KR100187900B1 - Method for preparing 3-aminopropane phosphoric acid - Google Patents

Abstract

The present invention relates to a method for preparing 3-aminopropane phosphoric acid represented by the following Chemical Formula 1, which is used as an anti-aging agent for treating skin or diseases related to cardiovascular diseases, and 3-amino in the presence of an organic solvent. It is characterized by reacting -1-propanol and phosphorus oxychloride at a temperature of 0-5 占 폚 for 1 hour, hydrolyzing it under an acid catalyst and crystallizing with alcohol.

[Formula 1]

The method for preparing 3-aminopropane phosphoric acid according to the present invention uses inexpensive phosphorus oxychloride and consists of a three-step reaction, which is economical and can be usefully used as an industrial method.

Description

Method for preparing 3-aminopropane phosphoric acid

The present invention relates to a method for preparing 3-aminopropane phosphoric acid.

3-aminopropane phosphate produced by phosphorylation of 3-amino-1-propanol proliferates human fibroblasts, promotes the synthesis of collagen fibers (collagen), and has high affinity with skin cells for side effects. It can be used as a raw material of the anti-aging cosmetic composition (The J. of Invest. Derm., Vol 66, No. 4, p895, Abs No. 535, 1996).

In addition, 3-aminopropane phosphate is similar in chemical structure to taurine (MARTINDAL, The Extra Pharmacopeia, 29TH.The Pharmaceutical Press, H2N-CH2-CH2-SO3H), which is well known as a drug for the treatment of diseases related to the blood flow of the heart. It has a structure similar to γ-aminobutyric acid (GABA, H2NCH2CH2CH2COOH) described in Japanese Patent Laid-Open No. 3-63211A and Japanese Patent Laid-Open No. 2-62810A and the like, which inhibits skin aging and has a whitening function.

As a method for preparing 3-aminopropane phosphoric acid, 3-amino-1-propanol and polyphosphoric acid are reacted under reduced pressure at 150 to 250 ° C. for 30 to 40 hours, and then calcium hydroxide (Reference: CIBA Ltd. Brit 861463, Fed. 22. 1961) or barium hydroxide (Ref. Helv. Chim. Acta 49 (8), 2608-15 (1966)) using primary calcium tablets, barium salts, etc. It is known to produce 3-aminopropane phosphoric acid by neutralizing the salts again with sulfuric acid. However, the above method is a long time (150 ~ 250 ℃, 30-40 hours) reaction at high temperature, energy consumption is high, yield is low, remove the calcium salt or barium salt produced in the process of removing excess phosphate by-products There are disadvantages that require complex purification steps.

In addition, 3-formamido-1-propanol and cyanoethylphosphoric acid were combined using dicyclohexylcarbodiimide (DCC), and neutralized with barium hydroxide. Hydrolysis with sodium hydroxide to form a barium salt, which was then passed through a cation exchange resin (amberlite IR 120 (H +)) to convert to formamidopropyl phosphoric acid, followed by hydrolysis with hydrochloric acid to produce 3-aminopropane phosphoric acid. How to Chem. Pharm, Bull. (1969, 17 (1), 202-206).

In addition, as shown in Scheme 1 below, phosphoric acid phenylesterdichloride was stirred at room temperature and purified by silica gel column to obtain a compound of formula (III), which was hydrolyzed with hydrochloric acid, followed by platinum oxide. And a method of producing 3-aminopropane phosphoric acid with a yield of about 38% using a hydrogen gas catalyst is J. Med. Chem. (1994, 37, 3986-3993).

However, Chem. Pharm. Bull. And J. Med. The production method described in Chem. Has a low yield and a complicated process. Especially J. Med. The manufacturing method described in Chem is inexpensive because it uses expensive platinum oxide as a catalyst, and has a problem that it is difficult to apply to mass production because a special apparatus for deprotection reaction of phenyl ester group is required under hydrogen gas and platinum oxide catalyst.

That is, the conventional methods for preparing 3-aminopropane phosphoric acid use expensive reagents, require complicated purification steps of several steps, and are low in yield and therefore unsuitable as industrial methods.

Therefore, the present inventors have repeatedly studied to provide a method for producing 3-aminopropane phosphoric acid in high yield by a simple process without using an expensive reagent, and using phosphorus oxychloride which can be purchased in large quantities at low cost. It was found that 3-aminopropane phosphoric acid can be prepared to complete the present invention.

It is therefore an object of the present invention to provide a method for producing 3-aminopropane phosphoric acid represented by the following general formula (I).

In order to achieve the above object, the production method of the present invention comprises the steps of reacting 3-amino-1-propanol and phosphorus oxychloride in an organic solvent for 1 hour at a temperature of 0 ~ 5 ℃; Hydrolyzing the reaction solution under an acid catalyst; And crystallizing (precipitating) with alcohol.

Hereinafter, the present invention will be described in more detail.

Referring to the production method of 3-aminopropane phosphoric acid according to the present invention in detail, as can be seen in the above scheme 2, the temperature of 0 to 5 ℃ of 3-amino-1-propanol and phosphorus oxychloride in the presence of an organic solvent Stirring for about 1 hour at 2,6 oxazacyclohexylphosphoryl chloride represented by the above formula (V) to produce (2,6-oxaza-cyclohexylphosphory1 chloride); The resulting filtrate was concentrated and water and an acid catalyst were added to raise the temperature to about 70-90 ° C. and refluxed for 1 to 3 hours, preferably 2 hours, and then cooled to room temperature, followed by an appropriate amount of triethylamine. Neutralizing the remaining acid; And slowly adding dropwise alcohol to crystallize 3-propaneamino phosphoric acid.

In the above-mentioned production method, after adding water and an acid catalyst, the temperature of the reaction solution is raised to 70-90 ° C. and refluxed, using a general property in which the binding portion of phosphorus and amine is weaker than that of phosphorus and alcohol. This is to hydrolyze the bond of phosphorus and amine of 2,6-oxaza-cyclohexylphosphoryl chloride produced in step 1, and consequently induce selective phosphorylation of alcohol functional group.

In the production method according to the present invention, 3-amino-1-propanol and phosphorus oxychloride are preferably reacted in an equivalent ratio of 1: 1 to 1.3. If the equivalent ratio is less than 1: 1, the desired product cannot be obtained, and if it is 1: 1.3 or more, an excess of by-products are produced in addition to the desired product.

When 3-aminopropane phosphoric acid is prepared by the above-described method, 95% or more of the intermediate in which 3-amino-1-propanol and phosphorus oxychloride is 1: 1 is produced, and 3-amino-1-propanol and phosphorus oxychloride By-products bound by 2: 1 are produced in 1 to 2% or less. However, the by-products can be separated by chromatography or easily removed by using a difference in solubility in alcohol solvents. Specifically, 2,6-oxaza-cyclohexylphosphoryl chloride, in which two chlorine atoms of the three chlorine atoms in the phosphorus oxychloride molecule are substituted by two functional groups of 3-amino-1-propanol, that is, a hydroxyl group and an amine group, Produced and the other chlorine atom remains unsubstituted because its reactivity decreases at a low temperature below 5 ° C. This is because the chlorine atom of 2,6-oxaza-cyclohexylphosphoryl chloride is stable in a low temperature anhydrous inert solvent and is not easily substituted with 3-amino-1-propanol. Therefore, in the preparation method of the present invention, 3-amino-1-propanol and phosphorus oxychloride are reacted at a temperature of 0 to 5 ° C. for about 1 hour at an equivalent ratio of 1: 1.0 to 1.3. It is possible to prevent the formation of by-products in which the phosphorus oxychloride reacts with 2: 1 or more, and in particular, it is unnecessary to introduce an ester group or an amide group to protect the chlorine atom of phosphorus oxychloride, thus reducing the reaction process. There are advantages to it.

As the organic solvent used in the present invention, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform and ethyl ether can be used. In addition, in order to obtain 3-aminopropane phosphoric acid in high yield, it is preferable to carry out the reaction under anhydrous conditions and in the presence of an inert gas such as nitrogen gas or argon gas.

When the reaction temperature is higher than 5 ° C, more than 2 equivalents of 3-amino-1-propanol is substituted by phosphorus oxychloride to increase the formation of by-products. At temperatures below 0 ° C, the solubility of the reactants decreases, making the reaction difficult to proceed. Temperatures in the range of 0-5 ° C. are preferred because the content of reactants is increased to lower the reaction yield.

In addition, the acid catalyst used for the manufacturing method of 3-aminopropane phosphoric acid of this invention is not specifically limited, For example, hydrochloric acid, sulfuric acid, or acetic acid can be used. The acid catalyst is added in an amount of 5.0 to 10.0 mol%, preferably 5.0 to 7.0 mol%, based on the amount of 2,6-oxa-cyclohexylphosphoryl chloride produced in the first step, and participates in less than 5 mol%. In case of addition, reduction of the overall yield is caused, and when added at 10 mol% or more, discoloration may occur during the reaction, and the final product may be colored.

Although the alcohol which is a precipitation solvent used in the present invention is not particularly limited, for example, methanol, ethanol and isopropanol can be used. In the present invention, the use of alcohol as a precipitation solvent, triethylammonium chloride produced by the neutralization of triethylamine is dissolved in alcohol, but 3-aminopropane phosphoric acid, which is a desired product, is insoluble in alcohol solvent and thus is precipitated as solid crystals. Because.

The following describes the method of the present invention in more detail.

EXAMPLE

In a 2 L flask equipped with a stirrer and a nitrogen gas injector, 112 g of phosphorus oxychloride and 650 ml of dichloromethane were added, followed by cooling the solution to 0-5 ° C. in an ice water bath while injecting nitrogen gas into the flask. In another vessel, 50 g of 3-amino-1-propanol and 186 ml of triethylamine were diluted with 180 ml of dichloromethane, and the reaction solution prepared above was added dropwise for 30 minutes. After the addition was completed, the mixture was further stirred for 30 minutes, and then triethylammonium chloride produced during the reaction was filtered off. The filtrate was concentrated under reduced pressure, and then the concentrate was transferred to a 1 L flask equipped with a reflux apparatus, and 300 ml of water and 3 ml of concentrated hydrochloric acid were added thereto, and the mixture was heated to reflux for 2 hours. The reaction solution was cooled to room temperature and 90 mL of triethylamine was added. After stirring at room temperature for 30 minutes, 800 ml of ethanol was added dropwise at room temperature, and the resulting crystals were filtered and recrystallized from a mixture of water and ethanol. It dried under reduced pressure at 50 degreeC so that water content may be less than 5%, and 93 g of 3-aminopropane phosphoric acid was obtained (yield: 90%).

Melting Point: 203 ~ 206 ℃ (Decomposition)

1 H-NMR (D 2 O): δ (ppm) = 1.9 (m, 2H), 3.1 (t, 2H), 3.9 (q, 2H)

13C-NMR (D2O): δ (ppm) = 40.5 (s), 30.6 (d, 6.6), 65.8 (d, 5.3)

3-aminopropane phosphate has the functions described above, which promotes oxygen consumption of cells to help skin respiration, promotes blood circulation and effectively reduces wrinkles on the skin, and slows skin aging. In the case of manufacturing by the method, it is economical because it uses phosphorus oxychloride, which can be purchased at low cost, and can be usefully used as an industrial method because it proceeds in a three-step reaction.

Claims (6)

In a method of preparing 3-aminopropane phosphoric acid by reacting 3-amino-1-propanol with a phosphorylation reagent, (A) reacting 3-amino-1-propanol with phosphorus oxychloride which is a phosphorylation reagent at a low temperature of 0 to 5 ° C. for about 1 hour in the presence of an organic solvent; (B) hydrolyzing the reaction solution under an acid catalyst; and (C) crystallizing with alcohol; Method for producing 3-aminopropane phosphoric acid, characterized in that it comprises a. The process for producing 3-aminopropane phosphoric acid according to claim 1, wherein the equivalent ratio of 3-amino-1-propanol and phosphorus oxychloride used in step (A) is 1: 1 to 1.3. The method of claim 1, wherein the organic solvent used in step (A) is dichloromethane, ethyl ether, tetrahydrofuran, ethyl acetate, acetonitrile and chloroform. The method for preparing 3-aminopropane phosphoric acid according to claim 1, wherein the acid catalyst used in step (B) is hydrochloric acid, sulfuric acid and acetic acid. The 3-aminopropane phosphoric acid according to claim 4, wherein the acid catalyst is added in an amount of 5.0 to 10.0 mol% based on the amount of 2,6-oxa-cyclohexylphosphoryl chloride produced in step (A). Manufacturing method. The method of claim 1, wherein the alcohol used in step (C) is methanol, ethanol and isopropanol.