KR20160101372A - A composition for skin regeneration for application to the skin - Google Patents

A composition for skin regeneration for application to the skin Download PDF

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KR20160101372A
KR20160101372A KR1020150023806A KR20150023806A KR20160101372A KR 20160101372 A KR20160101372 A KR 20160101372A KR 1020150023806 A KR1020150023806 A KR 1020150023806A KR 20150023806 A KR20150023806 A KR 20150023806A KR 20160101372 A KR20160101372 A KR 20160101372A
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aminolevulinic acid
weight
formula
compound represented
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KR1020150023806A
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서정훈
신동규
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제너럴바이오(주)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/44—Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms

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Abstract

The present invention relates to a method of preparing a 5-aminolevulinic acid hexyl ester hydrochloride comprising: a preparation step of preparing a 5-aminolevulinic acid hydrochloride; and a reaction step of mixing the 5-aminolevulinic acid hydrochloride, hexyl alcohol, and a thionyl chloride with one another such that they are made to react with one another. According to the present invention, since a two-step synthesis process is optimized, purity is improved and a yield can be considerably increased.

Description

Technical Field [0001] The present invention relates to a process for producing 5-aminolevulinic acid hexyl ester hydrochloride,

The present invention relates to a process for the preparation of 5-aminolevulinic acid hexyl ester hydrochloride, and more particularly to a process for the preparation of 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid hexyl ester hydrochloride therefrom, Aminolevulinic acid hexyl ester hydrochloride having a high purity and a remarkably high yield, while remarkably improving the method of producing the 5-aminolevulinic acid hexyl ester hydrochloride by a synthetic method.

Photodynamic therapy with 5-aminolevulinic acid (ALA) has been used for skin diseases such as actinic keratoses, psoriasis, verrucae and skin cancer .

5-aminolevulinic acid is a substance used in photodynamic therapy. When it is applied to the skin, ALA migrates into the cell and turns into a photosensitizer that is used for photodynamic therapy called protoporphyrin IX (PpIX) through biosynthesis .

PpIX is a photosensitizer that is excited by light energy into a triplet state and reacts with oxygen around it to produce generator oxygen. Generator oxygen generated can cause damage to cell membranes and cell death, and can treat skin diseases such as these, and is absorbed relatively selectively in such disease sites, so that it does not harm the surrounding normal tissues.

However, ALA can not penetrate all tumors and other tissues with sufficient efficiency to treat a wide range of tumors or other conditions, and is problematic due to formulation or properties. In addition, since ALA has high hydrophilicity and weak hydrophobicity and can not easily pass through barriers such as the stratum corneum and cell walls of skin, it takes a lot of time to accumulate ALA in the cells, or there is a problem that it is necessary to perform repeated treatment several times.

Accordingly, in order to solve such a problem, ALA derivatives are required, and development of a method for effectively synthesizing these derivatives is required.

Korean Patent Publication No. 10-2011-0015195

The object of the present invention is to provide a process for producing 5-aminolevulinic acid hexyl ester hydrochloride having high purity and a high yield by optimizing a two-stage synthesis process unlike the prior art .

In addition, conventionally, a separate fractional distillation process was needed because of the high risk of explosion and a large amount of side reactions during the synthesis reaction using the bromination reaction. However, by applying the optimized synthesis route and reaction conditions, there is almost no risk of explosion, It is an object of the present invention to provide a process for producing 5-aminolevulinic acid hexyl ester hydrochloride which can realize the efficiency and simplification of the process.

According to another aspect of the present invention, there is provided a process for preparing 5-aminolevulinic acid hexyl ester hydrochloride, comprising: preparing 5-aminolevulinic acid hydrochloride; And a reaction step in which 5-aminolevulinic acid hydrochloride, hexyl alcohol and thionyl chloride are mixed and reacted.

Removing the impurities by adding at least one of diethyl ether, acetone, acetonitrile, benzene, and toluene to the 5-aminolevulinic acid hexyl ester hydrochloride prepared in the reaction step after the reaction step; In the reaction step, the hexyl alcohol may be contained in an amount of 550 to 700 parts by weight based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride.

In addition, in the reaction step, the thionyl chloride may be contained in an amount of 150 to 200 parts by weight based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride, and the reaction step may include reacting the reactant prepared by the reaction The extraction solvent is an ether-based solvent which is at least one of diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diglyme; A hydrocarbon-based solvent of at least one of benzene, toluene, hexane or xylene; A halogenated hydrocarbon solvent which is at least one of dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; An alcohol-based solvent which is at least one of methanol, ethanol, isopropyl alcohol or tert-butyl alcohol; An ester solvent which is at least one of ethyl acetate, methyl acetate or butyl acetate; Or acetone, phenylacetone, benzoyl acetone, hexafluoroacetone, cyclohexyl acetone, 2,4-pentanedione, 4-methyl-3-pentene-2-one, 1,3-dichloroacetone, A polar solvent which is at least one of amide, N, N-dimethylacetamide, dimethylsulfoxide or acetonitrile; Or the like.

The extraction solvent may be contained in an amount of 100 to 400 parts by weight based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride. In the reaction step, the reaction product is concentrated at 10 to 30 ° C for 1 to 4 hours , The mixture is added to the extraction solvent at 60 to 90 ° C for 1 to 4 hours, and then added to the extraction solvent at 10 to 30 ° C for 20 to 30 hours.

In addition, the preparation step may include a first synthesis step of reacting a compound represented by the following formula (1) and a compound represented by the following formula (2) in an organic solvent to prepare a compound represented by the following formula (3); And a second synthesis step in which the 5-aminolevulinic acid hydrochloride is prepared by treating the compound represented by Formula 3 with an acid.

[Chemical Formula 1]

Figure pat00001

(2)

Figure pat00002

(3)

Figure pat00003

In the first synthesis step, the organic solvent may include a picoline-based solvent, and the picoline-based solvent may include 4-methylpyridine, 2-acetyl-4-methylpyridine ( 2-amino-4-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-bromo- 5-bromo-2-methoxy-4-methylpyridine, 2-chloro-4-methylpyridine or 3-cyano-4-methylpyridine. ≪ / RTI >

In the first synthesis step, the organic solvent may be included in an amount of 420 to 600 parts by weight based on 100 parts by weight of the compound represented by Formula 1. In the first synthesis step, the compound represented by Formula 1 And the compound represented by Formula 2 may range from 1: 1 to 1: 2.

In the first synthesis step, the compound represented by the formula (1) is dissolved in the extraction solvent at 40 to 60 ° C for 100 to 200 minutes and then mixed with the compound represented by the formula (2) at a temperature of 10 to 40 ° C for 5 to 12 hours The above reaction can be carried out.

And a purifying step of purifying the compound represented by Formula 3 by sequentially introducing the compound represented by Formula 3 into an aqueous solution of sodium hydroxide and chloroform between the first synthesizing step and the second synthesizing step, The concentration of sodium hydroxide in the aqueous sodium solution may be 1.5 to 2.5 wt%.

In the purification step, 50 to 90 parts by weight of the sodium hydroxide aqueous solution and 60 to 80 parts by weight of the chloroform may be contained in 100 parts by weight of the compound represented by the formula 3, Hydrolysis and decarboxylation can be performed by adding the compound represented by the above formula (3) to an aqueous hydrochloric acid solution.

In the aqueous hydrochloric acid solution, the concentration of hydrochloric acid may be 5 to 26% by weight. In the second synthesis step, the weight ratio of the compound represented by Formula 3 to the hydrochloric acid aqueous solution may be 4: 9 to 4:15.

In addition, the second synthesis step may be performed at 100 to 150 ° C for 3 to 5 hours, and the 5-aminolevulinic acid hydrochloride produced in the second synthesis step may be washed with acetone.

According to the process for producing 5-aminolevulinic acid hexyl ester hydrochloride of the present invention, unlike the prior art, by optimizing the two-step synthesis process, the purity is high and the yield is remarkably excellent.

In addition, conventionally, a separate fractional distillation process was needed because of the high risk of explosion and a large amount of side reactions during the synthesis reaction using the bromination reaction. However, by applying the optimized synthesis route and reaction conditions, there is almost no risk of explosion, There is an advantage that the efficiency and simplification of the process can be realized.

1 is a graph showing 13 C-NMR data of 5-aminolevulinic acid hexyl ester hydrochloride prepared by the present invention
2 is a graph showing 1 H-NMR data of 5-aminolevulinic acid hexyl ester hydrochloride prepared by the present invention
3 is a graph showing FT-IR analysis data of 5-aminolevulinic acid hexyl ester hydrochloride prepared by the present invention

Hereinafter, a preferred embodiment of the present invention will be described in detail with reference to the accompanying drawings, which show a method for producing 5-aminolevulinic acid hexyl ester hydrochloride according to the present invention. The present invention may be better understood by the following examples, which are for the purpose of illustrating the invention and are not intended to limit the scope of protection defined by the appended claims.

The process for preparing 5-aminolevulinic acid hexyl ester hydrochloride of the present invention comprises a preparation step (S10), a reaction step (S20); And an impurity removing step (S30).

First, the preparation step S10 is a step of synthesizing 5-aminolevulinic acid hydrochloride in one step for the reaction step S20. Unlike the prior art, it has developed an efficient synthesis process that can safely minimize side reaction materials by excluding the bromination process and the like.

The preparation step (S10) comprises: a first synthesis step (S11) of reacting a compound represented by the following formula (1) and a compound represented by the following formula (2) in an organic solvent to prepare a compound represented by the following formula (3); And a second synthesis step (S13) of producing the 5-aminolevulinic acid hydrochloride by treating the compound represented by the formula (3) with an acid.

[Chemical Formula 1]

Figure pat00004

(2)

Figure pat00005

(3)

Figure pat00006

In the first synthesis step S11, the organic solvent may include a picoline-based solvent. Preferably, the picoline-based solvent is 4-methylpyridine, 2- 4-methylpyridine, 2-amino-4-methylpyridine, 2-amino-5-bromo-4-methylpyridine (2- amino-5-bromo-4-methylpyridine, 5-bromo-2-methoxy-4-methylpyridine, 2- chloro-4-methylpyridine or 3-cyano-4-methylpyridine. More preferably, the picoline-based solvent may include at least one of 4-methylpyridine (4-methylpyridine). This is an optimized solvent for improving the yield in the synthesis reaction.

The organic solvent may be contained in an amount of 420 to 600 parts by weight, preferably 420 to 450 parts by weight, more preferably 424 to 436 parts by weight, based on 100 parts by weight of the compound represented by the formula (1) . When the amount is less than 420 parts by weight, there is a problem that the compound represented by the formula (1) is present in a powdery state without being dissolved. When the amount exceeds 600 parts by weight, the solvent is excessive and the reaction efficiency is lowered.

In the first synthesis step S11, the ratio of the compound represented by Formula 1 to the compound represented by Formula 2 may be 1: 1 to 1: 2, preferably 1: 1.2 to 1: 1: 1.4, and more preferably from 1: 1.3 to 1: 1.33. When the ratio is less than 1: 1, there is a problem that the yield increases and the side reaction material increases. When the ratio is more than 1: 2, the yield decreases sharply.

In the first synthesis step (S11), the compound represented by the general formula (1) is dissolved in the extraction solvent at 40 to 60 DEG C for 100 to 200 minutes and then mixed with the compound represented by the general formula (2) The compound represented by the general formula (1) is dissolved in the extraction solvent at 45 to 55 ° C for 130 to 170 minutes, and then the compound represented by the general formula (2) It is effective that the reaction is carried out at 23 to 27 캜 for 7 to 9 hours. This is the optimal reaction condition derived from several experiments.

Next, a purification step (S12) is performed between the first synthesis step (S11) and the second synthesis step (S13) in which the compound represented by the formula (3) is sequentially introduced into an aqueous solution of sodium hydroxide and chloroform to purify the compound . This is a step of purifying and extracting the compound represented by Formula 3 to improve the reaction yield in the second synthesis step S13.

In the purification step (S12), the concentration of sodium hydroxide in the aqueous sodium hydroxide solution may be 1.5 to 2.5 wt%, preferably 1.6 to 2.0 wt%, more preferably 1.7 to 1.9 wt% , It may be 1.8% by weight. If it is less than 1.5% by weight, there is a problem that a large amount of unreacted compound represented by the formula (1) precipitates. When the amount exceeds 2.5% by weight, the solubility in sodium hydroxide is significantly lowered and the yield drops sharply.

In the purification step (S12), 50 to 90 parts by weight of the sodium hydroxide aqueous solution and 60 to 80 parts by weight of the chloroform may be added to 100 parts by weight of the compound represented by the formula (3). Preferably, the sodium hydroxide aqueous solution may be contained in an amount of 60 to 80 parts by weight and the chloroform may be contained in an amount of 65 to 75 parts by weight, more preferably, 68 to 72 parts by weight of the sodium hydroxide aqueous solution, 68 to 72 parts by weight of the chloroform May be included in parts by weight. If the content of the aqueous sodium hydroxide solution is outside this range, the solubility and the yield are significantly lowered. When the chloroform content is out of this range, the separation time for purification and extraction is considerably increased and the boundaries are unclear. There is a problem of remarkably deteriorating.

Next, in the second synthesis step (S13), the compound represented by Formula 3 may be added to an aqueous hydrochloric acid solution to perform hydrolysis and decarboxylation. This is a reaction process which is easily carried out by stirring and which, unlike the prior art, is stable and can maximize purity and yield.

In the hydrochloric acid aqueous solution, the concentration of hydrochloric acid may be 5 to 26% by weight, and preferably 10 to 20% by weight. Within this range, the reaction yield can be maximized.

Further, in the second synthesis step (S13), the weight ratio of the compound represented by Formula 3 to the hydrochloric acid aqueous solution may be 4: 9 to 4:15, preferably 4:10 to 4:13, , It is effective that it is 4:12. When the ratio is less than 4: 9, there is a problem that mixing becomes difficult or agitation becomes difficult because it becomes dough, and when it exceeds 4:15, the yield is not improved any more and the side reaction material increases.

In the second synthesis step (S13), the reaction may be carried out by stirring at 100 to 150 DEG C for 3 to 5 hours. Preferably, the reaction may be carried out by stirring at 110 to 130 ° C for 3.5 to 4.5 hours, and more preferably, the reaction may be carried out by stirring at 120 ° C for 4 hours. This is an optimized process condition through several experiments in order to maximize the production yield of the 5-aminolevulinic acid hydrochloride.

In addition, it is preferable that the 5-aminolevulinic acid hydrochloride produced in the second synthesis step (S13) is washed with acetone. Various solutions such as isopropyl alcohol (IPA) can be used for washing, but as a result of several experiments, acetone is most effective in maximizing the reaction yield.

Next, the reaction step (S20) is a step of synthesizing the final target 5-aminolevulinic acid hexyl ester hydrochloride based on the 5-aminolevulinic acid hydrochloride prepared by the preparation step (S10).

In the reaction step (S20), the hexyl alcohol may be contained in an amount of 550 to 700 parts by weight, preferably 580 to 650 parts by weight, more preferably 580 to 650 parts by weight based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride May be 590 to 610 parts by weight. When the amount is less than 550 parts by weight, the yield is markedly lowered. When the amount is more than 700 parts by weight, the yield is somewhat lowered and the economical efficiency is lowered.

The thionyl chloride may be contained in an amount of 150-200 parts by weight, and preferably 165-180 parts by weight, based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride. When the amount is less than 150 parts by weight, the yield is markedly decreased. When the amount is more than 200 parts by weight, the increase in yield is insignificant and the economical efficiency is low.

In the reaction step (S20), the reaction product produced by the reaction is treated with an extraction solvent. The reactant is 5-aminolevulinic acid hexyl ester hydrochloride prepared by the reaction, which can be recrystallized by treating with the extraction solvent to produce 5-amino-levulic acid hexyl ester hydrochloride having high purity have.

Wherein the extraction solvent is an ether-based solvent which is at least one of diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diglyme; A hydrocarbon-based solvent of at least one of benzene, toluene, hexane or xylene; A halogenated hydrocarbon solvent which is at least one of dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; An alcohol-based solvent which is at least one of methanol, ethanol, isopropyl alcohol or tert-butyl alcohol; An ester solvent which is at least one of ethyl acetate, methyl acetate or butyl acetate; Or acetone, phenylacetone, benzoyl acetone, hexafluoroacetone, cyclohexyl acetone, 2,4-pentanedione, 4-methyl-3-pentene-2-one, 1,3-dichloroacetone, A polar solvent which is at least one of amide, N, N-dimethylacetamide, dimethylsulfoxide or acetonitrile; , And may preferably include at least one of acetone or acetonitrile, and more preferably, it may include acetone. This is a solvent capable of maximizing the reaction efficiency without adversely affecting the present reaction mechanism.

The extraction solvent may be contained in an amount of 100 to 400 parts by weight, preferably 150 to 300 parts by weight, more preferably 180 to 220 parts by weight, based on 100 parts by weight of the 5-aminolevulinic acid hydrochloride. . Within this range, recrystallization of the reactants can be maximized.

The reaction step (S20) may be carried out by condensing the reaction product at 10 to 30 ° C for 1 to 4 hours, adding the reaction product to the extraction solvent at 60 to 90 ° C for 1 to 4 hours, It is preferable to be charged at 30 DEG C for 20 to 30 hours. It is possible to improve the purity and yield of 5-aminolevulinic acid hexyl ester hydrochloride by performing three extraction steps through a solvent extraction method without a reduced pressure concentration step.

Finally, after the reaction step (S20), an impurity removing step (S30) for removing impurities by adding diethyl ether to the 5-aminolevulinic acid hexyl ester hydrochloride prepared in the reaction step (S20) . This is a step for purifying the 5-aminolevulinic acid hexyl ester hydrochloride synthesized in the reaction step (S20) to increase the purity.

The impurity removing step S30 may be performed by adding diethyl ether (or a polar solvent such as acetone, acetonitrile, benzene, toluene or the like) to 5-aminolevulinic acid hexyl ester hydrochloride and excess hexyl alcohol, After removing the oonyl chloride and diethyl ether, the 5-aminolevulinic acid hexyl ester hydrochloride can be finally prepared through vacuum drying.

The 5-aminolevulinic acid hexyl ester hydrochloride is represented by the following general formula (4).

[Chemical Formula 4]

Figure pat00007

As described above, the 5-aminolevulinic acid hexyl ester hydrochloride can be prepared by reacting 5-aminolevulinic acid hydrochloride with hexyl alcohol and thionyl chloride After the addition, stirring is carried out to carry out the esterification reaction. After the esterification reaction is confirmed, diethyl ether is added to recrystallize the reaction product to remove excess hexyl alcohol, thionyl chloride and diethyl ether, Followed by vacuum drying.

Of course, the present invention is not limited to this. Instead of the diethyl ether, a polar solvent such as acetone, acetonitrile, benzene, toluene or the like may be used or one or more of them may be contained.

The following are experimental results to demonstrate the superiority of the process for producing 5-aminolevulinic acid hexyl ester hydrochloride of the present invention.

1. Experimental Example 1 (Solubility Test of Compound Represented by Formula 1)


 (G) 4-methyl
Pyridine
(g) (G) Condition result (1)
Melting temperature (1)
Dissolution time Example 1 20 100 0 50 ℃ 150 min Full transparency recording Example 2 23.5 100 0 50 ℃ 150 min Full transparency recording Comparative Example 1 25 100 0 50 ℃ 150 min Powder dispersion state without completely dissolved Comparative Example 2 30 100 0 50 ℃ 150 min Powder dispersed state, not soluble

As shown in Table 1, in Examples 1 and 2 which contained 425 parts by weight and 500 parts by weight of the organic solvent with respect to 100 parts by weight of the compound represented by Formula 1, 2, and it was confirmed that the present invention can be applied to the present invention.

2. Experimental Example 2 (Experiment on the content ratio between the above formula (1) and the above formula (2)


 (G) 4-methyl
Pyridine
(g) (G) Condition yield The dissolution temperature of formula (1) The dissolution time of formula (1) Reaction internal temperature Reaction time Comparative Example 1 12.67 53.91 20 50 ℃ 150 min 25 ~ 27 ℃ 8hr 7.42 g Comparative Example 2 14.08 53.91 20 50 ℃ 150 min 25 ~ 27 ℃ 8hr 8.38 g Example 1 15.20 64.68 20 50 ℃ 150 min 25 ~ 27 ℃ 8hr 9.80g Example 2 16.33 64.68 20 50 ℃ 150 min 25 ~ 27 ℃ 8hr 9.81 g

As shown in Table 2, the yields of Examples 1 and 2, in which the content ratio between the compound represented by Formula 1 and the compound represented by Formula 2, fall within the scope of the present invention, are not less than 9.8 g, , The yields of Comparative Examples 1 and 2 were significantly reduced by about 15 to 25%.

3. Experimental Example 3 (Experiment on the yield according to the concentration of sodium hydroxide aqueous solution of the compound represented by Formula 3)

Of NaOH
density (3)
(g) NaOH solution
(g) Chloroform (g) Refining method yield conclusion Comparative Example 1 1.0% NaOH 170 120 30 NaOH solution → chloroform
→ NaOH solution → brine 17.4 g Unreacted Deposition Severity of Formula 1 Example 1 1.8% NaOH 170 120 30 NaOH solution → chloroform
→ NaOH solution → brine 19.2 g High yield Comparative Example 2 3.0% NaOH 170 120 30 NaOH solution → chloroform
→ NaOH solution → brine 18.4g Reduction in yield due to NaOH solubility Comparative Example 3 5.0% NaOH 170 120 30 NaOH solution → chloroform
→ NaOH solution → brine 15.2 g Reduction in yield due to NaOH solubility

As shown in the above Table 3, in the extraction process of Formula 3, the yield of Example 1 in which the concentration of sodium hydroxide is 1.8 wt%, which is within the scope of the present invention, is as good as 19.2 g, In Examples 1, 2 and 3, it was confirmed that precipitation of unreacted materials was large or the yields were 18.4 g and 15.2 g, respectively, which were significantly lower than those in Example 1.

4. Experimental Example 4 (Test on the yield according to the content of chloroform in the compound represented by Formula 3)

(c) NaOH
solution
(g) Chloroform (g) Refining method yield conclusion Comparative Example 1 170 120 30 NaOH solution → chloroform
→ NaOH solution → brine 19.1 g
The greater the amount of chloroform, the shorter the separation time and the clearer the interface
Accurate extraction is possible.
Comparative Example 2 170 120 60 NaOH solution → chloroform
→ NaOH solution → brine 19.2 g Comparative Example 3 170 120 90 NaOH solution → chloroform
→ NaOH solution → brine 19.2 g Example 1 170 120 120 NaOH solution → chloroform
→ NaOH solution → brine 20.0 g Comparative Example 4 170 120 150 NaOH solution → chloroform
→ NaOH solution → brine 20.1 g

As shown in Table 4, in the extraction process of Formula 3, the yield of Example 1 in which the content of chloroform was within the range of the present invention was very excellent, i.e., 20.1 g, while Comparative Examples 1 and 2 And 3 showed a remarkable decrease in the yield. In Comparative Example 4, in which the content was excessive, it was confirmed that the yield was not so much improved as the content was increased, and the efficiency was very low.

5. Experimental Example 5 (Test on the yield according to the content ratio of aqueous hydrochloric acid solution in the reaction for synthesizing 5-aminolevulinic acid hydrochloride from the compound represented by the above formula (3)

The reactants of formula (3) 6N HCl
(g) reaction
time Heating
Temperature Concentration, precipitation method yield result Comparative Example 1 40 30 - 120 DEG C - Become dough
No agitation Comparative Example 2 40 60 - 120 DEG C - Difficult to stir Example 1 40 90 4hr 120 DEG C Cooling → decompression concentration → IPA (40 g) → acetone (10 g) 12.4g Yellowish transparent liquid -> After concentration -> White powder Example 2 40 120 4hr 120 DEG C Cooling → decompression concentration → IPA (40 g) → acetone (10 g) 13.4 g Yellowish transparent liquid -> After concentration -> White powder Example 3 40 150 4hr 120 DEG C Cooling → decompression concentration → IPA (40 g) → acetone (10 g) 13.3g Yellowish transparent liquid -> After concentration -> White powder

As shown in Table 5, in the synthesis reaction of 5-aminolevulinic acid hydrochloride, the yields of Examples 1, 2 and 3 in which the ratio of the content of the compound of Formula 3 and the aqueous hydrochloric acid solution are within the ranges of the present invention are excellent, In Comparative Examples 1 and 2 which were beyond the scope of the invention, it was confirmed that the synthesis reaction could not be carried out because stirring itself was impossible.

6. Experimental Example 6 (Experiment on yield according to solvent in washing step after synthesis of 5-aminolevulinic acid hydrochloride)

Precipitation
menstruum The reactant (g) of formula (3) 6N HCl
(g) reaction
time Heating
Temperature Concentration, precipitation method yield result Comparative Example IPA
Precipitation 40 120 4hr 120 DEG C Cooling → decompression concentration → IPA (40 g) → acetone (10 g) 19.87 g Yellowish transparent liquid -> After concentration -> White powder Example Acetone precipitation 40 120 4hr 120 DEG C Cooling → concentration under reduced pressure → acetone (40 g) → acetone (10 g) 22.08 g Yellowish transparent liquid -> After concentration -> White powder

As shown in Table 6, the yield of the example of the present invention using acetone was excellent at 22.08 g, whereas the comparative example using isopropylene alcohol (IPA) was 19.87 g, and the yield was remarkably decreased by about 15% under the same conditions Respectively.

7. Experimental Example 7 (Test on the yield according to the content of hexanol alcohol to 5-aminolevulinic acid hydrochloride in the synthesis of 5-aminolevulinic acid hexyl ester hydrochloride)

ALA
(g) Hexane
Alcohol
(g) Thionyl chloride
(g) Reaction conditions
Precipitation method yield Comparative Example 1 20 80 25 20 ° C, 1.5 hr
80 ° C, 1.5 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 7.5g Comparative Example 2 20 100 25 20 ° C, 1.5 hr
80 ° C, 1.5 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 8.2 g Example 1 20 120 25 20 ° C, 1.5 hr
80 ° C, 1.5 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 9.7 g Comparative Example 3 20 150 25 20 ° C, 1.5 hr
80 ° C, 1.5 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 9.5 g

In Table 7 above, ALA refers to 5-aminolevulinic acid hydrochloride.

As shown in Table 7, the yield of Example 1 containing 600 parts by weight of the hexyl alcohol relative to 100 parts by weight of the 5-aminolevulinic acid hydrochloride was excellent, while the yield of Comparative Example 1 , And the yield was remarkably lowered in the case of 2,3.

8. Experimental Example 8 (Test on the yield according to the reaction conditions in the synthesis of 5-aminolevulonic acid hexyl ester hydrochloride)

ALA
(g) Hexane
Alcohol
(g) Thionyl
Chloride
(g) Reaction conditions
Precipitation method yield 20 120 25 20 ° C, 3 hr
60 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 13.7 g 20 120 25 20 ° C, 3 hr
70 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 15.9 g 20 120 25 20 ° C, 3 hr
80 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 17.9 g 20 120 25 20 ° C, 3 hr
90 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 16.2 g

As shown in Table 8, it was confirmed that the yield varied according to the reaction conditions. Particularly, stirring at 20 ° C for 3 hours, stirring at 80 ° C for 3 hours, and stirring at 20 ° C for 24 hours, yield Was the most excellent.

9. Experimental Example 9 (Test on the yield according to the reaction conditions in the synthesis of 5-aminolevulonic acid hexyl ester hydrochloride)

ALA
(g) Hexane
Alcohol
(g) Thionyl
Chloride
(g) Reaction conditions
Precipitation method yield Comparative Example 1 20 120 25 20 ° C, 3 hr
60 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 17.9 g Example 1 20 120 30 20 ° C, 3 hr
70 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 19.1 g Example 2 20 120 33.5 20 ° C, 3 hr
80 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 21.4 g Example 3 20 120 40 20 ° C, 3 hr
90 ° C, 3 hr
20 ° C, 24 hr Filter → acetone (40 g) → filter → acetone (40 g) → filter → acetone (40 g) 21.8g

As shown in Table 9, in Examples 1, 2 and 3 including 150 to 200 parts by weight of the thionyl chloride with respect to 100 parts by weight of the 5-aminolevulinic acid hydrochloride, the yield was excellent, It was confirmed that the yield of Comparative Example 1 which was outside this range was significantly lowered.

The final product prepared according to the process for producing 5-aminolevulinic acid hexyl ester hydrochloride of the present invention as described above was analyzed as shown in Table 10 and FIG. 1 to FIG. 3, and as a result, it was found that 5-aminolevulinic acid hexyl ester Hydrochloride was clearly synthesized.

C 11 H 21 NO 3 .HCl C H N O Cl Sum  Molecular formula C * 11 H * 21 N * 1 O * 3 Cl * 1  formula 12.115 * 11 =
133.2265 1.00797 * 21 =
21.1674 14 * 1 =
14 15.9994 * 3 =
47.9982 35.45 * 1 =
35.45 251.8421  Theoretical (%) 52.9 8.4 5.56 19.06 14.08
100 Elemental analysis of 5-aminolevulinic acid hexyl ester hydrochloride
result 52.43 8.87 5.73 16.62

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. It is clear that the present invention can be suitably modified and applied in the same manner. Therefore, the above description does not limit the scope of the present invention, which is defined by the limitations of the following claims.

Claims (21)

Preparing 5-aminolevulinic acid hydrochloride; And
And a reaction step in which the 5-aminolevulinic acid hydrochloride, hexyl alcohol and thionyl chloride are mixed and reacted with each other to produce a 5-aminolevulinic acid hexyl ester hydrochloride.
The method according to claim 1,
Removing the impurities by adding at least one of diethyl ether, acetone, acetonitrile, benzene, and toluene to the 5-aminolevulinic acid hexyl ester hydrochloride prepared in the reaction step after the reaction step; Lt; RTI ID = 0.0 > 5-aminolevulonic < / RTI > acid hexyl ester hydrochloride.
The method according to claim 1,
In the reaction step, 5-aminolevulinic acid hexyl ester hydrochloride containing 550 to 700 parts by weight of the hexyl alcohol is added to 100 parts by weight of the 5-aminolevulinic acid hydrochloride. The method according to claim 1,
The process according to claim 1, wherein, in the reaction step, 150 to 200 parts by weight of the thionyl chloride is added to 100 parts by weight of the 5-aminolevulinic acid hydrochloride.
The method according to claim 1,
In the reaction step, the reaction product prepared by the reaction is treated with an extraction solvent, and the extraction solvent is an ether-based solvent such as at least one of diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diglyme menstruum; A hydrocarbon-based solvent of at least one of benzene, toluene, hexane or xylene; A halogenated hydrocarbon solvent which is at least one of dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; An alcohol-based solvent which is at least one of methanol, ethanol, isopropyl alcohol or tert-butyl alcohol; An ester solvent which is at least one of ethyl acetate, methyl acetate or butyl acetate; Or acetone, phenylacetone, benzoyl acetone, hexafluoroacetone, cyclohexyl acetone, 2,4-pentanedione, 4-methyl-3-pentene-2-one, 1,3-dichloroacetone, A polar solvent which is at least one of amide, N, N-dimethylacetamide, dimethylsulfoxide or acetonitrile; Lt; RTI ID = 0.0 > 5-aminolevulonic < / RTI > acid hexyl ester hydrochloride.
6. The method of claim 5,
Aminolevulinic acid hexyl ester hydrochloride comprising 100 to 400 parts by weight of the extraction solvent to 100 parts by weight of the 5-aminolevulinic acid hydrochloride.
6. The method of claim 5,
In the reaction step, the reaction product is concentrated at 10 to 30 캜 for 1 to 4 hours, then added to the extraction solvent at 60 to 90 캜 for 1 to 4 hours, and then added to the extraction solvent at 10 to 30 캜 A process for preparing 5-aminolevulinic acid hexyl ester hydrochloride for 20 to 30 hours.
The method according to claim 1,
In the preparation step,
A first synthesis step of reacting a compound represented by formula (1) and a compound represented by formula (2) in an organic solvent to prepare a compound represented by formula (3); And
And a second synthesis step of treating the compound represented by Formula 3 with an acid to produce the 5-aminolevulinic acid hydrochloride.
[Chemical Formula 1]
Figure pat00008

(2)
Figure pat00009

(3)
Figure pat00010

 9. The method of claim 8,
In the first synthesis step, the organic solvent comprises a picoline-based solvent, and the 5-aminolevulinic acid hexyl ester hydrochloride is produced.
10. The method of claim 9,
The picoline-based solvent is preferably selected from the group consisting of 4-methylpyridine, 2-acetyl-4-methylpyridine, 2-amino-4- methylpyridine, 2-amino-5-bromo-4-methylpyridine, 5-bromo-2-methoxy- 2-chloro-4-methylpyridine, or 3-cyano-4-methylpyridine. 5-Aminolevulinic acid hexyl ester hydrochloride.
9. The method of claim 8,
The process for producing 5-aminolevulinic acid hexyl ester hydrochloride according to claim 1, wherein, in the first synthesis step, the organic solvent is contained in an amount of 420 to 600 parts by weight based on 100 parts by weight of the compound represented by the formula (1).
9. The method of claim 8,
Wherein the ratio of the compound represented by Formula 1 to the compound represented by Formula 2 is 1: 1 to 1: 2 in the first synthesis step.
9. The method of claim 8,
In the first synthesis step, the compound represented by the formula (1) is dissolved in the extraction solvent at 40 to 60 ° C for 100 to 200 minutes and then mixed with the compound represented by the formula (2) at a temperature of 10 to 40 ° C for 5 to 12 hours Aminolevulinic acid hexyl ester hydrochloride wherein said reaction takes place.
9. The method of claim 8,
And a purification step of sequentially purifying the compound represented by the formula (3) in an aqueous solution of sodium hydroxide and chloroform sequentially between the first synthesis step and the second synthesis step, ≪ / RTI >
15. The method of claim 14,
Wherein in the purification step, the concentration of sodium hydroxide in the aqueous sodium hydroxide solution is 1.5 to 2.5% by weight.

15. The method of claim 14,
In the purifying step, 50 to 90 parts by weight of the aqueous solution of sodium hydroxide and 60 to 80 parts by weight of chloroform are added to 100 parts by weight of the compound represented by the formula (3), and 5-aminolevulinic acid hexyl ester hydrochloride Gt;
9. The method of claim 8,
Wherein the second synthesis step is a step of hydrolyzing and decarboxylating 5-aminolevulinic acid hexyl ester hydrochloride by adding the compound represented by formula 3 to an aqueous hydrochloric acid solution.
18. The method of claim 17,
Wherein the concentration of hydrochloric acid in the hydrochloric acid aqueous solution is 5 to 26% by weight.
18. The method of claim 17,
Wherein the weight ratio of the compound represented by Formula 3 to the hydrochloric acid aqueous solution is in the range of 4: 9 to 4:15.
9. The method of claim 8,
Wherein the second synthesis step is carried out at 100 to 150 캜 for 3 to 5 hours.
9. The method of claim 8,
A process for preparing 5-aminolevulinic acid hexyl ester hydrochloride wherein the 5-aminolevulinic acid hydrochloride produced in the second synthesis step is washed with acetone.
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