WO2009128631A2 - Method for preparing racemic or optically active α-glycerophosphorylcholine and derivative thereof - Google Patents

Abstract

The present invention relates to a new method for preparing a racemic or optically active D or L-α-glycerophosphorylcholine and a derivative thereof which have excellent therapeutic effects on both secondary symptoms caused by cerebrovascular stroke and degenerative organic brain syndromes. More specifically, the invention relates to an economical method for mass-producing the racemic or optically active D or L-α-glycerophosphorylcholine and the derivative thereof at a high purity and high yield, by performing a ring-opening reaction of racemic and optionally high purity (S) or (R)-glycidol and a derivative thereof in a room-temperature aqueous solution using choline phosphate as a starting material and using inorganic bases or Lewis acids which increase a reaction rate in the aqueous solution.

Description

PROCESS FOR PREPARING RACEMIC OR OPTICALLY ACTIVE α-GLYCEROPHOSPHORYL CHOLINE, AND THER DERIVATIVES}

The present invention provides a novel racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof which have excellent therapeutic effects on secondary symptoms caused by cerebrovascular defects and degenerative or degenerative mental disorders of the brain. In more detail, the method of preparing the present invention, more specifically, a racemic and optically highly purified (S) or (R) -glycidol and its derivatives using choline phosphate as a starting material, an inorganic substance that increases the activity of the reaction even in an aqueous solution. The ring-opening reaction was carried out under an aqueous solution at room temperature using a base or Lewis acid, and a racemic and optically active D or L-α-glycerophosphoryl represented by the following Chemical Formula 1 in a one-pot reaction. An improved manufacturing method suitable for economical and mass production of choline and its derivatives in high purity and high yield.

[Formula 1]

(In Formula 1, * denotes a chiral center and represents a racemic and optically active D- or L-α-glycerophosphoryl choline isomer, and R represents a hydrogen atom, a benzyl group, or a benzoyl group ( Benzoyl), Mesyl, Trityl, Tostl, Nosyl, and acyl groups with substituted or unsubstituted saturated or unsaturated carbons having 2-30 carbon atoms do)

The racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof represented by the chemical chamber 1 are secondary to secondary symptoms caused by cerebrovascular defects and senile, such as degenerative or degenerative cerebral psychiatric syndrome. It is known to have excellent effects in treating senile pseudo depression, such as cognitive disorders (low memory, confusion, disorientation, decreased motivation and spontaneity, decreased concentration), and emotional and behavioral changes (emotional anxiety, irritability, lack of interest). In addition, it is known as an excellent drug that normalizes the abnormality of the choline nerve transmission system due to the lack of acetylcholine and normalizes the function of damaged nerve cells by promoting the production of acetylcholine, a neurotransmitter of the brain.

Such excellent pharmacological and racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof can be obtained by organic synthesis methods or by plants (lecithin of soy), animals (eg yolk or It can also be obtained by deacylating acyl phospholipid from the bovine brain).

First, a conventional example of preparing racemic and optically active D or L-α-glycerophosphoryl choline by deacylation reaction is described in Korean Patent Publication No. 10-0262281, as shown in Scheme 1 below. It is well known to deacylate the phospholipid mixture obtained by synthesis by alcoholicsis and to prepare glycerophosphoryl choline using basic ion exchange resin.

Scheme 1

(In the scheme, R and R ₁ may be the same or different, and represent C ₁₃ -C ₂₅ alkyl, or C ₁₃ -C ₂₅ mono or poly unsubstituted alkenyl.)

As shown in Scheme 1, a method of preparing glycerophosphoryl choline is prepared by deacylating and purifying a polypolipid containing excess impurities in a starting material, thereby preparing glycerophosphoryl choline. The recovery of glycerophosphorylcholine is low and there is a disadvantage that it is not suitable for mass production because the basic ion exchange resin is used in the purification process.

U.S. Patent No. 5,250,719 discloses a process for preparing L-α-glycerophosphoryl choline by a similar method as in Scheme 1, which is also complicated by the purification process such as purification using ion exchange resin and L-α. Low recovery of glycerophosphoryl choline

Particularly in Europe 217 765 B1, after deacylating a lecithin extracted from deoleated soybean or egg yolk, L-α-glycerophosphoryl choline and L-α-glycerophosphoryl ethanolamine are complexed with zinc salt. Formed to remove other impurities. Pyridine was used to decompose the complex and separated using an ion exchange resin. Also, a mixture of L-α-glycerophosphoryl choline and L-α-glycerophosphoryl ethanolamine was converted to L-α- as an ion exchange resin. Glycerophosphoryl choline was prepared by the process of separating. This manufacturing method is manufactured in several steps in the process of preparing L-α-glycerophosphoryl choline, which not only makes the manufacturing process complicated but also inefficiently purifies the product by using two ion exchange resins in the purification process, and the yield is very low. Has its drawbacks.

In addition, a method for producing glycerophosphoryl choline by deacylation by extraction from plant material or animal organ is disclosed in Biochim. Biophys. Acta 488, 36 (1977), Biochim. Biophys. Acta 1003, 277 (1989), which is obtained by a transphosphatidylation reaction catalyzed by phospholipase D. This deacylation reaction has the disadvantage of producing complicated by-products such as D-1.2-glycerophosphate, depending on the reaction conditions (reaction time, temperature, base and solvent type), resulting in complicated purification and low yield. have.

As can be seen from the above known examples, the method of obtaining a L-α-glycerophosphoryl choline by deacylation through extraction from plants or animals has an advantage that it can be easily obtained in nature, but excessive impurities in the extraction process such as lecithin Since it is purified using ion exchange resin, etc., the purification process is complicated, difficult to obtain with high purity, and low recovery rate, which is uneconomical and unsuitable for industrial mass production.

A conventional method for preparing glycerophosphoryl collyl by organic synthesis is described in J. Org. Chem. Vol. 26. pp 608 (1961) discloses a method for preparing D, L-α-glycerophosphoryl choline, and the reaction proceeds in four steps, starting with D and L-acetone glycerol, as shown in Scheme 2 below. There is a disadvantage that the reaction process is complicated because the reaction process is complicated and the reaction is performed under anhydrous conditions. In particular, the starting materials D and L-acetone glycerol are very expensive, and expensive compounds such as palladium and silver carbonate are used to remove phenyl groups and chlorine ions that act as protecting groups of the reaction, making them difficult to apply industrially. There are disadvantages.

Scheme 2

See also J. Am. Chem. Soc. Vol. 70. A method for preparing L-α-glycerophosphoryl choline is also known from pp 1394 (1948).

EP 468 100 A1 discloses racemic or L-α-glycerol from the substitution reaction of starting material isopropylidene chryserol with 2-chloro-2-oxy-3,3,2-dioxophospholane as in Scheme 3 below. It is known to prepare rophosphoryl choline.

Scheme 3

(* Denotes chiral and refers to racemic or L-form optical isomers.)

Like Scheme 3, this method also uses expensive starting materials such as isopropylidene glycerol and 2-chloro-2-oxy-3,3,2-dioxophospholane, and the reaction proceeds under anhydrous conditions. The condition is tricky. Finally, after hydrolysis reaction, racemic or L-α-glycerophosphoryl choline is prepared using an ion exchange resin, but there is a problem in that the purification process is complicated by using an ion exchange resin.

In addition, the method known in the Republic of Korea Patent Application Publication No. 10-2007-10019176 shows that calcium 2- (trimethylammonio) ethylphosphate chloride tetrahydrate is removed under acidic conditions to prepare calcium phosphate chlorite, which is prepared in alcohol solvent ( Ring opening reaction with R) -glycidol gave L-α-glycerophosphoryl choline chloride.

Subsequently, chlorine ions are removed using an ion exchange resin to prepare L-α-glycerophosphoryl choline as shown in Scheme 4 below.

Scheme 4

The problem of the manufacturing process of Scheme 4 requires a separate manufacturing process for preparing cholinephosphate chloride from 2- (trimethylammonio) ethylphosphate chloride tetrahydrate, and the ring of cholinephosphate chloride and (R) -glycidol It is supposed to produce L-α-glycerophosphoryl choline chloride by refluxing at a high temperature in an ethanol solvent during the opening reaction, and the reaction yield is high because (R) -glycidol is unstable at high temperature and is easily decomposed. This low and high purity is difficult to purify. In addition, in the final step to purify the ion exchange resin to remove the chlorine ions, due to a variety of problems to produce a large amount of L-α-glycerophosphoryl choline using the production method of Scheme 4 There is a problem.

In order to solve the above problems, the first object of the present invention is to develop a manufacturing process that can industrially mass-produce racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof. As a result, as a starting material, cholinephosphate was used as an inorganic base or Lewis acid to increase the activity of the reaction even in aqueous solution with racemic and optically pure (S) or (R) -glycidol and its derivatives. By the ring-opening reaction under an aqueous solution condition of room temperature using a one-pot reaction, racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof represented by the following Chemical Formula 1 The present invention provides an improved novel manufacturing method suitable for economical and mass production with high purity and high yield.

In addition, another object of the present invention is to use inexpensive starting materials, and because it is water-soluble, it is difficult to dissolve choline phosphate that is insoluble in organic solvents and has high racemic and optical purity (S) or (R) -glycidol and its By using inorganic base or Lewis acid which increases the activity of the reaction even in the derivative and aqueous solution, the reaction is carried out under the aqueous solution condition at room temperature. Therefore, it is synthesized quantitatively without by-products, so that the racemic and optical activity is not required without special purification process. D or L-α-glycerophosphoryl choline and derivatives thereof are provided to provide a method for producing high purity and high yield.

In order to achieve the above objects, to prepare a racemic and optically active α-glycerophosphoryl choline and its derivatives according to the present invention,

Choline phosphate represented by the following formula (2) and racemic and optically high purity (S) or (R)-glycidol represented by the following formula (3) and derivatives thereof through a ring opening reaction under aqueous solution (One- pot) reaction is characterized in that represented by the formula (1).

[Formula 2]

[Formula 3]

[Formula 1]

(* In Formula 1 and 3 means chiral center and represents racemic and optical isomer, R is hydrogen atom, benzyl group, benzoyl group, mesyl group, trityl group, tosyl group, nosyl group and carbon atom number 2 ~ Means an acyl group having 30 substituted or unsubstituted saturated or unsaturated carbons)

As described above, the present invention has the advantage of using a low-cost starting material in comparison with the conventional methods, the reaction is carried out in a one-pot reaction, the production process is convenient, and also in the aqueous solution By using the inorganic base Lewis acid to increase the activity, because the reaction is carried out under aqueous solution conditions at room temperature, the racemic and optically active D or L-α-glycerophosphoryl choline of Formula 1 and quantitatively without side reactions and Derivatives thereof can be prepared. Therefore, the racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives of Formula 1 can be prepared in high purity and yield in a simple and convenient process without the need for a separate purification process. Economical and low price makes industrial mass production easy. Therefore, the present invention not only can be usefully used for the treatment of improving brain function, but also can be usefully used for synthesizing various phosphatidyl choline derivatives that can be used as important raw materials for medicines or functional dietary supplements.

Hereinafter, the present invention will be described in more detail. The present invention is to prepare a racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives using the choline phosphate as a starting material, to the choline phosphate represented by the formula (2) The racemic and optically pure (S) or (R) -glycidol and derivatives thereof are ring-opened under aqueous solution conditions at room temperature by using inorganic bases or Lewis acids which increase the activity of the reaction even in aqueous solution. Through the reaction, a one-pot reaction provides a process for conveniently preparing the racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives represented by the following Chemical Formula 1 do.

[Formula 2]

[Formula 3]

[Formula 1]

(* In Formula 1 and 3 means chiral center and represents racemic and optical isomer, R is hydrogen atom, benzyl group, benzoyl group, mesyl group, trityl group, tosyl group, nosyl group and carbon atom number 2 ~ Means an acyl group having 30 substituted or unsubstituted saturated or unsaturated carbons)

The process for preparing racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives in Formula 1 of the present invention can be summarized by the following Scheme 5.

Scheme 5

(* In Formula 5 means a chiral center and represents racemic and optical isomers, R is hydrogen atom, benzyl group, benzoyl group, mesyl group, trityl group, tosyl group, nosyl group and 2 to 30 carbon atoms) Means an acyl group having a substituted or unsubstituted saturated or unsaturated carbon having

The starting materials used in the present invention, cholinephosphate and racemic, and optically pure (S) or (R) -glycidol and its derivatives are commercialized and can be supplied from various companies at relatively low prices. Commercial products were used.

In the process of preparing the racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives thereof as in Scheme 5 through a ring-opening reaction, the racease represented by the formula (3) Mic and optically pure (S) or (R) -glycidol and derivatives thereof are suitably used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, based on cholinephosphate.

Inorganic bases used when the inorganic base is used in the ring opening reaction include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like. Sodium and calcium hydroxide are suitable and from 1 to 5 equivalents, preferably from 1 to 2 equivalents, based on the reactants. At this time, the pH of the reaction is important and the pH of the reaction is preferably reacted at 3 to 10, preferably 6 to 8. In addition, the reaction temperature is 0 to 100 ° C, preferably 20 to 25 ° C, and the reaction time is 2 to 48 hours, preferably 20 to 24 hours.

In addition, when Lewis acid is used in the ring opening reaction, the Lewis acid which can be used includes CuI, CuSO ₄ , CuOTf ₂ , SnSO ₄ , AgPf ₆ , AgBH ₄ , Ag ₂ SO ₄ , BF ₃ / Et ₂ O, CsF, ZnOTf ₂ and the like can be used and preferably CuI, CuSO ₄ are preferred, and it is appropriate to use 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the reactants. The pH of the reaction is important here and the pH of the reaction is preferably reacted at 3 to 10, preferably 6 to 8. In addition, the reaction temperature is 0 to 100 ° C, preferably 20 to 25 ° C, and the reaction time is suitable for 2 to 24 hours, preferably 8 to 10 hours.

In addition, as the reaction solvent used in the ring opening reaction, water, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, etc. may be used, and water may be used. It is preferable to make it, and the said organic polar solvent can be added small amount as needed, and reaction can be advanced under mixed solvent.

Finally, after completion of the reaction, the reaction mass is concentrated, an aqueous solution is added, the layers are separated and concentrated using low alcohol, and the racemic and optically active D or L-α-glycerophosphate of the formula (1) are obtained in high purity and high yield. Foryl choline and its derivatives can be prepared. At this time, the lower alcohol that can be used is an alcohol having 1 to 5 carbon atoms can be used, preferably methanol or ethanol can be used.

Choline phosphate, the starting material used in the above manufacturing method, is water soluble, so that it is not soluble in a general organic solvent, and thus, when the reaction is carried out using an organic solvent, reaction feeding may be low, which may cause a lot of difficulties in industrialization. By reacting under an aqueous solution at room temperature using an inorganic base or Lewis acid which increases the activity, the reaction is quantitatively advanced due to excellent reactivity, and the economical method of racemic and optically active D or L of Chemical Formula 1 -α-glycerophosphoryl choline and its derivatives can be prepared with high purity and high yield.

Thus, according to the present invention, there is an advantage of using a low-cost starting material compared to the conventional methods, the reaction is carried out by a one-pot reaction, the production process is convenient, and the reaction activity under aqueous solution conditions By using the inorganic base, Lewis acid, which increases the amount, the reaction is carried out even under an aqueous solution at room temperature, thereby quantitatively racemic and optically active D or L-α-glycerophosphoryl choline of Formula 1 without side reactions. And derivatives thereof. Therefore, the racemic and optically active D or L of Formula 1 in high purity and high yield in a simple and convenient process without the need for a separate purification process using an ion exchange resin or the like as conventionally known methods Since it is possible to prepare -α-glycerophosphoryl choline and its derivatives, it is economical and easy to mass produce industrially at a low price. Therefore, the present invention not only can be usefully used for the treatment of improving brain function, but also can be useful for synthesizing various phosphatidyl choline derivatives that can be used as important raw materials for medicines or functional dietary supplements.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

<Comparative Example: L-α-glycerophosphoryl choline chloride was prepared (Korean Patent Information 10-2007-0119176)

In a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux condenser and a stirrer, 63.27 g of phosphorylcholine chloride (1 equivalent, 288.1 mmol) 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 cooling for 3 hours by adjusting the pH to 8.0 using isopropylamine. 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., after which 130.2 mL of isopropyl alcohol was added, and the obtained crystals were filtered to give L-α-glycerophosphoryl choline. 50.8 g (60% yield) of chloride were obtained.

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)

Example 1: Preparation of racemic-α-glycerophosphoryl choline

100 g of cholinephosphate (1 equivalent, 450 mmol) was dissolved in 200 ml of distilled water in a 1000 ml three-necked round bottom flask equipped with a thermometer and a stirrer. Dissolve 38.25 g of sodium hydroxide (2.2 equiv, 970 mmol) in 200 mL of distilled water and then slowly add this solution to the reaction. After stirring for 2 hours at room temperature and maintaining the pH at 7-8, 64.4 g of racemic glycidol (2 equivalents, 900 mmol) was slowly added, followed by stirring at room temperature for 24 hours. After the reaction was completed, 100 ml of ethyl acetate was added to the reaction solution, the reaction was washed twice, and the aqueous layer was concentrated under reduced pressure. After completely dissolved in 100 ml of distilled water, 300 ml of ethanol was added thereto to obtain an ethanol layer, and the obtained ethanol was concentrated under reduced pressure to obtain 99 g of racemic-α-glycerophosphoryl choline (yield 85%). .

¹ H NMR (D ₂ O, 300 MHz): δ 3.23 (s, 9H), 3.65 (m, 4H), 3.91 (m, 4H), 4.29 (m, 2H)

<Example 2: Preparation of optically active L-α-glycerophosphoryl choline>

100 g of cholinephosphate (1 equivalent, 450 mmol) was dissolved in 200 ml of distilled water in a 1000 ml three-necked round bottom flask equipped with a thermometer and a stirrer. Dissolve 38.25 g of sodium hydroxide (2.2 equiv, 970 mmol) in 200 mL of distilled water and then slowly add this solution to the reaction. After stirring for 2 hours at room temperature and maintaining a pH of 7-8, 64.4g of (R)-glycidol (2 equivalents, 900 mmol) is slowly added and stirred at room temperature for 24 hours. After the reaction was completed, 100 ml of ethyl acetate was added to the reaction solution, the reaction was washed twice, and the aqueous layer was concentrated under reduced pressure. After 100 ml of distilled water was completely dissolved therein, 300 ml of ethanol was added to obtain an ethanol layer, and the obtained ethanol was concentrated under reduced pressure to obtain 101 g of optically active L-α-glycerophosphoryl choline (yield 87). %) Was obtained. The obtained analysis result is the same as the analysis result of Example 1.

Example 3: Preparation of racemic-α-glycerophosphoryl choline

100 g of cholinephosphate (1 equivalent, 450 mmol) was dissolved in 400 ml of distilled water in a 1000 ml three-necked round bottom flask equipped with a thermometer and a stirrer. 86.7 g of Cooper iodide (1 equivalent, 450 mmol) is added thereto. After stirring for 1 hour at room temperature, 64.4 g racemic-glycidol (2 equivalents, 900 mmol) was slowly added to the reaction. The reaction is carried out at room temperature for 10 hours. After the reaction was completed, the reaction solution was washed twice with 100 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. After 100 ml of distilled water was completely dissolved therein, 300 ml of ethanol was added thereto, followed by stirring. After passing through diatomaceous earth, the precipitate was filtered, and the ethanol layer was separated and concentrated under reduced pressure to obtain racemic-α-glycerophosphate. 104 g of yield (89% yield) were obtained. The obtained analysis result is the same as the analysis result of Example 1.

Example 4 Preparation of Optically Active L-α-Glycerophosphoryl Choline

100 g of cholinephosphate (1 equivalent, 450 mmol) was dissolved in 400 ml of distilled water in a 1000 ml three-necked round bottom flask equipped with a thermometer and a stirrer. 86.7 g of Cooper iodide (1 equivalent, 450 mmol) is added thereto. After stirring for 1 hour at room temperature, 64.4 g of optically pure (R) -glycidol (2 equivalents, 900 mmol) was slowly added to the reaction. The reaction is carried out at room temperature for 10 hours. After the reaction was completed, the reaction solution was washed twice with 100 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. After 100 ml of distilled water was completely dissolved, 300 ml of ethanol was added to the mixture, followed by stirring. After passing through diatomaceous earth, the precipitate was filtered, and the ethanol layer was separated and concentrated under reduced pressure. 105 g (90% yield) of L-α-glycerophosphoryl choline was obtained. The obtained analysis result is the same as the analysis result of Example 1.

Example 5: Preparation of racemic-1-butyryl-α-glycero-3-phosphoryl choline

10 g of choline phosphate (1 equivalent, 45 mmol) was dissolved in 20 ml of distilled water in a 200 ml three-necked round bottom flask equipped with a thermometer and a stirrer. 3.82 g of sodium hydroxide (2.2 equivalents, 97 mmol) is dissolved in 20 ml of distilled water, and the solution is slowly added to the reaction. After stirring for 2 hours at room temperature, the pH was maintained at 7-8, and then 13 g of racemic glycidyl butyrate (2 equivalents, 900 mmol) was added to N and N-dimethylformamide (3 ml) to form a mixed solution. Add slowly to the reaction. The reaction is carried out at room temperature for 24 hours. After the reaction was completed, the reaction solution was washed twice with 10 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. After dissolving completely with 10 ml of distilled water, 30 ml of ethanol was added to separate the ethanol layer, and then the ethanol was concentrated under reduced pressure to obtain 9.2 g of racemic-1-butyryl-α-glycero-3-phosphoryl choline. Yield 62%).

¹ H NMR (D ₂ O, 300 MHz): δ 0.92 (t, 3H), 1.62 (m, 2H), 2.41 (m, 2H), 3.21 (s, 9H), 3.62 (m, 4H), 3.89 (m, 1H), 4.04 (m, 1H), 4.22 (m, 3H)

Example 6 Preparation of Optically Active (R) -1-butyryl-α-glycero-3-phosphoryl Choline

10 g of choline phosphate (1 equivalent, 45 mmol) was dissolved in 20 ml of distilled water in a 200 ml three-necked round bottom flask equipped with a thermometer and a stirrer. In another 100 ml Erlenmeyer flask, 3.82 g of sodium hydroxide (2.2 equivalents, 97 mmol) was dissolved in 20 ml of distilled water, and the solution was slowly added to the reaction. After stirring for 2 hours at room temperature, the pH was maintained at 7-8, and then 13 g of (R) -glycidyl butyrate (2 equivalents, 900 mmol) was added to N and N-dimethylformamide 3 ml to form a mixed solution. Slowly add to the reaction. The reaction is carried out at room temperature for 24 hours. After the reaction was completed, the reaction solution was washed twice with 10 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. After dissolving completely with 10 ml of distilled water, 30 ml of ethanol was added to separate the ethanol layer, and the ethanol was concentrated under reduced pressure, thereby optically active (R) -1-butyryl-α-glycero-3- 9.6 g (65% yield) of phosphoryl choline were obtained. The obtained analysis result is the same as the analysis result of Example 5.

Claims (10)

1. Choline phosphate represented by the following formula (2) and racemic and optically high purity (S) or (R)-glycidol represented by the following formula (3) and derivatives thereof through a ring opening reaction under aqueous solution (One- A method for producing a racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof, which is represented by the following Chemical Formula 1 by a pot) reaction.

   [Formula 2]

   

   [Formula 3]

   

   [Formula 1]

   

   (* In Formula 1 and 3 means chiral center and represents racemic and optical isomer, R is hydrogen atom, benzyl group, benzoyl group, mesyl group, trityl group, tosyl group, nosyl group and carbon atom number 2 ~ Means an acyl group having 30 substituted or unsubstituted saturated or unsaturated carbons)
2. According to claim 1,

   To prepare a racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof, which are represented by Chemical Formula 1 at a reaction temperature of 10 to 60 ° C. in the ring opening reaction. Way.
3. The method of claim 1,

   Newly prepared racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof, which are represented by Chemical Formula 1 by performing a reaction pH of 4 to 9 in the ring opening reaction. How to.
4. According to claim 1,

   Racemic and optically active D, characterized in that the ring-opening reaction is represented by the formula (1) by carrying out the reaction under aqueous solution conditions using an inorganic base or Woory acid to increase the activity in the reaction even in aqueous solution A method for producing novel L-α-glycerophosphoryl choline and its derivatives.
5. The method of claim 4, wherein

   When the reaction is carried out using an inorganic base in the ring opening reaction, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate are selected and used. A process for the novel preparation of racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof.
6. The method of claim 4, wherein

   When the reaction is performed using Lewis acid in the ring opening reaction, CuI, CuSO ₄ , CuOTf ₂ , SnSO ₄ , AgPf ₆ , AgBH ₄ , Ag ₂ SO ₄ , BF ₃ / Et ₂ O, CsF, ZnOTf ₂ are selected. Method for producing a racemic and optically active D or L-α-glycerophosphoryl choline and its derivatives, characterized in that for use.
7. The method of claim 4, wherein

   In the ring-opening reaction, a racemic and optically active D or L-α-glycerophos, characterized in that the reaction is performed under a solvent alone or, if necessary, a small amount of a polar organic solvent is carried out under a mixed solvent. Process for preparing foryl choline and its derivatives.
8. The method of claim 7, wherein

   As a solvent that can be used with water, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile are selected and used. D or L-α-glycerophosphoryl choline and its derivatives.
9. The method of claim 1

   In the process of finally preparing the racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof represented by Chemical Formula 1, the solvent used as the extraction solvent is lower alcohol at 1 carbon atom. A method for producing racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof characterized by selecting and using five alcohols.
10. The method of claim 4, wherein

    Characterized in that the racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof represented by Formula 1 wherein the reaction temperature is 10 to 60 ℃ and the reaction pH is 4 to 9, A process for preparing racemic and optically active D or L-α-glycerophosphoryl choline and derivatives thereof.