Copper-catalyzed chiral fluoro-alpha-amino acid compound and preparation method thereof

Abstract

The invention belongs to the field of organic compounds, and particularly relates to a copper-catalyzed chiral fluoro-alpha-amino acid compound and a preparation method thereof. According to the specific technical scheme, alpha-imine ester is used as an amino acid precursor, asymmetric functionalization is catalyzed through a transition metal catalyst, difluorobenzyl or polyfluoroaryl is introduced into amino acid molecules, and the chiral fluoro alpha-amino acid compound is synthesized. The method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, short steps, good yield, high selectivity, high product optical purity, rich functional group diversity and the like. The method provided by the invention can be used for synthesizing analogues of marketed drugs, and also can be used for carrying out structural post-modification on bioactive molecules, thereby providing a brand-new technical platform for discovery of novel bioactive molecules.

Description

Technical Field

[0001] The invention belongs to the field of organic compounds, and in particular relates to a copper-catalyzed chiral fluorinated α-amino acid compound and a preparation method thereof. Background Art

[0002] Amino acids are a class of small molecule compounds that are widely found in nature and can be divided into two categories: protein amino acids and non-protein amino acids. Among them, 20 α-amino acids are components of almost all proteins in nature and are called protein amino acids.

[0003] Introducing fluorine atoms or fluorine-containing groups into amino acids can improve the physical and chemical properties and biological activity of their molecules, and plays an important role in the field of pharmaceutical research and development. Therefore, how to efficiently introduce fluorine atoms or fluorine-containing fragments into amino acids is an important research direction in the field of medicinal chemistry. Due to the special properties of fluorine atoms (maximum electronegativity, small atomic radius, etc.), the synthesis and acquisition of chiral fluorinated α-amino acids with diverse structures is still extremely challenging, and there is a large room for development.

[0004] At present, there are few reports on the construction of chiral fluorinated α-amino acids by introducing fluorinated building blocks as electrophiles. Therefore, the introduction of new fluorinated electrophiles to achieve the synthesis of chiral fluorinated α-amino acids with diverse structures has very important research significance and application prospects.

[0005] Commonly used difluoro reagents (XCF2R) often need to go through free radical pathways or carbene intermediates, and it is difficult to achieve asymmetric reactions to prepare chiral compounds. Difluorobenzyl trifluoromethanesulfonyl can form difluorobenzyl metal intermediates or difluorobenzyl cationic intermediates through metal oxidative addition to participate in the reaction, providing more possibilities for achieving asymmetric catalytic reactions. However, there have been no related reports so far. In addition, difluorobenzyl substituted α-amino acids are a special class of fluorinated amino acids with interesting chemical structures and rich and diverse biological activities. They have attracted widespread attention in recent years, but their related synthetic studies are very rare. The existing synthetic routes of difluorobenzyl substituted α-amino acid compounds are cumbersome, and the preparation of chiral difluorobenzyl substituted α-amino acid compounds requires the use of enzyme resolution or chiral reagents, and the atom economy is poor. Therefore, the development of efficient asymmetric synthesis strategies to achieve their preparation has important research significance and application value.

[0006] Due to their unique physiological properties, polyfluoroaromatic groups are commonly found as basic skeletons in many important drug molecules. Selective functionalization of the CF bonds of cheap and readily available polyfluoroaromatics is one of the most direct and efficient methods to introduce polyfluoroaromatic groups into organic molecules. However, due to the inherent inertness of the CF bonds and the multiple reaction site selectivity of polyfluoroaromatics, the selective (regioselectivity, enantioselectivity) functionalization of polyfluoroaromatics under mild conditions has been a long-standing challenge in this field. At present, there have been reports on the synthesis of polyfluoroaromatic substituted amino acids as basic skeletons through the functionalization of polyfluoroaromatic CF bonds, but all of them are synthesized from racemic polyfluoroaromatic substituted α-amino acid compounds, and chiral versions have not been achieved. Summary of the invention

[0007] The purpose of the present invention is to provide a copper-catalyzed chiral fluorinated α-amino acid compound and a preparation method thereof.

[0008] To achieve the above-mentioned purpose of the invention, the technical scheme adopted by the present invention is: a method for synthesizing chiral fluorinated α-amino acid compounds, using difluorobenzyl trifluoromethanesulfonyl or polyfluoroaromatic hydrocarbons as fluorine-containing electrophilic reagents and α-imidate as amino acid precursors, and introducing difluorobenzyl or polyfluoroaromatic groups into amino acid molecules through asymmetric functionalization catalyzed by transition metal catalysts.

[0009] Preferably, a chiral ligand, a transition metal catalyst and a solvent are added to a reaction container, stirred evenly, and then difluorobenzyl trifluoromethanesulfonyl or polyfluoroaromatic hydrocarbon, α-imidate and a base are added, and the mixture is reacted at 0 to 60° C. for 5 to 24 hours.

[0010] Preferably, the chiral ligand is Any one of R 1 is any one of H, aryl, and C1-12 alkyl, R is any one of C1-12 alkyl and aryl, Ar is any one of aryl groups, and C1-12 alkyl includes but is not limited to C1-12 alkyl substituted by cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl, etc.

[0011] Preferably, the transition metal catalyst is any one of cuprous hexafluorophosphate, cuprous tetraacetonitrile, cuprous tetrafluoroborate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cupric acetate, cupric chloride, and cupric trifluoromethanesulfonate.

[0012] Preferably, the solvent is any one or a combination of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl ether, chloroform, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.

[0013] Preferably, the base is any one or a combination of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, DBU, and triethylamine.

[0014] Preferably, the reaction equation of the method is as follows:

[0015]

[0016] R 1 is any one of H and C1-12 alkyl, R 2 is any one of a C1-12 alkyl group and an aryl group, R 3 It is any one of hydrogen, halogen, alkyl, alkoxy, amino, acyl, ester, cyano and nitro, and the number of substituents is 1, 2, 3, 4 or 5; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted by cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl and the like.

[0017] The method comprises the following steps: based on the molar amount of difluorobenzyl trifluoromethanesulfonyl, adding 10 mol% of a transition metal catalyst, 12 mol% of a chiral ligand and a 0.1 M solvent into a dry reaction test tube, stirring evenly, then adding difluorobenzyl trifluoromethanesulfonyl, α-imidate and cesium carbonate, and then reacting at 0-60°C for 5-24 hours.

[0018] Preferably, the reaction equation of the method is as follows:

[0019]

[0020] R 1 is any one of H and C1-12 alkyl, R 2 is any one of C1-12 alkyl and aryl; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted by cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl, etc.; X is carbon or nitrogen; Fn is a fluorine atom substituent on the aromatic ring, the number is n, and n is 0, 1, 2, 3, 4 or 5;

[0021] The method comprises the following steps: based on the molar amount of the imine ester, adding 10 mol% of a transition metal catalyst, 12 mol% of a chiral ligand and 0.1M of a solvent into a dry reaction test tube, stirring evenly, adding polyfluoroaromatic hydrocarbons, α-imine ester and cesium carbonate, and reacting at 0-60°C for 5-24 hours.

[0022] Correspondingly, the compound synthesized by the method has the general structural formula of: R 1 is any one of H and C1-12 alkyl, R 2is any one of a C1-12 alkyl group and an aryl group, R 3 It is any one of hydrogen, halogen, alkyl, alkoxy, amino, acyl, ester, cyano and nitro, and the number of substituents is 1, 2, 3, 4 or 5; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted by cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl and the like.

[0023] Correspondingly, the compound synthesized by the method has the general structural formula of: R 1 is any one of H and C1-12 alkyl, R 2 It is any one of C1-12 alkyl and aryl. C1-12 alkyl includes but is not limited to C1-12 alkyl substituted by cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl, etc.; X is carbon or nitrogen; Fn is a fluorine atom substituent on the aromatic ring, the number is n, and n is 0, 1, 2, 3, 4 or 5.

[0024] Correspondingly, the compound synthesized by the method or its stereoisomer or its pharmaceutically acceptable salt is used in the pharmaceutical field. Alternatively, the compound or its stereoisomer or its pharmaceutically acceptable salt is used in the pharmaceutical field.

[0025] The present invention has the following beneficial effects: the present invention uses difluorobenzyl trifluoromethanesulfonyl or polyfluoroaromatic hydrocarbons as fluorine-containing electrophilic reagents and α-imidate as amino acid precursors, and introduces difluorobenzyl or polyfluoroaromatic hydrocarbons into amino acid molecules through copper-catalyzed asymmetric functionalization to obtain a single stereoconfiguration fluorinated non-natural α-amino acid. In the method provided by the present invention, difluorobenzyl trifluoromethanesulfonyl forms a difluorobenzyl cation (ArCF2 + ) intermediates, or polyfluoroaromatic hydrocarbons react with α-imidates through site-specific CF bond cleavage, and chiral catalysts (copper salts and chiral ligands) provide a good chiral environment, ultimately achieving chiral non-natural fluorinated α-amino acid derivatives: synthesis of chiral difluorobenzyl-substituted or polyfluoroaryl-substituted α-amino acid compounds.

[0026] The method provided by the invention has the advantages of readily available raw materials, mild reaction conditions, short steps, good yield, high selectivity, high optical purity of the product, and rich functional group diversity.

[0027] The method provided by the present invention can synthesize analogs of marketed drugs (such as L-Dopa, R-DFMO, etc.), and can also synthesize new biologically active molecules, providing a new technical platform for discovering new biologically active molecules. The method of the present invention has been used to synthesize and provide two new types of fluorinated amino acid compounds: chiral difluorobenzyl substituted α-amino acids and polyfluoroaryl substituted α-amino acids. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the single crystal spectrum of compound 3ac synthesized in the present invention;

[0029] Figure 2 This is the single crystal spectrum of compound 5dc synthesized in the present invention. DETAILED DESCRIPTION

[0030] The present invention provides a series of novel chiral fluorinated α-amino acid compounds, the general structural formula of which is: R F is a difluorobenzyl group or a polyfluoroaryl group, specifically including: (Formula I, difluorobenzyl substituted α-amino acid) or (Formula II, polyfluoroaryl substituted α-amino acid).

[0031] Among them, R 1 is any one of H and C1-12 alkyl, R 2 is any one of a C1-12 alkyl group and an aryl group, R 3 It is any one of hydrogen, halogen, alkyl, alkoxy, amino, acyl, ester, cyano and nitro, and the number of substituents is 1, 2, 3, 4 or 5; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted with cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, aryl and the like; X is carbon or nitrogen; Fn is a fluorine atom substituent on the aromatic ring, and the number is n, where n is 0, 1, 2, 3, 4 or 5.

[0032] The present invention also provides a method for preparing the chiral fluorinated α-amino acid compound, and the reaction equation and steps are as follows:

[0033]

[0034] Add a chiral ligand, a transition metal catalyst and a solvent to a dry reaction vessel, stir evenly, add a reaction substrate and a base (optionally cesium carbonate), and react at 0 to 60°C (preferably 40°C) for 5 to 24 hours (preferably 12 hours). After the reaction is completed, filter with diatomaceous earth, elute with ethyl acetate, and concentrate the eluent to obtain a crude product. Add a solvent and an acid solution to the crude product, stir at 0 to 40°C (preferably 25°C) for 2 hours of hydrolysis reaction. Extract with ethyl acetate, collect the organic phase, concentrate to obtain a crude product, and then separate and purify by silica gel column chromatography. The eluent used for separation is preferably: by volume, petroleum ether (PE): ethyl acetate (EA) = 5:1 to 1:1.

[0035] Among them, the chiral ligand is In PR2 of L1, 2 represents the number, R is any one of an aryl group and an alkyl group. In PAr2 of L2 and L3, 2 represents the number, Ar is any aryl group, and R 1 is any one of iPr (isopropyl), tBu (tert-butyl), Ph (phenyl and phenyl with various substituted groups), Bn (benzyl). The preferred scheme is: select Ph-L1-iPr (i.e. R is phenyl, R 1 When L1 is isopropyl, it is a chiral ligand.

[0036] The transition metal catalyst is any one of tetraacetonitrile cuprous hexafluorophosphate, tetraacetonitrile cuprous tetrafluoroborate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cupric acetate, cupric chloride, and copper trifluoromethanesulfonate, preferably tetraacetonitrile cuprous hexafluorophosphate. The solvent used in the first step of the reaction is any one or a combination of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ether, chloroform, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide. The base is any one or a combination of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, DBU (1,8-diazabicyclo[5.4.0]-7-undecene), and triethylamine.

[0037] During the hydrolysis reaction, the solvent is any one of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, toluene, and acetonitrile; the acid solution is any one of hydrochloric acid aqueous solution, citric acid aqueous solution, and p-toluenesulfonic acid aqueous solution; the reaction temperature is 0 to 40°C; and the reaction time is 1 to 5 hours. The preferred scheme is: the hydrolysis reaction solvent is dichloromethane, the acid solution is a hydrochloric acid solution, preferably with a concentration of 1 mol / L, the reaction temperature is 25°C, and the reaction time is 2 hours.

[0038] When the compound structure is as shown in Formula I, the general synthesis formula is as follows, Chiral ligand refers to chiral ligand, the same below, no further description is given:

[0039]

[0040] The method for synthesizing difluorobenzyl substituted α-amino acid comprises: in a glove box, based on the molar amount of difluorobenzyl trifluoromethanesulfonyl, adding 10 mol% of transition metal catalyst, 12 mol% of chiral ligand and 0.1M solvent to a dry reaction tube. Stirring for 10 to 30 minutes, then adding difluorobenzyl trifluoromethanesulfonyl (1 equivalent), α-imidate (1.5 equivalents) and cesium carbonate (2 equivalents, relative to the molar amount of difluorobenzyl trifluoromethanesulfonyl). Then, the test tube is transferred out of the glove box and reacted in an oil bath at 0 to 60° C. for 5 to 24 hours. After the reaction is completed, diatomaceous earth is filtered, ethyl acetate is eluted, and the eluent is concentrated to obtain a crude product. Dichloromethane (0.05M) and hydrochloric acid (10 equivalents, 1M) are added to the crude product, and stirred at 25° C. for 2 hours. The ethyl acetate is extracted and concentrated, and the crude product is separated and purified by silica gel column chromatography. The eluent used for separation is petroleum ether (PE): ethyl acetate (EA).

[0041] When the synthesized compound is a difluorobenzyl-substituted α-amino acid and the ligand is a racemic ligand, the synthesized compound is a racemate. When the chiral ligand used is L1 and the ligand configuration is (S, Sp), the synthesized compound configuration is R; when the chiral ligand used is L1 and the ligand configuration is (R, Rp), the synthesized compound configuration is S. When the chiral ligand used is L2 or L3 and the ligand configuration is R, the synthesized compound configuration is R; when the chiral ligand used is L2 or L3 and the ligand configuration is S, the synthesized compound configuration is S.

[0042] When the compound structural formula is shown in Formula II, the general synthesis formula is as follows:

[0043]

[0044] The method for synthesizing chiral polyfluoroaryl substituted α-amino acid comprises: in a glove box, based on the molar amount of imine ester, adding 10 mol% of transition metal catalyst, 12 mol% of chiral ligand and 0.1M solvent to a dry reaction tube. Stirring for 10 to 30 minutes, then adding polyfluoroaromatic hydrocarbon (1.2 equivalents), α-imine ester (1 equivalent) and cesium carbonate (2 equivalents, relative to the molar amount of imine ester). Then, the test tube is transferred out of the glove box and reacted in an oil bath at 0 to 60°C for 5 to 24 hours. After the reaction is completed, diatomaceous earth is filtered, ethyl acetate is eluted, and the eluent is concentrated to obtain a crude product. Dichloromethane (0.05M) and hydrochloric acid (10 equivalents, 1M) are added to the crude product, and stirred at 25°C for 2 hours. The ethyl acetate is extracted and concentrated, and the crude product is separated and purified by silica gel column chromatography. The eluent used for separation is petroleum ether (PE): ethyl acetate (EA).

[0045] When the synthesized compound is a polyfluoroaryl-substituted α-amino acid and the ligand is a racemic ligand, the synthesized compound is a racemate. When the chiral ligand L1 is used, the ligand configuration is (S,Sp ), the configuration of the synthesized compound is S; when the chiral ligand used is L1, the ligand configuration is (R,R p ), the configuration of the synthesized compound is R; when the chiral ligand L2 or L3 used has a ligand configuration of R, the configuration of the synthesized compound is S; when the chiral ligand L2 or L3 used has a ligand configuration of S, the configuration of the synthesized compound is R.

[0046] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. The data obtained are all average values ​​obtained after at least 3 repetitions, and all the data obtained in each repetition are valid data.

[0047] Example 1: Synthesis of difluorobenzyl substituted α-amino acids

[0048] 1. Synthesize compound 3aa.

[0049] (1) Synthesize compound (R)-3aa. The synthesis reaction equation is:

[0050]

[0051] The synthesis method is as follows: in a glove box, add copper tetraacetonitrile hexafluorophosphate (10 mol%, 0.01 mmol, 3.7 mg), chiral ligand (S,Sp)-Ph-L1-iPr (12 mol%, 0.01 mmol, 5.8 mg) and mixed solvent (1.0 mL, 0.1 M, THF / DCE=1:1, v / v) to a dry reaction tube. Stir for 30 minutes, then add difluorobenzyl trifluoromethanesulfonyl (compound 1a, 28.5 mg, 0.1 mmol, 1.0 equiv), α-imidate (compound 2a, 28.6 mg, 0.15 mmol, 1.5 equiv) and cesium carbonate (0.2 mmol, 65.2 mg, 2.0 equiv). Then transfer the test tube out of the glove box and react in an oil bath at 40°C for 12 hours. After the reaction is completed, filter with diatomaceous earth, elute with ethyl acetate, and concentrate the eluate to obtain a crude product. The crude product was added with dichloromethane (2 mL) and hydrochloric acid (2 mL, 1 M) and stirred at room temperature for 2 hours. The product was extracted and concentrated with ethyl acetate, and the crude product was separated and purified by silica gel column chromatography. The eluent used for separation was petroleum ether (PE): ethyl acetate (EA) = 3:1 to 1:1, and pure (R)-3aa was obtained.

[0052] The product 3aa was a yellow oil, 20.3 mg, with a yield of 80% and an ee value of 96%. 1H NMR, 13 CNMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0053] 1 H NMR (400MHz, Chloroform-d) δ7.73(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),3.76(s,3H),1.79(brs,2H),1.45(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-99.43–-116.10(dd). 13 C NMR(151MHz,Chloroform-d)δ171.82,138.28(t,J=27.1Hz),131.57,127.75(t,J=6.5Hz),120 .01(t,J=237.0Hz),117.99,114.21,63.39(t,J=27.4Hz),52.95,20.63.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 21 F2N2O2 255.0940; found 255.0937. HPLC analysis: 96%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 14.401min (major) and 15.825min (minor)].

[0054] (2) Synthesize compound (R)-3aa. The synthesis reaction equation is:

[0055]

[0056] The synthesis method is the same as (R)-3aa, except that the copper catalyst is replaced by cuprous chloride. The product 3aa is a yellow oil, 19.6 mg, with a yield of 77% and an ee value of 92%.

[0057] (3) Synthesize compound (R)-3aa. The synthesis reaction equation is:

[0058]

[0059] The synthesis method is the same as (R)-3aa, except that the chiral ligand is replaced by Ph-L1-tBu. The product 3aa is a yellow oil, 18.5 mg, with a yield of 73% and an ee value of 96%.

[0060] (4) Synthesize compound (R)-3aa. The synthesis reaction equation is:

[0061]

[0062] The synthesis method is the same as (R)-3aa, except that the base is replaced by K3PO4. The product 3aa is a yellow oil, 9.4 mg, with a yield of 37% and an ee value of 96%.

[0063] (5) Synthesize compound (S)-3aa. The synthesis reaction equation is:

[0064]

[0065] The synthesis method is the same as (R)-3aa, except that the chiral ligand is replaced and the catalyst is cuprous tetraacetonitrile hexafluorophosphate. The product (S)-3aa is a colorless oil (PE / EA=3:1), 17.1 mg, yield 67%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of FNMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0066] 1 H NMR (400MHz, Chloroform-d) δ7.73(d,J=8.1Hz,1H),7.63(d,J=8.2Hz,1H),3.75(s,2H),1.81(s,2H),1.45(s,2H). 13 C NMR(101MHz,Chloroform-d)δ171.80,138.31(t,J=27.1Hz),131.58,127.76(t,J=6.5Hz), 120.69(t,J=254.52Hz),118.00,114.24,63.45(t,J=27.6Hz),52.95,20.65(t,J=3.1Hz). 19 F NMR(376MHz,Chloroform-d)δ-105.75(d,J=246.7Hz),-107.19(d,J=247.1Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 21F2N2O2255.0940; found 255.0935.HPLC analysis:96%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 13.731min (minor) and 14.525min (major)].

[0067] 2. Synthesis of 3aa series compounds. The synthesis method is the same as (R)-3aa, and the catalyst is cuprous tetraacetonitrile hexafluorophosphate.

[0068] (1) Synthesis of compound 3ab. The synthesis reaction equation is as follows:

[0069]

[0070] The product (R)-3ab was a yellow oil (PE / EA=5:1), 24.1 mg, yield 86%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0071] 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.1Hz,2H),7.65(d,J=8.2Hz,2H),5.73–5.54(m,1H),5.22(d,J=10.3 Hz,1H),5.16(s,0H),3.77(s,3H),2.99(dd,J=13.6,6.2Hz,1H),2.26(dd,J=13.6,8.4Hz,1H),1.77(brs,2H). 13 C NMR(101MHz,Chloroform-d)δ171.19,138.40(t,J=26.8Hz),131.58,130.78,127.91(t,J=6 .3Hz),121.34,120.49(t,J=255.53Hz),118.04,114.27,66.34(t,J=27.3Hz),53.00,37.58. 19 F NMR(376MHz,Chloroform-d)δ-104.13(d,J=246.8Hz),-106.27(d,J=246.9Hz).HRMS(ESI)m / z:[M+H] +Calcd for C 14 H 15 F2N2O2 281.1096; found 281.1089. HPLC analysis: 94%ee [DaicelChiralpak IC, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 14.621min (minor) and 20.710min (major)].

[0072] (2) Synthesis of compound 3ac. The synthesis reaction equation is as follows:

[0073]

[0074] The product (R)-3ac is a yellow oil (PE / EA=1:1), 17.3 mg, 59% yield, 94% ee value. By growing a single crystal, the single crystal spectrum is as follows Figure 1 As shown, its absolute configuration is determined to be R configuration, and its CCDC number is: 2282716. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0075] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.0Hz,2H),7.58(d,J=8.1Hz,2H),6.75(brs,1H),3.7 8(s,3H),2.68(ddd,J=14.0,9.6,4.2Hz,1H),2.51(dt,J=14.2,9.4Hz,1H),2.40–2.22(m,2H). 13 C NMR(101MHz,Chloroform-d)δ176.77,168.65(d,J=3.6Hz),136.63(t,J=26.7Hz),132.28,127.19 (t,J=6.3Hz),119.58(t,J=256.54Hz),117.58,115.19,70.04(t,J=29.7Hz),53.49,29.48,25.50. 19 F NMR(376MHz,Chloroform-d)δ-105.41(d,J=251.6Hz),-108.25(d,J=251.8Hz).HRMS(ESI)m / z:[M+H]+ Calcd for C 14 H 13 F2N2O3 295.0889; found 295.0891.HPLC analysis:94%ee[Daicel Chiralpak OZ,n-hexane / iso-propanol=80 / 20, 1.0 mL / min, λ = 210 nm, retention time: 27.217min (major)and 36.128min(minor)].

[0076] (3) Synthesize compound (R)-3ad. The synthesis reaction equation is as follows:

[0077]

[0078] The product (R)-3ad is a colorless oil (PE / EA=3:1), 15.4 mg, yield 52%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0079] 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.0Hz,2H),7.61(d,J=8.1Hz,2H),3.73(s,3H),2.09(dd,J=13.9, 7.9Hz,1H),1.84–1.68(m,3H),1.61(dd,J=13.9,5.0Hz,1H),0.99(d,J=6.7Hz,3H),0.83(d,J=6.6Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.74,138.60(t,J=27.0Hz),131.49,127.90,123.99–118.11(m) ,120.70(t,J=256.05),118.06,114.15,66.87(t,J=26.3Hz),52.69,40.49,24.69,24.03,22.28. 19 F NMR(376MHz,Chloroform-d)δ-104.83(d,J=245.2Hz),-106.70(d,J=245.2Hz).HRMS(ESI)m / z:[M+H] +Calcd for C 15 H 19 F2N2O2 297.1409; found 297.1410. HPLC analysis: 91%ee [Daicel Chiralpak AD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 9.213min (major) and 14.890min (minor)].

[0080] (4) Synthesize compound (R)-3ae. The synthesis reaction equation is as follows:

[0081]

[0082] The product (R)-3ae was a yellow oil (PE / EA=2:1), 13.2 mg, yield 43%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0083] 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=8.0Hz,2H),7.59(d,J=8.1Hz,2H),3.75(s,3H),2.42(q,J=6.7Hz,2H) ,2.29(td,J=12.4,4.5Hz,1H),1.99–1.86(m,1H),1.76(dt,J=13.0,6.1Hz,4H),1.53(dq,J=12.5,5.7Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ170.02,137.97(t,J=27.2Hz),131.79,127.51,120.39(t,J=2 57.55Hz),118.97,117.85,114.55,67.21(t,J=26.9Hz),53.08,31.82,29.71,20.18,17.35. 19 F NMR(376MHz,Chloroform-d)δ-105.30(d,J=246.7Hz),-106.69(d,J=246.7Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 15 H16 F2N3O2 308.1205; found 308.1204. HPLC analysis: 93%ee [DaicelChiralpak AD, n-hexane / iso-propanol=80 / 20, 1.0mL / min, λ=210nm, retention time: 14.598min (major) and 18.858min (minor)].

[0084] (5) Synthesize compound (R)-3af. The synthesis reaction equation is as follows:

[0085]

[0086] The product (R)-3af was a yellow oil (PE / EA=3:1), 21.4 mg, with a yield of 68%. 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0087] 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.0Hz,2H),7.60(d,J=8.1Hz,2H),3.74(s,3H),2.64(td,J=12.0,11.2,4. 5Hz,1H),2.55–2.44(m,1H),2.37(dt,J=12.0,7.8Hz,1H),2.11(s,3H),1.90(dt,J=8.1,4.6Hz,1H),1.78(brs,2H). 13 C NMR(101MHz,Chloroform-d)δ170.34,138.17(t,J=27.1Hz),131.68,127.66(t,J=6.4Hz), 120.48(t,J=254.52Hz),117.93,114.39,67.09(t,J=26.8Hz),52.98,32.54,28.49,15.64. 19 FNMR(376MHz,Chloroform-d)δ-104.83(d,J=248.2Hz),-107.34(d,J=248.0Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 14 H 17F2N2O2S315.0973; found 315.0973. HPLC analysis:94%ee [Daicel Chiralpak AD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 12.536min (major) and 17.627min (minor)].

[0088] 3. Use the method for synthesizing (R)-3aa to synthesize other difluorobenzyl-substituted α-amino acid compounds, and the catalyst is cuprous tetraacetonitrile hexafluorophosphate.

[0089] (1) Synthesize compound (R)-3ba. The reaction equation for the synthesis is as follows:

[0090]

[0091] The product (R)-3ba was a colorless oil (PE / EA=5:1), 20.8 mg, yield 82%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0092] 1 H NMR (400 MHz, Chloroform-d) 1 H NMR (400MHz, Chloroform-d) δ7.83 (s, 1H), 7.76 (d, J = 8.0Hz, 2H), 7.56 (t, J = 7.9Hz, 1H), 3.77 (s, 3H), 1.77 (brs, 2H), 1.45 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ171.90,135.27(t,J=27.5Hz),133.62,131.20(t,J=5.9Hz),130.75( t,J=6.5Hz),128.75,120.75(t,J=251.49Hz),118.07,112.27,63.31(t,J=27.8Hz),52.96,20.66. 19 F NMR(376MHz,Chloroform-d)δ-105.18(d,J=248.4Hz),-106.84(d,J=248.7Hz).HRMS(ESI)m / z:[M+H] + Calcd for C12 H 13 F2N2O2 255.0940; found255.0935. HPLC analysis: 96%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 17.919min (minor) and 19.779min (major)].

[0093] (2) Synthesis of compound (R)-3ca. The reaction equation for the synthesis is as follows:

[0094]

[0095] The product (R)-3ca was a white solid (PE / EA=5:1), 16.6 mg, yield 58%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0096] 1 H NMR (400MHz, Chloroform-d) δ8.09(d,J=8.1Hz,2H),7.55(d,J=8.1Hz,2H),3.96(s,3H),3.73(s,3H),1.72(brs,2H),1.46(s,3H). 13 C NMR (101MHz, Chloroform-d) δ171.85, 166.28, 137.99 (t, J = 26.6Hz), 131.81, 129.05, 126.80 (t, J = 6.3Hz), 63.64 (t, J = 28.5Hz), 52.78, 52.35, 20.49. 19 F NMR(376MHz,Chloroform-d)δ-105.84(d,J=245.2Hz),-107.07(d,J=244.9Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 16F2NO4288.1042; found288.1042. HPLC analysis: 95%ee [Daicel Chiralpak IC, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retention time: 14.120min (major) and 15.721min (minor)].

[0097] (3) Synthesize compound (R)-3da. The reaction equation for the synthesis is as follows:

[0098]

[0099] The product (R)-3da was a yellow oil (PE / EA=3:1), 23.5 mg, yield 86%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0100] 1 H NMR (400MHz, Chloroform-d) δ8.29(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),3.77(s,3H),1.83(brs,2H),1.47(s,3H). 13 C NMR (101MHz, Chloroform-d) δ 171.86, 148.98, 140.03 (t, J = 27.0Hz), 128.25 (t, J = 6.3Hz), 122.92, 63.39 (t, J = 29.4Hz), 53.01, 20.70. (Note: the peaks of CF2 didn't appear in the spectrum.) 19 F NMR(376MHz,Chloroform-d)δ-105.31(d,J=247.7Hz),-106.75(d,J=247.5Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 11 H 13F2N2O4 275.0838; found 275.0833. HPLC analysis: 92%ee [DaicelChiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=210nm, retentiontime: 14.707min (major) and 17.360min (minor)].

[0101] (4) Synthesize compound (R)-3ea. The reaction equation for the synthesis is as follows:

[0102]

[0103] The product (R)-3ea was a white solid (PE / EA=3:1), 23.7 mg, yield 71%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0104] 1 H NMR (400MHz, Chloroform-d) δ7.83(dd,J=11.8,7.9Hz,4H),7.69–7.57(m,3H),7.51(t,J=7.6Hz,2H),3.75(s,3H),1.77(brs,2H),1.48(s,3H). 13 C NMR(101MHz,Chloroform-d)δ195.90,171.94,139.11,137.40(t,J=26.7Hz),137.03,132.83,13 0.06,129.36,128.43,126.80(t,J=6.2Hz),63.58(t,J=27.8Hz),52.85,20.60.(Note:thepeaks of CF2 didn't appear in the spectrum.) 19 F NMR(376MHz,Chloroform-d)δ-105.32(d,J=245.6Hz),-106.63(d,J=245.5Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 18F2NO3 334.1249; found 334.1250. HPLC analysis: 96%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 17.147min (major) and 18.792min (minor)].

[0105] (5) Synthesize compound (R)-3fa. The reaction equation for the synthesis is as follows:

[0106]

[0107] The product (R)-3fa was a white oil (PE / EA=2:1), 19 mg, yield 62%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0108] 1 H NMR (400MHz, Chloroform-d) δ8.01(d,J=8.2Hz,2H),7.73(d,J=8.2Hz,2H),3.76(s,3H),3.10(s,3H),1.81(brs,2H),1.46(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.83,142.21,139.28(t,J=26.9Hz),128.14(t,J=6 .4Hz),126.91,120.01(t,J=254.52Hz),63.43(t,J=27.6Hz),52.99,44.40,20.70. 19 F NMR(376MHz,Chloroform-d)δ-105.15(d,J=247.3Hz),-106.62(d,J=247.3Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 12 H 16F2NO4S 308.0763; found 308.0757HJ. HPLC analysis: 98%ee [Daicel Chiralpak IC, n-hexane / iso-propanol=70 / 30, 1.0mL / min, λ=210nm, retention time: 33.554min (major) and 35.631min (minor)].

[0109] (6) Synthetic product (R)-3ga. The synthetic reaction equation is:

[0110]

[0111] The product (R)-3ga was a light yellow solid (PE / EA=5:1), 28.5 mg, with a yield of 78%. The measurement conditions and results of nuclear magnetic resonance (1HNMR, 13C NMR, 19F NMR), high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0112] 1 H NMR (400MHz, Chloroform-d) δ7.82(d,J=8.2Hz,1H),7.80(s,1H),7.49(d,J=7.9Hz,1H),3.97(s,3H),3.75(s,3H),1.71(brs,2H),1.45(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.74,166.00,137.98(t,J=27.2Hz),133.75,132.74(t,J=6.5H z),130.58,125.66(t,J=6.2Hz),121.07,63.48(t,J=27.5Hz),52.91,52.70,20.56.(Note:the peaks of CF2 didn'tappear in the spectrum) 19 F NMR(376MHz,Chloroform-d)δ-105.58(d,J=246.5Hz),-107.07(d,J=246.4Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 15BrF2NO4 366.0147; found 366.0137. HPLC analysis: 93%ee [Daicel Chiralpak AD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 10.727min (major) and 15.172min (minor)].

[0113] (7) Synthesize product (R)-3ha. The synthesis reaction equation is:

[0114]

[0115] The product (R)-3ha was a brown oil (PE / EA=5:1), 24.8 mg, yield 71%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0116] 1 H NMR(400MHz,Chloroform-d)δ7.99(s,3H),3.77(s,3H),1.79(brs,2H),1.48(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.73,136.34(t,J=28.0Hz),131.36(q,J=33.9Hz),127.59–127.48(m),124.13– 123.92 (m), 122.95 (d, J = 2.73.71Hz), 120.28 (t, J = 255.53Hz), 63.27 (t, J = 27.5Hz), 52.95, 20.72 (t, J = 3.0Hz). 19 F NMR(376MHz,Chloroform-d)δ-62.94,-104.96(d,J=249.2Hz),-106.94(d,J=249.1Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 12F8NO2 366.0735; found 366.0731. HPLC analysis: 92%ee [Daicel Chiralpak OJ, n-hexane / iso-propanol=97 / 3, 1.0mL / min, λ=210nm, retention time: 6.555min (minor) and 7.097min (major)].

[0117] (8) Synthesize the product (R)-3ia. The reaction equation for the synthesis is:

[0118]

[0119] The product (R)-3ia was a yellow oil (PE / EA=3:1), 16.7 mg, yield 41%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0120] 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=8.3Hz,1H),7.93(s,1H),7.79(d,J=8.3Hz,1H),7.44–7. 29(m,5H),6.72(t,J=5.5Hz,1H),4.65(d,J=5.6Hz,2H),3.79(s,3H),1.84(brs,2H),1.53(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.52,164.13,149.24,137.64,137.32,130.73(t,J=6.8Hz),128.90,128 .65,128.36,127.95,127.93,122.46,120.53(t,J=255.53Hz),64.20(t,J=27.2Hz),53.22,44.44,20.80. 19 F NMR(376MHz,Chloroform-d)δ-98.71(d,J=259.1Hz),-101.28(d,J=259.0Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 14 H 15F2N2O2408.1366; found408.1367. HPLC analysis: 90%ee [DaicelChiralpak AD-H, n-hexane / iso-propanol=80 / 20, 1.0mL / min, λ=210nm, retentiontime: 12.117min (major) and 13.583min (minor)].

[0121] (9) Synthetic product 3ja, the synthetic reaction equation is:

[0122]

[0123] The product (R)-3ka was a colorless oil (PE / EA=5:1), 21.4 mg, yield 50%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0124] 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J=8.1Hz,2H),7.55(d,J=8.2Hz,2H),4.97(td,J=10.9,4.4Hz,1H),3.76(s,3H),2.21–2.08(m,1H),1.97(pd,J= 7.0,2.5Hz,1H),1.84–1.70(m,4H),1.65–1.52(m,2H),1.46(s,3H),1.14( p, J=12.4, 11.8Hz, 2H), 0.95 (dd, J=6.9, 5.1Hz, 7H), 0.81 (d, J=6.9Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 171.86, 165.30, 137.75 (t, J = 26.7Hz), 132.54, 129.03, 126.75 (t, J = 6.4Hz), 121.19 (t, J = 253. 4Hz),75.30,63.67(t,J=27.7Hz),52.82,47.26,40.93,34.28,31.46,26.49,23.59,22.02,20.77,20.51(t,J=3.0Hz),16.47. 19F NMR(376MHz,Chloroform-d)δ-105.74(d,J=244.9Hz),-106.90(d,J=245.1Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 32 F2NO4412.2294; found 412.2294. HPLC analysis: dr value: 98:2 [Daicel Chiralpak OD-H, n-hexane / iso-propanol=95 / 5, 1.0mL / min, λ=210nm, retention time: 7.797min (minor) and 8.574min (major)].

[0125] 4. Synthesize compound (R)-5aa. The reaction equation for the synthesis is:

[0126]

[0127] In a glove box, cuprous tetraacetonitrile hexafluorophosphate (10 mol%, 0.01 mmol, 3.7 mg), a chiral ligand (S, S p )-L1-iPr (12 mol%, 0.012 mmol, 5.8 mg) and a mixed solvent (1.0 mL, 0.1 M, THF / DCE = 1:1, v / v). Stir for 30 minutes, then add difluorobenzyl trifluoromethanesulfonyl (compound 1a, 34.2 mg, 0.12 mmol, 1.2 equiv), cyclic iminoester (compound 4a, 23.1 mg, 0.1 mmol, 1.0 equiv) and cesium carbonate (65.2 mg, 0.2 mmol, 2 equiv). Then transfer the test tube out of the glove box and react in an oil bath at 20 ° C for 12 hours. After the reaction is completed, filter with diatomaceous earth, elute with ethyl acetate, and concentrate the eluate to obtain a crude product. The crude product is separated and purified by silica gel column chromatography. The eluent used for separation is petroleum ether (PE): ethyl acetate (EA) = 8:1 to 1:1 to obtain pure (R)-5aa.

[0128] Compound (R)-5aa is a colorless oil, 27.1 mg, yield 71%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of FNMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0129] 1H NMR(400MHz,Chloroform-d)δ7.83(t,J=7.5Hz,4H),7.72(d,J=8.2Hz,2H),7.28(d,J=7.4Hz,2H),4.29–3.99(m,2H),3.11(qdd,J= 17.0,9.7,6.1Hz,2H),2.72(ddd,J=14.2,9.6,6.5Hz,1H),2.54(ddd,J=14.8,9.7,5.6Hz,1H),2.44(s,3H),1.17(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ178.34,169.54(d,J=8.8Hz),142.19,139.45(t,J=26.5Hz),131.42,130.57,129.31,128.71–127.60( m), 119.87 (dd, J = 254.52, 250.48Hz), 118.33, 113.82, 88.00 (dd, J = 28.5, 27.1Hz), 61.87, 35.81, 28.07 (t, J = 3.1Hz), 21.59, 13.92. 9 F NMR(376MHz,Chloroform-d)δ-100.47(d,J=256.0Hz),-104.21(d,J=256.0Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 21 F2N2O2 383.1566; found383.1564. HPLC analysis: 96%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 7.795min (major) and 13.808min (minor)].

[0130] 5. Use the method for synthesizing (R)-5aa to synthesize other difluorobenzyl substituted α-amino acid compounds.

[0131] (1) Synthetic product (R)-5ab, the synthetic reaction equation is:

[0132]

[0133] The product (R)-5ab was a colorless oil (PE / EA=5:1), 34.1 mg, yield 79%. NMR (1 HNMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0134] 1 H NMR(400MHz,Chloroform-d)δ7.85–7.77(m,4H),7.73(d,J=8.2Hz,2H),7.61(d,J=8.5Hz,2H),4.28–3.96(m,2H),3. 23–3.00(m,2H),2.75(ddd,J=14.0,9.4,6.9Hz,1H),2.56(dddd,J=13.9,9.4,5.8,1.3Hz,1H),1.17(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ 177.48, 169.20 (d, J = 7.8Hz), 139.27 (t, J = 26.5Hz), 132.08, 131.90, 131.47, 129.81, 128.22 (dd, J = 7. 4, 5.6Hz), 126.44, 119.67 (dd, J = 254.52, 250.48Hz), 118.23, 113.97, 88.16 (t, J = 28.0Hz), 61.98, 35.74, 28.13 (t, J = 3.0Hz), 13.91. 19 F NMR(376MHz,Chloroform-d)δ-100.38(d,J=256.7Hz),-104.25(d,J=256.7Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 18 BrF2N2O2 447.0514; found 447.0516. HPLC analysis: 97%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 9.828min (major) and 11.030min (minor)].

[0135] (2) Synthetic product (R)-5ac, the synthetic reaction equation is:

[0136]

[0137] The reaction temperature was 20°C, and the product (R)-5ac was a white solid (PE / EA=5:1), 32 mg, with a yield of 79%. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0138] 1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),8.16(dd,J=8.5,1.7Hz,1H),8.02–7.82(m,5H),7.74(d,J=8.2Hz,2H),7.67–7.52 (m,2H),4.26–4.06(m,2H),3.42–3.12(m,2H),2.80(ddd,J=14.0,9.6,6.6Hz,1H),2.70–2.52(m,1H),1.19(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ178.47, 169.44 (d, J = 8.8Hz), 139.42 (t, J = 26. 5Hz),134.93,132.80,131.47,130.74,129.37,128.90,128.41,128.40–128 .18(m),127.85,127.79,126.73,124.65,119.86(dd,J=254.52,250.48),11 8.31,113.91,88.18(t,J=28.28),61.95,35.87,28.28(t,J=3.03Hz),13.94. 19 F NMR(376MHz,Chloroform-d)δ-100.33(d,J=256.3Hz),-104.10(d,J=256.3Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 21 F2N2O2419.1566; found 419.1571.HPLC analysis:95%ee [Daicel Chiralpak OZ, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 12.686min (minor) and 15.350min (major)].

[0139] Example 2: Synthesis of polyfluoroaryl substituted α-amino acid compounds

[0140] 1. Synthesize compound (S)-7aa. The reaction equation for the synthesis is as follows:

[0141]

[0142] The synthesis method is as follows: in a glove box, add tetraacetonitrile cuprous hexafluorophosphate (10 mol%, 0.01 mmol, 3.7 mg), a chiral ligand (S, S p )-L1-iPr (12 mol%, 0.012 mmol, 5.8 mg) and a mixed solvent (1.0 mL, 0.1 M, THF / DCE = 1:1, v / v). Stir for 30 minutes, then add polyfluoroaromatic hydrocarbons (compound 4a, 25.6 mg, 0.12 mmol, 1.2 equiv), α-imidate (compound 2a, 19.1 mg, 0.1 mmol, 1.0 equiv) and cesium carbonate (65.2 mg, 0.15 mmol, 1.5 equiv). Then transfer the test tube out of the glove box and react in an oil bath at 20 ° C for 12 hours. After the reaction is completed, filter with diatomaceous earth, elute with ethyl acetate, and concentrate the eluate to obtain a crude product. Add dichloromethane (1 mL) and hydrochloric acid (2 mL, 1 M) to the crude product and stir for 2 hours. Extract and concentrate with ethyl acetate, and the crude product is separated and purified by silica gel column chromatography. The eluent used for separation was petroleum ether (PE): ethyl acetate (EA) = 3:1 to 1:1 to obtain pure product 5aa.

[0143] Compound (S)-7aa is a yellow oil, 28.1 mg, yield 95%. NMR ( 1 HNMR, 13 C NMR, 19 The measurement conditions and results of FNMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows (due to the influence of fluorine atoms in the molecule of the hydrolysis product 5aa, multiple carbon atoms in the nuclear magnetic carbon spectrum cannot be peaked, so the nuclear magnetic spectrum of the pre-hydrolysis product 5aa' is collected. The compounds involved in the whole text are all in the same situation and will not be repeated):

[0144] (S)-7aa: PE / EA=5:1, yellow oil (28.1 mg, 95% yield). HPLC analysis: 95%ee [Daicel Chiralpak OJ, n-hexane / iso-propanol=90 / 10, 1.0 mL / min, λ = 254 nm, retention time: 13.157 min (minor)and 14.953min(major)].HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 13 F4N2O4297.0493; found 297.0492.

[0145] (S)-7aa': 1 H NMR (400MHz, Chloroform-d) δ8.33 (s, 1H), 7.83 (d, J = 7.2Hz, 2H), 7.54–7.42 (m, 3H), 3.84 (s, 3H), 2.03 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ170.81,161.32,145.15(dm,J=254.52Hz),140.44(ddd,J=262.2,18.0,4.1Hz) ,135.43,134.46,131.80,129.74,129.00,128.77(d,J=5.9Hz),126.58(t,J=12.8Hz),69.99,53.49,24.51. 19 F NMR(376MHz,Chloroform-d)δ-132.09--135.98(m),-142.78--150.03(m).

[0146] 2. Use the method for synthesizing (S)-7aa to synthesize other difluorobenzyl substituted α-amino acid compounds.

[0147] (1) Synthesize compound (S)-7ba. The synthesis reaction equation is:

[0148]

[0149] The product (S)-7ba was a brown oil (E / EA=5:1), 18.5 mg, yield 63%. NMR ( 1 H NMR, 13 C NMR, 19The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0150] (S)-7ba: HPLC analysis: 94%ee [Daicel Chiralpak OJ, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 17.135min (major) and 19.295min (minor)]. HRMS (ESI) m / z: [M+H] + Calcd for C 12 H 11 F4NO3 294.0748; found294.0746.

[0151] (S)-7ba': 1 H NMR (400MHz, Chloroform-d) δ8.33 (s, 1H), 7.83 (d, J = 7.2Hz, 2H), 7.54–7.42 (m, 3H), 3.84 (s, 3H), 2.03 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 13 C NMR(101MHz,Chloroform-d)δ191.90,171.50,161.01,147.28–144.59(m),144.31–141.91(m),135.63,131.58, 128.74,128.67,124.47(t,J=13.1Hz),120.02–118.09(m),69.82,53.31,33.43–31.60(m),24.88(t,J=3.3Hz). 19 F NMR(376MHz,Chloroform-d)δ-132.09--135.98(m),-142.78--150.03(m).

[0152] (2) Synthesis of compound (S)-7ca. The synthesis reaction equation is:

[0153]

[0154] The product (S)-7ca was a white solid (PE / EA=20:1), 34.2 mg, yield 93%. 1 HNMR, 13 C NMR, 19The measurement conditions and results of F NMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0155] (S)-7ca:HPLC analysis:94%ee[Daicel Chiralpak OC,n-hexane / iso-propanol=90 / 10,1.0mL / min,λ=254nm,retention time:20.998min(major)and26.482min(minor)].HRMS(ESI)m / z:[M+H] + Calcd for C 12 H 11 F4NO3369.0857; found369.0860.

[0156] (S)-7ca': 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.93(d,J=7.5Hz,1H),7.85(d,J=7 .3Hz,2H),7.70(d,J=7.6Hz,1H),7.54–7.40(m,5H),3.86(s,3H),2.08(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.50,161.03,152.98,150.49,147.79–145.53(m),145.30–142.84(m),141.17,135.65,13 1.60,128.79,128.69,126.57,125.18,124.62(t,J=13.2Hz),120.99,111.06,107.65(t,J=14.3Hz),69.98,53.36,24.98. 19 F NMR(376MHz,Chloroform-d)δ-136.71–-137.12(m),-137.52–-137.87(m).

[0157] (3) Synthetic product (S)-7dc, the synthetic reaction equation is:

[0158]

[0159] (S)-7dc is a white solid (PE / EA=1:1), 20.4 mg, yield 49%. By growing a single crystal, the single crystal spectrum is as follows Figure 2As shown, its absolute configuration is determined to be S configuration, and its CCDC number is: 2284628. NMR ( 1 H NMR, 13 C NMR, 19 The measurement conditions and results of FNMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0160] 1 H NMR(400MHz,Chloroform-d)δ7.92(d,J=7.6Hz,1H),7.69(d,J=7.8Hz,1H),7.49(p,J=7.4Hz,2H),6.85 (s,1H),3.86(s,3H),3.16(t,J=10.8Hz,2H),2.90–2.70(m,1H),2.71–2.58(m,1H),2.57–2.45(m,1H). 13 C NMR(101MHz,Chloroform-d)δ176.68,170.32,152.48,150.48,147.84–145.43(m),145.43–142.72(m),141.0 9,126.79,125.31,121.79(t,J=13.0Hz),121.07,111.09,108.52(t,J=14.3Hz),65.19,53.99,32.32,28.65. 19 F NMR(376MHz,Chloroform-d)δ-135.91–-137.03(m),-139.17–-140.79(m).HRMS(ESI)m / z:[M+H] + Calcd for C 12 H 11 F4NO3 409.0806; found 409.0808. HPLC analysis: 88%ee [Daicel Chiralpak OD-H, n-hexane / iso-propanol=80 / 20, 1.0mL / min, λ=254nm, retention time: 14.720min (minor) and 20.318min (major)].

[0161] (4) Synthetic product 7ea, the synthetic reaction equation is:

[0162]

[0163] The product (R)-7ea was a white solid, 50.4 mg, with a yield of 76%. 1 HNMR, 13 C NMR, 19 The measurement conditions and results of FNMR, high resolution mass spectrometry (HRMS), and high performance liquid chromatography (HPLC) are as follows:

[0164] (S)-7ea: HPLC analysis: dr value: 97.5:2.5 [Daicel Chiralpak OZ, n-hexane / iso-propanol=90 / 10, 1.0mL / min, λ=254nm, retention time: 4.843min (major) and 6.030min (minor)]. HRMS (ESI) m / z: [M+H] + Calcd for C 38 H 54 F4NO4 664.3983; found 664.4001.

[0165] (S)-7ea': 1 H NMR(400MHz,Chloroform-d)δ8.23(s,1H),7.81(d,J=7.1Hz,2H),7.59–7.36(m,3H),5.46(d ,J=5.0Hz,1H),4.96(tt,J=10.7,5.4Hz,1H),3.82(s,3H),2.60(q,J=7.2Hz,1H),2.50(d,J= 7.3Hz,2H),2.12–1.98(m,6H),1.95–1.71(m,3H),1.66–1.44(m,6H),1.43–1.33(m,3H),1.3 0–1.14(m,5H),1.13–0.99(m,8H),0.95(d,J=6.4Hz,3H),0.89(d,J=6.6Hz,6H),0.71(s,3H). 13C NMR(101MHz,Chloroform-d)δ171.53,160.94,158.84,146.83–145.41(m),144.43–141.70(m),139.06 ,135.66,131.53,128.70(d,J=10.6Hz),124.29(t,J=13.1Hz),123.33,112.83(t,J=16.6Hz),69.82,5 6.69,56.16,53.26,50.02,46.22,42.33,39.73,39.53,37.90,36.92,36.61,36.20,35.81,31.89(d,J =7.5Hz),28.25,28.03,27.67,25.08,24.30,23.85,22.83,22.58,21.06,19.31,18.73,11.88,11.34. 19 F NMR(376MHz,Chloroform-d)δ-134.49–-138.37(m),-138.67–-143.01(m).

[0166] The embodiments described above are only descriptions of the preferred modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations, modifications, and substitutions made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for synthesizing chiral fluorinated α-amino acid compounds, characterized in that: Difluorobenzyl trifluoromethanesulfonyl or polyfluoroaromatic hydrocarbons are used as fluorine-containing electrophilic reagents and α-imidate is used as an amino acid precursor. Asymmetric functionalization is catalyzed by a transition metal catalyst to introduce difluorobenzyl or polyfluoroaromatic groups into amino acid molecules.

2. The method according to claim 1, characterized in that: Add a chiral ligand, a transition metal catalyst and a solvent into a reaction container, stir evenly, then add difluorobenzyl trifluoromethanesulfonyl or polyfluoroaromatic hydrocarbon, α-imidate and a base, and react at 0-60° C. for 5-24 hours.

3. The method according to claim 2, characterized in that: The chiral ligand is Any one of R 1 is any one of H, aryl, and C1-12 alkyl, R is any one of C1-12 alkyl and aryl, Ar is any one of aryl groups, and C1-12 alkyl includes but is not limited to cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, and aryl-substituted C1-12 alkyl.

4. The method according to claim 2, characterized in that: The transition metal catalyst is any one of cuprous hexafluorophosphate, cuprous tetraacetonitrile, cuprous tetrafluoroborate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cupric acetate, cupric chloride, and cupric trifluoromethanesulfonate.

5. The method according to claim 2, characterized in that: The solvent is any one or a combination of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethyl ether, chloroform, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; and / or; The base is any one or a combination of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, DBU, and triethylamine.

6. The method according to claim 1 or 2, characterized in that: The reaction equation of the method is as follows: R 1 is any one of H and C1-12 alkyl, R 2 is any one of a C1-12 alkyl group and an aryl group, R 3 Any one of hydrogen, halogen, alkyl, alkoxy, amino, acyl, ester, cyano, and nitro, and the number of substituents is 1, 2, 3, 4, or 5; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted with cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, and aryl; The method comprises the following steps: based on the molar amount of difluorobenzyl trifluoromethanesulfonyl, adding 10 mol% of a transition metal catalyst, 12 mol% of a chiral ligand and a 0.1 M solvent into a dry reaction test tube, stirring evenly, then adding difluorobenzyl trifluoromethanesulfonyl, α-imidate and a base, and then reacting at 0-60°C for 5-24 hours.

7. The method according to claim 1 or 2, characterized in that: The reaction equation of the method is as follows: R 1 is any one of H and C1-12 alkyl, R 2 is any one of C1-12 alkyl and aryl; C1-12 alkyl includes but is not limited to cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen, and aryl substituted C1-12 alkyl; X is carbon or nitrogen; Fn is a fluorine atom substituent on the aromatic ring, the number is n, and n is 0, 1, 2, 3, 4, or 5; The method comprises the following steps: based on the molar amount of the imine ester, adding 10 mol% of a transition metal catalyst, 12 mol% of a chiral ligand and 0.1M of a solvent into a dry reaction test tube, stirring evenly, adding polyfluoroaromatic hydrocarbons, α-imine ester and a base, and reacting at 0-60°C for 5-24 hours.

8. A compound synthesized by the method according to any one of claims 1 to 7, characterized in that: The general structural formula of the compound is: R 1 is any one of H and C1-12 alkyl, R 2 is any one of a C1-12 alkyl group and an aryl group, R 3 It is any one of hydrogen, halogen, alkyl, alkoxy, amino, acyl, ester, cyano and nitro, and the number of substituents is 1, 2, 3, 4 or 5; C1-12 alkyl includes but is not limited to C1-12 alkyl substituted with cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen and aryl.

9. A compound synthesized by the method according to any one of claims 1 to 8, characterized in that: The general structural formula of the compound is: R 1 is any one of H and C1-12 alkyl, R 2 It is any one of C1-12 alkyl and aryl. C1-12 alkyl includes but is not limited to cyano, allyl, alkynyl, amino, amide, methylthio, ester, halogen and aryl substituted C1-12 alkyl; X is carbon or nitrogen; Fn is a fluorine atom substituent on the aromatic ring, the number is n, and n is 0, 1, 2, 3, 4 or 5.

10. Use of a compound synthesized by the method of any one of claims 1 to 8 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a compound of claim 8 or 9 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the pharmaceutical field.

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