阅读说明：本技术 一种噁唑啉类配体、制备方法及其应用 (Oxazoline ligand, preparation method and application thereof ) 是由 刘国生 陈朝煌 亓晓旭 陈品红 于 2018-12-13 设计创作，主要内容包括：本发明公开了一种噁唑啉类配体、制备方法及其应用。本发明公开的一种如式I所示的噁唑啉类配体,其可实现在哌啶类化合物中引入手性三氟甲氧基或酯基,且反应操作简单、对映选择性高、产物收率高、底物普适性广。<Image he="283" wi="472" file="DDA0001904972260000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses an oxazoline ligand shown in a formula I, a preparation method and application thereof, which can realize the introduction of chiral trifluoromethoxy or ester group into piperidine compounds, and has the advantages of simple reaction operation, high enantioselectivity, high product yield and wide substrate universality)

1. An oxazoline ligand shown in a formula I,

Wherein the content of the first and second substances,

R¹And R²Each independently hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, or substituted or unsubstituted C_6-30Aryl radical, R¹And R²Is not hydrogen or methyl at the same time;

R³Is substituted or unsubstituted C_1-10Alkyl, or substituted or unsubstituted C_6-30An aryl group; preferably, when R is³When it is tert-butyl, R¹And R²Are not all hydrogen;

R⁴Is hydrogen, or substituted or unsubstituted C_6-30An aryl group; preferably, when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³Is not simultaneouslyA phenyl group;

Or, R³And R⁴With a carbon atom bound between them to form

Said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl and substituted or unsubstituted C_6-30By substituted in aryl is meant by halogen, C_1-10Alkyl radical, C_1-10Alkoxy radical,Cyano radicals, C_6-30Aryl and halogen substituted C_1-10One or more of the alkyl groups are substituted, and when the number of the substituents is plural, the substituents are the same or different; r⁵Is C_1-10An alkyl group;

The carbon marked with x is an S configuration or an R configuration chiral carbon.

2. The oxazoline ligand of claim 1, wherein the oxazoline ligand is further characterized in that,

When R is¹And R²Each independently is substituted or unsubstituted C_1-10When alkyl, said C_1-10Alkyl is C_1-4An alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or an isobutyl group, and more preferably an n-butyl group;

And/or when R¹And R²Each independently is substituted or unsubstituted C_3-8When there is a cycloalkyl group, said C_3-8Cycloalkyl being C_3-7Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

And/or when R¹And R²Each independently is substituted or unsubstituted C_6-30When aryl, said C_6-30Aryl is C_6-14Aryl, preferably phenyl, anthracyl or naphthyl;

And/or when R³Is substituted or unsubstituted C_1-10When alkyl, said C_1-10Alkyl is C_1-4An alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group, and more preferably a tert-butyl group;

And/or when R³Is substituted or unsubstituted C_6-30when aryl, said C_6-30Aryl is C_6-14Aryl, preferably phenyl, anthracyl or naphthyl;

And/or when R⁴Is substituted or unsubstituted C_6-30when aryl, said C_6-30Aryl is C_6-14Aryl, preferably phenyl, naphthyl or anthracenyl;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30When the substituted substituent in the aryl is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituent substituted in the aryl group is C_1-10When alkyl, said substituent C_1-10Alkyl is C_1-4An alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or an isobutyl group, and more preferably a methyl group or a tert-butyl group;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituent substituted in the aryl group is C_1-10At alkoxy, said C_1-10alkoxy is C_1-4An alkoxy group, preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group or an isobutoxy group, and more preferably a methoxy group;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituted substituents in the aryl radicals areWhen R is said⁵Is C_1-4Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituent substituted in the aryl group is C_6-30Aryl, said substituent C_6-30Aryl is C_6-14Aryl, preferably phenyl, anthracyl or naphthyl;

And/or, when said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30Said substituted substituents in the aryl group being halogen-substituted C_1-10When alkyl, said halogen being substituted by C_1-10Halogen in the alkyl is fluorine, chlorine, bromine or iodine, and the halogen is substituted C_1-10C in alkyl_1-10Alkyl is C_1-4Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

3. The oxazoline ligand of claim 1, wherein the oxazoline ligand is further characterized in that,

Said R¹And R²each independently hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, or substituted or unsubstituted C_6-30An aryl group; r³Is substituted or unsubstituted C_1-10Alkyl, or substituted or unsubstituted C_6-30An aryl group; r⁴Is hydrogen, or substituted or unsubstituted C_6-30An aryl group; or, R³And R⁴With a carbon atom bound between them to form

Said substituted or unsubstitutedC of (A)_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30By substituted in aryl is meant by halogen, C_1-10Alkyl radical, C_1-10Alkoxy and C_6-30And (b) one or more of the aryl groups are substituted, and when the number of the substituents is plural, the substituents are the same or different.

4. An oxazoline ligand as defined in claim 3, which is characterized in that,

R¹Is hydrogen, n-butyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl; r²Is hydrogen, n-butyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl; r³Is phenyl, tert-butyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-chlorophenyl; r⁴Is hydrogen or phenyl; or, R³And R⁴With a carbon atom bound between them to form

5. The oxazoline ligand represented by the formula I, as claimed in any of claims 1 to 4, wherein the oxazoline ligand is a oxazoline ligand,

The oxazoline ligand shown in the formula I is selected from compounds shown in any one of the following formulas:

6. A complex compound shown as a formula IV,

Wherein R is¹、R²、R³、R⁴and as defined in any one of claims 1 to 5.

7. A preparation method of oxazoline ligand shown in formula I is characterized by comprising the following steps: under the action of acid in an organic solvent and under the protection of gas, the compound shown as the formula V and the amino alcohol shown as the formula VI react as shown in the specification to obtain the oxazoline ligand shown as the formula I,

Wherein R is¹、R²、R³、R⁴And labelled carbon is as defined in any one of claims 1 to 5.

8. The process according to claim 7 for the preparation of compounds of formula I,

The protective gas is nitrogen and/or argon;

And/or the organic solvent is halogenated aromatic hydrocarbon solvent, preferably chlorobenzene;

And/or, the acid is inorganic acid, preferably hydrochloric acid; the hydrochloric acid is preferably concentrated hydrochloric acid; the concentration of the acid in the organic solvent is 1 drop/20 mL-1 drop/5 mL;

And/or the molar concentration of the compound shown as the formula V in the organic solvent is 0.1-2 mol/L, preferably 0.2-1 mol/L;

And/or the molar concentration ratio of the compound shown as the formula V to the amino alcohol shown as the formula VI is 1: 10-10: 1, preferably 1: 3-3: 1;

And/or the reaction temperature is 60-110 ℃, preferably 70-90 ℃;

and/or the reaction process takes the monitored disappearance of the compound shown as the formula IV or the amino alcohol shown as the formula VI as a reaction end point.

9. The process of claim 7, further comprising the steps of: in methanol, under the action of alkali, the compound shown as the formula VII is subjected to the following reaction to obtain the compound shown as the formula V,

Wherein R is¹And R²As defined in any one of claims 1 to 5.

10. The process according to claim 9 for the preparation of compounds of formula I,

In the preparation method of the compound shown in the formula V, the molar concentration of the compound shown in the formula VII in the methanol is 0.5-5 mol/L, preferably 0.5-2 mol/L;

And/or, in the preparation method of the compound shown as the formula V, the alkali is R ' OM ', and R ' is C_1-4Alkyl, M' is an alkali metal; m' is preferably sodium and/or potassium; r' is preferably methyl and/or ethyl; and/or, the alkali is preferably sodium methoxide and/or sodium ethoxide;

And/or in the preparation method of the compound shown in the formula V, the molar ratio of the compound shown in the formula VII to the alkali is 1: 1-10: 1, preferably 3: 1-4: 1;

And/or in the preparation method of the compound shown as the formula V, the reaction temperature is 20-60 ℃, and preferably 30-50 ℃;

And/or in the preparation method of the compound shown as the formula V, the reaction process takes the monitored disappearance of the compound shown as the formula VII as a reaction end point.

11. The method of claim 9, further comprising the step of reacting the compound of formula VIII in an organic solvent under the action of trimethylsilyl cyanide and N, N-dimethylcarbamoyl chloride to obtain the compound of formula VII,

Wherein R is¹and R²As defined in any one of claims 1 to 5.

12. The process according to claim 11 for the preparation of a compound of formula I,

In the preparation method of the compound shown as the formula VII, the organic solvent is a halogenated hydrocarbon solvent, preferably dichloromethane and/or chloroform;

And/or in the preparation method of the compound shown in the formula VII, the molar concentration of the compound shown in the formula VIII in the organic solvent is 0.1-1 mol/L, preferably 0.4-0.6 mol/L;

And/or in the preparation method of the compound shown in the formula VII, the molar ratio of the compound shown in the formula VIII to the trimethylsilyl cyanide is 2: 1-1: 2;

And/or in the preparation method of the compound shown in the formula VII, the molar ratio of the compound shown in the formula VIII to the N, N-dimethyl carbamyl chloride is 1: 1-1: 2;

And/or in the preparation method of the compound shown as the formula VII, the reaction temperature is room temperature;

And/or in the preparation method of the compound shown in the formula VII, the reaction process takes the monitored disappearance of the compound shown in the formula VIII as a reaction end point.

13. A process according to claim 11 for the preparation of a compound of formula I, which comprises the steps of: in an organic solvent, under the action of m-chloroperoxybenzoic acid, a compound shown as a formula IX is subjected to an oxidation reaction shown as the following formula to obtain a compound VIII,

Wherein R is¹and R²as defined in any one of claims 1 to 5.

14. The process according to claim 13 for the preparation of compounds of formula I,

In the preparation method of the compound shown as the formula VIII, the organic solvent is halogenated hydrocarbon solvent, preferably dichloromethane and/or chloroform;

And/or in the preparation method of the compound shown in the formula VIII, the molar concentration of the compound shown in the formula IX in the organic solvent is 0.01-1 mol/L, preferably 0.1-0.2 mol/L;

And/or in the preparation method of the compound shown in the formula VIII, the molar ratio of the compound shown in the formula IX to the m-chloroperoxybenzoic acid is 1: 1-1: 5, preferably 1: 1-1: 3;

And/or in the preparation method of the compound shown in the formula VIII, the reaction temperature is room temperature;

And/or in the preparation method of the compound shown in the formula VIII, the reaction process takes the monitored disappearance of the compound shown in the formula IX as a reaction end point.

15. The compound shown as the formula V or VII,

Wherein R is¹And R²as defined in any one of claims 1 to 5.

16. An application of the oxazoline ligand shown in the formula I as the catalyst ligand in the asymmetric amination reaction of the palladium-catalyzed olefin or an application of the complex shown in the formula IV as the catalyst in the asymmetric amination reaction of the palladium-catalyzed olefin as the catalyst in any one of claims 1 to 5.

Technical Field

The invention relates to an oxazoline ligand, a preparation method and application thereof.

Background

Oxazoline ligands, as a class of important chiral ligands, show good control of reaction enantioselectivity in Lewis acid catalyzed and transition metal catalyzed reactions, and oxazoline ligands can be better compatible in oxidative amination systems than phosphine ligands (chi.j.org.chem.2016, 36,1797).

Optically active nitrogen-containing heterocyclic compounds are widely found in pharmaceuticals, active molecules, and natural products. The development of asymmetric synthesis methods of such compounds is of great significance, wherein palladium-catalyzed intramolecular asymmetric oxidative amination is one of the effective methods for constructing such compounds, and research in this field is relatively rare at present, mainly due to the fact that the number of chiral ligands compatible with an oxidation system is small.

A nitrogenous chiral ligand can be compatible with an oxidation system, and the asymmetric oxidative amination cyclization reaction of palladium-catalyzed olefin is realized by using (-) -sparteine as a ligand reported in a document J.am.chem.Soc.2006,128,3130, and chiral indoline compounds are obtained by using the value of 91% ee at most. However, (-) -Sparteine is difficult to modify compared toIn addition, the oxazoline ligand has good modifiability and shows better enantioselectivity control in the oxidative amination reaction. For example, in Angew. chem. int. Ed.2012,51,9141, chiral pyridinooxazoline is reported as a ligand, palladium-catalyzed asymmetric Aza-Wacker reaction is realized, and isoindolones with chiral quaternary carbon at the ortho-position of nitrogen are synthesized. In the document org.Lett.2011,13,2830, Pd (TFA) is reported₂Under a pyrox catalytic system, the asymmetric Aza-Wacker reaction of common alkenyl sulfonamide is realized, and chiral tetrahydropyrrole compounds are obtained with an ee value as high as 98%. In angelw.chem.int.ed.2017, 56,5336, it is reported that asymmetric amine arylation is realized in a divalent palladium/chiral quinolinoxazole system, and a series of indoline compounds containing chiral quaternary carbon centers are obtained by reaction with high yield and excellent enantioselectivity. In document j.am.chem.soc.2013,135,8854, palladium catalyzed asymmetric bis-amination of olefins is reported, using quinolinoxazolines as chiral ligands, enabling bis-aminated products with 99% ee value. The above reactions are all chiral five-membered nitrogen-containing heterocyclic compounds obtained through 5-exo cyclization, and how to construct chiral six-membered nitrogen-containing heterocyclic compounds through asymmetric 6-exo cyclization by chiral ligand design is not reported so far.

Therefore, in view of the above-mentioned current reaction situation, there is a need for development of a novel chiral pyridine oxazoline ligand and development of a method for synthesizing an optically active β -ester group substituted piperidine heterocyclic compound with high efficiency and high selectivity.

Fluorine-containing compounds with optical activity are widely present in drug molecules and fine chemical products, so that the development of a method for efficiently synthesizing the compounds is significant. At present, how to introduce fluorine-containing groups with high enantioselectivity, e.g. -F, CF₃Etc., have been widely studied. However, direct introduction of OCF compared to other fluorine-containing groups₃The method of (2) is rarely reported, and contains OCF₃The research on the synthesis of chiral compounds is more rare. The reason for this is probably because the trifluoromethoxy anion is easily decomposed, and the number of types of trifluoromethoxy reagents is small at present. Thus, to date, there is only oneExample a report relating to the organically catalyzed asymmetric bromotrifluoromethoxylation of olefins [ Guo, s.; cong, F.; guo, r.; wang, l.; tang, p.nat. chem.2017,9,546.]。

in recent years, transition metal catalysts have been used as a powerful method for introducing fluorine atoms and fluorine-containing functional groups into molecules. Among them, asymmetric fluorination reaction induced by chiral ligand has been realized. The gagnee, Toste and Yu groups report palladium or platinum catalyzed asymmetric fluorination of olefins or C-H bonds, respectively, where the formation of chiral C-F bonds is believed to result from reductive elimination of higher valent metals (j.am. chem. soc.2013,135, 628; j.am. chem. soc.2014,136, 4101; j.am. chem. soc.2015,137, 12207; nat. chem.2018,10,755). These reactions illustrate that it is feasible to control the synthesis of fluorine-containing compounds with the participation of higher valent metals through the introduction of chiral ligands. However, so far, for metal catalyzed OCF-containing₃Studies on the asymmetric synthesis of compounds have not been realized.

to date, only one example of a method for synthesizing 3-trifluoromethoxypiperidine compounds has been reported (j.am. chem. soc.2015,137,15648), but chiral 3-trifluoromethoxypiperidine compounds have not been obtained.

To solve this problem, we have based on the easy occurrence of reductive elimination of high valence palladium to form C-OCF₃the bond strategy realizes the asymmetric amine trifluoromethoxylation reaction of palladium-catalyzed inactive olefin by introducing the chiral ligand, and the optically active 3-trifluoromethoxylated piperidine compound is efficiently synthesized under mild conditions.

Disclosure of Invention

The invention aims to overcome the defect that chiral trifluoromethoxy or ester group cannot be efficiently introduced into piperidine compounds in the prior art, and provides an oxazoline ligand, a preparation method and application thereof. The method realizes the introduction of chiral trifluoromethoxy groups or ester groups into piperidine compounds, and has the advantages of simple reaction operation, high enantioselectivity, high product yield and wide substrate universality.

the invention mainly solves the technical problems through the following technical scheme.

the invention provides an oxazoline ligand shown in a formula I,

Wherein R is¹And R²Each independently hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, or substituted or unsubstituted C_6-30Aryl radical, R¹And R²Is not hydrogen or methyl at the same time;

R³Is substituted or unsubstituted C_1-10Alkyl, or substituted or unsubstituted C_6-30An aryl group; preferably, when R is³When it is tert-butyl, R¹And R²Are not all hydrogen;

R⁴is hydrogen, or substituted or unsubstituted C_6-30An aryl group; or, R³And R⁴With a carbon atom bound between them to formI.e. the oxazoline ligand shown as the formula I isPreferably, when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³Is not phenyl at the same time;

Said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl and substituted or unsubstituted C_6-30By substituted in aryl is meant by halogen, C_1-10Alkyl radical, C_1-10Alkoxy radical,Cyano radicals, C_6-30Aryl and halogen substituted C_1-10One or more of the alkyl groups are substituted, and when the number of the substituents is plural, the substituents are the same or different; r⁵Is C_1-10An alkyl group;

The carbon marked with x is an S configuration or an R configuration chiral carbon.

In a preferred embodiment of the invention, when R is¹And R²Each independently is substituted or unsubstituted C_1-10When alkyl, said C_1-10Alkyl is C_1-4the alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or an isobutyl group, and more preferably an n-butyl group.

in a preferred embodiment of the invention, when R is¹And R²Each independently is substituted or unsubstituted C_3-8When there is a cycloalkyl group, said C_3-8Cycloalkyl being C_3-7Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In a preferred embodiment of the invention, when R is¹And R²Each independently is substituted or unsubstituted C_6-30When aryl, said C_6-30aryl is C_6-14aryl, preferably phenyl, anthracyl or naphthyl.

In a preferred embodiment of the invention, when R is³is substituted or unsubstituted C_1-10when alkyl, said C_1-10Alkyl is C_1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a tert-butyl group.

in a preferred embodiment of the invention, when R is³Is substituted or unsubstituted C_6-30When aryl, said C_6-30Aryl is C_6-14Aryl, preferably phenyl, anthracyl or naphthyl.

In a preferred embodiment of the invention, when R is⁴Is substituted or unsubstituted C_6-30When aryl, said C_6-30aryl is C_6-14Aryl, preferably phenyl, naphthyl or anthracenyl.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴Wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30When the substituted substituent in aryl is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴Wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30the substituent substituted in the aryl group is C_1-10When alkyl, said substituent C_1-10alkyl is C_1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or an isobutyl group, and more preferably a methyl group or a tert-butyl group.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituent substituted in the aryl group is C_1-10At alkoxy, said C_1-10Alkoxy is C_1-4The alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group or an isobutoxy group, and more preferably a methoxy group.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴Wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituted substituents in the aryl radicals areWhen R is said⁵Is C_1-4Alkyl, preferably methyl, ethyl, n-propyl, iso-propylPropyl, n-butyl, tert-butyl or isobutyl.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴Wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-30The substituent substituted in the aryl group is C_6-30aryl, said substituent C_6-30Aryl is C_6-14Aryl, preferably phenyl, anthracyl or naphthyl.

In a preferred embodiment of the invention, R¹、R²、R³Or R⁴wherein said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl and substituted or unsubstituted C_6-30Said substituted substituents in the aryl group being halogen-substituted C_1-10When alkyl, said halogen being substituted by C_1-10Halogen in the alkyl is fluorine, chlorine, bromine or iodine; said halogen substituted C_1-10C in alkyl_1-10Alkyl is C_1-4alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

In a preferred embodiment of the invention, R¹And R²Each independently hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, or substituted or unsubstituted C_6-30An aryl group; r¹And R²Not hydrogen at the same time and not methyl at the same time; r³Is substituted or unsubstituted C_1-10Alkyl, or substituted or unsubstituted C_6-30An aryl group; preferably, when R is³When it is tert-butyl, R¹And R²Are not all hydrogen; r⁴Is hydrogen, or substituted or unsubstituted C_6-30An aryl group; or, R³And R⁴With a carbon atom bound between them to formI.e. the oxazoline ligand shown as the formula I ispreferably, when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³Is not phenyl at the same time;

said substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl and substituted or unsubstituted C_6-30By substituted in aryl is meant by halogen, C_1-10Alkyl radical, C_1-10Alkoxy and C_6-30One or more of the aryl groups are substituted, and when the number of the substituents is plural, the substituents are the same or different;

The carbon marked with x is an S configuration or an R configuration chiral carbon.

In a preferred embodiment of the invention, R¹Is hydrogen, n-butyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl; r²Is hydrogen, n-butyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl; r¹And R²Not hydrogen at the same time and not methyl at the same time; r³Is phenyl, tert-butyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-chlorophenyl; when R is³When it is tert-butyl, R¹And R²Are not all hydrogen; r⁴Is hydrogen or phenyl; or, R³And R⁴With a carbon atom bound between them to formI.e. the oxazoline ligand shown as the formula I isAnd when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³is not phenyl at the same time; the carbon marked with x is an S configuration or an R configuration chiral carbon.

In a preferred embodiment of the invention, R¹And R²Each independently hydrogen, substituted or unsubstituted C_3-8Cycloalkyl, or R¹And R²and is simultaneously substituted or unsubstituted C_6-30An aryl group; r¹And R²Not hydrogen at the same time; r³Is substituted or unsubstituted C_6-30An aryl group; r⁴Is hydrogen, or substituted or unsubstituted C_6-30An aryl group; when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³Is not phenyl at the same time; or, R³And R⁴With a carbon atom bound between them to formi.e. the oxazoline ligand shown as the formula I isSaid substituted or unsubstituted C_3-8Cycloalkyl and substituted or unsubstituted C_6-30Substituted in aryl by C_1-10Alkyl, when the substituent is a plurality of, the substituent is the same or different; the carbon marked with x is an S configuration or an R configuration chiral carbon.

In a preferred embodiment of the invention, R¹Hydrogen, cyclopentyl, cyclohexyl; r²Hydrogen, cyclopentyl, cyclohexyl; or R¹And R²Simultaneously is 3, 5-dimethylphenyl or 3, 5-di-tert-butylphenyl; r¹And R²Not hydrogen at the same time; r³Is phenyl, 4-tert-butylphenyl; r⁴is hydrogen or phenyl; when R is⁴When it is hydrogen, R¹、R²And R³Not simultaneously being phenyl, and R²And R³Not being phenyl or R at the same time¹And R³Is not phenyl at the same time; or, R³And R⁴With a carbon atom bound between them to formI.e. the oxazoline ligand shown as the formula I isThe carbon marked with x is an S configuration or an R configuration chiral carbon.

In a preferred embodiment of the present invention, the oxazoline ligand represented by formula I is selected from any of the following schemes:

Wherein R is¹And R²Each independently hydrogen, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Cycloalkyl or substituted or unsubstituted C_6-30Aryl radical, R¹And R²is not hydrogen or methyl at the same time;

R³Is substituted or unsubstituted C_1-10Alkyl or substituted or unsubstituted C_6-30An aryl group;

R⁴Is hydrogen or substituted or unsubstituted C_6-30An aryl group;

Said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30the substituents in the aryl are each independently halogen, C_1-10Alkyl radical, C_1-10alkoxy radical,Cyano radicals, C_6-30aryl and halogen substituted C_1-10One or more of alkyl; r' is C_1-10An alkyl group; wherein, when the number of the substituents is plural, the substituents are the same or different;

The carbon marked with x is an S configuration or an R configuration chiral carbon.

R¹、R²Or R³Wherein said substituted or unsubstituted C_1-10C in alkyl_1-10alkyl is preferably C_1-4Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

R¹Or R²Wherein said substituted or unsubstituted C_3-8C in cycloalkyl of (2)_3-8Cycloalkyl of (C) is preferably C_3-6Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

R¹、R²、R³Or R⁴Wherein said substituted or unsubstituted C_6-30C in aryl_6-30Aryl is preferably C_6-14Aryl, for example, phenyl, naphthyl or anthracenyl.

When said substituted C_1-10Alkyl, substituted C_3-8cycloalkyl of (5) and said substituted C_6-30When the substituent in the aryl is halogen, the halogen is preferably F, Cl, Br or I.

When said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30the substituent in the aryl group being C_1-10When alkyl, said C_1-10Alkyl is preferably C_1-4Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

When said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30The substituent in the aryl group being C_1-10At alkoxy, said C_1-10Alkoxy is preferably C_1-4Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy or isobutoxy.

When said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30The substituent in the aryl group being C_6-30When aryl, said C_6-30Aryl is preferably C_6-14Aryl, for example, phenyl, naphthyl or anthracenyl.

When said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30The substituents in the aryl being halogen-substituted C_1-10When alkyl, said halogen being substituted by C_1-10Alkyl is preferably fluorine or chlorine substituted C_1-4An alkyl group.

saidR' in (A) is preferably C_1-4Alkyl group of (1).

in a preferred embodiment of the invention, R¹And R²Identical or different, each independently of the others are preferably hydrogen, substituted or unsubstituted C_6-30Aryl radical, C_1-10Alkyl or C_3-8Cycloalkyl of, R¹And R²Not simultaneously hydrogen or methyl.

Said substituted C_6-30The substituent in the aryl group is preferably C_1-10Alkyl, more preferably C_1-4An alkyl group, for example, a tert-butyl group or a methyl group, wherein, when the substituent is plural, the substituents are the same or different.

Said C_6-30aryl is preferably phenyl. Said C_1-10The alkyl group is preferably a methyl group. Said C_3-8The cycloalkyl group of (C) is preferably cyclohexyl.

In a preferred embodiment of the invention, R³Preferably C_6-30Aryl or substituted or unsubstituted C_1-10An alkyl group. Said C_6-30Aryl is preferably phenyl. Said substituted or unsubstituted C_1-10The alkyl group is preferably benzyl or isopropyl.

In a preferred embodiment of the invention, R⁴Preferably hydrogen or C_6-30And (4) an aryl group. Said C_6-30Aryl is preferably phenyl.

Preferably, R is¹And R²Each independently is any of the following structures:

Methyl, H,R¹And R²Not simultaneously hydrogen or methyl.

Said R³Preferably is

Said R⁴It is preferable thatGround is H or

SaidPreferably any of the following structures:

The oxazoline ligand shown in the formula I is preferably any one of the following compounds:

In a preferred embodiment of the present invention, the oxazoline ligand represented by formula I is selected from the group consisting of compounds represented by any one of the following:

The invention also provides a preparation method of the chiral 3-trifluoromethoxy piperidine compound, which comprises the following steps: under the protection of gas and in organic solvent, under the action of palladium catalyst, oxazoline ligand shown in formula I and oxidant, the compound shown in formula II and MOCF are reacted₃Carrying out the following reaction to obtain the compound shown in the formula III,

Wherein the content of the first and second substances,

R¹、R²、R³、R⁴And as previously defined; the configuration of the compound shown as the formula III and R³The configuration of the connected chiral carbons is consistent; r¹And R²May be both hydrogen and methyl;

R⁶And R⁷Each is independentthe place is hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₂₀Aryl radical, R⁶And R⁷Are linked to carbon atoms between them to form C₃-C₂₀Cycloalkyl, or R⁶and R⁷Are linked to carbon atoms between them to form substituted or unsubstituted C₃-C₂₀(iii) heterocyclyl, wherein the heteroatoms in the heterocyclyl are independently selected from N, O and S, the number of heteroatoms being 1,2 or 3; said substituted or unsubstituted C₁-C₆By substitution in alkyl is meant by-OCOR⁹and-CH ═ CH₂When there are a plurality of substituents, the substituents may be the same or different; said substituted or unsubstituted C₆-C₂₀Substituted in aryl by C₁-C₆Alkyl, halogen and C₁-C₆When there are a plurality of substituents, the substituents may be the same or different; said substituted or unsubstituted C₃-C₂₀by substitution in heterocycloalkyl is meant by-COOR¹⁰Substitution; said R⁹Is C₁-C₆An alkyl group; said R¹⁰Is C₁-C₆An alkyl group;

Said R⁸Is a substituted or unsubstituted phenylsulfonyl, said substitution in said substituted or unsubstituted phenylsulfonyl is by C₁-C₆Alkyl and C₁-C₆One or more substituents in the alkoxy group, and when there are a plurality of substituents, the substituents may be the same or different;

M is (Me)₂N)₃S、Me₄N or Cs.

In a preferred embodiment of the present invention, when said R is⁶And R⁷each independently is substituted or unsubstituted C₁-C₆When there is an alkyl group, said C₁-C₆Alkyl of (A) is C₁-C₄The alkyl group of (b) is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a methyl group, an ethyl group or an n-propyl group.

In a preferred embodiment of the present invention, when said R is⁶and R⁷Each independently is substituted or unsubstituted C₆-C₂₀When aryl, said C₆-C₂₀Aryl is C₆-C₁₀Aryl, preferably phenyl.

In a preferred embodiment of the present invention, when said R is⁶And R⁷Are linked to carbon atoms between them to form C₃-C₂₀When there is a cycloalkyl group, said C₃-C₂₀Cycloalkyl being C₄-C₁₀Cycloalkyl, preferably C₄-C₇Cycloalkyl is more preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

in a preferred embodiment of the present invention, when said R is⁶And R⁷Are linked to carbon atoms between them to form substituted or unsubstituted C₃-C₂₀When it is heterocyclic, said C₃-C₂₀Heterocyclyl is C₄-C₁₀Heterocyclic radical, preferably C₄-C₇Heterocyclic group, more preferably C₅And heterocyclic group, wherein hetero atom in heterocyclic group is preferably N or O, and the number of hetero atom is preferably 1.

In a preferred embodiment of the invention, R⁶or R⁷When said substituted or unsubstituted C is₆-C₂₀The substituent in the aryl group being C₁-C₆When there is an alkyl group, said C₁-C₆Alkyl of (A) is C₁-C₄The alkyl group of (3) is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a methyl group.

In a preferred embodiment of the invention, R⁶Or R⁷When said substituted or unsubstituted C is₆-C₂₀When the substituent in the aryl group is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

In a preferred embodiment of the invention, R⁶Or R⁷When said substituted or unsubstituted C is₆-C₂₀The substituent in the aryl group being C₁-C₆Alkoxy of (2), said C₁-C₆Alkoxy of C₁-C₄The alkoxy group of (3) is preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group or a tert-butoxy group, and more preferably a methoxy group.

In a preferred embodiment of the present invention, R is⁹Is C₁-C₄The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a methyl group.

In a preferred embodiment of the present invention, R is¹⁰Is C₁-C₄The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a tert-butyl group.

In a preferred embodiment of the present invention, R is⁶And R⁷The same is true.

In a preferred embodiment of the present invention, when the substituent in the substituted or unsubstituted benzenesulfonyl group is C₁-C₆When alkyl, said C₁-C₆Alkyl is C₁-C₄The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and more preferably a methyl group.

In a preferred embodiment of the present invention, when the substituent in the substituted or unsubstituted benzenesulfonyl group is C₁-C₆At alkoxy, said C₁-C₆Alkoxy is C₁-C₄The alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, or a tert-butoxy group, and more preferably a methoxy group.

In a preferred embodiment of the present invention, R is⁶Is hydrogen, methyl, ethyl, n-propyl, -CH₂OAc、-CH₂CH＝CH₂、-CH₂CH₂CH＝CH₂、-CH₂CH₂CH₂CH＝CH₂Phenyl, p-tolueneA phenyl group, a m-tolyl group, a p-chlorophenyl group, a p-fluorophenyl group, or a p-methoxyphenyl group; said R⁷Is hydrogen, methyl, ethyl, n-propyl, -CH₂OAc、-CH₂CH＝CH₂、-CH₂CH₂CH＝CH₂、-CH₂CH₂CH₂CH＝CH₂Phenyl, p-tolyl, m-tolyl, p-chlorophenyl, p-fluorophenyl, or p-methoxyphenyl; or R⁶And R⁷With a carbon atom bound between them to form Said R⁸Is composed of

In a preferred embodiment of the present invention, the compound represented by formula II is selected from any one of the following compounds:

Wherein the content of the first and second substances,

In a preferred embodiment of the present invention, M is Cs.

in the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the protective gas can be a protective gas conventional in the art, such as nitrogen and/or argon, and is preferably argon.

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the organic solvent may be one or more of organic solvents conventional in the art, such as nitrile solvents, ether solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents and ketone solvents. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran and/or diethyl ether. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform. The aromatic hydrocarbon solvent is preferably toluene. The ketone solvent is preferably acetone. The organic solvent is preferably a mixed solvent of a halogenated hydrocarbon solvent and a nitrile solvent, and more preferably a mixed solvent of dichloromethane and acetonitrile. When the organic solvent is a mixed solvent of dichloromethane and acetonitrile, the volume ratio of dichloromethane to acetonitrile can be 1: 1-10: 1, and preferably 3: 1-7: 1 (for example, 5: 1). The organic solvent is preferably a mixed solvent of an ether solvent and a nitrile solvent. When the organic solvent is a mixed solvent of tetrahydrofuran and acetonitrile, the volume ratio of tetrahydrofuran to acetonitrile can be 1: 1-10: 1, and preferably 1: 1-2: 1 (for example, 5: 3).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the palladium catalyst may be a palladium catalyst conventional in the art, such as one or more of palladium chloride, palladium iodide, palladium acetate, diacetonitrile palladium dichloride, dibenzonitrile palladium dichloride, palladium trifluoroacetate, tetranitrile palladium tetrafluoroborate and tetranitrile palladium trifluoromethanesulfonate, preferably dibenzonitrile palladium dichloride or diacetonitrile palladium dichloride, and most preferably dibenzonitrile palladium dichloride.

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the oxidant can be an oxidant conventional in the art, such as 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroborate) (Selectfluor).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the molar concentration of the compound shown in the formula II in the organic solvent can be the molar concentration conventional in the reaction in the field, and the invention is particularly preferably 0.001-1 mol/L, and further preferably 0.01-0.1 mol/L (for example 5/90 mol/L).

preparation of chiral 3-trifluoromethoxy piperidine compoundIn the preparation method, the MOCF₃The molar ratio of the compound shown as the formula II to the compound shown as the formula II can be a molar ratio which is conventional in the reaction in the field, and the molar ratio is particularly preferably 2: 1-5: 1, and is further preferably 3: 1-4: 1 (such as 3:1, 4: 1).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the molar ratio of the palladium catalyst to the compound shown as the formula II can be a molar ratio which is conventional in the reaction in the field, and the invention is particularly preferably 1: 20-1: 5, and is further preferably 1: 15-1: 8 (for example, 1: 10).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the molar ratio of the oxazoline ligand shown in the formula I to the compound shown in the formula II can be a molar ratio which is conventional in the reaction in the field, and the invention is particularly preferably 1: 30-1: 5, and is further preferably 1: 20-3: 20 (for example, 1:20, 3:20, 3: 25).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the molar ratio of the oxidant to the compound shown as the formula II can be a molar ratio which is conventional in the reaction in the field, and the invention is particularly preferably 2: 1-1: 1, and further preferably 2: 1-1.2: 1 (for example, 2:1, 1.2: 1).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the reaction temperature of the reaction can be the reaction temperature conventional in the reaction in the field, and the invention is particularly preferably-40-0 ℃, and further preferably-20-35 ℃ (for example, -20 ℃ and-30 ℃).

In the preparation method of the chiral 3-trifluoromethoxy piperidine compound, the reaction time of the reaction may be a reaction time conventional in the field, and the invention is particularly preferably 12 to 72 hours, and further preferably 24 to 48 hours (e.g. 36 hours, 24 hours).

In a preferred embodiment of the present invention, the preparation method of the chiral 3-trifluoromethoxy piperidine compound comprises the following steps: mixing the palladium catalyst, the oxazoline ligand shown in the formula I, the compound shown in the formula II and the oxidant to obtain a mixture, and adding the organic solvent into the mixture under the protection gas to react.

In a preferred embodiment of the present invention, when the compound represented by formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II iswhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III iswhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III isWhen the compound shown as the formula II isWhen the compound shown as the formula III iswhen the compound shown as the formula II isWhen the compound shown as the formula III is

The invention also provides a complex shown as the formula IV,

Wherein R is¹、R²、R³、R⁴And as previously defined.

The invention also provides a preparation method of the complex shown as the formula IV, which comprises the following steps: the oxazoline ligand shown in the formula I and the palladium catalyst are added into an organic solvent, wherein the organic solvent is the same as the organic solvent in the preparation method of the chiral 3-trifluoromethoxy piperidine compound.

The invention also provides a preparation method of the chiral 3-trifluoromethoxy piperidine compound, which is characterized by comprising the following steps: under the action of an oxidant and a complex compound shown as a formula IV in an organic solvent under the protection gas, a compound shown as a formula II and MOCF (metal organic chemical vapor deposition) are reacted₃Carrying out the following reaction to obtain the compound shown in the formula III,

Wherein R is⁶，R⁷，R⁸And M is as previously defined; the protective gas, the organic solvent and the oxide are as described above; the molar concentration of the compound shown as the formula II in the organic solvent, and the MOCF₃The molar ratio to the compound represented by the formula II, the molar ratio of the oxidizing agent to the compound represented by the formula II, the reaction temperature of the reaction and the reaction time of the reaction are as described above.

The molar ratio of the complex to the compound shown as the formula II can be a molar ratio which is conventional in the reaction in the field, and the molar ratio is particularly preferably 1: 8-1: 12 (for example, 1: 10).

The invention also provides a preparation method of the oxazoline ligand shown in the formula I, which comprises the following steps: under the action of acid in an organic solvent and under the protection of gas, the compound shown as the formula V and the amino alcohol shown as the formula VI react as shown in the specification to obtain the oxazoline ligand shown as the formula I,

Wherein R is¹、R²、R³、R⁴And the labeled carbons are as previously defined.

in the preparation method of the oxazoline ligand shown in the formula I, the protective gas can be a protective gas which is conventional in the field, and nitrogen and/or argon are particularly preferred in the invention.

In the preparation method of the oxazoline ligand shown in the formula I, the organic solvent can be an organic solvent which is conventional in the field, and the invention particularly preferably adopts a halogenated aromatic hydrocarbon solvent, and further preferably adopts chlorobenzene.

In the preparation method of the oxazoline ligand shown in the formula I, the acid can be an acid which is conventional in the reaction in the field, and the invention particularly preferably adopts an inorganic acid, and further preferably adopts hydrochloric acid. The hydrochloric acid is preferably concentrated hydrochloric acid (mass fraction is 36-38%). The amount of the acid may be an amount conventionally used in the art for carrying out such a reaction, and it is preferably 1 drop/20 mL to 1 drop/5 mL (e.g., 1 drop/15 mL, 2 drops/15 mL) in an organic solvent.

In the preparation method of the oxazoline ligand shown in the formula I, the molar concentration of the compound shown in the formula V in the organic solvent can be the molar concentration conventional in the reaction in the field, and the invention is particularly preferably 0.1-2 mol/L, and further preferably 0.2-1 mol/L (for example 1/3mol/L, 7/15 mol/L).

In the preparation method of the oxazoline ligand shown in the formula I, the molar concentration ratio of the compound shown in the formula V to the amino alcohol shown in the formula VI can be the conventional molar concentration of the reaction in the field, and the invention is particularly preferably 1: 10-10: 1, and is further preferably 1: 3-3: 1 (such as 1:1, 7: 5).

In the preparation method of the oxazoline ligand shown in the formula I, the reaction temperature can be the temperature conventional in the field, and the invention is particularly preferably 60-110 ℃, and further preferably 70-90 ℃ (for example 80 ℃).

In the preparation method of the oxazoline ligand shown in the formula I, the reaction progress can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and the disappearance of the compound shown in the formula V or the amino alcohol shown in the formula VI is generally monitored as a reaction end point.

in a preferred embodiment of the present invention, the preparation method of the oxazoline ligand shown in the formula I comprises the following steps: under the protection gas, the compound shown in the formula V and the amino alcohol shown in the formula VI are mixed with the organic solvent, and then the acid is added for reaction.

In the preparation method of the oxazoline ligand shown in the formula I, after the reaction is finished, a post-treatment step can be further included, the post-treatment step can be a post-treatment step which is conventional in the reaction in the field, and the invention particularly preferably concentrates and/or purifies. The concentration may be by conventional means in the art (e.g., concentration under reduced pressure). The purification method can be a conventional purification method in the field, and column chromatography is particularly preferred in the invention. The solvent used for the column chromatography can be a solvent which is conventional in the art, and the invention is particularly preferably a mixed solvent of petroleum ether and ethyl acetate (volume ratio of 10:1) or a mixed solvent of petroleum ether, ethyl acetate and triethylamine (volume ratio of 10:1: 0.5).

In a preferred embodiment of the invention, in the preparation method of the oxazoline ligand shown in the formula I, R is¹，R²，R³And R⁴The carbon marked with x is the chiral carbon of S configuration or R configuration.

in a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand represented by formula I, the organic solvent may be a conventional organic solvent used in the art for performing such a reaction, and is preferably one or more of an aromatic hydrocarbon solvent, an ether solvent and an ester solvent. The aromatic hydrocarbon solvent is preferably toluene and/or halogenated aromatic hydrocarbon solvent. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene fluorobenzene and benzotrifluoride, and more preferably chlorobenzene. The ether solvent is preferably tetrahydrofuran. The ester solvent is preferably ethyl acetate. The organic solvent may be used in an amount conventionally used in the art for carrying out such a reaction, as long as the reaction is not affected, and the volume molar ratio of the organic solvent to the compound V is preferably 0.5 to 5L/mol, more preferably 1 to 3L/mol, for example, 2.3L/mol.

In a preferred embodiment of the present invention, in the method for preparing the oxazoline ligand represented by the formula I, the amino alcohol is preferably valinol, phenylalaninol, phenylglycinol or 1, 2-diphenyl-2-aminoethanol, more preferably D-valinol, L-valinol, D-phenylalaninol, L-phenylalaninol, D-phenylglycinol, L-phenylglycinol or (1R,2S) -1, 2-diphenyl-2-aminoethanol. The molar ratio of amino alcohol to compound V is preferably 0.3 to 1.0, more preferably 0.5 to 0.8, e.g. 0.71.

In a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand represented by the formula I, the acid is preferably an inorganic acid, and more preferably hydrochloric acid. The hydrochloric acid is preferably concentrated hydrochloric acid (mass fraction is 36-38%). The amount of the substance of the acid may be an equivalent conventionally used in the art for carrying out such a reaction, and preferably the molar ratio thereof to the compound V is preferably 0.07 to 0.7, more preferably 0.07 to 0.21, for example, 0.14.

In a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand represented by the formula I, the reaction temperature is preferably 60 ℃ to 110 ℃, for example, 80 ℃.

In a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand shown in formula I, the reaction is preferably performed under the protection of nitrogen.

in a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand represented by formula I, the progress of the reaction in the reaction can be monitored by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and the disappearance of the compound V is generally monitored as a reaction end point.

In a preferred embodiment of the present invention, in the preparation method of the oxazoline ligand represented by formula I, after the reaction is finished, the method of the post-treatment can further comprise a post-treatment, and the method of the post-treatment is a conventional post-treatment method of the reaction, and preferably comprises the following steps: removing the organic solvent and purifying to obtain the compound I. For example, the organic solvent is removed under reduced pressure and column chromatography is performed to give compound I.

The invention also provides a preparation method of the compound shown in the formula I, which can also comprise the following steps: in methanol, under the action of alkali, the compound shown as the formula VII is subjected to the following reaction to obtain the compound shown as the formula V,

Wherein R is¹And R²As previously defined.

In the preparation method of the compound shown as the formula V, the molar concentration of the compound shown as the formula VII in the methanol can be the molar concentration which is conventional in the reaction in the field, and the invention is particularly preferably 0.3-5 mol/L, and further preferably 0.5-2 mol/L (for example, 0.77mol/L, 1.5 mol/L).

In the preparation method of the compound shown as the formula V, the base can be a base which is conventional in the reaction in the field, and the invention particularly preferably adopts R ' OM ' and R ' is C_1-4Alkyl, M' is an alkali metal. M' is preferably sodium and/or potassium; r "is preferably methyl and/or ethyl. The base is preferably sodium methoxide and/or sodium ethoxide.

In the preparation method of the compound shown as the formula V, the molar ratio of the compound shown as the formula VII and the alkali can be the molar ratio which is conventional in the reaction in the field, and the invention is particularly preferably 1: 1-10: 1, and is further preferably 3: 1-4: 1 (for example, 10: 3).

In the preparation method of the compound shown in the formula V, the reaction temperature can be the temperature conventional in the reaction in the field, and the temperature is particularly preferably 20-60 ℃, and further preferably 30-50 ℃ (for example 40 ℃).

In the preparation of the compound of formula V, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is typically monitored as the disappearance of the compound of formula VII.

In the preparation method of the compound shown in the formula V, after the reaction is finished, a post-treatment step can be further included, and the post-treatment step can be a post-treatment step which is conventional in the field. Particular preference is given to concentrating, extracting, washing, drying and concentrating according to the invention. The solvent used for the extraction may be a solvent conventional in the art (e.g., ethyl acetate). The solution used for the washing may be a solution conventional in the art (e.g., a saturated saline solution). The drying agent used for the drying may be a drying agent conventional in the art (e.g., anhydrous magnesium sulfate).

In a preferred embodiment of the present invention, the process for preparing the compound of formula V comprises the steps of: and mixing the compound shown as the formula VII with the methanol, and adding the alkali for reaction.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula V, the amount of the methanol may be the amount conventionally used in the art for performing such reactions, and preferably the volume molar ratio of the methanol to the compound VII is 0.5 to 3L/mol, for example, 1.3L/mol.

In a preferred embodiment of the present invention, in the preparation of the compound of formula V, the base is preferably R ' OM ', R ' is C_1-4Alkyl, M' is an alkali metal. M' is preferably sodium and/or potassium; r' is preferably methyl and/or ethyl. The base is preferably sodium methoxide and/or sodium ethoxide. The amount of the base may be an amount conventionally used in carrying out such a reaction in the art, and is preferably in a molar ratio of 0.1 to 1.0, for example, 0.3, to the compound VII.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula V, the reaction temperature is preferably 20 ℃ to 60 ℃, for example, 40 ℃.

In a preferred embodiment of the present invention, in the preparation process of the compound represented by formula V, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g. TLC, HPLC or NMR), and the disappearance of compound VII is generally monitored as the end point of the reaction.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula V, after the reaction is finished, the method may further comprise a post-treatment, and the post-treatment method is a conventional post-treatment method for such a reaction, and preferably comprises the following steps: concentrating, adding water and an organic solvent, washing with water, and drying to obtain a compound VII. For example, water and ethyl acetate were added, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, subjected to solid-liquid separation, and the liquid was distilled under reduced pressure to obtain compound VII.

The invention also provides a preparation method of the compound shown in the formula I, which can also comprise the following steps that in an organic solvent, under the action of trimethylsilyl cyanide and N, N-dimethyl carbamoyl chloride, the compound shown in the formula VIII is subjected to the following reaction to obtain the compound shown in the formula VII,

Wherein R is¹And R²As previously defined.

in the preparation method of the compound shown in the formula VII, the organic solvent can be an organic solvent which is conventional in the art, and the invention particularly preferably adopts a halogenated hydrocarbon solvent, and further preferably adopts dichloromethane and/or chloroform.

In the preparation method of the compound shown in the formula VII, the molar concentration of the compound shown in the formula VIII in the organic solvent can be the molar concentration which is conventional in the field of the reaction, and the invention is particularly preferably 0.1-1 mol/L, and further preferably 0.4-0.6 mol/L (for example, 0.45mol/L, 0.5 mol/L).

In the preparation method of the compound shown as the formula VII, the molar ratio of the compound shown as the formula VIII to the trimethylsilyl cyanide can be the conventional molar ratio of the reaction in the field, and the invention is particularly preferably 2: 1-1: 2 (such as 1:1, 10: 13).

In the preparation method of the compound shown as the formula VII, the molar ratio of the compound shown as the formula VIII to the N, N-dimethylcarbamoyl chloride can be the conventional molar ratio in the reaction in the field, and the invention is particularly preferably 2: 1-1: 2 (such as 18:35, 10: 13).

In the preparation method of the compound shown in the formula VII, the reaction temperature can be the reaction temperature which is conventional in the field, and the room temperature is particularly preferred in the invention.

In the preparation of the compound of formula VII, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g. TLC, HPLC or NMR), typically by monitoring the disappearance of compound VIII as the end point of the reaction, e.g. 3 days.

In the preparation method of the compound shown in the formula VII, the reaction can further comprise a post-treatment step, wherein the post-treatment step can be a conventional post-treatment step in the reaction in the field, and preferably comprises the steps of quenching, extracting, drying and purifying the reaction liquid. The solution used for the quenching may be a solution conventional in the art (e.g., aqueous potassium carbonate solution). The solvent used for the extraction may be a solvent conventional in the art (e.g., dichloromethane). The purification means may be any means conventional in the art (e.g., column chromatography).

In a preferred embodiment of the present invention, the process for preparing a compound of formula VII comprises the steps of: and mixing the compound shown as the formula VIII with the organic solvent, adding the trimethylsilyl cyanide, and then adding the N, N-dimethyl carbamoyl chloride for reaction.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the organic solvent may be a conventional organic solvent used in the art for performing such a reaction, preferably a halogenated hydrocarbon solvent, more preferably dichloromethane and/or chloroform. The organic solvent can be used in an amount which is conventional in the art for carrying out such a reaction, and preferably has a volume molar ratio of 0.5 to 4L/mol, for example, 2L/mol, to the compound VIII.

in a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the amount of the trimethylsilyl cyanide used may be the amount conventionally used in the art for performing such reactions, and preferably the molar ratio of the trimethylsilyl cyanide to the compound VIII is 1.0 to 2.0, for example, 1.3.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the molar ratio of the N, N-dimethylcarbamoyl chloride to the compound VIII is preferably 1.0 to 2.0, for example, 1.3.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the reaction temperature is preferably room temperature.

In a preferred embodiment of the present invention, in the preparation process of the compound represented by formula VII, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is usually monitored as disappearance of the compound VIII, for example, 3 days.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the reaction may further comprise a post-treatment, and the post-treatment is a conventional post-treatment method for such reaction, and preferably comprises the following steps: after the reaction is finished, quenching the reaction by using an aqueous solution of alkali, separating liquid, extracting an aqueous phase by using an organic solvent, combining organic phases, drying, separating and purifying to obtain a compound VII. For example, 10% K₂CO₃Quenching the reaction by the aqueous solution, separating liquid, extracting the aqueous phase by DCM, merging organic phases, drying, and purifying by column chromatography to obtain a compound VII.

The invention also provides a preparation method of the compound shown in the formula I, which can also comprise the following steps: in an organic solvent, under the action of m-chloroperoxybenzoic acid, a compound shown as a formula IX is subjected to an oxidation reaction shown as the following formula to obtain a compound VIII,

Wherein R is¹And R²as previously defined.

In the preparation method of the compound shown in the formula VIII, the organic solvent can be an organic solvent which is conventional in the reaction of the type in the field, and the invention particularly preferably adopts a halogenated hydrocarbon solvent, and more preferably adopts dichloromethane and/or chloroform.

In the preparation method of the compound shown in the formula VIII, the molar concentration of the compound shown in the formula IX in the organic solvent can be the molar concentration conventional in the reaction in the field, and the invention is particularly preferably 0.01-1 mol/L, and further preferably 0.1-0.2 mol/L (for example, 0.12mol/L, 1/3 mol/L).

In the preparation method of the compound shown as the formula VIII, the molar ratio of the compound shown as the formula IX to the m-chloroperoxybenzoic acid can be the molar ratio which is conventional in the reaction in the field, and the invention is particularly preferably 1: 1-1: 5, and is further preferably 1: 1-1: 3 (for example, 1:2, 4: 7).

In the preparation method of the compound shown in the formula VIII, the reaction temperature can be the reaction temperature which is conventional in the field, and room temperature is particularly preferred in the invention.

In the preparation of the compound of formula VIII, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally monitored as the disappearance of the compound of formula IX.

In the preparation method of the compound shown in the formula VIII, the reaction can further comprise a post-treatment step, and the post-treatment step can be a conventional post-treatment step of the reaction in the field, and the following steps are preferred: after the reaction is finished, the reaction is quenched by alkali, filtered and concentrated. For example, potassium carbonate is used for quenching reaction, vacuum filtration is carried out, and filtrate is concentrated to obtain the compound shown as the formula IX.

In a preferred embodiment of the present invention, the process for preparing a compound of formula VIII comprises the steps of: mixing the compound shown as the formula IX with the organic solvent, and adding the m-chloroperoxybenzoic acid in batches for reaction.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the organic solvent may be a conventional organic solvent used in the art for performing such a reaction, preferably a halogenated hydrocarbon solvent, more preferably dichloromethane and/or chloroform. The organic solvent may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably has a volume molar ratio to the compound V of 1.0 to 5.0L/mol, for example, 3.0L/mol.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the molar ratio of the m-chloroperoxybenzoic acid to the compound IX is preferably 1.0 to 2.0, for example, 1.75.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the m-chloroperoxybenzoic acid is preferably added in a batch manner.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the reaction temperature is preferably room temperature.

In a preferred embodiment of the present invention, in the preparation of the compound represented by formula VIII, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically by monitoring the disappearance of compound IX as the end point of the reaction.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the reaction may further comprise a post-treatment, and the post-treatment method is a conventional post-treatment method for such a reaction, and preferably comprises the following steps: after the reaction is finished, alkali is used for quenching reaction, liquid separation is carried out, an organic solvent is used for extracting a water phase, an organic phase is combined, and drying is carried out to obtain the compoundCompound IX. For example, K₂CO₃Quenching reaction, separating liquid, extracting water phase by DCM, combining organic phases and drying to obtain the compound IX.

the invention also provides a compound shown as the formula V or VII,

Wherein R is¹And R²As previously defined.

The room temperature of the invention is 10-40 ℃.

The invention also provides application of the oxazoline ligand shown in the formula I as a catalyst ligand in asymmetric amination reaction of palladium-catalyzed olefin. The amination reaction is preferably an amine oxidation reaction.

The invention also provides application of the oxazoline ligand shown in the formula I as a catalyst ligand in asymmetric amination reaction of palladium-catalyzed olefin.

The invention also provides application of the complex shown as the formula IV as a catalyst in asymmetric amination reaction of palladium-catalyzed olefin.

Said application preferably comprises the following steps: in an organic solvent, under the action of a palladium catalyst and the oxazoline ligand shown in the formula I, a compound shown in the formula X and PhI (OC (O) R) shown in the formula XI are reacted₂Carrying out the following reaction to obtain a compound shown as a formula XII;

Wherein R is¹，R²，R³And R⁴The carbon marked with x is the chiral carbon with S configuration or R configuration;

R is substituted or unsubstituted C_1-10Alkyl radical, C_6-30Aryl or adamantyl; preferably, R is not methyl:

Wherein, said substituted C_1-10The substituent in the alkyl group is halogen;

R¹¹、R¹²Each independently selected from hydroxy, substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_3-8Or substituted or unsubstituted C_6-30An aryl group; or R¹¹、R¹²Together with the carbon to which they are attached form a substituted or unsubstituted C_3-8Cycloalkyl or 2-6 membered heterocyclyl; the heteroatom in the 2-6 membered heterocyclic group is one or more of O, N and S; the number of heteroatoms in the 2-6-membered heterocyclic group is 1-4; said substituted C_1-10Alkyl, substituted C_3-8Cycloalkyl of (5) and said substituted C_6-30The substituents in the aryl are each independently halogen, C_1-10Alkyl radical, C_1-10alkoxy radical,(R' is selected from C_1-10Alkyl), cyano, alkenyl, aryl and halogen substituted C_1-10one or more of alkyl; wherein, when the number of the substituents is plural, the substituents are the same or different.

Z isr' is substituted or unsubstituted C_6-30Aryl, or C_1-4An alkyl group; said substituted C_6-30The substituent in the aryl group being C_1-4alkyl radical, C_1-4One or more of alkoxy and nitro; wherein, when the number of the substituents is plural, the substituents are the same or different.

In R, the C_1-10Alkyl is preferably C_1-4An alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, more preferably a methyl group, an ethyl group, a tert-butyl group or an isopropyl group; preferably, C is_1-10Alkyl is preferably C_2-4An alkyl group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, more preferably ethyl, tert-butyl or isopropyl;

Said C_6-30Aryl is preferably C_6-14An aryl group, a heteroaryl group,More preferably phenyl.

In R, when said substituted C_1-10When the substituent in the alkyl group is halogen, the halogen is preferably fluorine; said substituted C_1-10The alkyl group is preferably trifluoromethyl.

R¹¹And R¹²wherein said substituted or unsubstituted C_1-10C in alkyl_1-10Alkyl, preferably C_1-4For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or isobutyl.

R¹¹And R¹²In (b), the C_1-10Alkoxy is preferably C_1-4alkoxy of (2), for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy or isobutoxy.

R¹¹And R¹²Wherein said substituted or unsubstituted C_3-8C in cycloalkyl of (2)_3-8Cycloalkyl of (b) is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

R¹¹And R¹²Wherein said substituted or unsubstituted C_6-30C in aryl_6-30Aryl, preferably C_6-14Aryl, for example, phenyl, naphthyl or anthracenyl.

R¹¹And R¹²In (1), the halogen is preferably F, Cl, Br or I.

R¹¹And R¹²In (1), theR' in (A) is preferably C_1-4Alkyl group of (1).

In a preferred embodiment of the invention, R¹¹And R¹²Identical or different, each independently of the others preferably represents hydroxy, substituted or unsubstituted C_6-30Aryl and substituted or unsubstituted C_1-10An alkyl group. Said substituted C_6-30Aryl is preferably halogen-substituted C_6-30Aryl radical, C_1-10Alkyl-substituted aryl, C_1-10Alkoxy-substituted C_6-30Aryl or(R' is selected from C_1-10Alkyl) substituted C_6-30An aryl group; said substituted or unsubstituted C_6-30C in aryl_6-30Aryl is preferably phenyl; said C_1-10The alkyl group is preferably a methyl group, an ethyl group or an isopropyl group. Said halogen substituted C_6-30Halogen in aryl is preferably fluorine or chlorine; said C_1-10C in alkyl-substituted aryl_1-10Alkyl is preferably methyl; said C_1-10Alkoxy-substituted C_6-30C in aryl_1-10Alkoxy is preferably methoxy; r' is preferably ethyl.

When R is¹¹、R¹²Together with the carbon to which they are attached form a substituted or unsubstituted C_3-8In the case of a cycloalkyl group of (A), said C_3-8The cycloalkyl group of (a) is preferably a cyclopropyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.

When R is¹¹、R¹²When taken together with the carbon to which they are attached to form a 2-6 membered heterocyclic group, the 2-6 membered heterocyclic group is preferably a 2-6 membered heterocyclic group containing an oxygen or nitrogen atom, more preferably a six membered heterocyclic group containing an oxygen or nitrogen atom, and most preferably

In Z, said substituted or unsubstituted C_6-30Aryl is preferably substituted or unsubstituted C_6-14Aryl, for example, benzene, naphthyl or anthracenyl.

Z is preferably

R is preferably methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, phenyl or adamantylMore preferably methyl. Preferably, R is preferably ethyl, tert-butyl, isopropyl, trifluoromethyl, phenyl or adamantyl

Preferably, R is¹¹and R¹²Each independently is any of the following structures:

Methyl, ethyl, n-propyl, benzyl,Phenyl, phenyl, Or a hydroxyl group.

Preferably, R is¹¹、R¹²together with the carbon to which it is attached, form any of the following structures:

In the preparation method of the compound shown in the formula XII, the organic solvent is preferably one or more of aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents and ester solvents. The aromatic hydrocarbon solvent is preferably toluene; the halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, fluorobenzene and trifluorotoluene, and is more preferably trifluorotoluene; the ester solvent is preferably ethyl acetate. The organic solvent can be used in an amount which is conventional in the art for carrying out such a reaction, as long as the reaction is not affected, and the volume molar ratio of the organic solvent to the compound II is preferably 1 to 10L/mol, more preferably 2 to 4L/mol, for example, 3L/mol.

In the preparation method of the compound shown in the formula XII, the palladium catalyst is preferably palladium chloride, palladium acetate, palladium trifluoroacetate or dichlorodiacetonitrile palladium, and more preferably palladium acetate. The amount of the palladium catalyst may be the amount conventionally used in the art for carrying out such a reaction, as long as the reaction is not affected, and the molar ratio of the palladium catalyst to the compound X is preferably 0.02 to 0.2, more preferably 0.1 to 0.15, for example, 0.1.

In the preparation method of the compound shown in the formula XII, the oxazoline ligand shown in the formula I is preferably selected More preferably

In the preparation method of the compound shown in the formula XII, the amount of the oxazoline ligand shown in the formula I may be the conventional amount used in the field for performing such a reaction, as long as the reaction is not affected, and the molar ratio of the oxazoline ligand shown in the formula I to the compound II is preferably 0.05 to 0.2, more preferably 0.12 to 0.15, for example, 0.12.

In the preparation method of the compound shown in the formula XII, PhI (OOCR)₂The amount of (b) may be an amount conventionally used in carrying out such a reaction in the art, and preferably it is in a molar ratio of 1.5 to 5.0, more preferably 2.0 to 3.0, for example, 2.0, to the compound X.

In the process for the preparation of the compound of formula XII, the reaction may be carried out in the presence of HOAc or may not be carried out in the presence of HOAc. When carried out in the presence of HOAc, the molar ratio of HOAc to compound II is preferably 1.0 to 5.0, e.g. 5.0.

in the preparation method of the compound shown in the formula XII, the reaction temperature is preferably-10-30 ℃, and preferably 0 ℃.

In the preparation method of the compound shown in formula XII, the reaction progress can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of compound X is generally monitored as the reaction end point.

In the preparation method of the compound shown in formula XII, the reaction may further comprise a post-treatment, and the post-treatment is a conventional post-treatment method of the reaction, and preferably comprises the following steps: diluting with an organic solvent, filtering, concentrating and purifying to obtain the compound XII. For example, the reaction solution is diluted with ethyl acetate, filtered through a short column of silica gel, concentrated, and the crude sample is isolated by column chromatography to give compound XII.

In the present invention, the carbon marked with x is an S-configuration or R-configuration chiral carbon.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the oxazoline ligand takes olefin as a substrate under the action of a palladium catalyst, and obtains the optically active beta-ester group substituted piperidine compound with excellent yield, excellent regioselectivity and enantioselectivity through the asymmetric 6-endo cyclization reaction of the olefin. The chiral trifluoromethoxy group is introduced into the piperidine compound, and the method has the advantages of simple reaction operation, high enantioselectivity, high product yield and wide substrate universality.

Drawings

FIG. 1 is a single crystal diffraction pattern of compound X of example 18.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the specific operation temperature is not limited, and it is referred to that the operation is carried out at room temperature (10 to 40 ℃ C.). Equiv means equivalent; ee means enantiomeric excess; [ alpha ] to]Specific optical rotation;¹H NMR refers to nuclear magnetic resonance hydrogen spectroscopy;¹⁹F NMR refers to nuclear magnetic resonance fluorine spectroscopy;¹³C NMR refers to nuclear magnetic resonance carbon spectroscopy; IR refers to infrared spectroscopy; HRMS refers to high resolution mass spectrometry; calculated means calculated value and measured means actual value. IR (near, cm)^-1) The neat in (1) refers to that a pure sample is directly used for infrared test without KBr tablet pressing or solution smearing.