Preparation method of etoricoxib intermediate
Through the specific reaction route under alkaline and acidic conditions, the problems of high operating risk and low product yield in the coxie intermediate preparation method are solved, and the preparation of intermediates with high purity and high yield is achieved.
Patent Information
- Application Number
- CN202411787035.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-03-11
AI Technical Summary
The existing preparation method of cocoxib intermediates has problems such as high operational risk and low product yield.
The substitution reaction is carried out in the presence of alkaline substances, and the intermediate is formed by reacting methyl niacin with a specific compound, and then hydrolyzing is carried out under acidic conditions to obtain etocoxib intermediates of high purity and high yield.
It improves operational safety, increases the yield and purity of the intermediate, reduces the need for use of dangerous reagents, and achieves high purity and high yield of the product.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing an etoricoxib intermediate, and belongs to the technical field of drug intermediate synthesis. Background Art
[0002] Etoricoxib is a highly selective cyclooxygenase-2 (COX-2) inhibitor developed by Merck. It is a new type of COX-2 inhibitor that is mainly involved in the production of inflammatory prostaglandins, which can cause pain, inflammation, and fever. It is also used to treat acute and chronic osteoarthritis, including arthritis, rheumatoid arthritis, gouty arthritis, chronic musculoskeletal pain, chronic low back pain, etc. It has the following chemical structure:
[0003]
[0004] Since etoricoxib has a unique chemical structure (methylsulfonyl group), the introduction of this group not only increases the selectivity of the drug for COX-2, but also does not produce cross-allergic reactions with sulfonamide drugs. Compared with traditional non-steroidal anti-inflammatory drugs (NSAIDS), the former can reduce the risk of gastrointestinal peptic ulcers, perforation, and bleeding, and has no sulfonamide group, which is safer for patients allergic to sulfonamides and has broad market prospects. At present, the main process routes of etoricoxib are as follows:
[0005]
[0006] Compound I in this synthetic route is a key intermediate in the synthesis process of etoricoxib. The synthesis of this key intermediate is mainly achieved through the following three synthetic routes:
[0007]
[0008] Among the above three main synthetic routes, the route in route 1 using compound 1 as the raw material is lengthy, and metal reagents and Grignard reagents are used multiple times, the reaction is difficult to control, the risk is high, the yield is low, and it is not suitable for industrial production; in synthetic route 2, compound 6 and compound 1 are used as starting materials, and the yield of compound I is increased to 81% by alternately adding tert-butyl magnesium chloride and compound 1 separately and multiple times. However, since the intermediate product compound I obtained by this route will continue to react with compound 1 in series to form coupling impurities, and this impurity is difficult to remove in subsequent treatment, this feeding method is not conducive to the operational stability of the process; route 3 requires the use of hydrogen peroxide for oxidation treatment, the operation is highly dangerous, and N-oxide impurities will be generated, which are difficult to remove. Summary of the invention
[0009] The present invention aims at the defects existing in the above prior art and provides a method for preparing an etoricoxib intermediate, which solves the problem of how to reduce the operation risk and improve the product yield.
[0010] The object of the present invention is achieved by the following technical scheme, a method for preparing an etoricoxib intermediate, characterized in that the method comprises the following steps:
[0011] A. In the presence of an alkaline substance, subjecting the compound of formula III to a substitution reaction with the compound of formula IV, nicotinate methyl ester, to obtain the compound of formula II;
[0012]
[0013] The R group in the compound of formula III and the compound of formula II is selected from a C1-C5 alkyl group;
[0014] B. hydrolyzing the compound of formula II under the action of an acidic substance to convert it into a product compound of formula I;
[0015]
[0016] By adopting a new starting material, due to the presence of two carboxylate groups (-COOR) on the compound of formula III, the H on the C connected by the two carboxylate groups can be made more active. Only under the action of an alkaline substance, which is equivalent to making the reaction under alkaline conditions, the active H on the compound of formula III can be promoted to react with the group on the carboxylate in the nicotinate methyl ester compound of formula IV. The reaction has high selectivity and does not require the use of a Grignard reagent for the reaction, which greatly improves the operational safety. At the same time, due to the use of a new synthetic route starting material, the reaction can proceed in the positive direction under alkaline conditions, and the reaction conditions are mild, which is more conducive to improving the yield and purity of the intermediate product, and the purity reaches more than 96%. At the same time, the intermediate obtained can effectively remove the two carboxylate groups in the structure of the compound of formula II under the action of an acidic substance to obtain the desired key intermediate compound of formula I. Specifically, due to the presence of carbonyl (C=O) structures at adjacent positions in the structure of the intermediate compound of formula II, the two -COOR groups at adjacent positions C can be effectively removed under acidic conditions, the reaction efficiency is high, and the reaction conditions are stable, which is more conducive to operation, and the obtained product also has high yield and purity quality requirements; at the same time, the acidic substance used has the advantages of low toxicity, easy availability of raw materials and low cost, the reaction can be carried out mildly, and the use of dangerous reagents such as hydrogen peroxide to promote the reaction is avoided, which is more conducive to operation, the product yield reaches more than 90%, and the purity quality reaches more than 99%. As a further preference, the R group in the compound of formula III and the compound of formula II in step A is selected from Me, Et, i-Pr or t-Bu groups.
[0017] In the above-mentioned preparation method of etoricoxib intermediate, the purpose of adding alkaline substances is to make the reaction proceed under alkaline conditions, so that the active H at the C site connected by the two -COOR groups can react effectively, and at the same time, it can avoid the hydrolysis of the -COOR group during the reaction to reduce the reaction activity. The alkaline substance in step A is selected from an organic base or an inorganic base; the organic base is selected from one or more of alkali metal alkoxides, sodium hydrogen, LiHMDS (bis(trimethylsilyl) lithium amide), NaHMDS (bis(trimethylsilyl) sodium amide) and n-butyl lithium; the inorganic base is selected from one or more of alkali metal hydroxides, sodium carbonate, lithium carbonate and potassium carbonate. The above-mentioned alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. In order to better promote the reaction and avoid the hydrolysis of some -COOR groups during the reaction, as a further preference, it is best to use alkali metal alkoxide as the alkaline substance, which can effectively promote the reaction to replace the active H at the C site connected by the two -COOR groups, and can more effectively avoid the partial hydrolysis of the two -COOR groups and affect the active H at the C site, which is conducive to better ensuring that the reaction proceeds in the positive direction, and has the advantages of high yield of intermediate products, and the purity reaches more than 98%. The above-mentioned alkali metal alkoxide is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide and sodium tert-butoxide.
[0018] In the above-mentioned preparation method of etoricoxib intermediate, the raw materials of formula III compound and nicotinate methyl ester in step A can be fed according to the molar equivalent required by the chemical field reaction, and the amount of alkaline substance added can be any amount of catalytic amount that can promote the reaction. In order to better promote the reaction and optimize the feeding situation, it is preferred that the molar ratio of formula III compound: formula IV compound nicotinate methyl ester: alkaline substance in step A is 1: 0.5-3.0: 0.1-5.0. It can not only make the reaction effective, but also reduce the waste of feeding as little as possible, which is beneficial to cost control. As a further preference, the molar ratio of formula III compound: formula IV compound nicotinate methyl ester: alkaline substance in step A is 1: 1.0-1.5: 0.5-2.0.
[0019] In the above-mentioned preparation method of etoricoxib intermediate, the solvent system suitable for the substitution reaction in step A is preferably carried out in an organic solvent. For the selection of organic solvents, alcohol solvents such as C1-C5 alcohol solvents, aromatic solvents, ether solvents, amide solvents, sulfone solvents, etc. can be used; of course, it is best to make the solvent system of the reaction under substantially anhydrous conditions. Since it is carried out under alkaline conditions, the presence of a large amount of water may cause partial hydrolysis of the two -COOR groups in the compound of formula III, reduce the reaction activity, and is not conducive to improving the product yield. As a preference, it is best to make the reaction in step A be carried out in an organic solvent one, and the organic solvent one is selected from one or more of C1-C5 alcohol solvent one, acetonitrile, toluene, xylene, ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP). It is further preferred that the substitution reaction is carried out in an alcohol solvent system. In this way, when the alkaline substance is an alcohol salt, it is more conducive to the reaction, and the by-product alcohol of the reaction is the same or similar to the solvent, which is more conducive to the recovery and utilization of the solvent.
[0020] In the above-mentioned method for preparing etoricoxib intermediate, preferably, the temperature of the substitution reaction in step A is -10°C to 120°C. This has the advantage that the reaction is easy to carry out and the reaction temperature is also easier to control. As a further preference, the temperature of the substitution reaction in step A is 20°C to 80°C.
[0021] In the above-mentioned preparation method of etoricoxib intermediate, due to the presence of carbonyl groups at adjacent positions of the C site connected to two -COOR groups in the intermediate compound of formula II obtained by the present synthetic route, if hydrolysis is carried out under alkaline conditions, it is easy to cause side reactions at the carbonyl site and produce impurities, which is not conducive to the reaction and the control of product yield and purity quality. Therefore, by using an acidic substance to hydrolyze the reaction under acidic conditions, it can more effectively avoid the carbonyl groups at adjacent positions participating in the reaction during the hydrolysis process to produce impurities and other side reactions, and it is also more conducive to the hydrolysis and removal of the two COOR groups connected to the C at its adjacent sites, which has the advantages of high product yield and purity. Preferably, the acidic substance in step B is selected from inorganic acid or organic acid, and the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrochloric acid alcohol solution; the organic acid is selected from one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The above-mentioned hydrochloric acid alcohol solvent can be, for example, hydrochloric acid methanol solution, hydrochloric acid ethanol solution, etc. As a further preference, it is best to make the acidic substance selected from one or more of hydrochloric acid, hydrochloric acid methanol solution and sulfuric acid.
[0022] In the above-mentioned preparation method of etoricoxib intermediate, the use of each raw material in step B can be based on the molar equivalent amount required for the raw material to participate in the reaction in the chemical field, and the amount of acidic substance added can be controlled to a catalytic amount that can promote the hydrolysis reaction. In order to make the reaction proceed better and to better optimize the feeding method, as a preferred method, the molar ratio of the compound of formula II in step B: the acidic substance is 1: 0.1-5.0. It can make fuller use of the raw materials, effectively ensure the efficient hydrolysis reaction, and is also conducive to the guarantee of the purity and quality of the product. As a further preferred method, the molar ratio of the compound of formula II: the acidic substance is 1: 1.0-3.0.
[0023] In the above-mentioned preparation method of etoricoxib intermediate, the hydrolysis reaction in step B is preferably carried out in a solvent, which is conducive to the stable progress of the hydrolysis reaction, is also conducive to the operation, can better ensure the yield of the product, and has the advantages of high yield and high purity quality. The above-mentioned solvent can be water or an organic solvent. The organic solvent can be carried out in a solvent such as a halogenated alkane, a C1-C5 alcohol solvent, an aromatic solvent, an ether solvent, an amide solvent, a sulfone solvent, a nitrile solvent, an ester solvent, etc. As preferably, the hydrolysis reaction described in step B is carried out in water and / or an organic solvent II, and the organic solvent II is selected from one or more of halogenated alkanes, C1-C5 alcohol solvent II, acetonitrile, acetone, isopropyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dioxane, 2-butanone, dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP). It can make the reaction more stable and gentle, and it is also conducive to better removing unnecessary impurities, which is conducive to better ensuring the purity quality of the product. The above-mentioned halogenated alkanes are such as dichloromethane, chloroform, etc., and the alcohol solvent II is such as alcohol solvents such as methanol, ethanol, propanol, isopropanol, and n-butanol.
[0024] In the above-mentioned method for preparing etoricoxib intermediate, preferably, the temperature of the hydrolysis reaction in step B is 15° C. to 100° C. It is preferred that the hydrolysis reaction is fully carried out and easy to operate. As a further preference, the temperature of the hydrolysis reaction in step B is 30° C. to 80° C.
[0025] In the above-mentioned preparation method of etoricoxib intermediate, as a preference, after the substitution reaction in step A is completed, a post-treatment is further included, wherein the post-treatment is specifically: adding an acid to the reaction solution to adjust the pH value of the system to a weak alkalinity, and then removing the solvent to obtain the corresponding intermediate product of formula II. The main purpose is to remove the excess alkali in the system, so that the intermediate product can be better separated, and has the advantages of high purity and quality. The acid here can be an inorganic acid such as hydrochloric acid and dilute sulfuric acid.
[0026] In the above method for preparing etoricoxib intermediate, preferably, after the hydrolysis reaction in step B is completed, a base is added to the reaction solution to adjust the pH value of the system to 8-9. The purpose of adding the base here is to remove excess acid in the system.
[0027] The chemical synthesis route of the preparation method of the etoricoxib intermediate of the present invention is represented by the following equation:
[0028]
[0029] In summary, compared with the prior art, the present invention has the following advantages:
[0030] 1. The presence of two carboxylate groups in the starting material compound of formula III can make the H on the connected C more active. Under alkaline conditions, the active H on the starting material compound of formula III can be promoted to react with the carboxylate group in the nicotinate methyl ester compound. The reaction has high selectivity and does not require the use of Grignard reagents for the reaction, which greatly improves the operational safety. The reaction conditions are mild and the single-step intermediate product has the advantages of high purity and high yield.
[0031] 2. The presence of carbonyl (C=O) structures at adjacent positions in the structure of the intermediate compound of formula II makes it more effective to remove the two -COOR groups at adjacent positions C under acidic conditions, with high reaction efficiency and stable reaction conditions, which is more conducive to operation. The obtained product also has high yield and purity quality requirements.
[0032] 3. The acidic substance used has the advantages of low toxicity, easy availability of raw materials and low cost. The reaction can be carried out gently, and it also avoids the use of dangerous reagents such as double oxidation to promote the reaction, which is more conducive to operation. The single yield reaches more than 90%, and the purity quality reaches more than 99%. DETAILED DESCRIPTION
[0033] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0034] Example 1
[0035] Synthesis of intermediate formula II compound (II-A):
[0036]
[0037] Under stirring at room temperature, 250 mL of anhydrous methanol, 28.6 g of compound III-A and 15.16 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, stirred evenly, and then 5.67 g of sodium methoxide was added thereto in batches. After the addition, the reaction temperature was controlled at 25°C to 30°C for stirring reaction for 5 hours. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 9. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 150 mL of dichloromethane and 50 mL of water were added to the residue and stirred for 30 minutes. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 37.3 g of a yellow liquid compound II-A intermediate crude product with a molar yield of 92% and a purity of 97.1%. It was directly used in the next step of compound I synthesis without purification.
[0038] Synthesis of compounds of formula I:
[0039]
[0040] Under stirring at room temperature, 37.3 g of the yellow liquid compound II-A intermediate crude product and 50 g of water were added to a 500 mL clean reactor in sequence, and the mixture was stirred. 90 g of concentrated hydrochloric acid was added to the reaction solution. After the addition was completed, the reaction solution was heated to 60°C to 65°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 8 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 20% by mass aqueous solution of sodium hydroxide was added dropwise to adjust the pH of the system to 8-9. A large amount of solid was precipitated and filtered. The filter cake was washed twice with water to obtain a crude compound of formula I. The crude compound of formula I was purified by slurrying with methanol to obtain a light yellow solid compound I with a yield of 92% and a purity of 99.4%.
[0041] Example 2
[0042] Synthesis of intermediate formula II compound (II-B):
[0043]
[0044] Under stirring at room temperature, 250 mL of anhydrous tetrahydrofuran, 37.05 g of compound III-B and 15.16 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, and the mixture was stirred. Then, 11.78 g of potassium tert-butoxide was added thereto in batches. After the addition, the reaction temperature was controlled at 25° C. to 30° C. and the reaction was stirred for 6 hours. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 9. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 150 mL of dichloromethane and 50 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 45.45 g of a yellow liquid intermediate crude compound II-B with a molar yield of 91.3% and a purity of 96.8%. The crude product was directly used for the synthesis of compound I without purification.
[0045] Synthesis of compounds of formula I:
[0046]
[0047] Under stirring at room temperature, 45.45 g of the intermediate product obtained above, a crude yellow liquid compound II-B intermediate, 50 g of water and 200 mL of dichloromethane were added to a 500 mL clean reactor in sequence, and the mixture was stirred well. 35 g of trifluoroacetic acid was added to the reaction solution. After the addition was completed, the reaction solution was heated to 40°C to 45°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 10 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 20% by mass sodium hydroxide aqueous solution was added dropwise to adjust the pH value of the system to 8-9. The mixture was allowed to stand for stratification, and the collected organic phase was washed with water and saturated brine in sequence. The washed organic phase was concentrated under reduced pressure to recover the solvent to obtain a crude compound of formula I. The crude compound of formula I was purified by slurrying with methanol to obtain a light yellow solid compound of formula I with a yield of 93% and a purity of 99.5%.
[0048] Example 3
[0049] Synthesis of intermediate formula II compound (II-C):
[0050]
[0051] Under stirring at room temperature, 250 mL of anhydrous ethanol, 31.4 g of compound III-C and 16.32 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, and the mixture was stirred. Then, 10 g of potassium ethoxide was added in batches. After the addition, the reaction temperature was controlled at 30°C to 35°C and the reaction was stirred for 4 hours. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 9. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 200 mL of chloroform and 50 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 40.1 g of a crude yellow liquid intermediate compound II-C with a molar yield of 92.6% and a purity of 97.2%. The product was directly used in the next step of the synthesis of compound I without purification.
[0052] Synthesis of compounds of formula I:
[0053]
[0054] Under stirring at room temperature, 40.1 g of the yellow liquid compound II-C intermediate crude product, 50 g of water and 200 mL of dichloromethane were added to a 500 mL clean reactor in sequence, and the mixture was stirred. A methanol solution of hydrochloric acid was then added to the reaction solution to make the amount of hydrochloric acid added 80 g. After the addition was completed, the reaction solution was heated to 40°C to 42°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 7 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 20% by mass sodium carbonate aqueous solution was added dropwise to adjust the pH of the system to 8-9. The mixture was allowed to stand for stratification, and the collected organic phase was washed with water and saturated brine in sequence. The washed organic phase was concentrated under reduced pressure to recover the solvent to obtain a crude compound of formula I. The crude compound of formula I was purified by slurrying with methanol to obtain a light yellow solid compound of formula I with a yield of 92.8% and a purity of 99.6%.
[0055] Example 4
[0056] Synthesis of intermediate formula II compound (II-D):
[0057]
[0058] Under stirring at room temperature, 250 mL of anhydrous isopropanol, 34.2 g of compound III-D and 17.68 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, and the mixture was stirred. Then, 9.8 g of sodium isopropoxide was added in batches. After the addition, the reaction temperature was controlled at 30°C to 35°C for 6 hours under stirring. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction, a 10% by mass hydrochloric acid solution was added dropwise to the reaction solution to adjust the pH value of the reaction solution to 9. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 150 mL of dichloromethane and 80 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 43.0 g of a yellow liquid compound II-C intermediate crude product with a molar yield of 93.2% and a purity of 96.7%. The product was directly used in the next step of compound I synthesis without purification.
[0059] Synthesis of compounds of formula I:
[0060]
[0061] Under stirring at room temperature, 43.0 g of the yellow liquid compound II-D intermediate crude product and 250 mL of ethanol solvent were added to a 500 mL clean reactor in sequence, stirred evenly, and 40 g of p-toluenesulfonic acid was added to the reaction solution. After the addition was completed, the reaction solution was heated to 60°C to 65°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 5 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 20% by mass sodium carbonate aqueous solution was added dropwise, the pH of the system was adjusted to 8-9, and the solvent was recovered by vacuum concentration to obtain a crude compound of formula I. The crude compound of formula I was purified by ethanol pulping to obtain a light yellow solid compound of formula I with a yield of 91.7% and a purity of 99.2%.
[0062] Example 5
[0063] Synthesis of intermediate formula II compound (II-A):
[0064]
[0065] Under stirring at room temperature, 250 mL of anhydrous propanol, 28.6 g of compound III-A and 16.8 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, stirred evenly, and then 8.35 g of LiHMDS (bis(trimethylsilyl)amide lithium) was added thereto in batches. After the addition, the reaction temperature was controlled at 30°C to 35°C for 6 hours under stirring. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 9. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 150 mL of dichloromethane and 50 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 37.9 g of a yellow liquid compound II-A intermediate crude product with a molar yield of 92.6% and a purity of 97.4%. It was directly used in the next step of compound I synthesis without purification.
[0066] Synthesis of compounds of formula I:
[0067]
[0068] Under stirring at room temperature, 37.9 g of the yellow liquid compound II-A intermediate crude product and 50 g of water were added to a 500 mL clean reactor in sequence, and the mixture was stirred. 85 g of concentrated hydrochloric acid was added to the reaction solution. After the addition was completed, the reaction solution was heated to 55°C to 60°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 7 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 20% by mass aqueous solution of sodium hydroxide was added dropwise to adjust the pH of the system to 8-9. A large amount of solid was precipitated and filtered. The filter cake was washed twice with water to obtain a crude compound of formula I. The crude compound of formula I was purified by slurrying with propanol to obtain a light yellow solid compound I with a yield of 92.1% and a purity of 99.5%.
[0069] Example 6
[0070] Synthesis of intermediate formula II compound (II-A) (the chemical reaction equation of this embodiment can be expressed by referring to the corresponding reaction equation in Example 1):
[0071] Under stirring at room temperature, 220 mL of DMF solvent, 28.6 g of compound III-A and 27.2 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, and the mixture was stirred. Then, 7.68 g of n-butyl lithium was added thereto in batches. After the addition, the reaction temperature was controlled at 75° C. to 80° C. and the reaction was stirred for 4 hours. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 8.5. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 150 mL of dichloromethane and 50 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 37.1 g of a yellow liquid intermediate compound II-A crude product with a molar yield of 90.8% and a purity of 96.5%. The product was directly used in the next step of compound I synthesis without purification.
[0072] Synthesis of compounds of formula I:
[0073] Under stirring at room temperature, 37.1 g of the yellow liquid compound II-A intermediate crude product and 60 g of dimethylformamide obtained above were added to a 500 mL clean reactor in sequence, stirred evenly, and then 100 g of concentrated hydrochloric acid was added to the reaction solution. After the addition was completed, the temperature of the reaction solution was raised to 65°C to 70°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 7 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a saturated sodium carbonate aqueous solution with a mass percentage was added dropwise to adjust the pH of the system to 8-9. 130 mL of dichloromethane and 60 mL of water were added, stirred for 15 min, and allowed to stand for stratification. The collected organic phase was washed with water and saturated brine in sequence, and the washed organic phase was concentrated under reduced pressure to recover the solvent to obtain a crude compound of formula I. The crude compound of formula I was purified by methanol pulping to obtain a light yellow solid compound I with a yield of 92.3% and a purity of 99.2%.
[0074] Example 7
[0075] Synthesis of intermediate formula II compound (II-A) (the chemical reaction equation of this embodiment can be expressed by referring to the corresponding reaction equation in Example 1):
[0076] Under stirring at room temperature, 250 mL of anhydrous ethanol solvent, 28.6 g of compound III-A and 15.64 g of nicotinate methyl ester were added to a 500 mL clean reactor in sequence, stirred evenly, and then 17 g of sodium carbonate was added thereto in batches. After the addition, the reaction temperature was controlled at 70° C. to 78° C. for stirring reaction for 5 hours. During the reaction, HPLC detection confirmed that the reaction was complete. After the reaction was completed, 10% hydrochloric acid was added dropwise to the reaction solution, and the pH value of the reaction solution was adjusted to 8.5. After stabilization, the reaction solution was concentrated under reduced pressure to recover the solvent. After concentration was completed, 200 mL of dichloromethane and 80 mL of water were added to the residue and stirred for 30 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with saturated brine, and the obtained organic phase was concentrated under reduced pressure to remove the solvent to obtain 37.5 g of a yellow liquid compound II-A intermediate crude product with a molar yield of 91.8% and a purity of 96.7%. It was directly used in the next step of compound I synthesis without purification.
[0077] Example 8
[0078] Synthesis of compounds of formula I:
[0079]
[0080] Under stirring at room temperature, 37.5 g of the crude yellow liquid intermediate of Compound II-A obtained in Example 7 and 120 g of acetone were added to a 500 mL clean reactor in sequence, and the mixture was stirred. 15 g of methanesulfonic acid was then added to the reaction solution. After the addition was completed, the reaction solution was heated to 45°C to 50°C for reaction. A large number of bubbles were generated during the reaction. After the reaction was kept warm for 6 hours, HPLC monitoring confirmed that the reaction was complete. After the reaction was completed, the reaction system was cooled to room temperature, and a 15% by mass aqueous solution of hydrochloric acid was added dropwise to adjust the pH of the system to 8-9. 130 mL of dichloromethane and 60 mL of water were added, and the mixture was stirred for 15 min. The mixture was allowed to stand for stratification. The collected organic phase was washed with water and saturated brine in sequence. The washed organic phase was concentrated under reduced pressure to recover the solvent to obtain a crude compound of Formula I. The crude compound of Formula I was purified by slurrying with methanol to obtain a light yellow solid compound I with a yield of 92.7% and a purity of 99.5%.
[0081] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.
[0082] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.
Claims
1. A method for preparing an etoricoxib intermediate, characterized in that: The method comprises the following steps: A. In the presence of an alkaline substance, subjecting the compound of formula III to a substitution reaction with the compound of formula IV, nicotinate methyl ester, to obtain the compound of formula II; The R group in the compound of formula III and the compound of formula II is selected from a C1-C5 alkyl group; B. hydrolyzing the compound of formula II under the action of an acidic substance to convert it into a product compound of formula I; 2. The method for preparing an etoricoxib intermediate according to claim 1, characterized in that: In step A, the R group in the compound of formula III and the compound of formula II is selected from Me, Et, i-Pr or t-Bu.
3. The method for preparing an etoricoxib intermediate according to claim 1, characterized in that: The alkaline substance in step A is selected from an organic base or an inorganic base; the organic base is selected from one or more of alkali metal alkoxides, sodium hydrogen, LiHMDS, NaHMDS and n-butyl lithium; the inorganic base is selected from one or more of alkali metal hydroxides, sodium carbonate, lithium carbonate and potassium carbonate.
4. The method for preparing an etoricoxib intermediate according to claim 3, characterized in that: In step A, the molar ratio of the compound of formula III: the compound of formula IV nicotinate methyl ester: the alkaline substance is 1: 0.5-3.0: 0.1-5.
0.
5. The method for preparing an etoricoxib intermediate according to claim 1, characterized in that: The reaction in step A is carried out in an organic solvent 1; the organic solvent 1 is selected from one or more of a C1-C5 alcohol solvent 1, acetonitrile, toluene, xylene, ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
6. The method for preparing the etoricoxib intermediate according to any one of claims 1 to 5, characterized in that: The temperature of the substitution reaction in step A is -10°C to 120°C.
7. The method for preparing the etoricoxib intermediate according to any one of claims 1 to 5, characterized in that: The acidic substance in step B is selected from an inorganic acid or an organic acid, wherein the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and alcoholic hydrochloric acid solution; and the organic acid is selected from one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
8. The method for preparing an etoricoxib intermediate according to claim 7, characterized in that: In step B, the molar ratio of the compound of formula II: the acidic substance is 1:0.1-5.
0.
9. The method for preparing an etoricoxib intermediate according to claim 7, characterized in that: The hydrolysis reaction in step B is carried out in water and / or an organic solvent II, wherein the organic solvent II is selected from one or more of halogenated alkanes, C1-C5 alcohol solvent II, acetonitrile, acetone, isopropyl acetate, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-butanone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
10. The method for preparing an etoricoxib intermediate according to claim 9, characterized in that: The temperature of the hydrolysis reaction in step B is 15°C to 100°C.