CN113072448B - A kind of aryl gemfibrozil derivative hypervalent iodine compound and preparation method thereof - Google Patents

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

A kind of aryl gemfibrozil derivative hypervalent iodine compound and preparation method thereof

technical field

The invention belongs to the technical field of organic synthesis chemistry, in particular to an aryl gemfibrozil derivative hypervalent iodine compound and a preparation method thereof.

Background technique

Gemfibrozil belongs to the derivatives of clofibrate and is a commonly used lipid-lowering drug in clinical practice. The pharmacological effects mainly include the protective effect of myocardial ischemia-reperfusion injury, the effect of anti-hepatic fatty disease, the effect of reducing FFA and AFABP, the effect of hypoglycemia and the effect of dilating the aorta. For severe type IV or V hyperlipoproteinemia, coronary heart disease, high risk and ineffective diet control, weight loss; also for type IIb hyperlipoproteinemia, coronary heart disease, high risk and diet control , weight loss, and other blood lipid regulation drug treatment ineffective. Therefore, the field of synthesis of such compounds needs to develop an efficient, simple and economical method.

So far, common gemfibrozil derivatives are modified on the gemfibrozil aryl group by modifying the aliphatic chain hydrocarbon carboxyl group of gemfibrozil or directly performing C-H activation on the gemfibrozil aryl group, but this method Usually need to use transition metal catalyst, the selectivity is poor, and the scope of application is narrow. The gemfibrozil-like drug molecules obtained from the reactions reported above are very limited, which is not conducive to the construction of a huge gemfibrozil-like drug library. Therefore, the synthesis of gemfibrozil derivatives lacks an effective method with simple preparation process, good selectivity and wide application range.

Contents of the invention

The object of the present invention is to provide an aryl gemfibrozil derivative hypervalent iodine compound and a preparation method for the shortcomings of the above-mentioned prior art. The aryl gemfibrozil derivative hypervalent iodine compound of the present invention can synthesize various aryl-substituted gemfibrozil drug molecules through nucleophilic substitution reactions with nucleophiles, and then promote the activity of gemfibrozil drugs The discovery process of the lead.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows: a hypervalent iodine compound of aryl gemfibrozil derivative, its structure is shown in formula (I):

(I)

In formula (I), X is halogen, hydroxyl, acetate, tetrafluoroboric acid, sulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hexafluorophosphoric acid One of group, bistrifluoromethyl group, sulfonimide group;

Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, and the substituted aryl or substituted heteroaryl is that the H on the aryl or heteroaryl is independently replaced 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 hypervalent iodine compound of the aryl gemfibrozil derivative described in the present invention is a highly efficient electrophile, which can realize the nucleophilic substitution reaction of a specific site on the aryl group of the gemfibrozil molecule, and achieve the purpose of modifying the gemfibrozil class. Drug molecules, the purpose of expanding the molecular types of gemfibrozil drugs.

As a preferred embodiment of the present invention, the Ar includes the following groups:

、

、

、

、

、

,

,

,

,

,

、

、

;

,

,

;

The R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same group or different groups, 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:

。

.

The present invention also claims to protect the preparation method of the hypervalent iodine compound of the aryl gemfibrozil derivative, comprising the following steps:

Mix Koser's reagent derivatives or aryl iodide diacetic acid compounds with halogenated solvents and gemfibrozil derivatives at room temperature, then cool the mixed solution to -5~4°C, add trimethylsilicide 5~40 The reaction is carried out at ℃ for 0.5-1.5 hours to obtain the hypervalent iodine compound of the aryl gemfibrozil derivative.

As a preferred embodiment of the present invention, the structural formula of the Koser's reagent derivative is shown in formula (1):

(1)

As a preferred embodiment of the present invention, the structural formula of the aryl iodide diacetic acid compound is shown in formula (2):

(2)

As a preferred embodiment of the present invention, the structure of the gemfibrozil derivative is shown in formula (II):

(II)

In the present invention, gemfibrozil derivatives are subjected to anion ligand exchange reaction with Koser's reagent derivatives or aryl iodide diacetic acid compounds to prepare hypervalent iodine compounds of aryl gemfibrozil derivatives. The synthetic route is as follows:

As a preferred embodiment of the present invention, the trimethylsilicide is chlorine trimethylsilicide, bromine trimethylsilicide, iodine trimethylsilicide, trimethylsilyl acetic acid, sodium trimethylsilyl trifluoroacetate , trimethylsilyl methanesulfonate, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl benzenesulfonate; said Koser's reagent derivatives and gemfibrozil derivatives The molar ratio is 0.8~1.2:0.8~1.2; the ratio of Koser's reagent derivative and halogenated solvent is 1~2mmol:2~5mL; the molar ratio of trimethylsilicide and gemfibrozil derivative is 0.8~ 1.2: 0.8~1.2.

As a preferred embodiment of the present invention, the halogenated solvent is dichloromethane, chloroform, 1,1,2-trifluorotrichloroethane, carbon tetrachloride, hexafluoroisopropanol, 2,2,2- At least one of trifluoroethanol and dichloroethylene.

As a preferred embodiment of the preparation method of aryl gemfibrozil derivative hypervalent iodine compound of the present invention, after the reaction solution is reacted at room temperature for 0.5 to 24 hours, the solvent is removed by distillation under reduced pressure, and a weak polar solvent is added to obtain the Hypervalent iodine compounds of aryl gemfibrozil derivatives; the weakly polar solvent is at least one of ether, n-hexane and petroleum ether.

The present invention claims the application of the aryl gemfibrozil derivative hypervalent iodine compound in the preparation of aromatic ring modified gemfibrozil derivative drugs.

The present invention also claims a derivatization method for modifying the aromatic ring of gemfibrozil derivatives, characterized in that, the hypervalent iodine compound of the aryl gemfibrozil derivatives described in claim 1 and the nucleophilic reagent are mixed in a solvent reaction to generate aromatic ring-modified gemfibrozil derivative drugs; the solvent is dimethylformamide, toluene, ethylene dichloride, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, toluene , trifluorotoluene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, n-hexane, cyclohexane, petroleum ether at least one.

In addition, the present invention also claims to protect the aromatic ring modified gemfibrozil derivative drug prepared by the derivatization method of gemfibrozil derivative aromatic ring modification; the aromatic ring modified gemfibrozil derivative drug structure is as follows: Formula (III) shows:

(III)

The Nu is a nucleophilic group, and the nucleophilic group contains at least one nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, or fluorine atom.

The aryl gemfibrozil derivative hypervalent iodine compound of the present invention is a highly efficient electrophile, which can realize the nucleophilic substitution reaction of a specific site on the aryl group of gemfibrozil molecules with a nucleophile. The synthetic route of the gemfibrozil derivative drug molecule modified by the aromatic ring is:

Compared with the prior art, the present invention has the following beneficial effects: the aryl gemfibrozil derivative hypervalent iodine compound of the present invention is a highly efficient electrophile, and the compound can realize gemfibrozil-like molecular aryl Nucleophilic substitution reaction at a specific site, so as to achieve the purpose of modifying this type of drug molecule, expand the types of its type of drug molecule, and provide a preparation method for this type of compound. First, synthesize gemfibrozil derivatives, and then cooperate with Koser's The reagent derivative or aryl iodide diacetic acid compound is subjected to anion ligand exchange reaction to prepare aryl gemfibrozil derivative hypervalent iodine compound. The method can directly, concisely, efficiently and massively prepare aryl gemfibrozil derivative hypervalent iodine compounds. The compound is easy to prepare, stable and has high reactivity. This kind of hypervalent iodine compound can carry out concise and clear structural modification on gemfibrozil-like molecules, realize the rapid synthesis of structural diversity of this kind of drug molecules, and facilitate the rapid construction of huge drug-like compounds Compound libraries will greatly promote the discovery process of pharmaceutically active leads.

Description of drawings

Fig. 1 is the ¹ H NMR spectrum of the hypervalent iodine trifluoromethanesulfonate of phenyl gemfibrozil methyl ester prepared in Example 1 of the present invention;

Fig. 2 is the ¹³ C NMR spectrum of hypervalent iodine trifluoromethanesulfonate of phenyl gemfibrozil methyl ester prepared in Example 1 of the present invention;

Fig. 3 is the ¹ HNMR spectrum of hypervalent iodine trifluoromethanesulfonate of 4-methylphenyl gemfibrozil methyl ester prepared in Example 2 of the present invention;

Fig. 4 is the ¹³ CNMR spectrum of hypervalent iodine trifluoromethanesulfonate 4-methylphenyl gemfibrozil methyl ester prepared in Example 2 of the present invention;

Fig. 5 is the ¹ H NMR spectrum of hypervalent iodine trifluoromethanesulfonate 2,4,6-trimethylphenyl gemfibrozil methyl ester prepared in Example 3 of the present invention;

Fig. 6 is the ¹³ C NMR spectrum of hypervalent iodine trifluoromethanesulfonate 2,4,6-trimethylphenyl gemfibrozil methyl ester prepared in Example 3 of the present invention;

Fig. 7 is the ¹ H NMR spectrum of 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine prepared in Example 4 of the present invention;

Fig. 8 is the ¹³ C NMR spectrum of 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine prepared in Example 4 of the present invention;

Fig. 9 is the ¹ H NMR spectrum of hypervalent iodine trifluoromethanesulfonate phenyl gemfibrozil prepared in Example 5 of the present invention;

Figure 10 is the ¹³ C NMR spectrum of hypervalent iodine trifluoromethanesulfonate phenylgemfibrozil prepared in Example 5 of the present invention;

Figure 11 is the ¹ H NMR spectrum of gemfibrozil methyl ester fluoride prepared in Example 6 of the present invention;

Figure 12 is the ¹³ C NMR spectrum of gemfibrozil methyl ester fluoride prepared in Example 6 of the present invention;

Figure 13 is the ¹⁹ F spectrum of gemfibrozil methyl ester fluoride prepared in Example 6 of the present invention;

Figure 14 is the ¹ H NMR of gemfibrozil methyl p-toluate prepared in Example 7 of the present invention;

Fig. 15 is the ¹³ C NMR spectrum of gemfibrozil methyl p-toluate prepared in Example 7 of the present invention.

Detailed ways

In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific examples.

Example 1

The preparation of phenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate described in this embodiment comprises the following steps:

(1) In a 100 mL round bottom flask, add 10 mmol of hydroxy(p-toluenesulfonyloxy)iodobenzene into a mixed solution of 30 mL of dichloromethane and 5 mL of 2,2,2-trifluoroethanol, then Add 10 mmol gemfibrozil methyl ester compound, then add 10 mmol trimethylsilyl trifluoromethanesulfonate dropwise, then react at room temperature for 1 h;

(2) After the reaction was completed, the solvent was distilled off under reduced pressure, and 70 mL of diethyl ether was added to precipitate to obtain hypervalent iodine trifluoromethanesulfonate as a white solid with a yield of 83%.

Fig. 1 is the ¹ H NMR of hypervalent iodine trifluoromethanesulfonate of phenyl gemfibrozil methyl ester prepared in Example 1 of the present invention, and Fig. 2 is the phenyl gemfibrozil methyl ester trifluoromethane sulfonate prepared in Example 1 of the present invention ¹³ C NMR spectrum of hypervalent iodine methanesulfonate. It can be seen from the NMR spectra of Figures 1 and 2 that the NMR peaks of hypervalent iodine trifluoromethanesulfonate phenylgemfibrozil methyl ester: ¹ H NMR (400MHz, 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. It shows that Example 1 of the present invention successfully prepared hypervalent iodine trifluoromethanesulfonate phenyl gemfibrozil methyl ester.

The structural formula of phenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate is:

Example 2

The preparation of 4-methylphenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate described in this embodiment comprises the following steps:

(1) In a 100 mL round bottom flask, dissolve 10 mmol 4-methyliodobenzene in 40 mL methylene chloride, add 10 mmol m-chloroperoxybenzoic acid and then 10 mmol p-toluenesulfonate under stirring condition Acid monohydrate, stirred at room temperature for 1 h, after the reaction was completed, spin the solvent dry, add 70 mL of ether, stir well for 30 minutes to produce a precipitate, filter and dry in vacuum to obtain hydroxyl (p-toluenesulfonyloxy) 4-methyliodobenzene, the yield is 98%;

(2) In a 100 mL round bottom flask, add 8 mmol of hydroxy(p-toluenesulfonyloxy)4-methyliodobenzene in step (1) to 25 mL of dichloromethane and 4 mL of 2,2,2- In the mixed solution of trifluoroethanol, add 8 mmol gemfibrozil methyl ester compound subsequently, then add 8 mmol trimethylsilyl trifluoromethanesulfonate dropwise, then react at room temperature for 1h;

(3) Step (2) After the reaction was completed, the solvent was distilled off under reduced pressure, and 70 mL of diethyl ether was added to precipitate to obtain white solid 4-methylphenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate, with a total yield of 79% .

Fig. 3 is the hypervalent iodine ¹ H NMR spectrum of 4-methylphenyl gemfibrozil methyl trifluoromethanesulfonate prepared in Example 2 of the present invention, and Fig. 4 is the 4-methylphenyl prepared in Example 2 of the present invention Gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate ¹³ C NMR spectrum, as can be seen from the nuclear magnetic spectrum of Figure 3 and 4, 4-methylphenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate NMR peaks: 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, 113.40, 105.66, 51.93, 42.16, 42.16 , 36.95, 25.79, 25.29, 24.96, 21.42, 15.72. It shows that Example 2 of the present invention successfully prepared hypervalent iodine trifluoromethanesulfonate 4-methylphenyl gemfibrozil methyl ester.

The structural formula of 4-methylphenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate is:

Example 3

The preparation of hypervalent iodine trifluoromethanesulfonate 2,4,6-trimethylphenyl gemfibrozil methyl ester described in this example comprises the following steps:

(1) In a 250 mL round bottom flask, dissolve 10 mmol of iodine in 100 mL of dichloromethane, add 20 mmol of mesitylene under stirring, then add 30 mmol of m-chloroperoxybenzoic acid and 20 mmol of p-toluene Sulfonic acid monohydrate was reacted at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried, and 150 mL of diethyl ether was added, and stirred thoroughly for 30 minutes to produce a precipitate, which was filtered and dried in vacuum, and the obtained hydroxyl group (p-toluenesulfonyl Oxygen)-trimethyliodobenzene, the yield is 97%;

(2) In a 100 mL round-bottomed flask, add 8 mmol of hydroxy(p-toluenesulfonyloxy)-trimethyliodobenzene obtained in step (1) into 25 mL of dichloromethane and 3 mL of 2,2,2- In the mixed solution of trifluoroethanol, add 8 mmol gemfibrozil methyl ester compounds subsequently, then add 8 mmol trimethylsilyl trifluoromethanesulfonate dropwise, then react at room temperature for 1 hour;

(3) After the reaction in step (2) was completed, the solvent was distilled off under reduced pressure, and 70 mL of ether was added to precipitate to obtain white solid 2,4,6-trimethylphenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate, total Yield 54%.

Fig. 5 is the hypervalent iodine ¹ H NMR spectrum of 2,4,6-trimethylphenyl gemfibrozil methyl trifluoromethanesulfonate prepared in Example 3 of the present invention, and Fig. 6 is 2 prepared in Example 3 of the present invention. , 4,6-trimethylphenyl gemfibrozil methyl trifluoromethanesulfonic acid hypervalent iodine ¹³ C NMR spectrum, as can be seen from the nuclear magnetic spectrum in Figures 5 and 6, 2,4,6-trimethyl NMR peaks of phenylgemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate: 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, 311.84, 3 68.62, 51.92, 42.15, 36.95, 26.97, 25.28, 24.95, 21.13, 15.91. It shows that Example 3 of the present invention successfully prepared hypervalent iodine trifluoromethanesulfonate 2,4,6-trimethylphenyl gemfibrozil methyl ester.

The structural formula of hypervalent iodine trifluoromethanesulfonate 2,4,6-trimethylphenyl gemfibrozil methyl ester is:

Example 4

The preparation of 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine described in this embodiment comprises the following steps:

(1) In a 100 mL sealed tube, add 10 mmol p-iodoanisole, 11 mmol sodium periodate, 20 mmol sodium acetate, 15 mL acetic acid and 1.5 mL acetic anhydride, heat to 120°C, react for 3 hours, and react After completion, add water for treatment, then add dichloromethane for extraction three times, collect the organic phase, dry it with anhydrous sodium sulfate, spin dry under reduced pressure to obtain an oily substance, and finally add n-hexane to the oily substance, sonicate for 30 minutes, and filter to obtain iodine diacetate p-methoxybenzene, the productive rate is 92%;

(2) In a 100 mL round bottom flask, add 30 mL of hexafluoroisopropanol and 8.5 mmol of gemfibrozil methyl ester, then add 8.5 mmol of iodo-p-methoxybenzene diacetate, cool to 0°C, and drop by drop under stirring Add 8.5 mmol trimethylchlorosilane and react at room temperature for 1 h;

(3) After the reaction was completed, the solvent was distilled off under reduced pressure, and diethyl ether was added to precipitate to obtain a pink solid 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine compound, with a total yield of 59%.

Figures 7 and 8 are respectively hypervalent iodine ¹ H NMR and ¹³ C NMR spectra of 4-methoxyphenyl gemfibrozil methyl ester chloride prepared in Example 4 of the present invention, as can be seen from the NMR spectra of Figures 7 and 8 , 4-Methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine NMR peaks: 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. It shows that Example 4 of the present invention successfully prepared 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine.

The structural formula of 4-methoxyphenyl gemfibrozil methyl ester chlorine hypervalent iodine is:

Example 5

The preparation of hypervalent iodine trifluoromethanesulfonate phenyl gemfibrozil described in this embodiment comprises the following steps:

(1) In a 100 mL round bottom flask, add 10 mmol of hydroxy(p-toluenesulfonyloxy)iodobenzene into a mixed solution of 30 mL of dichloromethane and 5 mL of 2,2,2-trifluoroethanol, and then add 10 mmol gemfibrozil, then dropwise added 10 mmol trimethylsilyl trifluoromethanesulfonate, then reacted at room temperature for 1 h;

(2) After the reaction was completed, the solvent was distilled off under reduced pressure, and 70 mL of diethyl ether was added to precipitate to obtain hypervalent iodine phenyl gemfibrozil trifluoromethanesulfonate as a white solid with a yield of 89%.

Figures 9 and 10 are respectively the ¹ H NMR and ¹³ C NMR spectra of hypervalent iodine trifluoromethanesulfonate phenyl gemfibrozil prepared in Example 5 of the present invention. As can be seen from the NMR spectra of Figures 9 and 10, benzene NMR peaks of hypervalent iodine trifluoromethanesulfonate: 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-d6): δ 178.70, 159.89, 140.48, 138.33, 134.66, 131.76, 127.42, 122.34, 116.01, 113.837, 108.2 , 36.34, 24.94, 24.50, 15.16. It shows that Example 5 of the present invention successfully prepared hypervalent iodine trifluoromethanesulfonate phenyl gemfibrozil.

The structural formula of phenyl gemfibrozil methyl ester hypervalent iodine trifluoromethanesulfonate is:

Example 6

The preparation of gemfibrozil methyl fluoride described in the present embodiment comprises the following steps:

Add 0.4 mmol copper difluoride, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 18-crown-6 and 0.2 mmol 4-methoxyphenyl gemfibrox to a 25 mL sealed tube under nitrogen protection Add 2 mL of dry dimethylformamide and stir at 85°C for 10 h. After the reaction is completed, treat with saturated potassium bicarbonate aqueous solution, then add dichloromethane, wash the organic phase with water three times, and use After drying over anhydrous sodium sulfate, the mixture was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 40:1) to obtain a colorless transparent liquid with an isolation yield of 69%.

Figures 11, 12 and 13 are ¹ H NMR, ¹³ C NMR and ¹⁹ F NMR of gemfibrozil methyl ester fluoride prepared in Example 6 of the present invention, respectively. From the NMR spectra in Figures 11, 12 and 13, it can be seen that the NMR peaks of gemfibrozil methyl fluoride: ¹ HNMR (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 ): δ178.36, 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, CDCl3) δ -128.95 (s, 1F). It shows that embodiment 9 of the present invention successfully prepared gemfibrozil methyl ester fluoride.

The structural formula of gemfibrozil methyl fluoride is:

Example 7

The preparation of the reaction of gemfibrozil methyl p-toluate described in the present embodiment comprises the following steps:

In a sealed 25 mL tube, under nitrogen atmosphere, add 0.22 mmol potassium tert-butoxide and 2 mL dry toluene, keep stirring vigorously, then add 0.22 mmol p-toluic acid and 0.2 mmol 4-methoxyphenyl gemfibrozil Methyl chloride hypervalent iodine, react at 130°C for 3 hours, after the reaction is completed, add water and transfer to a separatory funnel, extract with dichloromethane, wash with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, and pass the reaction mixture through Silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1) was separated and purified to obtain a colorless transparent liquid with an isolation yield of 77%.

Figures 14 and 15 are respectively ¹ H NMR and ¹³ CNMR spectra of gemfibrozil methyl p-toluate prepared in Example 7 of the present invention, as can be seen from the NMR spectra of Figures 14 and 15, p-toluate NMR peaks of gemfibrozil methyl ester: ¹ HNMR (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 CNMR (101 MHz, CDCl ₃ ): δ 178.41, 165.52, 154.87, 144.32, 142.41, 130.27, 129.37, 127.87, 1215.03.8, 9 , 113.37, 68.49, 51.88, 42.21, 37.22, 25.32, 21.86, 16.38, 15.94. It shows that the embodiment 7 of the present invention successfully prepares methyl gemfibrozil p-toluate.

The structural formula of gemfibrozil methyl p-toluate is:

The above embodiments are only used to illustrate the technical solution of the present invention rather than limiting the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solution of the present invention can be carried out Modification or equivalent replacement without departing from the spirit and scope of the technical solution 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):

（I）

in the formula (I), X is chlorine, bromine, iodine or trifluoromethanesulfonyl;

r is alkyl;

ar is selected from

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):

（1）；

the structural formula of the aryl iododiacetic acid compound is shown as the formula (2):

（2）；

the reaction formula is shown as follows:

or

；

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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