A kind of monofluoromethyl etoricoxib and preparation method thereof

Abstract

The invention discloses a monofluoromethyl etoricoxib, the structure of which is shown below: the active group of the monofluoromethyl etoricoxib of the invention is similar to that of etoricoxib, and the fluorine atom changes the spatiality, electronegativity, biological properties, etc. of the molecule, thereby maintaining or increasing its inhibition and selectivity to cyclooxygenase COX-2 to a certain extent, and can be used as a potential anti-inflammatory and analgesic drug, and has wide application value and market value.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a novel monofluoromethyl etoricoxib and a preparation method thereof. Background Art

[0002] In the development of modern medicine, people have discovered a class of active substances composed of unsaturated fatty acids in animals and humans, and named them prostaglandins. Prostaglandins can bind to specific receptors to mediate a series of cell activities such as cell proliferation and differentiation, as well as regulate reproductive function. In addition, prostaglandins are also involved in the pathological processes of inflammation, cancer, and various cardiovascular diseases. However, prostaglandins can also cause pain, fever, and other symptoms related to inflammatory responses. Later, scientists discovered that cyclooxygenase in the human body is a key enzyme that catalyzes the conversion of arachidonic acid into prostaglandins. This enzyme exists in two forms, COX-1 is a structural type, mainly present in tissues such as the gastrointestinal tract, protecting the gastrointestinal mucosa. COX-2 is an inducible type and is expressed under inflammatory conditions. Traditional non-steroidal drugs often inhibit both enzymes at the same time, thereby producing adverse reactions of gastrointestinal dysfunction when inhibiting inflammation. Therefore, anti-inflammatory drugs that selectively inhibit COX-2 are the mainstream of the market. Etoricoxib, developed and produced by Merck, is an anti-inflammatory drug that can selectively inhibit COX-2 enzyme. Its main pharmacological action is to inhibit the COX-2 enzyme that produces prostaglandins in the body, but it will not inhibit the expression of COX-1 enzyme, thereby greatly reducing the side effects on gastrointestinal function. The methylsulfonyl structure on the benzene ring of Etoricoxib has high selectivity for COX-2 receptors and has no inhibitory effect on COX-1. Therefore, there are fewer modifications to the methylsulfonyl structure. Due to the spatial similarity and strong electronegativity of fluorine with hydrogen, fluorine is widely used to regulate the biological properties of drug molecules, such as acidity, alkalinity, protein binding affinity and lipophilicity. The introduction of fluorine can improve the metabolic stability of organic molecules, because the energy cost of destroying carbon-fluorine bonds to form carbon-oxygen bonds is unfavorable. Due to the large dipole moment of the CF bond, fluorine substitution can also cause significant changes in conformation through various stereoelectronic interactions, thereby changing the biological activity of organic molecules. Therefore, the introduction of fluorine atoms on the basis of retaining the structure of Etoricoxib will greatly change the drug properties of Etoricoxib.

[0003] Currently, monofluoromethyl etoricoxib has not been reported in the literature. Summary of the invention

[0004] The purpose of the present invention is to provide a monofluoromethyl etoricoxib with a new structure, which has two pyridine rings and one benzene ring to form a tricyclic structure, a chlorine atom is connected to the meta position of the central pyridine ring, a methyl group is connected to the ortho position of another pyridine ring, and a monofluoromethylbenzenesulfonyl group is connected to the central pyridine ring as the main active center.

[0005] The second object of the present invention is to provide a method for preparing the monofluoromethyl etoricoxib, which has low cost, concise steps and simple operation.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] The first aspect of the present invention provides a monofluoromethyl etoricoxib, the structure of which is shown below:

[0008]

[0009] The molecular formula of the monofluoromethyl etoricoxib is C 18 H 14 N2O2SFCl, molecular weight is 376.83, melting point is 156.8℃, and the solid state is light yellow powder.

[0010] The second aspect of the present invention provides a method for preparing the monofluoromethyl etoricoxib, comprising the following steps:

[0011] The first step, trifluoroacetylation:

[0012] Under nitrogen protection, sodium hydride is dissolved in tetrahydrofuran, and ethyl trifluoroacetate is added, and a tetrahydrofuran solution of etoricoxib is added, wherein the molar ratio of etoricoxib, sodium hydride and ethyl trifluoroacetate is 1:(5-6):(2-3) (preferably 1:5:2), and the reaction is refluxed. The raw material spot disappears under TLC monitoring to obtain a crude product intermediate A;

[0013] The second step is fluorination reaction

[0014] Under nitrogen protection, the crude intermediate A and copper nitrate trihydrate are dissolved in acetonitrile, and the raw material point disappears when monitored by TLC. The selective fluorine reagent is dissolved in a mixed solvent of acetonitrile and water and added to the above reaction solution, the volume ratio of acetonitrile to water is 3:2, and the molar ratio of intermediate A, copper nitrate trihydrate and selective fluorine reagent is 1:(0.1-0.3):(1.1-1.3). After the intermediate A disappears when monitored by TLC, the reaction is terminated to obtain intermediate B;

[0015] The third step is to remove the trifluoromethyl glycol group:

[0016] Under nitrogen protection, the intermediate B and potassium hydroxide at a molar ratio of (0.4-0.8):1 were dissolved in tetrahydrofuran, and the reaction was maintained at room temperature. The raw material point disappeared under TLC monitoring to obtain monofluoromethyl etoricoxib.

[0017] In the second step, the molar ratio of intermediate A, copper nitrate trihydrate and selective fluorine reagent is 1:0.2:1.2.

[0018] In the third step, the molar ratio of intermediate B to potassium hydroxide is 1:2.

[0019] The third aspect of the present invention provides a use of the monofluoromethyl etoricoxib in the preparation of anti-inflammatory and analgesic drugs.

[0020] Due to the adoption of the above technical solution, the present invention has the following advantages and beneficial effects:

[0021] The active group of the monofluoromethyl etoricoxib of the present invention is similar to that of etoricoxib, and the fluorine atom changes the spatiality, electronegativity, biological properties, etc. of the molecule, and maintains its inhibitory and selectivity to cyclooxygenase COX-2 to a certain extent. It can be used as a potential anti-inflammatory and analgesic drug and has wide application value and market value.

[0022] The present invention synthesizes monofluoromethyl etoricoxib with certain medicinal value for the first time, and maintains the medicinal activity of etoricoxib to a certain extent, making the new compound a potential analgesic and anti-inflammatory drug. The synthesis method of the present invention is simple to operate, low in cost, and easy to scale up for production.

[0023] The monofluoromethyl etoricoxib synthesized by the present invention exhibits activity similar to that of etoricoxib in a drug activity test and has similar inhibitory activity on cyclooxygenase COX-2, and can be used as a potential substitute for etoricoxib.

[0024] There is no method for synthesizing monofluoromethyl etoricoxib at present. The present invention is a method for synthesizing for the first time, and the steps are simple, and only three steps are required, and the intermediate can be subjected to the next step reaction without purification. The drugs and solvents used can be purchased commercially and are cheap. In addition, the synthesis conditions of this synthesis method are simple, the requirements for the reaction environment are small, and the reaction temperature only needs to be reflux temperature or room temperature, and the overall process is relatively safe. Compared with other fluorination methods of similar compounds, the steps are simple, the process is safe, and the cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The schematic diagram of the reaction route of monofluoromethyl etoricoxib of the present invention is shown in FIG.

[0026] Figure 2 The figure is the hydrogen nuclear magnetic spectrum of monofluoromethyl etoricoxib of the present invention.

[0027] Figure 3 The figure is the nuclear magnetic fluorine spectrum of monofluoromethyl etoricoxib of the present invention.

[0028] Figure 4 It is the nuclear magnetic carbon spectrum of monofluoromethyl etoricoxib of the present invention.

[0029] Figure 5 It is the mass spectrum of monofluoromethyl etoricoxib of the present invention.

[0030] Figure 6 It is the high performance liquid chromatogram of monofluoromethyl etoricoxib of the present invention. DETAILED DESCRIPTION

[0031] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0032] Example 1

[0033] A method for preparing monofluoromethyl etoricoxib comprises the following steps: Figure 1 As shown, Figure 1 The schematic diagram of the reaction route of monofluoromethyl etoricoxib of the present invention is shown in FIG.

[0034] The first step, trifluoroacetylation:

[0035] Under nitrogen protection, sodium hydride (5mmol, 120mg) was dissolved in 0.75mL tetrahydrofuran, and ethyl trifluoroacetate (2mmol, 0.24ml) was added, and 0.75mL of tetrahydrofuran solution of etoricoxib (1mmol, 358mg) was added, and the temperature was controlled at 75°C to keep the solvent reflux. After reacting for 12 hours, the raw material point disappeared after TLC monitoring, 1M hydrochloric acid was added to quench the reaction, and ethyl acetate was extracted three times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation to obtain 486mg of the crude product of intermediate A.

[0036] The second step is fluorination reaction

[0037] Under nitrogen protection, the crude intermediate A (1mmol, 454mg) and copper nitrate trihydrate (0.2mmol, 48mg) were dissolved in 2mL acetonitrile and reacted for two hours. The raw material point disappeared after TLC monitoring. The selective fluorine reagent (1.2mmol, 425mg) was dissolved in a mixed solvent of 0.6mL acetonitrile and 0.4mL water and added to the reaction solution. The volume ratio of acetonitrile to water was 3:2. The reaction was continued for 24 hours. The reaction was terminated after the disappearance of intermediate A under TLC monitoring. The organic phase was extracted with ethyl acetate three times, and the organic phase was collected and dried over anhydrous sodium sulfate. After the solution was spin-dried, 523mg of crude intermediate B was collected and directly put into the next step without purification.

[0038] The third step is to remove the trifluoromethyl glycol group:

[0039] Under nitrogen protection, intermediate B (1 mmol, 491 mg) and potassium hydroxide (2 mmol, 112 mg) were dissolved in 1 mL of tetrahydrofuran and kept at room temperature for 12 hours. The raw material point disappeared under TLC monitoring. The solvent was removed by rotary evaporation under reduced pressure and purified by column chromatography with an eluent of PE:EA=1:1 to obtain 130 mg of monofluoromethyl etoricoxib. The total yield was 34.5% and the purity was 99.6%.

[0040] The prepared monofluoromethyl etoricoxib has the following structure:

[0041]

[0042] The molecular weight of monofluoromethyl etoricoxib is 376.83, the melting point is 156.8°C, and the solid state is a light yellow powder.

[0043] NMR data such as Figure 2 to Figure 4 As shown, Figure 2 The figure is the hydrogen nuclear magnetic spectrum of monofluoromethyl etoricoxib of the present invention. 1 HNMR(600MHz,Chloroform-d)δ8.72(s,1H),8.40(s,1H),7.92(d,J=8.2Hz,2H),7.75(s,1H),7.54(d ,J=8.3Hz,1H),7.44(d,J=8.1Hz,2H),7.09(d,J=7.6Hz,1H),5.20(s,1H),5.12(s,1H),2.54(s,3H). Figure 3 The figure is the nuclear magnetic fluorine spectrum of monofluoromethyl etoricoxib of the present invention. 19 F NMR(600MHz,Chloroform-d)δ-78.37. Figure 4 It is the nuclear magnetic carbon spectrum of monofluoromethyl etoricoxib of the present invention. 13 C NMR (600MHz, Chloroform-d) δ152.30,149.72,148.58,144.90,137.93,137.38,135.59,135.08,131.20,130.49,129.56,92.65,91.1,29.75,24.13.

[0044] The mass spectrum is shown in Figure 5. Figure 5 HRMS (ESI) Calcd for C 18 H 16 N2O2SFCl376.0449(M+H),Found 377.0525. HPLC chromatogram is shown in Figure 6 As shown, Figure 6The HPLC chromatogram of monofluoromethyl etoricoxib of the present invention is shown in FIG.

[0045] Example 2

[0046] Reagents used: DMSO (N,N-dimethyl sulfoxide), COX-2 detection buffer (100 mM Tris-HCl, pH 8.0, containing 1.25 μg / rxn COX-2 enzyme), reference inhibitor DUP-697 (5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)thiophene), COX-2 enzyme ELISA (Caymen INC.) detection kit.

[0047] Test method: Take the test process of 10nM monofluoromethyl etoricoxib and etoricoxib as an example

[0048] 10nM monofluoromethyl etoricoxib and etoricoxib are dissolved in 10% DMSO solution respectively, and are diluted 10 × 10 times, 10 μl diluent is taken and added to the reaction, and it is ensured that the final concentration of DMSO in all reactions is 0.5%. COX-2 enzyme detection buffer (100mM Tris-HCl, pH 8.0, containing 1.25μg / rxn COX-2) is added to the reaction, and incubated for 10min, and then the substrate arachidonic acid (200μM final concentration, 1%EtOH final concentration) is added to the reaction, and for the negative control test, the detection buffer without COX-2 enzyme is used. Prostaglandin PGE2 and fluorescence intensity formed are detected by COX-2 enzyme ELISA (Caymen INC.) kit. Luminescent signal is measured using Tecan Infinite M1000 plate reader. Inhibition determination is carried out in duplicate at each concentration. Luminescent data is analyzed using computer software Graphpad Prism.

[0049] Results: Different molar amounts of monofluoromethyl etoricoxib and etoricoxib were used as test inhibitors to test the COX-2 inhibitory activity, and the average COX-2 enzyme activity was used as the basis for judging its activity.

[0050] The formula for calculating the activity of COX-2 enzyme is: % activity = [(F-Fb) / (Ft-Fb)] × 100

[0051] Wherein, F: measured value after adding inhibitors of various concentrations; Fb: background value; Ft: measured value without adding inhibitors.

[0052] Monofluoromethyl etoricoxib and etoricoxib were used as test inhibitors for COX-2 inhibitory activity test, and the average value of COX-2 enzyme activity at different concentrations was used as the basis for judging its activity.

[0053] Table 1

[0054]

[0055] Table 2

[0056]

[0057] Comparing the activity data of the two test inhibitors in Table 1 and Table 2, it can be seen that the percentage activity of COX-2 is similar at five different test concentrations, from which it can be inferred that monofluoromethyl etoricoxib and etoricoxib have similar inhibitory activities on COX-2 enzyme, which also confirms that the anti-inflammatory and analgesic effects of monofluoromethyl etoricoxib are similar to those of etoricoxib, so monofluoromethyl etoricoxib can be used as a potential anti-inflammatory and analgesic drug or an alternative to etoricoxib.

[0058] Comparative Example 1

[0059] A comparative experiment was conducted by replacing the molar ratio of etoricoxib, sodium hydride and ethyl trifluoroacetate in Example 1 from 1:5:2 to 1:7:2.

[0060] Under nitrogen protection, sodium hydride (7mmol, 168mg) was dissolved in 0.75mL tetrahydrofuran, and ethyl trifluoroacetate (2mmol, 0.24ml) was added, and 0.75mL of tetrahydrofuran solution of etoricoxib (1mmol, 358mg) was added, and the temperature was controlled at 75℃ to maintain the reflux of the solvent. After reacting for 12 hours, the raw material point disappeared under TLC monitoring, 1M hydrochloric acid was added to quench the reaction, ethyl acetate was extracted three times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The TLC spot plate confirmed the presence of side reactions, the increase of by-products, and the elution solution of PE:EA=1:1 was collected to determine the structure of each by-product, and the nuclear magnetic resonance confirmed that the reaction did not obtain intermediate A. Therefore, changing its ratio cannot carry out subsequent reactions.

[0061] Comparative Example 2

[0062] A comparative experiment was conducted by replacing the molar ratio of etoricoxib, sodium hydride and ethyl trifluoroacetate in Example 1 from 1:5:2 to 1:5:1.

[0063] Under nitrogen protection, sodium hydride (5mmol, 120mg) was dissolved in 0.75mL tetrahydrofuran, and ethyl trifluoroacetate (1mmol, 0.24ml) was added, and 0.75mL of tetrahydrofuran solution of etoricoxib (1mmol, 358mg) was added, and the temperature was controlled at 75°C to maintain the reflux of the solvent. After reacting for 12 hours, the raw material point monitored by TLC did not disappear. After continuing the reaction for 12 hours, the raw material point monitored by TLC disappeared, and 1M hydrochloric acid was added to quench the reaction, and ethyl acetate was extracted three times, and the organic phase was collected and dried over anhydrous sodium sulfate. After the solvent was removed by vacuum rotary evaporation, the TLC spot plate confirmed that the by-products increased, and the eluent of PE:EA=1:1 was collected and the structure of each by-product was determined, and only 12mg of intermediate A was obtained, and only 0.026mmol of the reactant was obtained, and the molar amount was too small to carry out subsequent reactions.

[0064] Therefore, the molar ratio of etoricoxib, sodium hydride and ethyl trifluoroacetate in the technical solution is 1:5:2, which is the optimal reaction ratio. Reducing or increasing the ratio cannot obtain the target product with the best yield.

[0065] Comparative Example 3

[0066] A comparative test was conducted by replacing the molar ratio of the second step intermediate A, copper nitrate trihydrate and the selective fluorine reagent in Example 1 from 1:0.2:1.2 to 1:1:0.8.

[0067] The first step, trifluoroacetylation:

[0068] Under nitrogen protection, sodium hydride (5mmol, 120mg) was dissolved in 0.75mL tetrahydrofuran, and ethyl trifluoroacetate (2mmol, 0.24ml) was added, and 0.75mL of tetrahydrofuran solution of etoricoxib (1mmol, 358mg) was added, and the temperature was controlled at 75°C to keep the solvent reflux. After reacting for 12 hours, the raw material point disappeared after TLC monitoring, 1M hydrochloric acid was added to quench the reaction, and ethyl acetate was extracted three times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation to obtain 486mg of the crude product of intermediate A.

[0069] The second step is fluorination reaction

[0070] Under nitrogen protection, the crude intermediate A (1mmol, 454mg) and copper nitrate trihydrate (1mmol, 241mg) were dissolved in 2mL acetonitrile and reacted for two hours. The TLC monitoring raw material point disappeared. The selective fluorine reagent (0.8mmol, 283mg) was dissolved in a mixed solvent of 0.6mL acetonitrile and 0.4mL water, the volume ratio of acetonitrile to water was 3:2, and the reaction was terminated after the TLC monitoring intermediate A disappeared. The organic phase was extracted with ethyl acetate three times, and the organic phase was collected and dried over anhydrous sodium sulfate. After the solvent was removed by vacuum rotary evaporation, the TLC spot plate confirmed the presence of various by-products. After the structure was confirmed by nuclear magnetic resonance, it was proved that the reaction did not generate intermediate B. Therefore, changing its ratio cannot obtain the target product intermediate B.

[0071] Comparative Example 4

[0072] A comparative test was conducted by replacing the molar ratio of intermediate B to potassium hydroxide in the third step of Example 1 from 1:2 to 2:1.

[0073] The first step, trifluoroacetylation:

[0074] Under nitrogen protection, sodium hydride (5mmol, 120mg) was dissolved in 0.75mL tetrahydrofuran, and ethyl trifluoroacetate (2mmol, 0.24ml) was added, and 0.75mL of tetrahydrofuran solution of etoricoxib (1mmol, 358mg) was added, and the temperature was controlled at 75°C to keep the solvent reflux. After reacting for 12 hours, the raw material point disappeared after TLC monitoring, 1M hydrochloric acid was added to quench the reaction, and ethyl acetate was extracted three times, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation to obtain 486mg of the crude product of intermediate A.

[0075] The second step is fluorination reaction

[0076] Under nitrogen protection, the crude intermediate A (1mmol, 454mg) and copper nitrate trihydrate (0.2mmol, 48mg) were dissolved in 2mL acetonitrile and reacted for two hours. The raw material point disappeared after TLC monitoring. The selective fluorine reagent (1.2mmol, 425mg) was dissolved in a mixed solvent of 0.6mL acetonitrile and 0.4mL water, the volume ratio of acetonitrile to water was 3:2, and the reaction was terminated after 24 hours of TLC monitoring. The organic phase was collected after extraction with ethyl acetate three times, dried over anhydrous sodium sulfate, and the crude intermediate B523mg was collected after the solution was spin-dried. It was directly put into the next step without purification.

[0077] The third step is to remove the trifluoromethyl glycol group:

[0078] Under nitrogen protection, intermediate B (1mmol, 491mg) and potassium hydroxide (0.5mmol, 28mg) were dissolved in 1mL tetrahydrofuran, and the reaction was kept at room temperature for 12 hours. The raw material point did not disappear after TLC monitoring. After continuing the reaction for 24 hours, the raw material point still did not disappear. The reaction was terminated, and the solvent was removed by vacuum rotary evaporation. TLC confirmed that the raw material was not completely reacted. Column chromatography purification was performed with an eluent of PE:EA=1:1 to obtain 11mg of monofluoromethyl etoricoxib. The total yield was 2.9% and the purity was 99.6%. The yield was too low. After changing the ratio, the highest yield of the product could not be obtained, proving that the ratio in the technical scheme was the optimal ratio.

[0079] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. A method for preparing monofluoromethyl etoricoxib, characterized in that: The method comprises the following steps: The first step, trifluoroacetylation: Under nitrogen protection, sodium hydride was dissolved in tetrahydrofuran, and ethyl trifluoroacetate was added, and a tetrahydrofuran solution of etoricoxib was added, and the molar ratio of etoricoxib, sodium hydride and ethyl trifluoroacetate was 1:(5-6):(2-3). The reaction was refluxed, and the raw material point disappeared under TLC monitoring to obtain a crude product intermediate A. The structure of intermediate A is shown below: The second step is fluorination reaction Under nitrogen protection, the crude intermediate A and copper nitrate trihydrate were dissolved in acetonitrile. The raw material point disappeared under TLC monitoring. The selective fluorine reagent was dissolved in a mixed solvent of acetonitrile and water and added to the above reaction solution. The volume ratio of acetonitrile to water was 3:

2. The molar ratio of intermediate A, copper nitrate trihydrate and selective fluorine reagent was 1:(0.1-0.3):(1.1-1.3). After the disappearance of intermediate A under TLC monitoring, the reaction was terminated to obtain intermediate B. The structure of intermediate B is shown below: The third step is to remove the trifluoromethyl glycol group: Under nitrogen protection, the intermediate B and potassium hydroxide at a molar ratio of (0.4-0.8):1 are dissolved in tetrahydrofuran, and the reaction is maintained at room temperature. The raw material point disappears under TLC monitoring to obtain monofluoromethyl etoricoxib; The structure of the monofluoromethyl etoricoxib is shown below:

2. The method according to claim 1, characterized in that In the second step, the molar ratio of intermediate A, copper nitrate trihydrate and the selective fluorine reagent is 1:0.2:1.

2.

3. The method according to claim 1, characterized in that In the third step, the molar ratio of intermediate B and potassium hydroxide is 1:2.

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