CN105628807B - A kind of quality determining method of the amino piperidines of 1 Boc 4 - Google Patents
A kind of quality determining method of the amino piperidines of 1 Boc 4 Download PDFInfo
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Abstract
The invention provides a kind of quality determining method of the amino piperidines of 1 Boc 4, belong to technical field of quality detection, it comprises the following steps：Precision weighs the amino piperidines of 1 Boc of test sample 4, and need testing solution is prepared into after being dissolved with solvent；The need testing solution is injected in high performance liquid chromatograph and is measured；Chromatographic condition：Mobile phase A is acetonitrile, and Mobile phase B is the 20mmol/L diammonium hydrogen phosphate aqueous solution；Gradient elution, flow velocity are 0.8 1.2ml/min；Column temperature is 25 35 DEG C；UV-detector, Detection wavelength 210nm.The quality determining method, make the amino piperidines of 1 Boc 4 and the wherein piperidones of impurity N Boc 4 and the hydroxy piperidines of N Boc 4 that there is good separating degree, and be easy to it is quick, accurate, mass content analysis delicately is carried out to the amino piperidines of 1 Boc 4.
Description
Technical field
The present invention relates to technical field of quality detection, is examined in particular to a kind of quality of 1-Boc-4- amino piperidines
Survey method.
Background technology
LAS-17177 piece (cinitapride) is the benzene of Spain Almirall Prodesfarma pharmaceutical factories exploitation
Carboxamides derivatives, ratify to list in Spain April nineteen ninety, suitable for gastrointestinal discomfort caused by bradygastria.
1-Boc-4- amino piperidines is synthesize the important source material of LAS-17177, wherein containing N-Boc-4- piperidones
With the impurity such as N-Boc-4- hydroxy piperidines.Because of 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines
UV absorption is weak, polarity is stronger, so causing 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxyl piperazines
Pyridine hardly possible in high performance liquid chromatography separates and is not easy to detect the mass content of 1-Boc-4- amino piperidines.
The content of the invention
In order to solve the above problems, it is an object of the invention to provide a kind of quality testing side of 1-Boc-4- amino piperidines
Method, so that 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines have good separating degree, and just
In it is quick, accurate, delicately to 1-Boc-4- amino piperidines carry out mass content analysis.
The technical solution adopted in the present invention is：
A kind of quality determining method of 1-Boc-4- amino piperidines, comprises the following steps：Precision weighs test sample 1-Boc-
4- amino piperidines, need testing solution is prepared into after being dissolved with solvent；The need testing solution is injected in high performance liquid chromatograph
It is measured；
Chromatographic condition：Mobile phase A is acetonitrile, and Mobile phase B is the 20mmol/L diammonium hydrogen phosphate aqueous solution；Gradient elution,
Flow velocity is 0.8-1.2ml/min；The column temperature of chromatographic column is 25-35 DEG C；The Detection wavelength of detector is 210nm.
Because 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines have maximum at 210nm
Absorbing wavelength, therefore, the Detection wavelength of detector is 210nm.Wherein, detector is preferably diode array (DAD) detector,
It can carry out laterally detection and longitudinal direction detection simultaneously, and can be used for the detection of peak purity.
Mobile phase A is acetonitrile, and Mobile phase B is the 20mmol/L diammonium hydrogen phosphate aqueous solution, and with 0.8-1.2ml/min's
Flow velocity carry out gradient elution, and column temperature be 25-35 DEG C, so as to so that 1-Boc-4- amino piperidines, N-Boc-4- piperidones and
N-Boc-4- hydroxy piperidines have good separating degree, and quickly elute.
Therefore, above-mentioned quality determining method can accurately, rapidly and sensitively detect 1-Boc-4- amino piperidines, N-
The mass content of Boc-4- piperidones and N-Boc-4- hydroxy piperidines and complete 1-Boc-4- amino piperidines mass content analysis,
Ensure that its purity meets the requirements.
And above-mentioned quality determining method also has good precision and durability.
Wherein, flow velocity is preferably 1ml/min, and column temperature is preferably 30 DEG C
Further, the program of the gradient elution is：At 0 minute, the ratio of the mobile phase A and the Mobile phase B is
77-87:18；At 15 minutes, the ratio of the mobile phase A and the Mobile phase B is 55-65:40；At 18 minutes, the flowing
The ratio of phase A and the Mobile phase B is 55-65:40；At 18.1 minutes, the ratio of the mobile phase A and the Mobile phase B is
77-87:18。
Wherein it is preferred to the program of the gradient elution is：At 0 minute, the ratio of the mobile phase A and the Mobile phase B
Example is 82:18；At 15 minutes, the ratio of the mobile phase A and the Mobile phase B is 60:40；At 18 minutes, the mobile phase A
Ratio with the Mobile phase B is 60:40；At 18.1 minutes, the ratio of the mobile phase A and the Mobile phase B is 82:18.
, can be quickly to 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N- by the program of above-mentioned gradient elution
Boc-4- hydroxy piperidines carry out quick separating, so as to shorten the detection time of above-mentioned quality determining method.
Further, the sample size of the need testing solution is 10 μ L, and the concentration of the need testing solution is 1-5mg/ml.
Wherein it is preferred to the concentration of the need testing solution is 3mg/ml.
Further, the chromatographic column is Kromasil phenyl chromatographic columns, and the internal diameter of the chromatographic column is 4.6mm, and length is
250mm；A diameter of 5 μm of the filler particles of the chromatographic column.
Above-mentioned quality determining method, the detection of the 1-Boc-4- amino piperidines in test sample are limited to 0.284ng, quantitative limit
For：3.485ng；The detection of N-Boc-4- piperidones is limited to 0.286ng, is quantitatively limited to 7.186ng；N-Boc-4- hydroxy piperidines
Detection is limited to 0.295ng, is quantitatively limited to 2.100ng.Wherein, the computational methods of test limit and quantitative limit compared with method without
Elaborate.
Further, the solvent is methanol.
When carrying out mass content analysis by high-efficient liquid phase technique, sample can select water, acetonitrile, methanol or acetone respectively
Dissolved Deng multi-solvents；Wherein, it is preferably methanol according to the property of 1-Boc-4- amino piperidines.
Beneficial effects of the present invention：
The quality determining method of 1-Boc-4- amino piperidines provided by the present invention, make 1-Boc-4- amino piperidines with wherein
Impurity N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines have good separating degree, and be easy to it is quick, accurate, delicately right
1-Boc-4- amino piperidines carry out mass content analysis.
Brief description of the drawings
Fig. 1 is that 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines go out peak figure；
Fig. 2 is the concentration and peak area linear graph of the 1-Boc-4- amino piperidines in embodiment 1；
Fig. 3 is the concentration and peak area Line Chart of the N-Boc-4- piperidones in embodiment 1；
Fig. 4 is the concentration and peak area Line Chart of the N-Boc-4- hydroxy piperidines in embodiment 1；
Fig. 5 is collection of illustrative plates of the 1-Boc-4- amino piperidines after acid destroys in embodiment 2；
Fig. 6 is collection of illustrative plates of the 1-Boc-4- amino piperidines after alkali destroys in embodiment 2；
Fig. 7 is the collection of illustrative plates after the oxidized destruction of 1-Boc-4- amino piperidines in embodiment 2；
Fig. 8 is collection of illustrative plates of the 1-Boc-4- amino piperidines after natural photo damage in embodiment 2；
Fig. 9 is collection of illustrative plates of the 1-Boc-4- amino piperidines after high temperature in embodiment 2.
Embodiment
Laboratory apparatus：The high performance liquid chromatographs of Agilent 1100, Agilent 1100DAD detectors, Kromasil
Eternity-5-Pheny chromatographic columns (chromatogram column internal diameter 4.6mm, length 250mm, 5 μm of filler particles diameter).
Experimental drug：Diammonium hydrogen phosphate, acetonitrile (chromatographic grade), redistilled water, 1-Boc-4- amino piperidines reference substance, N-
Boc-4- piperidones reference substance, N-Boc-4- hydroxy piperidine reference substances.
The preparation of compound stock solution：Precision weighs 1-Boc-4- amino piperidine reference substance 24.83mg, N-Boc-4- piperidines
Ketone reference substance 24.70mg and N-Boc-4- hydroxy piperidine reference substance 24.52mg adds first respectively in different 5ml volumetric flask
Alcohol dissolves and is diluted to scale, shakes up, constant volume, is then put in each compound stock solution stored refrigerated standby in refrigerator.
Embodiment 1
Precision measures each compound stock solution in right amount in same volumetric flask, is each configured to 0.28 μ g/ml~0.4mg/
The solution of ml concentration, and numbering is 1-7 respectively.
Wherein, in the solution of numbering 1, the μ of 0.28 μ g/ml, N-Boc-4- hydroxy piperidine of amino piperidine containing 1-Boc-4- 0.28
g/ml。
In the solution of numbering 2, μ g/ml of amino piperidine containing 1-Boc-4- 9.36, μ g/ml of N-Boc-4- hydroxy piperidines 9.51,
The μ g/ml of N-Boc-4- piperidones 1.20.
In the solution of numbering 3, μ g/ml of amino piperidine containing 1-Boc-4- 37.44, the μ g/ of N-Boc-4- hydroxy piperidines 38.05
The μ g/ml of ml, N-Boc-4- piperidones 4.81.
In the solution of numbering 4, μ g/ml of amino piperidine containing 1-Boc-4- 93.60, the μ g/ of N-Boc-4- hydroxy piperidines 95.12
The μ g/ml of ml, N-Boc-4- piperidones 12.03.
In the solution of numbering 5, μ g/ml of amino piperidine containing 1-Boc-4- 187.20, the μ g/ of N-Boc-4- hydroxy piperidines 190.24
The μ g/ml of ml, N-Boc-4- piperidones 24.06.
In the solution of numbering 6, μ g/ml of amino piperidine containing 1-Boc-4- 280.80, the μ g/ of N-Boc-4- hydroxy piperidines 285.36
The μ g/ml of ml, N-Boc-4- piperidones 36.09.
In the solution of numbering 7, μ g/ml of amino piperidine containing 1-Boc-4- 374.40, the μ g/ of N-Boc-4- hydroxy piperidines 380.48
The μ g/ml of ml, N-Boc-4- piperidones 48.12.
The solution of above-mentioned numbering is injected into liquid chromatograph with 10 μ L sample size respectively, the solution detection each numbered
Three times, chromatogram is recorded, and counts the peak area of each compound, calculates average peak area and relative standard deviation (RSD).
The chromatographic condition of high performance liquid chromatography is：Kromasil Eternity-5-Pheny chromatographic column (chromatogram column internal diameters
4.6mm, length 250mm, 5 μm of filler particles diameter), column temperature：30℃；Agilent 1100DAD detectors, Detection wavelength：
210nm；Mobile phase：A acetonitriles, the B 20mmol/L diammonium hydrogen phosphate aqueous solution, flow velocity：1.0ml/min, mobile phase are pressed with Gradient
Elution program is eluted：
The appearance time of 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines is as shown in Figure 1.
Wherein, 1-Boc-4- amino piperidines linear verification result is as shown in table 1 below, with the concentration of 1-Boc-4- amino piperidines
For abscissa, peak area is that ordinate draws standard curve, and its standard curve is as shown in Figure 2.
The 1-Boc-4- amino piperidine linear verification results of table 1
Known by table 1 and Fig. 2, the standard curve of 1-Boc-4- amino piperidines is：Y=3.132x+2.9409, coefficient R2
=1.000.
N-Boc-4- piperidones linear verification results are as shown in table 2 below, using the concentration of 1-Boc-4- amino piperidines as horizontal seat
Mark, peak area are that ordinate draws standard curve, and its standard curve is as shown in Figure 3.
The N-Boc-4- piperidones linear verification results of table 2
Known by table 2 and Fig. 3, the standard curve of N-Boc-4- piperidones is：Y=2.7229x-0.9591, coefficient R2
=0.9997.
N-Boc-4- hydroxy piperidine linear verification results are as shown in table 3 below, using the concentration of 1-Boc-4- amino piperidines as horizontal stroke
Coordinate, peak area are that ordinate draws standard curve, and its standard curve is as shown in Figure 4.
The N-Boc-4- hydroxy piperidine linear verification results of table 3
Known by table 3 and Fig. 4, the standard curve of N-Boc-4- hydroxy piperidines is：4.0759x+6.3945 coefficient R2=
0.9999。
As can be seen here, the coefficient R of each standard curve2≤ 1, standard curve is respectively provided with good linear relationship, therefore,
Above-mentioned quality determining method can be used for quantitative analysis detection 1-Boc-4- amino piperidines, N-Boc-4- piperidones and N-Boc-
The content of 4- hydroxy piperidines.
Embodiment 2
Specificity is tested：Take 1-Boc-4- amino piperidine test samples appropriate, by two annex XIXA of Chinese Pharmacopoeia 2010 edition
Regulation carried out the forced degradations such as acid, alkali, oxidation, natural light, high temperature experiment.
And by the high performance liquid chromatography described in embodiment 1 after the 1-Boc-4- amino piperidines after degraded are dissolved with methanol
Method carries out quality testing, and using methanol solution as the independent sample introduction of blank.Wherein, 1-Boc-4- amino piperidines are through acid, alkali, oxygen
Collection of illustrative plates difference after change, natural light, high temperature is as shown in figures 5-9.
Test result indicates that：Blank does not disturb the detection of impurity；Before and after forced degradation experiment, point of main peak and other impurities
1.5 are all higher than from degree, and peak purity meets the requirements；Material balance result is shown after forced degradation, and the impurity degraded can quilt
Detection.
Embodiment 3
Test limit, quantitative limit experiment
Precision measures each compound stock solution in right amount in same volumetric flask, and take progressively dilution method by embodiment 1
Described high performance liquid chromatography carries out quality testing to each dilute solution in progressively dilution method, with reference to standards of pharmacopoeia, according to
S/N=3 calculates test limit, and quantitative limit is calculated according to S/N=10.
Experimental result：The detection of 1-Boc-4- amino piperidines is limited to 0.284ng, is quantitatively limited to：3.485ng；N-Boc-4- piperazines
The detection of pyridine ketone is limited to 0.286ng, is quantitatively limited to 7.186ng；The detection of N-Boc-4- hydroxy piperidines is limited to 0.295ng, quantitative limit
For 2.100ng.
Embodiment 4
Accuracy test：By prepare N-Boc-4- piperidones, N-Boc-4- hydroxy piperidines limit be 0.5% 50%,
100%th, the sample solution of 150% concentration, and quality testing is carried out according to the high performance liquid chromatography described in embodiment 1, point
The rate of recovery of impurity N-Boc-4- piperidones and N-Boc-4- hydroxy piperidines is not measured, and statistical result is as in the table below.
The N-Boc-4- piperidones accuracy validations of table 4
The N-Boc-4- hydroxy piperidine accuracy validations of table 5
From table 4-5, the rate of recovery measured by the high performance liquid chromatography described in embodiment 1 is in 95%-
Between 108%, RSD is respectively less than 5%, and therefore, it has good accuracy.
Embodiment 5
Precision test is test solution (the i.e. test solution for preparing 6 part 100% of the concentration level containing known impurities
It is the concentration specified without the processing such as dilution), and by the high effective liquid chromatography for measuring 6 times described in embodiment 1, pass through it
Measurement result is evaluated.
Each solution calculates the amount of each impurity using external standard method, because the method that external standard method is this area routine is without doing in detail
Introduce.
Precision test requires that the RSD for determining the result of 6 times cannot be greater than 2.0%, so as to which substantive approach has well
Precision.The result of precision test is as shown in table 6 below：
The precision test of table 6 is verified
As shown in Table 6, the high performance liquid chromatography described in embodiment 1 has good precision.
Embodiment 6
Serviceability test：Refer to when small variation occurs for detection method, the impregnable Bearing degree of measurement result.
The present embodiment is according to the high performance liquid chromatography described in embodiment 1, to its column temperature ± 5 DEG C, flow velocity ± 0.2ml/
Min, ratio ± 5% of mobile phase A have carried out serviceability test, and its durability the result is as shown in table 7 below：
The durability of table 7 is verified
As shown in Table 7, the high performance liquid chromatography described in embodiment 1 has good durability.
In above-described embodiment, each compound is dissolved using methanol, it is readily appreciated that, it can also use acetonitrile, acetone etc.
Solvent dissolves.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (6)
1. a kind of detection method of 1-Boc-4- amino piperidines, it is characterised in that comprise the following steps：Precision weighs test sample 1-
Boc-4- amino piperidines, need testing solution is prepared into after being dissolved with solvent；The need testing solution is injected into high performance liquid chromatography
It is measured in instrument；Chromatographic condition：Mobile phase A is acetonitrile, and Mobile phase B is the 20mmol/L diammonium hydrogen phosphate aqueous solution；Gradient
Elution, flow velocity 0.8-1.2ml/min；Chromatographic column is Kromasil phenyl chromatographic columns, and the internal diameter of the chromatographic column is 4.6mm,
Length is 250mm, a diameter of 5 μm of the filler particles of the chromatographic column, and the column temperature of chromatographic column is 25-35 DEG C；The inspection of detector
Survey wavelength is 210nm, and the program of the gradient elution is：At 0 minute, the ratio of the mobile phase A and the Mobile phase B is
77-87:18；At 15 minutes, the ratio of the mobile phase A and the Mobile phase B is 55-65:40；At 18 minutes, the flowing
The ratio of phase A and the Mobile phase B is 55-65:40；18.1 during minute, the ratio of the mobile phase A and the Mobile phase B is
77-87:18。
2. detection method according to claim 1, it is characterised in that the flow velocity is 1ml/min, and the column temperature is 30
℃。
3. detection method according to claim 1, it is characterised in that the program of the gradient elution is：At 0 minute, institute
The ratio for stating mobile phase A and the Mobile phase B is 82:18；At 15 minutes, the ratio of the mobile phase A and the Mobile phase B is
60:40；At 18 minutes, the ratio of the mobile phase A and the Mobile phase B is 60:40；At 18.1 minutes, the mobile phase A with
The ratio of the Mobile phase B is 82:18.
4. according to the detection method described in claim any one of 1-3, it is characterised in that the sample size of the need testing solution is
10 μ L, the concentration of the need testing solution is 1-5mg/ml.
5. detection method according to claim 4, it is characterised in that the concentration of the need testing solution is 3mg/ml.
6. according to the detection method described in claim any one of 1-3, it is characterised in that the solvent is methanol.
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| CN104034814A (en) * | 2014-06-10 | 2014-09-10 | 河北科技大学 | HPLC (High Performance Liquid Chromatography) analysis method for 3-aminopiperidine |
| CN104628627A (en) * | 2014-12-23 | 2015-05-20 | 安徽德信佳生物医药有限公司 | Method for synthesizing 1-boc-4-aminopiperidine |
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| CN104034814A (en) * | 2014-06-10 | 2014-09-10 | 河北科技大学 | HPLC (High Performance Liquid Chromatography) analysis method for 3-aminopiperidine |
| CN104628627A (en) * | 2014-12-23 | 2015-05-20 | 安徽德信佳生物医药有限公司 | Method for synthesizing 1-boc-4-aminopiperidine |
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Effective date of registration: 20221208 Address after: 5/F, Building B7, No. 88, Keyuan South Road, Fengjiawan Industrial Park, Hi tech Zone, Chengdu, Sichuan 610095 Patentee after: CHENGDU XINJIE HI-TECH DEVELOPMENT Co.,Ltd. Patentee after: Guangzhou Yuanzhi Hengchuang Pharmaceutical Technology Co.,Ltd. Address before: 610000 5 building, 88 B7, Keyuan South Road, Feng Jia Wan Industrial Park, Chengdu hi tech Zone, Sichuan. Patentee before: CHENGDU XINJIE HI-TECH DEVELOPMENT Co.,Ltd. |