.8 ℃ of 99.52%, mp that HPLC method is surveyed purity, [α]
20 d=-2.68 ° of (c=2.6, H
2o).
embodiment 19
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.55g purifying by obtaining in embodiment 5, obtains L-α-Choline Glycerophosphate (I) sterling 6.68g, and it is 141.9 ~ 143.0 ℃ of 99.59%, mp that HPLC method is surveyed purity, [α]
20 d=-2.70 ° of (c=2.6, H
2o).
embodiment 20
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.93g purifying by obtaining in embodiment 6, obtains L-α-Choline Glycerophosphate (I) sterling 6.96g, and it is 141.8 ~ 142.9 ℃ of 99.61%, mp that HPLC method is surveyed purity, [α]
20 d=-2.70 ° of (c=2.6, H
2o).
embodiment 21
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.85g purifying by obtaining in embodiment 7, obtains L-α-Choline Glycerophosphate (I) sterling 6.59g, and it is 141.3 ~ 142.5 ℃ of 99.21%, mp that HPLC method is surveyed purity, [α]
20 d=-2.65 ° of (c=2.6, H
2o).
embodiment 22
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.18g purifying by obtaining in embodiment 8, obtains L-α-Choline Glycerophosphate (I) sterling 6.47g, and it is 141.5 ~ 142.3 ℃ of 99.08%, mp that HPLC method is surveyed purity, [α]
20 d=-2.66 ° of (c=2.6, H
2o).
embodiment 23
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.37g purifying by obtaining in embodiment 9, obtains L-α-Choline Glycerophosphate (I) sterling 6.52g, and it is 141.6 ~ 142.6 ℃ of 99.25%, mp that HPLC method is surveyed purity, [α]
20 d=-2.62 ° of (c=2.6, H
2o).
embodiment 24
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.57g purifying by obtaining in embodiment 10, obtains L-α-Choline Glycerophosphate (I) sterling 6.68g, and it is 141.8 ~ 142.9 ℃ of 99.32%, mp that HPLC method is surveyed purity, [α]
20 d=-2.68 ° of (c=2.6, H
2o).
embodiment 25
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.63g purifying by obtaining in embodiment 11, obtains L-α-Choline Glycerophosphate (I) sterling 6.76g, and it is 141.3 ~ 142.4 ℃ of 99.17%, mp that HPLC method is surveyed purity, [α]
20 d=-2.65 ° of (c=2.6, H
2o).
embodiment 26
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.31g purifying by obtaining in embodiment 12, obtains L-α-Choline Glycerophosphate (I) sterling 6.65g, and it is 141.2 ~ 142.3 ℃ of 99.21%, mp that HPLC method is surveyed purity, [α]
20 d=-2.66 ° of (c=2.6, H
2o).
embodiment 27
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.42g purifying by obtaining in embodiment 13, obtains L-α-Choline Glycerophosphate (I) sterling 6.71g, and it is 141.5 ~ 142.4 ℃ of 99.19%, mp that HPLC method is surveyed purity, [α]
20 d=-2.62 ° of (c=2.6, H
2o).
embodiment 28
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, (I) crude product 8.19g purifying by obtaining in embodiment 14, obtains L-α-Choline Glycerophosphate (I) sterling 6.49g, and it is 141.0 ~ 142.1 ℃ of 99.08%, mp that HPLC method is surveyed purity, [α]
20 d=-2.61 ° of (c=2.6, H
2o).
embodiment 29
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, the ion exchange resin that replaces 001 * 7 type and 201 * 7 types to mix with the ion exchange resin that 001 * 2 type and 201 * 2 types mix, by (I) purifying crude making by embodiment 1 method, obtain L-α-Choline Glycerophosphate (I) sterling 6.89g, it is 99.58% that HPLC method is surveyed purity, 141.7 ~ 142.7 ℃ of mp, [α]
20 d=-2.65 ° of (c=2.6, H
2o).
embodiment 30
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, the ion exchange resin that replaces 001 * 7 type and 201 * 7 types to mix with the ion exchange resin that 001 * 8 type and 201 * 8 types mix, by (I) purifying crude making by embodiment 1 method, obtain L-α-GPC(I) sterling 6.62g, it is 99.46% that HPLC method is surveyed purity, 141.6 ~ 142.7 ℃ of mp, [α]
20 d=-2.69 ° of (c=2.6, H
20).
embodiment 31
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, the ratio of weight and number of the ion exchange resin that strong acid type (001 * 7) strong base (201 * 7) is mixed changes 1:1 into by 1:2, (I) crude product that purifying makes by embodiment 1 method, obtain L-α-Choline Glycerophosphate (I) sterling 6.80g, it is 99.21% that HPLC method is surveyed purity, 141.5 ~ 142.5 ℃ of mp, [α]
20 d=-2.64 ° of (c=2.6, H
2o).
embodiment 32
The preparation of L-α-Choline Glycerophosphate (I) sterling
With embodiment 15 operations, the ratio of weight and number of the ion exchange resin that strong acid type (001 * 7) strong base (201 * 7) is mixed changes 1:6 into by 1:2, (I) crude product that purifying makes by embodiment 1 method, obtain L-α-Choline Glycerophosphate (I) sterling 6.50g, it is 99.01% that HPLC method is surveyed purity, 141.0 ~ 141.9 ℃ of mp, [α]
20 d=-2.62 ° of (c=2.6, H
2o).
embodiment 33
The pharmacodynamics test for the treatment of senile dementia (AD)
Get 120 of the clean level of 2 monthly age NTH mouse, male and female half and half, body weight (20.08 ± 2.28) g, [female (20.00 ± 2.11) g, male (20.16 ± 2.45) g], according to completely randomized design, in accordance with harmonious principle, first by animal male and female separately, then separate by body weight, then look into table of random number animal is divided into control group at random, I model group, the randomized controlled treatment group of II model L-α-Choline Glycerophosphate (commercial goods), III model L-α-Choline Glycerophosphate self-control (embodiment 11) treatment group, totally 4 groups, 30 every group.Use AlCl
3gavage is made AD disease model, and control group is with distilled water gavage; I model group is with AlCl
3gavage, every day 1 time, continuous 9 weeks; Randomized controlled treatment group is from AlCl
3gavage rises and gives AlCl the morning on the 7th day
3outside gavage, give corresponding control drug afternoon every day, every day 1 time, continuous 8 weeks; Self-control treatment group is from AlCl
3gavage rises and gives AlCl the morning on the 7th day
3outside gavage, give homemade L-α-Choline Glycerophosphate afternoon every day, every day 1 time, continuous 8 weeks.Gavage volume is 0.4ml/10g body weight.After finishing the course for the treatment of, the content of SOD, MDA and LF in the variation of survey AD disease model ability of learning and memory in mice and cerebral tissue.The experiment of result mouse diving tower shows: treatment group (contrast and self-control) and model group comparison, randomized controlled treatment group all can obviously reduce mnemonic learning obstacle with self-control treatment group, learning and memory of little mouse is consolidated to obstacle and also improve significantly, relatively have significant difference (P<0.05-0.01) with model group; SOD is active obviously to raise, MDA and LF content obviously decline (P>0.01).Randomized controlled treatment group and the ability of learning and memory indifference of self-control treatment group to mouse.
Above-mentioned evidence: homemade L-α-Choline Glycerophosphate is the same with commercially available L-α-Choline Glycerophosphate, can strengthen the ability of learning and memory of the sick mouse of AD, and it can significantly improve memory deficits in mice, and AD disease is had to good treatment improvement effect.
Claims (7)
1. the preparation method of a L-α-Choline Glycerophosphate; it is characterized in that halo-1 with (2S)-3-; 2-propylene oxide and PC salt are raw material; in solvent, after esterification, hydrolysis reaction, obtain L-α-Choline Glycerophosphate crude product, then obtain L-α-Choline Glycerophosphate sterling through silica gel column chromatography, ion-exchange resin purification.
2. the preparation method of L-α-Choline Glycerophosphate described in claim 1, the halogen in wherein said (2S)-3-halo-1,2 epoxy prapane is chlorine, bromine, iodine.
3. the preparation method of L-α-Choline Glycerophosphate described in claim 1, wherein said PC salt is PC metal-salt or PC ammonium salt; PC metal-salt comprises sodium salt or sylvite, and PC ammonium salt comprises tetramethyl ammonium or tetraethyl-ammonium salt.
4. the preparation method of L-α-Choline Glycerophosphate described in claim 1, wherein said PC salt is 1:1 ~ 2 with mole proportioning of (2S)-3-halo-1,2 epoxy prapane; Described esterification reaction temperature is 20 ~ 100 ℃.
5. the preparation method of L-α-Choline Glycerophosphate described in claim 1, wherein said solvent is selected from one or both solvent in methyl alcohol, ethanol, Virahol, acetone, acetonitrile, water.
6. the preparation method of L-α-Choline Glycerophosphate described in claim 1, wherein said silica gel column chromatography eluent is the mixed solvent of acetone, methyl alcohol, water and Glacial acetic acid, wherein said acetone: methyl alcohol: water: the volume ratio of Glacial acetic acid is 3:3:2:2.
7. the preparation method of L-α-Choline Glycerophosphate described in claim 1, wherein said ion exchange resin is the ion exchange resin that strong acid type and strong base are mixed, comprise that 001 * 7 type mixes with 201 * 7 types, 001 * 2 type mixes with 201 * 2 types, and 001 * 8 type mixes with 201 * 8 types; The ratio of weight and number of strong acid type and strong base ion exchange resin is 1:1 ~ 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310730881.8A CN103665028B (en) | 2013-12-27 | 2013-12-27 | A kind of preparation method of L-α-Choline Glycerophosphate |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104356160A (en) * | 2014-11-05 | 2015-02-18 | 合肥创新医药技术有限公司 | Purification process of L-alpha-glycerophosphoryl choline |
| CN104628766A (en) * | 2015-01-16 | 2015-05-20 | 王志训 | Industrial manufacturing method of glycerol phosphocholine |
| CN108017665A (en) * | 2017-09-05 | 2018-05-11 | 湖南托阳制药有限公司 | A kind of preparation of L- α-choline glycerophosphatide and purification process |
| CN108101936A (en) * | 2017-12-29 | 2018-06-01 | 中山百灵生物技术有限公司 | A kind of calcium removal methods of Phosphorylcholine calcium chloride |
| CN108440594A (en) * | 2018-04-21 | 2018-08-24 | 山东奥博生物科技有限公司 | The preparation method of phosphoryl chloride choline sylvite |
| 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 |
| CN110759942A (en) * | 2018-07-25 | 2020-02-07 | 江苏恒正合生命科学有限公司 | Method for industrially producing choline alfoscerate |
| CN113105500A (en) * | 2021-04-08 | 2021-07-13 | 沈阳金久奇科技有限公司 | Purification and desalination process in L-alpha-choline alfoscerate production by electrodialysis method |
| US11673974B2 (en) | 2019-04-29 | 2023-06-13 | Bausch & Lomb Incorporated | Glycophospholipid polymeric network and use thereof |
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| CN104356160A (en) * | 2014-11-05 | 2015-02-18 | 合肥创新医药技术有限公司 | Purification process of L-alpha-glycerophosphoryl choline |
| CN104628766A (en) * | 2015-01-16 | 2015-05-20 | 王志训 | Industrial manufacturing method of glycerol phosphocholine |
| CN104628766B (en) * | 2015-01-16 | 2017-02-22 | 王志训 | Industrial manufacturing method of glycerol phosphocholine |
| CN108017665A (en) * | 2017-09-05 | 2018-05-11 | 湖南托阳制药有限公司 | A kind of preparation of L- α-choline glycerophosphatide and purification process |
| CN108101936A (en) * | 2017-12-29 | 2018-06-01 | 中山百灵生物技术有限公司 | A kind of calcium removal methods of Phosphorylcholine calcium chloride |
| CN108440594A (en) * | 2018-04-21 | 2018-08-24 | 山东奥博生物科技有限公司 | The preparation method of phosphoryl chloride choline sylvite |
| 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 |
| CN110759942A (en) * | 2018-07-25 | 2020-02-07 | 江苏恒正合生命科学有限公司 | Method for industrially producing choline alfoscerate |
| US11673974B2 (en) | 2019-04-29 | 2023-06-13 | Bausch & Lomb Incorporated | Glycophospholipid polymeric network and use thereof |
| 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 |
| CN113105500A (en) * | 2021-04-08 | 2021-07-13 | 沈阳金久奇科技有限公司 | Purification and desalination process in L-alpha-choline alfoscerate production by electrodialysis method |
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