Method for detecting purity of BINAP

Abstract

The invention provides a BINAP purity detection method, and relates to the technical field of chemical detection. According to the detection method, a BINAP reference substance solution and a to-be-detected substance solution are prepared, the BINAP reference substance solution and the to-be-detected substance solution are detected through high performance liquid chromatography, a mobile phase A and a mobile phase B are arranged in the detection process, the mobile phase A is a mixed solution of phosphoric acid and water, the mobile phase B is a mixed solution of phosphoric acid and acetonitrile, and the mobile phase B is a mixed solution of phosphoric acid and acetonitrile. And a mobile phase is subjected to constant-gradient elution. According to the method, the defects in the prior art are overcome, isocratic elution is carried out by utilizing the high performance liquid chromatography and combining proper mobile phase setting, the BINAP and related substances thereof can be effectively detected, the separation degree R can reach 1.5 or above, a baseline is stable, drifting does not occur, accurate determination of the purity of the BINAP can be realized, the reproducibility is good, and the operation is simple and convenient.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical detection, and particularly relates to a method for detecting the purity of BINAP. Background Art

[0002] BINAP, whose Chinese name is (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene, is a chemical substance with the chemical formula C 44 H 32 P2, with a relative molecular mass of 622.67, and is a white to off-white powder at room temperature. In particular, BINAP is an important diphosphine ligand and can be used for the catalysis of reactions such as asymmetric hydrogenation and carbonyl reduction.

[0003] In 1980, Noyori first synthesized BINAP and used it in chiral catalysis, showing good enantioselectivity. Subsequently, catalysts formed by BINAP and various metals (such as Ru, Pd, Ag, Rh, Ir, Au, etc.) have been continuously used in various reactions. Such as asymmetric hydrogenation reactions for reducing aldehydes, ketones and olefins, as a phosphine ligand in Buchwald-Hartwig reactions, asymmetric Micheal addition reactions, asymmetric cycloaddition reactions, asymmetric Aldol reactions, and so on.

[0004] Specifically, as reported by Lin et al. in 2003, zirconium phosphate-modified Ru-BINAP-DPEN catalyst was used for the asymmetric catalytic reduction of aromatic ketones, with high enantioselectivity (90.6% ee - 99.2% ee) and a yield of up to 99%. Noyori et al. reported in 2005 the use of RuCl2(TolBINAP)(PICA) to catalyze the asymmetric hydrogenation of tert-butyl ketone, and the turnover number of the catalyst (the molar ratio of substrate to catalyst) could reach 100,000, with the ee value of the product above 98%. Under the catalysis of BINAP-based phosphine ligands, the asymmetric Heck reaction of 2,3-dihydrofuran and aryl trifluoromethanesulfonate can obtain high stereoselectivity (97%), and the ee of the product is 68%. However, when using the modified BINAP to catalyze this reaction, the enantioselectivity can be greatly improved (93% ee). The most common coupling reaction catalyzed by BINAP as a phosphine ligand is the Buchwald-Hartwig reaction. In addition, there are also reports on the use of BINAP-based catalysts in Stille coupling reactions and Suzuki reactions. Toma et al. reported the Tsuji-Trost reaction catalyzed by BINAP, etc. with [Bmin]PF6 as the solvent, obtaining high yields and enantioselectivities. The asymmetric Keck allylation reaction of allyltin compounds with aldehydes under the catalysis of BINAP-Ag(I) gives high yields and enantioselectivities. The asymmetric Mukaiyama-Aldol reaction catalyzed by the p-Tol-BINAP-AgF system has high stereoselectivity and enantioselectivity. The ee values of the product quaternary carbon chiral centers in the asymmetric Micheal addition reactions catalyzed by (R)-p-Tol-BINAP-Pd(II) and (R)-BINAP-Pd(II) both reach above 90%. In the process of synthesizing GABA analogs, Miyaura and Hayashi achieved good results in the asymmetric addition reaction using arylboronic acid as a nucleophile under the catalysis of Rh(I)–BINAP. The 1,3-dipolar cycloaddition reaction catalyzed by the BINAP-AgX system has high enantioselectivity. The [5+2] cycloaddition reaction catalyzed by [((R)-BINAP)Rh] + + SbF 6- obtains a high yield. In addition, there are also reports on the asymmetric Pauson–Khand reaction catalyzed by BINAP, etc.

[0005] Given that BINAP is a key catalyst in so many reactions, it is necessary to accurately evaluate its product quality to ensure its catalytic effect on each reaction. At the same time, one of the key indicators of the quality of chemical reagent products is purity. Therefore, it is of great significance to detect the purity of BINAP. However, at present, there is no method for detecting the purity of BINAP. Summary of the Invention

[0006] In order to achieve the purpose of detecting the purity of BINAP, the present invention proposes a method for detecting the purity of BINAP.

[0007] To achieve the above purpose, the present invention is realized through the following technical solutions:

[0008] A method for detecting the purity of BINAP, characterized in that the detection method comprises the following steps:

[0009] S1. Preparation of the reference solution: Dissolve the BINAP reference substance with dichloromethane and then dilute and make up the volume with acetonitrile to obtain the reference solution for standby;

[0010] S2. Preparation of the test solution: Dissolve the BINAP to be tested with dichloromethane and then dilute and make up the volume with acetonitrile to obtain the test solution for standby;

[0011] S3. Detect the reference solution and the test solution by high performance liquid chromatography, wherein the mobile phase of the high performance liquid chromatography comprises mobile phase A and mobile phase B, the mobile phase A is a mixed solution of phosphoric acid and water, the mobile phase B is a mixed solution of phosphoric acid and acetonitrile, and the mobile phase adopts isocratic elution.

[0012] Preferably, in steps S1 and S2, the volume ratio of dichloromethane to acetonitrile in the reference solution and the test solution is 1:3 - 5.

[0013] Preferably, the concentration of the BINAP reference substance in the reference solution in step S1 is 0.5 mg / mL - 1.5 mg / mL; the concentration of the BINAP to be tested in the test solution in step S2 is 0.5 mg / mL - 1.5 mg / mL.

[0014] Preferably, in step S2, the volume concentration of phosphoric acid in mobile phase A is 0.03% - 0.07%, and the volume concentration of phosphoric acid in mobile phase B is 0.03% - 0.07%.

[0015] Preferably, in step S2, the volume ratio of mobile phase A to mobile phase B during the isocratic elution process is 10 - 20:80 - 90.

[0016] Preferably, the detection conditions of the high performance liquid chromatography in step S2 include:

[0017] Chromatographic column: Reverse phase C18 chromatographic column; and / or

[0018] Flow rate: 0.8 mL / min - 1.2 mL / min; and / or

[0019] Detection wavelength: 200 nm to 250 nm; and / or

[0020] Column temperature: 30 °C to 40 °C.

[0021] Preferably, the particle size of the stationary phase in the chromatographic column is 3 μm - 7 μm, and the size of the chromatographic column is: diameter 4 mm - 5 mm, length 130 mm - 170 mm.

[0022] Preferably, in step S2, a DAD detector is used for detection.

[0023] The present invention provides a method for detecting the purity of BINAP. Compared with the prior art, the advantages are as follows:

[0024] The method for detecting the purity of BINAP of the present invention uses high performance liquid chromatography and performs isocratic elution in combination with a suitable mobile phase setting, which can effectively detect BINAP and its related substances, and the resolution R can reach more than 1.5, the baseline is stable without drift, the accurate determination of the purity of BINAP can be achieved, and it has good reproducibility and simple operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is the detection chromatogram and related parameters in Example 1 of the present invention;

[0026] Figure 2 It is the detection chromatogram and related parameters in Example 2 of the present invention;

[0027] Figure 3 It is the detection chromatogram and related parameters in Example 3 of the present invention;

[0028] Figure 4 It is the detection chromatogram and related parameters in Example 4 of the present invention;

[0029] Figure 5 It is the detection chromatogram and related parameters in Example 5 of the present invention;

[0030] Figure 6 It is the detection chromatogram and related parameters in Comparative Example 1 of the present invention; DETAILED DESCRIPTION OF THE INVENTION

[0031] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0032] The present invention provides a method for detecting the purity of BINAP ((±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene), comprising the following steps:

[0033] Prepare a reference solution and a test sample solution. Among them, the steps for preparing the reference solution include: mixing a BINAP reference with a first solvent, dissolving it to prepare the reference solution; the steps for preparing the test sample solution include: mixing the test sample with a second solvent, dissolving it to prepare the test sample solution.

[0034] Detect the reference solution and the test sample solution by high performance liquid chromatography (HPLC); the mobile phase of the high performance liquid chromatography includes mobile phase A and mobile phase B. Mobile phase A is a mixed solution of phosphoric acid and water, and mobile phase B is a mixed solution of phosphoric acid and acetonitrile. The mobile phase is eluted by isocratic elution.

[0035] It can be understood that the principle of high performance liquid chromatography is as follows: using a liquid as the mobile phase, adopting a high-pressure infusion system, pumping a single solvent with different polarities or a mixed solvent with different ratios, buffer solution, etc. as the mobile phase into a chromatographic column filled with a stationary phase. After the components in the column are separated, they enter the detector for detection, so as to realize the separation and analysis of the sample, record the chromatogram of the sample, and know the retention time of BINAP according to the chromatogram of the reference solution. Thus, the peak position of BINAP in the chromatogram of the test sample solution can be known, and the determination of the purity of BINAP is completed.

[0036] In some specific examples, in mobile phase A, the volume concentration of phosphoric acid is 0.03% - 0.07%. Specifically, in mobile phase A, the volume concentration of phosphoric acid includes but is not limited to: 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%. Further, in mobile phase A, the volume concentration of phosphoric acid is 0.04% - 0.06%.

[0037] In some specific examples, in mobile phase B, the volume concentration of phosphoric acid is 0.03% - 0.07%. Specifically, in mobile phase B, the volume concentration of phosphoric acid includes but is not limited to: 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%. Further, in mobile phase B, the volume concentration of phosphoric acid is 0.04% - 0.06%.

[0038] In some specific examples, during the isocratic elution process, the volume ratio of mobile phase A to mobile phase B is (10 - 20):(80 - 90). Specifically, during the isocratic elution process, the volume ratio of mobile phase A to mobile phase B includes but is not limited to: 10:90, 11:89, 12:88, 13:87, 14:86, 15:85, 16:84, 17:83, 18:82, 19:81, 20:80. Further, during the isocratic elution process, the volume ratio of mobile phase A to mobile phase B is (13 - 17):(83 - 87).

[0039] It can be understood that the sum of the volume percentages of mobile phase A and mobile phase B is 100%.

[0040] In some specific examples, the chromatographic column used in high performance liquid chromatography is a reversed-phase C18 chromatographic column. Specifically, the chromatographic column used in high performance liquid chromatography is an Inertsil ODS-SP chromatographic column.

[0041] In some specific examples, the particle size of the stationary phase in the chromatographic column is 3μm - 7μm. Specifically, the particle size of the stationary phase in the chromatographic column includes but is not limited to: 3μm, 3.5μm, 4μm, 4.5μm, 5μm, 5.5μm, 6μm, 6.5μm, 7μm. Further, the particle size of the stationary phase in the chromatographic column is 4μm - 6μm.

[0042] In some specific examples, the size of the chromatographic column is: the diameter is 4mm - 5mm, and the length is 130mm - 170mm. Further, the size of the chromatographic column is: the diameter is 4.5mm - 4.7mm, and the length is 145mm - 155mm.

[0043] In some specific examples, the flow rate used in high performance liquid chromatography is 0.8 mL / min - 1.2 mL / min. Specifically, the flow rate used in high performance liquid chromatography includes but is not limited to: 0.8 mL / min, 0.9 mL / min, 1 mL / min, 1.1 mL / min, 1.2 mL / min. Further, the flow rate used in high performance liquid chromatography is 0.9 mL / min - 1.1 mL / min.

[0044] In some specific examples, the detection wavelength used in high performance liquid chromatography is 200nm - 250nm. Specifically, the detection wavelength used in high performance liquid chromatography includes but is not limited to: 200nm, 210nm, 215nm, 220nm, 225nm, 230nm, 240nm, 250nm. Further, the detection wavelength used in high performance liquid chromatography is 215nm - 225nm.

[0045] In some of these specific examples, the column temperature used in high performance liquid chromatography is 30°C to 40°C. Specifically, the column temperature used in high performance liquid chromatography includes, but is not limited to: 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C. Further, the column temperature used in high performance liquid chromatography is 34°C to 36°C.

[0046] In some of these specific examples, the detection conditions of high performance liquid chromatography include:

[0047] Chromatographic column: reversed-phase C18 chromatographic column; Flow rate: 0.8 mL / min to 1.2 mL / min; Detection wavelength: 200 nm to 250 nm; Column temperature: 30°C to 40°C.

[0048] In some of these specific examples, the injection volume of high performance liquid chromatography is 2 μL to 10 μL. Specifically, the injection volume used in high performance liquid chromatography includes, but is not limited to: 2 μL, 3 μL, 4 μL, 5 μL, 6 μL, 7 μL, 8 μL, 9 μL, 10 μL. Further, the injection volume used in high performance liquid chromatography is 4 μL to 6 μL.

[0049] In some of these specific examples, the chromatograph used in high performance liquid chromatography is Agilent LC1260 InfinityⅡ.

[0050] In some of these specific examples, the first solvent is a mixture of dichloromethane and acetonitrile. Further, in the first solvent, the volume ratio of dichloromethane to acetonitrile is 1:(3 to 5).

[0051] In some of these specific examples, in the reference solution, the concentration of the BINAP reference is 0.5 mg / mL to 1.5 mg / mL. Specifically, in the reference solution, the concentration of the BINAP reference includes, but is not limited to: 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 08 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL. Further, in the reference solution, the concentration of the BINAP reference is 0.8 mg / mL to 1.2 mg / mL.

[0052] In some of these specific examples, the second solvent is a mixture of dichloromethane and acetonitrile. Further, in the second solvent, the volume ratio of dichloromethane to acetonitrile is 1:(3 to 5).

[0053] In some specific examples, the concentration of the analyte in the analyte solution is 0.5 mg / mL to 1.5 mg / mL. Specifically, the concentration of the analyte in the analyte solution includes, but is not limited to: 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL. Further, the concentration of the analyte in the analyte solution is 0.8 mg / mL to 1.2 mg / mL.

[0054] In some specific examples, the detector used in the detection process is a DAD detector.

[0055] The following are specific examples.

[0056] The BINAP reference substance used in the example is: Leyan, purity: 98% min.

[0057] The source of the analyte is: Jiangsu Xinnuoke Catalyst Co., Ltd.

[0058] Example 1:

[0059] Detection method for BINAP purity:

[0060] (1) Preparation of reference substance solution

[0061] Precisely weigh 10 mg of BINAP reference substance and place it in a 10 mL volumetric flask. Add 2 mL of dichloromethane to dissolve it, dilute it with acetonitrile and make up to 10 mL, and filter through a 0.45 μm filter membrane to obtain the reference substance solution;

[0062] (2) Preparation of analyte solution

[0063] Precisely weigh 10 mg of the analyte and place it in a 10 mL volumetric flask. Add 2 mL of dichloromethane to dissolve it, dilute it with acetonitrile and make up to 10 mL, and filter through a μm filter membrane to obtain the analyte solution;

[0064] (3) Detection

[0065] The high performance liquid chromatography conditions are as follows:

[0066] The high performance liquid chromatograph uses Agilent LC1260 InfinityⅡ;

[0067] The chromatographic column uses a reversed-phase C18 chromatographic column (Inertsil ODS-SP (4.6 mm * 150 mm, 5 μm));

[0068] The detector uses a DAD detector;

[0069] The mobile phase includes mobile phase A and mobile phase B:

[0070] Mobile phase A: an aqueous solution with a phosphoric acid volume concentration of 0.05%;

[0071] Mobile phase B: an acetonitrile solution with a phosphoric acid volume concentration of 0.05%;

[0072] Isocratic elution is adopted, and elution is carried out with mobile phase A∶mobile phase B = 15%∶85%;

[0073] The column length of the chromatographic column is 150 mm;

[0074] The flow rate is 1.0 mL / min;

[0075] The detection wavelength is 220 nm;

[0076] The column temperature is controlled at 35 °C;

[0077] The injection volume is 5 μL.

[0078] Inject the reference substance solution in step (1) and the test substance solution in step (2) successively under the above high performance liquid chromatography conditions, and record the chromatogram as Figure 1 shown. From the chromatogram of the reference substance solution, the retention time of BINAP can be known. From this, the peak position of BINAP in the chromatogram of the test substance solution can be known, and the resolution R is 16.62. Calculate the purity determination of BINAP according to the peak area, and the calculated purity of BINAP for the test substance is 99.08%

[0079] Example 2:

[0080] A method for detecting the purity of BINAP, the steps of which are basically the same as those in Example 1, except that: during isocratic elution, elution is carried out with mobile phase A∶mobile phase B = 10%∶90%.

[0081] Similarly, record the chromatogram as Figure 2 shown. From the chromatogram of the reference substance solution, the retention time of BINAP can be known. From this, the peak position of BINAP in the chromatogram of the test substance solution can be known, and the resolution R is 10.43. Calculate the purity determination of BINAP according to the peak area, and the calculated purity of BINAP for the test substance is 99.08%

[0082] Example 3:

[0083] A method for detecting the purity of BINAP, the steps of which are basically the same as those in Example 1, except that: during isocratic elution, elution is carried out with mobile phase A∶mobile phase B = 20%∶80%.

[0084] Similarly, record the chromatogram as Figure 3As shown, according to the chromatogram of the reference solution, the retention time of BINAP can be known, and thus the peak position of BINAP in the chromatogram of the test solution can be known. The resolution R is 13.68. For the determination of the purity of BINAP calculated based on the peak area, the calculated purity of BINAP in the test product is 99.19%.

[0085] Example 4:

[0086] The method for detecting the purity of BINAP is basically the same as that in Example 1, except that: mobile phase B is an acetonitrile solution with a volume concentration of 0.1% of phosphoric acid.

[0087] Similarly, record the chromatogram as Figure 4 As shown, according to the chromatogram of the reference solution, the retention time of BINAP can be known, and thus the peak position of BINAP in the chromatogram of the test solution can be known. The resolution R is 12.86. For the determination of the purity of BINAP calculated based on the peak area, the calculated purity of BINAP in the test product is 99.04%.

[0088] Example 5:

[0089] The method for detecting the purity of BINAP is basically the same as that in Example 1, except that: mobile phase A is an aqueous solution with a volume concentration of 0.01% of phosphoric acid.

[0090] Similarly, record the chromatogram as Figure 5 As shown, according to the chromatogram of the reference solution, the retention time of BINAP can be known, and thus the peak position of BINAP in the chromatogram of the test solution can be known. The resolution R is 11.50. For the determination of the purity of BINAP calculated based on the peak area, the calculated purity of BINAP in the test product is 99.04%.

[0091] Comparative Example 1:

[0092] The method for detecting the purity of BINAP is basically the same as that in Example 1, except that: mobile phase A is pure water and mobile phase B is pure methanol.

[0093] Similarly, record the chromatogram as Figure 6 As shown, according to the chromatogram of the reference solution, the retention time of BINAP can be known, and thus the peak position of BINAP in the chromatogram of the test solution can be known. The resolution R is 18.01. For the determination of the purity of BINAP calculated based on the peak area, the calculated purity of BINAP in the test product is 98.97%.

[0094] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for detecting the purity of BINAP, characterized in that: The detection method comprises the following steps: S1. Preparation of reference solution: Dissolve the BINAP reference substance in dichloromethane, dilute with acetonitrile and make up to volume to obtain a reference solution for use; S2. Preparation of the test solution: Dissolve the BINAP test product in dichloromethane, dilute with acetonitrile and make up to volume to obtain the test solution for later use; S3. Detecting the reference solution and the test solution by high performance liquid chromatography, wherein the mobile phase of the high performance liquid chromatography comprises mobile phase A and mobile phase B, the mobile phase A is a mixture of phosphoric acid and water, the mobile phase B is a mixture of phosphoric acid and acetonitrile, and the mobile phase adopts isocratic elution.

2. The detection method according to claim 1, characterized in that: In the steps S1 and S2, the volume ratio of dichloromethane to acetonitrile in the reference solution and the test solution is 1:3-5.

3. The detection method according to claim 1, characterized in that: The concentration of BINAP in the reference solution in step S1 is 0.5 mg / mL-1.5 mg / mL; the concentration of BINAP in the test solution in step S2 is 0.5 mg / mL-1.5 mg / mL.

4. The detection method according to claim 1, characterized in that: In step S2, the volume concentration of phosphoric acid in mobile phase A is 0.03%-0.07%, and the volume concentration of phosphoric acid in mobile phase B is 0.03%-0.07%.

5. The detection method according to claim 1, characterized in that: In the isogradient elution process in step S2, the volume ratio of mobile phase A to mobile phase B is 10-20:80-90.

6. The detection method according to claim 1, characterized in that: The detection conditions of the high performance liquid chromatography in step S2 include: Chromatographic column: reverse phase C18 column; and / or Flow rate: 0.8 mL / min to 1.2 mL / min; and / or Detection wavelength: 200nm~250nm; and / or Column temperature: 30℃~40℃.

7. The detection method according to claim 6, characterized in that: The particle size of the stationary phase in the chromatographic column is 3 μm-7 μm, and the dimensions of the chromatographic column are: a diameter of 4 mm-5 mm and a length of 130 mm-170 mm.

8. The detection method according to claim 6, characterized in that: In the step S2, a DAD detector is used for detection.

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