KR20160065496A - Recrystallization method for purification of phenoxy-2(1h)-pyrimidinone analogues - Google Patents

Abstract

The present invention relates to a process for purifying phenoxy-2 (1H) -pyrimidinone analogs, which comprises the steps of (1) reacting a phenoxypyrimidinone analog with an alkali metal hydroxide, alkaline earth metal hydroxide, Dissolving it in an aqueous solution of an alkali metal salt or an alkaline earth metal salt, or dissolving it in a mixture of the aqueous solution and a polar organic solvent, and regulating the pH by adjusting the pH with an organic acid or hydrochloric acid; Or (2) dissolving the phenoxypyrimidinone analogue in an aqueous solution of an organic acid or a mixture thereof with a polar organic solvent, and cooling and recrystallizing the phenoxypyrimidinone analogue, a phenoxypyrimidinone analogue, (3-methylphenoxy) -2 (1H) -pyrimidinone can be purified at a high purity. Therefore, a flexible substance which can not be removed by conventional methods can be purified at a level lower than the reported substance level according to ICH guidelines .

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a method for purifying a phenoxypyrimidinone analogue by recrystallization,

The present invention relates to a method for purifying a phenoxy-2 (1H) -pyrimidinone analogue. The present invention relates to a method for purifying a phenoxy-2 (1H) -pyrimidinone analogue by recrystallization, .

Recrystallization of a solid organic compound is a purification method in which a compound is dissolved in a solvent and then a new crystal is formed to increase crystal purity. The recrystallization method is selected in many cases as an organic compound purification method. If necessary, it may be purified by sublimation or chromatography and then further purified by recrystallization. Recrystallization uses the difference in solubility according to temperature, but since the solubility depends on the type of solvent in addition to the temperature, selection of an appropriate solvent for recrystallization is also required.

Phenoxypyrimidinone analogues of the following structures have been studied as antiulcer agents and bronchodilators in the 1970s and 1980s (US 3,922,345, Journal of Medicinal Chemistry, 1980, 23, 1026-1031) Recently, it has been suggested that the compound may be used as a therapeutic agent for diabetes (WO 2013/090319). Particularly, 5- (3-methylphenoxy) -2 (1H) -pyrimidinone in the phenoxypyrimidinone analogue is registered in the American Chemical Society (CAS No. 41964-07-2) Also known as Tolimidone (USAN). Tolimidone is a compound which has a solubility in water of not more than 20%, such as acetonitrile, ethanol and isopropanol, but slightly soluble in methanol, at a melting point of a white or light yellow solid of 163 to 164 ° C.

In this formula,

R ¹ is an alkyl group;

X is halogen;

Y is O, S, or NH;

Z is O or S;

n is an integer from 0 to 5;

m is 0 or 1;

In US Patent 3,922,345 (November 25, 1975) to Pfizer's Phenoxypyrimidinone-based compound as an anti-ulcer agent and bronchodilator, it has been found that 5- (4-chlorophenoxy (1H) -pyrimidinone is recrystallized using a mixture of 50% acetic acid and 50% benzene. In addition, 5- (3-methylphenoxy) -2 (1H) -pyrimidinone sodium salt (sodium salt) produced during synthesis is dissolved in hot water in Journal of Medicinal Chemistry, 1980, 23, 1026-1031 After dissolving, it was adjusted to pH 6.0 with acetic acid to obtain 5- (3-methylphenoxy) -2 (1H) -pyrimidinone, which was recrystallized with ethanol.

However, such a recrystallization method has a limitation in refining the phenoxypyrimidinone compound to a high purity.

The present inventors have systematically applied various solvents and conditions by recrystallizing a phenoxypyrimidinone compound in consideration of the problems of the conventional purification method of a phenoxypyrimidinone analogue. As a result, it has been found that a high purity And the present invention has been completed.

It is an object of the present invention to provide a method for purifying a phenoxypyrimidinone analogue, particularly a purifying substance which is difficult to remove by other methods, at a purity of not more than the reported level of the substance according to the ICH guidelines.

A method for purifying a phenoxypyrimidinone analog of the following structural formula for achieving the above object,

(1) dissolving the phenoxypyrimidinone analog in an aqueous solution of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal salt or an alkaline earth metal salt at a concentration of 0.5 to 5 N, or a mixture of the aqueous solution and the polar organic solvent, Recrystallizing by adjusting pH with organic acid or hydrochloric acid; or

(2) dissolving the phenoxypyrimidinone analogue in an aqueous solution of an organic acid or a mixture thereof with a polar organic solvent, and cooling and recrystallizing the phenoxypyrimidinone analogue.

(I)

In this formula,

R ¹ is an alkyl group;

X is halogen;

Y is O, S, or NH;

Z is O or S;

n is an integer from 0 to 5;

m is 0 or 1;

In the purification method according to the present invention, it is preferable that the step (1) and the step (2) are carried out two or more times respectively, and the step (2) is carried out after the step (1) 1) may be performed.

Further, in the purification of the above methods, an alkali metal hydroxide is KOH, NaOH or LiOH, alkaline earth metal hydroxides are Ca (OH) _2, alkali metal salt is _{Na 2 CO 3, Li 2 CO} 3, K 2 CO 3, KHCO 3 , or NaHCO ₃ , and the alkaline earth metal salt is preferably CaCO ₃ .

Examples of the organic acid include acetic acid, citric acid, malonic acid, fumaric acid, adipic acid, succinic acid, tartaric acid, glutaric acid, maleic acid ), Oxalic acid or lactic acid, and the polar organic solvent is preferably methanol, acetone, tetrahydrofuran or acetonitrile.

Hereinafter, the present invention will be described in detail.

The present invention relates to a method for purifying a phenoxypyrimidinone (Phenoxy-2 (1H) -pyrimidinone) analogue by recrystallization, and a method for purifying a flexible substance which is difficult to remove by a recrystallization method, Line (www.ich.org). ≪ / RTI >

According to the ICH guidelines, the reporting threshold for a clinical drug with a maximum daily dose of 2 g or less per day is 0.05%. Conventional methods of recrystallizing a phenoxypyrimidinone-based compound using an acetic acid / benzene mixed solvent or ethanol have limitations in refining them to high purity to meet these standards.

The present inventors have found that 5- (3-methylphenoxy) -2 (1H) -pyrimidinone can be synthesized from a phenoxypyrimidinone compound by the method described in Journal of Medicinal Chemistry 1980, 23, 1026-1031) and recrystallized from ethanol. As a result, it was confirmed that the relative retention time (RRT) of 0.87 remained unchanged at 0.18%. In addition, when a large amount of commercially available toluimidon was purchased and confirmed, it contained 0.23% of RRT 0.87 and 0.07% of RRT 1.05. Accordingly, the present inventors have applied recrystallization screening systematically applying various solvents and conditions to purify the phenoxypyrimidinone compound, and as a result, achieved high purity purification of not more than 0.05% based on the ICH guidelines I could.

All terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong. In the present specification, a polar, quantitative solvent refers to both water and a solvent having polarity such as methanol and having a hydroxyl group (-OH), but is not limited thereto. Polar aprotic solvents refer to all but polar solvents and solvents that do not have a hydroxyl group, such as acetone, tetrahydrofuran, and the like. A non-polar solvent means a solvent having no polarity such as hexane or carbon tetrachloride. Polar organic solvents include, but are not limited to, quantum organic solvents having polarity such as methanol and polar organic solvents having polarity such as tetrahydrofuran. Organic solvents include, but are not limited to, polar, non-polar, solvents containing halogen elements such as dichloromethane, and solvents containing hydrocarbon skeletons such as ethyl acetate. The organic acid is selected from the group consisting of acetic acid, citric acid, malonic acid, fumaric acid, adipic acid, succinic acid, tartaric acid, glutaric acid, But are not limited to, all organic materials that exhibit acidity such as maleic acid, oxalic acid, lactic acid, phenols, and the like. An acid is a substance that ionizes to form a hydrogen ion when it is dissolved in water, but it is not limited to organic acids such as acetic acid and inorganic acids such as hydrochloric acid. The base includes, but is not limited to, an inorganic substance such as sodium hydroxide, sodium phosphate, and sodium carbonate, which dissolves in water to make the aqueous solution basic, or an organic base such as triethylamine.

According to the present invention, it is possible to purify a phenoxypyrimidinone analogue, for example, 5- (3-methylphenoxy) -2 (1H) -pyrimidinone with high purity, Tougher substances can be reduced below the level of reported compliance with the ICH Guidelines.

FIG. 1 shows the results of HPLC measurement of tollimidone obtained by recrystallization by dissolving tolumidone in 1N KOH and neutralizing with 1N HCl as one embodiment of the purification method according to the present invention.
Fig. 2 is a flow chart schematically showing a condition for recrystallizing a compound in high purity.

Hereinafter, the present invention will be described more specifically with reference to examples. However, these examples are merely examples of the present invention, and the scope of the present invention is not limited thereto.

(Tolimidone, 5- (3-methylphenoxy) -2 (1H) -pyrimidinone, CAS No. 41964-07-2), one of the phenoxypyrimidinone analogues, Flexible materials that can not be removed after cyclization of dimethylamino acrolein occur at relative retention time (RRT): 0.87 and RRT: 1.05. The following examples show the process of removing these soft materials and obtaining high purity toluimidone using the recrystallization protocol shown in Fig.

Comparative Example : Identification of Tolimidon Flexible Substance

12.5 mg of commercially available toluimidon was precisely weighed and dissolved in a 5.0 mL diluent solvent (mixed with methanol and purified water at 90:10). Mobile phase A was prepared by dissolving 6.0 mL of triethylamine in 1000 mL of purified water and adjusting pH to 9.0 by adding 85% phosphoric acid. Mobile phase B was eluted with acetonitrile under liquid chromatography ≪ 621 >. As a result, it was confirmed that the flexible materials were 0.23% at RRT 0.87 and 0.07% at RRT 1.05, respectively.

division Contents column Phenomenex Gemini C18, 5 m, 250 mm x 4.6 mm Column temperature 40 ℃ flux 1.0 mL / min Detector wavelength 270 nm Dose 10 μL Gradient Condition 0 minutes (A: 90, B: 10), 25 minutes (A: 10, B: 90)

Example 1 : Recrystallization using a single solvent

Tollimidone (200 mg) was added to methanol (1.6 mL) at 70 ° C and stirred to obtain a clear solution, which was then cooled to 25 ° C. After the tollimide was precipitated, the mixture was further stirred for 2 hours, filtered, washed with 3.0 mL of methanol, and dried to obtain the tollimone. LC analysis showed 0.21% of RRT at 0.87 and 0.01% at RRT 1.05.

In addition, organic solvents containing a halogen element such as a polar aprotic solvent such as tetrahydrofuran, acetone, dichloromethane, or an organic solvent skeleton such as ethyl acetate were also tested, Some of the results are shown in Table 2 below.

Table 2 below shows the results of recrystallization of tollimidone using a single solvent according to a method similar to that of Example 1.

division Single solvent RRT  0.87 RRT 1.05 yield ^end) Melting temperature ^I) Before recrystallization - 0.23% 0.07% - - Method ^of literature ^{c )} EtOH 0.22% 0.01% B II ⁾ Condition 1 MeOH 0.21% 0.01% B II Condition 2 IPAc ^e) 0.23% 0.01% A II

A ⁾ Yield: A is 80% or more and B is 80% or less.

^B) After cooling to 25 캜, crystals were precipitated.

^{C) The} purchased Tolimidon is described in Journal of Medicinal Chemistry 1980, 23, 1026

   - 1031) using ethanol.

^D) Temperature: I is 60 ℃ or less, II is higher than 60 ℃.

^E) IPAc means isopropyl acetate.

Example 2 : Recrystallization using a mixed solvent

200 mg of tollimidone was added to methanol / ethyl acetate (1.0 mL / 1.0 mL) at 80 ° C and stirred to obtain a clear solution, which was then cooled to 25 ° C. After the tollimone was precipitated, the mixture was further stirred for 2 hours, filtered, washed with 3.0 mL of ethyl acetate, and dried to obtain the tollimon. LC analysis showed 0.23% of RRT at 0.87 and 0.01% at RRT 1.05.

In addition, a mixed solvent using an organic solvent containing a halogen element such as methanol and dichloromethane was also tested. Table 3 below shows a part of the result of recrystallization of toluimidone using a mixed solvent according to a similar method.

division Mixed solvent RRT  0.87 RRT 1.05 yield Melting temperature Before recrystallization - 0.23% 0.07% - Condition 1 MeOH / EtOAc 0.23% 0.01% B II Condition 2 MeOH / Water 0.19% 0.00% B II

Example 3 : Recrystallization using (mixed) solvent and acid

400 mg of tollimidone was added to methanol / 50% AcOH (3.2 mL / 0.4 mL) at 70 ° C and stirred to obtain a clear solution, which was then cooled to 25 ° C. After the tollimide was precipitated, the solution was further stirred for 2 hours, filtered, washed with 3.0 mL of 50% methanol, and dried to obtain the tollimide. LC analysis showed that 0.16% of RRT and 0.02% of RRT were detected in RRT 0.87 and RRT 1.05, respectively.

In addition, an organic acid such as citric acid, malonic acid, acetic acid, a polar aprotic organic solvent such as acetone and an inorganic acid such as hydrochloric acid, or a polar quantum organic solvent such as methanol, water, , And some of the results are shown in Table 4. < tb > < TABLE >

Table 4 below shows the results of recrystallization of toluimidone using a single or mixed solvent and an acid according to a method similar to Example 3. [

division Mixed solvent + acid RRT 0.87 RRT 1.05 yield Dissolution temperature Before recrystallization - 0.23% 0.07% - Condition 1 MeOH / Y% AcOH ⁾ 0.16% 0.02% B II Condition 2 EtOH / Y% AcOH 0.20% 0.03% B II Condition 3 Acetone / Y% AcOH 0.21% 0.01% B II Condition 4 X% AcOH 0.13% 0.18% A II Condition 5 ACN b ⁾ / 50% AcOH 0.18% 0.26% B II Condition 6 MeOH / 1N HCl 0.16% 0.02% B II

^end) AcOH means acetic acid, X% is less than 30%, Y% is less than 31%

  ~ 69%, and Z% means more than 70%.

^B) ACN means acetonitrile.

Example 4 : After dissolving in base, recrystallization by addition of acid

500 mg of tollimidone was added to 25.0 mL of 1N KOH at 50 DEG C and stirred to obtain a clear solution, which was further stirred for 30 minutes. 1 N HCl was added dropwise at 50 占 폚 to precipitate crystals. The mixture was cooled to 25 DEG C, stirred for an additional 2 hours, filtered, washed with 5.0 mL of purified water, and dried to obtain a tollimone. LC analysis showed 0.09% of RRT at 0.87 and 0.01% of RRT at 1.05.

In addition, the toluimidone was dissolved in an aqueous base solution, and then the solution was subjected to recrystallization with adjusting the pH to acidic, neutral or basic with organic or inorganic acid. The results are shown in Table 5 below.

division Base / acid RRT  0.87 RRT 1.05 yield Condition Before recrystallization - 0.23% 0.07% - - Condition 1 0.5N KOH / 1N HCl 0.12% 0.02% A b ^* , I Condition 2 1N KOH / X% AcOH 0.09% 0.01% B c, I Condition 3 1N KOH / Y% AcOH 0.09% 0.02% B b, I Condition 4 1N KOH / Z% AcOH 0.10% 0.01% A c, I

^* a: pH 6.99 or less;

b: pH between 7.00 and 8.99;

c means pH 9.00 or higher.

Example 5 : Repeated application of the same or different recrystallization conditions

The step of recrystallization using a solvent and an acid according to the method of Example 3 was carried out twice to analyze the toilimumone, followed by analysis of the liquid by LC analysis.

In addition, the step of recrystallization using a base and an acid according to the method of Example 4 was carried out twice to analyze the toilimumone, followed by analysis of the supernatant by LC analysis.

Table 6 below shows some of the results of repeated application of recrystallization conditions.

division menstruum RRT 0.87 RRT 1.05 yield Condition Before recrystallization - 0.23% 0.07% - - Condition 1 1st X% AcOH 0.08% 0.03% B II 2nd ^* X% AcOH 0.04% 0.03% B II Condition 2
1st 1N KOH / 1N HCl 0.09% 0.01% B I 2nd ^* 1N KOH / 1N HCl 0.04% 0.01% B I

^* Recrystallization of the tollimone obtained from 1st (recrystallization twice).

As described above, according to the method of the present invention, phenoxypyrimidinone analogs such as 5- (3-methylphenoxy) -2 (1H) -pyrimidinone can be purified by high purity, Can reduce the hard-to-remove contaminants below the reported level of conforming substances according to ICH guidelines.

Claims (9)

(1) dissolving the phenoxypyrimidinone analog in an aqueous solution of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal salt or an alkaline earth metal salt at a concentration of 0.5 to 5 N, or a mixture of the aqueous solution and the polar organic solvent, Recrystallizing by adjusting pH with organic acid or hydrochloric acid; or
(2) A process for purifying a phenoxypyrimidinone analogue of the following structural formula, which comprises dissolving a phenoxypyrimidinone analogue in an aqueous solution of an organic acid or a mixture thereof with a polar organic solvent, and cooling and recrystallizing the phenoxypyrimidinone analogue:
(I)

In this formula,
R ¹ is an alkyl group;
X is halogen;
Y is O, S, or NH;
Z is O or S;
n is an integer from 0 to 5;
m is 0 or 1; The method according to claim 1, wherein step (1) is carried out two or more times. 2. The method of claim 1, wherein step (2) is performed more than once. The method according to claim 1, wherein step (2) is performed after step (1), or step (1) is performed after step (2). The method according to claim 1, 2 or 4, wherein the alkali metal hydroxide is KOH, NaOH or LiOH, the alkaline earth metal hydroxide is Ca (OH) ₂ and the alkali metal salt is Na ₂ CO ₃ , Li ₂ CO ₃ , K ₂ CO ₃ , KHCO ₃ or NaHCO ₃ , and the alkaline earth metal salt is CaCO ₃ . The method according to claim 1, 3, or 4, wherein the organic acid is selected from the group consisting of acetic acid, citric acid, malonic acid, fumaric acid, adipic acid, succinic acid, tartaric acid, Characterized in that it is a glutaric acid, a maleic acid, an oxalic acid or a lactic acid. The method according to any one of claims 1 to 4, wherein the polar organic solvent is methanol, acetone, tetrahydrofuran or acetonitrile. The method of claim 1, wherein the phenoxypyrimidinone analog is 5- (3-methylphenoxy) -2 (1H) -pyrimidone. 9. The method according to any one of claims 1 to 8, wherein the content of the flexible substance of the phenoxypyrimidinone derivative is 0.05% or less.

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