CN112979511B - Method for analyzing and preparing tert-butyl sulfinamide enantiomer by using HPLC - Google Patents
Method for analyzing and preparing tert-butyl sulfinamide enantiomer by using HPLC Download PDFInfo
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- CN112979511B CN112979511B CN201911288835.0A CN201911288835A CN112979511B CN 112979511 B CN112979511 B CN 112979511B CN 201911288835 A CN201911288835 A CN 201911288835A CN 112979511 B CN112979511 B CN 112979511B
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Abstract
The application discloses a method for analyzing and preparing tert-butyl sulfinamide enantiomer by using HPLC, which comprises the following steps: analyzing and/or preparing a sample containing (RS) -tert-butyl sulfenamide by using an HPLC method and adopting normal phase chromatography; the surface of silica gel is coated with cellulose derivative as chiral stationary phase, and the mixed solution of alkane, lower alcohol and its ester is used as mobile phase. The method solves the problem of analysis and separation of the tert-butyl sulfinamide enantiomer, can quickly, accurately and efficiently analyze and separate the tert-butyl sulfinamide enantiomer, effectively controls the quality of tert-butyl sulfinamide, and obtains the optically pure tert-butyl sulfinamide.
Description
Technical Field
The application relates to a chromatographic analysis and separation method, in particular to a method for analyzing and preparing tert-butyl sulfinyl amine enantiomer by using HPLC.
Background
Most pharmaceutical and synthetic compounds contain chiral amine functional groups. Therefore, the asymmetric synthesis of chiral amine compounds is very widely applied. Tert-butyl sulfenamide is a novel chiral compound with stable physical, chemical and optical properties, and attracts attention of many chemists as an introduction agent of chiral amine. For example: the academic reports show that the method has application in synthesis of paclitaxel and synthesis of the antiallergic drug cetirizine hydrochloride. Chiral tert-butyl sulfinyl amine is also increasingly used as an auxiliary agent for constructing chiral amine in clinical and marketed new drugs. The tertiary butyl sulfinamide is taken as a chiral auxiliary agent and mainly has the following advantages: (1) is easy to form imine with various aldehydes or ketones; (2) due to the activation of the tert-butylsulfinyl group, the generated imine has stronger electrophilicity, is easier to react with a nucleophilic reagent or is reduced by a metal boron reagent, and induces high diastereoselectivity; (3) in addition products, tert-butylsulfinyl is also a good protective group and can resist strong base, transition metal and the like in reaction; (4) under the acidic condition, the tert-butylsulfinyl is easy to remove, and the obtained hydrochloride can be purified by an ether solvent. Therefore, the optically pure tert-butyl sulfinamide and the derivative thereof are widely used for synthesizing chiral drugs and natural products and can also be used as chiral ligands to induce and catalyze asymmetric synthesis reaction.
The single chiral compound can be obtained by asymmetric synthesis or by racemate resolution. Among the chiral resolution techniques of racemates, High Performance Liquid Chromatography (HPLC) is known as a powerful, fast and efficient separation technique, and has been successfully applied to separation analysis and preparation of enantiomeric drugs.
Chiral tert-butyl sulfinamide, known as 2-methylpropane-2-sulfinamide, having the molecular formula (CH)3)3CSONH2. Comprises two chiral configurations of S type and R type, and the structural formula is shown in the following figure
In the figure, A is (S) -tert-butyl sulfinamide, and B is (R) -tert-butyl sulfinamide.
In recent years, a large number of innovative synthetic methods related to optically pure tert-butyl sulfenamide are introduced, but the analysis and separation methods of two enantiomers of tert-butyl sulfenamide by using high performance liquid chromatography are still rarely reported. The method for simply, quickly and efficiently analyzing and preparing the two enantiomers of the tert-butyl sulfinyl amine is established, the quality control of the two enantiomers is realized, and the technical problem to be solved at present is solved.
In recent years, a large number of innovative synthetic methods related to optically pure tert-butyl sulfenamide are introduced, but the analysis and separation methods of two enantiomers of tert-butyl sulfenamide by using high performance liquid chromatography are still rarely reported. The establishment of a method for simply, quickly and efficiently analyzing and preparing two enantiomers of tert-butyl sulfinyl amine to realize the quality control of the two enantiomers is a technical problem to be solved at present
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a liquid chromatography method using a chiral stationary phase for analyzing and preparing two enantiomers of tert-butyl sulfinamide, thereby realizing quality control and preparation of a single enantiomer.
According to one aspect of the present application, there is provided a method for HPLC analysis and preparation of an enantiomer of tert-butyl sulfinamide, comprising the steps of:
analyzing and/or preparing a sample containing (RS) -tert-butyl sulfenamide by using an HPLC method and adopting normal phase chromatography; the surface of silica gel is coated with cellulose derivative as chiral stationary phase, and the mixed solution of alkane, lower alcohol and its ester is used as mobile phase.
Optionally, the chiral stationary phase is selected from one of a silica gel surface-coated cellulose-tris (3, 5-dimethylphenylcarbamate) chiral stationary phase and a silica gel surface-coated cellulose-tris (p-methylbenzoate) chiral stationary phase.
Optionally, the alkane is selected from at least one of n-hexane, cyclohexane, and n-heptane; the lower alcohol and its ester is at least one selected from isopropanol, ethanol and ethyl acetate.
Optionally, the volume ratio of the alkane to the lower alcohol and the ester thereof in the mobile phase is 85:15 to 99.5: 0.5.
Optionally, the volume ratio of the alkane to the lower alcohol and the ester thereof in the mobile phase is 88: 12-99: 1.
Optionally, the upper limit of the volume ratio of the alkane and the lower alcohol and the ester thereof in the mobile phase is selected from 88:12, 90:10, 92:8, 93:7, 95:5, 96:4, 97:3, 98:2, 99:1 or 99.5: 0.5; the lower limit is selected from 85:15, 88:12, 90:10, 92:8, 93:7, 95:5, 96:4, 97:3, 98:2, or 99: 1.
Optionally, when performing HPLC detection, the column temperature is 10-40 ℃, the sample injection amount is 5-15 uL, and the detection wavelength is 200-250 nm; the flow rate of the mobile phase is 0.3-2.5 mL/min.
Optionally, when the tert-butyl sulfinyl amide enantiomer is prepared, the column temperature is 10-40 ℃, the sample injection amount is 1-10 mL, and the detection wavelength is 200-250 nm; the flow rate of the mobile phase is 5-30 mL/min.
Optionally, before HPLC detection or preparation, the method further comprises a process of dissolving the (RS) -tert-butyl sulfinamide sample with isopropanol.
Optionally, the concentration of the (RS) -tert-butyl sulfinamide-containing sample dissolved in isopropanol is 0.5-10 mg/mL.
Alternatively, the (RS) -tert-butyl sulfenamide-containing sample refers to a mixture comprising R-tert-butyl sulfenamide and S-tert-butyl sulfenamide.
The analysis method comprises the following steps:
(1) dissolving R-tert-butyl sulfenamide and S-tert-butyl sulfenamide reference substance with isopropanol to obtain reference substance solution with concentration of 0.5mg/mL
(2) Dissolving the (RS) -tert-butyl sulfinamide industrial sample with isopropanol to prepare an industrial sample solution with the concentration of 1mg/mL (RS) -tert-butyl sulfinamide, wherein the sample injection amount is 5-10 mu L;
(3) setting the ratio of alkane to lower alcohol and ester thereof to 85: 15-99.5: 0.5, setting the temperature of a liquid chromatography column incubator to 30 ℃, the detection wavelength to 220nm and the flow rate to 0.5-1 mL/min;
(4) absorbing the R-tertiary butyl sulfinamide, S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial test solution, respectively injecting into a liquid chromatographic column, and finishing the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substances;
the preparation method comprises the following steps:
(1) dissolving R-tert-butyl sulfenamide and S-tert-butyl sulfenamide reference substances respectively with isopropanol to prepare reference substance solutions with the concentration of 1 mg/mL;
(2) dissolving the (RS) -tert-butyl sulfenamide industrial test sample with isopropanol to prepare an industrial test sample solution with the concentration of 5 mg/mL; the sample injection amount is 1-10 mL;
(3) setting the ratio of alkane to lower alcohol and ester thereof to be 85: 15-99.5: 0.5, the detection wavelength to be 220nm and the flow rate to be 5-30 ml/min;
(4) and (3) absorbing the R-tertiary butyl sulfinamide, S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial sample solutions, respectively injecting the solutions into a liquid chromatographic column, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide reference substances, concentrating and drying to complete the preparation of the R-tertiary butyl sulfinamide and the enantiomer thereof.
The experimental results show that: the method adopts a chiral chromatographic column with the surface of silica gel coated with cellulose-tri (3, 5-dimethylphenyl carbamate) and cellulose-tri (p-benzoate), adopts a mobile phase of n-hexane-isopropanol (85:15), n-heptane-isopropanol and cyclohexane-isopropanol mixture, selects a better wavelength, improves the symmetry of chromatographic peaks and obtains a better separation effect. The chiral chromatographic column with the surface coated with the cellulose-tri (3, 5-dimethylphenyl carbamate) on the silica gel can realize the baseline separation of (RS) -tert-butylsulfinamide, and the chiral chromatographic column with the surface coated with the cellulose-tri (p-benzoate) on the silica gel has a good separation effect, and the separation degree is more than 5.9.
Therefore, the method overcomes the defects of the prior art, solves the problem of analysis and separation of the enantiomer of the tertiary butyl sulfinyl amine, can quickly, accurately and efficiently analyze and separate the enantiomer of the tertiary butyl sulfinyl amine, effectively controls the quality of the tertiary butyl sulfinyl amine, and obtains the optically pure tertiary butyl sulfinyl amine.
Therefore, the development of an HPLC method for separating tert-butylsulfinamide isomers by normal phase chromatography with high efficiency analysis is necessary.
The beneficial effects that this application can produce include:
(1) the method adopts the liquid chromatography of the chiral stationary phase to analyze and separate the enantiomer of the tertiary butyl sulfinamide, has simple, accurate and high-efficiency operation, can effectively control the quality of the tertiary butyl sulfinamide, and obtains the optically pure tertiary butyl sulfinamide;
(2) on the basis of the method provided by the invention, the optically pure tert-butyl sulfinamide can be ensured to be obtained by adopting a proper chiral chromatographic column, a mobile phase, sample injection amount and wavelength, the symmetry of a chromatographic peak is improved, and a better separation effect is achieved.
(3) The two types of chiral chromatographic columns used in the invention, especially the chiral chromatographic column with the surface of silica gel coated with cellulose-tri (p-methyl benzoate), have higher separation degree and better separation effect.
Drawings
FIG. 1 is an HPLC chart of example 1, chromatographic conditions: OD-H (250mm 4.6mm, 5.0 μm) was prepared in the laboratory; mobile phase: n-hexane-isopropanol (98: 2);
FIG. 2 is an HPLC chart of example 2, chromatographic conditions: OD-H (250mm 4.6mm, 5.0 μm) was prepared in the laboratory; mobile phase: n-heptane-ethanol (97: 3);
FIG. 3 is an HPLC chart of example 3, chromatographic conditions: OJ-H (150mm 4.6mm, 5.0 μm) was prepared by the laboratory; mobile phase: n-hexane-ethanol (90: 10);
FIG. 4 is an HPLC chart of example 5, chromatographic conditions: OJ-H (150mm 4.6mm, 5.0 μm) was prepared by the laboratory; mobile phase: cyclohexane-isopropanol (85: 15);
FIG. 5 is an HPLC chart of example 6, chromatographic conditions: OJ-H (150mm 4.6mm, 5.0 μm) was prepared by the laboratory; mobile phase: n-heptane-ethyl acetate (93: 7);
FIG. 6 is an HPLC chart of example 8, chromatographic conditions: OJ-H (150mm 4.6mm, 5.0 μm) was prepared by the laboratory; mobile phase: n-hexane-isopropanol (96: 4).
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
The raw materials in the examples of the present application were all purchased commercially, unless otherwise specified.
The separation performance in the examples of the present application was evaluated on a high performance liquid chromatograph of LC-2030 type manufactured by Shimadzu corporation, Japan. The instrument was equipped with a quaternary low pressure gradient infusion pump with a 5-way degassing unit, an autosampler, a forced air circulation column oven and a UV detector, and the workstation was LabSolutions. The degree of separation is calculated by the workstation software.
The chromatographic column OD-H is self-made in a laboratory, is a chiral chromatographic column with silica gel surface coated with cellulose-tri (3, 5-dimethylphenyl carbamate), and is prepared by synthesizing microcrystalline cellulose and 3, 5-dimethylphenyl isocyanate as raw materials in pyridine to react to generate cellulose-tri (p-methylbenzoate) derivatives, coating the cellulose-tri (p-methylbenzoate) derivatives on macroporous silica gel to prepare a chiral stationary phase, dispersing the chiral stationary phase in a mixed solution containing n-hexane and isopropanol (n-hexane/isopropanol, 90/10, v/v), carrying out ultrasonic treatment for ten minutes, and then filling the mixture into an empty stainless steel column tube by taking the n-hexane as a displacement liquid under 40 MPa.
The chromatographic column OJ-H is a chiral chromatographic column which is self-made by a laboratory and is prepared by coating cellulose-tri (p-methyl benzoate) on the surface of silica gel, wherein microcrystalline cellulose and 4-methyl benzoyl chloride are used as raw materials to be synthesized in pyridine to generate a cellulose-tri (p-methyl benzoate) derivative, the cellulose-tri (p-methyl benzoate) derivative is coated on macroporous silica gel to prepare a chiral stationary phase, the chiral stationary phase is dispersed in a mixed solution containing normal hexane and isopropanol (normal hexane/isopropanol, 90/10, v/v), and after ultrasonic treatment for ten minutes, the chiral stationary phase is filled in an empty stainless steel column tube by taking the normal hexane as a displacement liquid under 40 MPa.
In the embodiment of the application, the separation degree refers to the ratio of the retention time difference of two adjacent peaks to the average peak width, and is calculated by Labsolutions software of a liquid chromatography workstation.
In the examples of the present application, peaks are assigned from left to right in the HPLC chart as solvent peak, R-tert-butylsulfinamide and S-tert-butylsulfinamide.
Example 1: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: laboratory homemade OD-H (250mm 4.6mm, 5.0 μm)
Mobile phase: n-hexane-isopropanol (98:2)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: as shown in FIG. 1, the HPLC spectrum is sequentially provided with a solvent peak, R-tert-butylsulfinamide and S-tert-butylsulfinamide from left to right. The separation degree of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 1.798, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 2: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: laboratory homemade OD-H (250mm 4.6mm, 5.0 μm)
Mobile phase: n-heptane-ethanol (97:3)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 5 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 5 mu L of mother liquor of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial test samples into a liquid chromatogram, and finishing the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof by referring to the retention time of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide reference substances.
The experimental results are as follows: FIG. 2 is an HPLC chart of this example, and it can be seen that the degree of separation of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 1.502, and that R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 3: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-hexane-ethanol (90:10)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: FIG. 3 is an HPLC chart of this example, and it can be seen that the degree of separation of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.891, and that R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 4: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-hexane-ethanol (99:1)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 6.372, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 5: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: cyclohexane-Isopropanol (85:15)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: FIG. 4 is an HPLC chart of this example, and it can be seen that the degree of separation of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.109, and that R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 6: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-heptane-ethyl acetate (93:7)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: FIG. 5 is an HPLC chart of this example, and it can be seen that the degree of separation of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 5.52, and that R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 7: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-heptane-ethanol (99.5:0.5)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 5 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 5 mu L of mother liquor of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial test samples into a liquid chromatogram, and finishing the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof by referring to the retention time of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide reference substances.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 3.423, and R-tert-butylsulfinamide and its enantiomers can be completely separated.
Example 8: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-hexane-isopropanol (96:4)
Column temperature: 30 deg.C
Flow rate: 0.5mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: FIG. 6 is an HPLC chart of this example, and it can be seen that the degree of separation of the two corresponding isomers of R-tert-butylsulfinamide and S-tert-butylsulfinamide is 5.919, and that R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 9: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: cyclohexane-acetic acid ethyl ester (92:8)
Column temperature: 30 deg.C
Flow rate: 1mL/min
Sample introduction volume: 5 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 5 mu L of mother liquor of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial test samples into a liquid chromatogram, and finishing the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof by referring to the retention time of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide reference substances.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.052, and R-tert-butylsulfinamide and its enantiomers can be completely separated.
Example 10: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: cyclohexane-ethanol (85:15)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 5 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 5 mu L of mother liquor of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide Reference Substances and (RS) -tertiary butyl sulfinamide industrial test samples into a liquid chromatogram, and finishing the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof by referring to the retention time of the R-tertiary butyl sulfinamide and S-tertiary butyl sulfinamide reference substances.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.878, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 11: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: cyclohexane-Isopropanol (96:4)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 5.919, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 12: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: n-heptane-isopropanol (88:12)
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.891, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 13: analytical separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (150mm 4.6mm, 5.0 μm) in laboratory
Mobile phase: hexane-acetic acid ethyl ester (95:5)
Column temperature: 30 deg.C
Flow rate: 0.5mL/min
Sample introduction volume: 10 μ L
Sample concentration: 1mg/mL
Detection wavelength: 220nm
Experimental procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. Accurately weighing 10mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 10mL volumetric flask, dissolving and diluting isopropanol, and shaking up to obtain the industrial sample mother liquor. And respectively and precisely sucking 10 mu L of mother liquor of the R-tertiary butyl sulfinamide, the S-tertiary butyl sulfinamide reference substance and the (RS) -tertiary butyl sulfinamide industrial test sample mother liquor, and entering a liquid chromatogram to finish the analysis of the R-tertiary butyl sulfinamide and the enantiomer thereof according to the retention time of the R-tertiary butyl sulfinamide and the S-tertiary butyl sulfinamide reference substance.
The experimental results are as follows: the degree of separation of the two corresponding isomers R-tert-butylsulfinamide and S-tert-butylsulfinamide is 4.269, and R-tert-butylsulfinamide and its enantiomer can be completely separated.
Example 14: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 10mm, 10.0 μm) in laboratory
Mobile phase: n-heptane-isopropanol (90:10)
Column temperature: at room temperature
Flow rate: 5.0mL/min
Sample introduction volume: 1mL of
Sample concentration 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. 50mg of (RS) -tert-butyl sulfenamide industrial product is precisely weighed and placed in a 10mL volumetric flask, and isopropanol is dissolved, diluted and shaken uniformly to be used as industrial sample mother liquor. Respectively and precisely sucking 1mL of mother liquor of an R-tertiary butyl sulfinamide reference product, an S-tertiary butyl sulfinamide reference product and an industrial sample mother liquor of (RS) -tertiary butyl sulfinamide into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide reference product and the S-tertiary butyl sulfinamide reference product, concentrating and drying to obtain 1.8mg of R-tertiary butyl sulfinamide and 1.9mg of S-tertiary butyl sulfinamide.
Example 15: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 20mm, 10.0 μm) in laboratory
Mobile phase: n-heptane-ethyl acetate (85:15)
Column temperature: at room temperature
Flow rate: 20mL/min
Sample introduction volume: 10mL
Sample concentration: 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Accurately measuring 100mg of R-tert-butyl sulfinamide and 100mg of S-tert-butyl sulfinamide respectively, placing in a 100mL volumetric flask, dissolving and diluting to a scale with isopropanol, and shaking up to serve as reference solution. Accurately weighing 500mg of (RS) -tert-butyl sulfenamide industrial product, placing the product in a 100mL volumetric flask, dissolving and diluting the product with isopropanol, and shaking up the product to obtain the industrial sample mother liquor. Respectively and precisely sucking 10mL of R-tert-butyl sulfinamide, S-tert-butyl sulfinamide Reference Substances and (RS) -tert-butyl sulfinamide industrial sample mother liquor into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tert-butyl sulfinamide and S-tert-butyl sulfinamide reference substances, concentrating and drying to obtain 21mg of R-tert-butyl sulfinamide and 19mg of S-tert-butyl sulfinamide.
Example 16: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 20mm, 10.0 μm) in laboratory
Mobile phase: n-hexane-isopropanol (85:15)
Column temperature: at room temperature
Flow rate: 30mL/min
Sample introduction volume: 3mL of
Sample concentration: 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. 50mg of (RS) -tert-butyl sulfenamide industrial product is precisely weighed and placed in a 10mL volumetric flask, and isopropanol is dissolved, diluted and shaken uniformly to be used as industrial sample mother liquor. Respectively and precisely sucking 3mL of mother liquor of an R-tertiary butyl sulfinamide reference product, an S-tertiary butyl sulfinamide reference product and an industrial sample mother liquor of (RS) -tertiary butyl sulfinamide into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide reference product and the S-tertiary butyl sulfinamide reference product, concentrating and drying to obtain 6mg of R-tertiary butyl sulfinamide and 7mg of S-tertiary butyl sulfinamide.
Example 17: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 20mm, 10.0 μm) in laboratory
Mobile phase: cyclohexane-ethanol (88:12)
Column temperature: at room temperature
Flow rate: 10mL/min
Sample introduction volume: 5mL
Sample concentration: 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. 50mg of (RS) -tert-butyl sulfenamide industrial product is precisely weighed and placed in a 10mL volumetric flask, and isopropanol is dissolved, diluted and shaken uniformly to be used as industrial sample mother liquor. Respectively and precisely sucking 5mL of mother liquor of an R-tertiary butyl sulfinamide reference product, an S-tertiary butyl sulfinamide reference product and an industrial sample mother liquor of (RS) -tertiary butyl sulfinamide into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide reference product and the S-tertiary butyl sulfinamide reference product, concentrating and drying to obtain 11mg of R-tertiary butyl sulfinamide and 10mg of S-tertiary butyl sulfinamide.
Example 18: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 10mm, 10.0 μm) in laboratory
Mobile phase: cyclohexane-acetic acid ethyl ester (92:8)
Column temperature: at room temperature
Flow rate: 8mL/min
Sample introduction volume: 2mL
Sample concentration 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. 50mg of (RS) -tert-butyl sulfenamide industrial product is precisely weighed and placed in a 10mL volumetric flask, and isopropanol is dissolved, diluted and shaken uniformly to be used as industrial sample mother liquor. Respectively and precisely sucking 2mL of mother liquor of an R-tertiary butyl sulfinamide reference product, an S-tertiary butyl sulfinamide reference product and an industrial sample mother liquor of (RS) -tertiary butyl sulfinamide into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide reference product and the S-tertiary butyl sulfinamide reference product, concentrating and drying to obtain 4.1mg of R-tertiary butyl sulfinamide and 4.3mg of S-tertiary butyl sulfinamide.
Example 19: preparation separation of R-tert-butylsulfinamide and S-tert-butylsulfinamide
Apparatus and conditions
A chromatographic column: homemade OJ-H (250mm 20mm, 10.0 μm) in laboratory
Mobile phase: n-heptane-ethanol (96:4)
Column temperature: at room temperature
Flow rate: 20mL/min
Sample introduction volume: 8mL
Sample concentration: 5mg/mL
Detection wavelength: 220nm
Preparation procedure
Precisely measuring 10mg of R-tert-butyl sulfinamide and 10mg of S-tert-butyl sulfinamide respectively, placing the R-tert-butyl sulfinamide and the S-tert-butyl sulfinamide in a 10mL volumetric flask, dissolving isopropanol, diluting to a scale, shaking up, and using the solution as a reference solution. 50mg of (RS) -tert-butyl sulfenamide industrial product is precisely weighed and placed in a 10mL volumetric flask, and isopropanol is dissolved, diluted and shaken uniformly to be used as industrial sample mother liquor. Respectively and precisely sucking 8mL of mother liquor of an R-tertiary butyl sulfinamide reference product, an S-tertiary butyl sulfinamide reference product and an industrial sample mother liquor of (RS) -tertiary butyl sulfinamide into a liquid chromatogram, respectively receiving corresponding main peaks according to the retention time of the R-tertiary butyl sulfinamide reference product and the S-tertiary butyl sulfinamide reference product, concentrating and drying to obtain 17mg of R-tertiary butyl sulfinamide and 18mg of S-tertiary butyl sulfinamide.
Although the present invention has been described with reference to a few preferred embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. A method for HPLC analysis and/or preparation of the enantiomers of tert-butyl sulfinamide, characterized in that it comprises the following steps:
analyzing and/or preparing a sample containing (RS) -tert-butyl sulfenamide by using an HPLC method and adopting normal phase chromatography; coating cellulose-tri (p-methyl benzoate) on the surface of silica gel as a chiral stationary phase, and taking a mixed solution of alkane, lower alcohol and ester thereof as a mobile phase;
the lower alcohol and the ester thereof are selected from at least one of isopropanol, ethanol and ethyl acetate;
the alkane is selected from at least one of n-hexane, cyclohexane and n-heptane;
in the mobile phase, the volume ratio of the alkane to the lower alcohol and the ester thereof is 85: 15-99.5: 0.5.
2. The method according to claim 1, wherein the volume ratio of the alkane to the lower alcohol and the ester thereof in the mobile phase is 88:12 to 99: 1.
3. The method according to claim 1, wherein the HPLC analysis is carried out at a column temperature of 10 to 40 ℃, a sample amount of 5 to 15. mu.L, and an analysis wavelength of 200 to 250 nm; the flow rate of the mobile phase is 0.3-2.5 mL/min.
4. The method according to claim 1, wherein when the preparation of the tert-butyl sulfinamide enantiomer is carried out, the column temperature is 10-40 ℃, the sample amount is 1-10 mL, and the analysis wavelength is 200-250 nm; the flow rate of the mobile phase is 5-30 mL/min.
5. The method of claim 1, further comprising the step of dissolving the sample containing (RS) -tert-butylsulfinamide with isopropanol before performing HPLC analysis or preparation.
6. The method according to claim 5, wherein the concentration of the (RS) -tert-butylsulfinamide-containing sample after dissolution in isopropanol is 0.5-10 mg/mL.
7. The method according to claim 1, wherein the sample containing (RS) -tert-butyl sulfinamide is a mixture comprising R-tert-butyl sulfinamide and S-tert-butyl sulfinamide.
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| CN108558715A (en) * | 2018-05-11 | 2018-09-21 | 上海晋鲁医药科技有限公司 | A method of preparing the pure t-butyl sulfonamide of mapping |
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