Chiral lanthanide shift reagent, its preparation method and application

Abstract

The present application relates to the technical field of enantiomer, in particular to a kind of chiral lanthanide shift reagent and its preparation method and application, the chiral lanthanide shift reagent includes the compound shown in the following formula III structure:In the formula, R 1 And R 2 Same or different, each independently selected from hydrogen atom or alkyl, but R 1 And R 2 Not connected to form a ring;M1 is lanthanide element;M2 is alkali metal element.The chiral lanthanide shift reagent obtained by the present application has low preparation cost, small dosage compared with commercial and reported lanthanide shift reagent;The enantiomeric shift difference caused by resolution or identification is large, and the degree of spectral line broadening is small.The preparation method of the chiral lanthanide shift reagent of the present application uses ultrapure water as solvent, and the reaction is simple, the post-treatment process is simple, and the yield is high.The chiral lanthanide shift reagent obtained by the present application has less irritancy and toxicity in the preparation and use stages, and reduces the potential health risks to experimental operators.

Description

Technical Field

[0001] This invention relates to the field of enantiomeric technology, specifically to a chiral lanthanide shift reagent, its preparation method, and its application. Background Technology

[0002] Chiral resolution-based nuclear magnetic resonance (NMR) spectroscopy is one of the most convenient, routine, and rapid analytical techniques for enantiomeric analysis due to its ability to directly provide structural information about enantiomeric organisms. For NMR-based analytical methods, chiral derivatizing agents (CDA), chiral solvating agents (CSA), and chiral lanthanide shift reagents (CLSR) are commonly used chiral distinguishing reagents. CDA requires prior chiral derivatization, CSA is costly to prepare, requires large quantities, and results in a small enantiomeric shift difference (ΔΔδ) after resolution. CLSR, on the other hand, has the advantages of simple preparation, a larger ΔΔδ, and a wider range of applications. Commercially available chiral lanthanide shift reagents (CLSR) include Pr(hfc)3, Eu(hfc)3, and Eu(tfc)3, which have achieved significant progress in the resolution of chiral alcohols, chiral acids, and chiral amines. However, these reagents still suffer from problems such as high cost, large investment in independent research and development, low output, and severe spectral broadening. These factors limit the feasibility and operability of practical research. Therefore, this invention is proposed. Summary of the Invention

[0003] Mandelic acid, also known as α-hydroxyphenylacetic acid (MA), is a widely used chemical intermediate. It can be used to synthesize drugs such as the vasodilator cyclomandelate and the urinary tract disinfectant urotropine mandelate. Optically active mandelic acid is currently the most promising acidic optical resolving agent. It can optically resolve most racemic amines and amino acids via diastereomeric salt formation; moreover, it can be used in some pharmaceutical intermediates. For example, R-mandelic acid is used as a side-chain modifier for the cephalosporin antibiotic hydroxybenzyltetrazole; S-mandelic acid is a precursor for the synthesis of S-oxybutynin, which is clinically used to treat urinary urgency, frequency, and incontinence. Compared to racemic oxybutynin, S-oxybutynin has a more effective pharmacological effect. In summary, mandelic acid has wide applications in pharmaceutical production, asymmetric synthesis, and optical resolution.

[0004] To address the issues of high development cost, large dosage, and severe spectral broadening associated with chiral NMR recognition reagents for racemic mandelic acid, the inventors conducted extensive research on chiral lanthanide shift reagents and their preparation methods. They discovered a specific chiral lanthanide shift reagent that can be applied to the resolution and / or recognition of racemic mandelic acid compounds. This reagent offers advantages such as simple preparation, low dosage, large enantiomeric shift difference (ΔΔδ), and minimal spectral broadening when used in NMR spectroscopy.

[0005] Based on this, one object of the present invention is to provide a chiral lanthanide shift reagent;

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned chiral lanthanide shift reagent;

[0007] Another object of the present invention is to provide the application of the above-mentioned chiral lanthanide shift reagent.

[0008] Specifically, the present invention provides the following technical solutions:

[0009] A chiral lanthanide shift reagent, wherein the chiral lanthanide shift reagent comprises a compound with the structure shown in Formula III:

[0010]

[0011] In the above formula, R 1 and R 2 Whether the same or different, each is independently selected from hydrogen atoms or alkyl groups, but R 1 and R 2 They are not connected in a ring; M1 is a lanthanide element; M2 is an alkali metal element.

[0012] Preferably, the alkyl group is methyl.

[0013] According to the chiral lanthanide shift reagent provided by the present invention, M2 is lithium, sodium, or potassium;

[0014] And / or, M1 is samarium, cerium or europium, preferably samarium or europium.

[0015] According to the chiral lanthanide shift reagent provided by the present invention, the chiral lanthanide shift reagent comprises one or more compounds with structures shown in formulas III1 to III5 as follows:

[0016]

[0017] The present invention also provides a method for preparing the chiral lanthanide shift reagent as described above, comprising: reacting the compound represented by formula (I) with a lanthanide oxide and adjusting the reaction system to alkaline using an alkaline solution to obtain the chiral lanthanide shift reagent;

[0018] The alkaline solution is an aqueous solution containing one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide;

[0019] Preferably, the alkaline solution is an aqueous solution of lithium hydroxide, an aqueous solution of sodium hydroxide, or an aqueous solution of potassium hydroxide;

[0020] The structure of the compound represented by formula (I) is as follows:

[0021]

[0022] In the formula: R 1 and R 2 Whether the same or different, each is independently selected from hydrogen atoms or alkyl groups, but R 1 and R 2 They are not connected to form a ring.

[0023] The method of this invention enables a simpler and more efficient preparation of chiral lanthanide shift reagents, significantly improving the problems of high development cost, large dosage, and severe spectral broadening of chiral lanthanide shift reagents.

[0024] According to the preparation method of the chiral lanthanide shift reagent provided by the present invention, the lanthanide oxide is one of samarium trioxide, europium trioxide, or cerium dioxide; preferably, the lanthanide oxide is samarium trioxide or europium trioxide.

[0025] According to the preparation method of the chiral lanthanide shift reagent provided by the present invention, the molar ratio of the compound shown in formula (I) to the lanthanide oxide is 1:0.8 to 1.2, preferably 1:0.9 to 1.1, and more preferably 1:0.95 to 1.05.

[0026] The method for preparing the chiral lanthanide shift reagent according to the present invention includes:

[0027] The first solution is obtained by mixing lanthanide oxides with water;

[0028] The compound represented by formula (I) was added dropwise to the first solution and reacted at a temperature above 25°C for more than 0.5 h. After the reaction was completed, the reaction system was adjusted to alkaline with an alkaline solution to obtain the chiral lanthanide shift reagent.

[0029] Preferably, the reaction temperature is above 80°C;

[0030] A further preferred method is to mix the compound shown in formula (I) with a lanthanide oxide and heat it to 80–105 °C, and maintain the temperature for 0.5–2.5 h.

[0031] More specifically, the preparation method of the present invention includes the following steps:

[0032] 1) Lanthanide oxides were mixed with ultrapure water to obtain an aqueous solution of lanthanide oxides;

[0033] 2) Add the compound shown in formula (I) to the aqueous solution of lanthanide oxides obtained in step 1), heat and react, cool to room temperature after the reaction is complete, adjust the pH to alkaline with an alkaline solution; then concentrate, elute the concentrate with an eluent, and concentrate again to obtain the chiral lanthanide shift reagent.

[0034] The eluent is a mixture of ethyl acetate and n-hexane; more preferably, the volume ratio of ethyl acetate to n-hexane is 15:1.

[0035] This invention also provides applications of the chiral lanthanide shift reagents described above;

[0036] Preferably, the chiral lanthanide shift reagent is used for enantiomeric resolution and / or identification;

[0037] The enantiomer is a racemic mandelic acid compound;

[0038] More preferably, the chiral lanthanide shift reagent is used to identify the racemic mandelic acid compounds using nuclear magnetic resonance spectroscopy.

[0039] The application of the chiral lanthanide shift reagent provided by the present invention includes: performing a complexation reaction between the chiral lanthanide shift reagent and the racemic mandelic acid compound;

[0040] The structure of the racemic mandelic acid compound is shown in formula (IV):

[0041]

[0042] Wherein, R3 is aryl, benzyl, aryl derivative or benzyl derivative; preferably, R 3 It is Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 4-OMe-Ph-, 4-CF3-Ph-, or Bn-; more preferably, R 3 It is Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 4-OMe-Ph-, 4-CF3-Ph-.

[0043] According to the application of the chiral lanthanide shift reagent provided by the present invention, in the complexation reaction, the molar ratio of the chiral lanthanide shift reagent to the compound shown in formula (IV) is 0.2 to 0.5:1, preferably 0.3 to 0.5:1, and most preferably 0.5:1; the pH value of the reaction system of the complexation reaction is >1.0, preferably ≥13.0.

[0044] The complexation reaction of the present invention is as follows: the chiral lanthanide shift reagent and the racemic mandelic acid compound are dissolved in an ultrapure water solvent containing 10% deuterium water with a certain pH value to form a premix; the premix is ​​then ultrasonically oscillated and mixed, and then placed on a vortex mixer and vortexed for 1 minute.

[0045] The mixture obtained after the complexation reaction was subjected to nuclear magnetic resonance spectroscopy to identify the enantiomeric mandelic acid in the racemic mandelic acid compounds.

[0046] Compared with the prior art, the beneficial effects of the present invention include at least the following:

[0047] Compared with commercially available lanthanide shift reagents, the chiral lanthanide shift reagents obtained in this invention have lower preparation costs and require less dosage; the enantiomeric shift difference (ΔΔδ) caused by resolution or recognition is large, and the degree of spectral line broadening is small.

[0048] The method for preparing the chiral lanthanide shift reagent of the present invention uses ultrapure water as a solvent, the reaction is simple, the post-processing is simple, and the yield is high.

[0049] The chiral lanthanide shift reagents obtained by this invention use solvents with low irritation and toxicity during preparation and use, reducing potential health risks to laboratory personnel. Attached Figure Description

[0050] Figure 1 The 1H NMR spectrum of the chiral lanthanide shift reagent provided in Example 1 of this invention;

[0051] Figure 2 The carbon NMR spectrum of the chiral lanthanide shift reagent provided in Example 1 of this invention;

[0052] Figure 3 The chiral lanthanide shift reagent provided in Example 8 of this invention is shown to be effective in resolving racemic mandelic acid.

[0053] Figure 4 The 1H NMR spectrum of the chiral lanthanide shift reagent provided in Comparative Example 1 of this invention;

[0054] Figure 5 The carbon NMR spectrum of the chiral lanthanide shift reagent provided in Comparative Example 1 of this invention;

[0055] Figure 6 The 1H NMR spectrum of the chiral lanthanide shift reagent provided in Comparative Example 2 of this invention;

[0056] Figure 7 The image shows the carbon NMR spectrum of the chiral lanthanide shift reagent provided in Comparative Example 2 of this invention. Detailed Implementation

[0057] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0058] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0059] The structural formulas of the compounds involved in this invention are numbered, and the correspondence is shown in Table 1 below:

[0060] Table 1. Compounds and their corresponding numbers

[0061]

[0062]

[0063]

[0064]

[0065] Example 1

[0066] A chiral lanthanide shift reagent, the synthetic route of which is as follows:

[0067]

[0068] The specific preparation method is as follows:

[0069] (1) Dissolve 5 mmol of Sm2O3 in a 250 mL round-bottom flask containing 50 mL of ultrapure water and stir on a magnetic stirrer to obtain the first solution.

[0070] (2) 5 mmol of compound I1 (the substituent R of chiral ethylenediaminetetraacetic acid) was added. 1 For methyl, R 2 (Hydrogen atoms) were slowly added to the first solution above, and heated to 105°C while stirring. After holding at this temperature and reacting for 1 hour, the solution was cooled to room temperature. Under stirring conditions, the pH was adjusted to 8 with a 2 mol / L sodium hydroxide solution. The reaction system was then cooled to room temperature and concentrated under reduced pressure to remove the solvent, yielding the reaction product.

[0071] (3) Use 30 mL of a mixture of ethyl acetate and n-hexane with a volume ratio of 15:1 as a washing agent to wash the reaction product in step (2) three times. Remove the residual solvent under reduced pressure and dry the product with a mechanical pump until the weight of the product no longer changes, and obtain 2.40 g of white solid, which is the chiral lanthanide shift reagent (denoted as compound III1), with a yield of 93.6%.

[0072] Nuclear magnetic resonance (NMR) spectroscopy was performed on the chiral lanthanide shift reagent (denoted as compound III1), and the proton NMR spectrum was obtained as follows: Figure 1 As shown; the carbon NMR spectrum is as follows. Figure 2 As shown.

[0073] Example 2

[0074] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that the reaction temperature in step (2) was reduced from 105°C to 80°C. The results showed that the yield of the chiral lanthanide shift reagent was 80%.

[0075] Example 3

[0076] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that the reaction temperature in step (2) was reduced from 105°C to 25°C. The results showed that the yield of the chiral lanthanide shift reagent was 24%.

[0077] As can be seen from Examples 1 to 3, the corresponding chiral lanthanide shift reagents can be successfully prepared using the method of the present invention;

[0078] The reaction temperature has a significant impact on the yield. The preferred reaction temperature is above 80°C. As the temperature increases further, the increase in yield gradually decreases. The preferred reaction temperature is 80-105°C, and the optimal reaction temperature is 105°C.

[0079] Example 4

[0080] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that the amount of compound I1 added in step (2) was reduced from 5 mmol to 4.75 mmol. The results showed that the yield of the chiral lanthanide shift reagent was 90.2%.

[0081] Example 5

[0082] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that the amount of compound I1 added in step (2) was increased from 5 mmol to 5.25 mmol. The results showed that the yield of the chiral lanthanide shift reagent was 86%.

[0083] As can be seen from Examples 1, 4 and 5, adjusting the amount of reactants has a certain impact on the yield. The preferred molar ratio of compound I to lanthanide oxide in this invention is 0.9 to 1.1:1, and more preferably 1:1.

[0084] Example 6

[0085] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that sodium hydroxide in step (2) was replaced with potassium hydroxide. The results showed that the yield of the chiral lanthanide shift reagent (compound III2) was 91%.

[0086] Example 7

[0087] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that sodium hydroxide in step (2) was replaced with lithium hydroxide. The results showed that the yield of the chiral lanthanide shift reagent (compound III3) was 87%.

[0088] As can be seen from Examples 1, 6 and 7, the type of cation in the alkaline solution has a certain impact on the yield. The preferred alkaline solution of the present invention is an aqueous solution of sodium hydroxide.

[0089] Example 8

[0090] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that Sm2O3 in step (1) was replaced with Eu2O3. The results showed that the yield of the chiral lanthanide shift reagent (compound III4) was 91%.

[0091] Example 9

[0092] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that Sm2O3 in step (1) was replaced with Ce2O3. The results showed that the yield of the chiral lanthanide shift reagent (compound III5) was <5%.

[0093] As can be seen from Examples 1, 8 and 9, the metal element in the lanthanide oxide has a significant impact on the yield. The preferred lanthanide oxide of the present invention is Sm2O3 or Eu2O3.

[0094] The racemic mandelic acid compounds in the embodiments of this invention are specifically the objects to be identified, each containing a structure of formulas IV1 to IV7 as described above. To verify the recognition effect of the chiral lanthanide shift reagent prepared in this invention on racemic mandelic acid compounds, the following experiments were conducted:

[0095] Application Example 1

[0096] A method for identifying racemic mandelic acid compounds using a chiral lanthanide shift reagent, the specific operation process is as follows: firstly, the chiral lanthanide shift reagent (compound III1) and the racemic mandelic acid compound (containing the target compound with the structural formula IV1) are dissolved in ultrapure water containing 10% deuterium water at pH 13 to form a premix; then, the premix is ​​ultrasonically vibrated and mixed, and then placed on a vortex mixer and vortexed for 1 min.

[0097] The molar ratio of the chiral lanthanide shift reagent (compound III1) to the racemic mandelic acid compound (formula IV1) is 0.2:1, and the molar concentration of the chiral lanthanide shift reagent (compound III1) is 0.02 mmol / mL.

[0098] During the above process, the following reaction occurs:

[0099]

[0100] Finally, 0.6 mL of the vortexed mixture was taken for nuclear magnetic resonance (NMR) spectroscopy analysis; the NMR spectroscopy analysis conditions were as follows:

[0101] Solvent: An ultrapure aqueous solution containing 10% deuterium;

[0102] 1 H NMR operating frequency: 600.13MHz;

[0103] Experimental temperature: 25℃;

[0104] Spectral width: 14 ppm;

[0105] Observation channel center: 7ppm;

[0106] Cumulative count: 16.

[0107] The test results showed that the enantiomeric chemical shift difference (ΔΔδ) of mandelic acid was 48.04 Hz.

[0108] Application Example 2-7

[0109] A method for identifying racemic mandelic acid compounds using a chiral lanthanide shift reagent is basically the same as in Application Example 1, except that compound III1 is used to identify racemic mandelic acid compounds containing formula IV1 under different pH conditions. The results show that the identification effects of Application Examples 1-7 are as follows:

[0110]

[0111] As can be seen from the table above, compound III1 significantly improves the recognition effect on racemic mandelic acid compounds containing formula IV1 at a pH of 13, with a pH value ≥ 13 being preferred.

[0112] Application Examples 8-10

[0113] A method for identifying racemic mandelic acid compounds using a chiral lanthanide shift reagent is basically the same as in Application Example 1, except that compound III1 is used to identify racemic mandelic acid compounds containing formula IV1 under different molar ratios of chiral lanthanide shift reagents and racemic mandelic acid compounds. The results showed that the identification effects in Application Examples 8-10 were as follows:

[0114]

[0115] As can be seen from the table above, the recognition effect of compound III1 on racemic mandelic acid compounds containing formula IV1 at pH 13 significantly improved with the increase of the amount of chiral lanthanide shift reagent added. The recognition results of application example 8 are shown below. Figure 3 As shown. Compared with the shift reagents reported in the literature (Bai L, Chen P, Xiang J, et al. Org. Biomol. Chem, 2019, 17, 1466; Ma Q, Ma M, Tian H, et al. Org. Lett, 2012, 14, 23, 5813.), the shift reagent described in this invention is simple to prepare and produces a moderate ΔΔδ, which can meet the requirements of quantitative analysis. Therefore, when using compound III1 of this invention to identify racemic mandelic acid compounds containing formula IV1, the molar ratio of the chiral lanthanide shift reagent to the racemic mandelic acid compound is preferably 0.2–0.5:1, more preferably 0.3–0.5:1, and most preferably 0.5:1.

[0116] Application Examples 11-16

[0117] A method for identifying racemic mandelic acid compounds using a chiral lanthanide shift reagent is basically the same as in Application Example 8, except that compound III1 is used to identify racemic mandelic acid compounds containing formulas IV2-7. The results showed that the identification effects in Application Examples 11-16 were as follows:

[0118]

[0119] As can be seen from the table above, compound III1 can resolve racemic mandelic acid compounds containing formulas IV1 to IV7, but its resolution effect on racemic mandelic acid compounds with formulas IV1 to IV6 is significantly better than that on formula IV7. Therefore, compound III1 is preferably used for the identification of formulas IV1 to IV6 (i.e., R...). 3 (For aryl groups and their derivatives), and more preferably for the resolution of formulas IV1, IV3 to IV6.

[0120] Comparative Example 1

[0121] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that compound I1 in step (2) was replaced with compound I2. The results showed that the yield of the chiral lanthanide shift reagent (compound III6) was 62%.

[0122] Nuclear magnetic resonance (NMR) spectroscopy was performed on the chiral lanthanide shift reagent (denoted as compound III2), and the proton NMR spectrum was obtained as follows: Figure 4 As shown; the carbon NMR spectrum is as follows. Figure 5 As shown.

[0123] Comparative Example 2

[0124] A chiral lanthanide shift reagent was prepared using the same method as in Example 1, except that compound I1 in step (2) was replaced with compound I3. The results showed that the yield of the chiral lanthanide shift reagent (compound III7) was 89%.

[0125] Nuclear magnetic resonance (NMR) spectroscopy was performed on a chiral lanthanide shift reagent (denoted as compound III7), and the proton NMR spectrum was obtained as follows: Figure 6 As shown; the carbon NMR spectrum is as follows. Figure 7 As shown.

[0126] Comparative Examples 1 and 2 were tested on racemic mandelic acid compounds (containing the target object with the structural formula IV1) according to the method of Application Example 1. The results showed that neither of them could effectively resolve the racemic mandelic acid compound, that is, the chemical shift difference was close to 0.

[0127] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of a chiral lanthanide shift reagent; the chiral lanthanide shift reagent is used for identifying a racemic mandelic acid compound by using nuclear magnetic resonance spectroscopy; The application comprises: a complexation reaction is carried out between the chiral lanthanide shift reagent and the racemic mandelic acid compound; the structure of the racemic mandelic acid compound is as shown in the following formula (IV): ； Among them, R 3 It is Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 4-OMe-Ph-, 4-CF3-Ph-; in the complexation reaction, the molar ratio of the chiral lanthanide shift reagent to the compound as shown in formula (IV) is 0.2-0.5:1; the pH value of the reaction system of the complexation reaction is greater than or equal to 13.0; the chiral lanthanide shift reagent comprises one or more than one compound having a structure as shown in the following formula III1-III5: 。 2. Use of a chiral lanthanide shift reagent according to claim 1, characterised in that, in the complexation reaction, the molar ratio of the chiral lanthanide shift reagent to the compound as shown in formula (IV) is 0.3-0.5:

1.

3. Use of a chiral lanthanide shift reagent according to claim 2, characterised in that, in the complexation reaction, the molar ratio of the chiral lanthanide shift reagent to the compound as shown in formula (IV) is 0.5:

1.

4. Use of a chiral lanthanide shift reagent according to any one of claims 1 to 3, characterized in that comprising: a compound as shown in formula (I) is reacted with a lanthanide oxide, and a basic solution is used to adjust the reaction system to be alkaline, so as to obtain the chiral lanthanide shift reagent; the basic solution is an aqueous solution containing one or more than one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the structure of the compound as shown in formula (I) is as follows: 。 5. Use of a chiral lanthanide shift reagent according to claim 4, characterised in that, the lanthanide oxide is one of samarium sesquioxide, europium sesquioxide or cerium dioxide.

6. Use of a chiral lanthanide shift reagent according to claim 5, characterised in that, the lanthanide oxide is samarium sesquioxide or europium sesquioxide.

7. Use of a chiral lanthanide shift reagent according to claim 4, characterised in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.8-1.

2.

8. Use of a chiral lanthanide shift reagent according to claim 7, characterised in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.9-1.

1.

9. Use of a chiral lanthanide shift reagent according to claim 8, characterised in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.95-1.

05.

10. Use of a chiral lanthanide shift reagent according to claim 5 or 6, characterised in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.8-1.

2.

11. Use of a chiral lanthanide shift reagent according to claim 10, characterized in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.9-1.

1.

12. Use of a chiral lanthanide shift reagent according to claim 11, characterised in that, the molar ratio of the compound as shown in formula (I) to the lanthanide oxide is 1:0.95-1.

05.

13. The application of the chiral lanthanide shift reagent according to claim 4, characterized in that, comprising: a lanthanide oxide is mixed with water to obtain a first solution; the compound as shown in formula (I) is added dropwise into the first solution, and the reaction is carried out at a temperature higher than 25℃ for more than 0.5h; after the reaction is completed, a basic solution is used to adjust the reaction system to be alkaline, so as to obtain the chiral lanthanide shift reagent.

14. Use of a chiral lanthanide shift reagent according to claim 13, characterized in that, the temperature of the reaction is higher than or equal to 80℃.

15. Use of a chiral lanthanide shift reagent according to claim 14, characterized in that, after the compound as shown in formula (I) is mixed with the lanthanide oxide, heating is carried out to 80-105℃, and the reaction is carried out for 0.5-2.5h.

16. The application of the chiral lanthanide shift reagent according to any one of claims 5-9 and 11-12, characterized in that, comprising: a lanthanide oxide is mixed with water to obtain a first solution; the compound as shown in formula (I) is added dropwise into the first solution, and the reaction is carried out at a temperature higher than 25℃ for more than 0.5h; after the reaction is completed, a basic solution is used to adjust the reaction system to be alkaline, so as to obtain the chiral lanthanide shift reagent.

17. Use of a chiral lanthanide shift reagent according to claim 16, characterised in that, the temperature of the reaction is higher than or equal to 80℃.

18. The application of the chiral lanthanide shift reagent according to claim 17, characterized in that, after the compound as shown in formula (I) is mixed with the lanthanide oxide, heating is carried out to 80-105℃, and the reaction is carried out for 0.5-2.5h.

19. The application of the chiral lanthanide shift reagent according to claim 10, characterized in that, comprising: a lanthanide oxide is mixed with water to obtain a first solution; The compound shown in formula (I) is added dropwise into the first solution to react at a temperature above 25℃ for more than 0.5h, and after the reaction is completed, the reaction system is adjusted to be alkaline by using an alkaline solution to obtain the chiral lanthanide shift reagent.

20. The application of the chiral lanthanide shift reagent according to claim 19, characterized in that, The temperature of the reaction is above 80℃.

21. The application of the chiral lanthanide shift reagent according to claim 20, characterized in that, The compound shown in formula (I) is mixed with a lanthanide oxide and heated to 80~105℃, and incubated to react for 0.5~2.5h.

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