Phosphoramidite and preparation method and application thereof

Abstract

The invention discloses phosphoramidite and a preparation method and application thereof.The framework of the phosphoramidite has the high resistance to rotation isomerism characteristic, meanwhile, R groups adjacent to P-O bonds 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 the phosphoramidite are further enhanced, and the phosphoramidite has the good anti-rotation performance. Therefore, excellent enantioselectivity is shown in the asymmetric catalytic hydrogenation reaction of enamine compounds, and the ee value can be up to 99% at most; in addition, according to the preparation method of phosphoramidite, raw materials are easy to obtain, the reaction is simple, the yield is high, the reaction conditions are mild, and the potential of large-scale production is huge.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a phosphoramidite and a preparation method and application thereof. Background Art

[0002] In the field of transition metal catalysis, ligand design is a key factor in regulating reaction activity and selectivity. Phosphoramidite ligands, through the coordination of phosphorus atoms with metal centers, can synergistically regulate electronic and steric effects, thereby improving reaction outcomes.

[0003] At present, the skeleton structure of the phosphoramidite ligand for the asymmetric hydrogenation of enamines is mainly based on the classic spirocyclic skeleton, and the types are limited. For example, patent CN1156482C discloses a spirocyclic phosphoramidite ligand, which can be used for the asymmetric hydrogenation of dehydroamino acids, enamines and itaconic acid. Patent CN108659046B discloses a phosphoramidite based on a tetramethyl spirodihydroindane skeleton for the asymmetric hydrogenation of rhodium-catalyzed (Z)-2-acetylamino-3-phenyl methyl acrylate. Patent CN111253439B discloses a class of spirodihydrobenzothiol phosphoramidites for palladium-catalyzed intramolecular asymmetric amine cyclization and rhodium-catalyzed (Z)-2-acetylamino-3-phenyl methyl acrylate. Meanwhile, the synthesis method of existing phosphoramidite ligands is complicated, or the raw materials are not easy to obtain, resulting in high production costs and being difficult to apply in large-scale production. Moreover, the existing phosphoramidite skeleton structure has poor atropisomerism properties, and its reaction activity and selectivity need to be further improved when used in asymmetric catalytic hydrogenation reactions.

[0004] Therefore, it is necessary to design a phosphoramidite ligand that is easy to synthesize and low in cost, and to improve its atropisomerism properties through skeleton structure design to enhance the activity and selectivity of the asymmetric catalytic hydrogenation reaction of enamines. Summary of the Invention

[0005] One object of the present invention is to provide a phosphoramidite whose skeleton is different from the traditional spirocyclic skeleton, has stronger atropisomerism characteristics, and can exhibit excellent enantioselectivity in the asymmetric catalytic hydrogenation reaction of enamine compounds. At the same time, this type of phosphoramidite has a short synthesis path, mild reaction conditions, and readily available raw materials, which can effectively reduce production costs and is suitable for large-scale production.

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

[0007] A phosphoramidite having the structure of Formula I:

[0008]

[0009] Wherein, R is selected from H, C1-C6 alkyl, and substituted or unsubstituted aryl.

[0010] In this technical solution, when the group R is H, there is no ortho-substituent on the phenyl ring of the OP bond. In some embodiments, R can also be selected from a C1-C6 alkyl group or a substituted or unsubstituted aryl group, thereby providing a substituent ortho-positioned on the phenyl ring of the OP bond to further improve the ablation barrier and optical properties of the phosphoramidite.

[0011] In the present technical solution, the group R can be a C1-C6 alkyl group, which can be either a straight-chain alkyl group or a branched-chain alkyl group. In one or more embodiments, R can be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or a tert-butyl group. In some preferred embodiments, the group R is a C1-C4 straight-chain alkyl group or a branched-chain alkyl group. In more preferred embodiments, R is a C3-C4 branched-chain alkyl group, for example, R can be an isopropyl group, a tert-butyl group, or an isobutyl group.

[0012] In the present technical solution, the group R can also be a substituted or unsubstituted aryl group. In one or more embodiments, the aryl group can be a monocyclic aryl group or a condensed ring aryl group. The number of carbon atoms of the aryl group is preferably C6 to C 24 , more preferably C6~C 18 , and more preferably C6~C 12 . In some preferred embodiments, the aryl group is a phenyl group or a naphthyl group. In the present technical solution, the aryl group can be either 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 phosphoramidite 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, thereby exhibiting excellent enantioselectivity in the asymmetric catalytic hydrogenation reaction of enamine compounds.

[0014] As a preferred embodiment of the phosphoramidite in the present invention, the phosphoramidite has any of the following structural formulas:

[0015]

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

[0017] Another object of the present invention is to provide a method for preparing phosphoramidite, which is used to prepare any of the aforementioned phosphoramidites. Specifically, the method comprises the following steps:

[0018] Under an inert atmosphere, mixing the compound represented by formula II, tris(dimethylamino)phosphine, and a first solvent, and subjecting the mixture to a reflux reaction to obtain the phosphoramidite;

[0019]

[0020] In this technical solution, the phosphoramidite ligand can be prepared by reacting the compound of formula II with tris(dimethylamino)phosphine, and its synthesis path is:

[0021]

[0022] In this technical solution, the inert atmosphere can be nitrogen or argon. A mixture of the compound of formula II, tris(dimethylamino)phosphine, and the first solvent is heated under reflux to react to obtain a phosphoramidite. In some preferred embodiments, after the reaction is completed, the reaction solution is decompressed to remove low-boiling point compounds to obtain a crude product, which is then washed with ethanol, n-hexane, and dichloromethane to obtain a white phosphoramidite solid.

[0023] In this technical solution, the compound of formula II is used as the starting material to prepare the phosphoramidite, so that the skeleton of the phosphoramidite has strong atropisomerism. At the same time, the compound of formula II can well introduce and adjust the R group adjacent to the OP bond on the benzene ring of the skeleton, and use groups such as tert-butyl and phenyl to increase steric hindrance, thereby further improving the atropisomerism barrier and optical properties of the phosphoramidite, so that the asymmetric catalytic hydrogenation reaction of enamine compounds catalyzed by the phosphoramidite has a higher conversion rate and ee value. In addition, the raw materials of this preparation method are easily available, the reaction is simple, the yield is high, the reaction conditions are mild, and the potential for large-scale production is huge.

[0024] In some preferred embodiments, the molar ratio of tri(dimethylamino)phosphine to the compound of formula II is 1-1.2, and tri(dimethylamino)phosphine is in excess to allow the compound of formula II to react completely.

[0025] In some preferred embodiments, the reflux reaction time is 0.5 to 2 hours.

[0026] Another object of the present invention is to provide a use of a phosphoramidite, wherein the phosphoramidite and a catalyst precursor constitute a catalyst composition for the asymmetric catalytic hydrogenation reaction of enamines.

[0027] Another object of the present invention is to provide an asymmetric catalytic hydrogenation reaction of an enamine. Specifically, the asymmetric catalytic hydrogenation reaction of an enamine comprises the following steps:

[0028] Mix the enamine, catalyst precursor, phosphoramidite and second solvent, introduce hydrogen to replace the oxygen in the reaction system, fill the hydrogen to 1.0-4.0 MPa, and react at room temperature until the reaction is complete;

[0029] Wherein, the phosphoramidite is any of the aforementioned phosphoramidites.

[0030] In some preferred embodiments, hydrogen is added to a pressure of 1.5 to 2.5 MPa after replacement.

[0031] In some preferred embodiments, the reaction is carried out at room temperature.

[0032] In some preferred embodiments, the reaction time is 8 to 16 hours.

[0033] In some preferred embodiments, the catalyst precursor is at least one of [Rh(cod)Cl]2 (cod = cyclooctadiene), [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Ir(cod)Cl]2, [Ir(cod)2]BF4 or [Ir(cod)2]PF6.

[0034] Furthermore, the molar ratio of the phosphoramidite to the catalyst precursor is 2-4.

[0035] In this technical solution, by setting the molar ratio of phosphoramidite to catalyst precursor at 2 to 4, the conversion rate of the asymmetric catalytic hydrogenation of enamines can reach 99%, while the ee value is above 90%. When the R group is tert-butyl or phenyl, the ee value of the asymmetric catalytic hydrogenation of enamines can reach as high as 99%, which has wide application value.

[0036] In some preferred embodiments, the molar ratio of the enamine to the catalyst precursor is 100 to 10,000.

[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0038] 1. The phosphoramidite 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 barrier and optical properties of the phosphoramidite, thereby exhibiting excellent enantioselectivity in the asymmetric catalytic hydrogenation reaction of enamine compounds, significantly improving the reaction activity, catalytic performance and stereoselectivity, and breaking through the limitations of enantioselectivity.

[0039] 2. The raw materials of the preparation method of the present invention are easily available, the reaction is simple, the yield is high, the reaction conditions are mild, and the potential for large-scale production is huge;

[0040] 3. The present invention sets the molar ratio of phosphoramidite to catalyst precursor at 2-4, so that the conversion rate of the asymmetric catalytic hydrogenation reaction of enamine can reach 99%, and the ee value is above 90%. DETAILED DESCRIPTION

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] The terms "first," "second," etc. (e.g., first solvent, second solvent, etc.) used in the present invention are used only to distinguish corresponding components for clarity of description and are not intended to limit any order or emphasize importance. The term "connected" used in the present invention, unless otherwise specified, may refer to direct connection or indirect connection via other groups.

[0046] 1. Preparation of phosphoramidites

[0047] Examples 1 to 3 exemplify the preparation methods of phosphoramidite ligands 1 to 3. This type of phosphoramidite ligand can be synthesized by reacting a compound of formula II with tris(dimethylamino)phosphine. The reaction is simple, the yield is high, the raw materials are easily available, and there is great potential for large-scale production.

[0048]

[0049] [Example 1]

[0050]

[0051] Under an argon atmosphere, (-)-6,6',7,7',8,8',9,9'-octahydro-[1,1'-bibenzo[b,d]furan]-2,2'-diol (4 mmol), tris(dimethylamino)phosphine (4.5 mmol), and toluene (15 mL) were added to a 100 mL three-necked flask and refluxed for 1 hour. The reaction was terminated, and the resulting solution was decompressed to remove low-boiling compounds to obtain a crude product. The crude product was then washed sequentially with ethanol, n-hexane, and dichloromethane to afford phosphoramidite 1 as a white solid in an 89% yield.

[0052] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 148.23.

[0053] [Example 2]

[0054]

[0055] 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 (4 mmol), tris(dimethylamino)phosphine (4.5 mmol), and toluene (15 mL). The mixture was refluxed for 1 hour. The reaction was terminated, and the resulting solution was decompressed to remove low-boiling compounds. The crude product was then washed sequentially with ethanol, n-hexane, and dichloromethane to afford phosphoramidite 2 as a white solid in an 83% yield.

[0056] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 147.05.

[0057] [Example 3]

[0058]

[0059] 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 (4 mmol), tris(dimethylamino)phosphine (4.5 mmol), and toluene (15 mL) were added to a 100 mL three-necked flask and refluxed for 1 hour. The reaction was terminated, and the resulting solution was decompressed to remove low-boiling compounds to obtain a crude product. The crude product was washed sequentially with ethanol, n-hexane, and dichloromethane to obtain phosphoramidite 3 as a white solid in a 77% yield.

[0060] Structural characterization by NMR spectroscopy: 31 P NMR (162 MHz, deuterated chloroform) δ 148.75.

[0061] 2. Application of phosphoramidites in asymmetric catalytic hydrogenation of enamines

[0062] [Examples 4 to 8]

[0063] The phosphoramidites 1 to 3 prepared in the above examples were used for the asymmetric hydrogenation of methyl (Z)-2-acetylamino-3-phenylacrylate.

[0064]

[0065] In a 50 mL autoclave, (Z)-2-acetylamino-3-phenylacrylate (110 mg), [Rh(cod)2]BF4 (1 mg), phosphoramidite and dichloromethane (7 mL) were added; hydrogen was then charged into the autoclave for replacement three times, and hydrogen was again charged into the autoclave to 2.0 MPa. The reaction was continued at room temperature for 12 h, and then stirring was stopped. The crude product was eluted with silica gel and then purified by 1 H NMR and HPLC analysis, the reaction results are shown in Table 1:

[0066] Table 1:

[0067] Example Phosphoramidites Phosphine-rhodium ratio Conversion rate ee 4 1 1 62％ 71％ 5 1 2 99％ 90％ 6 1 4 99％ 91％ 7 2 2 99％ 95％ 8 3 2 99％ 99％

[0068] As shown in Table 1, when the phosphine-rhodium ratio in the catalytic system composed of [Rh(cod)2]BF4 and phosphoramidite ligands is between 2 and 4, the conversion rates of the asymmetric hydrogenation reactions involving all three phosphoramidite ligands can reach 99%, and the ee values can reach over 90%. This reflects that the strong atropisomerism of the phosphoramidite backbone enables excellent enantioselectivity in the asymmetric catalytic hydrogenation of enamine compounds. In addition, by adjusting the R group adjacent to the PO bond of the phosphoramidite to increase its steric hindrance, the atropisomerism barrier and optical properties of the phosphoramidite can be further enhanced, with ee values as high as 99%.

[0069] 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 phosphoramidite, characterized in that It has the structure of Formula I: Wherein, R is selected from H, C1-C6 alkyl, and substituted or unsubstituted aryl.

2. The phosphoramidite according to claim 1, wherein R is selected from H, C1-C4 alkyl, and substituted or unsubstituted phenyl, wherein the substituent of the substituted phenyl is C1-C4 alkyl.

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

4. The phosphoramidite according to any one of claims 1 to 3, characterized in that: The phosphoramidite is a racemate, a levorotatory enantiomer or a dextrorotatory enantiomer.

5. A method for preparing phosphoramidite, characterized in that: The method for preparing a phosphoramidite according to any one of claims 1 to 4 comprises the following steps: Under an inert atmosphere, mixing the compound represented by formula II, tris(dimethylamino)phosphine, and a first solvent, and subjecting the mixture to a reflux reaction to obtain the phosphoramidite; 6. Use of a phosphoramidite according to any one of claims 1 to 4, characterized in that: The phosphoramidite and the catalyst precursor constitute a catalyst composition for the asymmetric catalytic hydrogenation reaction of enamine.

7. An asymmetric catalytic hydrogenation reaction of enamine, characterized in that: The following steps are involved: Mix the enamine, catalyst precursor, phosphoramidite and second solvent, introduce hydrogen to replace the oxygen in the reaction system, fill the hydrogen to 1.0-4.0 MPa, and react at room temperature until the reaction is complete; The phosphoramidite is the phosphoramidite according to any one of claims 1 to 4.

8. The asymmetric catalytic hydrogenation reaction of an enamine according to claim 7, characterized in that: The catalyst precursor is at least one of [Rh(cod)Cl]2 (cod=cyclooctadiene), [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Ir(cod)Cl]2, [Ir(cod)2]BF4 or [Ir(cod)2]PF6.

9. The asymmetric catalytic hydrogenation reaction of an enamine according to claim 8, characterized in that: The molar ratio of the phosphoramidite to the catalyst precursor is 2-4.

10. The asymmetric catalytic hydrogenation reaction of enamine according to claim 8, characterized in that: The molar ratio of the enamine to the catalyst precursor is 100 to 10,000.

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