CN115806521A - Monofluoromethyl etoricoxib and preparation method thereof - Google Patents
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- -1 Monofluoromethyl etoricoxib Chemical compound 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims description 7
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a monofluoromethyl etoricoxib, which has the following structure:
the active group of the monofluoromethyl etoxib is similar to that of etoxib, and fluorine atoms change the steric property, electronegativity, biological characteristics and the like of molecules, so that the inhibition and selectivity of the monofluoromethyl etoxib on cyclooxygenase COX-2 are maintained or increased to a certain extent, and the monofluoromethyl etoxib can be used as a potential anti-inflammatory analgesic drug and has wide application value and market value.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to novel monofluoromethyl etoxib and a preparation method thereof.
Background
In the course of the development of modern medicine, a class of active substances consisting of unsaturated fatty acids is found in the animal and human body and is named prostaglandin. Prostaglandins can bind to specific receptors and mediate a series of cell activities such as cell proliferation and differentiation and regulate reproductive functions. In addition, prostaglandins are involved in the pathological processes of inflammation, cancer, and various cardiovascular diseases. However, prostaglandins also cause symptoms associated with inflammatory reactions, such as pain and fever. Later, scientists found that the cyclooxygenase enzyme present in the human body was a key enzyme catalyzing the conversion of arachidonic acid to prostaglandins. The enzyme exists in two forms, COX-1 is structural type, and is mainly present in tissues such as gastrointestinal tract, etc., to protect gastrointestinal mucosa. COX-2 is inducible and is expressed under inflammatory conditions. Traditional non-steroidal drugs usually inhibit two enzymes simultaneously, so that adverse reactions of gastrointestinal dysfunction are generated during inflammation inhibition. Therefore, anti-inflammatory drugs that selectively inhibit COX-2 are the mainstream in the market. Etoxicib developed and produced by Moxidong company is an anti-inflammatory drug capable of selectively inhibiting COX-2 enzyme, the main pharmacological effect is COX-2 enzyme for producing prostaglandin in vivo, but the expression of the COX-1 enzyme is not inhibited, so that the side effect on the gastrointestinal function is greatly reduced. The mesyl structure on the benzene ring of etoricoxib has high selectivity on COX-2 receptors and has no inhibition effect on COX-1. Therefore, modifications to the methanesulfonyl structure are few, and fluorine is widely used to regulate biological properties of drug molecules such as acidity, basicity, protein-binding affinity, and lipophilicity due to its spatial similarity to hydrogen and strong electronegativity. The introduction of fluorine can improve the metabolic stability of the organic molecule, since the energy cost of breaking the carbon-fluorine bond to form a carbon-oxygen bond is disadvantageous. Due to the large dipole moment of the C-F bond, fluorine substitution can also cause significant conformational changes through various steric electronic interactions, thereby altering the biological activity of the organic molecule. Therefore, the introduction of fluorine atoms on the basis of keeping the structure of the etoricoxib can greatly change the drug characteristics of the etoricoxib.
At present, the monofluoromethyl etoxib is not reported in documents.
Disclosure of Invention
The invention aims to provide monofluoromethyl etoxib with a novel structure, wherein the structure comprises a tricyclic structure formed by two pyridine rings and a benzene ring, a chlorine atom is connected to the meta-position of the central pyridine ring, a methyl group is connected to the ortho-position of the other pyridine ring, and a monofluoromethyl benzenesulfonyl group is connected to the central pyridine ring as a main active center.
The second purpose of the invention is to provide a preparation method of the monofluoromethyl etoricoxib, which has the advantages of low cost, simple steps and simple operation.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the invention provides monofluoromethyl etoricoxib, the structure of which is as follows:
the molecular formula of the monofluoromethyl etoricoxib is C 18 H 14 N 2 O 2 SFCl, molecular weight 376.83, melting point 156.8 ℃, light yellow powder in solid state.
The second aspect of the invention provides a preparation method of the monofluoromethyl etoricoxib, which comprises the following steps:
first step, trifluoroacetylation:
under the protection of nitrogen, dissolving sodium hydride in tetrahydrofuran, adding ethyl trifluoroacetate, adding a tetrahydrofuran solution of etoxib, wherein the molar ratio of the etoxib to the sodium hydride to the ethyl trifluoroacetate is 1 (5-6) to (2-3) (preferably 1;
second, fluorination
Under the protection of nitrogen, dissolving a crude product intermediate A and copper nitrate trihydrate into acetonitrile, monitoring by TLC that a raw material point disappears, dissolving a selective fluorine reagent into a mixed solvent of the acetonitrile and water, adding the mixed solvent into the reaction solution, wherein the volume ratio of the acetonitrile to the water is 3;
step three, removing a trifluoromethyl ethylene glycol group:
under the protection of nitrogen, dissolving the intermediate B and potassium hydroxide in a molar ratio of (0.4-0.8): 1 in tetrahydrofuran, reacting at room temperature, and monitoring by TLC that the raw material point disappears to obtain the monofluoromethyl etoxib.
In the second step, the molar ratio of the intermediate A, the copper nitrate trihydrate and the selective fluorine reagent is 1.
In the third step, the molar ratio of the intermediate B to the potassium hydroxide is 1.
The third aspect of the invention provides an application of the monofluoromethyl etoricoxib in preparing anti-inflammatory and analgesic drugs.
Due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the active group of the monofluoromethyl etoxib is similar to that of etoxib, and fluorine atoms change the steric property, electronegativity, biological characteristics and the like of molecules, so that the inhibition and selectivity of the monofluoromethyl etoxib on cyclooxygenase COX-2 are maintained to a certain extent, and the monofluoromethyl etoxib can be used as a potential anti-inflammatory analgesic drug and has wide application value and market value.
The invention synthesizes the monofluoromethyl etoxib with certain medicinal value for the first time, and the invention keeps the medicinal activity of the etoxib to a certain extent, so that the new compound becomes a potential analgesic and anti-inflammatory medicament.
The monofluoromethyl etoxib synthesized by the invention shows activity similar to that of etoxib in a drug activity test, has similar inhibition activity on cyclooxygenase COX-2, and can be used as a potential alternative drug of the etoxib.
At present, no synthetic method of monofluoromethyl etoxib exists, the method for synthesizing the monofluoromethyl etoxib for the first time has simple steps, only three steps are needed, the next reaction can be carried out without purifying an intermediate, the used medicines and solvents can be purchased commercially and have low price, in addition, the synthetic method has simple synthetic conditions, the requirement on the reaction environment is low, the reaction temperature only needs reflux temperature or room temperature, and the whole process is safer. Compared with other similar compound fluorination methods, the method has the advantages of simple steps, safe process and low cost.
Drawings
FIG. 1 is a schematic reaction scheme of monofluoromethyl etoricoxib according to the present invention.
FIG. 2 is a nuclear magnetic hydrogen spectrum of monofluoromethyl etoricoxib of the present invention.
FIG. 3 is a nuclear magnetic fluorine spectrum of monofluoromethyl etoricoxib of the present invention.
FIG. 4 is a nuclear magnetic carbon spectrum of monofluoromethyl etoricoxib of the present invention.
FIG. 5 is a mass spectrum of monofluoromethyl etoricoxib of the present invention.
FIG. 6 is a high performance liquid chromatogram of monofluoromethyl etoricoxib of the present invention.
Detailed Description
In order to more clearly illustrate the present invention, the present invention is further described below in conjunction with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
A preparation method of monofluoromethyl etoricoxib comprises the following steps: as shown in fig. 1, fig. 1 is a reaction scheme of monofluoromethyl etoricoxib according to the present invention.
First step, trifluoroacetylation:
sodium hydride (5mmol, 120mg) was dissolved in 0.75mL of tetrahydrofuran under nitrogen, ethyl trifluoroacetate (2mmol, 0.24ml) was added, and Etoxicam (1mmol, 358mg) in 0.75mL of tetrahydrofuran was added, and the solvent was maintained under reflux at 75 ℃. Reacting for 12 hours, monitoring the disappearance of a raw material point by TLC, adding 1M hydrochloric acid to quench the reaction, extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, and carrying out rotary evaporation under reduced pressure to remove the solvent to obtain 486mg of a crude product of the intermediate A.
Second, fluorination
The crude intermediate A (1mmol, 454mg), copper nitrate trihydrate (0.2mmol, 48mg) was dissolved in 2mL acetonitrile under nitrogen protection, reacted for two hours and TLC monitored the disappearance of the starting material spots. The selective fluorine reagent (1.2mmol, 425mg) was dissolved in a mixed solvent of 0.6mL acetonitrile and 0.4mL water, and the mixture was added to the reaction solution at a volume ratio of acetonitrile to water of 3. Extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, and collecting crude intermediate B523mg after spin-drying the solution, wherein the crude intermediate B is directly put into the next step without purification.
Thirdly, removing a trifluoromethyl glycol group:
under the protection of nitrogen, dissolving the intermediate B (1mmol, 491mg) and potassium hydroxide (2mmol, 112mg) in 1mL of tetrahydrofuran, keeping the room temperature for reaction for 12 hours, monitoring by TLC that a raw material point disappears, carrying out reduced pressure rotary evaporation to remove a solvent, and carrying out column chromatography purification by using an eluent of PE: EA =1 to obtain 130mg of monofluoromethyl etoricoxib, wherein the total yield is 34.5% and the purity is 99.6%.
The structure of the prepared monofluoromethyl etoxib is shown as follows:
the molecular weight of the monofluoromethyl etoricoxib is 376.83, the melting point is 156.8 ℃, and the solid state is light yellow powder.
The nuclear magnetic data are shown in fig. 2-4, and fig. 2 is a nuclear magnetic hydrogen spectrum of the monofluoromethyl etoricoxib. 1 H NMR (600mhz, chloroform-d) δ 8.72 (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). Fig. 3 is a nuclear magnetic fluorine spectrum of monofluoromethyl etoxib of the present invention. 19 F NMR (600MHz, chloroform-d) delta-78.37 FIG. 4 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.
The mass spectrum is shown as 5, and figure 5 is the mass spectrum of the monofluoromethyl etoxib. HRMS (ESI) Calcd for C 18 H 16 N 2 O 2 SFCl376.0449 (M + H), found 377.0525. High performance liquid chromatogram, as shown in figure 6, figure 6 is the high performance liquid chromatogram of monofluoromethyl etoricoxib of the present invention. Retention timet =3.039min, peak area 99.5812%.
Example 2
Using the following reagents: DMSO (N, N-dimethyl sulfoxide), COX-2 assay buffer (100 mM Tris-HCl, pH 8.0, containing 1.25. Mu.g/rxn COX-2 enzyme), reference inhibitor DUP-697 (5-bromo-2- (4-fluorophenyl) -3- (4-methylsulfonylphenyl) thiophene), ELISA (Caymen INC.) assay kit for COX-2 enzyme.
The test method comprises the following steps: taking the test procedure of 10nM monofluoromethyl etoricoxib and etoricoxib as an example
10nM of monofluoromethyl etoricoxib and etoricoxib were dissolved in 10% DMSO solutions, respectively, and diluted 10X 10 fold, 10. Mu.l of the dilution was added to the reactions, ensuring that the final DMSO concentration was 0.5% in all reactions. To the reaction was added COX-2 enzyme assay buffer (100 mM Tris-HCl, pH 8.0, containing 1.25 μ g/rxn COX-2) and incubated for 10min, after which the substrate arachidonic acid (200 μ M final, 1% EtOH final) was added to the reaction, and for the negative control test, assay buffer without COX-2 enzyme was used. The prostaglandin PGE2 formed and the fluorescence intensity were measured by COX-2 enzyme ELISA (Caymen INC.) kit. Luminescence signals were measured using a Tecan Infinite M1000 plate reader. Inhibition assays were performed in duplicate at each concentration. Luminescence data were analyzed using computer software Graphpad Prism.
As a result: the different molar amounts of monofluoromethyl etoxib and etoxib are respectively used as test inhibitors to carry out COX-2 inhibitory activity tests, and the average value of the COX-2 enzyme activity is used as the activity judgment basis.
The activity value of COX-2 enzyme is calculated by the formula: % activity = [ (F-Fb)/(Ft-Fb) ]. Times.100
Wherein, F: measured values of inhibitor added at each concentration; fb: a background value; ft is the value measured without inhibitor.
The single-fluoromethyl etoricoxib and the etoricoxib are respectively used as test inhibitors to carry out COX-2 inhibitory activity tests, and the average value of the COX-2 enzyme activities at different concentrations is used as the activity judgment basis.
TABLE 1
TABLE 2
Comparing the activity data of the two test inhibitors in table 1 and table 2, it can be seen that the percentage values of COX-2 activity are similar at five different test concentrations, thereby inferring that the inhibitory activity of monofluoromethyl etoxib and etoxib on COX-2 enzyme is similar, and thus confirming that the anti-inflammatory analgesic effect of monofluoromethyl etoxib is also similar to that of etoxib, so that monofluoromethyl etoxib can be used as a potential anti-inflammatory analgesic or a substitute for etoxib.
Comparative example 1
The molar ratio of etoxib, sodium hydride and ethyl trifluoroacetate in example 1 is 1:5:2 is replaced by 1:7:2 comparative experiments were carried out.
Sodium hydride (7 mmol, 168mg) was dissolved in 0.75mL tetrahydrofuran under nitrogen, ethyl trifluoroacetate (2mmol, 0.24ml) was added, and Etoxicam (1mmol, 358mg) in 0.75mL tetrahydrofuran was added, and the solvent was maintained at reflux at 75 ℃. Reacting for 12 hours, monitoring the disappearance of a raw material point by TLC (thin layer chromatography), adding 1M hydrochloric acid to quench the reaction, extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to remove the solvent, confirming that side reactions exist on a TLC point plate, increasing byproducts and PE: EA =1:1, collecting and determining the structures of the byproducts after the elution of the eluent, and carrying out nuclear magnetic confirmation reaction to obtain no intermediate A. Therefore, the subsequent reaction cannot be carried out by changing the ratio thereof.
Comparative example 2
The molar ratio of etoxib, sodium hydride and ethyl trifluoroacetate in example 1 is 1:5:2 is replaced by 1:5:1 comparative experiments were carried out.
Sodium hydride (5mmol, 120mg) was dissolved in 0.75mL of tetrahydrofuran under nitrogen, and ethyl trifluoroacetate (1mmol, 0.24ml) and 0.75mL of a solution of etoricoxib (1mmol, 358mg) in tetrahydrofuran were added, and the solvent was maintained under reflux at 75 ℃. Reacting for 12 hours, monitoring that the raw material point does not disappear by TLC, monitoring that the raw material point disappears by TLC after continuing the reaction for 12 hours, adding 1M hydrochloric acid to quench the reaction, extracting for three times by ethyl acetate, collecting an organic phase, drying by anhydrous sodium sulfate, removing the solvent by reduced pressure rotary evaporation, confirming that the by-products are increased by TLC point plates, and determining that the PE: EA =1:1, collecting and determining the structures of the byproducts after elution, only obtaining 12mg of an intermediate A, only 0.026mmol of reactant, and too small a molar amount to carry out subsequent reaction.
Therefore, the mole ratio of sodium hydride to ethyl trifluoroacetate in etoxib in the technical scheme is 1:5:2 is the optimum reaction ratio, and the target product cannot be obtained at the optimum yield by reducing or increasing the ratio.
Comparative example 3
The molar ratio of the second step intermediate a, copper nitrate trihydrate and selective fluorine reagent of example 1 was 1:0.2:1.2 replacement by 1:1:0.8 comparative tests were carried out.
First step, trifluoroacetylation:
sodium hydride (5mmol, 120mg) was dissolved in 0.75mL of tetrahydrofuran under nitrogen, ethyl trifluoroacetate (2mmol, 0.24ml) was added, and Etoxicam (1mmol, 358mg) in 0.75mL of tetrahydrofuran was added, and the solvent was maintained under reflux at 75 ℃. The reaction was carried out for 12 hours, TLC monitored the disappearance of the starting material spot, 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 rotary evaporation under reduced pressure to obtain 486mg of a crude intermediate A product.
Second, fluorination
The crude intermediate A (1mmol, 454mg), copper nitrate trihydrate (1mmol, 241mg) was dissolved in 2mL acetonitrile under nitrogen protection, reacted for two hours and TLC monitored the disappearance of the starting material spots. The selective fluorine reagent (0.8mmol, 283mg) was dissolved in a mixed solvent of 0.6mL of acetonitrile and 0.4mL of water at a volume ratio of acetonitrile to water of 3, and the reaction was terminated after TLC monitoring disappearance of intermediate A, for 24 hours. Extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to remove the solvent, confirming that a plurality of byproducts exist on a TLC point plate, and confirming the structure with nuclear magnetism, wherein the intermediate B is not generated in the reaction. Therefore, the target intermediate B cannot be obtained by changing the ratio of the intermediate B.
Comparative example 4
The molar ratio of intermediate B to potassium hydroxide in the third step in example 1 was 1:2 is replaced by 2:1 comparative tests were carried out.
First step, trifluoroacetylation:
sodium hydride (5mmol, 120mg) was dissolved in 0.75mL of tetrahydrofuran under nitrogen, ethyl trifluoroacetate (2mmol, 0.24ml) was added, and Etoxicam (1mmol, 358mg) in 0.75mL of tetrahydrofuran was added, and the solvent was maintained under reflux at 75 ℃. Reacting for 12 hours, monitoring the disappearance of a raw material point by TLC, adding 1M hydrochloric acid to quench the reaction, extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, and carrying out rotary evaporation under reduced pressure to remove the solvent to obtain 486mg of a crude product of the intermediate A.
Second, fluorination reaction
The crude intermediate A (1mmol, 454mg), copper nitrate trihydrate (0.2mmol, 48mg) was dissolved in 2mL acetonitrile under nitrogen protection, reacted for two hours and TLC monitored the disappearance of the starting material spots. The selective fluoro reagent (1.2mmol, 425mg) was dissolved in a mixed solvent of 0.6mL acetonitrile and 0.4mL water at a volume ratio of acetonitrile to water of 3, and the reaction was terminated after TLC monitored for disappearance of intermediate a. Extracting with ethyl acetate for three times, collecting an organic phase, drying with anhydrous sodium sulfate, and collecting crude intermediate B523mg after spin-drying the solution, wherein the crude intermediate B is directly put into the next step without purification.
Step three, removing a trifluoromethyl ethylene glycol group:
under the protection of nitrogen, dissolving the intermediate B (1mmol, 491mg) and potassium hydroxide (0.5mmol, 28mg) in 1mL tetrahydrofuran, keeping the room temperature for reaction for 12 hours, monitoring by TLC that the raw material point does not disappear, continuing to react for 24 hours, then the raw material point does not disappear, ending the reaction, decompressing and rotary steaming to remove the solvent, confirming by TLC that the raw material does not completely react, and carrying out column chromatography purification by using an eluent of PE: EA =1 to obtain 11mg of monofluoromethyl etoxib. The total yield is 2.9%, and the purity is 99.6%. The yield was too low. The highest yield of the product can not be obtained after the proportion is changed, and the proportion in the technical scheme is proved to be the optimal proportion.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (5)
1. The monofluoromethyl etoxib is characterized by having the following structure:
2. a method of preparing monofluoromethyl etoricoxib according to claim 1, which comprises the steps of:
first step, trifluoroacetylation:
under the protection of nitrogen, dissolving sodium hydride in tetrahydrofuran, adding ethyl trifluoroacetate, adding a tetrahydrofuran solution of etoricoxib, wherein the molar ratio of the etoricoxib to the sodium hydride to the ethyl trifluoroacetate is 1 (5-6) to 2-3, carrying out reflux reaction, and monitoring by TLC (thin layer chromatography) that a raw material point disappears to obtain a crude product intermediate A;
second, fluorination reaction
Under the protection of nitrogen, dissolving a crude product intermediate A and copper nitrate trihydrate into acetonitrile, monitoring by TLC that a raw material point disappears, dissolving a selective fluorine reagent into a mixed solvent of the acetonitrile and water, adding the mixed solvent into the reaction solution, wherein the volume ratio of the acetonitrile to the water is 3;
thirdly, removing a trifluoromethyl glycol group:
under the protection of nitrogen, dissolving the intermediate B and potassium hydroxide in a molar ratio of (0.4-0.8): 1 in tetrahydrofuran, reacting at room temperature, and monitoring by TLC that the raw material point disappears to obtain the monofluoromethyl etoxib.
3. The process for preparing monofluoromethyl etoricoxib according to claim 2, wherein in the second step, the molar ratio of intermediate a, copper nitrate trihydrate and selective fluorine reagent is from 1.2.
4. The process for preparing monofluoromethyl etoricoxib according to claim 2, wherein in the third step, the molar ratio of intermediate B to potassium hydroxide is 1.
5. Use of monofluoromethyl etoricoxib according to claim 1 in the preparation of an anti-inflammatory analgesic medicament.
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| CN1225085A (en) * | 1996-07-18 | 1999-08-04 | 麦克弗罗斯特(加拿大)有限公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
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