Synthesis method of parecoxib sodium intermediate

Abstract

The invention discloses a synthesis method of a parecoxib sodium intermediate, simple and easily available alpha-phenyl acetophenone, acetaldehyde and hydroxylamine are used as raw materials, an important intermediate 5-methyl-3, 4-diphenyl-4, 5-oxazoline-5-alcohol is obtained through Adol reaction and electrooxidation conditions, the whole reaction process can be carried out under mild conditions, and the synthesis method has the advantages of high yield, high purity, high purity and high purity. The method has the advantages of simple operation, no harsh reaction condition requirements, high reaction efficiency in each step, simple and controllable reaction process, and good industrialization prospect.

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, structural formula is as follows:

[0003]

[0004] At present, there are four main synthetic routes of parecoxib sodium given in domestic and foreign literature and patents, and the similarities of various routes are that valdecoxib is first synthesized, then reacted to generate parecoxib, and then salted to prepare the final product (such as CN102329277A; WO2005085218A1; WO2005123701A1; EP1550658A1; WO2003029230A1, etc.).

[0005] Method 1: Patent EP1550658A1 uses 1-phenyl-2-propanone as a raw material, reacts with benzonitrile N-oxide to obtain 5-methyl-3,4-diphenyl-4,5-oxazoline-5-ol, and the latter is refluxed and dehydrated in a sodium carbonate-THF mixed solution to obtain 5-methyl-3,4-diphenylisoxazole. Then react with chlorosulfonic acid and ammonia water in sequence to obtain valdecoxib. Valdecoxib reacts with propionic anhydride under the action of sulfuric acid to produce parecoxib, which is then salified in sodium hydroxide ethanol solution to obtain the final product. The starting raw material 1-phenyl-2-propanone of this route is relatively expensive and belongs to a type of easily made poison, and the source of benzonitrile N-oxide is limited, which is not suitable for industrial production and preparation. The reaction formula is as follows:

[0006]

[0007] Method 2: Patent WO2005123701A1 uses diphenylacetophenone to protect with tetrahydropyrrole to obtain 1-(1,2-diphenylvinyl) tetrahydropyrrole, which reacts with acetyl chloride under pyridine catalysis to obtain 3,4-diphenyl 4-(1-pyrrolidinyl)-3-butene-2-one, which is then deprotected with sodium acetate and reacted with hydroxylamine hydrochloride to form a ring to obtain 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol. Then, it is dehydrated under the action of trifluoroacetic acid to obtain 5-methyl-3,4-diphenylisoxazole, which is then sulfonated with fuming sulfuric acid, chlorinated with thionyl chloride, and then reacted with ammonia water to obtain valdecoxib. This method can avoid the use of alkyl lithium, but 2,6-lutidine is used as an acid-binding agent, which is more expensive. The chloroacetylation reaction requires 24 hours, and the reaction time is relatively long. The protection and deprotection process of C=O is increased, the steps are longer, and the industrial cost is increased, which is not suitable for expanded production. The reaction formula is shown below:

[0008]

[0009] Method 3: Patent WO2003029230A1 uses diphenylacetophenone to react with hydroxylamine hydrochloride under the catalysis of sodium acetate to obtain 1,2-diphenylacetophenone oxime, which is condensed with ethyl acetate under the catalysis of n-butyl lithium or n-hexyl lithium to obtain 5-methyl-3,4-diphenyl 4,5-oxazolin-5-ol, which is then dehydrated under the action of trifluoroacetic acid to obtain 5-methyl-3,4-diphenylisoxazole, which is then reacted with chlorosulfonic acid and ammonia water in sequence to obtain valdecoxib. The alkyl lithium used in this method is relatively expensive, and because of its strong activity, it requires absolute anhydrous and oxygen-free operation, which is highly dangerous and faces difficulties in industrial production. The reaction formula is as follows:

[0010]

[0011] Method 4: Patent CN102329277A uses 1,2-diphenylacetone as a raw material, and obtains 1-phenyl-2-(4-sulfonylphenyl)ethanone through sulfonation reaction. In the presence of a base, it is condensed with acetyl chloride to prepare 1-phenyl-2-(4-sulfonylphenyl)-2-acetyl acetone. It is then cyclized with hydroxylamine hydrochloride to obtain 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonic acid, which is then chlorinated and aminolyzed to prepare valdecoxib, and finally 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, which can cause combustion and explosion when exposed to open flames and high heat. It is heated and decomposed in the air to produce highly toxic phosgene and hydrogen chloride gas. It reacts violently and even explodes when exposed to water, water vapor or ethanol. In addition, a large amount of toxic, irritating and flammable pyridine is used in the reaction, which may remain in the final product. Sulfonyl chloride is also highly corrosive and irritating, and can cause burns to the human body. The temperature is high and the conditions are harsh. The reaction formula is as follows:

[0012]

[0013] At present, the existing technology for preparing the intermediate oxazoline of parecoxib sodium has the defects of 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 of the intermediate of parecoxib sodium. Summary of the invention

[0014] In view of the above-mentioned deficiencies in the prior art, the purpose of the present 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 electro-oxidation 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, stirred at room temperature for reaction, and after thin layer chromatography is used to determine that the reactants have been completely consumed, water is added to the system, and solid substances are collected after 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.

[0021] Preferably, the inorganic base includes one of K2CO3, Na2CO3, Cs2CO3, and Li2CO3; the organic base includes one of triethylamine or 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 obtained by the following steps to obtain compound 4:

[0023] Compound 3, hydroxylamine hydrochloride and potassium acetate are added to methanol solvent, and 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 separate compound 4; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5);

[0024] Preferably, compound 4 is obtained by the following steps to obtain compound 5:

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

[0026] Preferably, compound 3 is obtained by the following steps to obtain compound 5:

[0027] Compound 3, hydroxylamine hydrochloride and potassium acetate are added to a 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. Subsequently, N-phenylphenothiazine and tetrabutylammonium bromide are added thereto, and then acetonitrile is added thereto. A graphite electrode is inserted as an anode and a carbon paper electrode is used as a cathode. Constant current electrolysis is performed at a current of 60 mA for 8 hours under stirring conditions. After the reaction is completed, the solvent is removed under reduced pressure to separate and obtain compound 5. 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 the 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. The present application has adjusted the synthetic route, firstly through the Adol condensation reaction of α-phenylacetophenone and acetaldehyde under alkaline conditions. The core of the Adol reaction is the nucleophilic addition of carbonyl compounds under base catalysis, followed by intramolecular or intermolecular dehydration process, and finally forming a β-hydroxy ketone (compound 3) connected by a carbon-carbon double bond. This process avoids the strong base conditions commonly used in traditional Adol condensation reactions, not only reduces the generation of by-products, 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 transformation of the reaction to industrialization.

[0030] 2. The present 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 constructing an oxazoline ring. The alkaline environment in this step is conducive to the formation of hydroxylamine anions, thereby increasing its activity as a nucleophilic reagent and promoting effective 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 addition of chemical oxidants, reducing the generation of hazardous wastes. At the same time, the electrochemical process is easy to control, and the current density and voltage can be accurately adjusted to meet different reaction requirements, ensuring the selectivity and efficiency of the reaction. In addition, the electrochemical reaction used 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 belong to 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 method for synthesizing a parecoxib sodium intermediate

[0036]

[0037] The present application conceived and designed a synthetic route for an intermediate compound (compound 5) having an oxazoline structure. First, β-hydroxy ketone (compound 3) was formed by an Adol condensation reaction of α-phenylacetophenone and acetaldehyde under alkaline conditions. In this process, the core of the Adol reaction lies in the nucleophilic addition of carbonyl compounds under base catalysis, and finally forms β-hydroxy ketone 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, 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 transformation 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 an 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 adding chemical oxidants, reducing the generation of harmful wastes. At the same time, the electrochemical process is easy to control, and the current density and voltage can be precisely adjusted to meet 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 reflecting 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, showing 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, and the solid matter is collected after filtration, washed and dried to obtain compound 3; wherein, the molar ratio of α-phenylacetophenone, acetaldehyde and alkaline substances is 1: (2-10): (0.1-2), and this range 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 substances 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 the present 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 or 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 are added to the solvent methanol, stirred at 65-75°C, and after the reactants are completely consumed as determined by thin layer chromatography, the solvent is removed under reduced pressure to separate compound 4; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5), and this amount ensures 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., 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 the present 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, a carbon paper electrode was used as a cathode, constant current electrolysis was performed for 8 hours at 60 mA under stirring conditions, and after the reaction was completed, the solvent was removed under reduced pressure to separate compound 5; wherein, in the acetonitrile solvent, the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide was 1: (0.1-0.6): (0.5-2), ensuring the formation of compound 5. Therefore, in the 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 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, and compound 4 can be directly used for electrochemical oxidative dehydrogenation cyclization without purification, and the intermediate product will not affect the formation of the final product, and can also have a higher yield. Compound 3 is obtained by the following steps:

[0047] Compound 3, hydroxylamine hydrochloride and potassium acetate were added to the solvent methanol, 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; N-phenylphenothiazine and tetrabutylammonium bromide were then added thereto, and acetonitrile was added, a graphite electrode was inserted as an anode, and a carbon paper electrode was used 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 separate compound 5. The "in acetonitrile solvent" mentioned here refers to the product of the reaction of compound 3 with hydroxylamine hydrochloride and potassium acetate, and the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide in the entire reaction system after the solvent was removed under reduced pressure and the acetonitrile solvent was added again. 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 the present application.

[0048] 2. Embodiment

[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), K2CO3 (0.552 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylformamide (30 mL), and stirred at room temperature for reaction. After the reactants were completely consumed as determined by thin layer chromatography, 200 mL of water was added to the system, filtered, and the filter cake was washed with ethyl acetate and petroleum ether, and dried to obtain the target product 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.41 g, with a yield of 92%.

[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), Cs2CO3 (1.30 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylformamide (30 mL), and stirred at room temperature for reaction. After the reactants were completely consumed as determined by thin layer chromatography, 200 mL of water was added to the system, filtered, and the filter cake was washed with ethyl acetate and petroleum ether, and dried to obtain the target product 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.56 g, with a yield of 95%.

[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), K2CO3 (0.552 g, 4 mmol) were added to a round-bottom flask, followed by N,N-dimethylacetamide (30 mL), and stirred at room temperature for reaction. After the reactants were completely consumed as determined by thin layer chromatography, 200 mL of water was added to the system, filtered, and the filter cake was washed with ethyl acetate and petroleum ether, and dried to obtain the target product 3-hydroxy-2-methyl-1-phenylbutan-1-one, 4.18 g, with a yield of 87%.

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

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

[0060] 3-Hydroxy-2-methyl-1-phenylbutan-1-one (2.4 g, 10 mmol), hydroxylamine hydrochloride (0.83 g, 12 mmol), 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 the reactants were completely consumed as determined by thin layer chromatography, the solvent was removed under reduced pressure, and silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 4:1) was used to obtain the target product [3-hydroxy-2-methyl-1-phenylbutanyl]hydroxylamine, 2.4 g, with a yield of 96%.

[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-phenylbutylene]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 an anode and a carbon paper electrode was used 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 and 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-oxazoline-5-ol, 1.1 g, 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-oxazoline-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), potassium acetate (0.59 g, 6 mmol) were added to a round-bottom flask, followed by methanol (10 mL) and stirred at 70°C. After the reactants were completely consumed by thin-layer chromatography, the solvent was removed under reduced pressure, N-phenylphenothiazine (0.068 g, 0.25 mmol) and tetrabutylammonium bromide (0.967 g, 3 mmol) were added, followed by 30 ml of acetonitrile, a graphite electrode was inserted as an anode, a carbon paper electrode was used as a cathode, and 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, and silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 4:1) was used to obtain the target product 5-methyl-3,4-diphenyl-4,5-oxazolin-5-ol, 0.97 g, with a yield of 77%.

[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 solution of the present application rather than to limit the technical solution. Ordinary technicians in this field should understand that those modifications or equivalent substitutions of the technical solution of the present application that do not depart from the purpose and scope of the technical solution 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:

2. The synthesis method according to claim 1, characterized in that: α-Phenylacetophenone and acetaldehyde undergo Adol reaction under alkaline conditions to obtain compound 3, compound 3 reacts with hydroxylamine hydrochloride under alkaline conditions to generate compound 4, and compound 4 undergoes dehydrogenation cyclization under electro-oxidation conditions to obtain compound 5.

3. The synthesis method according to claim 2, characterized in that: α-Phenylacetophenone and acetaldehyde are used to obtain compound 3 by the following steps: α-phenylacetophenone, acetaldehyde and an alkaline substance are added to an organic solvent, stirred at room temperature for reaction, and after thin layer chromatography determines that the reactants are completely consumed, water is added to the system, and the solid matter is collected after 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, characterized in that: 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.

5. The synthesis method according to claim 2, characterized in that: Compound 3 is obtained 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 separate compound 4; wherein the molar ratio of compound 3, hydroxylamine hydrochloride and potassium acetate is 1:(1-5):(1-5).

6. The synthesis method according to claim 2, characterized in that: Compound 4 is obtained by the following steps: Compound 4, N-phenylphenothiazine and tetrabutylammonium bromide are added to an electrolytic cell, followed by acetonitrile, and a graphite electrode is inserted as an anode and a carbon paper electrode as a cathode. Under stirring conditions, constant current electrolysis is carried out at a current of 60 mA for 8 hours. After the reaction is completed, the solvent is removed under reduced pressure to separate and obtain compound 5; wherein, in the acetonitrile solvent, the molar concentration ratio of compound 4, N-phenylphenothiazine and tetrabutylammonium bromide is 1:(0.1-0.6):(0.5-2).

7. The synthesis method according to claim 2, characterized in that: Compound 3 is used to obtain compound 5 by the following steps: Compound 3, hydroxylamine hydrochloride and potassium acetate are added to a 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. Subsequently, N-phenylphenothiazine and tetrabutylammonium bromide are added thereto, and then acetonitrile is added thereto. A graphite electrode is inserted as an anode and a carbon paper electrode is used as a cathode. Constant current electrolysis is performed at a current of 60 mA for 8 hours under stirring conditions. After the reaction is completed, the solvent is removed under reduced pressure to separate and obtain compound 5. 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 the acetonitrile solvent is 1:(0.1-0.6):(0.5-2).

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