A method for preparing an etoricoxib intermediate

Abstract

This invention is entitled "A Method for Preparing an Intermediate of Aericoxib," belonging to the field of pharmaceutical preparation technology. The technical problem to be solved is to provide a method for preparing an intermediate of Aericoxib that is simple to operate, uses readily available raw materials, and has simple post-processing. The key points of the technical solution are that the preparation method includes the following steps: (1) 2-bromo-1-(4-methanesulfonyl)acetophenone, hexamethylenetetramine and solvent are reacted, filtered, hydrochloric acid and methanol are added, and the reaction is continued to obtain 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride; (2) 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, base 1 and solvent are mixed, reacted, cooled to -5℃-15℃, base 2 and 1-bromopropane are added, and the reaction is continued to obtain the intermediate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and more specifically, to a method for preparing an intermediate of etoricoxib. Background Technology

[0002] Imrecoxib is a selective cyclooxygenase (COX-2) inhibitor used to treat and relieve pain symptoms caused by osteoarthritis and postoperative inflammation. Its chemical name is N-n-propyl-3-p-methylphenyl-4-p-methanesulfonylphenyl-3-pyrrolidine-2-one, and its chemical structural formula is as follows: .

[0003] Relevant patent documents retrieved: This document, published in China (CN120208838A) on June 27, 2025, discloses a method for synthesizing etoricoxib. It involves reacting 2-bromo-1-(4-methanesulfonyl)acetophenone with p-methylphenylacetic acid to form a cyclic lactone, followed by transesterification with n-propylamine to obtain the target product. The reaction involves high temperatures and a large amount of wastewater. The reaction route is as follows: .

[0004] The publication, published in China (CN107586268A) on January 16, 2018, discloses a method for preparing etoricoxib. The method involves the condensation of a 2-(4-methanesulfonylphenyl)oxalanine ring with n-propylamine, followed by condensation with p-methylphenylacetic acid, oxidation, and cyclization to obtain the target product etoricoxib. The reaction route is as follows: .

[0005] In the above technical solution, it is not difficult to see that the pre-ring-closing product is the key intermediate of etoricoxib (Formula I), but this technical solution involves the dangerous reaction of oxidation.

[0006]

[0007] Formula I In conclusion, it is essential to develop a method for preparing the intermediate of atorcoxib shown in Formula I that is simple to operate, has controllable quality, and is suitable for industrial production. Summary of the Invention

[0008] The purpose of this invention is to provide: A method for preparing an etoricoxib intermediate, and related technologies, to solve the technical problems of providing a new method for preparing an etoricoxib intermediate with fewer steps, readily available raw materials, simple post-processing, low waste, and suitability for industrial production, or a combination thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2), Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06."

[0012] Unless otherwise stated, conventional methods within the scope of the art, such as filtration and mixing, shall be used.

[0013] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0014] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0015] The term "crystallization" as used in this article refers to the process by which a solute in a solution precipitates out of a supersaturated state to form crystals. By controlling conditions such as temperature and stirring speed, crystal products with high purity can be obtained.

[0016] As used in this article, "rinsing" refers to the process of washing a solid surface with a solvent to remove residual impurities. For example, after crystallization, rinsing the crystal with a low-boiling-point solvent can facilitate subsequent drying.

[0017] As used in this article, "drying" refers to the process of removing moisture or other solvents from a compound by heating, vacuuming, or using a desiccant.

[0018] As used in this article, "mixing" refers to the process of uniformly distributing two or more components through manipulation, with the aim of achieving consistency in component content. For example, in pharmaceutics, mixing involves combined operations of solids with solids, solids with liquids, or liquids with liquids to ensure the homogeneity of the final product.

[0019] In a first aspect, the present invention provides: a method for preparing an intermediate of ericyclophosphamide, comprising the following steps:

[0020] (1) 2-bromo-1-(4-methanesulfonyl)acetophenone, hexamethylenetetramine and solvent were reacted, filtered, hydrochloric acid and methanol were added, and the reaction was continued to give 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride; (2) 2-Amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, base 1 and solvent are mixed and reacted, cooled to -5℃-15℃, base 2 and 1-bromopropane are added, and the reaction is continued to obtain the product.

[0021] Preferably, in step (1), the molar ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone and hexamethylenetetramine is 0.9-1.1:2.8-3.2.

[0022] Any point value or sub-range value within the range of 0.9-1.1:2.8-3.2 can achieve the technical effect of the present invention, including but not limited to 0.9:2.8, 0.9:2.9, 0.9:3.0, 0.9:3.1, 0.9:3.2, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1.1:2.8, 1.1:2.9, 1.1:3.0, 1.1:3.1, and 1.1:3.2.

[0023] More preferably, in step (1), the molar ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone and hexamethylenetetramine is 1:3.0.

[0024] Preferably, in step (1), the solvent is selected from at least one of acetonitrile, acetone, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, and methanol.

[0025] More preferably, in step (1), the solvent is acetonitrile.

[0026] Preferably, in step (1), the 2-bromo-1-(4-methanesulfonyl)acetophenone, hexamethylenetetramine and solvent are mixed and then reacted.

[0027] Preferably, the mixing is performed by stirring, and the temperature is 0-10℃.

[0028] The technical effects of this invention can be achieved at any point or sub-range value within the range of 0-10℃, including but not limited to 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, and 10℃.

[0029] Preferably, in step (1), the reaction temperature is 20-25℃ and the time is 16-24h.

[0030] The technical effects of this invention can be achieved at any point or sub-range value within the range of 20-25℃, including but not limited to 20℃, 21℃, 22℃, 23℃, 24℃, and 25℃.

[0031] Any point value or sub-range value within the range of 16-24h can achieve the technical effect of the present invention, including but not limited to 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, and 24h.

[0032] Preferably, in step (1), the concentration of the hydrochloric acid is 36 wt%.

[0033] Preferably, in step (1), the mass ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone, hydrochloric acid and methanol is 0.9-1.1:0.9-1.1:4.8-5.2.

[0034] Any point value or sub-range value within the range of 0.9-1.1:0.9-1.1:4.8-5.2 can achieve the technical effect of this invention, including but not limited to 0.9:0.9:4.8, 0.9:1.0:4.9, 0.9:1.1:5.0, 0.9:1.0:5.1, 0.9:0.9:5.1, 0.9:1.1:5.2, 1.0:0.9:4.8, 1.0:1.0:4.9, 1.0:1.1:5.0, 1.0:1.0:5.1, 1.0:0.9:5.1, 1.0:1.1:5.2, 1.1:0.9:4.8, 1.1:1.0:4.9, 1.1 More preferably, in step (1), the mass ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone, hydrochloric acid and methanol is 1.0:1.0:5.0.

[0035] Preferably, step (1) further includes post-processing: cooling and crystallization, filtration, and drying.

[0036] Preferably, in step (2), the molar ratio of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, and base 1 is 1.0:1.3-1.7:1.8-2.2.

[0037] Any point value or sub-range value within the range of 1.0:1.3-1.7:1.8-2.2 can achieve the technical effect of the present invention, including but not limited to 1.0:1.2:1.8, 1.0:1.3:1.9, 1.0:1.4:2.0, 1.0:1.5:2.1, 1.0:1.6:2.2, 1.0:1.7:1.8, 1.0:1.3:1.9, 1.0:1.4:2.0, 1.0:1.5:2.1, 1.0:1.6:2.2, 1.0:1.7:1.8, 1.1:1.3:1.9, 1.1:1.4:2.0, 1.1:1.5:2.1, 1.1:1.6:2.2, and 1.1:1.7:1.8.

[0038] More preferably, in step (2), the molar ratio of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, and base 1 is 1:1.5:2.

[0039] Preferably, in step (2), the solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and N,N-dimethylacetamide.

[0040] More preferably, in step (2), the solvent is N,N-dimethylformamide.

[0041] Preferably, in step (2), the molar ratio of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, bromopropane, and base 2 is 1.0:1.8-2.2:2.8-3.2.

[0042] Any point value or sub-range value within the range of 1.0:1.8-2.2:2.8-3.2 can achieve the technical effect of this invention, including but not limited to 1.0:1.8:2.8, 1.0:1.9:2.9, 1.0:2.0:3.0, 1.0:2.1:3.1, 1.0:2.2:3.2, 1.0:2.0:3.3, and 1.0:1.8:2. 8, 1.0:1.9:2.9, 1.0:2.0:3.0, 1.0:2.1:3.1, 1.0:2.2:3.2, 1.0:2.0:3.3, 1.1:1.8:2.8, 1.1:1.9:2.9, 1.1:2.0:3.0, 1.1:2.1:3.1, 1.1:2.2:3.2, 1.1:2.0:3.2.

[0043] Preferably, in step (2), the base 2 is potassium tert-butoxide.

[0044] Preferably, in step (2), the temperature of the mixing reaction is 20-25°C.

[0045] The technical effects of this invention can be achieved at any point or sub-range value within the range of 20-25℃, including but not limited to 20℃, 21℃, 22℃, 23℃, 24℃, and 25℃.

[0046] In step (2), any point value or sub-range value within the range of -5℃ to 15℃ can achieve the technical effect of the present invention, including but not limited to -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, and 15℃.

[0047] Preferably, in step (2), after the reaction is completed, post-processing is also included: the reaction solution is poured into water, stirred and filtered, the filter cake is washed with ice-cold ethanol and dried.

[0048] The beneficial effects of this invention are as follows: This invention provides a method for preparing a key intermediate of etoricoxib. In step (2), a one-pot method is used to prepare the key intermediate of etoricoxib, which is simple to operate, the raw materials are readily available, the post-processing is simple, and the amount of waste is small, making it suitable for industrial production. Attached Figure Description

[0049] Figure 1 The intermediate of atorcitabine prepared in Example 1 1 H-NMR spectrum.

[0050] Figure 2 The LC-MS spectrum of the etoricoxib intermediate prepared in Example 1. Detailed Implementation

[0051] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0052] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0053] Example 1 A method for preparing an intermediate of atorcoxib, comprising the following steps:

[0054] (1) In a 1000mL three-necked flask, 600mL of acetonitrile was added, and 200g of 2-bromo-1-(4-methanesulfonyl)acetophenone (MW: 277.14, 0.722mol, 1.0eq.) was added with stirring. The mixture was cooled to 0-10℃ in an ice-water bath, and 303g of hexamethylenetetramine (MW: 140.19, 2.16mol, 3.0eq.) was added. The mixture was heated to 20-25℃ and reacted for 20h, then filtered. The filter cake was added to a 250mL three-necked flask, and 600g of methanol was added. 150g of 36% concentrated hydrochloric acid was added with stirring. The mixture was refluxed for 16h, cooled to 20-25℃ to crystallize for 2h, filtered, and dried to obtain 110g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, with a molar yield of 61%.

[0055] (2) In a 250 mL three-necked flask, add 100 mL of N,N-dimethylformamide, and add 15 g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride (MW: 249.71, 60.0 mmol, 1.0 eq.), 12 g of p-methylphenylacetic acid (MW: 136.15, 88.1 mmol, 1.5 eq.), and 16.5 g of potassium carbonate (MW: 138.21, 119 mmol, 2.0 eq.) while stirring. Keep the mixture at 22 °C for 4 h. The mixture was cooled to 5°C, and 20.2 g of potassium tert-butoxide (MW: 112.21, 180 mmol, 3.0 eq.) was added. After stirring for 1 h, 15 g of 1-bromopropane (MW: 122.99, 122 mmol, 2.0 eq.) was added. The mixture was heated to 22°C and reacted for 8 h. The reaction solution was poured into 1000 mL of water, stirred for 2 h, and then filtered. The filter cake was washed twice with 20 mL of ice-cold ethanol and dried to obtain 15 g of the target product. The molar yield was 64%.

[0056] Example 1 Preparation of the intermediate of atorcoxib 1 H-NMR spectrum as follows Figure 1 As shown, the LC-MS spectrum is as follows Figure 2 As shown.

[0057] 1 H-NMR (d6-DMSO, 400MHz) δ (ppm): 8.21-7.53 (d, 4H), 7.13-6.97 (d, 4H), 4.79 (s, 2H), 3.72 (s, 2H) ,3.31-3.30(d,3H),3.26-3.19(m,2H),2.28-2.24(d,3H),1.50-1.45(m,2H),0.85-0.77(m,3H). m / z: (M+H) + =388.1598.

[0058] Example 2 In a 250 mL three-necked flask, add 100 mL of N,N-dimethylacetamide, and while stirring, add 15 g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride (MW: 249.71, 60.0 mmol, 1.0 eq.), 12 g of p-methylphenylacetic acid (MW: 136.15, 88.1 mmol, 1.5 eq.), and 16.5 g of potassium carbonate (MW: 138.21, 119 mmol, 2.0 eq.). Incubate the mixture at 22 °C for 4 h. The mixture was cooled to 5°C, and 20.2 g of potassium tert-butoxide (MW: 112.21, 180 mmol, 3.0 eq.) was added. After stirring for 1 h, 15 g of 1-bromopropane (MW: 122.99, 122 mmol, 2.0 eq.) was added. The mixture was heated to 22°C and reacted for 8 h. The reaction solution was poured into 1000 mL of water, stirred for 2 h, and then filtered. The filter cake was washed twice with 20 mL of ice-cold ethanol and dried to obtain 14 g of the target product. The molar yield was 60%.

[0059] Comparative Example 1: A method for preparing an etoricoxib intermediate, which, compared with Example 1, only changes the amount of p-methylphenylacetic acid in step (2), and the rest is the same as Example 1.

[0060] In a 250 mL three-necked flask, add 100 mL of N,N-dimethylformamide, and while stirring, add 15 g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride (MW: 249.71, 60.0 mmol, 1.0 eq.), 24.5 g of p-methylphenylacetic acid (MW: 136.15, 180 mmol, 3.0 eq.), and 16.5 g of potassium carbonate (MW: 138.21, 119 mmol, 2.0 eq.). Incubate the mixture at 22 °C for 4 h. The mixture was cooled to 5°C, and 40.4 g of potassium tert-butoxide (MW: 112.21, 180 mmol, 3.0 eq.) was added. After stirring for 1 h, 22.1 g of 1-bromopropane (MW: 122.99, 180 mmol, 3.0 eq.) was added. The mixture was heated to 22°C and reacted for 8 h. The reaction solution was poured into 2000 mL of water, stirred for 2 h, and then filtered. The filter cake was washed twice with 40 mL of ice-cold ethanol and dried to obtain 10 g of the target product. The molar yield was 43%.

[0061] Comparative Example 2: A method for preparing an etoricoxib intermediate, which, compared with Example 1, only changes the alkali 2 in step (2), and the rest is the same as Example 1.

[0062] In a 250 mL three-necked flask, add 100 mL of N,N-dimethylformamide, and while stirring, add 15 g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride (MW: 249.71, 60.0 mmol, 1.0 eq.), 12 g of p-methylphenylacetic acid (MW: 136.15, 88.1 mmol, 1.5 eq.), and 16.5 g of potassium carbonate (MW: 138.21, 120 mmol, 2.0 eq.). Incubate the mixture at 22 °C for 4 h. The temperature was lowered to 5°C, and 10.1 g of potassium hydroxide (MW: 56.11, 180 mmol, 3.0 eq.) was added. After stirring at this temperature for 1 h, 15 g of 1-bromopropane (MW: 122.99, 122 mmol, 2.0 eq.) was added. The temperature was raised to 22°C and the reaction was carried out for 8 h. The reaction solution was poured into 1000 mL of water, stirred for 2 h, and then filtered. The filter cake was washed twice with 20 mL of ice-cold ethanol and dried to obtain 8 g of the target product. The molar yield was 34%.

[0063] Comparative Example 3: A method for preparing an etoricoxib intermediate, which, compared with Example 1, only changes the reaction temperature in step (2), and is otherwise the same as Example 1.

[0064] In a 250 mL three-necked flask, add 100 mL of N,N-dimethylformamide, and while stirring, add 15 g of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride (MW: 249.71, 60.0 mmol, 1.0 eq.), 12 g of p-methylphenylacetic acid (MW: 136.15, 88.1 mmol, 1.5 eq.), and 16.5 g of potassium carbonate (MW: 138.21, 119 mmol, 2.0 eq.). Incubate the mixture at 22 °C for 4 h. The mixture was cooled to 5°C and 20.2 g of potassium tert-butoxide (MW: 112.21, 180 mmol, 3.0 eq.) was added. After stirring for 1 h, 15 g of 1-bromopropane (MW: 122.99, 122 mmol, 2.0 eq.) was added. The mixture was heated to 45°C and reacted for 8 h. The reaction solution was poured into 1000 mL of water and stirred for 2 h. The mixture was then filtered. The filter cake was washed twice with 20 mL of ice-cold ethanol and dried to obtain 10 g of the target product. The molar yield was 43%.

[0065] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing an intermediate of etoricoxib, characterized in that, Includes the following steps: (1) 2-bromo-1-(4-methanesulfonyl)acetophenone, hexamethylenetetramine and solvent were reacted, filtered, hydrochloric acid and methanol were added, and the reaction was continued to give 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride; (2) 2-Amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, base 1 and solvent are mixed and reacted, cooled to -5℃-15℃, base 2 and 1-bromopropane are added, and the reaction is continued to obtain the product.

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone and hexamethylenetetramine is 0.9-1.1:2.8-3.

2.

3. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is 20-25℃ and the time is 16-24h.

4. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of 2-bromo-1-(4-methanesulfonyl)acetophenone, hydrochloric acid and methanol is 0.9-1.1:0.9-1.1:4.8-5.

2.

5. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, p-methylphenylacetic acid, and base 1 is 1.0:1.3-1.7:1.8-2.

2.

6. The preparation method according to claim 1, characterized in that, In step (2), the solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and dimethylacetamide.

7. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of 2-amino-1-(4-methanesulfonyl)acetophenone hydrochloride, bromopropane, and base 2 is 1.0:1.8-2.2:2.8-3.

2.

8. The preparation method according to claim 1, characterized in that, In step (2), the temperature of the mixing reaction is 20-25℃.

9. The preparation method according to claim 1, characterized in that, In step (2), after the reaction is completed, post-processing is also included: the reaction solution is poured into water, stirred and filtered, the filter cake is washed with ice-cold ethanol and dried.

10. The preparation method according to claim 1, characterized in that, In step (2), the base 2 is potassium tert-butoxide.

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