Purification method for 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one and novel crystalline form B of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one

Abstract

The present invention relates to a method for purifying 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one, which is formed by reacting N-benzoylglycine with succinic acid monoalkyl ester chloride in 4-methylpyridine and which can be obtained in the form of red crystals after neutralization with excess hydrochloric acid, characterized in that the red crystals are suspended in an organic solvent or a mixture of organic solvents until they lose color, the organic solvent being selected from the group consisting of organic solvents having an elution strength E0 ranging from 0.40 to 0.55 and an organic solvent or solvents having a water content ranging from 1 to 10% by volume.

Description

[Technical Field]

[0001] The present invention relates to a method for purifying 2-phenyl-4-(3-carbosoxypropionyl)-1,3-oxazolin-5-one, which is formed by reacting N-benzoylglycine with succinic acid monoalkyl ester chloride in 4-methylpyridine and obtained in the form of red crystals after neutralization with excess hydrochloric acid. The present invention also relates to 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one purified by the purification method of the present invention and to a novel crystalline form B of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one. The present invention further relates to the use of 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one purified by the method according to the present invention for preparing 5-aminolevulinic acid hydrochloride or other salts of 5-aminolevulinic acid.

[0002] German Patent No. 22 08 800 (A1) discloses the preparation of 5-aminolevulinic acid hydrochloride by hydrolysis of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one in dilute hydrochloric acid. German Patent No. 22 08 800 (A1) also discloses the preparation of the starting product 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one as red crystals by reacting N-benzoylglycine with succinic acid monomethyl ester chloride in 4-methylpyridine and neutralizing with excess hydrochloric acid. As has become apparent during the applicant's development work, it is not possible to remove the red coloration of the crystals using the washing method described in Example 1 of German Patent No. 22 08 800 (A1).

[0003] The object of the present invention was to provide 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one of higher purity than the red crystalline material prepared analogously to German Patent No. 22 08 800 (A1), in particular to provide 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one of higher purity than the red crystalline material obtainable according to Example 1 of German Patent No. 22 08 800 (A1).

[0004] As can be seen from the following description, the applicant has surprisingly found that impurities causing red coloration in 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one, in particular 2-phenyl-4-(3-carbmethoxypropionyl)-1,3-oxazolin-5-one, which can be prepared analogously to or in accordance with German Patent No. 22 08 800 (A1), can be removed in a surprisingly simple and effective manner by suspending the respective red crystals in a wet organic solvent of suitable polarity, more precisely in an organic solvent of suitable polarity and with a specially adjusted water content, for a sufficiently long time. However, the applicant has also surprisingly found that during this suspension, impurities can be removed, and therefore not only can 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one be recovered, but it is also more suitable for the production of 5-aminolevulinic acid hydrochloride or other salts thereof, since it is purer. More precisely, the known crystalline form A of the red 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one, which can be obtained, for example, according to Example 1 of German Patent No. 22 08 800 A1, can be converted into the new crystalline form B during suspension.

[0005] The present invention therefore provides a method for purifying 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one, which is formed by reacting N-benzoylglycine with succinic acid monoalkyl ester chloride in 4-methylpyridine and which can be obtained in the form of red crystals after neutralization with an excess of hydrochloric acid, by suspending the red crystals in an organic solvent or a mixture of organic solvents until they lose their color, the organic solvent having an elution strength E in the range of 0.40 to 0.55. 0 and organic solvents having a water content in the range of 1 to 10% by volume.

[0006] The 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one, preferably 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one, particularly preferably 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one, purified according to the process of the invention and present in the form of red crystals, can, as already mentioned, be prepared analogously or according to German Patent No. 22 08 800 A1, in particular analogously or according to Example 1 thereof. In this case, the purity of the relevant 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one present in the form of red crystals, determined by HPLC, is in each case, for example, in the range from 90 to 95 HPLC area %, i.e. generally not more than 95 HPLC area %. In this case, the HPLC area % specification refers to non-volatile material, i.e., dry material free of organic solvent, or, in the case of material still containing organic solvent residues, to the proportion of material free of organic solvent residues. In other words, 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one purified by the method according to the present invention (hereinafter also referred to as "original 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one") does not need to be completely dried. It may contain organic solvent residues that are not included in the purity assessment. Such a proportion of organic solvent may, in particular, originate from downstream washing steps in the synthesis of 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one and may remain in the washed but not yet fully purified red crystals after, for example, suction filtration. Such a residual organic solvent proportion may, for example, range up to 10 grams per 100 grams of solvent-wet red crystals.

[0007] The aforementioned purity determination by HPLC can be carried out, for example, using the following parameters: column (250 x 4.6 mm, RP-18, 5 μm), injection 5 μL, flow rate 1 mL / min, column temperature 25°C, UV detection at 254 nm, mobile phase A = 0.1% trifluoroacetic acid (TFA) in water, mobile phase B = 0.1% TFA in acetonitrile, gradient from 90% A to 10% A within 15 min.

[0008] The organic solvent used as the liquid suspending medium in the process according to the invention, or the organic solvent contained as the liquid suspending medium in the mixture of organic solvents used, has an elution strength E in the range of 0.40 to 0.55. 0 The organic solvent used herein must be selected from the group consisting of organic solvents having an elution strength E 0 In the case of , this is an empirical value according to the concept of elution series known to those skilled in the art [see W. Trappe; Biochem. Z. 305, 150 (1940); 306, 316 (1940)]. The elution series selects organic solvents according to their elution effect during chromatography (elution selectivity), in this case using silica gel as the adsorbent. The elution strength E ranges from 0.40 to 0.54. 0 An example of such an organic solvent is acetone (E 0 =0.43), dioxane (E 0 =0.43), ethyl acetate (E 0 =0.45), tetrahydrofuran (E 0 =0.48), acetonitrile (E 0 =0.50). Preferred examples include acetone, acetonitrile and ethyl acetate.

[0009] It is also essential that the organic solvent or mixture of organic solvents used in the process according to the invention has a water content in the range of 1 to 10% by volume, preferably 2 to 5% by volume. In this case, the water content is always such that the organic solvent does not form a two-phase system with water. In this context, those skilled in the art also refer to wet organic solvents, as opposed to anhydrous organic solvents, also known as dry organic solvents.

[0010] The suspension carried out in the method according to the present invention does not involve any methodological peculiarities and is carried out, for example, in the temperature range of 10 to 40°C, preferably 15 to 30°C.

[0011] The suspension can be carried out, for example, at a ratio of 20 to 100 g of 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one per liter of organic solvent, preferably at a ratio of 40 to 60 g of 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one per liter of organic solvent.

[0012] Suspension can be achieved, for example, by stirring and / or shaking.

[0013] It is also essential that the suspension be carried out until decolorization, i.e., until at least the red crystals are decolorized. Suspension for a longer period of time is not problematic. The duration of suspension can range, for example, from 8 to 24 hours. At the start of or during suspension, the liquid phase of the suspension will have a red color, which will fade over time and eventually disappear. The decolorization, i.e., the achievement of decolorization, can be visually recognized by those skilled in the art, for example, by the fact that the crystals have lost their red color or become colorless, and preferably the liquid phase has also lost its red color, e.g., only possessing a pale yellow color. The decolorization corresponds to a corresponding HPLC measurement using UV / VIS detection in the range of 500 to 600 nm, i.e., the specific absorption range of the impurity(s) causing the red coloration. In other words, signals initially detectable in this wavelength range decrease during the visually perceptible decolorization process until they disappear.

[0014] If the suspension is carried out in the same, but anhydrous, dry organic solvent (mixture) under otherwise identical conditions, the red coloration does not disappear. It is believed that the impurities causing the red coloration are chemically altered during suspension according to the method of the invention, and optionally hydrolyzed to form a colorless product soluble in the organic solvent (mixture) used, while the 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one remains chemically unchanged and can be recovered as crystals, more precisely as colorless crystals, after the suspension has ended.

[0015] To obtain purified 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one, conventional solid-liquid separation methods known to those skilled in the art, such as decantation, filtration, suction filtration, and centrifugation, can be used. The 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one thus separated and still wet with the solvent can then be dried, for example, at 20-40°C, optionally with the aid of reduced pressure, to remove the organic solvent residue. The purified 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one is colorless, or in other words, its original red color has been removed, i.e., it exists as colorless crystals.

[0016] The 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one purified and dried by the method of the present invention is itself chemically unchanged compared to the red 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one that still needs to be purified. It does not contain any water of crystallization, i.e., it is not a hydrate, as can be demonstrated by Karl Fischer titration. Its purity, as measured by HPLC, is higher than that of the red 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one, generally ranging from greater than 95 to 99 HPLC area percent.

[0017] Surprisingly, the 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one purified and dried using the method according to the invention has a modified crystalline form B compared to the original, i.e., as yet unpurified, red-colored 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one, as can be evidenced by X-ray powder diffraction (XRPD). Thus, 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one (crystalline form B), purified according to the present invention and present in the form of colorless rod-shaped crystals, has a powder X-ray diffraction pattern comprising the following reflections: 7.8, 9.1, 13.3, 16.6, 19.5, 19.7, 20.4, 23.0, 23.6, 23.9, 24.1, 24.5, 25.1, 26.1, and 28.0±0.2°2θ, unlike the unpurified red 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one. In particular, 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one purified according to the present invention has the following XRPD powder diffractogram: *) It has.

[0018] [Table 1]

[0019] For comparison, the red crystalline form A of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one has the following XRPD powder diffractogram: *) It is characterized in detail by

[0020] [Table 2]

[0021] *)Note: Only signals with an intensity of 10% or higher are shown. The two listed XRPD powder diffractograms were recorded under the same conditions, i.e., using a STOE powder diffraction system with CuKα radiation (40 kV, 25 mA). The accuracy of the 2θ values ​​was ±0.2°.

[0022] The 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one purified by the method according to the present invention, particularly in this case 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one, can be used to prepare 5-aminolevulinic acid hydrochloride or other salts of 5-aminolevulinic acid. For example, it can be converted to 5-aminolevulinic acid hydrochloride by hydrolysis in the presence of hydrochloric acid according to known preparation procedures, for example, from German Patent No. 22 08 800 A1. In this case, it is advantageous to be able to carry out the preparation of 5-aminolevulinic acid hydrochloride or other salts of 5-aminolevulinic acid using a purer 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one starting product in the form of 2-phenyl-4-(3-carbalkoxypropionyl)-1,3-oxazolin-5-one purified according to the present invention. In this respect, the invention also relates to its use for the preparation of 5-aminolevulinic acid hydrochloride by hydrolysis in the presence of hydrochloric acid or for the preparation of other salts of 5-aminolevulinic acid.

[0023] Example: The procedure was initially as in Example 1 of German Patent No. 22 08 800 (A1). For this purpose, 56 ml of succinic acid monomethyl ester chloride were added to a solution of 40 g of N-benzoylglycine in 200 ml of 4-methylpyridine, placed in a 500 ml three-necked flask equipped with a thermometer, a stirrer and a dropping funnel, cooled with ice and salt, with stirring, so that the temperature of the reaction mixture was in the range of -5 to 0°C.

[0024] After the addition of the acid chloride was complete, the reaction mixture was stirred at this temperature for a further 5 hours, and then poured into a mixture of 1 kg of ice and 160 ml of concentrated hydrochloric acid with stirring.

[0025] The precipitated red crystals of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one (crystalline form A) were filtered off.

[0026] 10 g of the red crystals were washed with 45 mL of water, filtered, and then washed twice with 20 mL of dry ethyl acetate. The solid was then suspended in 20 mL of wet ethyl acetate (3% by volume of water). The mixture was then stirred for 10 hours until the red color of the crystals and the red color of the ethyl acetate phase disappeared. The suspension was filtered, and the collected rod-shaped crystals of 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one (crystal form B) were then washed once with 20 mL of dry ethyl acetate and dried.

[0027] The yield was 7.1 g for 10 g of red crystals.

[0028] Purity was determined using the following parameters: column (250 × 4.6 mm, RP-18, 5 μm), injection 5 μL, flow rate 1 mL / min, column temperature 25 °C, UV detection at 254 nm, mobile phase A = 0.1% trifluoroacetic acid (TFA) in water, mobile phase B = 0.1% TFA in acetonitrile, gradient from 90% A to 10% A within 15 min. The purity thus determined was 97.2 HPLC area %.

[0029] With regard to XRPD measurements, reference is made herein above.

[0030] Comparative Example 1: The procedure was the same as in Example 1, except that wet ethyl acetate was not used. The red color did not disappear.

[0031] Comparative Example 2: The procedure was the same as in Example 1, except that stirring was only performed for 1 hour. The red color was still clearly visible.

Claims

1. 1. A method for purifying 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one, which is formed by reacting N-benzoylglycine with succinic acid monoalkyl ester chloride in 4-methylpyridine and can be obtained in the form of red crystals after neutralization with excess hydrochloric acid, comprising suspending the red crystals in an organic solvent or a mixture of organic solvents until they become discolored, the organic solvent having an elution strength E in the range of 0.40 to 0.55, ０ and an organic solvent having a water content in the range of 1 to 10% by volume.

2. The method according to claim 1, wherein the succinic acid monoalkyl ester chloride is a succinic acid mono-C1-C4-alkyl ester chloride, and the 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one is 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one.

3. 3. The method of claim 2, wherein the succinic acid mono-C1-C4-alkyl ester chloride is succinic acid monomethyl ester chloride, and the 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one is 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one.

4. 4. The method according to claim 1, wherein the organic solvent or mixture of organic solvents has a water content in the range of 2 to 5% by volume.

5. 5. The method according to claim 1, wherein the water content of the organic solvent or mixture of organic solvents is such that the organic solvent does not form a two-phase system with water.

6. The method according to any one of claims 1 to 5, wherein the suspending is carried out at a temperature in the range of 10 to 40°C.

7. 7. The method according to claim 1, wherein the suspension is carried out at a ratio of 20 to 100 g of red crystals per liter of organic solvent.

8. The method of any one of claims 1 to 7, wherein the suspension is achieved by stirring and / or shaking.

9. The method according to any one of claims 1 to 8, wherein the purified 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one is separated as crystals by solid-liquid separation after the suspension is completed.

10. 10. The method of claim 9, wherein the separated crystals are dried.

11. Purified 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one obtainable by the method according to either claim 9 or claim 10.

12. The purified 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one of claim 11, wherein the 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one is 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one.

13. The purified 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one according to claim 12, wherein the 2-phenyl-4-(3-carbo-C1-C4-alkoxypropionyl)-1,3-oxazolin-5-one is 2-phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one.

14. 2-Phenyl-4-(3-carbomethoxypropionyl)-1,3-oxazolin-5-one, crystalline form B, having an X-ray powder diffraction pattern comprising the following reflections: 7.8, 9.1, 13.3, 16.6, 19.5, 19.7, 20.4, 23.0, 23.6, 23.9, 24.1, 24.5, 25.1, 26.1 and 28.0±0.2 degrees 2θ.

15. Use of 2-phenyl-4-(3-carboalkoxypropionyl)-1,3-oxazolin-5-one according to any one of claims 11 to 14 for the preparation of 5-aminolevulinic acid hydrochloride by hydrolysis in the presence of hydrochloric acid or for the preparation of other salts of 5-aminolevulinic acid.

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