CN111943874A - Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof - Google Patents
Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN111943874A CN111943874A CN202010820845.0A CN202010820845A CN111943874A CN 111943874 A CN111943874 A CN 111943874A CN 202010820845 A CN202010820845 A CN 202010820845A CN 111943874 A CN111943874 A CN 111943874A
- Authority
- CN
- China
- Prior art keywords
- naproxen
- aryl
- derivative
- compound
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C71/00—Esters of oxyacids of halogens
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an aryl naproxen derivative hypervalent iodine compound, a preparation method and application thereof, namely a series of naproxen derivatives are prepared by preparing and derivatizing a naproxen hypervalent iodine compound. The compound can realize nucleophilic substitution reaction of a specific site on naproxen-like molecule aryl, thereby achieving the purpose of modifying the drug molecules and expanding the types of the drug molecules. The preparation method of the compound is provided, firstly, the naproxen derivative is synthesized, and then the naproxen derivative and koser reagent derivative or aryl iododiacetic acid compound are subjected to anion ligand exchange reaction to prepare the aryl naproxen derivative high-valence iodine compound. The high-valence iodine compound can carry out simple and definite structural modification on naproxen molecular aryl, realizes the rapid synthesis of the structural diversity of the drug molecules by precise modification at specific sites, is convenient for rapidly constructing a large drug compound library, and greatly promotes the discovery process of active leads of naproxen drugs.
Description
Technical Field
The invention relates to an aryl naproxen derivative high-valence iodine compound and a preparation method and application thereof, namely a series of naproxen derivatives are prepared by preparing and derivatizing a naproxen high-valence iodine compound, belonging to the technical field of organic synthetic chemistry.
Background
Naproxen is aryl propionic acid non-steroidal anti-inflammatory analgesics (NSAIDs), has the function of obviously inhibiting prostaglandin synthesis, can stabilize lysosome activity, and has stronger anti-inflammatory, antirheumatic, antipyretic and analgesic functions. The medicine has strong action and small toxic and side effect, and has indispensable effect in nonsteroidal anti-inflammatory analgesics. Therefore, the field of synthesis of the compounds needs to develop an efficient, simple and economical method.
At present, common naproxen derivatives are modified on naproxen aryl by modifying aliphatic chain hydrocarbon carboxyl of naproxen or directly performing C-H activation on naproxen aryl, but the method generally needs to use a transition metal catalyst, and has poor selectivity and narrow application range. The naproxen-type drug molecules obtained by the above reported reactions are very limited, and are not beneficial to constructing a huge naproxen-type drug library.
In conclusion, an effective method with simple preparation process, good selectivity and wide application range is lacked in the synthesis of the naproxen derivative. The invention provides a method for preparing aryl naproxen high-valence iodine compounds, and then synthesizing various aryl-substituted naproxen drug molecules through nucleophilic substitution reaction, thereby promoting the discovery process of active leads of naproxen drugs.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an aryl naproxen derivative hypervalent iodine compound and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that: an aryl naproxen derivative high-valence iodine compound, which has the following structural general formula:
wherein X is an anion selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, acetate, tetrafluoroborate, sulfonate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, hexafluorophosphate, or bistrifluoromethylsulfonylimide;
ar is aryl, substituted aryl, aromatic heterocyclic group or substituted aromatic heterocyclic group;
r is alkyl.
As a preferred embodiment of the aryl naproxen derivative hypervalent iodine compound according to the invention, the substituent in the substituted aryl group or the substituted aromatic heterocyclic group is selected from halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl or alkoxy.
As a preferred embodiment of the aryl naproxen derivative hypervalent iodine compound according to the invention, Ar is selected from:
wherein R is1、R2、R3、R4、R5Each independently selected from halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl or alkoxy.
As a preferred embodiment of the aryl naproxen derivative hypervalent iodine compound according to the present invention, the structure of the aryl naproxen derivative hypervalent iodine compound is as follows:
in a second aspect, the present invention provides a method for preparing the above aryl naproxen derivative hypervalent iodine compound, comprising the steps of:
(1) dissolving iodine in dichloromethane, adding an aromatic compound under the stirring condition, then adding m-chloroperoxybenzoic acid and p-toluenesulfonic acid monohydrate, reacting at room temperature, after the reaction is finished, spin-drying the solvent, adding diethyl ether, strongly stirring to generate white precipitate, cooling at-20 ℃, filtering the obtained white solid, and drying in vacuum to obtain a koser reagent derivative for later use;
(2) adding a halogenated solvent and a naproxen derivative into the koser reagent derivative obtained in the step (1), stirring at room temperature, then cooling the reaction liquid to 0 ℃, dropwise adding a trimethylsilylate, and reacting at room temperature;
(3) and (3) after the reaction in the step (2) is finished, distilling under reduced pressure to remove the solvent, adding a weak polar solvent, and precipitating to obtain a white solid product, namely the aryl naproxen derivative high-valence iodine compound.
As a preferred embodiment of the preparation process of the present invention, in the step (1), the reaction time at room temperature is 1 hour, the strong stirring time is 30min, the molar ratio of iodine to the aromatic compound is 1:2, the molar ratio of m-chloroperoxybenzoic acid to the aromatic compound is 3:2, and the molar ratio of p-toluenesulfonic acid monohydrate to the aromatic compound is 1: 1.
As a preferable embodiment of the preparation method of the present invention, in the step (2), the ratio of the number of moles of the koser reagent derivative to the volume of the halogenated solvent is 1mmol:8mL, the ratio of the naproxen derivative to the koser reagent derivative is 1:1, the ratio of the trimethyl silicide to the naproxen derivative is 1:1, and the reaction time at room temperature is 1 h.
As a preferred embodiment of the preparation method of the present invention, in the step (2), the trimethylsilicane is at least one of TMSCl, TMSBr, TMSI, trimethylsilylacetic acid, trimethylsilylacetate, trimethylsilylmethane sulfonate, trimethylsilylphenylsulfonate, and the halogenated solvent is at least one of dichloromethane, chloroform, 1, 2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol, 2,2, 2-trifluoroethanol, and 1, 1-dichloroethane; in the step (3), the weak polar solvent is at least one of diethyl ether, n-hexane and petroleum ether.
In a third aspect, the invention provides an application of the aryl naproxen derivative hypervalent iodine compound in preparing a naproxen derivative.
In a fourth aspect, the present invention provides a derivatization method of naproxen drugs, comprising the steps of: reacting the aryl naproxen derivative high-valence iodine compound with the compound shown in the formula (2) in a solvent to generate a compound shown in the formula (3),
wherein Nu is selected from C, N, O, P or S.
As a preferred embodiment of the method of the present invention, the solvent is at least one of dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, trifluorotoluene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, n-hexane, cyclohexane, and petroleum ether.
Compared with the prior art, the invention has the beneficial effects that: the invention provides an aryl naproxen derivative high-valence iodine compound, which is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on naproxen molecular aryl, thereby achieving the purpose of modifying the drug molecules and expanding the types of the drug molecules. The preparation method of the compound is provided, firstly, the naproxen derivative is synthesized, and then the naproxen derivative and koser reagent derivative or aryl iododiacetic acid compound are subjected to anion ligand exchange reaction to prepare the aryl naproxen derivative high-valence iodine compound. The method can directly, simply, efficiently and massively prepare the aryl naproxen derivative high-valence iodine compound. The compound is easy to prepare, stable and high in reaction activity, the high-valence iodine compound can be used for carrying out simple and clear structural modification on naproxen molecules, the structural diversity and the rapid synthesis of the drug molecules are realized, a large drug compound library is convenient to construct rapidly, and the discovery process of a drug active precursor is greatly promoted.
Drawings
FIG. 1 shows the preparation of phenyl naproxen methyl ester triflate higher iodine prepared in example 1 of the present invention1H NMR spectrum.
FIG. 2 shows the high iodine content of 4-methylphenylnaproxen methyl ester triflate prepared in example 2 of the present invention1H NMR spectrum.
FIG. 3 shows the high iodine content of 2,4, 6-trimethylphenylnaproxen methyl ester triflate prepared in example 3 of the present invention1H NMR spectrum.
FIG. 4 shows the 4-methoxyphenyl naproxen methyl ester chloride higher iodine prepared in example 4 of the present invention1H NMR spectrum.
FIG. 5 is a graph of naproxen methyl ester fluoride prepared in test example 1 of the present invention1H NMR spectrum.
FIG. 6 shows the preparation of naproxen methyl ester p-toluate according to test example 2 of the present invention1H NMR spectrum.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The preparation of phenyl naproxen methyl ester trifluoromethanesulfonate high-valence iodine comprises the following steps:
1) 10mmol of hydroxy (p-toluenesulfonyloxy) iodobenzene was added to a mixed solution of 80mL of methylene chloride and 8mL of 2,2, 2-trifluoroethanol, followed by addition of 10mmol of naproxen methyl ester compound, and after cooling the reaction solution to 0 ℃, 10mmol of trimethylsilyl trifluoromethanesulfonate was added dropwise and then reacted at room temperature for 1 hour.
2) After the reaction is finished, the solvent is removed by reduced pressure distillation, and the white solid product is obtained by adding ether and stirring and precipitating, wherein the yield is 88%.
Nuclear magnetic characterization of phenyl naproxen methyl ester triflate high valence iodine is shown in figure 1: 1H NMR (400MHz, CHLOROFORM-D)8.10(D, J ═ 9.0Hz,1H),7.95(D, J ═ 8.7Hz,1H),7.86(D, J ═ 7.5Hz,2H),7.76(s,1H),7.63(D, J ═ 7.1Hz,1H),7.47-7.50(m,1H),7.40(D, J ═ 9.1Hz,1H), 7.37-7.30 (m,2H),4.09(s,3H),3.90(q, J ═ 7.2Hz,1H),3.66(s,3H),1.58(D, J ═ 7.1Hz, 3H).
Example 2
The preparation of 4-methyl phenyl naproxen methyl ester trifluoromethanesulfonate high-valence iodine comprises the following steps:
1) in a 250mL round bottom flask, 10mmol of 4-methyliodibenzene was dissolved in 100mL dichloromethane, 10mmol of m-chloroperoxybenzoic acid was added under stirring, 10mmol of toluenesulfonic acid monohydrate was then added, stirring was carried out at room temperature for 30min, after completion of the reaction, the solvent was dried by spinning, 150mL of diethyl ether was added, and stirring was carried out sufficiently for 30min, resulting in a precipitate. After filtration and drying in vacuo, hydroxy (p-toluenesulfonyloxy) 4-methyliodobenzene was obtained in 98% yield.
2) In a 250mL round-bottom flask, 8mmol of the hydroxyl group (p-toluenesulfonyloxy group) obtained in step 1) was added to a mixed solution of 65mL of methylene chloride and 6.5mL of 2,2, 2-trifluoroethanol or hexafluoroisopropanol, followed by addition of 8mmol of naproxen methyl ester compound, and after cooling the reaction solution to 0 ℃, 8mmol of trimethylsilyl trifluoromethanesulfonate was added dropwise, followed by reaction at room temperature for 1 hour.
3) And 2) after the reaction is finished, distilling under reduced pressure to remove the solvent, adding ether, stirring and precipitating to obtain white solid 4-methyl phenyl naproxen methyl ester trifluoromethanesulfonic acid high-valence iodine with the yield of 82%.
The nuclear magnetic characterization of 4-methylphenylnaproxen methyl ester triflate higher iodine is shown in figure 2: 1H NMR (400MHz, CHLOROFORM-D)8.09(D, J ═ 9.0Hz,1H),7.95(D, J ═ 8.7Hz,1H), 7.80-7.71 (m,3H),7.64(D, J ═ 7.2Hz,1H),7.39(D, J ═ 9.1Hz,1H),7.13(D, J ═ 8.0Hz,2H),4.09(s,3H),3.90(q, J ═ 7.1Hz,1H),3.67(s,3H),2.31(s,3H),1.58(D, J ═ 7.2Hz,3H).
Example 3
The preparation of 2,4, 6-trimethylphenyl naproxen methyl ester trifluoromethanesulfonate high-valence iodine comprises the following steps:
1) in a 250mL round bottom flask, 10mmol of iodine is dissolved in 80mL of dichloromethane, 20mmol of mesitylene is added under stirring, 30mmol of m-chloroperoxybenzoic acid and 20mmol of p-toluenesulfonic acid monohydrate are added, reaction is carried out at room temperature for 1 hour, after the reaction is finished, the solvent is dried by spinning, 150mL of diethyl ether is added, and stirring is carried out fully for 30 minutes, so that a precipitate is generated. After filtration and drying in vacuo, the obtained hydroxy (p-toluenesulfonyloxy) mesityliodobenzene was obtained in 97% yield.
2) In a 250mL round-bottom flask, 8mmol of hydroxy (p-toluenesulfonyloxy) mesityliodobenzene obtained in step 1) was added to a mixed solution of 65mL of methylene chloride and 6.5mL of 2,2, 2-trifluoroethanol or hexafluoroisopropanol, followed by addition of 8mmol of naproxen methyl ester compound, and after cooling the reaction solution to 0 ℃, 8mmol of trimethylsilyl trifluoromethanesulfonate was added dropwise and then reacted at room temperature for 1 hour.
3) And 2) after the reaction is finished, distilling under reduced pressure to remove the solvent, adding ether, stirring and precipitating to obtain white solid 2,4, 6-trimethylphenyl naproxen methyl ester trifluoromethanesulfonate high-valence iodine with the total yield of 68%.
2.4.6-Trimethylphenylnaproxen methyl ester triflate high iodine nuclear magnetic characterization as shown in FIG. 3: 1H NMR (400MHz, CHLOROFORM-D)8.04(D, J ═ 9.0Hz,1H),7.97(D, J ═ 8.7Hz,1H),7.75(s,1H),7.66(D, J ═ 8.7Hz,1H),7.29(D, J ═ 9.0Hz,1H),6.98(s,2H),3.94(s,4H),3.90(q, J ═ 14.3,7.1Hz,1H),3.68(s,3H),2.57(s,6H),2.27(s,3H),1.58(D, J ═ 7.2Hz, 4H).
Example 4
The preparation of 4-methoxyphenyl naproxen mechlor high-valence iodine comprises the following steps:
1) adding 10mmol of iodoanisole, 11mmol of sodium periodate, 20mmol of sodium acetate, 15mL of acetic acid and 1.5mL of acetic anhydride into a 100mL sealed tube, heating to 120 ℃, reacting for 3 hours, adding water after the reaction is finished, adding dichloromethane for extraction for three times, collecting an organic phase, drying by using anhydrous sodium sulfate, performing reduced pressure spin drying to obtain an oily substance, finally adding n-hexane into the oily substance, performing ultrasonic treatment for 30 minutes, and filtering to obtain iodoanisole diacetate with the yield of 92%.
2) In a 100mL round-bottom flask, 30mL hexafluoroisopropanol and 8.5mmol naproxen methyl ester are added, then 8.5mmol iodomethoxybenzene diacetate is added, the temperature is cooled to 0 ℃, 8.5mmol trimethylchlorosilane is added dropwise with stirring, and the reaction is carried out at room temperature for 1 h.
3) After the reaction is finished, the solvent is distilled under reduced pressure, and diethyl ether is added to be stirred and precipitated to obtain light green solid 4-methoxyphenyl naproxen mechlor high-valence iodine with the total yield of 33 percent.
The nuclear magnetic characterization of 4-methoxyphenyl naproxen mechlor high-valence iodine is shown in figure 4: 1H NMR (400MHz, CHLOROFORM-D)8.09(D, J ═ 9.0Hz,1H),7.95(D, J ═ 8.7Hz,1H), 7.82-7.70 (m,3H),7.64(D, J ═ 8.3Hz,1H),7.39(D, J ═ 9.0Hz,1H),7.14(D, J ═ 8.3Hz,2H),4.10(s,3H),3.90(q, J ═ 7.1Hz,1H),3.67(s,3H),2.31(s,3H),1.58(D, J ═ 7.2Hz,3H).
Test example 1
Preparation of naproxen methyl ester fluoride compound
Adding 0.4mmol of copper difluoride, 0.2mmol of copper trifluoromethanesulfonate, 18-crown ether-60.2 mmol of 4-methoxyphenyl naproxen and 0.2mmol of high-valent iodine under the protection of nitrogen into a 25mL sealed tube, magnetically stirring, adding 2mL of dried dimethylformamide, reacting at 85 ℃ for 10 hours, treating with saturated aqueous potassium bicarbonate solution after the reaction is finished, adding dichloromethane, washing an organic phase for three times with water, drying with anhydrous sodium sulfate, separating and purifying the mixture by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 10:1) to obtain a light yellow transparent liquid, wherein the separation yield is 69%.
Naproxen methyl ester fluoride is characterized as shown in figure 5: 1H NMR (400MHz, CHLOROFORM-D)8.10(D, J ═ 8.7Hz,1H),7.79(D, J ═ 8.9Hz,1H),7.64(s,1H),7.49(D, J ═ 7.6Hz,1H),7.20(D, J ═ 8.9Hz,1H),4.01(s,3H),3.89(q, J ═ 6.9,4.3Hz,1H),3.67(s,3H),1.58(D, J ═ 7.6Hz, 3H).
Test example 2
Reaction of compound 4-methoxyphenyl naproxen methyl ester chlorine high-valence iodine and p-toluic acid
Adding 0.22mmol of potassium tert-butoxide and 2mL of dried toluene in a 25mL sealed tube under the protection of nitrogen, keeping strong stirring, then adding 0.22mmol of p-toluic acid and 0.2mmol of 4-methoxyphenyl naproxen methyl ester chloride high-valent iodine, reacting for 3h at 130 ℃, adding water after the reaction is finished, transferring into a separating funnel, extracting with dichloromethane, washing with saturated salt water, collecting an organic phase, drying with anhydrous sodium sulfate, separating and purifying the reaction mixture by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 8:1) to obtain a light yellow transparent liquid, and separating the yield to 77%.
The characterization of the compound naproxen methyl ester p-toluate is shown in figure 6: 1H NMR (400MHz, CHLOROFORM-D)8.22(D, J ═ 8.1Hz,2H), 7.81-7.71 (m,3H), 7.42-7.34 (m,4H),3.93(s,3H),3.65(s,3H),2.48(s,3H),1.56(D, J ═ 7.2Hz,3H).
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The aryl naproxen derivative high-valence iodine compound is characterized by having a structural general formula as follows:
wherein X is an anion selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, acetate, tetrafluoroborate, sulfonate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, hexafluorophosphate, or bistrifluoromethylsulfonylimide;
ar is aryl, substituted aryl, aromatic heterocyclic group or substituted aromatic heterocyclic group;
r is alkyl.
2. The aryl naproxen derivative hypervalent iodine compound according to claim 1, wherein the substituent in the substituted aryl group or the substituted aromatic heterocyclic group is selected from the group consisting of a halogen, a saturated alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an acyl group, a nitro group, a trifluoromethyl group and an alkoxy group.
3. The aryl naproxen derivative hypervalent iodine compound of claim 1, wherein Ar is selected from the group consisting of:
wherein R is1、R2、R3、R4、R5Each independently selected from halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl or alkoxy.
4. The method for preparing an arylnaproxen derivative hypervalent iodine compound according to any one of claims 1 to 3, comprising the steps of:
(1) dissolving iodine in dichloromethane, adding an aromatic compound under the stirring condition, then adding m-chloroperoxybenzoic acid and p-toluenesulfonic acid monohydrate, reacting at room temperature, after the reaction is finished, spin-drying the solvent, adding diethyl ether, strongly stirring to generate white precipitate, cooling at-20 ℃, filtering the obtained white solid, and drying in vacuum to obtain a koser reagent derivative for later use;
(2) adding a halogenated solvent and a naproxen derivative into the koser reagent derivative obtained in the step (1), stirring at room temperature, then cooling the reaction liquid to 0 ℃, dropwise adding a trimethylsilylate, and reacting at room temperature;
(3) and (3) after the reaction in the step (2) is finished, distilling under reduced pressure to remove the solvent, adding a weak polar solvent, and precipitating to obtain a white solid product, namely the aryl naproxen derivative high-valence iodine compound.
5. The process according to claim 4, wherein in the step (1), the reaction time at room temperature is 1 hour, the vigorous stirring time is 30 minutes, the molar ratio of iodine to the aromatic compound is 1:2, the molar ratio of m-chloroperoxybenzoic acid to the aromatic compound is 3:2, and the molar ratio of p-toluenesulfonic acid monohydrate to the aromatic compound is 1: 1.
6. The preparation method according to claim 4, wherein in the step (2), the ratio of the number of moles of the koser reagent derivative to the volume of the halogenated solvent is 1mmol:8mL, the ratio of the naproxen derivative to the koser reagent derivative is 1:1, the ratio of the trimethyl silicide to the naproxen derivative is 1:1, and the reaction time at room temperature is 1 h.
7. The method according to claim 4, wherein in the step (2), the trimethylsilylated compound is at least one selected from the group consisting of TMSCl, TMSBr, TMSI, trimethylsilylacetic acid, trimethylsilylacetate, trimethylsilylmethane sulfonate, trimethylsilylphenylsulfonate, and the halogenated solvent is at least one selected from the group consisting of dichloromethane, chloroform, 1, 2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol, 2,2, 2-trifluoroethanol, and 1, 1-dichloroethane; in the step (3), the weak polar solvent is at least one of diethyl ether, n-hexane and petroleum ether.
8. Use of the aryl naproxen derivative hypervalent iodine compound according to any one of claims 1 to 3 for the preparation of a naproxen derivative.
9. A method for derivatizing a naproxen drug, the method comprising the steps of: reacting an arylnaproxen derivative hypervalent iodine compound as defined in any one of claims 1 to 3 with a compound of formula (2) in a solvent to produce a compound of formula (3),
wherein Nu is selected from F, C, N, O, P or S.
10. The method of claim 9, wherein the solvent is at least one of dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, trifluorotoluene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, n-hexane, cyclohexane, petroleum ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010820845.0A CN111943874B (en) | 2020-08-14 | 2020-08-14 | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010820845.0A CN111943874B (en) | 2020-08-14 | 2020-08-14 | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111943874A true CN111943874A (en) | 2020-11-17 |
| CN111943874B CN111943874B (en) | 2022-11-15 |
Family
ID=73343154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010820845.0A Active CN111943874B (en) | 2020-08-14 | 2020-08-14 | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111943874B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113072448A (en) * | 2021-03-31 | 2021-07-06 | 五邑大学 | Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof |
-
2020
- 2020-08-14 CN CN202010820845.0A patent/CN111943874B/en active Active
Non-Patent Citations (6)
| Title |
|---|
| ELEANOR A.MERRITT ET AL.: "Facile synthesis of koser’s reagent and derivatives from iodine or aryl iodides", 《J.ORG.CHEM.》 * |
| JUN ZHOU ET AL.: "Preparation and Synthetic Application of Naproxen-Containing Diaryliodonium Salts", 《MOLECULES》 * |
| MATTHEW S.MCCAMMANT ET AL.: "Cu-Mediated C-H 18F-Fluorination of electron-rich （Hetero）arenes", 《ORGANIC LETTERS》 * |
| MOTOKI ITO ET AL.: "Syntheis of Boron-substituted diaryliodonium salts and selective transformation into functionalized aryl boronates", 《ANGEW.CHEM.INT.ED.》 * |
| STACY C. FOSU ET AL.: "Site-Selective C-H Functionalization of (Hetero)Arenes via Transient, Non-symmetric lodanes", 《CHEM》 * |
| TOSHIFUMI DOHI ET AL.: "Recyclable synthesis of mesityl iodonium（III）salts", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113072448A (en) * | 2021-03-31 | 2021-07-06 | 五邑大学 | Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof |
| CN113072448B (en) * | 2021-03-31 | 2022-11-11 | 五邑大学 | Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111943874B (en) | 2022-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109718851B (en) | Chiral quaternary phosphonium salt phase transfer catalyst and preparation method and application thereof | |
| CN111943874B (en) | Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof | |
| CN109096162B (en) | Sc-catalyzed nucleophilic addition reaction method of mercaptan to o-methylenebenzoquinone | |
| CN111718372B (en) | Axial chiral phosphine-alkene ligand and preparation method and application thereof | |
| CN111995554A (en) | Method for preparing asymmetric organic selenium ether compound by metal-free chemical oxidation method | |
| CN111848480A (en) | Method for synthesizing aryl difluoromethyl seleno ether from arylboronic acid and application thereof | |
| CN113072448B (en) | Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof | |
| CN111217847B (en) | Thiosilane ligand, preparation method thereof and application thereof in aryl boronization catalytic reaction | |
| CN114989063A (en) | Synthesis method of beta-halopyrrole compound | |
| CN110684043B (en) | C-N axis chiral arylamine compound and preparation method thereof | |
| CN113105408A (en) | Novel asymmetric catalytic nucleophilic fluorine heterocyclic reaction system and application thereof in chiral unnatural amino acid module synthesis | |
| CN108794420B (en) | Bis-oxazoline ligand compound based on tetramethyl spiroindane skeleton, intermediate thereof, preparation method and application | |
| JP4104871B2 (en) | Method for purifying optically active 1,1'-bi-2-naphthols | |
| CN112430228A (en) | Chiral 2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide, derivative and preparation method | |
| CN113511984B (en) | Preparation method and application of beta-azido acid and beta-amino acid compound | |
| Xi et al. | Copper-Catalyzed Enantioselective Radical Esterification of Propargylic C–H Bonds | |
| CN115108979B (en) | Preparation method of 8-hydroxyquinoline derivative | |
| CN115583902B (en) | Preparation method of alkynyl thioether compound | |
| CN114213370B (en) | Method for synthesizing alkylated electron-rich heterocyclic aromatic hydrocarbon by photo-induced NHPI ester decarboxylation coupling | |
| CN110183298B (en) | Preparation method of dibenzopentene derivative | |
| CN116836107B (en) | Carbazol eight-membered ring large conjugated structure OLED material and preparation method thereof | |
| CN112142791B (en) | Alpha-fluoro-beta-carbonyl-diaryl phosphine oxide compound and synthesis method of enantioselective diversity thereof | |
| CN114057717B (en) | Quinoline-substituted bisoxazoline ligand, and synthetic method and application thereof | |
| CN114160206B (en) | Catalyst for catalytic synthesis of optically active indole compound, application and synthesis method thereof, and optically active indole compound | |
| CN114213278B (en) | Synthesis method of benzyl diazoacetophenone compound and benzyl diazoacetophenone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |