CN113072448B - Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof - Google Patents

Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof Download PDF

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CN113072448B
CN113072448B CN202110345557.9A CN202110345557A CN113072448B CN 113072448 B CN113072448 B CN 113072448B CN 202110345557 A CN202110345557 A CN 202110345557A CN 113072448 B CN113072448 B CN 113072448B
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gemfibrozil
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iodine
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CN113072448A (en
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周均
吴盼盼
陈超
陈泗林
李冬利
张焜
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Wuyi University
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    • 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
    • C07C69/67—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 saturated acids
    • C07C69/708—Ethers
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    • 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
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/06—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing halogen atoms, or nitro or nitroso groups bound to the carbon skeleton
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    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C59/40—Unsaturated compounds
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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Abstract

The invention discloses a high-valence iodine compound of an aryl gemfibrozil derivative and a preparation method thereof. The aryl gemfibrozil derivative hypervalent iodine compound has a structural formula (I), is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of gemfibrozil molecules, so that the aims of modifying the gemfibrozil drug molecules and expanding the species of the gemfibrozil drug molecules are fulfilled. Meanwhile, the invention provides a preparation method of the compound, and the method is direct, simple and efficient, and is suitable for preparing aryl gemfibrozil derivative high-valence iodine compounds in a large scale.

Description

Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to an aryl gemfibrozil derivative high-valence iodine compound and a preparation method thereof.
Background
Gefilosin belongs to a chlorine Bei Dingsuan derivative and is a commonly used lipid-lowering drug in clinic. The pharmacological actions mainly comprise the protection action of myocardial ischemia reperfusion injury, the action of resisting hepatic cell fatty lesion, the action of reducing FFA and AFABP, the action of reducing blood sugar and the action of relaxing aorta. Can be used for treating severe IV or V type hyperlipoproteinemia, coronary heart disease, and patients with high risk and ineffective diet control and weight loss; it is also used for treating type IIb hyperlipoproteinemia, coronary heart disease, high risk, diet control, weight loss, and other blood lipid regulating medicines. Therefore, the field of synthesis of the compounds needs to develop an efficient, simple and economical method.
So far, the modification on the gemfibrozil aryl is realized by modifying the aliphatic chain hydrocarbon carboxyl of the gemfibrozil or directly performing C-H activation on the gemfibrozil aryl, but the method usually needs to use a transition metal catalyst, has poor selectivity and has narrow application range. The gemfibrozil drug molecules obtained by the above reported reactions are very limited, and are not beneficial to constructing a huge gemfibrozil drug library. Therefore, an effective method with simple preparation process, good selectivity and wide application range is lacked for synthesizing the gemfibrozil derivatives.
Disclosure of Invention
The invention aims to provide a high-valence iodine compound of an aryl gemfibrozil derivative and a preparation method thereof aiming at the defects of the prior art. The aryl gemfibrozil derivative high-valence iodine compound can be used for synthesizing various aryl-substituted gemfibrozil drug molecules through a nucleophilic substitution reaction with a nucleophilic reagent, and further promotes the discovery process of active leads of the gemfibrozil drugs.
In order to realize the purpose, the technical scheme adopted by the invention is as follows: an aryl gemfibrozil derivative hypervalent iodine compound, the structure of which is shown as the formula (I):
Figure 553324DEST_PATH_IMAGE001
（I）
in the formula (I), X is one of halogen, hydroxyl, acetoxy, tetrafluoroborate, sulfonic group, methanesulfonic group, trifluoromethanesulfonic group, benzenesulfonic group, p-toluenesulfonic group, hexafluorophosphoric acid group, bistrifluoromethyl and sulfonimide group;
ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, and H on the aryl or the heteroaryl is independently substituted by halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl or alkoxy;
r is alkyl or aryl;
the halogen is selected from fluorine, chlorine, bromine or iodine.
The aryl gemfibrozil derivative high-valence iodine compound is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of the gemfibrozil molecules, so that the aims of modifying the gemfibrozil drug molecules and expanding the species of the gemfibrozil drug molecules are fulfilled.
As a preferred embodiment of the present invention, ar comprises the following groups:
Figure 25893DEST_PATH_IMAGE002
、
Figure DEST_PATH_IMAGE003
、
Figure 77026DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE005
、
Figure 189207DEST_PATH_IMAGE006
、
Figure DEST_PATH_IMAGE007
、
Figure 351198DEST_PATH_IMAGE008
、
Figure DEST_PATH_IMAGE009
;
said R is 1 、R 2 、R 3 、R 4 And R 5 The groups are the same or different and are respectively and independently selected from halogen, saturated alkyl, substituted alkyl, aryl, substituted aryl, acyl, nitro, trifluoromethyl and alkoxy.
As a preferred embodiment of the present invention, the compound represented by the formula (1) includes the following compounds:
Figure 101111DEST_PATH_IMAGE010
。
the invention also claims a preparation method of the aryl gemfibrozil derivative hypervalent iodine compound, which comprises the following steps:
mixing Koser's reagent derivatives or aryl iododiacetic acid compounds with halogenated solvents and gemfibrozil derivatives uniformly at room temperature, cooling the mixed solution to-5~4 ℃, adding trimethyl silicide at 5-40 ℃ and reacting for 0.5-1.5 hours to obtain the aryl gemfibrozil derivative high-valence iodine compounds.
As a preferred embodiment of the present invention, the Koser's reagent derivative has a structural formula shown in formula (1):
Figure DEST_PATH_IMAGE011
（1）
as a preferred embodiment of the present invention, the structural formula of the aryl iododiacetic acid compound is represented by formula (2):
Figure 323145DEST_PATH_IMAGE012
（2）
as a preferred embodiment of the present invention, the gemfibrozil derivative has the structure shown in formula (II):
Figure 735671DEST_PATH_IMAGE013
（II）
the invention carries out anion ligand exchange reaction on gemfibrozil derivatives and Koser's reagent derivatives or aryl iododiacetic acid compounds to prepare aryl gemfibrozil derivative hypervalent iodine compounds, and the synthetic route is as follows:
Figure 950621DEST_PATH_IMAGE014
as a preferred embodiment of the present invention, the trimethylsilicand is one of trimethylsilicand chloride, trimethylsilicand bromide, trimethylsilicand iodide, trimethylsilicane acetic acid, sodium trifluoroacetate trimethylsilicane, trimethylsilicane methanesulfonate, trimethylsilicane trifluoromethanesulfonate, trimethylsilicane benzenesulfonate; the molar ratio of the Koser's reagent derivative to the gemfibrozil derivative is 0.8-1.2: 0.8-1.2; the ratio of the Koser's reagent derivative to the halogenated solvent is 1 to 2mmol:2 to 5mL; the molar ratio of the trimethyl silicide to the gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2.
As a preferred embodiment of the invention, the halogenated solvent is at least one of dichloromethane, chloroform, 1,1,2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol, 2,2,2-trifluoroethanol, and dichloroethylene.
As a preferable embodiment of the method for preparing the aryl gemfibrozil derivative hypervalent iodine compounds according to the invention, the reaction solution is reacted at room temperature for 0.5 to 24 hours, then the solvent is distilled off under reduced pressure, and a weakly polar solvent is added to obtain the aryl gemfibrozil derivative hypervalent iodine compounds; the weak polar solvent is at least one of diethyl ether, n-hexane and petroleum ether.
The invention claims the application of aryl gemfibrozil derivative hypervalent iodine compounds in preparing aromatic ring modified gemfibrozil derivative medicines.
The invention also claims a derivatization method for aromatic ring modification of gemfibrozil derivatives, which is characterized in that aryl gemfibrozil derivative hypervalent iodine compounds as described in claim 1 are reacted with nucleophilic reagent in solvent to produce gemfibrozil derivative drugs modified by aromatic rings; the solvent is at least one of dimethylformamide, toluene, dichloroethane, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene, trifluorotoluene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, n-hexane, cyclohexane and petroleum ether.
In addition, the invention also claims a gemfibrozil derivative drug modified by an aromatic ring, which is prepared by a derivatization method modified by the aromatic ring of the gemfibrozil derivative; the aromatic ring modified gemfibrozil derivative has a drug structure shown in formula (III):
Figure 132204DEST_PATH_IMAGE015
（III）
nu is a nucleophilic group, and the nucleophilic group at least contains one nitrogen atom, one oxygen atom, one phosphorus atom, one sulfur atom and one fluorine atom.
The aryl gemfibrozil derivative hypervalent iodine compound is a high-efficiency electrophilic reagent, can realize nucleophilic substitution reaction of a specific site on the aryl of a gemfibrozil molecule with a nucleophilic reagent, and the synthetic route of the aromatic ring modified gemfibrozil derivative medicine molecule is as follows:
Figure 259560DEST_PATH_IMAGE016
compared with the prior art, the invention has the following beneficial effects: the aryl gemfibrozil derivative high-valence iodine compound is a high-efficiency electrophilic reagent, and can realize nucleophilic substitution reaction of a specific site on the aryl of gemfibrozil molecules, so that the aim of modifying the drug molecules is fulfilled, the types of the drug molecules are expanded, and meanwhile, the preparation method of the compound is provided. The method can directly, simply, efficiently and massively prepare the aryl gemfibrozil 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 gemfibrozil 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 gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 1 H NMR spectrum;
FIG. 2 shows the preparation of phenyl gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 13 A C NMR spectrum;
FIG. 3 shows the preparation of higher iodine 4-methylphenyl gemfibrozil methyl triflate prepared according to example 2 of the present invention 1 H NMR spectrum;
FIG. 4 shows the preparation of higher iodine 4-methylphenyl gemfibrozil methyl triflate prepared according to example 2 of the present invention 13 A C NMR spectrum;
FIG. 5 shows the preparation of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 1 H NMR spectrum;
FIG. 6 shows the preparation of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 13 A C NMR spectrum;
FIG. 7 shows the preparation of 4-methoxyphenyl gemfibrozil methyl ester with higher iodine chloride value prepared in example 4 of the present invention 1 H NMR spectrum;
FIG. 8 shows the preparation of 4-methoxyphenyl gemfibrozil methyl ester with higher iodine chloride value prepared in example 4 of the present invention 13 A C NMR spectrum;
FIG. 9 shows the preparation of higher iodine phenyl gemfibrozil triflate according to the invention in example 5 1 H NMR spectrum;
FIG. 10 shows the higher iodine content of phenyl gemfibrozil triflate prepared in example 5 of the present inventionIs/are as follows 13 A C NMR spectrum;
FIG. 11 is a graph of gemfibrozil methyl fluoride prepared in example 6 of the present invention 1 H NMR spectrum;
FIG. 12 is a graphic representation of gemfibrozil methyl ester fluoride, prepared in example 6 of the invention 13 A C NMR spectrum;
FIG. 13 is a graphic representation of gemfibrozil methyl ester fluoride, prepared in example 6 of the invention 19 F, atlas;
FIG. 14 shows the preparation of gemfibrozil methyl ester p-toluate according to example 7 of the present invention 1 H NMR；
FIG. 15 is a graphic representation of gemfibrozil methyl ester p-toluate prepared in example 7 of the present invention 13 C NMR spectrum.
Detailed Description
To better illustrate the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
The preparation of phenyl gemfibrozil methyl ester triflate higher iodine described in this example comprises the following steps:
(1) In a 100 mL round bottom flask, 10 mmol of hydroxy (p-toluenesulfonyloxy) iodobenzene was added to a mixed solution of 30 mL dichloromethane and 5mL of 2, 2-trifluoroethanol, followed by addition of 10 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 10 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature of 1h;
(2) After the reaction is finished, the solvent is removed by reduced pressure distillation, 70 mL ethyl ether is added for precipitation, and white solid phenyl gemfibrozil methyl ester trifluoromethanesulfonate high-valence iodine is obtained, wherein the yield is 83%.
FIG. 1 shows the preparation of phenyl gemfibrozil methyl ester triflate higher iodine prepared according to example 1 of the present invention 1 H NMR, FIG. 2 is a graphic representation of higher iodine phenyl gemfibrozil methyl ester triflate prepared according to example 1 of the present invention 13 C NMR spectrum. As can be seen from the nuclear magnetic spectra of fig. 1 and fig. 2, the nuclear magnetic characterization peaks of the iodine valence of phenyl gemfibrozil methyl triflate are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 5.9 Hz, 3H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.81 (s, 1H), 3.94 (t, J = 5.7 Hz, 2H), 3.64 (s, 3H), 2.52 (s, 3H), 2.17 (s, 3H), 1.77 – 1.63 (m, 4H), 1.20 (s, 6H)； 13 C NMR (100 MHz, CDCl 3 ) δ 7.81, 7.79, 7.54, 7.52, 7.51, 7.42, 7.40, 7.38, 6.81, 3.95, 3.94, 3.93, 3.64, 2.52, 2.17, 1.73, 1.72, 1.72, 1.69, 1.68, 1.66, 1.20. The invention example 1 is shown to successfully prepare phenyl gemfibrozil methyl ester triflate high-valence iodine.
The structural formula of phenyl gemfibrozil methyl ester triflate high-valence iodine is as follows:
Figure 159382DEST_PATH_IMAGE017
example 2
The preparation of 4-methylphenyl gemfibrozil methyl triflate higher iodine described in this example comprises the following steps:
(1) Dissolving 10 mmol of 4-methyliodibenzene in 40 mL dichloromethane in a 100 mL round-bottom flask, adding 10 mmol of m-chloroperoxybenzoic acid under stirring, then adding 10 mmol of p-toluenesulfonic acid monohydrate, stirring at room temperature for 1h, after the reaction is completed, spin-drying the solvent, adding 70 mL ethyl ether, stirring fully for 30 min to generate a precipitate, filtering, and drying in vacuum to obtain hydroxyl (p-toluenesulfonyloxy) 4-methyliodibenzene with the yield of 98%;
(2) In a 100 mL round bottom flask, 8 mmol of hydroxy (p-toluenesulfonyloxy) 4-methyliodobenzene from step (1) was added to a mixed solution of 25 mL dichloromethane and 4 mL of 2, 2-trifluoroethanol, followed by addition of 8 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 8 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature for 1h;
(3) And (3) after the reaction in the step (2) is finished, distilling under reduced pressure to remove the solvent, adding 70 mL diethyl ether for precipitation to obtain white solid 4-methylphenyl gemfibrozil methyl ester high-valence iodine trifluoromethanesulfonate, wherein the total yield is 79%.
FIG. 3 is the 4-methylphenyl gemfibrozil methyl ester trifluoromethyl ester prepared in example 2 of the inventionSulfonic acid high valence iodine 1 H NMR spectrum, FIG. 4 is a higher iodine value of 4-methylphenyl gemfibrozil methyl triflate prepared in example 2 of the present invention 13 C NMR spectrum, and as can be seen from the nuclear magnetic spectra of FIGS. 3 and 4, the nuclear magnetic characterization peak of the high-valence iodine of 4-methylphenyl gemfibrozil methyl ester triflate is as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.78 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 3.95 (t, J = 5.9 Hz, 2H), 3.65 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H), 1.77 – 1.65 (m, 4H), 1.21 (s, 6H)； 13 C NMR (101 MHz, CDCl 3 ) δ 178.25, 161.27, 143.19, 141.37, 138.99, 133.83, 133.12, 129.55, 113.91, 109.40, 105.66, 68.61, 51.93, 42.16, 36.95, 25.79, 25.29, 24.96, 21.42, 15.72. The invention example 2 is shown to successfully prepare the high-valence iodine 4-methyl phenyl gemfibrozil methyl triflate.
The structural formula of the 4-methyl phenyl gemfibrozil methyl triflate high-valence iodine is as follows:
Figure 725493DEST_PATH_IMAGE018
example 3
This example, which describes 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate, provides a process for the preparation of higher iodine comprising the steps of:
(1) Dissolving 10 mmol of iodine in 100 mL dichloromethane in a round-bottom flask of 250 mL, adding 20 mmol of mesitylene under stirring, then adding 30 mmol of m-chloroperoxybenzoic acid and 20 mmol of p-toluenesulfonic acid monohydrate, reacting at room temperature for 1 hour, after the reaction is finished, spin-drying the solvent, adding 150 mL ethyl ether, stirring fully for 30 minutes to generate a precipitate, filtering, and drying in vacuum to obtain hydroxyl (p-toluenesulfonyloxy) mesitylene with the yield of 97 percent;
(2) In a 100 mL round bottom flask, 8 mmol of hydroxy (p-toluenesulfonyloxy) mesityliodobenzene obtained in step (1) was added to a mixed solution of 25 mL dichloromethane and 3 mL of 2, 2-trifluoroethanol, followed by addition of 8 mmol of gemfibrozil methyl ester compound, followed by dropwise addition of 8 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction at room temperature for 1 hour;
(3) And (3) after the reaction in the step (2) is finished, removing the solvent by reduced pressure distillation, adding 70 mL diethyl ether for precipitation to obtain a white solid 2,4,6-trimethylphenyl gemfibrozil methyl ester trifluoromethanesulfonate high-valence iodine with the total yield of 54%.
FIG. 5 shows 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate hypervalent iodine prepared in example 3 of the invention 1 H NMR spectrum, FIG. 6 is a 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine prepared in example 3 of the present invention 13 C NMR spectrum, and nuclear magnetic characterization peaks of 2,4,6-trimethylphenyl gemfibrozil methyl ester triflate higher iodine can be seen from the nuclear magnetic spectra of FIGS. 5 and 6: 1 H NMR (400 MHz, CDCl 3 ): δ 7.35 (s, 1H), 7.07 (s, 2H), 6.76 (s, 1H), 3.93 (t, J = 5.9 Hz, 2H), 3.65 (s, 3H), 2.61 (s, 6H), 2.51 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H), 1.76 – 1.65 (m, 4H), 1.21 (s, 6H)； 13 C NMR (101 MHz, CDCl 3 ) δ 178.23, 160.63, 144.22, 142.29, 140.36, 136.70, 130.70, 129.54, 119.84, 114.23, 103.38, 68.62, 51.92, 42.15, 36.95, 26.97, 25.28, 24.95, 21.13, 15.91. The invention example 3 shows that 2,4,6-trimethylphenyl gemfibrozil methyl ester trifluoro methanesulfonic acid high valence iodine is successfully prepared.
2,4,6-Trimethylphenylgemfibrozil methyl triflate hypervalent iodine has the structural formula:
Figure 715577DEST_PATH_IMAGE019
example 4
The preparation of 4-methoxyphenyl gemfibrozil methyl chloride higher iodine described in this example comprises the following steps:
(1) Adding 10 mmol of p-iodoanisole, 11 mmol of sodium periodate, 20 mmol of sodium acetate, 15 mL acetic acid and 1.5 mL acetic anhydride into a 100 mL 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 anhydrous sodium sulfate, decompressing and 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 the iodine-p-methoxybenzene diacetate with the yield of 92%;
(2) Adding 30 mL hexafluoroisopropanol and 8.5 mmol gemfibrozil methyl ester into a 100 mL round-bottom flask, then adding 8.5 mmol iodop-methoxybenzene diacetate, cooling to 0 ℃, adding 8.5 mmol trimethylchlorosilane dropwise with stirring, and reacting 1h at room temperature;
(3) After the reaction is finished, the solvent is distilled and suspended under reduced pressure, and diethyl ether is added for precipitation to obtain pink solid 4-methoxyphenyl gemfibrozil methyl chloride high-valence iodine compound with the total yield of 59 percent.
FIGS. 7 and 8 are schematic views showing the preparation of 4-methoxyphenyl gemfibrozil methyl ester chloride higher iodine according to example 4 of the present invention 1 H NMR and 13 c NMR spectrum, and as can be seen from the nuclear magnetic spectra of FIGS. 7 and 8, the nuclear magnetic characterization peak of the high-valence iodine of 4-methoxyphenyl gemfibrozil methyl chloride is as follows: 1 H NMR (400 MHz, CDCl 3 ):δ 7.76 (s, 1H), 7.75 (d, J = 3.2 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 6.70 (s, 1H), 3.90 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.64 (s, 3H), 2.56 (s, 3H), 2.13 (s, 3H), 1.72 – 1.63 (m, 4H), 1.19 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 178.25, 162.75, 161.19, 141.13, 138.71, 136.14, 129.53, 118.08, 113.86, 106.35, 101.51, 68.61, 55.84, 51.93, 42.16, 36.96, 25.74, 25.30, 24.97, 15.73. The invention example 4 is shown to successfully prepare the 4-methoxyphenyl gemfibrozil methyl chloride high-valence iodine.
The structural formula of the 4-methoxyphenyl gemfibrozil methyl chloride higher iodine is as follows:
Figure 76151DEST_PATH_IMAGE020
example 5
The preparation of higher iodine phenyl gemfibrozil triflate described in this example comprises the following steps:
(1) In a 100 mL round bottom flask, 10 mmol of hydroxy (p-toluenesulfonyloxy) iodobenzene was added to a mixed solution of 30 mL dichloromethane and 5mL of 2, 2-trifluoroethanol, followed by 10 mmol of gemfibrozil, followed by dropwise addition of 10 mmol of trimethylsilyl trifluoromethanesulfonate, followed by reaction of 1h at room temperature;
(2) After the reaction is finished, the solvent is removed by reduced pressure distillation, 70 mL ethyl ether is added for precipitation, and white solid phenyl gemfibrozil triflate high-valence iodine is obtained, wherein the yield is 89%.
FIGS. 9 and 10 are respectively a graphic representation of the higher iodine phenyl gemfibrozil triflate prepared in example 5 of the present invention 1 H NMR and 13 c NMR spectrum, as can be seen from the nuclear magnetic spectra of FIGS. 9 and 10, the nuclear magnetic characteristic peak of the high-valence iodine of phenyl gemfibrozil triflate is: 1 H NMR (400 MHz,DMSO-d6): δ 8.18 – 8.08 (m, 3H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.10 (s, 1H), 3.99 (t, J = 5.4 Hz, 2H), 2.55 (s, 3H), 2.13 (s, 3H), 1.70 – 1.53 (m, 4H), 1.10 (s, 6H)； 13 c NMR (101 MHz, DMSO-d 6) delta 178.70, 159.89, 140.48, 138.33, 134.66, 131.76, 127.42, 122.34, 116.01, 113.87, 109.27, 68.30, 41.02, 36.34, 24.94, 24.50, 15.16. The invention example 5 shows that phenyl gemfibrozil triflate higher iodine is successfully prepared.
The structural formula of phenyl gemfibrozil methyl ester triflate high-valence iodine is as follows:
Figure 463270DEST_PATH_IMAGE021
example 6
The preparation of gemfibrozil methyl ester fluoride as described in this example comprises the following steps:
in a 25 mL sealed tube, 0.4 mmol copper difluoride, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 18-crown ether-6 and 0.2 mmol 4-methoxyphenyl gemfibrozil methyl chloride are added under the protection of nitrogen and stirred, 2 mL dried dimethylformamide is added to react at 85 ℃ for 10 h, saturated potassium bicarbonate aqueous solution is used for treatment after the reaction is finished, dichloromethane is added, an organic phase is washed for three times and dried by anhydrous sodium sulfate, and the mixture is separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 40: 1) to obtain colorless transparent liquid with the separation yield of 69%.
FIGS. 11, 12 and 13 are, respectively, gemfibrozil methyl ester fluoride, prepared in example 6 of the present invention 1 H NMR， 13 C NMR and 19 f NMR. As can be seen from the nuclear magnetic spectra of fig. 11, 12 and 13, the nuclear magnetic characterization peaks of gemfibrozil methyl ester fluoride: 1 H NMR (400 MHz, CDCl 3 ):δ 6.76 (d, J = 9.9 Hz, 1H), 6.54 (d, J = 6.5 Hz, 1H), 3.86 (t, J = 2.7 Hz, 2H), 3.65 (s, 3H), 2.20 (d, J = 1.3 Hz, 3H), 2.15 (s, 3H), 1.71 (dd, J = 7.1, 3.4 Hz, 4H), 1.21 (s, 6H)； 13 C NMR (101 MHz, CDCl 3 ) δ 178.36, 156.39, 154.04, 152.87, 125.64, 121.81, 116.80, 113.87, 68.79, 51.82, 42.19, 37.20, 25.28, 15.86, 14.62.19F NMR (376 MHz, CDCl 3) δ -128.95 (s, 1F). Indicating the success of the present invention, example 9, in the preparation of gemfibrozil methyl fluoride.
Gemfibrozil methyl ester fluoride has the structural formula:
Figure 770755DEST_PATH_IMAGE022
example 7
The preparation of the reaction for the p-toluate ester of gemfibrozil described in this example comprises the following steps:
adding 0.22 mmol of potassium tert-butoxide and 2 mL dried toluene in a 25 mL sealed tube under nitrogen atmosphere, keeping strong stirring, then adding 0.22 mmol of p-toluic acid and 0.2 mmol of 4-methoxyphenyl gemfibrozil methyl 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 saline, 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 = 30: 1) to obtain colorless transparent liquid, wherein the separation yield is 77%.
FIGS. 14 and 15 are gemfibrozil methyl ester p-toluate, prepared for example 7 of the present invention 1 H NMR and 13 c NMR spectrum from the chartThe nuclear magnetic spectrum of 14 and 15 shows the nuclear magnetic characteristic peaks of the methyl p-toluate gemfibrozil: 1 H NMR (400 MHz, CDCl 3 ): 8.09 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.88 (s, 1H), 6.65 (s, 1H), 3.92 (t, J = 4.9 Hz, 2H), 3.67 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 1.72 (d, J = 2.8 Hz, 4H), 1.22 (s, 6H)； 13 C NMR (101 MHz, CDCl 3 ) δ 178.41, 165.52, 154.87, 144.32, 142.41, 130.27, 129.37, 127.87, 127.01, 125.48, 123.92, 113.37, 68.49, 51.88, 42.21, 37.22, 25.32, 21.86, 16.38, 15.94. The present invention, example 7, shows the successful preparation of methyl ester p-toluate of gefitinib.
The structural formula of gemfibrozil methyl ester p-toluate is as follows:
Figure 661350DEST_PATH_IMAGE023
although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the present invention.

Claims (2)

1. A preparation method of aryl gemfibrozil derivative hypervalent iodine compounds is characterized in that the structure of the aryl gemfibrozil derivative hypervalent iodine compounds is shown as a formula (I):
Figure 891683DEST_PATH_IMAGE001
（I）
in the formula (I), X is chlorine, bromine, iodine or trifluoromethanesulfonyl;
r is alkyl;
ar is selected from
Figure 158717DEST_PATH_IMAGE002
Wherein R is 1 、R 2 、R 3 、R 4 And R 5 Each independently selected from halogen, saturated alkyl, aryl, nitro, trifluoromethyl or alkoxy;
the preparation method comprises the following steps:
mixing Koser's reagent derivatives or aryl iododiacetic acid compounds with halogenated solvents and gemfibrozil derivatives uniformly at room temperature, cooling the mixed solution to-5~5 ℃, adding trimethyl silicide at 5 to 40 ℃ and reacting for 0.5 to 24 hours to obtain aryl gemfibrozil derivative high-valence iodine compounds;
the Koser's reagent derivative has a structural formula shown as a formula (1):
Figure 295300DEST_PATH_IMAGE003
（1）；
the structural formula of the aryl iododiacetic acid compound is shown as the formula (2):
Figure 964179DEST_PATH_IMAGE004
（2）；
the reaction formula is shown as follows:
Figure 957543DEST_PATH_IMAGE005
or
Figure 649555DEST_PATH_IMAGE006
；
The trimethyl silicide is one of TMSCl, TMSBr, TMSI and trimethylsilyl trifluoromethanesulfonate;
the halogenated solvent is at least one of dichloromethane, chloroform, 1,1,2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol and 2,2,2-trifluoroethanol.
2. The method of claim 1, wherein the molar ratio of Koser's reagent derivative to gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2; the ratio of the Koser's reagent derivative to the halogenated solvent is 1 to 2mmol:2 to 5mL; the molar ratio of the trimethyl silicide to the gemfibrozil derivative is 0.8 to 1.2: 0.8 to 1.2.
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