Phosphite ester as well as preparation method and application thereof

Abstract

The invention discloses phosphite ester and a preparation method and application thereof, the skeleton of the phosphite ester has strong resistance to rotation isomerization, and the R1 group adjacent to the P-O bond of the phosphite ester and the R2 group connected to the R1 group can be adjusted by changing the position of a substituent group in a raw material so as to further enhance the resistance to rotation energy barrier and optical characteristics of the phosphite ester. Therefore, the catalyst shows excellent enantioselectivity in the asymmetric catalytic hydrogenation reaction of ketone compounds; in addition, the reaction conditions of the phosphite ester are milder, and the phosphite ester is easy to amplify, so that the safety in industrial production is improved, and the production cost is reduced.

Description

Technical Field

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

[0002] Phosphites can act as ligands in transition metal-catalyzed reactions, coordinating with metal centers to modify the metal's electronic properties and spatial environment, thereby regulating reaction activity and selectivity. In some asymmetric catalytic reactions, they can facilitate the precise construction of chiral molecules.

[0003] In recent years, there has been an increasing number of structural designs for phosphite ligands for transition metal-catalyzed reactions. For example, patent CN116655691A discloses a chiral spirocyclic phosphite monophosphorus ligand developed with chiral spiro[chroman-4,1'-dihydroindene]phenol as its backbone, aiming to achieve excellent enantioselectivity in the rhodium-catalyzed asymmetric catalytic hydrogenation of amino acid esters. However, existing synthetic routes for phosphite ligands have long reaction pathways, relatively harsh reaction conditions, and higher production costs, making them unsuitable for industrial scale-up. Furthermore, the atropisomerism properties of existing phosphite backbone structures are poor, and their reactivity and selectivity need to be further improved when used in asymmetric catalytic hydrogenation reactions of ketone compounds. Therefore, the current types of phosphite ligand backbones are very limited, and it is difficult to strike a balance between cost and effectiveness. Summary of the Invention

[0004] One object of the present invention is to provide a phosphite whose skeleton has stronger atropisomerism, stronger atropisomerism energy barrier and optical properties, which is beneficial to improving the selectivity of asymmetric catalytic reactions when the phosphite is used as a ligand. Moreover, this type of phosphite has a shorter synthesis path and milder reaction conditions, which can effectively reduce production costs and is suitable for large-scale production.

[0005] The present invention is achieved through the following technical solutions:

[0006] A phosphite, the structural formula of which is shown in Formula I:

[0007]

[0008] In Formula I, R 1 is selected from H, C1-C6 alkyl, substituted or unsubstituted phenyl, R 2 selected from C1 to C4 alkyl, substituted or unsubstituted C6 to C 12 of aromatic groups.

[0009] In this technical solution, the group R 1 When R is H, there is no ortho substituent on the phenyl ring of the OP bond. 1It can also be selected from C1-C6 alkyl or substituted or unsubstituted phenyl, so as to set 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 phosphite.

[0010] In this technical solution, R 1 It can be a C1 to C6 alkyl group, which can be a straight chain alkyl group or a branched chain alkyl group. In one or more embodiments, R 1 It can be methyl, ethyl, propyl, isopropyl, butyl or tert-butyl. In some preferred embodiments, R 1 is a C3-C6 branched alkyl group, such as R 1 It can be isopropyl, tert-butyl, isobutyl, isopentyl. In this technical solution, R 1 It may also be a substituted or unsubstituted phenyl group, wherein the substituent of the substituted phenyl group may be a methyl group or an ethyl group.

[0011] In this technical solution, R 2 It can be a C1 to C4 alkyl group, which can be a straight chain alkyl group or a branched chain alkyl group. In one or more embodiments, R 1 It can be methyl, ethyl, propyl, n-butyl or tert-butyl.

[0012] In this technical solution, R 2 It can be substituted or unsubstituted C6~C 12 In one or more embodiments, the aryl group is a substituted or unsubstituted phenyl, naphthyl or biphenyl group. In some preferred embodiments, R 2 is substituted or unsubstituted C6~C 12 phenyl, wherein the substitution of the phenyl group may be monosubstituted, disubstituted or trisubstituted, and the substituent of the phenyl group is a C1-C4 alkyl group, preferably, the substituent of the phenyl group is a methyl group, an ethyl group, an isopropyl group or a tert-butyl group.

[0013] In this technical solution, the skeleton of the phosphite has a strong atropisomerism characteristic. At the same time, the R adjacent to the PO bond 1 Group, and the substituent R on the PO bond 2 The phosphites can be adjusted by changing the positions of substituents in the raw materials to further enhance the anti-transfer energy barrier and optical properties, thereby exhibiting excellent enantioselectivity in the asymmetric catalytic hydrogenation of ketone compounds. In addition, the reaction conditions of such phosphites are milder and easy to scale up, which is beneficial to improving safety in industrial production and reducing production costs.

[0014] Furthermore, the phosphite has any of the following structural formulas:

[0015]

[0016] Furthermore, the phosphite 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 phosphite, which is used to synthesize any of the above-mentioned phosphites, wherein R 2 The group is substituted or unsubstituted C6~C 12 The preparation method comprises the following steps:

[0018] Under an inert atmosphere, phosphorus trichloride is added to the compound represented by Formula II to react to obtain an intermediate;

[0019] Add substituted or unsubstituted phenol or naphthol to the intermediate to react to obtain R 2 The group is substituted or unsubstituted C6~C 12 Aryl phosphites;

[0020]

[0021] In this technical solution, select the desired R 1 The compound of formula II is dissolved in a solvent under the protection of an inert gas such as nitrogen or argon, and a phosphorus trichloride solution is added dropwise at low temperature. After the addition is completed, the mixture is reacted at room temperature to obtain an intermediate; then, a compound having the desired R 2 The phenol or naphthol of the group is then reacted at room temperature to obtain the desired R 1 and R 2 The specific synthesis route is:

[0022]

[0023] In some preferred embodiments, the temperature during the dropwise addition of phosphorus trichloride or phenol or naphthol is 0-5°C.

[0024] In some preferred embodiments, the reaction time at room temperature is 0.5 to 2 hours.

[0025] In some preferred embodiments, phosphorus trichloride and triethylamine are dissolved in a solvent and then added dropwise to the solution of the compound of formula II.

[0026] Furthermore, a method for preparing a phosphite is provided, which is used to synthesize any of the aforementioned phosphites, wherein R 2 The group is a C1-C4 alkyl group, and the preparation method comprises the following steps:

[0027] Under an inert atmosphere, alkoxyphosphorus dichloride is added to the compound shown in formula II to react to obtain R 2 Phosphites whose groups are C1 to C4 alkyl groups.

[0028] In the present technical solution, under the protection of an inert gas, such as nitrogen or argon, the compound of formula II is dissolved in a solvent, and an alkoxyphosphorus dichloride, such as methoxyphosphorus dichloride or ethoxyphosphorus dichloride, is added dropwise at low temperature. After the addition is complete, the mixture is reacted at room temperature to obtain a phosphite.

[0029] In some preferred embodiments, the temperature during the dropwise addition of alkoxyphosphorus dichloride is 0-5°C.

[0030] In some preferred embodiments, the reaction time at room temperature is 0.5 to 2 hours.

[0031] In some preferred embodiments, alkoxyphosphonium dichloride and triethylamine are dissolved in a solvent and then added dropwise to the solution of the compound of formula II.

[0032] In the technical solution, the preparation method uses the compound of formula II as the starting material, the raw material is easily available, and the reaction temperature is room temperature, the reaction conditions are mild, and the production cost can be effectively reduced and the production safety can be improved in the scaled-up reaction; moreover, the preparation method can more easily adjust the R adjacent to the OP bond in the phosphite by selecting the raw materials. 1 and R 2 The groups further increase the anti-transfer energy barrier and optical properties of the phosphite, and both have higher yields.

[0033] The present invention also provides use of any of the aforementioned phosphites in the asymmetric catalytic hydrogenation reaction of ketone compounds.

[0034] Furthermore, the application includes the following steps:

[0035] A ketone compound, a catalyst composition and a solvent are mixed to obtain a mixture, and the mixture is reacted with hydrogen until the reaction is completed, wherein the catalyst composition includes a catalyst precursor and the phosphite.

[0036] In this technical solution, the phosphite acts as a ligand and together with the catalyst precursor constitutes a catalyst composition. Before the reaction, the catalyst composition, ketone compound and solvent are mixed, and then hydrogen is used to replace the oxygen in the reaction system, and finally the reaction is carried out under high pressure.

[0037] In some preferred embodiments, the reaction pressure is 1.5 to 3.0 MPa. In one or more embodiments, the reaction temperature is room temperature. In one or more embodiments, the reaction time is 1 to 2.5 hours.

[0038] Furthermore, the phosphine to rhodium ratio of the catalyst composition is 1 to 5. Preferably, the phosphine to rhodium ratio of the catalyst composition is 2 to 4, and more preferably, the phosphine to rhodium ratio of the catalyst composition is 2.

[0039] In some preferred embodiments, the catalyst precursor is at least one of [Rh(cod)Cl]2, [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Ir(cod)Cl]2, [Ir(cod)2]BF4 or [Ir(cod)2]PF6, wherein cod is cyclooctadiene.

[0040] In some preferred embodiments, the molar ratio of the ketone compound to the catalyst precursor is 100 to 10,000.

[0041] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0042] 1. The skeleton of the phosphite of the present invention has strong atropisomerism. At the same time, the R adjacent to the PO bond 1 Group, and the substituent R on the PO bond 2 The phosphite can be adjusted by changing the position of the substituents in the raw materials to further enhance the anti-transfer energy barrier and optical properties, thereby exhibiting excellent enantioselectivity in the asymmetric catalytic hydrogenation of ketones;

[0043] 2. The preparation method of the present invention uses the compound of formula II as the starting material, which is readily available, and the reaction temperature is room temperature, the reaction conditions are mild, and can effectively reduce production costs and improve production safety in the scaled-up reaction;

[0044] 3. The preparation method of the present invention can more easily adjust the R adjacent to OP in the phosphite by selecting raw materials. 1 and R 2 The groups further increase the anti-transfer energy barrier and optical properties of the phosphite, and both have higher yields. DETAILED DESCRIPTION

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The term "connection" used herein, unless otherwise specified, may refer to direct connection or indirect connection via other groups.

[0050] 1. Preparation of Phosphite

[0051] [Example 1]

[0052]

[0053] Under an argon atmosphere, a 100 mL three-necked flask was charged with (-)-3,3'-di-tert-butyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (3 mmol) and toluene (20 mL). A mixed solution of phosphorus trichloride (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 1 hour. The reaction was stopped, the insoluble matter was removed by filtration, and the resulting solution was decompressed to remove low-boiling compounds to obtain the intermediate product.

[0054] A mixed solution of phenol (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise to the intermediate product at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction was stopped, and the insoluble matter was removed by filtration. The resulting solution was then decompressed to remove low-boiling compounds to obtain a crude product. Phosphite 1 was separated and purified by column chromatography to obtain a white solid in an 82% yield.

[0055] Structural characterization by NMR spectroscopy: 31P NMR (162 MHz, deuterated chloroform) δ 140.04.

[0056] [Example 2]

[0057]

[0058] Under an argon atmosphere, a 100 mL three-necked flask was charged with (-)-3,3'-di-tert-butyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (3 mmol) and toluene (20 mL). A mixed solution of phosphorus trichloride (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 1 hour. The reaction was stopped, the insoluble matter was removed by filtration, and the resulting solution was decompressed to remove low-boiling compounds to obtain the intermediate product.

[0059] A mixed solution of 2,6-dimethylphenol (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise to the intermediate product at 0-5°C. After completion of the addition, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction was terminated, and the insoluble matter was removed by filtration. The resulting solution was then decompressed to remove low-boiling compounds, yielding a crude product. Phosphite 2 was isolated and purified by column chromatography as a white solid in 80% yield.

[0060] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 142.75.

[0061] [Example 3]

[0062]

[0063] Under an argon atmosphere, a 100 mL three-necked flask was charged with (-)-3,3'-di-tert-butyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (3 mmol) and toluene (20 mL). A mixed solution of phosphorus trichloride (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 1 hour. The reaction was stopped, the insoluble matter was removed by filtration, and the resulting solution was decompressed to remove low-boiling compounds to obtain the intermediate product.

[0064] A mixed solution of 3,5-di-tert-butylphenol (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise to the intermediate product at 0-5°C. After completion of the addition, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction was terminated, and the insoluble matter was removed by filtration. The resulting solution was then decompressed to remove low-boiling compounds, yielding a crude product. Phosphite 3 was isolated and purified by column chromatography as a white solid in an 82% yield.

[0065] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 144.35.

[0066] [Example 4]

[0067]

[0068] Under an argon atmosphere, a 100 mL three-necked flask was charged with (-)6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (3 mmol) and toluene (20 mL). A mixed solution of phosphorus trichloride (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 1 hour. The reaction was stopped, the insoluble matter was removed by filtration, and the resulting solution was decompressed to remove low-boiling compounds to obtain the intermediate product.

[0069] A mixed solution of phenol (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise to the intermediate product at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction was stopped, and the insoluble matter was removed by filtration. The resulting solution was then decompressed to remove low-boiling compounds to obtain a crude product. Phosphite 4 was isolated and purified by column chromatography as a white solid in a 73% yield.

[0070] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 143.61.

[0071] [Example 5]

[0072]

[0073] Under an argon atmosphere, a 100 mL three-necked flask was charged with (-)-3,3'-di-tert-butyl-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (3 mmol) and toluene (20 mL). A mixed solution of methoxyphosphonium dichloride (3 mmol), triethylamine (10 mmol), and toluene (15 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and reacted for 1 hour. The reaction was terminated, and the insoluble matter was removed by filtration. The resulting solution was then decompressed to remove low-boiling compounds to obtain a crude product. Phosphite 5 was isolated and purified by column chromatography as a white solid in an 86% yield.

[0074] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 143.21.

[0075] 2. Asymmetric catalytic hydrogenation of ketones

[0076] [Examples 6 to 12]

[0077] Phosphite 1 to phosphite 5 prepared in the above examples were used for the asymmetric hydrogenation reaction of 2,6-dichloro-3-fluoroacetophenone.

[0078]

[0079] In a 50 mL high pressure reactor, 2,6-dichloro-3-fluoroacetophenone (103 mg), [Rh(cod)2]BF4 (1 mg) and phosphite, methanol (10 mL) were added; hydrogen was then charged for replacement three times, and hydrogen was again charged to 2.0 MPa. After the reaction at room temperature for 2 h, stirring was stopped and the crude product was eluted with silica gel and then passed through 1 H NMR and HPLC analysis, the reaction results are shown in Table 1:

[0080] Table 1:

[0081] Example Phosphites Phosphine-rhodium ratio Yield ee 6 1 1 75％ 65％ 7 1 2 95％ 93％ 8 1 4 95％ 93％ 9 2 2 94％ 99％ 10 3 2 93％ 93％ 11 4 2 90％ 83％ 12 5 2 93％ 87％

[0082] As can be seen from the table, when the phosphite prepared in the present application is used for the asymmetric hydrogenation reaction of 2,6-dichloro-3-fluoroacetophenone, the selectivity of the asymmetric catalytic reaction is high, especially when the phosphine-rhodium ratio of the catalytic system is between 2 and 4, the ee value can reach more than 83%, and the highest can reach 99%, showing excellent enantioselectivity, and is suitable for the fields of drug synthesis and fine chemical preparation.

[0083] 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 phosphite, characterized in that Its structural formula is shown in Formula I: In Formula I, R 1 is selected from H, C1-C6 alkyl, substituted or unsubstituted phenyl, R 2 selected from C1 to C4 alkyl, substituted or unsubstituted C6 to C 12 of aromatic groups.

2. A phosphite according to claim 1, characterized in that, R 1 is selected from H, C3-C6 branched alkyl, R 2 selected from C1 to C4 alkyl, substituted or unsubstituted C6 to C 12 wherein the substituent of the substituted aryl is a C1-C4 alkyl group.

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

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

5. A method for preparing phosphite, characterized in that: Used for synthesizing a phosphite according to any one of claims 1 to 4, wherein R 2 The group is substituted or unsubstituted C6~C 12 The preparation method comprises the following steps: Under an inert atmosphere, phosphorus trichloride is added to the compound represented by Formula II to react to obtain an intermediate; Add substituted or unsubstituted phenol or naphthol to the intermediate to react to obtain R 2 The group is substituted or unsubstituted C6~C 12 Aryl phosphites; 6. A method for preparing phosphite, characterized in that: Used for synthesizing a phosphite according to any one of claims 1 to 4, wherein R 2 The group is a C1-C4 alkyl group, and the preparation method comprises the following steps: Under an inert atmosphere, alkoxyphosphorus dichloride is added to the compound shown in formula II to react to obtain R 2 Phosphites with C1-C4 alkyl groups 7. Use of a phosphite according to any one of claims 1 to 4 in the asymmetric catalytic hydrogenation reaction of ketone compounds.

8. The use according to claim 7, characterized in that The following steps are involved: A ketone compound, a catalyst composition and a solvent are mixed to obtain a mixture, and the mixture is reacted with hydrogen until the reaction is completed, wherein the catalyst composition includes a catalyst precursor and the phosphite.

9. The use according to claim 8, characterized in that The phosphine-rhodium ratio of the catalyst composition is 1-5.

10. The use according to claim 8, characterized in that The catalyst precursor is at least one of [Rh(cod)Cl]2, [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Ir(cod)Cl]2, [Ir(cod)2]BF4 or [Ir(cod)2]PF6, wherein cod is cyclooctadiene.

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