阅读说明：本技术 一种含手性亚砜的苯乙烯单体的制备方法 (Preparation method of styrene monomer containing chiral sulfoxide ) 是由 董志兵 徐小虎 于 2020-12-31 设计创作，主要内容包括：本发明公开了一种含手性亚砜的苯乙烯单体的制备方法,双缩酮葡萄糖与甲基亚磺酰氯在有机溶剂中于-78℃下搅拌反应1～3小时,用水淬灭反应,用二氯甲烷萃取有机相,有机相先后用稀盐酸和碳酸氢钠水溶液进行洗涤,再用无水硫酸钠干燥有机相,最后分离得到含手性亚砜取代的双缩酮葡萄糖；将含手性亚砜的双缩酮葡萄糖和(4-乙烯基苯基)氯化镁格氏试剂在甲苯中低温反应1～3小时,用饱和氯化铵淬灭,用二氯甲烷萃取有机相,干燥分离有机相即得含手性亚砜的1-(甲基亚磺酰基)-4-乙烯基苯高分子单体,本方法制备工艺简单,成本低,速度快、易操作,所得产品的ee值最高可达98％。(The invention discloses a preparation method of a styrene monomer containing chiral sulfoxide, which comprises the steps of stirring and reacting bis-ketal glucose and methyl sulfinyl chloride in an organic solvent at-78 ℃ for 1-3 hours, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing the organic phase by using dilute hydrochloric acid and sodium bicarbonate aqueous solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and finally separating to obtain the bis-ketal glucose containing chiral sulfoxide substitution; reacting bis-ketal glucose containing chiral sulfoxide and (4-vinyl phenyl) magnesium chloride Grignard reagent in toluene at low temperature for 1-3 hours, quenching with saturated ammonium chloride, extracting an organic phase with dichloromethane, drying and separating the organic phase to obtain the 1- (methyl sulfinyl) -4-vinyl benzene high molecular monomer containing chiral sulfoxide.)

1. A preparation method of a styrene monomer containing chiral sulfoxide is characterized by comprising the following steps:

stirring and reacting the bisketal glucose and methylsulfinylchloride in an organic solvent at-78 ℃ for 1-3 hours; after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing the organic phase by using dilute hydrochloric acid with the mass fraction of 5% and a sodium bicarbonate aqueous solution with the mass fraction of 2%, drying the organic phase by using anhydrous sodium sulfate, concentrating the organic phase, and separating by using column chromatography to obtain the bisketal glucose containing chiral sulfoxide substitution; reacting bis-ketal glucose containing chiral sulfoxide and (4-vinylphenyl) magnesium chloride Grignard reagent in toluene at a low temperature of 0-5 ℃ for 1-3 hours, quenching with saturated ammonium chloride, extracting an organic phase with dichloromethane, and drying and separating the organic phase to obtain a 1- (methylsulfinyl) -4-vinylbenzene macromolecular monomer containing chiral sulfoxide;

wherein, the structural formula of the styrene monomer containing the chiral sulfoxide is as follows:

the structural formula of the bisketal glucose is as follows:

the structural formula of the methyl sulfinyl chloride is as follows:

the structural formula of the bisketal glucose containing chiral methyl sulfoxide substitution is as follows:

the structural formula of the (4-vinyl phenyl) magnesium chloride Grignard reagent is as follows:

2. the method for preparing a styrene monomer containing chiral sulfoxide according to claim 1, wherein: the organic solvent is a mixed solvent of pyridine/tetrahydrofuran and toluene/diisopropylethylamine.

3. The method for preparing a styrene monomer containing chiral sulfoxide according to claim 1, wherein: the molar ratio of the diacetone glucose to the methyl sulfinyl chloride is 1: 1-3.

4. The method for preparing a styrene monomer containing chiral sulfoxide according to claim 1, wherein: the molar ratio of the glucose compound containing the chiral sulfoxide to the (4-vinyl phenyl) magnesium chloride Grignard reagent is 1: 1.5-3.

5. The method for preparing a styrene monomer containing chiral sulfoxide according to claim 1, wherein: and stirring and reacting the bisketal glucose and methylsulfinylchloride in a tetrahydrofuran/pyridine mixed organic solvent at-78 ℃ for 1-3 hours. And after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing by using dilute hydrochloric acid and dilute sodium bicarbonate aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and finally separating to obtain the R-configuration glucose containing the chiral methyl sulfoxide substituted bisketal.

6. The method for preparing a styrene monomer containing chiral methyl sulfoxide according to claim 1, wherein: stirring and reacting the bisketal glucose and methylsulfinylchloride in a mixed organic solvent of toluene/diisopropylethylamine at-78 ℃ for 1-3 hours; and after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing by using dilute hydrochloric acid and dilute sodium bicarbonate aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and finally separating to obtain the chiral methyl sulfoxide substituted bisketal glucose with the S configuration.

7. The method for preparing a styrene monomer containing chiral methyl sulfoxide according to claim 6-7, wherein: reacting the R-type or S-type chiral sulfoxide substituted bis-ketal glucose with a (4-vinylphenyl) magnesium chloride Grignard reagent in toluene at a low temperature of 0-5 ℃ for 1-3 hours, quenching with saturated ammonium chloride, performing subsequent treatment, and separating by column chromatography to obtain the chiral sulfoxide-containing 1- (methylsulfinyl) -4-vinylbenzene high-molecular monomer.

Technical Field

The invention relates to the technical field of preparation of neutral coordination organic catalysts, in particular to a preparation method for synthesizing a styrene monomer containing chiral methyl sulfoxide by two steps by taking bis-ketal glucose and methyl thionyl chloride as raw materials.

Background

Neutral coordination organic catalysts generally employ uncharged Lewis bases such as N, N-dimethylformamide, pyridine nitroxide, phosphoramide (HMPA), phosphine oxide and sulfoxide. Among them, chiral sulfoxide catalysts are widely used in asymmetric catalytic synthesis of some molecules with important pharmaceutical activities, but in many asymmetric catalysis, chiral sulfoxide catalysts need to use chemical dose (1-3 times equivalent), and are unrecoverable, and have low use efficiency and a certain burden on the environment. In view of this background, there is a need for the preparation of a chiral sulfoxide that can be copolymerized to be supported on a polymer backbone, i.e., a styrene monomer containing a chiral sulfoxide.

Disclosure of Invention

Based on the defects of the prior art, the technical problem solved by the invention is to provide a low-cost, fast and efficient method for preparing styrene monomers containing chiral methyl sulfoxide, wherein the monomers can be copolymerized into various chiral sulfoxide-containing polymers in future, and the chiral sulfoxide-containing polymers can be used as chiral sulfoxide neutral ligand organic catalysts which can be repeatedly used and can also be loaded in microchannels to realize efficient mobile phase reaction.

In order to solve the above technical problems, the present invention provides a method for preparing a styrene monomer containing chiral sulfoxide, comprising the following steps:

stirring and reacting the bisketal glucose and methylsulfinylchloride in an organic solvent at-78 ℃ for 1-3 hours; after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing the organic phase by using dilute hydrochloric acid with the mass fraction of 5% and a sodium bicarbonate aqueous solution with the mass fraction of 2%, drying the organic phase by using anhydrous sodium sulfate, concentrating the organic phase, and performing column chromatography separation to obtain the bisketal glucose containing chiral sulfoxide substitution; reacting bis-ketal glucose containing chiral sulfoxide and (4-vinylphenyl) magnesium chloride Grignard reagent in toluene at a low temperature of 0-5 ℃ for 1-3 hours, quenching with saturated ammonium chloride, extracting an organic phase with dichloromethane, and drying and separating the organic phase to obtain a 1- (methylsulfinyl) -4-vinylbenzene macromolecular monomer containing chiral sulfoxide;

wherein, the structural formula of the styrene monomer containing the chiral sulfoxide is shown as follows (wherein, the sulfoxide can be R type or S type):

the structural formula of the bisketal glucose is as follows:

the structural formula of the methyl sulfinyl chloride is as follows:

the structural formula of the bisketal glucose containing chiral methyl sulfoxide substitution is as follows:

the structural formula of the (4-vinyl phenyl) magnesium chloride Grignard reagent is as follows:

as a preferred aspect of the above technical solution, the preparation method of the styrene monomer containing chiral sulfoxide provided by the present invention further includes part or all of the following technical features:

as an improvement of the technical scheme, the organic solvent is a mixed solvent of pyridine/tetrahydrofuran and toluene/diisopropylethylamine.

As an improvement of the technical scheme, the molar ratio of the diacetone glucose to the methyl sulfenyl chloride is 1: 1-3.

As an improvement of the technical scheme, the molar ratio of the chiral sulfoxide-containing glucose compound to the (4-vinylphenyl) magnesium chloride Grignard reagent is 1: 1.5-3.

As an improvement of the technical scheme, the bis-ketal glucose and the methylsulfinylchloride are stirred and reacted for 1 to 3 hours in a tetrahydrofuran/pyridine mixed organic solvent at a temperature of minus 78 ℃. And after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing by using dilute hydrochloric acid and dilute sodium bicarbonate aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and finally separating to obtain the R-configuration glucose containing the chiral methyl sulfoxide substituted bisketal.

As an improvement of the technical scheme, the bis-ketal glucose and the methylsulfinylchloride are stirred and reacted for 1 to 3 hours at a temperature of minus 78 ℃ in a mixed organic solvent of toluene/diisopropylethylamine; and after the reaction is finished, quenching the reaction by using water, extracting an organic phase by using dichloromethane, washing by using dilute hydrochloric acid and dilute sodium bicarbonate aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and finally separating to obtain the chiral methyl sulfoxide substituted bisketal glucose with the S configuration.

As an improvement of the technical scheme, the R-type or S-type chiral sulfoxide substituted bis-ketal glucose and the (4-vinylphenyl) magnesium chloride Grignard reagent react in toluene at a low temperature of 0-5 ℃ for 1-3 hours, are quenched by saturated ammonium chloride and subjected to subsequent treatment, and then the 1- (methylsulfinyl) -4-vinylbenzene high molecular monomer containing the chiral sulfoxide (the highest ee value can reach 98%) is obtained through column chromatographic separation.

Compared with the prior art, the technical scheme of the invention has the following beneficial effects: the method for synthesizing the styrene monomer containing the chiral methyl sulfoxide (R type and S type) by using the bis-ketal glucose and the methylsulfonyl chloride as raw materials has the advantages of easily available raw materials, short synthetic route, simple process operation, easy industrial production, low production cost and higher ee value (the highest ee value can reach 98 percent) of the obtained chiral methyl sulfoxide.

1. The sulfoxide synthesis scheme of the conventional process usually uses a strong oxidant and has low yield. Importantly, no literature report on the scheme for synthesizing the styrene monomer containing chiral methyl sulfoxide is found.

2. The preparation process of the styrene monomer containing chiral methyl sulfoxide adopts bisketal glucose and methyl sulfinyl chloride as raw materials, and can obtain R-type or S-type chiral sulfoxide substituted bisketal glucose by reacting in conventional pyridine/tetrahydrofuran or toluene/diisopropylethylamine and other organic solvents, and the subsequent reaction with a (4-vinyl phenyl) magnesium chloride Grignard reagent prepared on site can efficiently obtain the 1- (methyl sulfinyl) -4-vinyl benzene high molecular monomer containing chiral sulfoxide (the highest ee value can reach 98%). The method has the advantages of cheap and easily-obtained raw materials, simple and convenient operation, excellent yield and high ee value of the obtained chiral sulfoxide. The monomers can be copolymerized into various chiral sulfoxide-containing polymers in future, and the chiral sulfoxide-containing polymers can be used as a reusable chiral sulfoxide neutral ligand organic catalyst and can also be loaded in a microchannel to realize efficient fluid phase reaction, so that the method has important academic value and application prospect.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.

FIG. 1 shows the synthesis of R-configuration styrene monomer containing chiral methyl sulfoxide in example 1 of the invention¹H NMR characterization spectrum;

FIG. 2 shows the synthesis of R-configuration styrene monomer containing chiral methyl sulfoxide in example 1¹³C NMR characterization spectrum;

FIG. 3 shows the synthesis of S-configuration chiral methyl sulfoxide-containing styrene monomer in example 2 of the invention¹H NMR characterization spectrum;

FIG. 4 shows the S-configuration chiral methyl sulfoxide-containing styrene monomer synthesized in example 2 of the invention¹³C NMR characterization spectrum.

Detailed Description

Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.

EXAMPLE 1 Synthesis of R-configuration chiral methyl sulfoxide-containing styrene monomer

The bisketal glucose (12mmol) and pyridine (14mmol) are added into a reaction bottle, 10mL of tetrahydrofuran is added, the mixed solution is cooled to-78 ℃, methyl thionyl chloride (30mmol) dissolved in 15mL of tetrahydrofuran is slowly added dropwise into the reaction solution, the mixed solution reacts for 2 hours at-78 ℃, and then the reaction solution slowly rises to room temperature. After the reaction was completed, the reaction was quenched with water, the organic phase was extracted with dichloromethane, washed with hydrochloric acid (5%) and sodium bicarbonate (2%), and dried over anhydrous sodium sulfate to give a white solid R-configuration chiral sulfoxide substituted bisketal glucose. To a reaction flask which had been dried in advance and filled with nitrogen (or argon), 5mL of toluene was added, the mixture was cooled to 0 ℃, and then the chiral sulfoxide-substituted bisketal glucose (5mmol) in the R configuration described above was added, and then (4-vinylphenyl) magnesium chloride Grignard reagent (10mmol) was slowly added dropwise to the reaction solution, and the progress of the reaction was monitored by gas chromatography, and after about 1 hour, the exchange reaction was terminated. Then slowly heating the reaction liquid to room temperature, quenching the reaction by using saturated ammonium chloride, extracting an organic phase by using dichloromethane, drying the organic phase by using anhydrous magnesium sulfate, and concentrating the organic phase to obtain 0.32g (colorless oily liquid) of the chiral sulfoxide-containing (R) -1- (methylsulfinyl) -4-vinyl benzene high-molecular monomer, wherein the yield is 40%, ee: 98% and the purity is more than or equal to 95%. FIG. 1 shows the synthesis of R-configuration styrene monomer containing chiral methyl sulfoxide in example 1 of the invention¹H NMR characterization spectrum; FIG. 2 shows the synthesis of R-configuration styrene monomer containing chiral methyl sulfoxide in example 1¹³C NMR characterization spectrum.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.62-7.55(m,4H),6.79-6.72(m,1H),5.86(d,J＝20.0Hz,1H),5.38(d,J＝8.0Hz,1H),2.74(d,J＝4.0Hz,3H).

¹³C NMR(151MHz,CDCl₃):δ(ppm)144.7,140.4,135.6,127.0,123.8,116.2,43.9.

HRMS(ESI)Calcd for C₉H₁₀OS(166.0452),found:166.0450.

Example 2 Synthesis of S-configuration chiral methyl sulfoxide-containing styrene monomer

The bisketal glucose (20mmol) and diisopropylethylamine (24mmol) were added to a reaction flask, 24mL of toluene was added, the mixture was cooled to-78 deg.C, methyl thionyl chloride (50mmol) dissolved in 14mL of toluene was slowly added dropwise to the reaction solution, the mixture was reacted at-78 deg.C for 3 hours, and then the reaction solution was slowly warmed to room temperature. After the reaction was completed, the reaction was quenched with water, the organic phase was extracted with dichloromethane, washed with hydrochloric acid (5%) and sodium bicarbonate (2%), and dried over anhydrous sodium sulfate to give a white solid, S-configuration, chiral methyl sulfoxide substituted bisketal glucose. To a reaction flask which had been dried in advance and filled with nitrogen (or argon), 7mL of toluene was added, the mixture was cooled to 0 ℃, followed by addition of the chiral methylsulfoxide-substituted bisketal glucose (7mmol) having the S configuration described above, and then (4-vinylphenyl) magnesium chloride Grignard reagent (14mmol) was slowly added dropwise to the reaction solution, and the progress of the reaction was monitored by gas chromatography, and after about 1 hour, the exchange reaction was terminated. Then slowly raising the reaction liquid to room temperature, quenching the reaction by using saturated ammonium chloride, extracting an organic phase by using ethyl acetate, drying the organic phase by using anhydrous magnesium sulfate, and concentrating the organic phase to obtain 2.47g (colorless oily liquid) of the (S) -1- (methylsulfinyl) -4-vinyl benzene high-molecular monomer containing the chiral methyl sulfoxide, wherein the yield is 54%, ee: 94% and the purity is more than or equal to 95%. FIG. 3 shows the synthesis of S-configuration chiral methyl sulfoxide-containing styrene monomer in example 2 of the invention¹H NMR characterization spectrum; FIG. 4 shows the S-configuration chiral methyl sulfoxide-containing styrene monomer synthesized in example 2 of the invention¹³C NMR characterization spectrum.

¹H NMR(500MHz,CDCl₃):δ(ppm)7.62-7.55(m,4H),6.78-6.72(m,1H),5.86(d,J＝15Hz,1H),5.38(d,J＝10Hz,1H),2.73(s,3H).

¹³C NMR(151MHz,CDCl₃):δ(ppm)144.7,140.4,135.6,127.0,123.8,116.2,43.9.

HRMS(ESI)Calcd for C₉H₁₀OS(166.0452),found:166.0454.

The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.

While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.