CN107884492A - The HPLC analytical method of the diaminourea pyrimidine of 1,3 dimethyl 5,6 - Google Patents
The HPLC analytical method of the diaminourea pyrimidine of 1,3 dimethyl 5,6 Download PDFInfo
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- CN107884492A CN107884492A CN201711090299.4A CN201711090299A CN107884492A CN 107884492 A CN107884492 A CN 107884492A CN 201711090299 A CN201711090299 A CN 201711090299A CN 107884492 A CN107884492 A CN 107884492A
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- dau
- potassium dihydrogen
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- 238000004458 analytical method Methods 0.000 title claims abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 10
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 8
- CTVOMOLYHRVSBT-UHFFFAOYSA-N N1=CN=CC=C1.NNC(NN)=O Chemical compound N1=CN=CC=C1.NNC(NN)=O CTVOMOLYHRVSBT-UHFFFAOYSA-N 0.000 title abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 84
- 235000019796 monopotassium phosphate Nutrition 0.000 claims abstract description 27
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims abstract description 16
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 238000010790 dilution Methods 0.000 claims abstract description 3
- 239000012895 dilution Substances 0.000 claims abstract description 3
- 238000010812 external standard method Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 13
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 11
- 238000005070 sampling Methods 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- 239000007791 liquid phase Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 238000003113 dilution method Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000013507 mapping Methods 0.000 claims description 2
- ZENDWEPAVHORFD-UHFFFAOYSA-N pyrimidine;urea Chemical compound NC(N)=O.C1=CN=CN=C1 ZENDWEPAVHORFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000002386 leaching Methods 0.000 abstract 1
- 238000002604 ultrasonography Methods 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- ZGTMCPKEDXPXGI-UHFFFAOYSA-N 1,3-dimethyl-2,4-dihydropyrimidine-5,6-diamine Chemical compound NC=1CN(CN(C=1N)C)C ZGTMCPKEDXPXGI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The present invention relates to a kind of HPLC analytical method of the diaminourea pyrimidine (dimethyl DAU) of 1,3 dimethyl 5,6, include the pretreatment of analysis raw material, the analysis condition of high performance liquid chromatography and qualitative, quantitative approach.The pretreatment of analysis raw material includes hot leaching sample, ultrasound, flows phase dilution；Chromatographiccondition is：The μ L of sample size 20；Mobile phase is that volume ratio is 95:5 0.02mol/L potassium dihydrogen phosphate and acetonitrile, flow velocity 1ml/min；Chromatographic column is the post 250mm × 4.6mm of Syncronis C 18,25 DEG C of column temperature；Detector is UV-detector, and Detection wavelength is 275 300nm；Dimethyl DAU residence time is 5.66min；Quantitative approach used is external standard method.The inventive method is simple to operate, and cost is low, and quickly, efficiently and accurately dimethyl DAU can be analyzed.
Description
Technical field：
The present invention relates to a kind of high performance liquid chromatography of 1,3- dimethyl -5,6- diaminoureas pyrimidine (dimethyl-DAU) point
Analysis method.
Background technology：
Dimethyl-DAU be 1,3- dimethyl -5,6- diaminourea pyrimidines abbreviation, 1,3- dimethyl -5,6- diaminourea
Pyrimidine is otherwise referred to as 1,3- dimethyl -4,5- diaminourea pyrimidines or 1,3- dimethyl -5,6- di-amino-pyrimidine -2,4- bis-
Ketone.At present, the analysis method of 1,3- dimethyl -5,6- diaminoureas pyrimidine (dimethyl-DAU) is by two in most documents
Methyl D AU is filtered while hot, adds formic acid, in 95 DEG C~100 DEG C formylateds, stable dimethyl-FAU is generated, as a result with diformazan
Base-FAU contents (mg/100mL) represent, using industrial iodimetric analysis, by the Na consumed2S2O3Liquor capacity calculates content.
This method and step is cumbersome, takes time and effort.
Zheng Xianglong, Hu Xien quickly analyze dimethyl-DAU using RPLC, and mobile phase is containing concentration
The acetonitrile solution (pH3~4) of 0.02mol/L potassium dihydrogen phosphates (volume fraction 4%), flow velocity 1mL/min, Detection wavelength are
226nm, the μ L of sample size 5.Although Hu Xien, Zheng Xianglong have used efficient liquid phase chromatographic analysis dimethyl-DAU, but inspection used
Survey wavelength is 226nm, and this wavelength has the following disadvantages when analyzing the dimethyl-DAU as caffeine important intermediate：1,3-
During dimethyl -5- nitroso -6- semicarbazides pyrimidines hydrogenating reduction is dimethyl-DAU, impurity is more, is detected under 226nm dry
Disturb greatly, response may be produced to impurity.And turn to 1,3- dimethyl -6- amino -5- formamidos in dimethyl-DAU formyls
During urea pyrimidine, under the conditions of 226nm can not to the dimethyl in 1,3- dimethyl -6- amino -5- formamido urea pyrimidines -
DAU is analyzed.And 300nm is strong for dimethyl-DAU selectivity, problem above can be overcome, in some impurity or 1,
In the presence of 3- dimethyl -6- amino -5- formamido urea pyrimidines, dimethyl-DAU is analyzed.
The content of the invention：
A kind of the shortcomings that it is an object of the invention to overcome prior art, there is provided quick, efficient, convenient 1,3- diformazans
The liquid phase chromatography analytical method of base -5,6- diaminoureas pyrimidine (dimethyl-DAU).The inventive method includes-DAU points of dimethyl
Analyse the preprocess method and its high performance liquid chromatography qualitative and quantitative analysis method of raw material.
In order to realize foregoing invention purpose, the high-efficient liquid phase color of 1,3- dimethyl -5,6- diaminourea pyrimidines of the invention
Spectral analysis method operates according to following steps：
The first step, 1,3- dimethyl -5,6- diaminourea pyrimidine (dimethyl-DAU) analyze the pretreatment of raw material
Dimethyl-DAU is analyzed into raw material heat filtering, sampling, it is dilute that ultrasonic 5min, dimethyl-DAU analyze raw material mobile phase
2500 times or 5000 times are released, obtains dimethyl-DAU analysis samples, the mobile phase is that volume ratio is 95:5 biphosphate
Potassium (0.02mol/L) and acetonitrile；
Dilution process is：Volume ratio is added to be 95 first for the dimethyl-DAU of sampling:5 potassium dihydrogen phosphate (0.02mol/
L) and acetonitrile constant volume is in 50ml volumetric flasks, then therefrom accurately takes 1ml to add volume ratio to be 95:5 potassium dihydrogen phosphate (0.02mol/L)
With acetonitrile constant volume in 50ml volumetric flasks, that is, whole dimethyl-DAU samples are diluted to 2500ml dimethyl-DAU solution；
Or dimethyl-DAU adds volume ratio to be 95 first:5 potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume is in 50ml capacity
Bottle, then therefrom accurately take 1ml to add volume ratio to be 95:5 potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume is in 100ml capacity
Bottle, that is, whole dimethyl-DAU samples are diluted to 5000ml dimethyl-DAU solution, preferably 5000 times；
Second step, dimethyl-DAU efficient liquid phase chromatographic analysis
Dimethyl-DAU is analyzed into sample by high performance liquid chromatography detection, liquid chromatogram sample size is 20 μ L, liquid phase color
Mobile phase is composed as 0.02mol/L potassium dihydrogen phosphate and the solution of acetonitrile, the volume ratio of 0.02mol/L potassium dihydrogen phosphates and acetonitrile
For 95:5, pH=2.68, flow velocity 1ml/min；Chromatographic column uses Syncronis C-18 post 250mm × 4.6mm, chromatographic column temperature
Spend for 25 DEG C, the detector of liquid chromatogram is UV-detector；According to pure dimethyl-DAU spectrogram, the inspection of UV-detector
Survey wavelength is 275nm-300nm, preferably 300nm, and dimethyl-DAU residence time is 5.66min, and dimethyl-DAU's quantifies
Method is external standard method, at room temperature in weighing 0.2g, 0.3g, 0.4g on precision balance respectively, 0.5g sterling dimethyl-DAU, and essence
Really record quality, respectively at constant volume in 1L volumetric flasks, is made into dimethyl-DAU standard liquids；F=standard specimens concentration (mg/L)/standard specimen
Peak area, f be a series of concentration of dimethyl-DAU standard specimens to the slope of its respective straight line of peak area mapping, the referred to as f factors,
Sample percentage composition=sample peak area × f × extension rate/sampling amount/10000.
The inventive method is simple to operate, and cost is cheap, and quickly, efficiently and accurately dimethyl-DAU can be analyzed,
During to being analyzed as the dimethyl-DAU of caffeine important intermediate, it can be responded for dimethyl-DAU, to miscellaneous
Matter and dimethyl-FAU responses are very weak.
Brief description of the drawings：
Fig. 1 is the analysis of spectra of dimethyl-DAU standard specimens；
Fig. 2 is the analysis of spectra of dimethyl-DAU in embodiment 1；
Fig. 3 is the analysis of spectra of dimethyl-DAU in embodiment 2；
Fig. 4 is the analysis of spectra of dimethyl-DAU in embodiment 3.
Embodiment：
The inventive method is further elaborated with reference to specific embodiments and the drawings.
Embodiment 1,
Dimethyl-DAU samples are taken in 50ml volumetric flasks, accurate weighing, quality 2.3421g, it is 95 to add volume ratio:5
Potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume, ultrasonic 5min, then therefrom accurately measure 1ml in 100ml volumetric flasks,
It is 95 to add volume ratio:5 potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume.
20 μ L, sample introduction are extracted with micro-sampling pipe, chromatographiccondition is：Chromatographic column uses Syncronis C-18 posts
250mm × 4.6mm, 25 DEG C of column temperature, liquid chromatogram mobile phase be 0.02mol/L potassium dihydrogen phosphate and acetonitrile solution,
The volume ratio of 0.02mol/L potassium dihydrogen phosphates and acetonitrile is 95:5, pH=2.68, flow velocity 1ml/min, the detector of liquid chromatogram
For UV-detector, the Detection wavelength of UV-detector is 275nm-300nm, preferably 300nm.
The analysis of spectra of dimethyl-DAU standard specimens is as shown in figure 1, the mAU in figure represents absorbance, when min represents to retain
Between, wherein, dimethyl-DAU residence time is 5.66min, and the present embodiment analysis of spectra is as shown in Fig. 2 ordinate is in figure
Absorbance, abscissa are retention time, and machine integrates to obtain peak area, sample percentage composition=sample peak area × f × dilution times
Number/sampling amount/10000.Dimethyl-DAU residence time is 5.66min in embodiment analysis sample, and dimethyl-DAU contains
Measure as 17.3306%.
Embodiment 2,
Dimethyl-DAU samples are taken in 50ml volumetric flasks, accurate weighing, quality 2.2587g, it is 95 to add volume ratio:5
Potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume, ultrasonic 5min, then therefrom accurate measuring 1ml in 100ml volumetric flasks,
It is 95 to add volume ratio:5 potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume.
20 μ L, sample introduction are extracted with micro-sampling pipe.Chromatographiccondition is：Chromatographic column uses Syncronis C-18 posts
250mm × 4.6mm, 25 DEG C of column temperature, liquid chromatogram mobile phase be 0.02mol/L potassium dihydrogen phosphate and acetonitrile solution,
The volume ratio of 0.02mol/L potassium dihydrogen phosphates and acetonitrile is 95:5, pH=2.68, flow velocity 1ml/min, the detector of liquid chromatogram
For UV-detector, the Detection wavelength of UV-detector is 300nm.
The present embodiment analysis of spectra is as shown in figure 3, ordinate is absorbance in figure, and abscissa is retention time, and machine accumulates
Get peak area, sample percentage composition=sample peak area × f × extension rate/sampling amount/10000.The embodiment analyzes sample
Dimethyl-DAU residence time is 5.66min in product, content 17.6168%.
Embodiment 3,
Dimethyl-DAU samples are taken in 50ml volumetric flasks, accurate weighing, quality 3.1659g, it is 95 to add volume ratio:5
Potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume, ultrasonic 5min, then therefrom accurate measuring 1ml in 100ml volumetric flasks,
It is 95 to add volume ratio:5 potassium dihydrogen phosphate (0.02mol/L) and acetonitrile constant volume.
20 μ L, sample introduction are extracted with micro-sampling pipe.Chromatographiccondition is that chromatographic column uses Syncronis C-18 posts
250mm × 4.6mm, 25 DEG C of column temperature, liquid chromatogram mobile phase be 0.02mol/L potassium dihydrogen phosphate and acetonitrile solution,
The volume ratio of 0.02mol/L potassium dihydrogen phosphates and acetonitrile is 95:5, pH=2.68, flow velocity 1ml/min, the detector of liquid chromatogram
For UV-detector, the Detection wavelength of UV-detector is 300nm.
The present embodiment analysis of spectra is as shown in figure 4, ordinate is absorbance in figure, and abscissa is retention time, and machine accumulates
Get peak area, sample percentage composition=sample peak area × f × extension rate/sampling amount/10000.The embodiment analyzes sample
Dimethyl-DAU residence time is 5.66min in product, content 17.6876%.
Claims (2)
1. one kind 1, the HPLC analytical method of 3- dimethyl -5,6- diaminourea pyrimidines, it is characterised in that according to
Lower step operation：The first step, analyze the pretreatment of raw material：Dimethyl-DAU is analyzed into raw material heat filtering, sampled, ultrasonic 5min,
Dimethyl-DAU analysis raw materials 2500 times or 5000 times of phase dilution of flowing, obtain dimethyl-DAU analysis samples, the stream
Dynamic is mutually that volume ratio is 95:5 0.02mol/L potassium dihydrogen phosphates and acetonitrile；Second step, dimethyl-DAU high performance liquid chromatography
Analysis：Dimethyl-DAU is analyzed into sample by high performance liquid chromatography detection, liquid chromatogram sample size is 20 μ L, liquid chromatogram stream
Phase is moved as 0.02mol/L potassium dihydrogen phosphate and the solution of acetonitrile, the volume ratio of 0.02mol/L potassium dihydrogen phosphates and acetonitrile is
95:5, pH=2.68, flow velocity 1ml/min；Chromatographic column uses Syncronis C-18 post 250mm × 4.6mm, chromatogram column temperature
For 25 DEG C, the detector of liquid chromatogram is UV-detector；According to pure dimethyl-DAU spectrogram, the detection of UV-detector
Wavelength is 275nm-300nm, and dimethyl-DAU residence time is 5.66min, and dimethyl-DAU quantitative approach is external standard method,
At room temperature in weighing 0.2g, 0.3g, 0.4g on precision balance respectively, 0.5g sterling dimethyl-DAU, quality is accurately recorded, point
The constant volume not in 1L volumetric flasks, it is made into dimethyl-DAU standard liquids；F=standard specimens concentration (mg/L)/standard specimen peak area, f mono-
The concentration of series of dimethyl-DAU standard specimens is to the slope of its respective straight line of peak area mapping, referred to as the f factors, sample percentage composition
=sample peak area × f × extension rate/sampling amount/10000；Dimethyl-the DAU is 1,3- dimethyl -5,6- diaminourea
The abbreviation of urea pyrimidine.
A kind of 2. efficient liquid phase chromatographic analysis side of 1,3- dimethyl -5,6- diaminourea pyrimidines according to claim 1
Method, it is characterised in that dimethyl-DAU analyzes raw material is with mobile phase dilution process：Add body first for the dimethyl-DAU of sampling
Product is than being 95:5 0.02mol/L potassium dihydrogen phosphates and acetonitrile constant volume accurately takes 1ml to add volume ratio in 50ml volumetric flasks, then therefrom
For 95:5 0.02mol/L potassium dihydrogen phosphates and acetonitrile constant volume is in 50ml volumetric flasks；Or dimethyl-DAU adds volume ratio first
For 95:5 0.02mol/L potassium dihydrogen phosphates and acetonitrile constant volume is in 50ml volumetric flasks, then therefrom accurately takes 1ml to add the volume ratio to be
95:5 0.02mol/L potassium dihydrogen phosphates and acetonitrile constant volume is in 100ml volumetric flasks.
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Citations (3)
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| CN102344451A (en) * | 2011-10-19 | 2012-02-08 | 吉林省舒兰合成药业股份有限公司 | Method for preparing caffeine |
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2017
- 2017-11-08 CN CN201711090299.4A patent/CN107884492A/en active Pending
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|---|---|---|---|---|
| CN102344451A (en) * | 2011-10-19 | 2012-02-08 | 吉林省舒兰合成药业股份有限公司 | Method for preparing caffeine |
| CN103360488A (en) * | 2013-07-05 | 2013-10-23 | 杭州博林生物技术有限公司 | Preparation method for artificial antigen of theophylline |
| CN104003941A (en) * | 2014-06-13 | 2014-08-27 | 石药集团新诺威制药股份有限公司 | Preparation method of caffeine intermediate N,N-1,3-dimethyl-4,5-diamido urazine |
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Effective date of registration: 20200119 Address after: 266061 Shandong Province, Qingdao city Laoshan District Songling Road No. 99, Qingdao University of Science & Technology Applicant after: Qingdao University of Science & Technology Applicant after: Qingdao YKHY Process and Information Technology Co., Ltd. Applicant after: Shandong Xinhua Pharmaceutical Co., Ltd. Address before: 266061 Shandong Province, Qingdao city Laoshan District Songling Road No. 99, Qingdao University of Science & Technology Applicant before: Qingdao University of Science & Technology Applicant before: Qingdao YKHY Process and Information Technology Co., Ltd. |
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Application publication date: 20180406 |
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