KR20180026653A - Method for Preparation of Choline alfoscerate - Google Patents

Abstract

The present invention relates to a method for preparing a choline alfoscerate useful for the treatment of brain dysfunction caused by cerebrovascular diseases economically through a process suitable for mass production, and more particularly, to the method for preparing the choline alfoscerate, which comprises the following steps: (A) reacting phosphorylcholine chloride calcium salt with potassium oxalate to prepare an alkali metal-substituted salt; and (B) preparing the choline alfoscerate by a reaction of the alkali metal-substituted salt with (R)-(+)-3-chloro-1,2-propanediol.

Description

TECHNICAL FIELD The present invention relates to a method for preparing choline alfoscerate,

The present invention relates to a method for economically producing choline alfoscerate useful for the treatment of brain dysfunction caused by cerebrovascular diseases by a process suitable for mass production.

Choline alfoscerate (alpha-GPC, also known as L-Alpha glycerylphosphorylcholine) is a choline compound present in the brain and is represented by the following formula (1).

[Chemical Formula 1]

Choline alfoscerate is a precursor of acetylcholine, a stimulant of parasympathetic nerves, which plays a role in rapidly transporting choline to the brain through the blood-brain barrier, thus normalizing cranial nerve cells and the cholinergic system. In addition, since it acts directly on the brain, it has excellent effects and safety, and is widely used as a non-prescription drug in many countries, including the United States, as an agent for treating Alzheimer's disease and dementia and improving brain function.

As a method of producing choline alfoscerate, phosphatidylcholine (phosphatidylcholine), which is contained in lecithin isolated from soybean, yolk or animal organs, is diacetylated by chemical or biochemical method and then cholinesterase A method for purifying and obtaining a rate is known. This method has an advantage that it can be easily obtained from a natural substance inexpensive, but since it is necessary to purify the compound from a complicated mixture, the purification process is complicated and the recovery rate is low and it is suitable for mass production such as generating a large amount of waste liquid in the purification process There are various problems that are not solved.

To overcome these disadvantages, various methods for producing choline alfoscerate by an organic synthesis method have been attempted. First, J. Maurukas et al. (J. Org. Chem. 26, 608, 1961) disclosed a method of preparing choline alfoscerate by acetone glycerol as a starting material in a total of four steps. However, since the starting material acetone glycerol is expensive, the reaction process is complicated, the reaction conditions are severe, and the expensive catalyst is used, the production cost of choline alfoscerate is increased, so that the method is not competitive.

European Patent Publication No. 0486100 and Italian Patent No. 1,243,724 also disclose a process for preparing choline alfoscerate from acetone glycerol. These methods have an advantage in that choline alfoscerate can be produced by a relatively simple process but still use expensive acetone glycerol as a starting material and purify by an ion exchange resin in order to remove impurities generated during the reaction The problem of generating a large amount of waste liquid has not been solved yet.

Japanese Patent Application No. 10-0966627 discloses a method for producing choline alfoscerate by the following reaction scheme in which phosphoryl choline chloride prepared from calcium phosphate salt of phosphoryl choline chloride is reacted with glycidol.

This method has solved the problem of the prior art due to the advantage of the low cost of the calcium phosphate salt of phosphoryl choline chloride as a starting material, but the glycidol, which is one of the reactive substances, is high in price and low in stability and easy to store And since the decomposition is easy during the reaction, there are many by-products, resulting in a low yield and a difficulty in purification. In addition, the purification method using an ion exchange resin is still adopted, and thus the problem caused by the purification has not been solved at all.

As a method for solving such a problem, Patent Document 10-0951108 discloses a following method using choline phosphate as a starting material instead of phosphorylcholine chloride.

However, since choline phosphate is relatively expensive compared to phosphoryl choline chloride, it is not easily commercially available, and because of its low reactivity with glycidol despite the disclosure, it is practically applicable to the production of choline alfoscerate it's difficult.

Accordingly, attention has focused on a process for eliminating the problems of the prior art while using phosphorylcholine chloride calcium salt as a starting material.

Patent No. 10-1330814 discloses a process for producing calcium phosphate by treating an alkali metal base with a calcium phosphate salt of phosphoryl chloride to replace calcium ions with an alkali metal and then reacting the salt with glycidol and lewis acid in- Acid was treated to produce choline alfoscerate. It is significant that the above-mentioned patent discloses a method for producing choline alfoscerate by a simpler process by omitting the step of separating phosphoryl chloride as a reaction intermediate. However, when K ₂ HPO ₄ is used as an alkali metal base and other reagents are used without using ZnCl ₂ or ZnBr ₂ as a Lewis acid, the yield of choline alfoscerate is greatly lowered. K ₂ HPO ₄ is relatively expensive to be. Zinc is an essential trace element in the human body, but excessive zinc causes inorganic imbalance in the body and zinc ion damages the gastrointestinal lining. It is known that men who ingest about 80mg daily cause urinary complications. Therefore, if the zinc content in the final product increases, the safety of the final drug product may become a problem. The production method in when the reacted water as a solvent complete filtering the insoluble salt was removed, and however is described as re-purification of the choline alpo three rate using an ion exchange resin and then removing the insoluble salt from methanol, ZnCl ₂ is water (430.0g / 100ml) as well as the solubility (432.0g / 100g at 25 ° C) in alcohol is also very high, so it is not easy to remove by filtration process. In addition, problems caused by the use of glycidol and ion exchange resin have not been solved at all.

The inventors of the patent 10-1330814 propose, as a further improved method, a method of preparing glycidol from 3-chloro-1,2-propane and then using it as an in-situ, .

In this patent, when tripotassium phosphate (K ₃ PO ₄ ) is used as a base, phosphorylcholine chloride potassium salt is prepared and then (R) -3-chloro-1,2-propanediol and ZnCl ₂ are added It was suggested that choline alfoscerate can be obtained in high purity by refluxing stirring, and sequentially treating the mixture with a weakly acidic cation-exchange resin and a mixed ion-exchange resin. This method partially solves the problem further by using a starting material which is cheaper and stable than glycidol in comparison with the patent 10-1330814. However, for the reaction, an additional amount corresponding to the number of moles of the phosphorylcholine chloride calcium salt and the molar amount of 3-chloro-1,2-propane for producing the glycidol is added to produce the alkali metal substitute salt, A base of 3 molar equivalents of calcium chloride calcium salt is needed. In addition, the calcium triphosphate (Ca ₃ (PO ₄ ) ₂ ) and calcium hydrogenphosphate (CaHPO ₄ ) among calcium phosphate produced when K ₃ PO ₄ is used as a base have relatively low solubility in water (calcium tertiary phosphate (2 mg / 100 g, calcium hydrogen phosphate: 4.3 mg / 100 g at 20 ° C) and calcium hydrogen phosphate (Ca (H ₂ PO ₄ ) ₂ ) dissolve in water at a concentration of 2.8 g / It is not easy and affects the purity of the final choline alfoscerate. Since calcium ions in the reaction solution inhibit the reaction with glycidol in the next step, calcium ions should be removed as much as possible. However, in the case of using an excessive amount of potassium triphosphate for the effective removal of calcium ions, calcium phosphorus calcium chloride As well as the phosphate group derived from the salt, the phosphate group derived from potassium triphosphate also reacts with glycidol, thereby increasing byproducts. In addition, problems with the use of Lewis acid, ZnCl ₂ , remain.

European Patent No. 0486100 Italy Patent No. 1,243,724 Patent No. 10-0966627 Patent No. 10-0951108 Patent No. 10-1330814 Patent No. 10-1233138

J. Org. Chem. 26, 608, 1961

Disclosure of the Invention In order to solve the problems of the prior art as described above, it is an object of the present invention to provide a process for producing choline alfoscerate, which can be easily applied to mass production using a raw material that is easily available and low in cost, And a method thereof.

It is another object of the present invention to provide a method for producing choline alfoscerate of high purity by facilitating the removal of salts produced as reaction by-products.

According to an aspect of the present invention, there is provided a method for preparing a metal salt, comprising the steps of: (A) reacting calcium phosphate salt with potassium oxalate to produce an alkali metal salt; And (B) reacting the alkali metal substituted salt with (R) - (+) - 3-chloro-1,2-propanediol to prepare choline alfoscerate. And a method for producing serrate.

Such choline alfoscerate of the present invention can be represented by the following reaction formula (1).

[Reaction Scheme 1]

Hereinafter, each step will be described in detail.

(A) Production of alkali metal substituted salt

The first step is to replace the calcium in the phosphorylcholine chloride calcium salt with an alkali metal to improve the reactivity of the phosphorylcholine chloride.

To this end, potassium oxalate was added to a solution of phosphorylcholine chloride calcium salt and stirred. The solubility of potassium oxalate was 36.4 g / 100 g (20 ° C.) in water, whereas the solubility of calcium oxalate was 0.67 mg / Calcium precipitation reaction is irreversible. Subsequently, the phosphorylcholine chloride calcium salt is substituted with potassium, which is an alkali metal, to form a potassium salt of phosphorylcholine chloride.

In patent No. 10-1233138, potassium phosphate is used for the formation of the alkali metal substitute salt in this step. Calcium oxalate has higher solubility in water than the mixture of calcium triphosphate, calcium hydrogen phosphate and dihydrogen phosphate produced at this time The reaction for generating an alkali metal substituted salt proceeds more effectively. In addition, when potassium phosphate is used, the alkali metal substitution reaction can not be completed when potassium phosphate equivalent is used because the solubility of calcium hydrogen phosphate produced as an intermediate is low. However, the present invention is not limited to the case where potassium oxalate is used in an equivalent amount . In addition, due to its low solubility, the removal of calcium as a salt form in aqueous solution is also easy. According to the preliminary experiment, when the concentration of calcium in the reaction solution is high, the reaction in the step (B) proceeds slowly, and thus the reaction of (R) - (+) - 3-chloro-1,2-propanediol or glycidol The yield of the by-product is increased due to the self-reaction of the reaction product (data not shown).

The potassium oxalate used in this step is preferably used in an amount of 1 to 1.2 equivalents based on the phosphoryl choline chloride calcium salt, more preferably 1 to 1.1 equivalents. If the equivalent amount of potassium oxalate is too low, the production yield of the alkali metal substitution salt is lowered. If the equivalent is too high, the excess amount of potassium oxalate is accompanied with an incidental problem of removing an excessive amount of potassium oxalate as well as raising the unit price.

The above process can be carried out at 5 to 50 ° C for 0.5 to 4 hours, and most preferably at room temperature for process efficiency. The lower the reaction temperature, the longer the reaction time, and even if the reaction temperature exceeds 50 ° C, there is no problem. However, since there is no need to raise the temperature, it is preferable not to exceed 50 ° C considering the process efficiency.

The reaction of this step proceeds quantitatively with no side reaction, and the resulting calcium oxalate can be easily removed by filtration. Therefore, the reaction solution is filtered and the filtrate is concentrated to obtain an in-situ solution without further purification. The reaction of the next step can be carried out.

(B) Step of producing choline alfoscerate

This step is a step of producing choline alfoscerate by reacting the alkali metal substituted salt produced in the step (A) with (R) -3-chloro-1,2-propanediol.

In the prior art, glycidol is prepared from (R) -3-chloro-1,2-propanediol and purified or used in the next reaction in situ. In the present invention, however, -1,2-propanediol itself as a reaction material. Because of this difference, the prior art requires additional bases for glycidol formation, but according to the present invention, since (R) -3-chloro-1,2-propanediol itself is used as a reactant, I do not need it. In addition, Lewis acid catalysts for the ring opening reaction of glycidol are also not required.

The reaction of this step can be carried out using C1-C3 lower alcohol as a solvent.

The (R) -3-chloro-1,2-propanediol is preferably used in an amount of 1 to 2 equivalents, more preferably 1 to 1.5 equivalents, of the calcium phosphate salt of phosphoryl choline chloride used in step (A) . If the equivalent of (R) -3-chloro-1,2-propanediol is too low, the reaction is not completed and the yield is low. If the equivalent is too large, excess (R) -3-chloro-1,2- There arises a problem that must be removed.

The reaction in this step is preferably carried out at 5 to 50 ° C for 2 to 10 hours, more preferably 10 to 30 ° C. If the reaction temperature is too low, the reaction rate becomes slow, so the time required for the reaction becomes long. If the reaction temperature is too high, by-products may be produced. Most preferably, the reaction is carried out at room temperature in consideration of process efficiency.

The reaction of this step may be carried out by adding (R) -3-chloro-1,2-propanediol without a catalyst as in Example 1, or by using a catalytic amount of base as in Example 2 . As the base, NaOH or KOH may be used, and it is preferable to use 0.5 equivalent or less based on phosphoryl choline chloride calcium salt. Since the reaction proceeds even when the base is not present, the minimum use amount is not meaningful. As the amount of the used amount increases, the purification process of choline alfoscerate becomes complicated after completion of the reaction. In the reaction of the present invention, unlike the prior art, Lewis acid containing heavy metals is not used, so there is no fear of containing heavy metals in the final product, choline alfoscerate.

When the reaction is complete, the insoluble salts are removed by filtration. The insoluble salt is KCl produced as a reaction product, and the remaining KCl in the reaction solution can be further removed by concentrating the reaction solution and precipitating by treating with alcohol.

Although the above step can obtain choline alfoscerate of good quality, it may further include a step of treating the ion exchange resin to obtain higher purity choline alfoscerate. As the ion exchange resin, a weakly acidic ion exchange resin or a mixed ion exchange resin can be used. Those skilled in the art will be able to easily use an appropriate one in consideration of the cost and characteristics of the ion exchange resin.

As described above, according to the choline alpocellate production method of the present invention, since the reaction is completed within a short period of time under a simple and mild condition, the entire reaction process is simple and the raw material is easily supplied and consumed at low cost, It is possible to produce choline alfoscerate more economically.

In addition, the calcium oxalate produced as a reaction by-product in the present invention has a very low solubility in water, so that an alkali metal substitute salt is effectively generated and also easily removed. In addition, since the base for glycidol formation is not needed, the amount of salt produced is greatly reduced, which can greatly shorten the processing time when applied to mass production.

In addition, the production method of the present invention is advantageous in that it is easy to remove a salt generated without using Lewis acid which contains a heavy metal in the reaction and is difficult to remove, and since no unstable glycidol is used, no by-product is produced, It is not necessary to use an excess amount of the reactant, so that a high purity choline alfoscerate can be provided.

1 is a P-NMR spectrum shows the residual of the reaction of calcium phosphate when substituted with K ₃ PO _4.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these embodiments are merely examples for explaining the content and scope of the technical idea of the present invention, and thus the technical scope of the present invention is not limited or changed. It will be apparent to those skilled in the art that various changes and modifications can be made within the scope of the technical idea of the present invention based on these examples.

[Example]

Preliminary Experiment: Calcium Salt Removal Efficiency Evaluation

3.30 g (10 mmol) of phosphoryl choline chloride calcium salt tetrahydrate was dissolved in 10 ml of purified water. The sample shown in Table 1 below was added to this solution, reacted at 45 DEG C for 3 hours, cooled to room temperature, and the precipitate was removed by filtration. The filtrate was concentrated to prepare a 5% (w / w) aqueous solution, and the concentration of calcium ion was measured by ICP.

As can be seen from the above table, when the potassium salt of potassium oxalate is used in an amount equivalent to that of KOH or K ₂ CO ₃ used in replacing the calcium salt with potassium salt in the prior art, the content of the residual calcium salt is greatly reduced to 1/10 level . When the minimum equivalent weight for the substitution of calcium salt and the production of glycidol is used (6.7 mmol) with K ₃ PO ₄ as a base as shown in the Japanese Patent No. 10-1330814, the content of residual calcium is as high as 384.0, It is not effective. When K ₃ PO ₄ was excessively used, the removal efficiency of calcium was excellent, but as a result of P-NMR analysis, it was confirmed that a large amount of phosphorus remained as shown in FIG.

The residual Phosphate competitively reacts with 3-chloro-1,2-propanediol in combination with the phospate group of the phosphoryl choline chloride potassium salt, so that in the case of using excess K ₃ PO ₄ for effective removal of the calcium salt, And the purification is also difficult.

Example 1

33.1 g (0.1 mol) of phosphorylcholine chloride calcium salt · tetrahydrate was added to a 500 ml reaction vessel and dissolved in 100 ml of purified water. To this solution was added a solution of 16.6 g (0.1 mol, 1 equivalent) of oxalic dipotassium in purified water (75 ml) and stirred at room temperature for 2 hours. The precipitate was removed by filtration and the filtrate was concentrated.

To the concentrated residue, 130 ml of ethanol was added, and 11.1 g (0.1 mol, 1 equivalent) of (R) - (+) - 3-chloro-1,2-propanediol was added thereto at room temperature and stirred for 6 hours.

The reaction was analyzed by HPLC under the following conditions.

- Equipment used: Shimadzu 20A

- Column: Kromasil 60-5 HILIC-D 4.6 mm x 25 cm

- mobile phase: 15 mM Ammonium acetate 60% Acetonitrile

           (pH 3.2 to 3.5 by conc. HCl)

- Speed: 0.5ml / min

Detector: RI-dector (shimadzu RID-20A)

- Oven temp. : 35 degrees

After the reaction was completed, the insoluble salt was firstly filtered and the filtrate was concentrated under reduced pressure. To the concentrated residue, 8 ml of MeOH was further added to precipitate an insoluble salt, which was then subjected to secondary filtration and then the filtrate was concentrated under reduced pressure. The concentrated residue was treated with ion exchange resin SM210 (Samyang Corp.) and concentrated under reduced pressure to obtain 21.8 g (85%) of high purity choline alfoscerate. The NMR data of the obtained choline alfoscerate are as follows.

_{^{1 H NMR (D 2 O,}} 500MHz): δ 3.0 (s, 9H), 3.4-3.48 (m, 1H), 3.49-3.51 (m, 3H), 3.67-3.78 (m, 3H), 4.14 (m, 2H).

Example 2

33.1 g (0.1 mol) of phosphorylcholine chloride calcium salt · tetrahydrate was dissolved in 100 ml of purified water in a 500 ml reaction vessel. To this solution was added a solution of 16.6 g (0.1 mol, 1 equivalent) of potassium oxalate in 75 ml of purified water. After stirring at room temperature for 2 hours, the precipitate was removed by filtration, and the filtrate was concentrated. The concentrated residue was dissolved in 130 ml of ethanol and then 12.16 g (0.11 mol, 1.1 equivalent) of (R) - (+) - 3-chloro-1,2-propanediol and 0.56 g And the mixture was stirred for 6 hours.

After the reaction was completed, the insoluble salt was firstly filtered and the filtrate was concentrated under reduced pressure. To the concentrated residue, 8 ml of MeOH was further added to precipitate an insoluble salt, which was then subjected to secondary filtration and then the filtrate was concentrated under reduced pressure. The concentrated residue was treated with ion exchange resin SM210 (Samyang Corp.) and concentrated under reduced pressure to obtain 22.1 g (86%) of choline alfoscerate.

Claims (7)

(A) reacting phosphorylcholine chloride calcium salt with potassium oxalate to produce an alkali metal substituted salt; And
(B) generating choline alfoscerate by the reaction of said alkali metal substituted salt with (R) -3-chloro-1,2-propanediol;
≪ / RTI >
The method according to claim 1,
Characterized in that in step (A), potassium oxalate is used in an amount of 1 to 1.2 equivalents based on the calcium phosphate salt of phosphoryl chloride.
The method according to claim 1,
Wherein the (R) - (+) - 3-chloro-1,2-propanediol is used in an amount of 1 to 1.5 equivalents based on the phosphoryl choline chloride calcium salt.
The method according to claim 1,
Wherein the reaction of step (B) is carried out at 5 to 50 ° C for 2 to 10 hours.
5. The method of claim 4,
Wherein the reaction of step (B) is carried out using a base as a catalyst.
6. The method of claim 5,
Wherein the base is 0.01-0.5 equivalents of KOH or NaOH.
7. The method according to any one of claims 1 to 6,
Treating the ion exchange resin after step (B);
≪ / RTI > wherein the choline alfoscerate is selected from the group consisting of: < RTI ID = 0.0 >

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