KR20110066004A - Preparation of choline alfoscerate - Google Patents

Abstract

PURPOSE: A method for preparing choline alfoscerate is provided to finish in situ reaction without reaction intermediates and to cheaply prepare the choline alforscerate of high purity. CONSTITUTION: A method for preparing choline alfoscerate of chemical formula 1 comprises: a step of reacting phosphoryl choline chloride calcium anhydride of chemical formula 2 with alkali metal base under the presence of a solution to prepare an alkali metal salt of chemical formula 3; and a step of reacting with R-(+)-glycidol of chemical formula 4 without isolation of the alkali metal salt. The alkali metal base is lithium phosphate, dilithium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium phosphate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate.

Description

Preparation method of choline alfoscerate {Preparation of Choline alfoscerate}

The present invention relates to a method for preparing choline alfoscerate, which is useful for treating brain dysfunction caused by cerebrovascular diseases such as aging or dementia by normalizing brain neurons and choline neurotransmitter. In-situ of the reaction intermediates can be easily obtained at low cost by using phosphorylcholine chloride calcium anhydride and R-(+)-glycidol as starting materials and reactants, respectively. By completing the reaction in the phase, the present invention relates to a new method for preparing choline alfoscerate that can produce high purity choline alfoscerate at low cost.

Choline alfoscerate represented by Chemical Formula 1 is a known compound having the chemical name L-α-Glyceryl phosphoryl choline, and forms a brain neuron and choline neurotransmitter system. As it has a function to normalize, it is usefully used as an agent for improving brain function or treating dementia.

[Formula 1]

(In the above formula, (S) is stereoselectively.

As for the method of preparing choline alfoscerate, various organic synthesis methods have been developed, including a method of hydrolyzing soybean extract from lecithin.

First, European Patent No. 217,765 discloses a method of hydrolyzing crude lecithin to form a metal complex, treating metal with pyridine to remove metal ions, and then purifying choline alfoscerate using a cationic resin. It is. However, this method is inefficient because the overall process is long due to the addition and formation of zinc metal complexes, and the final purification process is not improved.

Scheme 1

Wherein GPC means L-α-glycerophosphoryl choline, ie choline alfoscerate, GPE means L-α-glycerophosphoryl choline ethanolamine, Zn is zinc, X is chlorine or Bromine, n and m are the equivalent number of GPC and GPE, and n + m is 1.)

In addition, US Pat. No. 5,250,719 discloses a method of extracting crude soy lecithin with methanol, hydrolyzing with sodium methoxide, and then purifying with ion exchange resin several times to obtain choline alfoscerate. However, this manufacturing method has a disadvantage in that the purification process is very complicated and the productivity is low, such as using various resins in the purification process.

British Patent No. 2,058,792 discloses a method of extracting lecithin from crude soy lecithin, purifying lecithin using an alumina column, hydrolyzing with sodium methoxide, and then purifying choline alfoscerate using alumina. . This method has the advantage of a relatively simplified purification process, but has a disadvantage that the process of purifying lecithin using a commercially expensive alumina column.

Also, Korean Patent No. 10-0262281 discloses a method of hydrolyzing a phospholipid mixture obtained by natural or synthetically and preparing choline alfoscerate using a basic ion exchange resin as in Scheme 2 below. However, this method also has a disadvantage in that the separation and purification process using the ion exchange resin is difficult and the yield is low.

Scheme 2

(R 'and R "in the above schemes represent the same or different C13-C25 alkyl, or C13-C25 alkenyl.)

In Korean Patent Publication No. 10-2009-0084194, a method of separating and purifying by using an ion exchange resin after hydrolysis from soybean extract lecithin is introduced as in Scheme 3 below. This method has the advantage of preparing the choline alfoscerate in a relatively inexpensive method to partially compensate for the disadvantages of the methods exemplified above, but also a long process for removing a large amount of by-products generated after extraction and hydrolysis, many The problem of having to dispose of the waste liquid remains.

Scheme 3

As described above, since soybean lecithin, which is a by-product of soybean, is relatively inexpensive, various methods for producing choline alfoscerate have been developed. However, the extraction process is long, the content of impurities is high, the yield is low, and the ion resin There are disadvantages such as having to go through several times of separate purification. Therefore, the development of an organic synthesis method that can compensate for these shortcomings are made, a few of the typical methods are as follows.

First, Italian Patent No. 1,243,724 introduces a preparation method such as the following Scheme 4. This method is a relatively simple method of preparing the target product after phosphorylation using phosphorus oxychloride (POCl ₃ ), which is a relatively inexpensive reagent, but to remove impurities generated during the reaction. There is a disadvantage that the aberration separation purification process using the ion exchange resin.

Scheme 4

In addition, Italian Patent No. 1,247,496 discloses an organic synthesis method such as Scheme 5 below. This preparation method has the advantage of shortening the reaction step by preparing choline alfoscerate using choline phosphonate sodium salt and 3-bromo solketal as starting materials, Synthesis is not easy and the price is high and it is not economical.

Scheme 5

In Korean Patent Laid-Open No. 10-2007-0119176, as shown in Scheme 6, cholinephosphoryl chloride calcium salt was treated under acidic conditions to prepare cholinephosphate chloride from which calcium ions were removed, and this was (R) -glycohol in an alcohol solvent. L-α-glycerophosphoryl choline chloride was prepared by carrying out a ring opening reaction with sidol, and then choline alfoscerate was prepared by removing chlorine ions using an ion exchange resin.

Scheme 6

However, the preparation method of Scheme 6 requires a separate preparation process for preparing cholinephosphate chloride from cholinephosphoryl chloride calcium salt. In addition, L-α-glycerophosphoryl choline chloride is prepared by performing a reflux reaction at high temperature in an ethanol solvent during the ring opening reaction of cholinephosphate chloride and (R) -glycidol, wherein the (R) -glycol Since cobblestone is unstable at a high temperature, it is easy to decompose and has a large number of byproducts, so that the reaction yield is low, and it is difficult to purify it with high purity. Moreover, since the purification is performed by using an ion exchange resin to remove chlorine ions in the final step, there are many problems in mass production of choline alfoscerate in this way.

Lastly, Korean Patent Publication No. 10-2009-0109172 discloses an inorganic base such as sodium hydroxide or Lewis acid such as copper iodide in one pot reaction using choline phosphate as a starting material, as shown in Scheme 7 below. It is known to produce high purity choline alfoscerate in high yield by reacting with (R) -glycidol in the presence of a) and then by simple ethanol extraction.

However, the choline phosphate is a relatively expensive compound, and there is a problem that it is not commercially easy to purchase, and also it is difficult to obtain water-soluble choline alfoscerate with high purity and high yield only by ethanol extraction process.

Scheme 7

The technical problem to be solved by the present invention is to prepare choline alfoscerate in order to improve the problems of the prior art as described above, firstly, commercially available starting materials and reactants can be used at low cost, and secondly, reaction It is possible to complete the reaction on in situ without separating the reaction intermediate in the process, and third, to provide a new method for preparing choline alfoscerate suitable for mass production of high purity choline alfoscerate which can be used as a raw material drug. .

In order to achieve the above technical problem, the present invention provides a method for preparing choline alfoscerate of formula (1), by reacting a phosphoryl choline chloride calcium anhydride salt of formula (2) with an alkali metal base in an aqueous solution Producing an alkali metal substitution salt of; Reacting with the R-(+)-glycidol of Formula 4 without separating the alkali metal substitution salt; Characterized in that comprises a.

[Formula 1]

(In the above formula, (S) is stereoselectively.

[Formula 2]

(3)

(Wherein, M ⁺ represents an alkali metal such as lithium, sodium or potassium cation.

[Formula 4])

(Wherein, (R) is stereoselective means priority.)

In addition, the present invention is choline alfoscerate prepared by the above method XAD 1600, Amberite IRA-410, Amberite IRA-93, Lewatit SM-94, IONAC NM-73, Dowex MB-46, MB-400, NRW-37 Purifying with any one ion exchange resin selected from CNP 80 and IONAC NM60; Characterized in that it further comprises.

According to the present invention, the phosphorylcholine chloride calcium anhydride salt used as a starting material and the R-(+)-glycidol used as a reactant can be purchased at low cost in the market, and thus, the overall manufacturing cost is very low. .

In addition, since the alkali metal base is used to replace calcium of phosphorylcholine chloride calcium anhydride salt with an alkali metal to increase the reactivity of the starting material, the reaction yield is greatly improved.

In addition, calcium ions liberated in the phosphorylcholine chloride calcium anhydride salts form insoluble calcium salts that are easily separated and removed in aqueous solution, and at the same time R-(+ Because the reaction can proceed with) -glycidol, the overall process is very simple and economical, especially for mass production.

Finally, the crude choline alfoscerate prepared according to the present invention can be obtained by simply separating and purifying with ion exchange resin to obtain high purity choline alfoscerate that can be used as a drug substance.

If the method for preparing choline alfoscerate according to the present invention is represented by one reaction scheme, it is as in Scheme 8 below.

Scheme 8

(In the above scheme, M ⁺ represents an alkali metal such as lithium, sodium or potassium cation, and Cl ⁻ represents a chlorine anion.)

As shown in Scheme 8, in the present invention, first, the phosphorylcholine chloride calcium anhydride salt of Chemical Formula 2 is reacted with an alkali metal base in an aqueous solution to generate an alkali metal substituted salt of Chemical Formula 3. Substitution of calcium with an alkali metal in the phosphorylcholine chloride calcium anhydride salt has an effect of greatly improving its reactivity. At this time, it is important that the free calcium ions are precipitated in the form of insoluble calcium carbonate or calcium phosphate in the aqueous solution to irreversible reaction.

Examples of the alkali metal base include lithium phosphate, dilithium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, Potassium bicarbonate and the like can be used, preferably disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium bicarbonate is preferred.

The alkali metal base may be used in an amount of 1 to 4 equivalents based on the phosphorylcholine chloride calcium anhydride salt of Chemical Formula 2, but preferably an inorganic salt such as calcium carbonate or calcium phosphate, which is insoluble in an aqueous solution, may be completely precipitated. It is recommended to use within 2 equivalents.

In addition, the temperature of the aqueous solution used as the reaction solvent can be reacted in the range of 0 ℃ ~ 100 ℃, preferably proceed in the range of 20 ℃ to 40 ℃, the reaction time is 30 minutes to 5 hours, preferably One hour to three hours is suitable.

Next, choline alfoscerate is synthesized quantitatively by reacting R-(+)-glycidol of Formula 4 on in situ without separating the alkali metal substituent salt of Formula 3. In this case, the amount of the R-(+)-glycidol may be used in an amount of 1 to 5 equivalents based on the phosphorylcholine chloride calcium anhydride salt of Formula 2, but preferably used in an amount of 1 to 2 equivalents.

In the step of reacting the alkali metal substituted salt with R-(+)-glycidol, a catalytic amount of Lewis acid may be added to promote the ring-opening reaction of the epoxide. As the Lewis acid, any one or two or more selected from ZnCl ₂ , ZnBr ₂ , ZnI ₂ , Zn (OTf) ₂ , SnCl ₂ , SnCl ₄ , TiCl ₄ , AlCl ₃ , PCl _5, and p-TsOH may be used. It is preferable to use ZnCl ₂ , TiCl ₄ , PCl ₅ or p-TsOH.

Although the reaction temperature of the said alkali metal substituted salt and R-(+)-glycidol can be made to react in 100 degreeC range at room temperature, Preferably it is 60 to 100 degreeC. The reaction time is completed within 1 to 24 hours, but preferably 2 to 12 hours.

In the present invention, phosphorylcholine chloride calcium anhydride salt used as a starting material and R-(+)-glycidol used as a reactant can be purchased at low cost on the market.

On the other hand, choline alfoscerate prepared by the above method is obtained as a crude product. Therefore, in order to obtain a high-purity target substance that can be used as a drug substance, the preparation should be separated and purified using an ion exchange resin. The ion exchange resin used at this time is XAD 1600 (manufactured by Rohm & Haas, hereinafter, indicates the manufacturer), Amberite IRA-410 (Rohm & Haas), Amberite IRA-93 (Rohm & Haas) , Lewatit SM-94 (Sybron Chemicals Inc.), IONAC NM-73 (Sybron Chemicals Inc.), Dowex MB-46 (Dow Chemical), MB-400 (Purolite), NRW-37 (Purolite), CNP 80 (Bayer) ) Or IONAC NM60 and the like can be used, but is not limited thereto. More preferably, XAD 1600 (Rohm & Haas), Amberite IRA-410 (Rohm & Haas) or CNP 80 (Bayer) may be used.

Hereinafter, examples of the present invention will be described. The following examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited by the following examples.

≪ Example 1 >

50 g (194.05 mmol, 1 equiv) of phosphorylcholine chloride calcium anhydride salt was dissolved in 200 ml of purified water in a 500 ml reaction vessel. A solution of 33.80 g (194.05 mmol, 1 equivalent) of K ₂ HPO ₄ dissolved in 75 ml of purified water was added to the solution, followed by reaction at room temperature for 2 hours to be replaced with an alkali metal, and then the reaction solution was concentrated. Subsequently, 28.75 g (388.09 mmol, 2 equivalents) of (R)-(+)-Glycidol was added to the reaction solution and stirred for 6 hours to quantitatively synthesize choline alfoscerate.

After the reaction is completed, the insoluble salts are first filtered and the filtrate is concentrated under reduced pressure. MeOH was added to the concentrated residue again to precipitate an insoluble salt, which was filtered secondly and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in MeOH, loaded on ion exchange resin Amberite IRA-410, separated and purified by water and MeOH, and concentrated under reduced pressure to obtain 46 g (92%) of high purity choline alfoscerate having the following NMR data. do.

¹ H NMR (D ₂ O, 300 MHz): δ 3.25 (s, 9H), 3.58 (m, 2H), 3.65 (m, t), 3.75 (1H, m), 3.88 (m, 2H), 4.27 (m , 2H).

[HPLC Analysis Conditions and Equipment]

-Equipment: Waters 1525

Column: Optimapak Sil-51002546 4.6mm * 25cm

Mobile phase: water (1.0 ml / min)

Detector: RI-dectector (Waters 410)

Oven temp. 40 degrees

<Examples 2-4>

The target material was prepared in the same manner as in <Example 1> except for using the alkali metal base described in Table 1 below, and the yield of the target material obtained in each Example is shown in Table 1 below.

TABLE 1

Example Alkali metal base yield 2 K ₂ CO ₃ 75% 3 K ₃ PO ₄ 85% 4 Na ₂ HPO ₄ 70%

<Example 5>

50 g (194.05 mmol, 1 equivalent) of phosphorylcholine chloride calcium anhydride salt was dissolved in 200 ml of purified water in a 500 ml reaction vessel. A solution of 33.80 g (194.05 mmol, 1 equivalent) of K ₂ HPO ₄ dissolved in 75 ml of purified water was added to the solution, followed by reaction at room temperature for 2 hours to replace the alkali metal.

Subsequently, 28.75 g (R)-(+)-Glycidol (388.09 mmol, 2 equiv) and 10.58 g (77.62 mmol, 0.4 equiv) of ZnCl ₂ were sequentially added to the reaction solution at room temperature in situ, followed by 3 hours at 80 ° C. The reaction results in quantitative synthesis of choline alfoscerate.

After the reaction was completed, the insoluble salts were first filtered and the filtrate was concentrated under reduced pressure. 150 ml of MeOH was added to the concentrated residue to precipitate an insoluble salt, which was then filtered secondly and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in MeOH, loaded on ion exchange resin Amberite IRA-410, separated and purified by water and MeOH, and concentrated under reduced pressure to obtain 45 g (90%) of high purity choline alfoscerate.

<Examples 6 to 8>

    Except for using the Lewis acid (Lewis acid) described in Table 2 was carried out in the same manner as in the <Example 5> to prepare the target material, the yield of the target material obtained in each Example is shown in Table 2 It was.

TABLE 2

Example Lewis acid yield 6 ZnBr ₂ 85% 7 TiCl ₄ 83% 8 p-TsOH 75%

As can be seen from the results of Examples 1 to 8, according to the present invention, high purity choline alfoscerate can be prepared in a high yield of 70 to 92%.

Claims (5)

In the method for preparing choline alfoscerate of the formula (1), Reacting the phosphorylcholine chloride calcium anhydride salt of Formula 2 with an alkali metal base in an aqueous solution to produce an alkali metal substituted salt of Formula 3; Reacting the R-(+)-glycidol of Formula 4 without separating the alkali metal substitution salt; Method for producing choline alfoscerate comprising a. [Formula 1]

(In the above formula, (S) is stereoselectively. [Formula 2]

(3)

(In the above formula, M ⁺ represents an alkali metal such as lithium, sodium or potassium cation.) [Formula 4]

(Wherein, (R) is stereoselective means priority.) The method of claim 1, wherein the alkali metal base is lithium phosphate, dilithiumhydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassiumhydrogen phosphate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium Method for producing choline alfoscerate, characterized in that any one or two or more selected from bicarbonate, potassium carbonate, potassium bicarbonate. The method for preparing choline alfoscerate according to claim 1 or 2, wherein the alkali metal base is used in an amount of 1 to 4 equivalents based on the phosphorylcholine chloride calcium anhydride salt of the formula (2). The method of claim 1 or 2, wherein reacting the alkali metal substitution salt with R-(+)-glycidol comprises ZnCl ₂ , ZnBr ₂ , ZnI ₂ , Zn (OTf) ₂ , SnCl ₂ , and SnCl _4. , TiCl ₄ , AlCl ₃ , PCl ₅ And p-TsOH, wherein any one or two or more Lewis acids are added in a catalytic amount to react the choline alfoscerate. According to claim 1 or 2, wherein the choline alfoscerate is XAD 1600, Amberite IRA-410, Amberite IRA-93, Lewatit SM-94, IONAC NM-73, Dowex MB-46, MB-400, NRW- Purifying with any one ion exchange resin selected from 37, CNP 80 and IONAC NM60; Choline alfoscerate production method characterized in that it further comprises.