A method for purifying 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol

Abstract

The present invention provides a purification method of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (compound 13), and the prepared pemabet has high purity, low impurity content, and high yield. The operation in the present invention is simple and easy to operate, and has strong resistance to adverse reactions. There is good tolerance to the large polar solvent in the extract, and under normal operation, there is no need to pay attention to the influence of the large polar solvent residue, and there is no need to strictly control the dripping rate, cooling rate and stirring time of the reagent or solvent, which greatly reduces the difficulty of production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and purification, and specifically relates to a method for refining 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol. Background Art

[0002] There is increasing evidence that triglyceride-rich lipoproteins (TRL) are a trigger for atherosclerosis. It is estimated that at least one-third of patients with T2DM treated with statins will have hypertriglyceridemia. Subgroup analyses after the fibrate trial suggest that patients with T2DM, mild to moderate hypertriglyceridemia, and low HDL-C may benefit substantially. Pemafibrate is a potent and selective peroxisome proliferator-activated receptor α (PPARα) modulator with a stronger effect of lowering triglycerides and raising HDL-C, and fewer non-target effects.

[0003] There are not many references for the synthesis and production of Pemabet, and the current mainstream process is still the original research route, as shown in the following process route. In the route, since compound 14 is an oily substance, the process from compound 13 to compound 15 is usually a continuous operation, and compound 14 is usually not controlled separately as an intermediate, so 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (compound 13) is the key intermediate in the route; the quality of compound 13 directly affects the quality of the crude final product, and the impurities it contains will be brought into the crude final product, which poses a great challenge to the quality of the final product in the subsequent refining process.

[0004]

[0005] Studies have shown that when preparing compound 13, byproducts (compound 16) are easily left in compound 13 and are very difficult to remove; at the same time, byproducts (compound 16) remain in the preparation of the final product and decompose to form compound 13, affecting the quality of the final product. There are also more N, N-diethylaminobenzoxazole (compound 17) and a small amount of 2-hydroxybenzoxazole (compound 18) in the reaction. Studies have also found that the crude product of compound 13 is difficult to control during crystallization. When the process control is poor or a large polar solvent such as N-methylpyrrolidone, N, N-dimethylformamide, etc. remains a little more, it will significantly affect the yield, reduce the refining effect, and even precipitate oily substances, which significantly increases the difficulty of production.

[0006]

[0007] In the existing published literature, in addition to column chromatography purification, two refining methods are mentioned, as shown in Table 1. Studies have shown that in method one, column chromatography is first used for refining, and then crystallization is performed, which increases the workload and waste liquid volume in production, and the cost is relatively high; if the crude product is directly refined with methyl tert-butyl ether, crystallization cannot be achieved. In method two, dilute hydrochloric acid washing is used in the extraction washing, which fails to effectively degrade impurities (compound 16) and wash away impurities (compound 17), and in the subsequent crystallization operation, the method provided by patent IN202041005093 A cannot achieve effective crystallization, but obtains an oily substance containing more impurities.

[0008] Table 1 Refining methods in the literature

[0009] Serial number operate Yield source Method 1 Column chromatography followed by crystallization from methyl tert-butyl ether 91.1％ US11816472 Method 2 Tetrahydrofuran-n-heptane crystallization 75.8％ IN202041005093 A

[0010] In order to obtain 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (Compound 13) of stable quality, the prior art can usually be optimized from three directions. First, strictly control the purity of starting materials, intermediates, reagents, etc., strictly control reasonable reaction conditions and various process parameters, which can appropriately reduce various impurities, but cannot achieve the removal of by-products, and a single refining cannot obtain clean compound 13. The second is to increase the number of washing times of the extract, reduce the content of highly polar solvents in the extract, and reduce the risk of crystallization, but such operation will significantly increase the production workload and wastewater treatment costs, and the yield will be significantly reduced. The third is to repeat the refining operation. The yield of a single conventional refining is 65-82%, and the total yield after 3 refinings is only 27-55%, which is a large loss. Summary of the invention

[0011] In view of the shortcomings of the prior art, the present invention provides a method for purifying 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (Compound 13). The purification method is simple to operate, and the prepared pemabet has high purity, low impurity content, and high yield.

[0012]

[0013] Compound 13

[0014] A method for purifying 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol comprises the following steps:

[0015] 1) controlling the reaction solution containing 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol at a suitable temperature, adding an acid or an acid solution, and stirring;

[0016] 2) adding water and an organic solvent to the solution of step 1), stirring, standing and separating to obtain an organic phase; extracting the aqueous phase again with an organic solvent, standing and separating to obtain an organic phase, and combining the two batches of organic phases;

[0017] 3) adding an acid or an acid solution dropwise to the organic phase in step 2), stirring, and filtering;

[0018] 4) washing the filter cake with an organic solvent, draining the wet product, and drying to obtain 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol.

[0019] Preferably, in step 1), the reaction liquid is controlled at 20-70°C, preferably 40-50°C.

[0020] Preferably, the acid in step 1) is selected from an organic acid, an inorganic acid, an aqueous solution of an acidic salt, or a reagent that generates an acidic substance in water or alcohol.

[0021] The organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, trifluoroacetic acid, trifluoroformic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or nitric acid; the acid salt is selected from potassium hydrogen sulfate, potassium dihydrogen phosphate, potassium hydrogen sulfite, sodium hydrogen sulfate, sodium dihydrogen phosphate, and sodium hydrogen sulfite; and the reagent that generates an acidic substance in water or alcohol is selected from trimethylchlorosilane and triethylchlorosilane.

[0022] Preferably, the acid in step 1) is selected from hydrochloric acid, formic acid or trifluoroacetic acid.

[0023] Preferably, the acid solution in step 1) refers to the above-mentioned various acidic substances dissolved in water or a solvent such as tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.

[0024] Preferably, the equivalent of the acid used in step 1) is 0.8-2.0 eq, preferably 1.5 eq.

[0025] Preferably, the stirring time in step 1) is 0.5-24 h, preferably 1-2 h.

[0026] Preferably, in step 2), the organic solvent is selected from ethyl acetate, isobutyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, toluene, benzene or methyltetrahydrofuran, preferably ethyl acetate.

[0027] Preferably, the volume ratio of the added water, organic solvent and organic solvent for extraction in step 2) is 2:2:1.

[0028] Preferably, the stirring time in step 2) is 3-8 min, preferably 5 min.

[0029] Preferably, the acid used in step 3) is selected from an organic acid, an inorganic acid, an aqueous solution of an acidic salt, or a reagent that generates an acidic substance in water or alcohol.

[0030] The organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, trifluoroacetic acid, trifluoroformic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or nitric acid; the acid salt is selected from potassium hydrogen sulfate, potassium dihydrogen phosphate, potassium hydrogen sulfite, sodium hydrogen sulfate, sodium dihydrogen phosphate, and sodium hydrogen sulfite; and the reagent that generates an acidic substance in water or alcohol is selected from trimethylchlorosilane and triethylchlorosilane.

[0031] Preferably, the acid used in step 3) is selected from hydrochloric acid, concentrated sulfuric acid or trifluoroacetic acid.

[0032] Preferably, the equivalent of the acid used in step 3) is 1.0-3.0 eq, with 2.0 eq being preferred.

[0033] Preferably, the stirring time in step 3) is 0.5-24 h, preferably 2-10 h.

[0034] Preferably, the organic solvent used in step 4) is ethyl acetate, isobutyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, toluene, benzene or methyltetrahydrofuran, preferably ethyl acetate.

[0035] Preferably, the volume ratio of the amount of the organic solvent used in step 4) to the amount of water added in step 2) is 1:3.

[0036] Preferably, the drying temperature in step 4) is 40-50°C, preferably 45°C.

[0037] Furthermore, the purification method of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol provided by the present invention comprises the following steps: controlling the temperature of the reaction solution to 40-50°C, adding hydrochloric acid (1.5eq), and stirring for 1-2h. Adding water and ethyl acetate, stirring for 5min, standing and separating to obtain an organic phase; returning the aqueous phase to the separating funnel, extracting with ethyl acetate, standing and separating to obtain an organic phase; combining two batches of organic phases, stirring, adding hydrochloric acid (2.0eq) dropwise, stirring for 2h, filtering, washing the filter cake with ethyl acetate, draining to obtain a wet product, and drying at 45°C to obtain the product.

[0038] Beneficial effects of the present invention:

[0039] 1. The refining and purification method of the present invention is a simple, easy and low-cost refining and purification method, which can effectively reduce various impurities in the product.

[0040] 2. The 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (Compound 13) obtained by the method of the present invention has a chromatographic purity higher than 99.90%, wherein the difficult-to-remove impurity (Compound 16) is not detected, the total impurities are less than 0.10%, and the yield is greater than 90%.

[0041] 3. The operation of the present invention is simple and easy, and has strong resistance to adverse effects. It has good tolerance to highly polar solvents in the extract, and under normal operation, there is no need to pay attention to the influence of highly polar solvent residues, and there is no need to strictly control the drop rate, cooling rate and stirring time of reagents or solvents, which greatly reduces the difficulty of production.

[0042] 4. The yield of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (Compound 13) purified by the method of the present invention is high, reaching 90-96%. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the chromatogram of the untreated reaction solution of Example

[0044] Figure 2 It is the chromatogram of Example 1 of the present invention

[0045] Figure 3 It is the chromatogram of Example 2 of the present invention

[0046] Figure 4 It is the chromatogram of Example 3 of the present invention

[0047] Figure 5 It is the chromatogram of comparative example 1 of the present invention

[0048] Figure 6 It is the chromatogram of comparative example 3 of the present invention DETAILED DESCRIPTION

[0049] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.

[0050] In the examples and comparative examples, the 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (Compound 13) to be refined and purified was prepared according to the references, and the reaction solution was divided into 10 portions for later use.

[0051] Reference: Yamazaki Y, Araki T, Koura M, et al. Process for production of optically active PPAR-activating compound and intermediate ofthesame. USPatent 7,790,903[P].

[0052] Central control detection method:

[0053]

[0054] The specific synthesis operation is as follows:

[0055] Add intermediate III (100.00 g, 0.34 mol), triethylamine (49.30 g, 0.48 mol), and DMF (500 mL) to a 1 L reaction bottle, replace the atmosphere with nitrogen three times and protect with nitrogen, heat to 80 ° C and stir to dissolve. Dissolve 2-chlorobenzoxazole (62.65 g, 0.41 mol) in DMF (100 mL) and add dropwise to the reaction bottle, and control the internal temperature not to exceed 90 ° C. Continue stirring for 0.5-1 h to complete the reaction. The test data of the reaction solution is shown in Figure 1 , of which RT 12.239min (3.36%) is a byproduct (Compound 16), and RT 7.110min (2.91%) is another byproduct (Compound 7). The reaction solution was divided into 10 portions for standby use, each with a volume of 74mL, which was converted to the volume corresponding to 10.00g of intermediate III according to the feed amount.

[0056] In the examples and comparative examples, the detection method of the product (Compound 13) is as follows:

[0057]

[0058]

[0059] Example 1

[0060] The temperature of the above 1 / 10 reaction solution (74 mL) was controlled at 40-50°C, hydrochloric acid (1.5 eq, 0.051 mol, 4.3 mL) was added, and the mixture was stirred for 1-2 h. Water (60 mL) and ethyl acetate (60 mL) were added, stirred for 5 min, and the mixture was allowed to stand for separation to obtain an organic phase; the aqueous phase was returned to the separatory funnel, extracted with ethyl acetate (30 mL), and the mixture was allowed to stand for separation to obtain an organic phase; the two batches of organic phases were combined, stirred, and hydrochloric acid (2.0 eq, 0.068 mol, 5.7 mL) was added dropwise, stirred for 2 h, filtered, and the filter cake was washed with ethyl acetate (20 mL), and the wet product was dried at 45°C to obtain 12.95 g of the intermediate hydrochloride (compound 13) with a yield of 92.0%. The chromatogram of the product is shown in Figure 2 , its chromatographic purity is 99.81%, and all impurities are less than 0.1%.

[0061] Example 2

[0062] 1 / 10 of the reaction solution (74 mL) was kept at 40-50°C, and formic acid (1.5 eq, 0.051 mol, 2.35 g) was added, and the mixture was stirred for 1-2 h. Water (60 mL) and ethyl acetate (60 mL) were added, and the mixture was stirred for 5 min. The mixture was allowed to stand for separation to obtain an organic phase. The aqueous phase was returned to the separatory funnel, extracted with ethyl acetate (30 mL), and the mixture was allowed to stand for separation to obtain an organic phase. The two batches of organic phases were combined, stirred, and concentrated sulfuric acid (1.0 eq, 0.034 mol, 3.40 g) was added dropwise. The mixture was stirred for 2 h, filtered, and the filter cake was washed with ethyl acetate (20 mL). The wet product was dried at 45°C to obtain compound 1312.63 g, with a yield of 89.7%. The chromatogram of the product is shown in Figure 3 , its chromatographic purity is 99.70%, all impurities are less than 0.1%, and the total impurity is 0.30%.

[0063] Example 3

[0064] 1 / 10 of the reaction solution (74 mL) was kept at 40-50°C, trifluoroacetic acid (1.5 eq, 0.051 mol, 5.82 g) was added, and the mixture was stirred for 1-2 h. Water (60 mL) and ethyl acetate (60 mL) were added, stirred for 5 min, and the mixture was allowed to stand for separation to obtain an organic phase. The aqueous phase was returned to the separatory funnel, extracted with ethyl acetate (30 mL), and the mixture was allowed to stand for separation to obtain an organic phase. The two batches of organic phases were combined, stirred, and trifluoroacetic acid (2.0 eq, 0.064 mol, 7.30 g) was added dropwise, stirred for 10 h, filtered, and the filter cake was washed with ethyl acetate (100 mL). The wet product was dried at 45°C to obtain compound 1312.47 g, with a yield of 88.6%. The chromatogram of the product is shown in FIG. Figure 4 As shown, its chromatographic purity is 99.72%, all impurities are less than 0.1%, and the total impurity is 0.28%.

[0065] Comparative Example 1

[0066] Reference: Yamazaki Y, Araki T, Koura M, et al. Process for production of optically active PPAR-activating compound and intermediate ofthesame. USPatent 7,790,903[P].

[0067] Reference content: First try to recrystallize the crude product directly from methyl tert-butyl ether; then try column chromatography first, followed by recrystallization from methyl tert-butyl ether.

[0068] Add water (60 mL) and ethyl acetate (60 mL) to 1 / 10 of the reaction solution (74 mL), stir for 5 min, stand for separation to obtain an organic phase; return the aqueous phase to the separatory funnel, extract with ethyl acetate (30 mL), stand for separation to obtain an organic phase; combine the two batches of organic phases, and remove the solvent by rotary evaporation to obtain a crude intermediate (compound 13). Add MTBE (50 mL) to the crude intermediate (compound 13) (13.20 g) and stir until it is clear, then cool to 25-30 ° C, stir for 24 h, and no solid is precipitated; continue to cool to 0-5 ° C, stir for 12 h, and no solid is precipitated. Continue to cool to -5 to -10 ° C, stir for 12 h, and an oily substance is precipitated. Crystallization failed and was not detected.

[0069] The sample was concentrated and purified by silica gel column, with petroleum ether: ethyl acetate = 5:1-15:1 as the mobile phase. The fraction obtained by concentration was 10.84 g of oil. Methyl tert-butyl ether (30.90 mL) was added to the oil, and the solid was precipitated by stirring at room temperature. The solid was filtered until no liquid dripped. The filter cake was dried under reduced pressure at 30-40°C to constant weight, and 9.53 g was obtained, with a yield of 67.68%. The chromatogram of the product is shown in Figure 5 , its chromatographic purity is 98.38%, the maximum single impurity is 0.15%, and the total impurity is 0.62%.

[0070] Comparative Example 2

[0071] References: Timmanagouda, Karabasanagouda; Mohanakrishna, Jeyakumar; Manickam, Chandirasekar; Yeshaiah, Sudarsanam; Adaikkalasamy, Devaraj; Kumar, Ray Uttam; Swaminathan, Srinivasan. India, IN202041005093 A[P].

[0072] Reference content: The crude product was purified by recrystallization from tetrahydrofuran-n-heptane.

[0073] Add water (60 mL) and ethyl acetate (60 mL) to 1 / 10 of the reaction solution (74 mL), stir for 5 min, stand for separation to obtain an organic phase; return the aqueous phase to the separatory funnel, extract with ethyl acetate (30 mL), stand for separation to obtain an organic phase; combine the two batches of organic phases, add hydrochloric acid (10 mL) and water (90 mL), stir for 5 min, separate, and remove the solvent by rotary evaporation to obtain a crude intermediate (compound 13) oil. Add tetrahydrofuran (10 ml), and then slowly add heptane (100 ml) at 25 ° C. Then stir at 25 ° C for 12 hours, and an oily substance precipitates, but no solid is obtained.

[0074] Comparative Example 3

[0075] Add water (60mL) and ethyl acetate (60mL) to 1 / 10 of the reaction solution (74mL), stir for 5min, and stand to separate to obtain an organic phase; return the aqueous phase to the separatory funnel, extract with ethyl acetate (30mL), stand to separate to obtain an organic phase; remove the solvent by rotary evaporation to obtain a crude intermediate (compound 13) as an oily substance. Add methyl tert-butyl ether (30ml) and n-heptane (30mL), stir until clear, then cool to 5-10℃ and stir for 2-3h. Cool to -5~-10℃, stir for 2-3h, filter with suction, rinse the filter cake with n-heptane (20mL), and pump until no liquid drips. Dry the filter cake under reduced pressure at 30~40℃ to constant weight to obtain 9.23g, with a yield of 65.6%. The chromatogram of the product is shown in Figure 6 As shown, its chromatographic purity is 98.01%, of which the maximum single impurity is 1.13% and the total impurities are 1.99%.

[0076] It can be seen from the above comparative examples that the method mentioned in the literature cannot effectively achieve the effective purification of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol (intermediate 13). The refining process in the present invention has a significant effect on removing various impurities, is simple to operate, has a high yield, and can ensure that the product meets the expected quality requirements.

[0077] The above embodiments are only used to illustrate the present invention, but not to limit the present invention. Although the present invention is described in detail with reference to the embodiments, it should be understood by those skilled in the art that various combinations, modifications or equivalent substitutions of the technical solutions of the present invention do not depart from the spirit and scope of the technical solutions of the present invention, and should be included in the scope of the claims of the present invention.

Claims

1. A method for purifying 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol, comprising the following steps: 1) controlling the reaction solution containing 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol at a suitable temperature, adding acid, and stirring; 2) adding water and an organic solvent to the solution of step 1), stirring, standing and separating to obtain an organic phase; extracting the aqueous phase again with an organic solvent, standing and separating to obtain an organic phase, and combining the two batches of organic phases; 3) adding acid dropwise to the organic phase in step 2), stirring, and filtering; 4) washing the filter cake with an organic solvent, draining the wet product, and drying to obtain 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol hydrochloride; The acid in step 1) is selected from hydrochloric acid, formic acid or trifluoroacetic acid; the equivalent of the acid used in step 1) is 1.5 eq; The acid used in step 3) is selected from hydrochloric acid, concentrated sulfuric acid or trifluoroacetic acid; the equivalent of the acid used in step 3) is 1.0-2.0 eq.

2. The purification method according to claim 1, characterized in that In the step 1), the reaction liquid is controlled at 40-50°C.

3. The purification method according to claim 1, characterized in that The stirring time in step 1) is 1-2h.

4. The purification method according to claim 1, characterized in that In the step 2), the organic solvent is selected from ethyl acetate, isobutyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, toluene, benzene or methyltetrahydrofuran.

5. The purification method according to claim 1, characterized in that The stirring time in step 3) is 2-10 hours.

6. The purification method according to claim 1, characterized in that The organic solvent used in step 4) is ethyl acetate, isobutyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, toluene, benzene or methyltetrahydrofuran.

7. The purification method according to claim 1, characterized in that The drying temperature in step 4) is 45°C.

8. The purification method according to claim 1, characterized in that The following steps are involved: The reaction solution was temperature controlled at 40-50°C, 1.5 eq of hydrochloric acid was added, and the mixture was stirred for 1-2 h; water and ethyl acetate were added, the mixture was stirred for 5 min, and the mixture was allowed to stand for separation to obtain an organic phase; the aqueous phase was returned to the separatory funnel, extracted with ethyl acetate, and the mixture was allowed to stand for separation to obtain an organic phase; the two batches of organic phases were combined, the stirring was started, 2.0 eq of hydrochloric acid was added dropwise, the mixture was stirred for 2 h, and the mixture was filtered. The filter cake was washed with ethyl acetate, the wet product was dried, and the product was dried at 45°C to obtain 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol hydrochloride.

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