A preparation method of etodolac impurities

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis. The present invention provides a preparation method of etodolac impurities, which is obtained by ring-opening reaction of etodolac as a raw material under the action of a catalyst. The present invention has the characteristics of simple operation and mild reaction conditions. The product obtained by the present invention has a high yield and purity, providing a guarantee for the quality research of etodolac.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of etodolac impurities. Background Art

[0002] Etodolac is a pyranose carboxylic acid steroid anti-inflammatory drug. By blocking the activity of cyclooxygenase, it inhibits the synthesis of prostaglandin (PG), and has anti-inflammatory, antipyretic and analgesic effects. Clinically, it is used to treat postoperative pain and relieve the symptoms of rheumatoid arthritis and osteoarthritis. Its chemical structural formula is shown as follows:

[0003]

[0004] Currently, there are many reported synthesis methods of etodolac. For example, in US Patent US4585877A and the literature "Research on the Synthesis Process of Etodolac", Tianjin Chemical Industry, 2004, 18(5), 22 - 23, and "Synthesis Process of Etodolac", Acta Chimica Sinica, 2005, 56(8), 1536 - 1540, o-nitroethylbenzene is used as the raw material, reduced with iron powder to obtain o-ethylaniline, then after diazotization reaction, it is reduced with sodium sulfite (sodium bisulfite or stannous chloride) to obtain o-ethylphenylhydrazine hydrochloride, and then refluxed with 2,3-dihydrofuran in 1,4-dioxane to obtain 7-ethylchromanol. Then, 7-ethylchromanol is cyclized with methyl 3-methoxy-2-pentenoate or methyl 3-oxopentanoate to obtain methyl etodolac, and finally hydrolyzed under alkaline conditions to obtain etodolac. The route is as follows:

[0005]

[0006] Etodolac has poor stability and can be damaged by acids, bases, light and heat, generating dozens of impurities. The generation of these impurities poses a potential threat to clinical medication. In order to better realize the economic and social benefits of this drug, it is necessary to strictly control various impurities in the standard, and clarifying each impurity item is an urgent problem to be solved.

[0007] Xu Meiju et al. (Determination of the content of etodolac by high performance liquid chromatography, Guangdong Chemical Industry, 2013, 40, (5) 19 - 23) disclosed the acid destruction, base destruction, oxidation destruction, light destruction and heat destruction tests of etodolac respectively, and detected the components after the destruction tests to obtain the high performance liquid chromatography diagram after the destruction tests, but did not give the corresponding impurity items. Yang Wanhua, (Determination of related substances in etodolac sustained release tablets by high performance liquid chromatography, China Pharmacy, Vol. 16, No. 17, 2005, 1330 - 1332) disclosed four impurities in several etodolac sustained release tablet destruction tests and their high performance liquid chromatography detection conditions.

[0008] However, obtaining impurity samples with high purity and high yield has posed quite a few problems for researchers. The European Pharmacopoeia 10.0 also lists more than a dozen impurities of etodolac, among which impurity L is less in content and more difficult to obtain during the research process. The structure of impurity L is as follows:

[0009]

[0010] To provide more samples of impurity L, there is an urgent need to find a synthesis scheme for impurity L. SUMMARY OF THE INVENTION

[0011] Aiming at the problems existing in the current preparation technology of etodolac impurity L in the European Pharmacopoeia, the present invention provides a preparation method for etodolac impurities. The target products obtained by this method are characterized by easily available raw materials, simple operation, high purity and yield, and low production cost.

[0012]

[0013] The technical solution of the present invention is as follows:

[0014] A preparation method for (EZ)-3-(7-ethyl-3-(2-hydroxyethyl)-1H-indol-2-yl)pent-3-enoic acid (impurity L), an etodolac impurity, uses etodolac as the raw material, reacts under the action of a catalyst, and obtains the target product through purification. The reaction formula is as follows:

[0015]

[0016] The specific technical solution of the present invention is as follows:

[0017] Step A: Preparation of crude etodolac impurity L

[0018] At room temperature, add etodolac and a certain amount of catalyst to the reaction solvent, control the temperature and stir to react. After the reaction is completed, obtain the crude target impurity L through post-treatment.

[0019] Step B: Purification of the crude product

[0020] Dissolve the crude impurity L in solvent b by heating, then add solvent c, control the temperature to precipitate crystals, filter, and dry to obtain impurity L.

[0021] Preferably, the catalyst in step A is one or a combination of trifluoromethanesulfonic acid and scandium trifluoromethanesulfonate, and among them, scandium trifluoromethanesulfonate is particularly preferred.

[0022] Preferably, the reaction solvent in step A is one or a combination of dichloromethane, toluene, and chloroform, and among them, dichloromethane is particularly preferred.

[0023] Preferably, in step A, the molar ratio of etodolac to the catalyst is 1:0.1 - 0.5, and particularly preferably 1:0.2.

[0024] Preferably, the reaction temperature in step A is 35 - 60 °C; for low-boiling solvents such as dichloromethane and chloroform, the maximum temperature can be controlled at their reflux temperature.

[0025] Preferably, the reaction time in step A is 2 - 10 h.

[0026] Preferably, the post-treatment of step A is as follows: after detecting the completion of the reaction, the reaction solution is washed with water, the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain the crude product of impurity L.

[0027] Preferably, the solvent b in step B is one of ethyl acetate, dichloromethane, and acetone; more preferably ethyl acetate; the solvent c is petroleum ether.

[0028] Preferably, the mass-volume ratio of the crude product in step B to the solvent b is 1:5 - 8, g / ml; preferably 1:6, g / ml; the volume ratio of the solvent c to the solvent b is 1:2 - 4, preferably 1:3.

[0029] Preferably, the crystallization temperature in step B is 0 - 10 °C.

[0030] The technical effects of the present invention:

[0031] The present invention provides a preparation method of etodolac impurity L, which can effectively prepare etodolac impurity L, with a total yield as high as 75.8%. The purity is above 95.9%, meeting the requirements for the research of etodolac impurities. Description of the Drawings

[0032] Figure 1 is the mass spectrometry pattern of etodolac impurity L;

[0033] Figure 2 is the hydrogen spectrum pattern of etodolac impurity L;

[0034] Figure 3 is the carbon spectrum pattern of etodolac impurity L;

[0035] Figure 4 is the HPLC pattern of etodolac finished product;

[0036] Figure 5 is the HPLC pattern of etodolac impurity L obtained in Example 1;

[0037] Figure 6 is the HPLC pattern of etodolac impurity L obtained in Example 2;

[0038] Figure 7It is the HPLC chromatogram of etodolac finished product and etodolac impurity L. Detailed implementation manners

[0039] The present invention will be further illustrated by the following examples. It should be understood correctly that the examples of the present invention are only for illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope protected by the present invention.

[0040] The present invention uses HPLC to determine the purity of etodolac finished product and etodolac impurity L. The chromatographic conditions are as follows:

[0041] Chromatographic column: Agilent ZORBAX SB-Aq, 4.6 mm × 150 mm, 3.5 μm or a chromatographic column with equivalent performance;

[0042] Mobile phase A: 0.1% (ml / ml) phosphoric acid solution;

[0043] Mobile phase B: methanol;

[0044] Gradient elution:

[0045]

[0046] Column temperature: 35 °C;

[0047] Detection wavelength: 225 nm;

[0048] Flow rate: 0.9 mL / min;

[0049] Injection volume: 10 μL.

[0050] Identification data of etodolac impurity L:

[0051]

[0052] Table 1 Molecular ion peak and attribution of etodolac impurity L sample (see details in Figure 1 )

[0053] sample attribution molecular ion peak 288.2 <![CDATA[[M+H] + >

[0054] The results show that the molecular ion peak [M + H] of this product measured by mass spectrometry + , and its mass-to-charge ratio m / z is 288.2, which is consistent with the molecular ion peak (molecular weight is 287.15) of etodolac ring-opening impurity L.

[0055] Table 2 1H-NMR data of etodolac impurity L sample in DMSO-d6 (see details in 1 ), Figure 2 )

[0056] serial number chemical shift δ multiplicity number of protons 18 12.145 brs 1 1 10.411 s 1 5 7.288 d 1 6 6.894 t 1 7 6.854 d 1 19 5.966 q 1 14 4.629 brs 1 13 3.588 t 2 16 3.550 s 2 12 2.876 t 2 10 2.836 q 2 20 1.840 d 3 11 1.239 t 3

[0057] Table 3 C-NMR data (ppm) of Etodolac impurity L sample in DMSO-d6 (see 13 for details) Figure 3 )

[0058]

[0059]

[0060] In addition, Figure 4 , Figure 5 , Figure 6 , Figure 7 are the HPLC detection chromatograms of etodolac finished product, etodolac impurity L, and the mixed sample of etodolac and etodolac impurity L, respectively, and the relative retention times of each sample are determined. Among them, Figure 7 , the retention time of etodolac impurity L is 14.709 min, and the retention time of etodolac finished product is 16.213 min.

[0061] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0062] Example 1

[0063] At room temperature, etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (9.84 g, 0.02 mol) were successively added to dichloromethane (500 mL). After stirring evenly, the temperature was controlled for reflux reaction for 8 h. After detection, the reaction was complete. The reaction solution was washed with purified water, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 28.32 g of crude product of impurity L;

[0064] The above 28.32 g of crude product was dissolved in 170 ml of ethyl acetate, refluxed and dissolved, and then 56 ml of petroleum ether was added to the solution. The temperature was controlled at 0 - 5 °C, and crystallization was carried out with stirring for 2 h. Then, filtration was carried out to obtain a white solid. The total yield was 75.8% (calculated based on etodolac), and the HPLC purity was 99.135%.

[0065] Example 2

[0066] At room temperature, etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (4.92 g, 0.01 mol) were successively added to dichloromethane (500 mL). After stirring evenly, the temperature was controlled for reflux reaction for 8 h. After detection, the reaction was complete. The reaction solution was washed with purified water, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 27.53 g of crude product of impurity L;

[0067] Dissolve 27.53 g of the above crude product in 138 ml of ethyl acetate, reflux to dissolve, then add 35 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 70.4% (calculated based on etodolac), and the HPLC purity is 95.925%.

[0068] Example 3

[0069] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (24.60 g, 0.05 mol) to dichloromethane (500 mL) in sequence. After stirring evenly, control the temperature for reflux reaction for 8 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 27.32 g of crude product of impurity L;

[0070] Dissolve 27.32 g of the above crude product in 160 ml of ethyl acetate, reflux to dissolve, then add 55 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 73.6% (calculated based on etodolac), and the HPLC purity is 98.756%.

[0071] Example 4

[0072] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (2.46 g, 0.005 mol) to dichloromethane (500 mL) in sequence. After stirring evenly, control the temperature for reflux reaction for 8 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 28.35 g of crude product of impurity L;

[0073] Dissolve 28.35 g of the above crude product in 170 ml of ethyl acetate, reflux to dissolve, then add 56 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 67.7% (calculated based on etodolac), and the HPLC purity is 98.436%.

[0074] Example 5

[0075] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (9.84 g, 0.02 mol) to chloroform (500 mL) in sequence. After stirring evenly, control the temperature at 60 °C (with reflux phenomenon) and react for 6 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 27.35 g of crude product of impurity L;

[0076] Dissolve 27.35 g of the above crude product in 136 ml of ethyl acetate, reflux to dissolve, then add 45 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 74.3% (calculated based on etodolac), and the HPLC purity is 98.019%.

[0077] Example 6

[0078] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (9.84 g, 0.02 mol) to toluene (500 mL) in sequence. After stirring evenly, control the temperature at 65 °C and react for 6 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 27.31 g of crude product of impurity L;

[0079] Dissolve 27.31 g of the above crude product in 165 ml of ethyl acetate, reflux to dissolve, then add 55 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 70.4% (calculated based on etodolac), and the HPLC purity is 98.685%.

[0080] Example 7

[0081] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and scandium trifluoromethanesulfonate (9.84 g, 0.02 mol) to toluene (500 mL) in sequence. After stirring evenly, control the temperature at 35 °C and react for 8 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 28.43 g of crude product of impurity L;

[0082] Dissolve 28.43 g of the above crude product in 220 ml of acetone, reflux to dissolve, then add 55 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 67.3% (calculated based on etodolac), and the HPLC purity is 99.006%.

[0083] Example 8

[0084] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and trifluoromethanesulfonic acid (3.00 g, 0.02 mol) to dichloromethane (500 mL) in sequence. After stirring evenly, control the temperature at reflux and react for 10 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 28.53 g of crude product of impurity L;

[0085] Dissolve 28.53 g of the above crude product in 172 ml of acetone, reflux to dissolve, then add 86 ml of petroleum ether to the solution, control the temperature at 0 - 5 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 73.1% (calculated based on etodolac), and the HPLC purity is 98.985%.

[0086] Example 9

[0087] Under room temperature conditions, add etodolac (28.74 g, 0.10 mol) and trifluoromethanesulfonic acid (3.00 g, 0.02 mol) to toluene (500 mL) in sequence. After stirring evenly, control the temperature at 60 °C and react for 6 h. After detection, the reaction is complete. Add purified water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 28.40 g of crude product of impurity L;

[0088] Dissolve 28.40 g of the above crude product in 170 ml of dichloromethane, reflux to dissolve, then add 56 ml of petroleum ether to the solution, control the temperature at 5 - 10 °C, stir for crystallization for 2 h, filter by suction to obtain a white solid, with an overall yield of 74.2% (calculated based on etodolac), and the HPLC purity is 98.821%.

Claims

1. A method for preparing etodolac impurities, characterized in that, Using etodolac as a raw material, reacting under the action of a catalyst, and obtaining the target product etodolac impurity L through purification; the reaction formula is as follows: ； The catalyst is one or a combination of trifluoromethanesulfonic acid and scandium trifluoromethanesulfonate; The reaction solvent is one or a combination of dichloromethane, toluene, and chloroform; The reaction temperature is 35 - 60 °C.

2. The preparation method according to claim 1, characterized in that, Specifically, it includes the following steps: Step A: Preparation of crude etodolac impurity L At room temperature, add etodolac and a certain amount of catalyst to the reaction solvent, control the temperature and stir for reaction. After the reaction is completed, obtain the crude target impurity L through post-treatment; Step B: Refinement of the crude product Dissolve the crude etodolac impurity L by heating with solvent b, then add solvent c, control the temperature to precipitate crystals, filter, and dry to obtain etodolac impurity L.

3. The preparation method according to claim 2, characterized in that, In step A, the molar ratio of etodolac to the catalyst in the feed is 1:0.1 - 0.

5.

4. The preparation method according to claim 2, characterized in that, The post-treatment in step A is as follows: After detecting that the reaction is completed, add water to wash the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the crude etodolac impurity L.

5. The preparation method according to claim 2, characterized in that, In step B, solvent b is one of ethyl acetate, dichloromethane, and acetone; solvent c is petroleum ether.

6. The preparation method according to claim 2, characterized in that, In step B, solvent b is ethyl acetate.

7. The preparation method according to claim 5, characterized in that, In step B, the mass-volume ratio of the crude product to solvent b is 1:5 - 8, g / ml; the volume ratio of solvent c to solvent b is 1:2 - 4.

8. The preparation method according to claim 5, characterized in that In step B, the mass-volume ratio of the crude product to solvent b is 1:6, g / ml; the volume ratio of solvent c to solvent b is 1:

3.

9. The preparation method according to claim 2, characterized in that, The crystallization temperature in step B is 0 - 10 °C.

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