Method for purifying 3-phenyl-5-vinyl-4h-isoxazole-5-carboxylic acids

Abstract

The application relates to an extraction method for purifying 3-phenyl-5-vinyl-4H-isoxazole-5-carboxylic acids of formulae (Ia) and / or (Ib), in particular those which are contaminated with by-products of a preceding elimination reaction.

Description

[0001] BCS241014 Foreign NR / ed 11,12,2025

[0002] -1- Method for the purification of 3-phenyl-5-vinyl-4H-isoxazole-5-carboxylic acids

[0003] The present application relates to an extraction process for the purification of 3-phenyl-5-vinyl-4H-isoxazol-5 carboxylic acids, in particular those contaminated with by-products of a previous elimination reaction.

[0004] The production of substituted alkenes is an essential step in numerous synthesis processes in the agrochemical and pharmaceutical industries. Substituted alkenes can usually only be produced costly and under harsh conditions.

[0005] 3-Phenyl-5-vinyl-4H-isoxazol-5-carboxylic acids of general formulas (1a) and (Ib) are important precursors of agrochemical active ingredients (see WO 2018 / 228985). WO2018 / 228985 describes a process for the preparation of a mixture of 3-phenyl-5-vinyl-4H-isoxazol-5-carboxylic acids of general formulas (1a) and (Ib). This mixture can be obtained in high purity. However, due to the use of reagents not available on an industrial scale, such as trifluoromethanesulfonic anhydride or the base diazabicycloundecene (DBU), the process is not suitable for large-scale synthesis.

[0006] Suitable processes for the large-scale production of 3-phenyl-5-vinyl-4H-isoxazol-5-carboxylic acids, such as compounds (1a) and (1b), are disclosed in WO2023 / 099641 and W02024 / 038036. However, a disadvantage of these processes is that these compounds are produced by elimination reactions under harsh conditions or are contaminated with a high salt load, and are therefore generally highly impure. This makes the isolation of the desired 3-phenyl-5-vinyl-4H-isoxazol-5-carboxylic acids in pure form on a large industrial scale difficult. For example, these impurities prevent a sharp separation of the aqueous and organic phases in extractive purification processes and reproducible depletion in crystallizations, thus complicating the purification process.Furthermore, these impurities complicate the production and purification of derivative products starting from compounds of formulas (1a), (1b), or their mixtures, due to similar solubilities or the problems described above. The present invention therefore aimed to provide an improved process for the purification of compounds of formulas (1a), (1b), and their mixtures. The process should be achievable on an industrial scale with minimal effort and yield losses.

[0007] This problem was solved by a method for the purification of a compound of the general formula (1a), (1b) or a mixture of (1a) and (1b) BCS241014 Foreign NR / ed 11,12,2025

[0008] - 2 -

[0009]

[0010] where R 1 and R 2The following steps, which stand independently for fluorine, chlorine or bromine, are included:

[0011] (i) an organic phase comprising the compound of formula (1a) and / or (1b), impurities and an organic solvent is mixed with water,

[0012] (ii) if necessary, the pH of the aqueous phase is adjusted to below 4.0 by adding mineral acid,

[0013] (iii) the organic phase is separated from the aqueous phase and mixed with water and a base until the pH of the aqueous phase in the two-phase mixture is at least 5.0,

[0014] (iv) the phases are separated and an aqueous phase comprising the salt of the compound of formula (1a) and / or (1b) obtained in step (iii).

[0015] It was surprisingly discovered that the unwanted byproducts can be separated by a specific sequence of acidification with aqueous mineral acid, extraction, alkaline treatment of the separated organic phase, and renewed extraction. This makes it possible to obtain the 3-phenyl-5-vinyl-4H-isoxazol-5-carboxylic acid of the general formula (1a) or (1b), or a mixture thereof, in high purity or pure form. The process is feasible on an industrial scale, and the solvent used can be recycled.

[0016] Detailed description of the invention

[0017] The process according to the invention relates to the purification of a compound of the general formula (1a), (1b) or a mixture of (1a) and (1b)

[0018]

[0019] BCS241014 Foreign NR / ed 11,12,2025

[0020] - 3 -where R 1 and R 2 stand independently for fluorine, chlorine or bromine.

[0021] Preferably R 1 and R 2 Both are for fluoride.

[0022] According to the invention, the stereoisomer (1a) or the stereoisomer (Ib) or a mixture of the stereoisomers (1a) and (Ib) is present. Preferably, a mixture of the stereoisomers (1a) and (Ib) is present, wherein (1a) and (Ib) can be present in any desired mixing ratio. Particularly preferably, the stereoisomers (1a) and (Ib) are present in a weight ratio (Ia) / (Ib) of at least 90:10, and most preferably at least 95:5.

[0023] The compounds of formulas (1a) and (1b) or their mixture can be prepared according to the methods described in WO 2018 / 228985 and WO2023 / 099641.

[0024] Step (i)

[0025] In step (i) of the process according to the invention, an organic phase comprising the compound(s) of formula(s) (1a) and / or (1b), impurities, and an organic solvent is mixed with water. Preferably, the organic solvent is selected from the group consisting of aromatic solvents, ether solvents, ketone solvents, ester solvents, and mixtures thereof.

[0026] Particularly preferred organic solvents are selected from the group consisting of toluene, benzene, the xylenes, chlorobenzene, methyl tert-butyl ether, methyl isobutyl ketone, isopropyl acetate and mixtures of these solvents.

[0027] Toluene is particularly preferred.

[0028] Preferably, the proportion of compounds of general formulas (1a) and (1b) in the organic phase is at least 5.0 wt.%, preferably at least 10 wt.%, and particularly preferably 15-40 wt.%. According to the invention, the organic phase also comprises impurities. Preferably, these impurities originate from a prior elimination reaction for the formation of the vinyl function. The organic compounds can be identified, at least partially, by a black or brown coloration and make it difficult to separate the aqueous and organic phases.

[0029] Preferably, enough water is added so that the volume ratio of organic phase to aqueous phase is in the range of 10:1 to 1:10, particularly preferably 4:1 to 1:4.

[0030] Step (ii)

[0031] According to the invention, in step (ii) of the process according to the invention, the pH value of the aqueous phase is adjusted to below 4.0 by adding mineral acid, insofar as this is necessary (i.e., insofar as the aqueous phase does not already have a pH value below 4.0). BCS241014 Foreign NR / ed 11,12,2025

[0032] - 4 - Suitable mineral acids are hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[0033] Hydrochloric acid and sulfuric acid are particularly preferred.

[0034] Hydrochloric acid is particularly preferred.

[0035] According to the invention, the pH value of the aqueous phase is adjusted to below 4.0, preferably below 3.0, particularly preferably at most 1.0, and especially at most 0.5, by adding the mineral acid.

[0036] Preferably, the mineral acid is added in such a way that the temperature of the phase mixture does not exceed 50°C, particularly preferably 35°C. This can be achieved by adding the mineral acid in portions or continuously, preferably using a dosing device, e.g. a dropping funnel, while stirring and monitoring the temperature.

[0037] Preferably, the two phases are mixed by stirring or shaking.

[0038] Step (Ui)

[0039] According to the invention, in step (iii) of the process the organic phase is separated from the aqueous phase and mixed with water and a base until the pH of the aqueous phase in the two-phase mixture has a value of at least 5.0.

[0040] First, the phase mixture obtained in step (ii) is allowed to stand until the phases have separated. Then, the aqueous phase is separated and the organic phase is mixed with water and the base.

[0041] Basic aqueous solutions or organic bases in water can be used as a combination of water and base.

[0042] Suitable basic aqueous solutions include alkali hydroxide solutions, alkaline earth hydroxide solutions, alkali carbonate solutions, alkali hydrogen carbonate solutions and aqueous ammonia solutions.

[0043] An aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution is particularly preferred.

[0044] Suitable organic bases are tertiary, secondary or primary amine compounds as well as pyridine compounds.

[0045] Particularly favored organic bases are trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, diisopropylethylamine and tributylamine.

[0046] According to the invention, the pH value of the aqueous phase is increased to at least 5.0, preferably to at least 5.5, by the addition of the basic aqueous solution. BCS241014 Foreign NR / ed 11,12,2025

[0047] - 5 - Preferably, the organic phase is first mixed with water, and then the basic aqueous solution or, optionally, the organic base is added portionwise or continuously, preferably using a dosing device, e.g., a dropping funnel, while stirring and pH control until the desired pH value is reached.

[0048] Preferably, enough water is added so that the total concentration of compounds of formulas (1a) and (1b) in the aqueous phase is 5 to 40 wt.%, preferably 5 to 30 wt.%. Step (iv)

[0049] According to the invention, in step (iv) the phases are separated and an aqueous phase is obtained comprising the salt of the compound of formula (1a) and / or (1b) formed in step (iii).

[0050] Preferably the salt of the compound of formula (1a) is a salt of formula (1a) and the salt of the compound of formula (1b) is preferably a salt of formula (1lb).

[0051]

[0052] where

[0053] R 1 and R 2 stand independently for fluorine, chlorine or bromine, and

[0054] M + for Na + , K + or NHR 1 R 2 R 3+ stands,

[0055] where R 1 , R 2 and R 3 They were selected independently from the group consisting of hydrogen and (C1-C4) alkyl.

[0056] In this context, "(Ci-C4)-alkyl" refers to a saturated, branched or unbranched carbon hydrogen chain with 1, 2, 3 or 4 carbon atoms, i.e. a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl group.

[0057] Another subject of invention is therefore salts of the general formula (Ha) or (Ilb) and mixtures of (Ila) and (Ilb).

[0058] Salts of formulas (Ha) or (Ilb) containing R are particularly preferred. 1 and R 2 for fluorine, and its mixtures. BCS241014 Foreign NR / ed 11,12,2025

[0059] Salts of formulas (Ha) or (üb) are particularly preferred, in each case containing R 1 and R 2 stand for fluorine and M + for Na + or K + stands, and their mixtures.

[0060] The salts of the general formulas (Ha) and (Ilb) can be used directly in a subsequent synthesis step or alternatively converted into the corresponding free carboxylic acid of formula (Ia) or (Ib) using a mineral acid, such as hydrochloric acid. BCS241014 Foreign NR / ed 11,12,2025

[0061] - 7 - Examples

[0062] The invention is further illustrated by the following non-limiting examples.

[0063] Measurement methods

[0064] The products were characterized by nuclear magnetic resonance (NMR) spectroscopy and / or liquid chromatography with mass spectrometry (LC / MS), high pressure ion chromatography (HPIC) and / or photometry.

[0065] The 1¹H NMR spectra were recorded using a Broker Avance Neo 600 MHz spectrometer. LC chromatograms were measured on an Agilent HPLC instrument. Ionic chromatographic analyses were performed using a Dionex ICS 6000 HPIC instrument with integrated conductivity and UV detectors.

[0066] Photometric characterizations were performed on a Specord 200 plus from Analytik Jena and a Nanocolor Vis II colorimetric analyzer from Macherey-Nagel. Samples were measured at a concentration of 1% in acetonetrile / water 70:30 (v / v) against the solvent as a standard. The result is reported as color using a colorimeter according to CieLAB. The parameters "L" (brightness), "A" (color between red and green), and "B" (color between blue and yellow) are determined. The L*A*B coordinate system allows for the precise calculation of color differences, as well as for calibration of corresponding concentrations or impurities. The starting material for Examples 1 and 2 is a technical-grade solution of (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid in toluene, obtained according to the method described in WO2023 / 099641.

[0067] Example 1: Sodium (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate

[0068] 400 g (20.41 wt%, 0.32 mol) of a technical solution of (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazol-5-carboxylic acid in toluene are mixed with 200 g of water and, at 20–30 °C, are treated with 20.2 g of 32 wt% hydrochloric acid using a dropping funnel until a pH of 0.5 is reached. The phases are separated, and the organic phase is then mixed with 545 g of water. The pH of the two-phase mixture is adjusted to 6 by adding a 20 wt% aqueous potassium hydroxide solution. The phases are separated at 20 °C, and the product is obtained as a red to reddish aqueous solution. Yield: 683.1 g, 11.7 wt%, 90% of theory.

[0069] An analytical sample was prepared by distilling a portion of the aqueous solution to remove the solvent and crystallizing it from a mixture of methanol and tert-butyl methyl ether. ¹H NMR (600 MHz, CDC13): 7.29 (m ²H), 7.01 (tt ¹H), 6.23 (dd ¹H), 5.45 (dd ¹H), 5.18 (dd ¹H), 3.77 (d ¹H), (3.35 d ¹H) ppm. BCS241014 Foreign NR / ed 11,12,2025

[0070] - 8 - IC cations: 8.0% sodium.

[0071] Photometry: L: 92.1%; A: -4.3%; B: 41.7% (1% solution prepared from the obtained product solution) Reference solutions for the photometry measurements:

[0072] 1) 1% measuring solution prepared from pure (5S)-3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid (obtained according to the method described in WO2018 / 228985): L: 99.2%; A: -0.1; B: 1.7.

[0073] 2) 1% measuring solution prepared from the technical solution of (5S)-3-(3,5-diffusionphenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid in toluene (i.e., the starting material of Examples 1 and 2):

[0074] L: 65.1%; A: 22.3%; B: 83.2%.

[0075] A comparison of the L, A and B values ​​of the obtained 1% product solution with the corresponding values ​​of the reference solutions 1) and 2) indicates a high purity of the sodium-(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxy lats contained in the product solution.

[0076] Example 2: Potassium-(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate

[0077] 400 g (20.41 wt%, 0.32 mol) of a technical solution of (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazol-5-carboxylic acid in toluene are mixed with 200 g of water and, at 20–30 °C, are treated with 20.2 g of 32 wt% hydrochloric acid using a dropping funnel until a pH of 0.5 is reached. The phases are separated, and the organic phase is then mixed with 537 g of water. The pH of the two-phase mixture is adjusted to 6 by adding 20 wt% aqueous potassium hydroxide solution. The phases are separated at 20 °C, and the product is obtained as an approximately 11 wt% reddish aqueous solution. Yield: 686.5 g, 13.0 wt%, 95% of theory.

[0078] An analytical sample was produced by distilling a subset of the aqueous solution free of the solvent and crystallizing it from a mixture of methanol and tert-butyl methyl ether.

[0079] 'H-NMR (600 MHz, CDC13): 5 7.29 (m 2H), 7.01 (dd 1H), 6.23 (dd 1H), 5.45 (dd 1H), 5.18 (dd 1H), 3.77 (d 1H), (3.35 d 1H) ppm.

[0080] IC cations: 12.9% potassium.

[0081] Photometry: L: 94.9%; A: -3.5%; B: 22.6% (1% solution prepared from the obtained product solution). A comparison of the L, A, and B values ​​of the obtained 1% product solution with the corresponding values ​​of reference solutions 1) and 2) indicates a high purity of the potassium (5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate contained in the product solution.

Claims

BCS241014 Foreign NR / ed 11,12,2025 - 9 - Patent claims 1. Method for purifying a compound of general formula (1a), (1b) or a mixture of (1a) and (1b) where R 1 and R 2 The following steps, which can be independent of each other, represent fluorine, chlorine or bromine, include: (i) an organic phase comprising the compound of formula (1a) and / or (1b), impurities and an organic solvent is mixed with water, (ii) if necessary, the pH of the aqueous phase is adjusted to below 4.0 by adding mineral acid, (iii) the organic phase is separated from the aqueous phase and mixed with water and a base until the pH of the aqueous phase in the two-phase mixture is at least 5.0, (iv) the phases are separated and an aqueous phase comprising the salt of the compound of formula (1a) and / or (1b) formed in step (iii) is obtained.

2. Method according to claim 1, characterized in that R 1 and R 2 stand for fluorine.

3. Method according to claim 1 or 2, characterized in that the organic solvent is selected from the group consisting of aromatic solvents, ether solvents, ester solvents, ketone solvents and mixtures thereof.

4. Method according to one of the preceding claims, characterized in that the organic solvent is selected from the group consisting of toluene, benzene, xylenes, chlorobenzene, methyl tert-butyl ether, methyl isobutyl ketone, isopropyl acetate and mixtures of these solvents.

5. Method according to one of the preceding claims, characterized in that hydrochloric acid is used as the acid. BCS241014 Foreign NR / ed 11,12,2025 - 10 - 6. Method according to one of the preceding claims, characterized in that in step (i) the total proportion of the compounds of formulas (1a) and (1b) in the organic phase is at least 5.0 wt.%, preferably at least 10 wt.%, particularly preferably 15-40 wt.%.

7. Method according to one of the preceding claims, characterized in that the volume ratio of organic phase to aqueous phase in step (i) is in the range of 4:1 to 1:

4.

8. Method according to one of the preceding claims, characterized in that in step (ii) the pH value of the aqueous phase is adjusted to a value of at most 1.0 by the addition of the mineral acid.

9. Method according to one of the preceding claims, characterized in that an aqueous sodium hydroxide solution or aqueous potassium hydroxide solution is used in step (iii).

10. Method according to one of the preceding claims, characterized in that the concentration of compounds of formulas (1a) and (1b) in the aqueous phase at the end of step (iii) is 5 to 40 wt.%.

11. Salt of formula (Ila) or (üb) or of a mixture of (Ila) and (Hb) where R 1 and R 2 stand independently for fluorine, chlorine or bromine, and M + for Na + , K + or NHR 1 R 2 R 3+ stands, where R 1 , R 2 and R 3 They were selected independently from the group consisting of hydrogen and (C1-C4)-alkyl.

12. Salt according to claim 11, wherein R 1 and R2 stand for fluorine and M + for Na + or K + stands.

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