CN103869004B - A kind of chirality detection method of gas phase of R-3-quinuclidinol isomeride and application thereof - Google Patents
A kind of chirality detection method of gas phase of R-3-quinuclidinol isomeride and application thereof Download PDFInfo
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Abstract
The invention provides a kind of chirality detection method of gas phase of R-3-quinuclidinol isomeride, this detection method adopts vapor-phase chromatography.Detection method provided by the invention has higher sensitivity and specificity, simple to operation, degree of separation meets standard, the isomeride of R-3-quinuclidinol can be detected fast and accurately, can be used for the quality control of R-3-quinuclidinol, this synthesis tool for many anticholinergic agentses is of great significance.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, be specifically related to a kind of chirality detection method and application thereof of gas phase of R-3-quinuclidinol isomeride.
Background technology
R-3-quinuclidinol (English name: R-3-Quinuclidinol) chemistry 1-azabicyclo [2.2.2] octane-3-alcohol by name, molecular formula is C
7h
13nO, molecular weight is 127.18, CAS accession number: 25333-42-0.R-3-quinuclidinol sterling is white crystal, and its fusing point is 217-224 DEG C, and boiling point is 120 DEG C (27mmHg), and specific rotatory power is-44.5 ° (c=3,1NHCI), and water-soluble is 100g/100mL.Its structure is such as formula shown in I.It has a chiral center, and its isomeride is (S)-(+)-3-quinuclidinol, its structure such as formula shown in II,
Formula I formula II
R-3-quinuclidinol is research human red blood ball acetylcholinesterase, synthesize several muscarinic receptor antagonists class medicine, the important intermediate for the treatment of Alzheimer and asthmatic medicament, it is the important intermediate of a lot of anticholinergic agent, such as Suo Linaxin, Revatropate etc. are all the up-to-date anticholinergic agents containing R-3-quinuclidinol structure, good curative effect is had for the treatment urinary incontinence and chronic obstructive pulmonary disease (COPD), also be the precursor of Chiral liquids catalyzer simultaneously, be widely used in chiral catalysis.Therefore, need to detect the chiral purity of R-3-quinuclidinol, this synthesis tool for many anticholinergic agentses is of great significance.Needs set up the isomeride and the standard compliant detection method of degree of separation that detect R-3-quinuclidinol.
Summary of the invention
The object of this invention is to provide a kind of gas phase chirality detection method and application thereof of quinuclidinol isomeride.This detection method adopts vapor-phase chromatography, and its chromatographic condition is as follows:
Carrier gas: be selected from nitrogen, hydrogen, helium;
Flow rate of mobile phase: 0.2-8.0mL/min;
Detecting device: be selected from FID, ECD, TCD;
Column temperature: 50 ~ 250 DEG C.
Wherein:
The sample injection method of detection method can be headspace injection method, also can be direct-injection technique, is preferably direct-injection technique.
Carrier gas is preferably helium.
Preferably, the solvent dissolving test sample is dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF), methyl alcohol, water, is preferably dimethyl formamide (DMF).
The concentration of need testing solution is 0.1-10mg/mL, is preferably 1mg/mL.
The sample size of direct-injection technique is 0.1-10 μ L, is preferably 1 μ L.
According to detection method provided by the invention, wherein, described chromatographic column is selected from DB-624 capillary column (30.0m × 0.53mm × 3.00 μm), DM-624 capillary column (75.0m × 0.53mm × 3.00 μm), DB-17 capillary column (30.0m × 0.53mm × 3.00 μm), DB-35 capillary column (30.0m × 0.53mm × 3.00 μm), HP-1 capillary column (30.0m × 0.53mm × 3.00 μm), HP-5 capillary column (30.0m × 0.53mm × 3.00 μm), Cyclosil-B capillary column (30.0m × 0.25mm × 0.25 μm), Cyclodex-B capillary column (30.0m × 0.25mm × 0.25 μm), HP-Chiral20 β capillary column (30.0m × 0.25mm × 0.25 μm), be preferably HP-5 capillary column (30.0m × 0.53mm × 3.00 μm), HP-Chiral20 β capillary column (30.0m × 0.25mm × 0.25 μm), be more preferably HP-Chiral20 β capillary column (30.0m × 0.25mm × 0.25 μm).According to detection method provided by the invention, wherein, the column temperature system of selection of described chromatographic column is constant temperature method and temperature programme, is preferably constant temperature method.
According to detection method provided by the invention, wherein, the column temperature of direct-injection technique is 50 ~ 250 DEG C, preferably 100 ~ 140 DEG C, is more preferably 120 DEG C.
According to detection method provided by the invention, wherein, the flow velocity of mobile phase is 0.2-8.0mL/min, is preferably 5mL/min.
According to detection method provided by the invention, wherein, the split ratio of direct injected is 100:1-1:100, is preferably 10:1.According to detection method provided by the invention, detecting device is preferably FID(flame ionization ditector).
The gas phase chirality detection method of a kind of R-3-quinuclidinol isomeride provided by the invention achieves the separation of R-3-quinuclidinol isomeride, and have higher sensitivity and specificity, simple to operation, degree of separation meets standard, and (that is, degree of separation is greater than 1.50.Degree of separation is the difference of the retention time at adjacent two peaks and the ratio of average peak width, is also resolution, represents the separation degree at adjacent two peaks.R is larger, shows that two adjacent groups separation is better.In general as R < 1, two peaks overlap; As R=1.0, degree of separation can reach 98%; As R=1.5, degree of separation can reach 99.7%.Usual R=1.5 divides the mark be separated completely as two adjacent groups.As R=1, be called that 4 σ are separated, two peaks are separated substantially, and exposed peak area is 95.4%, peak, inner side basic weight folded about 2%.During R=1.5, be called that 6 σ are separated, exposed peak area is 99.7%.R >=1.5 are called and are separated completely." Chinese Pharmacopoeia " regulation R should be greater than 1.5.Degree of separation computing formula: R=2 (tR2-tR1)/(W1+W2)), can be used for the quality control of R-3-quinuclidinol, there is realistic meaning.
Accompanying drawing explanation
Fig. 1 is the gas chromatogram of system flexibility solution in embodiment 3;
Fig. 2 is the gas chromatogram of system flexibility solution in embodiment 5.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
embodiment 1
The selection of the selection of solvent and the concentration of solution::
The selection of the solvent of sample dissolution, we use dimethyl sulfoxide (DMSO), dimethyl formamide, methyl alcohol, water sample dissolution respectively, and wherein the solubleness of dimethyl formamide to sample is best.
We use dimethyl formamide as the solvent of sample, be made into 0.1mg/mL, 1mg/mL and 10mg/mL respectively, because the response of 0.1mg/mL is too little, and the concentration of 10mg/mL is unfavorable for too greatly the separation of sample, and we finally select 1mg/mL as the concentration of need testing solution.
embodiment 2
The selection of type carrier gases and flow velocity:
The carrier gas that vapor-phase chromatography is commonly used is nitrogen, hydrogen, helium.Consider the security in laboratory, we use nitrogen or helium as experiment carrier gas, and because helium is more better than the separation of nitrogen to sample as carrier gas, we finally select helium to be carrier gas.(see embodiment 3 and 5)
The selection of flow rate of carrier gas, we investigate flow rate of carrier gas, and the flow velocity of 0.2mL/min is too slow, and sample appearance time is too slow; The flow velocity of 8.0mL/min is unfavorable for the separation of sample.Within the scope of this, We conducted the screening of flow rate of carrier gas, screen 2.0mL/min, 4.0mL/min, 5.0mL/min respectively.(see embodiment 3,4,5)
embodiment 3
1) instrument and testing conditions
The Agilent7890N gas chromatograph that Agilent company of the U.S. produces, automatic sampler, the HP-chiral-20 β capillary column (chromatographic column specification is: 30.0m × 0.25mm × 0.25 μm) produced by Agilent company; Column temperature: 120 DEG C maintain 25 minutes; Vaporizer temperature: 230 DEG C; Flow rate of carrier gas: nitrogen, 4.0mL/min; Detecting device: flame ionization ditector (FID); Detector temperature: 230 DEG C; Sample size: 1 μ L, split ratio: 10:1.
2) experimental procedure
Precision takes the racemoid 10mg of quinuclidinol in 10mL volumetric flask, dissolves, be diluted to scale with dimethyl formamide (DMF), and mixing, obtains system flexibility solution (1mg/ml).
embodiment 4
1) instrument and testing conditions
The Agilent7890N gas chromatograph that Agilent company of the U.S. produces, automatic sampler, the HP-chiral-20 β capillary column (chromatographic column specification is: 30.0m × 0.25mm × 0.25 μm) produced by Agilent company; Column temperature: 50 DEG C maintain 1 minute, are warming up to 200 DEG C, maintain 5 minutes with the heating rate of 5 DEG C/min; Vaporizer temperature: 230 DEG C; Flow rate of carrier gas: helium, 2.0mL/min; Detecting device: flame ionization ditector (FID); Detector temperature: 230 DEG C; Sample size: 1 μ L, split ratio: 10:1.
2) experimental procedure
Precision takes the racemoid 10mg of quinuclidinol in 10mL volumetric flask, dissolves, be diluted to scale with dimethyl formamide (DMF), and mixing, obtains system flexibility solution (1mg/ml).
embodiment 5
1) instrument and testing conditions
The Agilent7890N gas chromatograph that Agilent company of the U.S. produces, automatic sampler, the HP-chiral-20 β capillary column (chromatographic column specification is: 30.0m × 0.25mm × 0.25 μm) produced by Agilent company; Column temperature: 120 DEG C maintain 25 minutes; Vaporizer temperature: 230 DEG C; Flow rate of carrier gas: helium, 5.0mL/min; Detecting device: flame ionization ditector (FID); Detector temperature: 230 DEG C; Sample size: 1 μ L, split ratio: 10:1.
2) experimental procedure
Precision takes the racemoid 10mg of quinuclidinol in 10mL volumetric flask, dissolves, be diluted to scale with dimethyl formamide (DMF), and mixing, obtains system flexibility solution (1mg/ml).
Different column temperature on the impact of degree of separation in table 1.
Table 1 column temperature screens
| Column temperature DEG C | Degree of separation | |
| Embodiment 1-1 | 100 | 1.54 |
| Embodiment 1-2 | 110 | 1.70 |
| Embodiment 1-3 | 120 | 1.88 |
| Embodiment 1-4 | 130 | 1.42 |
| Embodiment 1-5 | 140 | 1.35 |
As can be seen from Table 1, when column temperature is 120 DEG C, (R)-(-)-3-quinuclidinol reaches 1.88 with the degree of separation of (S)-(+)-3-quinuclidinol, and separating effect is best.
System flexibility measured in solution result and precision test (n=6)
Get system flexibility solution, continuous sample introduction measures successively, calculates the RSD% of toluene, dimethyl formamide peak area.Test findings is in table 2.
Table 2 system flexibility measured in solution result and precision test
| Sequence number | (R)-(-) peak area of-3-quinuclidinol | (S)-(+) peak area of-3-quinuclidinol |
| 1 | 90.2 | 86.6 |
| 2 | 91.3 | 88.3 |
| 3 | 93.2 | 89.6 |
| 4 | 94.3 | 85.7 |
| 5 | 92.5 | 89.1 |
| 6 | 93.2 | 92.5 |
| Mean value | 92.5 | 88.6 |
| RSD% | 1.60 | 2.72 |
Linear relationship is tested
Take respectively the racemoid 1.0 of quinuclidinol, 2.0,5.0,10.0,12.0, put in 10mL volumetric flask, dimethyl formamide (DMF) dissolves, and is diluted to scale, is made into the test solution of variable concentrations, and sample introduction measures successively.Result shows: (R)-(-)-3-quinuclidinol is in 0.1-1.2mg/mL concentration range, and linear relationship is good; (S)-(+)-3-quinuclidinol is in 0.1-1.2mg/mL concentration range, and linear relationship is good.Test findings is in table 3.
Table 3 linear relationship test findings
Solution stability testing
Get system flexibility solution respectively at 0h, 2h, 6h, 8h, 24h, sample introduction measures, record chromatogram.Calculate the RSD% of the peak area of each solvent, in table 4.(R)-(-) RSD% of-3-quinuclidinol, (S)-(+)-3-quinuclidinol chromatography peak integration area is respectively 1.97%, 1.20%, shows that (R)-(-)-3-quinuclidinol, (S)-(+)-3-quinuclidinol are basicly stable in 24h.
Table 4 solution stability testing result (n=5)
| Sequence number | (R)-(-) peak area of-3-quinuclidinol | (S)-(+) peak area of-3-quinuclidinol |
| 0h | 90.2 | 86.6 |
| 2h | 91.0 | 86.9 |
| 6h | 92.3 | 87.6 |
| 8h | 94.1 | 88.3 |
| 24h | 94.3 | 89.2 |
| Mean value | 92.4 | 87.7 |
| RSD% | 1.97 | 1.20 |
Claims (10)
1. a chirality detection method for R-3-quinuclidinol isomeride, is characterized in that, this detection method adopts vapor-phase chromatography, and its chromatographic condition is as follows:
Chromatographic column: HP-Chiral20 β capillary column 30.0m × 0.25mm × 0.25 μm;
Carrier gas: be selected from nitrogen, hydrogen, helium any one;
Flow rate of mobile phase: 0.2-8.0mL/min;
Detecting device: be selected from FID, ECD, TCD;
Column temperature: 50 ~ 250 DEG C.
2. the chirality detection method of a kind of R-3-quinuclidinol isomeride according to claim 1, is characterized in that, this detection method adopts vapor-phase chromatography, and its chromatographic condition is as follows:
Chromatographic column: HP-Chiral20 β capillary column 30.0m × 0.25mm × 0.25 μm;
Carrier gas: be helium;
Flow rate of mobile phase: 5mL/min;
Detecting device: be FID;
Column temperature: 100 ~ 140 DEG C.
3. the chirality detection method of a kind of R-3-quinuclidinol isomeride according to claim 2, is characterized in that, this detection method adopts vapor-phase chromatography, and its chromatographic condition is as follows:
Chromatographic column: HP-Chiral20 β capillary column 30.0m × 0.25mm × 0.25 μm;
Carrier gas: be helium;
Flow rate of mobile phase: 5mL/min;
Detecting device: be FID;
Column temperature: 120 DEG C.
4. the detection method according to any one of claim 1-3, the solvent dissolving test sample is dimethyl sulfoxide (DMSO), dimethyl formamide, methyl alcohol, water.
5. detection method according to claim 4, the solvent dissolving test sample is dimethyl formamide.
6. the detection method according to any one of claim 1-3, the concentration of need testing solution is 0.1-10mg/mL.
7. detection method according to claim 6, the concentration of need testing solution is 1mg/mL.
8. the detection method according to any one of claim 1-3, the column temperature system of selection of described chromatographic column is constant temperature method or temperature programme.
9. detection method according to claim 8, the column temperature system of selection of described chromatographic column is constant temperature method.
10. the application of the detection method described in any one of claim 1-3 in the detection of R-3-quinuclidinol isomeride.
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| Production of (R)-3-Quinuclidinol by E. coli Biocatalysts Possessing NADH-Dependent 3-Quinuclidinone Reductase (QNR or bacC) from Microbacterium luteolum and Leifsonia Alcohol Dehydrogenase (LSADH);Kentaro Isotani，et al;《Int. J. Mol. Sci.》;20121019;第13卷;第13551页第3.2.6节 * |
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