KR100966627B1 - A process for preparation of L­?­glycerophosphoryl choline - Google Patents

Abstract

The present invention relates to a method for preparing L-α-glycerophosphoryl choline comprising reacting phosphorylcholine chloride with R-(+)-glycidol, wherein the compound of Formula 1 is reacted with a short reaction step and high yield. It can be produced by the effect.

L-α-glycerophosphoryl choline, phosphorylcholine chloride, R-(+)-glycidol

Description

A process for preparation of L-α-glycerophosphoryl choline

The present invention relates to a method for preparing L-α-glycerophosphorylcholine of Chemical Formula 1, and more specifically, to a compound of Chemical Formula 1 using phosphorylcholine chloride and R-(+)-glycidol It relates to a manufacturing method.

[Formula 1]

L-α-glycerophosphorylcholine of Formula 1 normalizes neurotransmitter function, normalizes function of damaged neurons, and is widely used as a treatment for dementia because it has excellent effects and no side effects because it directly affects the brain. .

EP 0 217 765 B1 discloses a process for preparing L-α-glycerophosphorylcholine from lecithin according to the method described in Scheme 1.

Scheme 1

Where

GPC means L-α-glycerophosphorylcholine,

GPE means L-α-glycerophosphorylcholineethanolamine,

X represents chlorine or bromine,

n and m are the equivalent number of GPC and GPE, n + m is 1.

The method of Scheme 1 prepares L-α-glycerophosphorylcholine by separating GPC and GPE using lecithin extracted from soybeans and eggs as starting materials. However, the process requires ion exchange resin equipment to separate GPC and GPE, and the excess water used in this process and the acidic and basic materials used for resin regeneration generate large amounts of waste liquor. In addition, the price of starting material is high and the yield is very low.

EP 0 486 100 A1 discloses a process for preparing L-α-glycerophosphorylcholine from isopropylidene-glycerol according to the method described in Scheme 2.

 Scheme 2

However, since the method of Scheme 2 requires the use of trimethylamine gas, it is difficult to store and apply the raw materials when applied on an industrial scale.

It is an object of the present invention to synthesize a L-α-glycerophosphoryl choline of formula (1) in high yield from a low cost starting material and to provide a novel preparation method which can be easily applied on an industrial scale.

The present invention relates to a process for preparing a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4.

(3)

[Formula 4]

[Chemical Formula 5]

Hereinafter, the present invention will be described in detail with the reaction scheme.

L-α- Glycerophosphoryl  Preparation of Choline Chloride (5)

The compound of Formula 3 is reacted with the compound of Formula 4 to form a compound of Formula 5, as shown in Scheme 3 below. Preferably, it is preferable to crystallize the compound of formula 5 formed.

Scheme 3

The amount of the compound of formula 4 used in this step is 1 to 4 equivalents, preferably 1 to 3.5 equivalents, more preferably 1.2 to 2.5 equivalents, based on the compound of formula 3. If the amount of the compound of formula 4 exceeds 4 equivalents based on the compound of formula 3, the by-products increase; if less than 1 equivalent the reaction is not complete. The reaction solvent used in this step is not particularly limited as long as it does not adversely affect the reaction, but is not limited to alcohol, ether or ketone, preferably C ₁ -C ₆ -alcohol, C ₁ -C ₆ -ether or C ₁ -C ₆ -ketone, more preferably methanol, ethanol or tetrahydrofuran, most preferably methanol or ethanol and one or more solvents may 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 exceeds 10, the reaction is not completed. If the reaction pH is less than 5, the reaction is not completed. Bases used to maintain the pH of the reactants include, but are not limited to, triethylamine, pyridine, isopropylamine or diisopropylamine. The reaction temperature is not limited as long as the reaction solvent is refluxed, but is 40 ° C to 120 ° C, preferably 45 ° C to 100 ° C, more preferably 50 ° C to 90 ° C. Impurities increase when the reaction temperature exceeds 120 ° C, and the reaction rate becomes very slow below 40 ° C.

After completion of the reaction, the compound of formula 5 can be crystallized by adding an excess crystallization solvent to the reaction mixture based on the compound of formula 5 formed. The amount of the crystallization solvent to be added may be freely selected within the range in which the compound of formula 5 can be crystallized in consideration of various conditions including the reaction solvent, the crystallization solvent and the crystallization temperature, but preferably 18 equivalents is used. Crystallization solvents added to the reaction mixture include, but are not limited to, alcohols or ketones, preferably C ₁ -C ₆ -alcohols or C ₁ -C ₆ -ketones, more preferably isopropyl alcohol, acetone The above crystallization solvents may be mixed and used together. Crystallization may be carried out in a temperature range of 0 to 25 ° C, preferably 0 to 10 ° C. If the crystallization temperature exceeds 25 ℃ crystal formation is not good, if it is below 0 ℃ crystals do not form and agglomeration like porridge occurs.

Preferably, this step may further comprise the step of removing impurities from the compound of the formula (5) before the crystallization step in order to perform the crystallization more efficiently. Reaction impurity removal may be carried out by removing the reaction solvent from the reactant formed by, for example, vacuum concentration, dissolving the formed concentrate in water, and then washing the aqueous layer with an organic solvent. Organic solvents used to remove the reaction impurities include halogenated C ₁ -C ₄ -alkanes such as dichloromethane; Alkoxycarbonyl _{C 1 -C 4 - - C 1} -C 4 alkanes, such as ethyl acetate; C ₃ -C ₈ -alcohols, such as sec-butanol, cyclohexanol or cyclopentanol, more preferably dichloromethane or sec-butanol, including but not limited to one or more organic solvents may be mixed and used together Can be. If the impurity removal step is included before the crystallization step, water is removed from the aqueous layer in which the compound of Formula 5 is dissolved after the impurity removal step, and the formed concentrate is heated to be dissolved in the organic solvent. The organic solvent is alcohol, ether or ketone, preferably C ₁ -C ₆ -alcohol, C ₁ -C ₆ -ether or C ₁ -C ₆ -ketone, more preferably methanol, ethanol or tetrahydrofuran, most Preferably, but not limited to, methanol or ethanol, one or more organic solvents may be mixed and used together.

L-α- Glycerophosphoryl  Preparation of Choline (1)

As in Scheme 4 below, chlorine ions are removed from the compound of Formula 5 to form a compound of Formula 1. Removal of chlorine ions may be carried out by dissolving the compound of Formula 5 in water and then passing through an ion exchange resin.

Scheme 4

The ion exchange resin used in this step is not particularly limited as long as it has a cation functional group capable of removing chlorine ions from the compound of formula 5, but is a weak base type ion exchange having primary, secondary or tertiary amino groups. Suzy; Strong base type ion exchange resin having a quaternary ammonium base; Amphoteric ion exchange resins having a sulfonic acid group or a carboxyl group together with an amino group or an ammonium group. Examples of preferred ion exchange resins used in this step are IONAC NM-60 (Sybron Chemicals Inc.), Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MB-46 ( Dow Chemical), Dowex MR-3 (Dow Chemical), 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 NM-60 SG (Bayer), but is not limited thereto.

Of phosphorylcholine chloride (3)  Produce

The compound of formula 3 used to prepare the compound of formula 5 may be formed by removing calcium ions from the compound of formula 2 under acidic conditions. This is shown in Scheme 5 below.

Scheme 5

The compound of formula 2 used in this reaction is in anhydrous form or in hydrate form, preferably tetrahydrate with calcium 2- (trimethylammonio) ethylphosphate chloride. The compound of formula 2 can be obtained from various commercial sources including the Chinese chem.-sourcing company. The acid used to remove calcium ions from the compound of formula (2) is an inorganic or organic acid, preferably sulfuric acid, boric acid, phosphoric acid, nitric acid, hydrochloric acid, oxalic acid, acetic acid, EDTA (ethylenediaminetetraacetic acid) or citric acid, more preferably Sulfuric acid, EDTA or oxalic acid, but is not limited thereto. The amount of acid used in this step depends on the type of acid used, but an amount which can make the pH of the reactants 2 or less, preferably 1.2 or less, more preferably 1 or less, is used. If the pH of the reactants exceeds 2, the reaction is not complete. The temperature at which the present reaction is carried out is -10 ° C to 60 ° C, preferably 0 ° C to 50 ° C, more preferably 0 ° C to 40 ° C. If the reaction temperature exceeds 60 ℃, calcium salts remain to interfere with the next reaction, if it is less than -10 ℃ the reaction rate is very slow. The solvent used in this step is not particularly limited as long as it does not adversely affect the reaction and can dissolve the compound of Formula 2, but is not limited to water, alcohol or ketone, preferably water, C ₁ -C ₆ -alcohol or C ₁ —C ₆ -ketone, more preferably water, ethanol, methanol or acetone, and one or more solvents may be mixed and used together.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to aid the understanding of the present invention and are not intended to limit the scope of the present invention in any sense.

EXAMPLE

Equipment and condition

HPLC: JASCO HPLC 2000

Column: capcellpak C18 MG 5 μm 4.6 mm I.D. x 230mm column

Mobile phase: water (0.5 mL / min)

Detector: RI-detector

Example  One: Of phosphorylcholine chloride (3)  Produce

100 g of calcium 2- (trimethylammonio) ethylphosphate chloride tetrahydrate (350 ml of water, Chem.-Sorucing; 1 equivalent, 303.2 mmol) was dissolved in 350 mL of water, heated to 50 ° C., and then 60 g of oxalic acid ( 1.5 eq, 475.9 mmol) was added and stirred for 2 hours. EDTA (ethylenediaminetetraacetic acid) was used to complete the reaction when the weight percent of calcium was 0.1% or less. Thereafter, the filtrate was collected by filtration and concentrated under reduced pressure. The obtained product was dissolved in 100 mL of ethanol and then concentrated under reduced pressure to give phosphorylcholine chloride (63.27 g, yield 95%). ¹ H NMR (D ₂ O, 300 MHz): δ 3.09 (s, 9H), 3.54 (m, 2H), 4.18 (m, 2H).

Example  2: L-α- Glycerophosphoryl  Preparation of Choline Chloride (5)

63.27 g phosphorylcholine chloride (1 equivalent, 288.1 mmol) obtained in Example 1 was dissolved in 189.8 mL ethanol and heated to reflux at 80 ° C. 40 g of R-(+)-glycidol (1.87 equivalents, 539.9 mmol) was slowly added thereto, followed by reaction for 12 hours, followed by further reaction for 3 hours by adjusting the pH to 8.0 using isopropylamine. I was. The resulting solution was concentrated under reduced pressure, and the resulting concentrate was dissolved in 313.2 ml of water, and then washed three times with 156.1 g of sec-butanol. The obtained aqueous layer was concentrated under reduced pressure to bring the water content to within 5%. 260.4 mL of ethanol was added thereto, heated to 80 ° C. to dissolve, and cooled to 0 ° C. Thereafter, 130.2 mL of isopropyl alcohol was added, and the obtained crystals were filtered to give L-α-glycerophosphoryl choline chloride (52.08 g, 70.3% yield). ¹ H NMR (D ₂ O, 300 MHz): δ 3.18 (s, 9H), 3.41 (m, 4H), 3.86 (m, 4H), 4.27 (m, 2H). ¹³ C NMR (D ₂ O, 100 MHz): δ 53.88, 59.35, 61.90, 65.91, 66.45, 70.54

Example  3: L-α- Glycerophosphoryl  Preparation of Choline (1)

52.08 g of L-α-glycerophosphoryl choline chloride obtained in Example 2 was dissolved in 156.24 mL of purified water and passed through IONAC NM60 SG ion exchange resin (Bayer). Removal of chlorine ions was confirmed using 0.1 N silver nitrate reagent. The resulting material was concentrated under reduced pressure to obtain the final material, L-α-glycerophosphoryl choline (49.45 g, 97% yield). ¹ H NMR (D ₂ O, 300 MHz): δ 3.21 (s, 9H), 3.63 (m, 4H), 3.90 (m, 4H), 4.30 (m, 2H). ¹³ C NMR (D ₂ O, 100 MHz): δ 53.87, 59.35, 61.90, 65.93, 66.44, 70.53

The present invention uses phosphorylcholine chloride and R-(+)-glycidol to synthesize L-α-glycerophosphorylcholine of Formula 1 in high yield from low cost starting materials, It can be easily applied on an industrial scale. In addition, the amount of ion exchange resin used is very small, and the cost is reduced because the formed compound is simply passed through the ion exchange resin.

Claims (15)

A method of preparing a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4. (3)

[Formula 4]

[Chemical Formula 5]

The method of claim 1, wherein the amount of the compound of formula 3 is 1 to 4 equivalents based on the amount of the compound of formula 4. The method according to claim 1, wherein the reaction pH is 5 to 10 and the reaction temperature is 40 to 120 ° C. The method of claim 1 wherein the reaction is C ₁ -C ₆ - alcohols, C ₁ -C ₆ - ether, C ₁ -C ₆ - methods carried out in a reaction solvent selected from the group consisting of ketones, and mixtures thereof. The process of claim 4 wherein the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran and mixtures thereof. 5. The method of claim 4, C ₁ -C ₆ - alcohols, C ₁ -C ₆ - ketone and a method for crystallization by the addition of a solvent selected from the group consisting of a mixture further comprises the step of crystallizing the compound of formula (5). 7. The process of claim 6 wherein the crystallization solvent is isopropyl alcohol, acetone or mixtures thereof. The method of claim 6, wherein the crystallization is performed within a temperature range of 0 ° C. to 25 ° C. 8. The method of claim 6, further comprising removing the reaction solvent to form a concentrate; The concentrate formed was dissolved in water and then grouped with halogenated C ₁ -C ₄ -alkane, C ₁ -C ₄ -alkoxycarbonylC ₁ -C ₄ -alkane, C ₃ -C ₈ -alcohol and mixtures thereof Removing impurities from the aqueous layer using an organic solvent selected from; And after removing the water from the water column, the formed concentrate C ₁ -C ₆ - alcohols, C ₁ -C ₆ - ether, C ₁ -C ₆ - dissolving in an organic solvent selected from the group consisting of ketones, and mixtures thereof Further comprising before the addition of the crystallization solvent. The method of claim 1, wherein the compound of formula 3 is formed by removing calcium from the compound of formula 2 under acidic conditions. [Formula 2]

(3)

The process of 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, ethylenediaminetetraacetic acid and citric acid. The method of claim 10, wherein the reaction pH is 2 or less and the reaction temperature is -10 to 60 ° C. The process of claim 10 wherein the reaction is performed in a solvent selected from the group consisting of water, C ₁ -C ₆ -alcohols, C ₁ -C ₆ -ketones, and mixtures thereof. A method of preparing a compound of Formula 1 comprising removing chlorine ions from a compound of Formula 5 as defined in claim 1 using an ion exchange resin. [Chemical Formula 5]

[Formula 1]

The method of claim 14, wherein the ion exchange resin is IONAC NM-60 (Sybron Chemicals Inc.), Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MB-46 (Dow Chemical). ), Dowex MR-3 (Dow Chemical), Amberite IRN-150 (Rohm & Haas), Amberite MB-20 (Rohm & Haas), MB-400 (Purolite), NRW-37 (Purolite) and IONAC NM60 SG (Bayer) Selected from a group consisting of).