WO2007145476A1 - A process for preparation of l-alpha-glycerophosphoryl choline - Google Patents

A process for preparation of l-alpha-glycerophosphoryl choline Download PDF

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Publication number
WO2007145476A1
WO2007145476A1 PCT/KR2007/002889 KR2007002889W WO2007145476A1 WO 2007145476 A1 WO2007145476 A1 WO 2007145476A1 KR 2007002889 W KR2007002889 W KR 2007002889W WO 2007145476 A1 WO2007145476 A1 WO 2007145476A1
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formula
compound
preparing
reaction
acid
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PCT/KR2007/002889
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French (fr)
Inventor
Yoon Seok Song
Eun Seob Song
Doo Sung Kang
In Woong Song
Phil Goo Kang
Seong Soo Oh
Seong Cheol Moon
Byung Goo Lee
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Kim, Hyun Joo
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    • 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 System
    • 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
    • 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 System
    • 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
    • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid

Definitions

  • the present invention relates to a process for preparation of L- ⁇ - glycerophosphoryl choline represented by the following formula (1), particularly to a process for preparation of the compound of formula (1) by using phosphocholine chloride and R-(+)-glycidol: [Formula I]
  • L- ⁇ -glycerophosphoryl choline of the formula (1) has a superior effect, without side effect, since it can normalize the function of neural transmission and injured nerve cell and can act to brain directly. Thus, it has been widely used as an agent for Alzheimer's disease.
  • EP 0 217 765 Bl discloses a process for preparation of L- ⁇ -glycerophosphoryl choline from lecithin, according to the following Scheme 1 : [Scheme 1] ZnX 9 pyridine Lecithin ⁇ (n GPC+m GPE)ZnX 2 * * (n GPC+m GPE) + ZnX 2 (py) 2
  • GPC is L- ⁇ -glycerophosphorylcholine
  • GPE is L- ⁇ -glycerophosphorylcholine ethanol amine
  • X is Cl or Br
  • n and m are equivalent weights of GPC and GPE, and n+m is equal to 1.
  • L- ⁇ -glycerophosphorylcholine is prepared by using a soy and/or egg lecithin as a starting material, and isolating GPC and GPE.
  • the preparation needs ion exchange resin to isolate GPC and GPE, and excess water used in the preparation process, and acidic and basic material used in resin recycle generate a large amount of wastewater. Also, the cost of the starting material is high, and the yield is very low.
  • EP 0 486 100 Al discloses the process for preparation of L- ⁇ -glycerophosphoryl choline from isopropylidene-glycerol, according to the following Scheme 2:
  • the Scheme 2 should use a triemethylamine gas, but it is difficult to store and apply as raw material in industrial scale.
  • the object of the present invention is to provide a novel process which synthesizes L- ⁇ -glycerophosphorylcholine of formula (1) from a cheap starting material with high yield, and can be easily applied to industrial scale.
  • the present invention relates to a process for preparation of a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4.
  • the compound of formula 5 is obtained by reacting the compound of formula 3 to the compound of formula 4.
  • the compound of formula 5 formed therein is crystallized.
  • the amount of the compound of formula 4 used in the above scheme is 1 to 4 equivalent, preferably 1 to 3.5 equivalent, more preferably 1.2 to 2.5 equivalent, based on the compound of formula 3. If the amount of the compound of formula 4 is more than 4 equivalent based on the compound of formula 3, the amount of byproduct is increased. If the amount of the compound of formula 4 is less than 1 equivalent based on the compound of formula 3, the reaction cannot be completed.
  • the reaction solvent used in the present step includes alcohol, ether or ketone, but is not limited thereto as long as there is no bad effect to the reaction, preferably Ci-C 6 - alcohol, Ci-C 6 -ether or Ci-C 6 -ketone, more preferably methanol, ethanol or tetrahydropuran, most preferably methanol or ethanol. And, one or more solvents can be mixed and used together.
  • the reaction pH is 5 to 10, preferably 6 to 10, more preferably 6 to 9. If the reaction pH is more than 10, the reaction cannot be completed. If the reaction pH is less than 5, the reaction cannot be completed.
  • the base used to maintain the pH of the reactant includes triethylamine, pyridine, isopropylamine or di- isopropylamine, but is not limited thereto.
  • the reaction temperature is 40 to 120 ° C , preferably 45 to 100 ° C, more preferably 50 to 90 ° C , and is not limited as long as the reaction solvent can reflux. If the reaction temperature is more than 120 ° C , impurities can be increased. If the reaction temperature is less than 40 ° C , the reaction speed may be slow.
  • crystallization can be carried out by adding an excess amount of crystallization solvent based on the formed compound of formula 5 to the reaction mixture.
  • the amount of crystallization solvent may be selected in the range to crystallize the compound of formula 5, preferably 18 equivalent.
  • the crystallization solvent added to the reaction mixture includes alcohol or ketone, preferably Ci-C 6 -alcohol, Ci-C 6 -ether or Ci-C 6 -ketone, more preferably isopropylalcohol or acetone, but is not limited thereto. And, one or more crystallization solvents may be mixed and used together.
  • Crystallization may be carried out in the temperature range of 0 to 25 ° C, preferably 0 to 10 ° C . If the temperature is more than 25 ° C , crystals cannot be formed. If the temperature is less than 0 ° C , crystals cannot be formed, and a phenomenon to be lumped like gruel occurs.
  • the present invention further comprises a step of eliminating impurities from the compound of formula 5 in order to carry out the crystallization more effectively before the crystallization step.
  • Impurities may be eliminated by removing the reaction solvent from the reactant by decompressed concentration, dissolving the concentrate in water, and washing a water layer.
  • the organic solvent used for eliminating the reaction impurities includes halogenated Ci-C 4 -alkane such as dichloromethane; Ci-C 4 -alkoxycarbonyl Ci-C 4 -alkane such as ethylacetate; or C 3 -Cg- alcohol such as sec-butanol, cyclohexanol, or cyclopentanol, more preferably dichloromethane or sec-butanol, but is not limited thereto. And, one or more organic solvents may be mixed and used together.
  • the water layer in which the compound of formula 5 is dissolved is concentrated by eliminating water, and the concentrate is heated and dissolved in an organic solvent.
  • the organic solvent includes alcohol, ether or ketone, preferably Ci-C 6 -alcohol, Ci-C ⁇ -ether or Cj-C 6 -ketone, more preferably methanol, ethanol or tetrahydropuran, most preferably methanol or ethanol, but is not limited thereto. And, one or more organic solvents may be mixed and used together.
  • the compound of formula 1 is obtained by eliminating chlorine ion from the compound of formula 5.
  • the elimination of chlorine ion may be carried out by dissolving the compound of formula 5 in water, and passing it through ion exchange resin.
  • the ion exchange resin used in the present step is not limited as long as it has a functional group which can eliminate the chlorine ion from the compound of formula 5, and includes a weak base form of ion exchange resin having primary, second or tertiary amino group; a heavy base form of ion exchange resin having quaternary ammonium base; amphoteric ion exchange resin having both amino group or ammonium group, and sulfone or carboxyl.
  • the preferable ion exchange resin used in the present step includes IONAC NM-60 (Sybron Chemicals Inc.), Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MR-3 (Dow Chemicals), Amberite IRN-150 (Rohm & Haas), Amberite MB-20 (Rohm & Haas), MB-400 (Purolite), NRW- 37 (Purolite) or IONAC-NM60 SG (Bayer), more preferably Lewatit SM-94 (Sybron Chemicals Inc.) or IONAC-NM60 SG (Bayer), but is not limited thereto.
  • the compound of formula 2 used in the present step is in the form of anhydride or hydrate, preferably calcium 2-(trimethylammonio)ehtylphosphate chloride tetrahydrate.
  • the compound of formula 2 may be obtained from diverse producers including Chinese chem.-sourcing.
  • the acid used for eliminating the calcium ion from the compound of formula 2 includes inorganic acid or organic acid, preferably sulfuric acid, boric acid, phosphoric acid, nitric acid, hydrochloric acid, oxalic acid, acetic acid, EDTA (ethyldiaminetetraacetic acid) or citric acid, more preferably sulfuric acid, EDTA or oxalic acid, but is not to limited thereto.
  • the amount of acid used in the present step may be changed, depending on the kinds of acid used, and is sufficient if the pH of reactant becomes to less than 2, preferably less than 1.2, more preferably less than 1. If the pH of reactant is more than 2, the reaction cannot be completed.
  • the temperature of the reaction is -10 to 60 ° C, preferably 0 to 50 ° C , more preferably 0 to 40 ° C . If the reaction temperature is more than 60 ° C , the calcium salt remains and interferes next reaction. If the reaction temperature is less than -10 ° C , the reaction speed becomes very slow.
  • the solvent used in the present step is not limited as long as it does not have a bad effect to the reaction, and can dissolve the compound of formula 2, but includes water, alcohol or ketone, preferably water, Ci-C 6 -alcohol or Ci-C 6 -ketone, more preferably water, ethanol. methanol or acetone. And, one or more organic solvents can be mixed and used together.
  • the present invention can synthesize L- ⁇ -glycerophosphorylcholine of formula 1 with high yield from a cheap starting material by using phosphocholine chloride and R-
  • (+)-glycidol the present invention can be easily applied to industrial scale. Also, the amount of ion exchange resin used in the present invention is very small, and the cost can be saved by simply passing the formed compound through ion exchange resin.

Abstract

The present invention relates to a process for preparing L-α- glycerophosphorylcholine by reacting phosphocholine chloride to R-(+)-glycidol. The present invention can prepare a compound of formula 1 in short reaction step and high yield.

Description

A PROCESS FOR PREPARATION OF L-ALPHA-GLYCEROPHOSPHORYL
CHOLINE
TECHNICAL FIELD
The present invention relates to a process for preparation of L-α- glycerophosphoryl choline represented by the following formula (1), particularly to a process for preparation of the compound of formula (1) by using phosphocholine chloride and R-(+)-glycidol: [Formula I]
Figure imgf000002_0001
L-α-glycerophosphoryl choline of the formula (1) has a superior effect, without side effect, since it can normalize the function of neural transmission and injured nerve cell and can act to brain directly. Thus, it has been widely used as an agent for Alzheimer's disease.
BACKGROUND ART
EP 0 217 765 Bl discloses a process for preparation of L-α-glycerophosphoryl choline from lecithin, according to the following Scheme 1 : [Scheme 1] ZnX9 pyridine Lecithin ^ (n GPC+m GPE)ZnX2 ** (n GPC+m GPE) + ZnX2 (py)2
IR 120 HH
IR 401 OH" GPC -* (n GPC+m GPE)
wherein GPC is L-α-glycerophosphorylcholine,
GPE is L-α-glycerophosphorylcholine ethanol amine, X is Cl or Br, and n and m are equivalent weights of GPC and GPE, and n+m is equal to 1.
In the Scheme 1 , L-α-glycerophosphorylcholine is prepared by using a soy and/or egg lecithin as a starting material, and isolating GPC and GPE. However, the preparation needs ion exchange resin to isolate GPC and GPE, and excess water used in the preparation process, and acidic and basic material used in resin recycle generate a large amount of wastewater. Also, the cost of the starting material is high, and the yield is very low.
EP 0 486 100 Al discloses the process for preparation of L-α-glycerophosphoryl choline from isopropylidene-glycerol, according to the following Scheme 2:
[Scheme 2]
Figure imgf000004_0001
trimethyl aijnine
Figure imgf000004_0002
However, the Scheme 2 should use a triemethylamine gas, but it is difficult to store and apply as raw material in industrial scale.
TECHNICAL SOLUTION
The object of the present invention is to provide a novel process which synthesizes L-α-glycerophosphorylcholine of formula (1) from a cheap starting material with high yield, and can be easily applied to industrial scale.
BEST MODE
The present invention relates to a process for preparation of a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4.
[Formula 3]
Figure imgf000004_0003
[Formula 4]
Figure imgf000004_0004
[Formula 5]
Figure imgf000005_0001
The present invention is explained in more detail below.
Preparation of L-α-elycerophosphoryl choline chloride (5)
As described in the Scheme 3 below, the compound of formula 5 is obtained by reacting the compound of formula 3 to the compound of formula 4. Preferably, the compound of formula 5 formed therein is crystallized. [Scheme 3]
O
HO. OH
O
- 'N' O OH
Cl -N' -p
OH Δ Cl
OH
(3) (5)
The amount of the compound of formula 4 used in the above scheme is 1 to 4 equivalent, preferably 1 to 3.5 equivalent, more preferably 1.2 to 2.5 equivalent, based on the compound of formula 3. If the amount of the compound of formula 4 is more than 4 equivalent based on the compound of formula 3, the amount of byproduct is increased. If the amount of the compound of formula 4 is less than 1 equivalent based on the compound of formula 3, the reaction cannot be completed.
The reaction solvent used in the present step includes alcohol, ether or ketone, but is not limited thereto as long as there is no bad effect to the reaction, preferably Ci-C6- alcohol, Ci-C6-ether or Ci-C6-ketone, more preferably methanol, ethanol or tetrahydropuran, most preferably methanol or ethanol. And, one or more solvents can be mixed and used together. The reaction pH is 5 to 10, preferably 6 to 10, more preferably 6 to 9. If the reaction pH is more than 10, the reaction cannot be completed. If the reaction pH is less than 5, the reaction cannot be completed. The base used to maintain the pH of the reactant includes triethylamine, pyridine, isopropylamine or di- isopropylamine, but is not limited thereto. The reaction temperature is 40 to 120°C , preferably 45 to 100°C, more preferably 50 to 90 °C , and is not limited as long as the reaction solvent can reflux. If the reaction temperature is more than 120 °C , impurities can be increased. If the reaction temperature is less than 40 °C , the reaction speed may be slow.
After the reaction is completed, crystallization can be carried out by adding an excess amount of crystallization solvent based on the formed compound of formula 5 to the reaction mixture. Considering several conditions including reaction solvent, crystallization solvent, crystallization temperature, etc., the amount of crystallization solvent may be selected in the range to crystallize the compound of formula 5, preferably 18 equivalent. The crystallization solvent added to the reaction mixture includes alcohol or ketone, preferably Ci-C6-alcohol, Ci-C6-ether or Ci-C6-ketone, more preferably isopropylalcohol or acetone, but is not limited thereto. And, one or more crystallization solvents may be mixed and used together. Crystallization may be carried out in the temperature range of 0 to 25 °C, preferably 0 to 10°C . If the temperature is more than 25 °C , crystals cannot be formed. If the temperature is less than 0 °C , crystals cannot be formed, and a phenomenon to be lumped like gruel occurs.
Preferably, the present invention further comprises a step of eliminating impurities from the compound of formula 5 in order to carry out the crystallization more effectively before the crystallization step. Impurities may be eliminated by removing the reaction solvent from the reactant by decompressed concentration, dissolving the concentrate in water, and washing a water layer. The organic solvent used for eliminating the reaction impurities includes halogenated Ci-C4-alkane such as dichloromethane; Ci-C4-alkoxycarbonyl Ci-C4-alkane such as ethylacetate; or C3-Cg- alcohol such as sec-butanol, cyclohexanol, or cyclopentanol, more preferably dichloromethane or sec-butanol, but is not limited thereto. And, one or more organic solvents may be mixed and used together. In the case of comprising the step of eliminating impurities before the crystallization step, the water layer in which the compound of formula 5 is dissolved is concentrated by eliminating water, and the concentrate is heated and dissolved in an organic solvent. The organic solvent includes alcohol, ether or ketone, preferably Ci-C6-alcohol, Ci-Cό-ether or Cj-C6-ketone, more preferably methanol, ethanol or tetrahydropuran, most preferably methanol or ethanol, but is not limited thereto. And, one or more organic solvents may be mixed and used together.
Preparation of L-α-glycerophosphoryl choline (1)
As described in the Scheme 4 below, the compound of formula 1 is obtained by eliminating chlorine ion from the compound of formula 5. The elimination of chlorine ion may be carried out by dissolving the compound of formula 5 in water, and passing it through ion exchange resin. [Scheme 4]
Figure imgf000008_0001
(5) (D
The ion exchange resin used in the present step is not limited as long as it has a functional group which can eliminate the chlorine ion from the compound of formula 5, and includes a weak base form of ion exchange resin having primary, second or tertiary amino group; a heavy base form of ion exchange resin having quaternary ammonium base; amphoteric ion exchange resin having both amino group or ammonium group, and sulfone or carboxyl. The preferable ion exchange resin used in the present step includes IONAC NM-60 (Sybron Chemicals Inc.), Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MR-3 (Dow Chemicals), Amberite IRN-150 (Rohm & Haas), Amberite MB-20 (Rohm & Haas), MB-400 (Purolite), NRW- 37 (Purolite) or IONAC-NM60 SG (Bayer), more preferably Lewatit SM-94 (Sybron Chemicals Inc.) or IONAC-NM60 SG (Bayer), but is not limited thereto.
Preparation of phosphocholine chloride (1) The compound of formula 3 used in preparing the compound of formula 5 is obtained by eliminating the calcium ion from the compound of formula 2 under acid condition, as shown in the following Scheme 5: [Scheme 5]
Figure imgf000008_0002
(2) (3)
The compound of formula 2 used in the present step is in the form of anhydride or hydrate, preferably calcium 2-(trimethylammonio)ehtylphosphate chloride tetrahydrate. The compound of formula 2 may be obtained from diverse producers including Chinese chem.-sourcing. The acid used for eliminating the calcium ion from the compound of formula 2 includes inorganic acid or organic acid, preferably sulfuric acid, boric acid, phosphoric acid, nitric acid, hydrochloric acid, oxalic acid, acetic acid, EDTA (ethyldiaminetetraacetic acid) or citric acid, more preferably sulfuric acid, EDTA or oxalic acid, but is not to limited thereto. The amount of acid used in the present step may be changed, depending on the kinds of acid used, and is sufficient if the pH of reactant becomes to less than 2, preferably less than 1.2, more preferably less than 1. If the pH of reactant is more than 2, the reaction cannot be completed. The temperature of the reaction is -10 to 60 °C, preferably 0 to 50°C , more preferably 0 to 40 °C . If the reaction temperature is more than 60 °C , the calcium salt remains and interferes next reaction. If the reaction temperature is less than -10°C , the reaction speed becomes very slow. The solvent used in the present step is not limited as long as it does not have a bad effect to the reaction, and can dissolve the compound of formula 2, but includes water, alcohol or ketone, preferably water, Ci-C6-alcohol or Ci-C6-ketone, more preferably water, ethanol. methanol or acetone. And, one or more organic solvents can be mixed and used together.
The present invention as described above will be described in more detail based on the following examples. However, the examples are to help understanding on the present invention, and are not intended to limit the scope of the present invention in any way. [Examples]
Used instrument and condition HPLC: JASCO HPLC 2000
Column: capcellpak Cl 8 MG 5/im 4.6mmI.D. x 230mm column Mobile phase: water (0.5mL/min) Detector: RI-detector
Example 1 : Preparation of phosphocholine chloride (3)
Figure imgf000010_0001
lOOg of calcium 2-(trimethylammonio)ethylphosphate chloride tetrahydrate
(Chinese, Chem-Sourcing product; 1 equivalent, 303.2 mmol) was dissolved in 350ml of water and heated at 50 °C . Then, 6Og of oxalic acid (1.5 equivalent, 475.9 mmol) was added thereto and shaken for 2 hours. When the weight % of calcium became to less than 0.1%, the reaction was completed by using the EDTA (ethylenediaminetetraacetic acid). Then, the filtrate was collected by filtering and decompressed for concentration. The obtained product was dissolved in 10OmL of ethanol, and the phosphocholine chloride was obtained by decompressed concentration (63.27g, yield 95%). 1H NMR (D2O, 300MHz): δ 3.09 (s, 9H), 3.54 (m, 2H), 4.18 (m, 2H).
Example 2: Preparation of L-α-glycerophosphorylcholine chloride (5)
Figure imgf000011_0001
63.27g of phosphorylcholine chloride (1 equivalent weight, 288.1 mmol) obtained in the above Example 1 was dissolved in 189.8mL of ethanol and then shaken at 80 °C . 4Og of R-(+)-glycidol (1.87 equivalent weight, 539.9 mmol) was slowly added thereto, reacted for 12 hours, adjusted to 8.0 of pH by using isoprophyamine, further reacted for 3 hours, and cooled. The concentrate obtained by decompressed concentration of the obtained solution was dissolved in 313.2 mL of water, and washed three times with 156. Ig of sec-butanol. Thus obtained water layer was decompressed and concentrated to adjust the water content within 5%. 260.4mL of ethanol was added thereto, which was heated at 80 °C and then cooled 0°C . Then, 130.2mL of isoprophylalcohol was added thereto. L-α-glycerophosphorylcholine chloride was obtained by filtering the crystal obtained therefrom. 1H NMR (D2O, 300MHz): δ 3.18 (s, 9H), 3.41 (m, 4H), 3.86 (m, 4H), 4.27 (m, 2H). 13C NMR (D2O, 100MHz): δ 53.88, 59.35, 61.90, 65.91, 66.45, 70.54 Example 3: Preparation of L-oglycerophosphorylcholine (1)
Figure imgf000011_0002
52.08g of L-α-glycerophosphorylcholine chloride obtained in the above Example
2 was dissolved in purified water, and passed through IONAC NM60 SG ion exchange resin (Bayer). 0.1N silver nitrate was used to confirm the elimination of chloride ion.
L-α-glycerophosphorylcholine which is the final product was obtained by decompressed concentration of the resultant (49.45g, yield 97%). 1H NMR (D2O, 300MHz): δ 3.21 (s, 9H), 3.63 (m, 4H), 3.90 (m, 4H), 4.30 (m, 2H). 13C NMR (D2O, 100MHz): δ 53.87, 59.35, 61.90, 65.93, 66.45, 70.53
INDUSTRIAL APPLICABILITY
The present invention can synthesize L-α-glycerophosphorylcholine of formula 1 with high yield from a cheap starting material by using phosphocholine chloride and R-
(+)-glycidol. And, the present invention can be easily applied to industrial scale. Also, the amount of ion exchange resin used in the present invention is very small, and the cost can be saved by simply passing the formed compound through ion exchange resin.

Claims

1. A process for preparing a compound of formula 5 by reacting a compound of formula 3 to a compound of formula 4.
[Formula 3]
Figure imgf000013_0001
[Formula 4]
Figure imgf000013_0002
[Formula 5]
OH
cr I OH
2. The process for preparing the compound of formula 5 according to claim 1, wherein the amount of the compound of formula 3 is 1 to 4 equivalent based on the amount of the compound of formula 4.
3. The process for preparing the compound of formula 5 according to claim 1, wherein the reaction pH is 5 to 10, and the reaction temperature is 40 to 120°C .
4. The process for preparing the compound of formula 5 according to claim 1, wherein the reaction is carried out by a reaction solvent selected from the group consisting of Ci-C6-alcohol, Ci-C6-ether or Ci-C6-ketone, and a mixture thereof.
5. The process for preparing the compound of formula 5 according to claim 4, wherein the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydropuran, and a mixture thereof.
6. The process for preparing the compound of formula 5 according to claim 4, wherein the process further comprises a step of crystallizing the compound of formula 5 by adding a crystallization solvent selected from the group consisting of C1-C6- alcohol,Ci-C6-ketone, and a mixture thereof.
7. The process for preparing the compound of formula 5 according to claim 6, wherein the crystallization solvent is isopropylalcohol, acetone, or a mixture thereof.
8. The process for preparing the compound of formula 5 according to claim 6, wherein the temperature for crystallization is within 0 to 25 °C .
9. The process for preparing the compound of formula 5 according to claim 6, wherein the process further comprises a step of forming a concentrate by eliminating the reaction solvent; a step of dissolving the formed concentrate in water and then eliminating impurities from a water layer by using organic solvent selected from the group consisting of halogenated Ci-C4-alkane; Ci-C4-alkoxycarbonylCi-C4-alkane, C3-Cg-alcohol, or a mixture thereof; and a step of eliminating water from the water layer and then dissolving the formed concentrate in organic solvent selected from the group consisting of C1-C6- alcohol, Ci-Cό-ether or Ci-C6-ketone, and a mixture thereof, prior to adding a crystallization solvent.
10. The process for preparing the compound of formula 5 according to claim 1, wherein the compound of formula 3 is formed by eliminating calcium from the compound of formula 2 under acid condition.
11. The process for preparing the compound of formula 5 according to claim 10, wherein the acid is selected from the group consisting of sulfuric acid, boric acid, phosphoric acid, nitric acid, hydrochloric acid, oxalic acid, acetic acid, ethyldiaminetetraacetic acid, and citric acid.
12. The process for preparing the compound of formula 5 according to claim 10, wherein the reaction pH is less than 2, and the reaction temperature is -10 to 60 "C .
13. The process for preparing the compound of formula 5 according to claim 10, wherein the reaction is carried out by a reaction solvent selected from the group consisting of Ci-C6-alcohol, Ci-C6-ketone, and a mixture thereof.
14. A process for preparing the compound of formula 1 comprising a step of eliminating chlorine ion from the compound of formula 5 according to claim 1 by using ion exchange resin.
15. The process for preparing the compound of formula 1 according to claim 14, wherein the ion exchange resin is selected from the group consisting of IONAC NM-60 (Sybron Chemicals Inc.), Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MR-3 (Dow Chemicals), Amberite IRN- 150 (Rohm & Haas), Amberite MB-20 (Rohm & Haas), MB-400 (Purolite), NRW-37 (Purolite) and IONAC-NM60 SG (Bayer).
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Cited By (12)

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WO2011054429A1 (en) 2009-11-05 2011-05-12 Merck Patent Gmbh Synthesis of phosphoric esters
CN102093410A (en) * 2011-01-11 2011-06-15 江南大学 Method for separating and purifying L-alpha-glycerophosphorylcholine (L-alpha-GPC) by silica gel column chromatography
CN103172659A (en) * 2013-03-29 2013-06-26 山东罗欣药业股份有限公司 L-alpha-glyceryl phosphoryl choline crystal form compound
CN104628766A (en) * 2015-01-16 2015-05-20 王志训 Industrial manufacturing method of glycerol phosphocholine
KR101622376B1 (en) * 2014-06-10 2016-05-18 케미 에스.피.에이. Process for the purification of L-Alpha-glycerophosphorylcholine
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