Phosphoric acid compound as well as preparation method and application thereof

Abstract

The invention discloses a phosphoric acid compound and a preparation method and application thereof.The framework of the phosphoric acid compound has the strong resistance to rotation isomerization, meanwhile, R groups adjacent to a P-O bond can be adjusted by changing the positions of substituent groups in raw materials, so that the resistance to rotation energy barrier and optical characteristics of phosphoramidite are further enhanced, and the stability of the phosphoric acid compound is improved. Therefore, when being used as a catalyst to be applied to asymmetric catalytic reaction, the compound shows excellent enantioselectivity, and the reaction yield is effectively improved. Meanwhile, the phosphoric acid compound is simple in synthetic reaction and mild in reaction condition, a large steric hindrance group can be more conveniently introduced to the ortho-position of a P-O bond, and the phosphoric acid compound has wide popularization value.

Description

Technical Field

[0001] The present invention relates to the field of asymmetric catalysis, and in particular to a phosphoric acid compound and a preparation method and application thereof. Background Art

[0002] Asymmetric catalysis is an important means of obtaining chiral compounds, with chiral catalysts playing a key role. Small organic molecule catalysts have attracted widespread attention because they can avoid the metal residue issues associated with traditional metal complex catalysts in asymmetric catalytic reactions. Phosphoric acid, a new class of green small organic molecule catalysts, has demonstrated excellent catalytic activity and chiral induction capabilities in a variety of asymmetric reactions over the past two decades.

[0003] In the prior art, phosphoric acids used for asymmetric catalysis are primarily based on spirocyclic and binaphthol structures. For example, patent CN109535018B discloses a method for catalyzing the synthesis of binaphtholamines using phosphoric acids with spirocyclic and binaphthol skeletons. Patent CN111233932B discloses a phosphoric acid with a spirodihydroindane skeleton for use in the asymmetric reaction of 2-nitrosonaphthalene with 7-methoxy-2-naphthol. These phosphoric acids based on spirocyclic and binaphthol structures have more complex skeleton preparation processes and more stringent reaction conditions. Furthermore, when used in asymmetric catalytic reactions, existing phosphoric acids have poor atropisomerism, leaving the yield of asymmetric catalytic reactions to be further improved.

[0004] Therefore, it is necessary to develop phosphoric acid with a novel skeleton to further improve the atropisomerism of phosphoric acid and help explore more categories of catalytic reactions. Summary of the Invention

[0005] One object of the present invention is to provide a phosphate compound having a skeleton with stronger atropisomerism, a higher atropisomer energy barrier, and superior optical properties, so that this type of phosphate compound can be used as a catalyst to improve the yield of the [3+3] cycloaddition reaction; in addition, this type of compound has a simple synthesis route and mild reaction conditions, which helps to reduce synthesis costs and has good prospects for industrial scale-up application.

[0006] The present invention is achieved through the following technical solutions:

[0007] A phosphoric acid compound having the structure of Formula I:

[0008]

[0009] Wherein, R is H, C1-C6 alkyl, or C6-C 12 of aromatic groups.

[0010] In this technical solution, when the group R is H, there is no ortho substituent on the benzene ring of the OP bond. In some embodiments, R can also be selected from C1 to C6 alkyl or C6 to C 12 The aromatic group is added, thereby setting a substituent located at the ortho position of the OP bond on the benzene ring of the skeleton to further improve the anti-transfer energy barrier and optical properties of the phosphate compound.

[0011] In the present technical solution, the group R can be a C1-C6 alkyl group, and the alkyl group can be a chain alkyl group, such as ethyl, n-butyl, or a cyclic alkyl group, such as cyclohexyl. Further, the group R can be a straight-chain alkyl group or a branched-chain alkyl group. In one or more embodiments, R can be a methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl group. In some preferred embodiments, the group R is a C1-C6 straight-chain alkyl group, for example, R can be a methyl, ethyl, or n-hexyl group; the group R can also be a C1-C4 branched-chain alkyl group. In a preferred embodiment, R is a C3-C4 branched-chain alkyl group, for example, R can be isopropyl, tert-butyl, or isobutyl.

[0012] In the present technical solution, the R group can also be a substituted or unsubstituted aryl group. In one or more embodiments, the aryl group can be either a monocyclic aryl group or a condensed ring aryl group. The number of carbon atoms of the aryl group is C6 to C 12 In some embodiments, the aryl group is a phenyl group or a naphthyl group. In some preferred embodiments, R is a phenyl group. In the present technical solution, the aryl group can be an unsubstituted aryl group or a substituted aryl group, such as a monosubstituted or disubstituted aryl group. In some preferred embodiments, R is a substituted phenyl group. In one or more embodiments, the substituent of the phenyl group can be a C1-C4 alkyl group, such as a monosubstituted or disubstituted methyl group, ethyl group, tert-butyl group, etc.

[0013] In this technical solution, the skeleton of the phosphate compound has strong atropisomerism. At the same time, the R group adjacent to the PO bond can be adjusted by changing the position of the substituent in the raw material to further enhance the atropisomerism energy barrier and optical properties of the phosphoramidite. Thus, when used as a catalyst in an asymmetric catalytic reaction, it exhibits excellent enantioselectivity and effectively improves the reaction yield.

[0014] As a preferred embodiment of the phosphate compound of the present invention, the phosphate compound has any one of the following structural formulas:

[0015]

[0016] Furthermore, the phosphate compound is a racemate, a levorotatory enantiomer or a dextrorotatory enantiomer.

[0017] Another object of the present invention is to provide a method for preparing a phosphoric acid compound, which is used to prepare any of the aforementioned phosphoric acid compounds, comprising the following steps:

[0018] Under an inert atmosphere, phosphorus oxychloride is added dropwise to the compound of formula II at room temperature, the reaction solution is reacted at 40-70° C., then cooled to room temperature, and water is added to the reaction solution at room temperature, and then the reaction is further carried out at 40-70° C. to obtain the phosphoric acid compound;

[0019]

[0020] In this technical solution, the phosphoric acid compound can be prepared by reacting the compound of formula II with phosphorus oxychloride, and its synthesis path is:

[0021] In this technical solution, the inert atmosphere can be nitrogen or argon. In some preferred embodiments, phosphorus oxychloride is added dropwise to the compound of Formula II at room temperature. After the addition is complete, the reaction solution is reacted at 40-70°C for 8-16 hours, cooled to room temperature, and water is added. The reaction is then continued at 40-70°C to obtain a phosphoric acid compound. In one or more embodiments, after the reaction is completed, the reaction solution is adjusted to a weak acidic state, the aqueous phase is extracted, dried and filtered, and low-boiling point compounds are removed under reduced pressure to obtain a crude product, which is then purified to obtain a phosphoric acid compound.

[0022] In the present technical solution, the phosphate compound prepared based on the compound of formula II can utilize the skeleton characteristics of the compound of formula II to make the phosphate compound have strong atropisomerism. At the same time, large steric hindering groups such as tert-butyl and phenyl groups at the ortho position of the PO bond can be simply introduced through the compound of formula II. The reaction is simple and the reaction conditions are mild. After the introduction of the large steric hindering group, the atropisomerism energy barrier and optical properties of the phosphate compound can be further enhanced, and the yield and ee value of the reaction in the catalytic [3+3] cycloaddition reaction are greatly improved, which has broad promotion value.

[0023] Another object of the present invention is to provide a use of any of the aforementioned phosphoric acid compounds in catalyzing a [3+3] cycloaddition reaction.

[0024] In some preferred embodiments, the [3+3] cycloaddition reaction comprises the following steps:

[0025] The compound of formula III, the compound of formula IV, a solvent and a phosphoric acid compound are mixed, and the reaction system is refluxed to obtain a compound of formula V:

[0026]

[0027] Among them, R 1 、R 2 The groups are independently selected from substituted or unsubstituted aryl groups.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0029] 1. The phosphate compound skeleton of the present invention has strong atropisomerism. At the same time, the R group adjacent to the PO bond can be adjusted by changing the position of the substituent in the raw material to further enhance the atropisomerism energy barrier and optical properties of the phosphoramidite. Thus, when used as a catalyst in an asymmetric catalytic reaction, it exhibits excellent enantioselectivity and effectively improves the reaction yield.

[0030] 2. The phosphate compound prepared based on the compound of formula II of the present invention can utilize the skeleton characteristics of the compound of formula II to make the phosphate compound have strong atropisomerism. At the same time, large steric groups such as tert-butyl and phenyl groups at the ortho position of the PO bond can be simply introduced through the compound of formula II. The reaction is simple and the reaction conditions are mild. After the introduction of the large steric group, the atropisomerism energy barrier and optical properties of the phosphate compound can be further enhanced, and the yield and ee value of the reaction in the catalytic [3+3] cycloaddition reaction are greatly improved, which has broad promotion value. DETAILED DESCRIPTION

[0031] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with examples. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not intended to limit the present invention.

[0032] All raw materials in the present invention are not particularly limited in their sources and can be purchased commercially or prepared according to conventional methods known to those skilled in the art. The compound represented by structural formula II can be synthesized according to the method reported in [J] Tetrahedron, 2011, 67, 3685-3689. All raw materials in the present invention are not particularly limited in their purity; however, analytically pure or conventional purity requirements in the chemical industry are preferably used.

[0033] All raw materials of the present invention, their brands and abbreviations are conventional brands and abbreviations in the field. Each brand and abbreviation is clear and unambiguous in the field of its relevant use. Those skilled in the art can purchase them from the market or prepare them by conventional methods based on the brand, abbreviation and corresponding use.

[0034] The present invention has no particular limitation on the expression of the substituents, and all expressions familiar to those skilled in the art are adopted. Based on common sense, those skilled in the art can correctly understand the meaning of the substituents according to the expressions.

[0035] The term "connected" used in the present invention may refer to direct connection or indirect connection via other groups unless otherwise specified.

[0036] 1. Preparation of Phosphate Compounds

[0037] Examples 1 to 3 exemplify the preparation methods of phosphoric acid compounds 1 to 3. This type of phosphoric acid compound can be synthesized by reacting the compound of formula II with phosphorus oxychloride. The reaction is simple and the raw materials are easily available.

[0038]

[0039] [Example 1]

[0040]

[0041] Under an argon atmosphere, (-)6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (5 mmol) and pyridine (25 mL) were added to a 100 mL three-necked flask, and phosphorus oxychloride (15 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was reacted at 60°C for 12 hours. After cooling to room temperature, water (10 mL) was added and the mixture was reacted at 50°C for 2 hours. After cooling to room temperature, the reaction solution was adjusted to weak acidity with 1M HCl, and the aqueous phase was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and filtered. The resulting solution was subjected to reduced pressure to remove low-boiling point compounds to obtain a crude product, which was separated and purified by column chromatography to obtain a white solid, namely, phosphoric acid compound 1, with a yield of 58.5%.

[0042] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 5.99.

[0043] [Example 2]

[0044]

[0045] Under an argon atmosphere, (-)3,3'-di-tert-butyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (5 mmol) and pyridine (25 mL) were added to a 100 mL three-necked flask, and phosphorus oxychloride (15 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was reacted at 60°C for 12 hours. After cooling to room temperature, water (10 mL) was added and the mixture was reacted at 50°C for 2 hours. After cooling to room temperature, the reaction solution was adjusted to weak acidity with 1M HCl, and the aqueous phase was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and filtered. The resulting solution was subjected to reduced pressure to remove low-boiling point compounds to obtain a crude product, which was separated and purified by column chromatography to obtain a white solid, namely, phosphoric acid compound 2, with a yield of 40.9%.

[0046] Structural characterization by NMR spectroscopy: 31P NMR (162 MHz, deuterated dimethyl sulfoxide) δ -0.60.

[0047] [Example 3]

[0048]

[0049] Under an argon atmosphere, (-)3,3'-diphenyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (5 mmol) and pyridine (25 mL) were added to a 100 mL three-necked flask, and phosphorus oxychloride (15 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was reacted at 60°C for 12 hours. After cooling to room temperature, water (10 mL) was added and the mixture was reacted at 50°C for 2 hours. After cooling to room temperature, the reaction solution was adjusted to weak acidity with 1M HCl, and the aqueous phase was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and filtered. The resulting solution was subjected to reduced pressure to remove low-boiling point compounds to obtain a crude product, which was separated and purified by column chromatography to obtain a white solid, namely, phosphate compound 3, with a yield of 45.5%.

[0050] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated dimethyl sulfoxide) δ 6.30.

[0051] 2. Application of Phosphate Compounds in Catalyzing [3+3] Cycloaddition Reactions

[0052] [Example 4]

[0053] In this Example 4, the phosphate compounds 1 to 3 prepared in the above examples were used to catalyze the cycloaddition reaction of the compound of formula III and the compound of formula IV, wherein the cycloaddition reaction is:

[0054]

[0055] After mixing the compound of formula III (0.4 mmol), the compound of formula IV (0.48 mmol), the phosphoric acid compound (0.08 mmol), and dichloromethane (3 mL), the reaction system was refluxed for 12 hours and separated by column chromatography to obtain a red solid. The experimental results are shown in Table 1.

[0056] Table 1:

[0057]

[0058] As shown in Table 1, when phosphoric acid compound is not added as a catalyst, the yield of the reaction is only 19%. After adding phosphoric acid compound, the reaction yield and ee value are significantly improved, indicating that the strong atropisomerism characteristic of the phosphoric acid compound of the present application is conducive to improving the yield of asymmetric catalytic reaction, while having excellent enantioselectivity. Further, when the R group adjacent to the PO bond adopts a large sterically hindered group, such as a tert-butyl group, the atropisomerism of the phosphoric acid compound can be improved, the yield of the cycloaddition reaction can be as high as 71%, and the ee value can reach more than 85%. Not only that, as shown in Table 1, for the formula III compound of different R1 groups and the formula IV compound of different R2 groups, the phosphoric acid compound of the present application has been able to obtain better yield and ee value, proving that the advantage of its skeleton structure has universality.

[0059] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A phosphoric acid compound, characterized in that It has the structure of Formula I: Wherein, R is H, C1-C6 alkyl, or C6-C 12 of aromatic groups.

2. A phosphate compound according to claim 1, characterized in that R is H, a C1-C6 linear alkyl group, a C1-C4 branched alkyl group, or a substituted or unsubstituted phenyl group, wherein the substituent of the substituted phenyl group is a C1-C4 alkyl group.

3. A phosphate compound according to claim 2, characterized in that: The phosphate compound has any of the following structural formulas:

4. A phosphate compound according to any one of claims 1 to 3, characterized in that The phosphate compound is a racemate, a left-handed enantiomer or a right-handed enantiomer.

5. A method for preparing a phosphoric acid compound, characterized in that: The method for preparing a phosphate compound according to any one of claims 1 to 4 comprises the following steps: Under an inert atmosphere, phosphorus oxychloride is added dropwise to the compound of formula II at room temperature, the reaction solution is reacted at 40-70° C., then cooled to room temperature, and water is added to the reaction solution at room temperature, and then the reaction is further carried out at 40-70° C. to obtain the phosphoric acid compound; 6. An application of a phosphoric acid compound, characterized in that: The phosphate compound according to any one of claims 1 to 4 is used as a catalyst for a [3+3] cycloaddition reaction.

7. The use according to claim 6, characterized in that The [3+3] cycloaddition reaction comprises the following steps: The compound of formula III, the compound of formula IV, a solvent and a phosphoric acid compound are mixed, and the reaction system is refluxed to obtain a compound of formula V: Among them, R 1 、R 2 The groups are independently selected from substituted or unsubstituted aryl groups.

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