Process for the preparation of an intermediate of irrexio

Abstract

This invention provides a method for preparing etoricoxib intermediate A. The method includes: by using a specified solvent and a basic reagent in combination, the yield and purity of intermediate A are significantly improved, the production cost is reduced, and it is suitable for industrial production.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis technology, and in particular to a method for preparing an etoricoxib intermediate. Background Technology

[0002] Eriprexib is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain symptoms of osteoarthritis. The structural formula of Eriprexib is as follows: .

[0003] Patent CN102206178B protects a method for preparing etoricoxib, the method comprising: preparing intermediate (II) using intermediate (V), and then preparing etoricoxib using intermediate (II), the specific route being as follows: .

[0004] In the process of synthesizing intermediate (II) using intermediate (V), this patent uses acetonitrile, ethanol or n-butanol as solvents and triethylamine, tetramethylguanidine, diisopropylethylamine or 1,8-diazabicyclo(5,4,0)-7-undecene (DBU) as basic reagents. However, intermediate II has the problems of low yield and low purity, and it is impossible to obtain intermediate II product with high yield and high purity at the same time. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a method for preparing an etoricoxib intermediate, which has the advantages of high product yield and high purity.

[0006] This invention provides a method for preparing intermediate A of ericyclophosphamide, the preparation method comprising:

[0007] In an alkaline environment, intermediate B undergoes a cyclization reaction in a solvent to generate intermediate A;

[0008] ;

[0009] The alkaline reagent is selected from one or more of triethylamine, tri-n-propylamine, N,N-diisopropylethylamine, pyridine, and methylpiperidine;

[0010] The solvent is selected from one or more of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), ethanol, n-propanol, isopropanol, acetone, and toluene;

[0011] In some embodiments, the alkaline reagent is selected from triethylamine;

[0012] The solvent is selected from dimethyl sulfoxide (DMSO);

[0013] In some embodiments, the alkaline reagent is selected from triethylamine;

[0014] The solvent is selected from dimethylformamide (DMF);

[0015] In some embodiments, the mass ratio of intermediate B to the volume of the solvent is selected from (1:1) to (1:20) (g / mL), preferably (1:5) to (1:15) (g / mL). The mass ratio of intermediate B to the volume of the solvent is selected from 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20.

[0016] In some embodiments, the reaction temperature of the cyclization reaction is selected from 50°C to 130°C; for example, the reaction temperature of the cyclization reaction is selected from 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, or 130°C.

[0017] In some embodiments, the reaction temperature of the cyclization reaction is selected from 60°C to 110°C;

[0018] In some embodiments, the reaction temperature of the cyclization reaction is selected from 70°C to 80°C;

[0019] In some embodiments, the molar ratio of intermediate B to the alkaline reagent is selected from (1:10) to (10:1); for example, the molar ratio of intermediate B to the alkaline reagent is selected from (1:10), (1:5), (1:2), (1:1), (2:1), (2.5:1), (3:1), (5:1) or (10:1).

[0020] In some embodiments, the preparation method further includes:

[0021] After the cyclization reaction is completed, the mixture is cooled, water is added and stirred to induce crystallization, and then filtered to obtain crude intermediate A.

[0022] The crude intermediate A was added to an organic solvent for recrystallization, filtered, and dried to obtain intermediate A.

[0023] In some embodiments, the mixture is cooled to 20°C to 40°C to crystallize; for example, the mixture is cooled to 20°C, 25°C, 30°C, 35°C, 40°C or room temperature to crystallize.

[0024] In some embodiments, during the steps of cooling the mixture after the cyclization reaction and adding water for stirring and crystallization, the mass ratio of intermediate B to the volume of water added is selected from (1:1) to (1:20) (g / mL), preferably (1:5) to (1:15) (g / mL). The mass ratio of intermediate B to the volume of water added is selected from 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20.

[0025] In some embodiments, the organic solvent used for recrystallization is selected from one or more of ethyl acetate and alcohols;

[0026] In some embodiments, the alcohol used for recrystallization is selected from one or more of methanol, ethanol, and propanol;

[0027] In some embodiments, the organic solvent used for recrystallization is selected from ethyl acetate and ethanol;

[0028] In some embodiments, the volume ratio of ethyl acetate to alcohol used for recrystallization is selected from (1:5) to (5:1); for example, the volume ratio of ethyl acetate to alcohol is selected from 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:3, 2:5, 3:1, 3:2, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3 or 5:4;

[0029] In some embodiments, the volume ratio of ethyl acetate to alcohol used for recrystallization is selected from (1:1) to (1:5); the volume ratio of ethyl acetate to alcohol used for recrystallization is selected from 1:1, 1:2, 1:3, 1:4 or 1:5;

[0030] In some embodiments, during recrystallization, the weight ratio of crude intermediate A to the volume ratio of the organic solvent is selected from (1:1) to (1:20), preferably (1:5) to (1:15); for example, the weight ratio of crude intermediate A to the volume ratio of the organic solvent is selected from 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20;

[0031] In some embodiments, the organic solvent used for recrystallization is selected from ethyl acetate and ethanol, and the weight ratio of crude intermediate A to the volume of ethyl acetate and the volume ratio of ethanol is selected from 1:2:8 (g / mL / mL).

[0032] This invention provides a method for preparing intermediate A using atorcoxib intermediate B. By combining a specified solvent and a basic reagent, the yield and purity of intermediate A are significantly improved, production costs are reduced, and the method is suitable for industrial production. Detailed Implementation

[0033] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative of this application and are not intended to limit the scope of this application. Unless otherwise specified, the methods used in this invention are conventional methods; the raw materials and apparatus used, unless otherwise specified, are conventional commercially available products.

[0034] Example 1

[0035] Intermediate B (10 g, 28.87 mmol), DMSO (100 mL), and triethylamine (5.8 g, 57.3 mmol) were added to a reaction flask. The mixture was heated to 70-80 °C and reacted for 2 h. After cooling to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 h. The mixture was then filtered to obtain crude intermediate A. The crude intermediate A (9.4 g) was added to ethyl acetate (18.8 mL) and ethanol (75.2 mL) for recrystallization. The mixture was filtered and dried to obtain intermediate A (9.1 g, yield 96%, HPLC purity 98%).

[0036] Example 2

[0037] Intermediate B (10 g, 28.87 mmol), DMF (100 mL), and triethylamine (5.8 g, 57.3 mmol) were added to a reaction flask. The mixture was heated to 70-80 °C and reacted for 2 h. After cooling to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 h. The mixture was then filtered to obtain crude intermediate A. Crude intermediate A (8.7 g) was added to ethyl acetate (17.4 mL) and ethanol (69.6 mL) for recrystallization. The mixture was filtered and dried to obtain intermediate A (8.15 g, yield 86%, HPLC purity 92%).

[0038] Example 3

[0039] Intermediate B (10 g, 28.87 mmol), DMSO (100 mL), and N,N-diisopropylethylamine (7.41 g, 57.3 mmol) were added to a reaction flask. The mixture was heated to 110-120 °C and reacted for 2 h. After cooling to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 h. The crystals were then filtered to obtain crude intermediate A. Crude intermediate A (6.1 g) was recrystallized from ethyl acetate (12.2 mL) and ethanol (48.8 mL), filtered, and dried to obtain intermediate A (6.83 g, yield 72%, HPLC purity 81%).

[0040] Example 4

[0041] Intermediate B (10 g, 28.87 mmol), DMSO (100 mL), and tri-n-propylamine (8.20 g, 57.3 mmol) were added to a reaction flask. The mixture was heated to 100-110 °C and reacted for 2 h. After cooling to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 h. The mixture was then filtered to obtain crude intermediate A. Crude intermediate A (4.8 g) was added to ethyl acetate (9.6 mL) and ethanol (38.4 mL) for recrystallization. The mixture was filtered and dried to obtain intermediate A (6.45 g, yield 68%, HPLC purity 83%).

[0042] Example 5

[0043] Intermediate B (10 g, 28.87 mmol), DMSO (100 mL), and pyridine (4.53 g, 57.3 mmol) were added to a reaction flask. The mixture was heated to 70-80 °C and reacted for 2 h. The mixture was then cooled to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 h. After filtration, crude intermediate A was obtained. Crude intermediate A (6.2 g) was added to ethyl acetate (12.4 mL) and ethanol (49.6 mL) for recrystallization. After filtration and drying, intermediate A (4.55 g, yield 48%, HPLC purity 76%) was obtained.

[0044] Example 6

[0045] Intermediate B (10 g, 28.87 mmol) and acetonitrile (100 mL) were added to a reaction flask. The mixture was cooled to 0 °C, and 10 g of DBU acetonitrile solution (60 mL) was added dropwise. The mixture was reacted at 0 °C for 15 minutes. The mixture was then heated to room temperature, water (80 mL) was added, and the mixture was stirred to crystallize for 2 hours. The crystals were filtered to obtain crude intermediate A. Crude intermediate A (8.8 g) was added to ethyl acetate (17.6 mL) and ethanol (70.4 mL) for recrystallization. The crystals were filtered and dried to obtain intermediate A (8.53 g, yield 90%, HPLC purity 86%).

[0046] Example 7

[0047] Intermediate B (10 g, 28.87 mmol) and acetonitrile (100 mL) were added to a reaction flask. The mixture was cooled to 0 °C, and 10 g of DBU acetonitrile solution (60 mL) was added dropwise. The mixture was reacted at 0 °C for 15 minutes. Ethyl acetate and water were added, the organic phase was separated, and the product was concentrated to obtain crude intermediate A (oily substance, 9.2 g). Ethyl acetate (18.4 mL) and ethanol (73.6 mL) were added, the mixture was stirred, filtered, and dried to obtain intermediate A (8.62 g, yield 91%, HPLC purity 80%).

[0048] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing atorcoxib intermediate A, characterized in that, The preparation method includes: In an alkaline environment, intermediate B undergoes a cyclization reaction in a solvent to generate intermediate A; ； The alkaline reagent is selected from one or more of triethylamine, tri-n-propylamine, N,N-diisopropylethylamine, pyridine, and methylpiperidine; The solvent is selected from one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, ethanol, n-propanol, isopropanol, acetone and toluene.

2. The preparation method according to claim 1, characterized in that, The alkaline reagent is selected from triethylamine; the solvent is selected from dimethyl sulfoxide.

3. The preparation method according to claim 1, characterized in that, The alkaline reagent is selected from triethylamine; the solvent is selected from dimethylformamide.

4. The preparation method according to claim 1, characterized in that, The reaction temperature for the cyclization reaction is selected from 50℃ to 130℃.

5. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate B to the alkaline reagent is selected from (1:10) to (10:1).

6. The preparation method according to claim 1, characterized in that, The ratio of the mass of intermediate B to the volume of the solvent is selected from (1:1) to (1:20).

7. The preparation method according to any one of claims 1-6, characterized in that, The preparation method further includes: After the cyclization reaction was completed, the mixture was cooled to crystallize, filtered, and crude intermediate A was obtained. The crude intermediate A was added to an organic solvent for recrystallization, filtered, and dried to obtain intermediate A.

8. The preparation method according to claim 7, characterized in that, The organic solvent used for recrystallization is selected from one or more of ethyl acetate and alcohols.

9. The preparation method according to claim 8, characterized in that, The organic solvent used for recrystallization is selected from ethyl acetate and alcohol; the volume ratio of ethyl acetate to alcohol is selected from (1:5) to (5:1), preferably (1:1) to (1:5).

10. The preparation method according to claim 7, characterized in that, The mass ratio of the crude intermediate A to the volume ratio of the organic solvent is selected from (1:1) to (1:20) (g / mL).

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