A synthetic method of celecoxib

Abstract

The present invention provides a method for synthesizing celecoxib, comprising the following steps: using benzaldehyde as a starting material, reacting with propyne to obtain 1-phenylbut-2-yn-1-ol I, converting the intermediate into 5-methyl-3-phenylisoxazole II by a one-pot reaction based on the Meyer-Schuster rearrangement reaction, adding bromine at the 4-position of the isoxazole ring by the action of NBS to obtain 4-bromo-5-methyl-3-phenylisoxazole III, and then coupling with (4-aminosulfonylphenyl)boronic acid through metal palladium-catalyzed Suzuki, and finally completing the total synthesis of celecoxib through 4 steps of reactions. Compared with the prior art, this synthesis method first applies the Meyer-Schuster rearrangement reaction to the synthesis of celecoxib, and reduces the number of reaction steps and the number of times of separation and purification of intermediates through a two-step one-pot method.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and relates to a method for synthesizing valdecoxib. Background Art

[0002] Valdecoxib has the following structural formula:

[0003]

[0004] Valdecoxib belongs to cyclooxygenase-2 inhibitors and is a new type of non-steroidal anti-inflammatory drug. It has strong anti-inflammatory and analgesic effects, is widely used in postoperative analgesia, and can also treat depression. Currently, there are mainly three synthetic routes for valdecoxib according to different raw materials:

[0005] 1. Using phenylacetic acid 1 as the starting material, it is an earlier synthetic process route for valdecoxib, and its synthetic process route is as follows:

[0006]

[0007] In this synthetic route, phenylacetic acid 1 is converted into diphenylacetone 2 through acyl chlorination, etc.; then further converted into oxime 3; cyclized with ethyl acetate to obtain 4; dehydrated with trifluoroacetic acid to obtain 5; and finally obtained valdecoxib through sulfonation, chlorination, and ammoniation. This preparation method requires 7 steps of reaction, and the route is relatively long.

[0008] 2. Using diphenylacetone as the starting material, it can be divided into three schemes according to different specific process routes, and its synthetic process route is as follows:

[0009]

[0010] Scheme 1: To ensure that the subsequent hydroxylamine and acyl cyclization reaction is not interfered, first, the carbonyl group of the raw material diphenylacetone 2 needs to be protected. Pyrrolidine is used as a carbonyl protecting agent to react with the raw material diphenylacetone in the first step to obtain intermediate 6, and then acetylation is carried out to obtain 7. Then, sodium acetate is used to deprotect the protected carbonyl group, and further react with hydroxylamine hydrochloride to form a ring to obtain 4. After sulfonation, chlorination, and ammoniation, the final product valdecoxib is obtained. This method adds the protection and deprotection of the carbonyl group, and the overall synthesis requires 7 steps of reaction, and the steps are relatively long.

[0011] Scheme 2: Diphenylacetone 2 reacts with chlorosulfonic acid / thionyl dichloride / ammonia water to obtain a sulfonamide product 8. Since the amino group is easily oxidized, 2,5-hexanedione is used as a protecting agent, and 9 is obtained after the reaction. Then, pyrrolidine is used to protect the carbonyl group, then acetylation, reaction with hydroxylamine hydrochloride to form an oxime and a series of reactions to obtain 10, and finally the protection of the amino group is removed by trifluoroacetic acid to obtain the final product. The limitation of this route is that 2,5-hexanedione is added to protect the amino group, and the overall synthesis steps are relatively long.

[0012] Scheme 3: Acetophenone 2 first reacts with chlorosulfonic acid to obtain a sulfonated product 11, which is acetylated with acetyl chloride to obtain 12, and then cyclized with hydroxylamine hydrochloride to obtain an isoxazole intermediate 13. Then, it reacts with thionyl chloride and ammonia respectively, and undergoes chlorination and ammonolysis to obtain desoxocortisol. The overall reaction steps are 5 steps.

[0013] 3. Two synthetic routes using 1-phenyl-2-propanone 14 as the raw material are as follows:

[0014]

[0015] One is that the raw material 1-phenyl-2-propanone directly undergoes a cyclization reaction with benzonitrile N-oxide to synthesize an isoxazole intermediate 4. Then, the intermediate 4 is refluxed and dehydrated in a mixed solution of sodium carbonate - THF to obtain an intermediate 5, and then the synthesis of desoxocortisol is completed; the other is that first, pyrrolidine is used to protect the carbonyl group to obtain an intermediate 15, and then it is further converted into an isoxazole intermediate 16 with benzonitrile N-oxide or N-hydroxyphthalimide chloride. Finally, the synthesis of desoxocortisol is completed through 6 steps, and the overall synthesis steps are also relatively long.

[0016] The above reaction routes for synthesizing desoxocortisol are long, time-consuming, and the process is cumbersome. Therefore, it is still necessary to simplify the synthesis steps of desoxocortisol and reduce the number of times of intermediate separation and purification. Summary of the Invention

[0017] The purpose of the present invention is to provide a synthesis method of desoxocortisol with simple operation and a short synthetic route to overcome the defects existing in the above-mentioned prior art.

[0018] The purpose of the present invention can be achieved by the following technical solutions:

[0019] The present invention provides a synthesis method of desoxocortisol, including the following steps:

[0020] S1: Using benzaldehyde as the raw material, reacting with propyne, tetrahydrofuran (THF), and n-butyllithium (n-BuLi) at a certain temperature and atmosphere to obtain an intermediate 1-phenylbut-2-yn-1-ol I;

[0021] S2: Based on the one-pot reaction of the Meyer-Schuster rearrangement reaction, converting the intermediate 1-phenylbut-2-yn-1-ol I into 5-methyl-3-phenylisoxazole II;

[0022] S3: Adding bromine at the 4-position of the isoxazole ring of 5-methyl-3-phenylisoxazole II through the action of N-bromosuccinimide (NBS) to obtain 4-bromo-5-methyl-3-phenylisoxazole III;

[0023] S4: 4-Bromo-5-methyl-3-phenylisoxazole III was coupled with (4-sulfamoylphenyl)boronic acid through a palladium-catalyzed Suzuki reaction to obtain desikoxib IV.

[0024] Further, in S1, the feeding ratio of tetrahydrofuran, propyne, n-butyllithium, and benzaldehyde is 1-20 mL: 1-1.5 mmol: 1.2-1.8 mmol: 1 mmol.

[0025] Further, in S1, the reaction temperature is -78 °C and the atmosphere is nitrogen.

[0026] Further, in S2, the process of the one-pot reaction of the Meyer-Schuster rearrangement reaction is specifically as follows: Bismuth trifluoromethanesulfonate (Bi(OTf)3) and N-iodosuccinimide (NIS) were successively added to a solution of 1-phenylbut-2-yn-1-ol I in dioxane, and the mixture was refluxed until 1-phenylbut-2-yn-1-ol I completely disappeared. After cooling slightly, a hydroxylamine derivative was added to obtain 5-methyl-3-phenylisoxazole II.

[0027] Further, the feeding ratio of 1-phenylbut-2-yn-1-ol I, Bi(OTf)3, NIS, dioxane, and the hydroxylamine derivative is 1 mmol: 0.05-0.5 mmol: 1-2 mmol: 1-20 mL: 1-3 mmol in sequence.

[0028] Further, the hydroxylamine derivative is tert-butyl hydroxylamine hydrochloride. There is a reported preparation method of an isoxazole derivative in the prior art. The hydroxylamine derivatives used in the reaction are 6 kinds including hydroxylamine hydrochloride, N-tert-butoxycarbonylhydroxylamine, N-hydroxytoluenesulfonamide, N-benzyloxycarbonylhydroxylamine, N-benzylhydroxylamine, or N-(9-fluorenylmethoxycarbonyl)hydroxylamine. This method will simultaneously produce 2 isoxazole derivatives with very similar polarities. Therefore, the yield is not high and the post-treatment such as separation and purification is not convenient. If the hydroxylamine derivative in S2 is hydroxylamine hydrochloride, 1-phenylbut-2-yn-1-ol I will be converted into 5-methyl-3-phenylisoxazole II and its isomer 3-methyl-5-phenylisoxazole, and the yield of 5-methyl-3-phenylisoxazole II does not exceed 30%. If the hydroxylamine derivative in S2 is tert-butyl hydroxylamine hydrochloride, the single product 5-methyl-3-phenylisoxazole II can be obtained in high yield without the generation of the isomer 3-methyl-5-phenylisoxazole. Therefore, the use of tert-butyl hydroxylamine hydrochloride is the key technology of this route, and the highest yield of this step can reach 65%.

[0029] Further, in S3, the specific reaction process is as follows: N-bromosuccinimide (NBS) is added to a solution of 5-methyl-3-phenylisoxazole II dissolved in dimethylformamide (DMF), and the reaction is carried out at room temperature to obtain 4-bromo-5-methyl-3-phenylisoxazole III.

[0030] Further, the feeding ratio of 5-methyl-3-phenylisoxazole II, NBS, and DMF is 1 mmol: 1-3 mmol: 1-20 mL in sequence.

[0031] Further, in S4, the specific process of the metal palladium-catalyzed Suzuki reaction is as follows: Under the protection of a nitrogen atmosphere, 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, tetrakis(triphenylphosphine)palladium (Ph(PPh3)4), cesium carbonate (Cs2CO3), dioxane, and water are added in sequence, and the mixture is refluxed until 4-bromo-5-methyl-3-phenylisoxazole III completely disappears to obtain desoxyclopidogrel IV.

[0032] Further, the feeding ratio of 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, Ph(PPh3)4, Cs2CO3, dioxane, and water is 1 mmol: 1-2 mmol: 0.05-0.5 mmol: 1-6 mmol: 1-20 mL: 0.2-4 mL in sequence.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] 1. The present invention applies the Meyer-Schuster rearrangement reaction to the synthesis of desoxyclopidogrel for the first time, reduces the reaction steps to 4 steps through a two-step one-pot method, and reduces the number of times of intermediate separation and purification.

[0035] 2. The reaction conditions of the present invention are mild, the operation is convenient, and the post-treatment is simple.

[0036] 3. The total yield of desoxyclopidogrel in the present invention can reach 44.2%. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is a synthetic route of desoxyclopidogrel;

[0038] Figure 2 is the NMR spectrum of intermediate 1-phenylbut-2-yn-1-ol;

[0039] Figure 3 is the NMR spectrum of intermediate 5-methyl-3-phenylisoxazole;

[0040] Figure 4 is the NMR spectrum of intermediate 4-bromo-5-methyl-3-phenylisoxazole;

[0041] Figure 5 1H NMR spectrum of desidroxyciclohexadienylideneacetonitrile; 1 1H NMR spectrum;

[0042] Figure 6 13C NMR spectrum of desidroxyciclohexadienylideneacetonitrile; 13 13C NMR spectrum.

[0043] Figure 1 Marking instructions:

[0044] I, 1-phenylbut-2-yn-1-ol, II, 5-methyl-3-phenylisoxazole, III, 4-bromo-5-methyl-3-phenylisoxazole, Ⅳ, desidroxyciclohexadienylideneacetonitrile. Detailed implementation mode

[0045] The following is a detailed description of the specific implementation mode of the present invention through examples. These examples are implemented on the premise of the solution described in the present invention, and the detailed implementation mode and specific operation process are given. However, the protection scope of the present invention is not limited to the following examples.

[0046] The following further describes the present invention in conjunction with the accompanying drawings and specific examples. In the technical solution of the present invention, features such as preparation means, materials, structures or composition ratios that are not clearly described are regarded as common technical features disclosed in the prior art.

[0047] Experimental process

[0048] A synthesis method of desidroxyciclohexadienylideneacetonitrile, as Figure 1 shown, includes the following steps:

[0049] S1: Synthesis of intermediate 1-phenylbut-2-yn-1-ol I: Add THF and propyne to a dry reaction flask in sequence, then cool the reaction solution to -78°C, slowly add 2.5N n-BuLi under nitrogen protection, and then slowly add benzaldehyde after 40 minutes. Monitor the reaction by TLC. When benzaldehyde is completely converted, let the reaction solution warm up to room temperature naturally, then quench the reaction with water, extract the organic phase with ethyl acetate, combine the organic phases and wash the organic phase with saturated brine, and purify by column chromatography to obtain intermediate 1-phenylbut-2-yn-1-ol I;

[0050] NMR data of intermediate 1-phenylbut-2-yn-1-ol I: 1H NMR(500MHz,CDCl3)δ7.40(d,J = 7.5Hz,2H),7.24(t,J = 6.5Hz,2H),7.20 - 7.17(m,1H),5.27(s,1H),2.73(s,1H),1.76(d,J = 2.0Hz,3H), and the NMR spectrum is as Figure 2 shown.

[0051] S2: Synthesis of intermediate 5-methyl-3-phenylisoxazole II: 1-phenylbut-2-yn-1-ol I, NIS, dioxane and Bi(OTf)3 were successively added to a reaction flask, and then the reaction was heated to reflux. After 2 hours, when 1-phenylbut-2-yn-1-ol I was completely converted into the iodide, hydroxylamine hydrochloride tert-butyl was slowly added to the reaction flask. Then the reaction was monitored by TLC. When the iodide intermediate was completely converted, the reaction solution was naturally cooled to room temperature, followed by quenching with water. The organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine. Finally, the intermediate 5-methyl-3-phenylisoxazole II was obtained by column chromatography purification;

[0052] 1H NMR data of intermediate 5-methyl-3-phenylisoxazole II: 1H NMR (500 MHz, CDCl3) δ 7.84–7.80 (m, 2H), 7.51–7.45 (m, 3H), 6.33 (s, 1H), 2.51 (s, 3H). The NMR spectrum is as Figure 3 shown.

[0053] S3: Synthesis of intermediate 4-bromo-5-methyl-3-phenylisoxazole III: Intermediate 5-methyl-3-phenylisoxazole II, DMF and NBS were successively added to a reaction flask, and then the reaction flask was stirred at room temperature. The reaction was monitored by TLC. When intermediate 5-methyl-3-phenylisoxazole II was completely converted, the reaction was quenched with water. The organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine. The intermediate 4-bromo-5-methyl-3-phenylisoxazole III was obtained by column chromatography purification;

[0054] 1H NMR data of intermediate 4-bromo-5-methyl-3-phenylisoxazole III: 1H NMR (500 MHz, CDCl3) δ 7.91–7.86 (m, 2H), 7.54–7.51 (m, 3H), 2.53 (s, 3H). The NMR spectrum is as Figure 4 shown.

[0055] S4: Synthesis of deracoxib IV: Intermediate 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, Cs2CO3, dioxane and water were successively added to a reaction flask, and then Ph(PPh3)4 was added under nitrogen protection. The reaction was placed under reflux and stirred. The reaction was monitored by TLC. When intermediate 4-bromo-5-methyl-3-phenylisoxazole III was completely converted, the reaction was quenched with water. The organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine. The target product deracoxib IV was obtained by column chromatography purification;

[0056] NMR data of desidroxycarbazepine: 1H NMR (500 MHz, DMSO) δ 7.85 (d, J = 10.5 Hz, 2H), 7.46–7.40 (m, 7H), 7.36 (dd, J = 2.0, 2.0 Hz, 2H), 2.48 (s, 3H). 13C NMR (125 MHz, DMSO) δ 168.09, 161.15, 143.71, 133.74, 130.47, 130.25, 129.30, 128.86, 128.66, 126.56, 114.72, 11.87. The NMR spectra are as Figure 5 and Figure 6 shown.

[0057] Example 1

[0058] In S1, when the feeding amounts of THF, propyne, n-BuLi, and benzaldehyde were 10 mL: 1.3 mmol: 1.5 mmol: 1 mmol in sequence, the yield of intermediate 1-phenylbut-2-yn-1-ol I was 97%.

[0059] In S2, when the feeding amounts of intermediate 1-phenylbut-2-yn-1-ol I, Bi(OTf)3, NIS, dioxane, and tert-butyl hydroxylamine hydrochloride were 1 mmol: 0.1 mmol: 1.5 mmol: 1 mL: 3 mmol in sequence, the yield of intermediate 5-methyl-3-phenylisoxazole II was 65%.

[0060] In S3, when the feeding amounts of intermediate 5-methyl-3-phenylisoxazole II, NBS, and DMF were 1 mmol: 3 mmol: 2 mL in sequence, the yield of intermediate 4-bromo-5-methyl-3-phenylisoxazole III was 96%.

[0061] In S4, when the feeding amounts of intermediate 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, Ph(PPh3)4, Cs2CO3, dioxane, and water were 1 mmol: 1.5 mmol: 0.1 mmol: 3 mmol: 2 mL: 0.4 mL in sequence, the yield of desidroxycarbazepine was 73%.

[0062] Example 2

[0063] In S1, when the feeding amounts of THF, propyne, n-BuLi, and benzaldehyde were 2 mL: 1.1 mmol: 1.2 mmol: 1 mmol in sequence, the yield of intermediate 1-phenylbut-2-yn-1-ol I was 88%.

[0064] In S2, when the feeding amounts of intermediate 1-phenylbut-2-yn-1-ol I, Bi(OTf)3, NIS, dioxane, and hydroxylamine hydrochloride tert-butyl are 1 mmol: 0.05 mmol: 1.5 mmol: 1 mL: 2 mmol in sequence, the yield of intermediate 5-methyl-3-phenylisoxazole II is 50%.

[0065] In S3, when the feeding amounts of intermediate 5-methyl-3-phenylisoxazole II, NBS, and DMF are 1 mmol: 2 mmol: 5 mL in sequence, the yield of intermediate 4-bromo-5-methyl-3-phenylisoxazole III is 89%.

[0066] In S4, when the feeding amounts of intermediate 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, Ph(PPh3)4, Cs2CO3, dioxane, and water are 1 mmol: 1.2 mmol: 0.05 mmol: 2 mmol: 1 mL: 0.2 mL in sequence, the yield of desidroxycorticosterone is 57%.

[0067] Example 3

[0068] In S1, when the feeding amounts of THF, propyne, n-BuLi, and benzaldehyde are 20 mL: 1.5 mmol: 1.8 mmol: 1 mmol in sequence, the yield of intermediate 1-phenylbut-2-yn-1-ol I is 94%.

[0069] In S2, when the feeding amounts of intermediate 1-phenylbut-2-yn-1-ol I, Bi(OTf)3, NIS, dioxane, and hydroxylamine hydrochloride tert-butyl are 1 mmol: 0.5 mmol: 2 mmol: 20 mL: 3 mmol in sequence, the yield of intermediate 5-methyl-3-phenylisoxazole II is 60%.

[0070] In S3, when the feeding amounts of intermediate 5-methyl-3-phenylisoxazole II, NBS, and DMF are 1 mmol: 3 mmol: 20 mL in sequence, the yield of intermediate 4-bromo-5-methyl-3-phenylisoxazole III is 92%.

[0071] In S4, when the feeding amounts of intermediate 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, Ph(PPh3)4, Cs2CO3, dioxane, and water are 1 mmol: 2 mmol: 0.5 mmol: 6 mmol: 20 mL: 4 mL in sequence, the yield of desidroxycorticosterone is 70%.

[0072] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A synthetic method of celecoxib, characterized in that, It includes the following steps: S1: Using benzaldehyde as a raw material, reacting with propyne, tetrahydrofuran and n-butyllithium at a certain temperature and atmosphere to obtain intermediate 1-phenylbut-2-yn-1-ol I; S2: Converting intermediate 1-phenylbut-2-yn-1-ol I into 5-methyl-3-phenylisoxazole II based on the one-pot reaction of the Meyer-Schuster rearrangement reaction; S3: Adding bromine at the 4-position of the isoxazole ring of 5-methyl-3-phenylisoxazole II through the action of N-bromosuccinimide to obtain 4-bromo-5-methyl-3-phenylisoxazole III; S4: Coupling 4-bromo-5-methyl-3-phenylisoxazole III with (4-sulfamoylphenyl)boronic acid through the Suzuki reaction catalyzed by palladium metal to obtain deracoxib Ⅳ; Among them, in S1, the feeding ratio of tetrahydrofuran, propyne, n-butyllithium and benzaldehyde is 1-20 mL: 1-1.5 mmol: 1.2-1.8 mmol: 1 mmol, the reaction temperature is -78 °C, and the atmosphere is nitrogen; In S2, the specific process of the one-pot reaction of the Meyer-Schuster rearrangement reaction is as follows: adding bismuth trifluoromethanesulfonate and N-iodosuccinimide successively to the solution of 1-phenylbut-2-yn-1-ol I dissolved in dioxane, refluxing until 1-phenylbut-2-yn-1-ol I completely disappears, and adding tert-butylhydroxylamine hydrochloride after slightly cooling to obtain 5-methyl-3-phenylisoxazole II. The feeding ratio of 1-phenylbut-2-yn-1-ol I, bismuth trifluoromethanesulfonate, N-iodosuccinimide, dioxane and tert-butylhydroxylamine hydrochloride is 1 mmol: 0.05-0.5 mmol: 1-2 mmol: 1-20 mL: 1-3 mmol in sequence.

2. The synthetic method of celecoxib according to claim 1, wherein In S3, the specific reaction process is as follows: adding N-bromosuccinimide to the solution of 5-methyl-3-phenylisoxazole II dissolved in dimethylformamide and reacting at room temperature to obtain 4-bromo-5-methyl-3-phenylisoxazole III.

3. A synthesis method of celecoxib according to claim 2, characterized in that, The feeding ratio of 5-methyl-3-phenylisoxazole II, N-bromosuccinimide and dimethylformamide is 1 mmol: 1-3 mmol: 1-20 mL in sequence.

4. A synthesis method of celecoxib according to claim 1, characterized in that, In S4, the specific process of the Suzuki reaction catalyzed by palladium metal is as follows: under the protection of nitrogen atmosphere, adding 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, tetrakis(triphenylphosphine)palladium, cesium carbonate, dioxane and water successively, and refluxing until 4-bromo-5-methyl-3-phenylisoxazole III completely disappears to obtain deracoxib Ⅳ.

5. A synthesis method of celecoxib according to claim 4, characterized in that, The feeding ratio of 4-bromo-5-methyl-3-phenylisoxazole III, (4-sulfamoylphenyl)boronic acid, tetrakis(triphenylphosphine)palladium, cesium carbonate, dioxane and water is 1 mmol: 1-2 mmol: 0.05-0.5 mmol: 1-6 mmol: 1-20 mL: 0.2-4 mL in sequence.

Images