CN111999416B - Method for resolving R/S-N-Boc-piperidinol by chiral derivative reagent pre-column derivatization high performance liquid chromatography - Google Patents
Method for resolving R/S-N-Boc-piperidinol by chiral derivative reagent pre-column derivatization high performance liquid chromatography Download PDFInfo
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Abstract
The invention belongs to the technical field of analytical chemistry, and particularly discloses a method for resolving R/S-N-Boc-piperidinol by using a chiral derivatization reagent pre-column derivatization high performance liquid chromatography, which comprises the following steps: firstly, performing esterification reaction on R/S-N-Boc-piperidinol and (+) -naproxen to obtain (+) -naproxen-R/S-N-Boc-piperidinol ester; and then a high performance liquid chromatograph is adopted, a chromatographic column with octadecylsilane chemically bonded silica as a filler, a water phase and an organic phase are used as mobile phases, the flow rate of the (+) -naproxen-R/S-N-Boc-piperidinol ester sample solution is controlled to be 0.4-0.8mL/min, the sample injection amount is 2-10 mu L, the detection wavelength is 260nm, and the column temperature is 20-35 ℃, so that the R/S-N-Boc-piperidinol is separated. The chromatographic peak obtained by the method has good peak type and symmetry, high separation degree and can sensitively split R/S-N-Boc-piperidinol.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry, and relates to a method for resolving R/S-N-Boc-piperidinol by using a chiral derivatization reagent pre-column derivatization high performance liquid chromatography.
Background
S-N-Boc-piperidinol
Is an important drug intermediate, is widely applied to the synthesis of drugs for analgesia, antipsychotic, anti-tumor and the like, and is mainly used for the synthesis of anti-congestive heart failure drug Carmorelin and the synthesis of drugs for treating mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma and EGFR mutant type non-small cell lung cancer ibrutinib. S-N-Boc-piperidinol is used as an important intermediate, and the optical purity of the S-N-Boc-piperidinol directly influences the optical purity of the synthesized bulk drug. Therefore, the method has important industrial value for researching the chiral separation method of the R/S-N-Boc-piperidinol.
At present, the chiral resolution method of R/S-N-Boc-piperidinol is mainly an enzymatic method. According to the literature search, CN105420307A discloses a method for preparing (S) -N-tert-butyloxycarbonyl-3-hydroxypiperidine, which is a patent for enzymatically resolving N-tert-butyloxycarbonyl-3-piperidone, but does not describe the detection method. CN103789368A discloses a method for producing N-protected piperidinol, which uses enzyme catalysis N-tert-butoxycarbonyl-3-piperidone and 1-benzyl-3-piperidone to produce corresponding piperidinol, and detects the final product, wherein the detection method comprises: by using a Chiralpak ODH column (250 × 4.6mm, 5 μm) chromatography column, mobile phase n-hexane/isopropanol-95/5; the peak time: 7.0min for S type and 7.4min for R type; the method has low response and does not achieve complete separation. In addition, no method for resolving R/S-N-Boc-piperidinol by adopting a chiral derivatization reagent pre-column derivatization and a reverse chromatography system is adopted at present.
Disclosure of Invention
The invention aims to solve the problems that the existing resolution method of R/S-N-Boc-piperidinol is high in cost, low in sensitivity, and the chromatographic peak separation degree does not meet the requirement.
In order to solve the technical problems, the invention provides the following technical scheme: a method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization high performance liquid chromatography comprises the following steps:
a. carrying out pre-column derivatization esterification reaction on R/S-N-Boc-piperidinol and (+) -naproxen to obtain (+) -naproxen-R/S-N-Boc-piperidinol ester;
b. the method comprises the steps of adopting a high performance liquid chromatograph, using octadecylsilane chemically bonded silica as a chromatographic column of a filler, using a water phase and an organic phase as a reverse phase mobile phase, preparing (+) -naproxen-R/S-N-Boc-piperidinol ester into a sample solution with the concentration of 0.2-1.0mg/mL, controlling the flow rate to be 0.4-0.8mL/min, the sample injection amount to be 2-10 mu L, detecting the wavelength to be 210-260nm, and separating the R/S-N-Boc-piperidinol at the column temperature of 20-35 ℃.
Wherein, the method for resolving R/S-N-Boc-piperidinol by using chiral derivation reagent pre-column derivation high performance liquid chromatography comprises the following steps: dissolving R/S-N-Boc-piperidinol and (+) -naproxen in oxalyl chloride solvent, and carrying out esterification reaction by taking pyridine as a catalyst to obtain R/S-Boc-piperidinol ester; the (+) -naproxen: R/S-N-Boc-piperidinol: the molar ratio of pyridine is 0.80-0.84: 1.00: 1.20 to 1.24.
In the method for resolving R/S-N-Boc-piperidinol by using chiral derivatization reagent pre-column derivatization high performance liquid chromatography, in the step b, the organic phase is methanol.
In the method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization high performance liquid chromatography, in the step b, the volume ratio of methanol to water in the mobile phase is 74-82: 18 to 26.
In the method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization with high performance liquid chromatography, in step b, the volume ratio of methanol to water in the mobile phase is 76: 24.
in the method for resolving R/S-N-Boc-piperidinol by using chiral derivatization reagent pre-column derivatization high performance liquid chromatography, in the step b, when the chromatographic separation is performed, the flow rate is 0.6mL/min, the sample injection amount is 10 mu L, and the column temperature of a chromatographic column is 25 ℃.
In the method for resolving R/S-N-Boc-piperidinol by using chiral derivatization reagent pre-column derivatization high performance liquid chromatography, in the step b, the chromatographic column is Akzo Nobel Kromail 100-3.5-C, and octadecyl is bonded on the surface of 3.5 mu m silica gel as a stationary phase 18 4.6 x 250mm chromatography column.
In the method for resolving R/S-N-Boc-piperidinol by using chiral derivatization reagent pre-column derivatization high performance liquid chromatography, in the step b, the high performance liquid chromatography is as follows: agilent 1260Infinity II 1260Quat VL G7111A 1260VWD G7114A 1260Viaisample G7129C.
Compared with the prior art, the invention has the beneficial effects that:
the method adopts cheap (+) -naproxen as a chiral derivative reagent to react with R/S-N-Boc-piperidinol, so that the derivative has stronger ultraviolet absorption and higher sensitivity when being detected by a widely used ultraviolet detector; and (+) -naproxen is selected as a derivative reagent, and the derivative can be separated and detected only by adopting a common C18 chromatographic column instead of using a chiral chromatographic column with expensive filler. In addition, the invention uses a reverse phase mobile phase system consisting of an organic phase (methanol) and a water phase as a mobile phase, has better separation effect and has the separation degree of more than 1.5. The method overcomes the defects and shortcomings in the prior art, has the technical effects of simple and convenient operation, quick and sensitive detection, good chromatographic peak shape and symmetry, high separation degree and the like, and has practical popularization prospect in the field of medicine synthesis analysis.
Drawings
FIG. 1 is a nuclear magnetic spectrum of (+) -naproxen-S-N-Boc-piperidinol ester as a white solid obtained in example 1;
FIG. 2 is a liquid phase chromatogram of the white solid (+) -naproxen-S-N-Boc-piperidinol ester obtained in example 1;
FIG. 3 is a nuclear magnetic spectrum of (+) -naproxen-R/S-N-Boc-piperidinol ester as a white solid obtained in example 2;
FIG. 4 is a liquid chromatography mapping of the white solid (+) -naproxen-R/S-N-Boc-piperidinol ester obtained in example 2;
Detailed Description
The invention is further illustrated, but not limited, by the following specific examples and the accompanying drawings.
The high performance liquid chromatograph used by the invention is as follows: agilent 1260Infinity II 1260Qua tPomp VL G7111A 1260VWD G7114A 1260Viaisample G7129C.
Example 1
(1) To a 50mL three-necked flask equipped with a thermometer and drying tube were added, (+) -naproxen (1.00g,4.34mmol), oxalyl chloride (1.38g,10.87mmol) followed by 15mL dichloromethane, refluxing for 2h, followed by spin-drying dichloromethane, addition of S-N-Boc-piperidinol control (1.05g, 5.22mmol) and pyridine (0.51g, 6.46mmol), followed by temperature control at 20 ℃ and stirring for 1 hour with incubation, followed by concentration of the system, with petroleum ether: and (3) performing silica gel column chromatography by using ethyl acetate (10: 1, v/v) as eluent to obtain a white solid (+) -naproxen S-Boc-piperidinol ester pure product, wherein the yield is 85%, and the purity is more than 98% by liquid phase detection.
The white solid obtained above was measured with a nuclear magnetic resonance instrument (Bruker-500/VANCEIII), and the resonance data of nuclear magnetic spectrum 1 were as follows:
1 H NMR(400MHz,CDCl 3 )δ7.70-7.66(m,3H),7.40(d,J＝7.9Hz,1H),7.14-7.11(m,2H),4.79(s,1H),3.91(s,3H),3.83(d,J＝6.7Hz,1H),3.37(br,4H),1.83-1.69(m,3H),1.58(d,J＝6.6Hz,3H),1.46-1.29(m,10H).
as can be seen from the NMR data above, the resulting white solid contained (+) -naproxen-S-Boc-piperidinol ester, which has the following respective structures:
(2) taking 50mg of (+) -naproxen-S-Boc-piperidinol ester obtained in the step (1), dissolving with a mobile phase and fixing the volume to a 50mL volumetric flask to obtain a 1.0mg/mL positioning solution; performing high performance liquid chromatography analysis under the following liquid phase conditions;
the conditions for the liquid chromatography analysis were as follows:
the instrument comprises the following steps: agilent 1260Infinity II;
and (3) chromatographic column: akzo nobel Kromail 100-3.5-C184.6 x 250mm column;
flow rate of mobile phase: 0.6 mL/min;
the temperature of the chromatographic column is 25 ℃;
the sample injection amount is 10 mu L;
the detection wavelength is 230 nm;
mobile phase: methanol-water 76-24(v/v)
As can be seen from the liquid phase mapping of FIG. 2, the (+) -naproxen-S-Boc-piperidinol ester retention time is 32.596 min.
Example 2
(1) In a 50mL three-necked flask with thermometer and drying tube were added, (+) -naproxen (1.00g,4.34mmol), oxalyl chloride (1.38g,10.87mmol) followed by 15mL dichloromethane sequentially, refluxed for 2h, then dichloromethane was spin dried, R/S-N-Boc-piperidinol (1.05g, 5.22mmol) and pyridine (0.51g, 6.46mmol) were added, then the temperature was controlled at 20 ℃ and stirring was maintained for 1 hour, then the system was concentrated, with petroleum ether: ethyl acetate (10: 1, v/v) is used as eluent to carry out silica gel column chromatography to obtain a white solid (+) -naproxen R/S-Boc-piperidinol ester pure product, the yield is 82%, and the purity is more than 99% by liquid phase detection.
The white solid obtained above was measured with a nuclear magnetic resonance instrument (Bruker-500/VANCEIII), and the resonance data of nuclear magnetic spectrum 3 were as follows:
1 H NMR(400MHz,CDCl 3) δ7.70-7.65(m,3H),7.40(br,1H),7.14-7.10(m,2H),4.79(s,1H),3.89(s,3H),3.83-3.82(m,1H),3.55-3.24(m,4H),1.82-1.57(m,6H),1.46(br,5H),1.38(br,5H).
as can be seen from the NMR data above, the resulting white solid contained (+) -naproxen-S-Boc-piperidinol ester and (+) -naproxen-R-Boc-piperidinol ester, which have the respective structures:
(2) dissolving 25mg of (+) -naproxen-R/S-Boc-piperidinol ester diastereoisomer derivative obtained in the step (1) by using a mobile phase to a volumetric flask with the volume of 50mL to obtain a test solution with the volume of 0.5 mg/mL; performing high performance liquid chromatography analysis under the following liquid phase conditions; performing high performance liquid chromatography analysis under the following liquid phase conditions;
the conditions for the liquid chromatography analysis were as follows:
the instrument comprises the following steps: agilent 1260Infinity II;
a chromatographic column: akzo Nobel Kromail 100-3.5-C184.6 x 250mm column;
flow rate of mobile phase: 0.6 mL/min;
the temperature of the chromatographic column is 25 ℃;
the sample injection amount is 10 mu L;
the detection wavelength is 230 nm;
mobile phase: methanol-water-76-24 (v/v);
as can be seen from FIG. 4, the retention time of 32.248min is (+) -naproxen-S-Boc-piperidinol ester, the retention time of 33.674min is (+) -naproxen-R-Boc-piperidinol ester, the separation degree of the two is 2.10, and the symmetry is 0.99 and 1.00, so that the method is higher in separation degree, better in chromatographic peak shape and symmetry, proper in peak emergence time, and capable of rapidly and sensitively detecting the (+) -naproxen-R/S-Boc-piperidinol ester.
Example 3
(1) Same as in step (1) of example 1;
(2) obtaining a test solution in the same step (2) as the step (2) of the example 2;
(3) the obtained sample solution was analyzed by high performance liquid chromatography under different chromatographic conditions (column temperature, flow rate or mobile phase) and other chromatographic conditions as in example 2, and the separation degrees of (+) -naproxen-S-Boc-piperidinol ester and (+) -naproxen-R-Boc-piperidinol ester under different chromatographic conditions were obtained from the chromatogram as follows:
1) the results of the chromatographic separation are shown in the table for different mobile phase ratios:
wherein t is 1 Is (+) -naproxen-S-Boc-piperidinol ester retention time, t 2 Is (+) -naproxen-R-Boc-piperidinol ester, and R is the resolution between two peaks.
From the results in the above table, it can be seen that the chromatographic peak separation degree of the different flow phases in this example has an effect. As methanol increases, retention time decreases but resolution decreases. The amount of organic phase was reduced and the degree of separation increased but the retention time increased. Therefore, the final choice of mobile phase ratio methanol: water 76: 24;
2) mobile phase: the results of the chromatographic separation are shown in the table, with methanol-water ratio of 76-24 and different flow rate ratios:
| flow rate mL/min | t 1 /min | t 2 /min | R |
| 0.4 | 49.150 | 51.332 | 2.09 |
| 0.5 | 38.905 | 40.622 | 2.09 |
| 0.6 | 32.248 | 33.674 | 2.10 |
| 0.7 | 26.749 | 27.903 | 1.96 |
| 0.8 | 22.970 | 23.952 | 1.90 |
The different flow rates in this example have an effect on the chromatographic peak separation. As the flow rate increases, the retention time decreases, and the degree of separation decreases. Comprehensively considering the factors of retention time and separation degree, and finally selecting the optimal flow rate of 0.6 mL/min;
3) the chromatographic separation results are shown in the table for different column temperatures:
| temperature/. degree.C | t 1 /min | t 2 / | R | |
| 20 | 36.535 | 38.239 | 1.84 | |
| 25 | 32.248 | 33.674 | 2.10 | |
| 30 | 31.749 | 33.129 | 2.09 | |
| 35 | 30.058 | 31.313 | 1.98 |
As can be seen from the results in the above table, the different column temperatures in this example have little effect on the chromatographic peak separation; the retention time decreases with increasing temperature. Considering environmental factors, 25 ℃ was finally selected.
In conclusion, the invention provides a method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization high performance liquid chromatography. The influence of factors such as mobile phase proportion, chromatographic column temperature, flow velocity and the like on the resolution, peak emergence time, chromatographic peak type and symmetry of chromatographic peaks is comprehensively considered, and the (+) -naproxen-R/S-N-Boc-piperidinol ester provides a liquid phase method capable of quickly and sensitively detecting the configuration and proportion of the chromatographic peaks.
The foregoing is merely an example of the embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (4)
1. A method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization high performance liquid chromatography is characterized by comprising the following steps:
a. performing pre-column derivatization esterification reaction on R/S-N-Boc-piperidinol and (+) -naproxen to obtain (+) -naproxen-R/S-N-Boc-piperidinol ester;
the pre-column derivatization esterification reaction comprises the following steps: dissolving R/S-N-Boc-piperidinol and (+) -naproxen in an oxalyl chloride solvent, and carrying out esterification reaction by using pyridine as a catalyst to obtain R/S-Boc-piperidinol ester; the (+) -naproxen: R/S-N-Boc-piperidinol: the molar ratio of pyridine is 0.80-0.84: 1.00: 1.20 to 1.24;
b. adopting a high performance liquid chromatograph, using octadecylsilane chemically bonded silica as a chromatographic column of a filler, using a water phase and methanol as a reverse phase mobile phase, preparing (+) -naproxen-R/S-N-Boc-piperidinol ester into a sample solution with the concentration of 0.2-1.0mg/mL, controlling the flow rate to be 0.4-0.8mL/min, the sample injection amount to be 2-10 mu L, the detection wavelength to be 210-260nm, and the column temperature of the chromatographic column to be 20-35 ℃, thereby separating the R/S-N-Boc-piperidinol, wherein the volume ratio of the methanol to the water in the mobile phase is 76: 24.
2. the method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent column pre-column derivatization high performance liquid chromatography as claimed in claim 1, wherein the flow rate is 0.6mL/min, the sample amount is 10 μ L, and the column temperature of the chromatographic column is 25 ℃ during the chromatographic separation in step b.
3. The method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent pre-column derivatization high performance liquid chromatography as claimed in claim 2, wherein the chromatographic column in step b is Akzo Nobel Kromail 100-3.5-C with octadecyl group bonded on 3.5 μm silica gel surface as stationary phase 18 4.6 x 250mm column.
4. The method for resolving R/S-N-Boc-piperidinol by chiral derivatization reagent according to claim 3, wherein in the step b, the high performance liquid chromatograph is: agilent 1260Infinity II, 1260Quat Pump VL G7111A, 1260VWD G7114A, 1260Viaisample G7129C.
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