A kind of synthetic method of parecoxib sodium intermediate

Abstract

The present application discloses a method for synthesizing a parecoxib sodium intermediate, which utilizes readily available α-phenylacetophenone, acetaldehyde, and hydroxylamine as raw materials to obtain an important intermediate, 5-methyl-3,4-diphenyl-4,5-oxazoline-5-ol, through an Adol reaction and electrooxidation conditions. The entire reaction process can be carried out under mild conditions without requiring harsh reaction conditions. In addition, each step has high reaction efficiency, the reaction process is simple and controllable, and the method has good industrialization prospects.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for synthesizing a parecoxib sodium intermediate. Background Art

[0002] Parecoxib sodium is chemically known as N-[[4-(5-methyl-3-phenyl-isoxazolyl)phenyl]sulfonyl]propionamide sodium salt. It is a non-steroidal anti-inflammatory drug that can be used as a selective cyclooxygenase-2 inhibitor and is mainly used for the short-term treatment of postoperative pain. The molecular formula of parecoxib sodium is C 19 H 19 N2NaO4S, molecular weight is 394.42, and the structural formula is as follows:

[0003]

[0004] Currently, there are four main synthetic routes for parecoxib sodium described in domestic and international patents. These routes all share the similarity of first synthesizing valdecoxib, then reacting to produce parecoxib, and then salting to prepare the final product (e.g., CN102329277A; WO2005085218A1; WO2005123701A1; EP1550658A1; WO2003029230A1, etc.).

[0005] Method 1: Patent EP1550658A1 uses 1-phenyl-2-propanone as a raw material, which reacts with benzonitrile N-oxide to produce 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol. The latter is then refluxed and dehydrated in a sodium carbonate-THF mixture to produce 5-methyl-3,4-diphenylisoxazole. This is then reacted sequentially with chlorosulfonic acid and ammonia to produce valdecoxib. Valdecoxib reacts with propionic anhydride in the presence of sulfuric acid to produce parecoxib, which is then salted in an ethanolic sodium hydroxide solution to obtain the final product. This route uses the relatively expensive starting material, 1-phenyl-2-propanone, which is easily synthesized as a toxin. Furthermore, the limited availability of benzonitrile N-oxide makes it unsuitable for industrial production. The reaction equation is shown below:

[0006]

[0007] Method 2: Patent WO2005123701A1 uses acetophenone to protect the tetrahydropyrrole to obtain 1-(1,2-diphenylvinyl)tetrahydropyrrole. The latter reacts with acetyl chloride under pyridine catalysis to produce 3,4-diphenyl-4-(1-pyrrolidinyl)-3-butene-2-one. This is then deprotected with sodium acetate and reacted with hydroxylamine hydrochloride to form a ring to produce 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol. This is then dehydrated with trifluoroacetic acid to produce 5-methyl-3,4-diphenylisoxazole, which is then sulfonated with fuming sulfuric acid, chlorinated with thionyl chloride, and reacted with ammonia to produce valdecoxib. This method avoids the use of alkyl lithium, but the use of 2,6-lutidine as an acid-binding agent is costly. The chloroacetylation reaction requires a relatively long reaction time of 24 hours, adding the C=O protection and deprotection steps. This lengthy process increases industrial costs and makes it unsuitable for scale-up production. The reaction equation is shown below:

[0008]

[0009] Method 3: Patent WO2003029230A1 describes the reaction of diphenylacetophenone with hydroxylamine hydrochloride under the catalysis of sodium acetate to produce 1,2-diphenylacetophenone oxime. The oxime is then condensed with ethyl acetate under the catalysis of n-butyllithium or n-hexyllithium to produce 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol. This is then dehydrated under the action of trifluoroacetic acid to produce 5-methyl-3,4-diphenylisoxazole, which is then reacted sequentially with chlorosulfonic acid and ammonia to produce valdecoxib. The alkyl lithium used in this method is relatively expensive, and due to its high reactivity, it requires absolute anhydrous and oxygen-free operation, which is highly dangerous and poses difficulties in industrial production. The reaction formula is shown below:

[0010]

[0011] Method 4: Patent CN102329277A uses 1,2-diphenylethanone as a raw material, undergoing a sulfonation reaction to produce 1-phenyl-2-(4-sulfonatophenyl)ethanone. In the presence of a base, this is condensed with acetyl chloride to produce 1-phenyl-2-(4-sulfonatophenyl)-2-acetylethanone. This is then cyclized with hydroxylamine hydrochloride to produce 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonic acid, which is then chlorinated and aminolyzed to produce valdecoxib. Finally, it is reacted with propionic anhydride to synthesize parecoxib. The acetyl chloride used in the reaction is flammable, and its vapor can form an explosive mixture with air, causing combustion and explosion upon exposure to open flames or high heat. Heat decomposes in air to release highly toxic phosgene and hydrogen chloride gases. It reacts violently and may even explode upon contact with water, water vapor, or ethanol. The reaction also uses a large amount of toxic, irritating, and flammable pyridine, which may remain in the final product. Thionyl chloride is also highly corrosive and irritating, causing burns. The temperature is high and the conditions are harsh. The reaction formula is as follows:

[0012]

[0013] Currently, the existing technology for preparing the intermediate oxazoline of parecoxib sodium has the following defects: low reaction efficiency, high waste discharge, and harsh reaction conditions. Therefore, it is of great significance to develop a greener and more efficient synthesis method for the intermediate of parecoxib sodium. Summary of the Invention

[0014] In view of the above-mentioned deficiencies in the prior art, the purpose of this application is to provide a method for synthesizing a parecoxib sodium intermediate to solve the problems of harsh reaction conditions, low reaction efficiency and high waste emissions in the prior art.

[0015] In order to solve the above technical problems, this application adopts the following technical solutions:

[0016] A method for synthesizing a parecoxib sodium intermediate, the synthetic route is as follows:

[0017]

[0018] Preferably, α-phenylacetophenone and acetaldehyde are reacted under alkaline conditions by Adol reaction to obtain compound 3, compound 3 is reacted with hydroxylamine hydrochloride under alkaline conditions to generate compound 4, and compound 4 is dehydrogenated and cyclized under electrooxidation conditions to obtain compound 5.

[0019] Preferably, α-phenylacetophenone and acetaldehyde are reacted to obtain compound 3 by the following steps:

[0020] α-Phenylacetophenone, acetaldehyde and an alkaline substance are added to an organic solvent and reacted by stirring at room temperature. After the reactants are completely consumed as determined by thin-layer chromatography, water is added to the system, the solid matter is collected by filtration, and the solid matter is washed and dried to obtain compound 3; wherein the molar ratio of α-phenylacetophenone, acetaldehyde and the alkaline substance is (1): (2-10): (0.1-2); the alkaline substance is an inorganic base or an organic base.

[0021] Preferably, the inorganic base includes one of K2CO3, Na2CO3, Cs2CO3, and Li2CO3; the organic base includes one of triethylamine and N,N-diisopropylethylamine; and the organic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, and N-methylpyrrolidone.

[0022] Preferably, compound 3 is converted into compound 4 by the following steps:

[0023] Compound 3, hydroxylamine hydrochloride, and potassium acetate were added to methanol as a solvent, and the mixture was stirred at 65-75° C. After the reactants were completely consumed as determined by thin-layer chromatography, the solvent was removed under reduced pressure to isolate compound 4; wherein the molar ratio of compound 3, hydroxylamine hydrochloride, and potassium acetate was 1:(1-5):(1-5);

[0024] Preferably, compound 4 is converted into compound 5 by the following steps:

[0025] Compound 4, N-phenylphenothiazine and tetrabutylammonium bromide were added to an electrolytic cell, followed by acetonitrile. A graphite electrode was inserted as an anode and a carbon paper electrode was used as a cathode. Constant current electrolysis was carried out at a current of 60 mA for 8 hours under stirring conditions. After the reaction was completed, the solvent was removed under reduced pressure to separate compound 5. The molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide in the acetonitrile solvent was 1:(0.1-0.6):(0.5-2).

[0026] Preferably, compound 3 is converted into compound 5 by the following steps:

[0027] Compound 3, hydroxylamine hydrochloride and potassium acetate are added to methanol solvent, and the mixture is stirred at 65-75° C. After the reactants are completely consumed as determined by thin-layer chromatography, the solvent is removed under reduced pressure; N-phenylphenothiazine and tetrabutylammonium bromide are subsequently added, followed by acetonitrile, a graphite electrode is inserted as an anode, a carbon paper electrode is used as a cathode, and constant current electrolysis is performed at 60 mA for 8 hours under stirring. After the reaction is completed, the solvent is removed under reduced pressure to separate compound 5; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5); and the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide in acetonitrile solvent is 1:(0.1-0.6):(0.5-2).

[0028] Compared with the prior art, this application has the following beneficial effects:

[0029] 1. This application adjusts the synthetic route by first performing an Adol condensation reaction with α-phenylacetophenone and acetaldehyde under alkaline conditions. The core of the Adol reaction lies in the nucleophilic addition of a carbonyl compound under base catalysis, followed by an intramolecular or intermolecular dehydration process, ultimately forming a β-hydroxyketone (compound 3) with a carbon-carbon double bond. This process avoids the strong base conditions commonly used in traditional Adol condensation reactions, not only reducing the formation of by-products, but also improving the selectivity and yield of the target product, making the reaction conditions milder and simplifying the post-processing process, which provides favorable conditions for the conversion of this reaction to industrialization.

[0030] 2. This application uses compound 3 to react with hydroxylamine hydrochloride under alkaline conditions to form compound 4 through a nucleophilic substitution mechanism. This compound is a key precursor for the construction of the oxazoline ring. The alkaline environment in this step is conducive to the formation of the hydroxylamine anion, thereby enhancing its activity as a nucleophile and promoting efficient reaction with β-hydroxyketone.

[0031] 3. Under electrochemical oxidation conditions, compound 4 underwent a dehydrogenation cyclization reaction and successfully synthesized the target product, 5-methyl-3,4-diphenyl-4,5-oxazoline-5-ol (compound 5). The present application utilizes the advantages of the electrochemical method to provide a green and efficient oxidation method without the need to add chemical oxidants, thereby reducing the generation of hazardous waste. At the same time, the electrochemical process is easy to control, and the current density and voltage can be accurately adjusted to adapt to different reaction requirements, thereby ensuring the selectivity and efficiency of the reaction. In addition, the electrochemical reaction adopted in the present application can be carried out over a wide temperature range, which further reflects the mildness and environmental friendliness of the synthesis method described in the present application.

[0032] 4. The synthetic route designed in this application not only achieves the goals of high efficiency and environmental protection by optimizing the reaction conditions, but also opens up a new path for the synthesis of complex organic molecules, showing good potential for industrial application. DETAILED DESCRIPTION

[0033] This application will be combined with the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on this application are within the scope of protection of this application.

[0034] Unless otherwise indicated in specific cases in this application, the numerical ranges listed herein include the upper and lower limits, as well as all integers and fractions within the range, and are not limited to the specific values ​​listed when defining the range.

[0035] 1. A Synthesis Method for Parecoxib Sodium Intermediates

[0036]

[0037] This application conceived and designed a synthetic route for an intermediate compound (Compound 5) with an oxazoline structure. First, an Adol condensation reaction is carried out with α-phenylacetophenone and acetaldehyde under alkaline conditions to form a β-hydroxyketone (Compound 3). In this process, the core of the Adol reaction lies in the nucleophilic addition of carbonyl compounds under base catalysis, which ultimately forms a β-hydroxyketone connected by a carbon-carbon double bond. This process avoids the strong base conditions commonly used in traditional Adol reactions, which not only reduces the formation of by-products and improves the selectivity and yield of the target product, but also makes the reaction conditions milder and simplifies the post-processing process, which provides favorable conditions for the conversion of the reaction to industrialization. Next, compound 3 reacts with hydroxylamine hydrochloride under alkaline conditions to form compound 4 through a nucleophilic substitution mechanism. The formation of compound 4 is a key precursor for the construction of the oxazoline ring. Finally, under electrochemical oxidation conditions, compound 4 undergoes a dehydrogenation cyclization reaction and successfully synthesizes the target product - 5-methyl-3,4-diphenyl-4,5-oxazoline-5-ol (Compound 5). The advantage of the electrochemical method is that it provides a green and efficient oxidation method, without the need for the addition of chemical oxidants, reducing the generation of hazardous waste. At the same time, the electrochemical process is easy to control, and the current density and voltage can be precisely adjusted to suit different reaction requirements, ensuring the selectivity and efficiency of the reaction. In addition, the electrochemical reaction used in this application can be carried out at room temperature, further demonstrating the mildness and environmental friendliness of the synthesis method described in this application.

[0038] In summary, the synthetic route designed in this application not only achieves the goals of high efficiency and environmental protection by optimizing the reaction conditions, but also opens up a new way for the synthesis of complex organic molecules and demonstrates good potential for industrial application.

[0039] In some embodiments of the present application, α-phenylacetophenone and acetaldehyde are used to obtain compound 3 by the following steps:

[0040] α-phenylacetophenone, acetaldehyde and alkaline substances are added to an organic solvent, stirred at room temperature for reaction, and after the reactants are determined to be consumed by thin layer chromatography, water is added to the system, the solid matter is collected after filtration, and it is washed and dried to obtain compound 3; wherein, the molar ratio of α-phenylacetophenone, acetaldehyde and alkaline substance is 1: (2 to 10): (0.1 to 2), which can ensure the synthesis of compound 3; the alkaline substance is an inorganic base or an organic base. Therefore, the molar ratio of α-phenylacetophenone, acetaldehyde and alkaline substance can be 1:2:0.1, 1:10:0.1, 1:2:2, 1:10:2, 1:10:0.1, 1:5:1, etc., as well as all ranges and sub-ranges between the above values; it should be understood that in the embodiment, any of the above ranges can be combined with any range of other reaction conditions in this application.

[0041] In some embodiments of the present application, the inorganic base includes one of K2CO3, Na2CO3, Cs2CO3, and Li2CO3; the organic base includes one of triethylamine and N,N-diisopropylethylamine; and the organic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, and N-methylpyrrolidone.

[0042] In some embodiments of the present application, compound 3 is used to obtain compound 4 by the following steps:

[0043] Compound 3, hydroxylamine hydrochloride and potassium acetate were added to methanol solvent, stirred at 65-75°C, and after the reactants were completely consumed as determined by thin layer chromatography, the solvent was removed under reduced pressure to isolate compound 4; wherein, the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate was 1:(1-5):(1-5), and this amount ensured the formation of compound 4. Therefore, the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate can be 1:1:1, 1:1:5, 1:5:1, 1:5:5, 1:2:3, etc., as well as all ranges and sub-ranges between the above values; it should be understood that, in embodiments, any of the above ranges can be combined with any range of other reaction conditions in this application.

[0044] In some embodiments of the present application, compound 4 is used to obtain compound 5 by the following steps:

[0045] Compound 4, N-phenylphenothiazine, and tetrabutylammonium bromide were added to an electrolytic cell, followed by acetonitrile. A graphite electrode was inserted as an anode and a carbon paper electrode was inserted as a cathode. Constant current electrolysis was performed at 60 mA for 8 hours under stirring conditions. After the reaction was completed, the solvent was removed under reduced pressure to isolate compound 5. The molar concentration ratio of compound 4, N-phenylphenothiazine, and tetrabutylammonium bromide in the acetonitrile solvent was 1:(0.1-0.6):(0.5-2), ensuring the formation of compound 5. Therefore, the molar concentration ratio of compound 4, N-phenylphenothiazine, and tetrabutylammonium bromide in the acetonitrile solvent can be 1:0.1:0.5, 1:0.1:2, 1:0.6:0.5, 1:0.6:2, 1:0.4:1.5, etc., as well as all ranges and sub-ranges between the above values. It should be understood that in embodiments, any of the above ranges can be combined with any range of other reaction conditions in the present application.

[0046] In some embodiments of the present application, compound 3 can be directly synthesized into compound 5 by a one-pot method. Without purifying compound 4, it can also be directly used for electrochemical oxidative dehydrogenation cyclization. The intermediate product will not affect the formation of the final product, and a high yield can be obtained. Compound 3 is obtained by the following steps:

[0047] Compound 3, hydroxylamine hydrochloride, and potassium acetate were added to the methanol solvent, stirred at 65-75°C, and after confirming that the reactants were completely consumed by thin-layer chromatography, the solvent was removed under reduced pressure; N-phenylphenothiazine and tetrabutylammonium bromide were then added, and acetonitrile was added. A graphite electrode was inserted as the anode and a carbon paper electrode was used as the cathode. Constant current electrolysis was performed at 60 mA for 8 hours under stirring conditions. After the reaction was completed, the solvent was removed under reduced pressure to isolate compound 5. The "in acetonitrile solvent" mentioned here refers to the product of the reaction of compound 3 with hydroxylamine hydrochloride and potassium acetate, the molar concentration ratio of compound 4, N-phenylphenothiazine, and tetrabutylammonium bromide in the entire reaction system after removing the solvent under reduced pressure and re-adding the acetonitrile solvent. Among them, the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate can be 1:1:1, 1:1:5, 1:5:1, 1:5:5, 1:2:3, etc., and all ranges and sub-ranges between the above values; in acetonitrile solvent, the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide can be 1:0.1:0.5, 1:0.1:2, 1:0.6:0.5, 1:0.6:2, 1:0.4:1.5, etc., and all ranges and sub-ranges between the above values; it should be understood that, in the embodiment, any of the above ranges can be combined with any range of other reaction conditions in this application.

[0048] 2. Example

[0049] Example 1: Synthesis of 3-hydroxy-2-methyl-1-phenylbutan-1-one (Compound 3)

[0050] α-Phenylacetophenone (3.92 g, 20 mmol), acetaldehyde (1.76 g, 40 mmol), and K2CO3 (0.552 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylformamide (30 mL). The reaction was stirred at room temperature. After complete consumption of the reactants was confirmed by thin-layer chromatography, 200 mL of water was added to the system, and the mixture was filtered. The filter cake was washed with ethyl acetate and petroleum ether, and then dried to obtain the desired product, 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.41 g, in a 92% yield.

[0051] LC-MS (ES) m / z = 240.1 [M+H] + . 1 H NMR (600MHz, Chloroform-d) δ7.93 (ddd, J=9.3,

[0052] 8.4,1.3Hz,2H),7.48–7.41(m,1H),7.38–7.30(m,3H),7.30–7.25(m,3H),7.24–7.17(m,1H),4.56–4.52(m ,1H),4.52–4.49(m,0.44H),4.49(t,J=2.8Hz,0.56H),1.20(d,J=6.2Hz,0.88H),1.10(d,J=6.1Hz,2.21H).

[0053] Example 2: Synthesis of 3-hydroxy-2-methyl-1-phenylbutan-1-one (Compound 3)

[0054] α-Phenylacetophenone (3.92 g, 20 mmol), acetaldehyde (1.76 g, 40 mmol), and Cs2CO3 (1.30 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylformamide (30 mL). The reaction was stirred at room temperature. After complete consumption of the reactants was confirmed by thin-layer chromatography, 200 mL of water was added to the system, and the mixture was filtered. The filter cake was washed with ethyl acetate and petroleum ether, and then dried to obtain the desired product, 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.56 g, in a 95% yield.

[0055] LC-MS (ES) m / z = 240.3 [M+H] + .

[0056] Example 3: Synthesis of 3-hydroxy-2-methyl-1-phenylbutan-1-one (Compound 3)

[0057] α-Phenylacetophenone (3.92 g, 20 mmol), acetaldehyde (1.76 g, 40 mmol), and K2CO3 (0.552 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylacetamide (30 mL). The reaction was stirred at room temperature. After complete consumption of the reactants was confirmed by thin-layer chromatography, 200 mL of water was added to the system, and the mixture was filtered. The filter cake was washed with ethyl acetate and petroleum ether, and then dried to obtain the desired product, 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.18 g, in an 87% yield.

[0058] LC-MS (ES) m / z = 240.1 [M+H] + .

[0059] Example 4: Synthesis of [3-hydroxy-2-methyl-1-phenylbutylidene]hydroxylamine (Compound 4)

[0060] 3-Hydroxy-2-methyl-1-phenylbutan-1-one (2.4 g, 10 mmol), hydroxylamine hydrochloride (0.83 g, 12 mmol), and potassium acetate (1.18 g, 12 mmol) were added to a round-bottom flask, followed by methanol (20 mL) and stirred at 70°C. After complete consumption of the reactants was confirmed by thin-layer chromatography, the solvent was removed under reduced pressure and the product was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 4:1) to obtain the desired product, [3-hydroxy-2-methyl-1-phenylbutan-1-ylidene]hydroxylamine, 2.4 g, in a 96% yield.

[0061] LC-MS (ES) m / z = 255.1 [M+H] + . 1 H NMR(600MHz,Chloroform-d)δ9.21(s,1H),7.45–

[0062] 7.04(m,10H),4.48–4.28(m,1H),3.75–3.62(m,1H),1.21–1.07(m,3H).

[0063] Example 5: Synthesis of 5-methyl-3,4-diphenyl-4,5-oxazoline-5-ol (Compound 5)

[0064] [3-Hydroxy-2-methyl-1-phenylbutylidene]hydroxylamine (1.28 g, 5 mmol), N-phenylphenothiazine (0.068 g, 0.25 mmol), and tetrabutylammonium bromide (0.967 g, 3 mmol) were added to an electrolytic cell, followed by 30 ml of acetonitrile. A graphite electrode was inserted as the anode and a carbon paper electrode as the cathode. Under stirring conditions, constant current electrolysis was carried out at 60 mA for 8 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the target product, 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol, was obtained by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 4:1) to obtain 1.1 g of the target product, 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol, with a yield of 83%.

[0065] LC-MS (ES) m / z = 253.1 [M+H] + .

[0066] Example 6: One-pot synthesis of 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol (Compound 5)

[0067] 3-Hydroxy-2-methyl-1-phenylbutan-1-one (1.2 g, 5 mmol), hydroxylamine hydrochloride (0.42 g, 6 mmol), and potassium acetate (0.59 g, 6 mmol) were added to a round-bottom flask, followed by methanol (10 mL) and stirring at 70°C. After complete consumption of the reactants was confirmed by thin-layer chromatography, the solvent was removed under reduced pressure, and N-phenylphenothiazine (0.068 g, 0.25 mmol) and tetrabutylammonium bromide (0.967 g, 3 mmol) were added. Then, 30 mL of acetonitrile was added. A graphite electrode was inserted as the anode and a carbon paper electrode as the cathode. Constant-current electrolysis was carried out at 60 mA for 8 hours with stirring. After completion of the reaction, the solvent was removed under reduced pressure, and the product was separated by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 4:1) to obtain the target product, 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol, 0.97 g, in a 77% yield.

[0068] LC-MS (ES) m / z = 253.1 [M+H] + . 1 H NMR(600MHz,Chloroform-d)δ7.63–7.60(m,1.71H),

[0069] 7.52–7.49(m,0.28H),7.38–7.26(m,6.11H),7.21–7.13(m,1.86H),4.52(s,0.86H) ,4.46(s,0.14H),3.40(s,0.83H),2.72(s,0.13H),1.77(s,0.42H),1.27(s,2.59H). 13 C NMR (151MHz, CDCl3) δ160.7,159.8,134.7,130.2,130.0,129.3,129.2,129.2,128.9 ,128.6,128.58,128.3,128.1,127.3,127.1,109.35,108.6,63.1,60.8,26.1,22.1.

[0070] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application and not to limit the technical solutions. Those skilled in the art should understand that modifications or equivalent replacements of the technical solutions of the present application that do not depart from the purpose and scope of the technical solutions of the present application should be included in the scope of the claims of the present application.

Claims

1. A method for synthesizing a parecoxib sodium intermediate, characterized in that: The synthetic route is as follows: Compound 4, N-phenylphenothiazine and tetrabutylammonium bromide were added to an electrolytic cell, followed by acetonitrile. A graphite electrode was inserted as an anode and a carbon paper electrode was used as a cathode. Constant current electrolysis was carried out at a current of 60 mA for 8 hours under stirring conditions. After the reaction was completed, the solvent was removed under reduced pressure to separate compound 5. The molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide in the acetonitrile solvent was 1:(0.1-0.6):(0.5-2).

2. The synthesis method according to claim 1, wherein α-Phenylacetophenone and acetaldehyde undergo Adol reaction under alkaline conditions to obtain compound 3, which reacts with hydroxylamine hydrochloride under alkaline conditions to generate compound 4, which is then dehydrogenated and cyclized under electrooxidation conditions to obtain compound 5.

3. The synthesis method according to claim 2, characterized in that α-Phenylacetophenone and acetaldehyde are reacted to give compound 3 by the following steps: α-Phenylacetophenone, acetaldehyde and an alkaline substance are added to an organic solvent and reacted with stirring at room temperature. After the reactants are completely consumed as determined by thin-layer chromatography, water is added to the system, and the solid substance is collected by filtration, washed and dried to obtain compound 3; wherein the molar ratio of α-phenylacetophenone, acetaldehyde and the alkaline substance is 1:(2-10):(0.1-2); the alkaline substance is an inorganic base or an organic base.

4. The synthesis method according to claim 3, wherein The inorganic base is selected from one of K2CO3, Na2CO3, Cs2CO3, and Li2CO3; the organic base is selected from one of triethylamine and N,N-diisopropylethylamine; and the organic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, and N-methylpyrrolidone.

5. The synthesis method according to claim 2, characterized in that Compound 3 is converted into compound 4 by the following steps: Compound 3, hydroxylamine hydrochloride and potassium acetate are added to methanol solvent, and the mixture is stirred at 65-75° C. After the reactants are completely consumed as determined by thin layer chromatography, the solvent is removed under reduced pressure to isolate compound 4; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5).

6. A method for synthesizing a parecoxib sodium intermediate, characterized in that: The synthetic route is as follows: Compound 3, hydroxylamine hydrochloride and potassium acetate are added to methanol solvent, and the mixture is stirred at 65-75° C. After the reactants are completely consumed as determined by thin-layer chromatography, the solvent is removed under reduced pressure; N-phenylphenothiazine and tetrabutylammonium bromide are subsequently added, followed by acetonitrile, a graphite electrode is inserted as an anode, a carbon paper electrode is used as a cathode, and constant current electrolysis is performed at 60 mA for 8 hours under stirring. After the reaction is completed, the solvent is removed under reduced pressure to separate compound 5; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5); and the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide in acetonitrile solvent is 1:(0.1-0.6):(0.5-2).

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