A method for synthesizing a key intermediate of ketorolac

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing a key intermediate of ketorolac. The method involves reacting 2-benzoylpyrrole with triethyl methanetricarboxylate in the presence of tert-butanol peroxide, potassium iodide, cuprous iodide, and tetrabutylammonium iodide, followed by post-treatment to yield 5-benzoylpyrrole-2-methanetricarboxylate triethyl ester (M-1). The reaction conditions are mild, the operation is simple, the reaction steps are few, and the product yield and purity are high, making it suitable for industrial-scale production. It avoids the problem of large amounts of manganese ions and acetic acid present in the system in existing technologies.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a method for synthesizing a key intermediate of ketorolac. Background Technology

[0002] Ketoroxyprotein tromethamine is a novel, injectable nonsteroidal anti-inflammatory drug (NSAID) with potent analgesics and moderate anti-inflammatory and antipyretic properties. Its mechanism of action involves inhibiting the production of peripheral and central prostaglandins (PGs), thereby reducing PG levels in both the peripheral and central nervous systems. The chemical structure of its main component, ketoroxylic acid, is as follows:

[0003]

[0004] In the synthesis of ketorolac tromethamine, the synthesis of ketorolac is particularly important. Currently, the synthesis of ketorolac tromethamine mostly starts with 2-benzoylpyrrole as the starting material, proceeding through oxidative condensation, cyclization, deacidification, and finally salt formation to obtain ketorolac tromethamine. The reaction route is as follows:

[0005]

[0006] Especially under the catalysis of trivalent manganese ions, 2-benzoylpyrrole reacts with triethyl methanetricarboxylate via a free radical reaction, followed by an oxidative condensation reaction to generate 5-benzoylpyrrole-2-methanetricarboxylate (M-1). However, due to the inherent instability of trivalent manganese acetate, most of the preparation methods of ketorolac tromethamine disclosed in patent literature US5082950; Synthesis, 1991, (7): 567-568; Chinese Journal of Pharmaceutical Industry, 2001, 32(5): 202-203; Chinese Journal of Medicinal Chemistry, 1995, 5(3): 223-225 adopt a "one-pot" method to synthesize the ketorolac intermediate 5-benzoylpyrrole-2-methanetricarboxylate. In the synthesis process, due to the limitations of the solvent used to prepare trivalent manganese acetate compounds, acetic acid is used as the solvent in almost all free radical reactions involving the synthesis of this intermediate. Therefore, in the post-processing, a large amount of manganese ions and acetic acid are inevitably present in the system, leading to difficulties in liquid-liquid extraction and the inability to remove high-boiling-point acetic acid solvent. In addition, in order to remove a large amount of manganese ion compounds and impurities, patent US5082950 has to use column chromatography, but this method is obviously not suitable for the requirements of large-scale industrial production. Although Zhu Ju et al. (Chinese Journal of Pharmaceutical Chemistry, 1995, 5(3): 223-225) optimized the post-processing by using water quenching and then using toluene for extraction, although the literature did not explicitly point out the problems encountered in liquid-liquid extraction, it is undeniable that the reaction still has the problems of difficult liquid-liquid extraction and the inability to remove a large amount of high-boiling-point acetic acid solvent in the subsequently concentrated organic phase.

[0007] CN202110305138.2 discloses an improved method for preparing a ketorolac intermediate, wherein the intermediate is 5-benzoylpyrrole-2-methanetricarboxylic acid triethyl ester (M-1). The method involves reacting 2-benzoylpyrrole, methanetricarboxylic acid triethyl ester, manganese acetate dihydrate (trivalent), sodium acetate, and acetic anhydride in an organic solvent. The mixture is then extracted with an aqueous sodium bisulfite solution, and the organic phase is concentrated under reduced pressure and slurried with an alcohol solvent to obtain the final product. This method effectively solves the post-processing problems caused by the presence of large amounts of manganese ions and acetic acid, while also reducing the high energy consumption, long cycle time, and high cost associated with later concentration. The obtained intermediate has advantages such as high purity and high yield, making it suitable for industrial production.

[0008] CN202111483639.6 discloses an improved method for preparing ketorolac. This method uses 2-benzoylpyrrole as the main raw material and directly reacts it under the catalysis of manganese acetate dihydrate (trivalent). After simple liquid-liquid separation, the organic phase directly undergoes a cyclization reaction, followed by hydrolysis and decarboxylation. The reaction solution is then adjusted to obtain ketorolac. This method employs a one-pot continuous reaction of oxidative condensation, cyclization, and hydrolysis, simplifying the operation, improving yield and purity, while reducing production costs and waste emissions, making it suitable for industrial production.

[0009] Although existing techniques for synthesizing 5-benzoylpyrrole-2-methanetricarboxylic acid triethyl ester (M-1) involve separating the trivalent manganese acetate compound, replacing acetic acid (which affects subsequent reaction processes) with N-methylpyrrolidone or toluene solvent, and adding an aqueous solution of a reducing inorganic compound after the reaction to further destroy manganese ions, these techniques suffer from several drawbacks. First, the inherent instability of the trivalent manganese acetate compound limits its ability to react with free radicals. Second, the presence of large amounts of manganese ions and impurities significantly impacts the overall reaction. Through repeated experimentation and research during process optimization, the inventors have found a new catalytic system and solvent that avoids the problems associated with large amounts of manganese ions and acetic acid in the system. Summary of the Invention

[0010] To overcome the shortcomings of existing technologies, this invention provides a method for synthesizing a key intermediate of ketorolac. The method for synthesizing 5-benzoylpyrrole-2-methanetricarboxylic acid triethyl ester (M-1) of this invention features mild reaction conditions, simple operation, few reaction steps, high product yield, and low cost, making it suitable for industrial-scale production.

[0011] To achieve the above objectives, the present invention is implemented through the following solution:

[0012] Compound SM, triethyl methanetricarboxylate, tert-butanol peroxide, catalyst, and reaction solvent were added to a reaction vessel. The system was stirred overnight at a controlled temperature (T). After post-treatment, the target product M-1 was obtained. The reaction formula is as follows:

[0013]

[0014] In a preferred embodiment, the molar ratio of compound SM, triethyl methanetricarboxylate, tert-butanol peroxide, and catalyst is 1.00:(1.20~2.20):(2.00~4.00):(0.05~0.30), preferably 1.00:1.50:3.00:0.15.

[0015] In a preferred embodiment, the reaction solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, and 1,4-dioxane, with dimethyl sulfoxide being preferred.

[0016] In a preferred embodiment, the temperature T is 90–110°C; more preferably 95–105°C.

[0017] In a preferred embodiment, the catalyst is one of potassium iodide, cuprous iodide, and tetrabutylammonium iodide (TBAI), with tetrabutylammonium iodide (TBAI) being the most preferred.

[0018] In a preferred embodiment, the tert-butanol peroxide is preferably an aqueous solution with a mass fraction of 65-80%, and more preferably an aqueous solution with a mass fraction of 70%.

[0019] In the preferred embodiment, the post-processing is as follows: after the reaction is completed, the reaction solution is cooled and poured into an aqueous solution of Na2S2O3. After stirring, the solution is filtered and the filter cake is washed with water. The resulting filter cake is pulped with methyl tert-butyl ether, filtered, and the filter cake is washed with methyl tert-butyl ether and then dried under vacuum to obtain compound M-1.

[0020] In a preferred embodiment, the water-soluble Na2S2O3 has a mass fraction of 8-15%.

[0021] In a preferred embodiment, the pulping temperature of the methyl tert-butyl ether is 0–10°C.

[0022] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0023] This invention provides a method for synthesizing triethyl 5-benzoylpyrrole-2-methanetricarboxylate (M-1), a key intermediate in ketorolac. The reaction conditions are mild, the operation is simple, the number of reaction steps is small, and the product yield and purity are high, making it suitable for industrial-scale production. It avoids the problem of large amounts of manganese ions and acetic acid present in the system in existing technologies. Detailed Implementation

[0024] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0025] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0026] Example 1

[0027] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and TBAI (5.54 g, 15 mmol, 0.15 eq.) were added to DMSO (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The resulting filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1, with a yield of 93.1% and an HPLC purity of 97.59%.

[0028] Example 2

[0029] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (25.75 g, 200 mmol, 2.00 eq.), and TBAI (1.85 g, 5 mmol, 0.05 eq.) were added to DMSO (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The resulting filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1, with a yield of 87.1% and an HPLC purity of 97.54%.

[0030] Example 3

[0031] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (51.49 g, 400 mmol, 4.00 eq.), and TBAI (11.08 g, 30 mmol, 0.30 eq.) were added to N,N-dimethylformamide (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The obtained filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and then vacuum dried at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1 with a yield of 93.3% and an HPLC purity of 96.89%.

[0032] Example 4

[0033] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and potassium iodide (2.50 g, 15 mmol, 0.15 eq.) were added to DMSO (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The resulting filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1, with a yield of 92.0% and an HPLC purity of 97.57%.

[0034] Example 5

[0035] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and potassium iodide (2.50 g, 15 mmol, 0.15 eq.) were added to 1,4-dioxane (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The obtained filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and then dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1 with a yield of 92.0% and an HPLC purity of 97.57%.

[0036] Example 6

[0037] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and cuprous iodide (2.86 g, 15 mmol, 0.15 eq.) were added to 1,4-dioxane (200 mL), and the mixture was heated and stirred overnight at 95–105 °C. After cooling, the reaction mixture was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The obtained filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and then vacuum dried at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1 with a yield of 91.0% and an HPLC purity of 97.55%.

[0038] Example 7

[0039] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and TBAI (5.54 g, 15 mmol, 0.15 eq.) were added to DMSO (200 mL), and the mixture was heated and stirred overnight at 90 °C. After cooling, the reaction solution was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The resulting filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1, with a yield of 89.0% and an HPLC purity of 97.56%.

[0040] Example 8

[0041] Compound SM (17.12 g, 100 mmol, 1.00 eq.), triethyl methanetricarboxylate (34.83 g, 150 mmol, 1.50 eq.), 70% tert-butanol peroxide (38.62 g, 300 mmol, 3.00 eq.), and TBAI (5.54 g, 15 mmol, 0.15 eq.) were added to DMSO (200 mL), and the mixture was heated and stirred overnight at 110 °C. After cooling, the reaction solution was poured into a 10% Na₂S₂O₃ aqueous solution (800 mL), stirred for 1–2 hours, filtered, and the filter cake was washed with water. The resulting filter cake was slurried with methyl tert-butyl ether (50 mL) at 0–10 °C for 3–4 hours, filtered, washed with methyl tert-butyl ether (20 mL), and dried under vacuum at 40–50 °C for 6–8 hours to obtain a light yellow solid product M-1, with a yield of 88.0% and an HPLC purity of 97.46%.

Claims

1. A process for the synthesis of a key intermediate of ketorolac characterized in that, The compound SM, triethyl methane tricarboxylate, tert-butyl hydroperoxide, a catalyst, and a reaction solvent are added into a reaction container, the system is controlled to a temperature T and stirred overnight, and the target product M-1 is obtained through post-treatment, and the reaction formula is as follows: ； The reaction solvent is dimethyl sulfoxide, N,N- one of dimethylformamide, 1,4-dioxane; The temperature T is 90-110 ℃. The catalyst is one of potassium iodide, cuprous iodide, and tetrabutylammonium iodide.

2. The method of synthesis of claim 1, wherein, The molar ratio of the compound SM, triethyl methane tricarboxylate, tert-butyl hydroperoxide, and the catalyst is 1.00:(1.20-2.20):(2.00-4.00):(0.05-0.30).

3. The method of synthesis of claim 1, wherein, The molar ratio of the compound SM, triethyl methane tricarboxylate, tert-butyl hydroperoxide, and the catalyst is 1.00:1.50:3.00:0.

15.

4. The method of synthesis of claim 1, wherein, The reaction solvent is dimethyl sulfoxide.

5. The method of synthesis of claim 1, wherein, The temperature T is 95-105 ℃.

6. The method of synthesis of claim 1, wherein, The catalyst is tetrabutylammonium iodide.

7. The method of synthesis of claim 1, wherein, The post-treatment is as follows: after the reaction is completed, the reaction solution is cooled and poured into an aqueous Na2S2O3 solution, stirred, and then filtered under suction and washed with water, the obtained filter cake is slurried with methyl tert-butyl ether, filtered under suction, washed with methyl tert-butyl ether, and then dried in vacuum to obtain the compound M-1.

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