CN114088830B - Method for detecting isomer in 4- (3-fluorobenzyloxy) benzaldehyde - Google Patents
Method for detecting isomer in 4- (3-fluorobenzyloxy) benzaldehyde Download PDFInfo
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- CN114088830B CN114088830B CN202111328872.7A CN202111328872A CN114088830B CN 114088830 B CN114088830 B CN 114088830B CN 202111328872 A CN202111328872 A CN 202111328872A CN 114088830 B CN114088830 B CN 114088830B
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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
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
Abstract
The invention relates to the technical field of analysis and detection, and particularly discloses a method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde. The detection method comprises the following steps: preparing a test solution and a reference solution; detecting the test solution and the reference solution by adopting a gas chromatography, wherein the gas chromatography has the following chromatographic conditions: the stationary liquid of the chromatographic column is 2, 3-di-O-methyl-6-tert-butylsilyl modified beta-cyclodextrin, the detector is a hydrogen flame ionization detector, the temperature of the detector is 225-235 ℃, the initial temperature is 48-52 ℃, the temperature is increased to 175-185 ℃ at the temperature increase rate of 28-32 ℃/min, the temperature is kept for 35min, and the temperature of a sample inlet is 175-185 ℃. The detection method provided by the application has the advantages of strong specificity, high sensitivity and wide application prospect.
Description
Technical Field
The invention relates to the technical field of analysis and detection, and particularly relates to a method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde.
Background
Safinamide mesylate, also known as safinamide mesylate, is an alpha-aminoamide derivative as an active ingredient, is a highly selective, highly potent and reversible third generation amine oxidase B (MAO-B) inhibitor, and can be used as a monotherapy in patients with early stage Parkinson's disease, or added to the treatment regimen of patients with late stage Parkinson's disease to better control symptoms and reduce the dosage of other Parkinson's disease drugs required.
The 4- (3-fluorobenzyloxy) benzaldehyde with the structural formula shown as the formula I is an important intermediate for synthesizing the methanesulfonic acid saflufenamine. In the process of synthesizing 4- (3-fluorobenzyloxy) benzaldehyde by the prior art, an isomer of 4- (4-fluorobenzyloxy) benzaldehyde is inevitably generated, and the structural formula is shown as a formula II. The isomer directly influences the subsequent reaction for synthesizing the salbutamol mesylate, and further influences the purity of the salbutamol mesylate. In order to further ensure the product quality of the salfinamide mesylate and the medication safety of patients, the product quality of the salfinamide mesylate starting material and the intermediate product needs to be monitored, and particularly, a method for detecting the position isomer in the 4- (3-fluorobenzyloxy) benzaldehyde product needs to be developed.
Disclosure of Invention
In view of this, the application provides a method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde, which has excellent sensitivity, precision and accuracy, can meet the detection requirement of the isomer 4- (4-fluorobenzyloxy) benzaldehyde in a 4- (3-fluorobenzyloxy) benzaldehyde bulk drug, and reduces the content of isomer impurities as much as possible in an intermediate stage, thereby improving the purity of a final product.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
the application provides a method for detecting isomers in 4- (3-fluorobenzyloxy) benzaldehyde, which comprises the following steps:
step one, preparing a test solution and a reference solution;
preparing a reference substance solution: preparing a 4- (4-fluorobenzyloxy) benzaldehyde reference substance into a reference substance solution by using a solvent;
preparing a test solution: preparing a 4- (3-fluorobenzyloxy) benzaldehyde sample into a test solution by using a solvent;
step two, detecting the test solution and the reference solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography are as follows:
the stationary liquid of the chromatographic column is 2, 3-di-O-methyl-6-tert-butylsilyl modified beta-cyclodextrin, the detector is a hydrogen flame ionization detector, the temperature of the detector is 225-235 ℃, the initial temperature is 48-52 ℃, the temperature is raised to 175-185 ℃ at the temperature raising rate of 28-32 ℃/min, the temperature is kept for 35min, and the temperature of the injection port is 175-185 ℃.
Compared with the prior art, the method for detecting the isomer in the 4- (3-fluorobenzyloxy) benzaldehyde provided by the invention has the following advantages:
the method for detecting the isomer in the 4- (3-fluorobenzyloxy) benzaldehyde provided by the application realizes quantitative and qualitative analysis of the position isomer 4- (4-fluorobenzyloxy) benzaldehyde in a 4- (3-fluorobenzyloxy) benzaldehyde raw material drug, is strong in specificity and high in sensitivity, meets the requirement of chromatographic peak separation degree, meets the detection requirement of the 4- (4-fluorobenzyloxy) benzaldehyde in the 4- (3-fluorobenzyloxy) benzaldehyde raw material drug, and is good in linear relation, high in repeatability, and the correlation coefficient in the linear range of a standard curve is larger than 0.99; in addition, the detection method has the advantages of fast analysis time, capability of quickly and accurately detecting the position isomer 4- (4-fluorobenzyloxy) benzaldehyde in the 4- (3-fluorobenzyloxy) benzaldehyde bulk drug, reliable and controllable whole operation process, suitability for practical application and popularization and wide application prospect.
Optionally, the carrier gas is nitrogen, the flow rate is 0.9 ml/min-1.1 ml/min, and the split ratio is 2-4: 1.
Further optionally, the flow rate is 1ml/min and the split ratio is 3: 1.
Optionally, the detector temperature is 230 ℃.
Optionally, the initial temperature is 50 ℃, the temperature is increased to 180 ℃ at a temperature increase rate of 30 ℃/min, the temperature is kept for 35min, and the temperature of the injection port is 180 ℃.
The initial temperature, the temperature rise rate and the final temperature are preferably selected, so that the impurity 4- (4-fluorobenzyloxy) benzaldehyde can be rapidly separated from the 4- (3-fluorobenzyloxy) benzaldehyde bulk drug, and the two materials also have excellent separation degree.
Optionally, the column has a size of 30m × 0.25mm × 0.12 μm.
Optionally, the model of the chromatographic column is B-DM.
Different chromatographic columns have larger difference on the retention performance of the compounds, so the model of the chromatographic column adopted by the method is B-DM, the specification is 30m multiplied by 0.25mm multiplied by 0.12 mu m, the target object can be quickly and effectively separated, and the peak shape is better.
Optionally, the sample amount is 1 to 3 μ l.
Further alternatively, the sample size is 1. mu.l.
Optionally, the concentration of the test solution is 3mg/ml to 5 mg/ml.
Further optionally, the concentration of the test solution is 4 mg/ml.
Optionally, the concentration of the control solution is 7 μ g/ml to 9 μ g/ml.
Further optionally, the concentration of the control solution is 8 μ g/ml.
Optionally, the solvent is acetonitrile.
Acetonitrile is preferably used as a solvent, so that isomer 4- (4-fluorobenzyloxy) benzaldehyde in the 4- (3-fluorobenzyloxy) benzaldehyde bulk drug can be extracted, the detection of gas chromatography is basically free of interference, and the detection result of the gas chromatography provided by the invention is more accurate.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a gas chromatogram of a blank solution provided in example 1 of the present invention;
FIG. 2 is a gas chromatogram of a control solution provided in example 1 of the present invention;
FIG. 3 is a gas chromatogram of a labeled sample test solution provided in example 1 of the present invention;
FIG. 4 is a linear regression curve provided in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment of the application provides a method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde, which comprises the following steps:
step one, preparing a blank solution, a reference substance solution and a standard sample adding test sample solution;
the blank solution is acetonitrile solvent;
preparing a reference substance solution: preparing a 4- (4-fluorobenzyloxy) benzaldehyde reference substance into a reference substance solution with the concentration of 8 mu g/ml by using an acetonitrile solvent;
preparing a standard sample test solution: preparing a 4- (3-fluorobenzyloxy) benzaldehyde sample and a 4- (4-fluorobenzyloxy) benzaldehyde reference substance into a sample solution for adding a standard sample by using acetonitrile, wherein the concentration of the 4- (3-fluorobenzyloxy) benzaldehyde sample is 4mg/ml, and the concentration of the 4- (4-fluorobenzyloxy) benzaldehyde reference substance is 8 mu g/ml;
and step two, detecting the blank solution, the reference solution and the standard sample test solution by adopting gas chromatography, and recording chromatograms, wherein the results are shown in fig. 1, fig. 2 and fig. 3.
Wherein, the chromatographic conditions of the gas chromatography are as follows:
a chromatographic column with the model of B-DM and the specification of 30m multiplied by 0.25mm multiplied by 0.12 mu m is adopted, the detector is a hydrogen flame ionization detector, the temperature of the detector is 230 ℃, the initial temperature is 50 ℃, the temperature is increased to 180 ℃ at the temperature increase rate of 30 ℃/min, the temperature is kept for 35min, the temperature of a sample inlet is 180 ℃, the carrier gas is nitrogen, the flow rate is 1ml/min, the split ratio is 3:1, and the sample injection amount is 1 mu l.
As can be seen from FIGS. 1 to 3, the acetonitrile solvent and the 4- (3-fluorobenzyloxy) benzaldehyde sample do not interfere with the detection of the impurity 4- (4-fluorobenzyloxy) benzaldehyde, indicating that the gas chromatography provided by the present invention has good specificity.
As can be seen from FIG. 3, the chromatographic peak of the control 4- (4-fluorobenzyloxy) benzaldehyde control appeared at a retention time of 30.02min, the chromatographic peak of 4- (3-fluorobenzyloxy) benzaldehyde appeared at 29.081min, and the degrees of separation of the chromatographic peaks were good.
The degrees of separation of 4- (3-fluorobenzyloxy) benzaldehyde and 4- (4-fluorobenzyloxy) benzaldehyde are shown in Table 1 below, respectively, and it can be seen from the table that the degrees of separation between the components meet the degree of separation requirements.
TABLE 1
| Composition (I) | Degree of separation |
| Solvent(s) | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.18 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.74 |
Example 2 detection and quantitation limits
Detection limit: the control solution prepared in example 1 was analyzed by gas chromatography under the conditions specified in example 1, and the spectrum was recorded with a peak height of 3 times the baseline noise to obtain the detection limit, the results of which are shown in Table 2.
And (4) quantitative limit: the control solution prepared in example 1 was analyzed by gas chromatography under the conditions specified in example 1, and the spectra were recorded with a limit of quantitation at a peak height of 10 times the baseline noise, and the results are shown in Table 2.
TABLE 2 detection limit and quantitative limit detection results
According to the method, 6 parts of the reference substance solution is prepared in parallel, and then the reference substance solution is detected by adopting the gas chromatography, the result is shown in table 3, and the RSD of the peak area repeatedly measured 6 times is 2.84% as can be seen from table 3, thereby demonstrating that the detection method provided by the application has good repeatability of the limit of quantitation.
TABLE 3 quantitative limit repeatability test results
Example 3 Linear relationship
4- (4-fluorobenzyloxy) benzaldehyde is precisely measured, dissolved in acetonitrile and quantitatively diluted to prepare a series of concentration solutions, gas chromatography is adopted for detection, the gas chromatography conditions are specifically shown in example 1, a spectrogram is recorded, a standard curve is drawn by taking the concentration (mu g/ml) as a horizontal coordinate and a peak area as a vertical coordinate, a regression equation is calculated, and the results are shown in table 4 and figure 4. As can be seen from the results, 4- (4-fluorobenzyloxy) benzaldehyde was found to be excellent in linear relationship in the concentration range of 1.64. mu.g/ml to 9.81. mu.g/ml.
TABLE 44 Linear test results for (4-fluorobenzyloxy) benzaldehyde
Example 4 recovery
Preparing a reference substance solution:
precisely weighing a 4- (4-fluorobenzyloxy) benzaldehyde reference substance, and preparing a reference substance storage solution with the concentration of 80 mu g/ml by using an acetonitrile solvent;
recovery 1 solution: taking 40mg of a test sample, placing the test sample in a 10ml volumetric flask, adding 0.5ml of the reference sample storage solution, fixing the volume to a scale mark by using acetonitrile, and shaking up to obtain three parts in parallel;
recovery 3 solution: taking 40mg of a test sample, placing the test sample in a 10ml volumetric flask, adding 1.2ml of the reference stock solution, fixing the volume to the scale mark by using acetonitrile, and shaking up to obtain the three parts in parallel.
The recovery rate of the solution prepared above was measured by gas chromatography, and the results are shown in Table 5, and the specific conditions of gas chromatography were as described in example 1. As can be seen from Table 5, the recovery rates of the solutions with different concentrations are between 84% and 101%, and the RSD is 5.76%, so that the detection method provided by the application has good accuracy.
The recovery was calculated according to the following formula:
recovery (%) - (measured-original)/theoretical addition × 100%
TABLE 54 detection results of recovery of (4-fluorobenzyloxy) benzaldehyde
Example 5 reproducibility
The same batch of samples was sampled, 6 test solutions (4- (3-fluorobenzyloxy) benzaldehyde sample was prepared in parallel with acetonitrile to prepare a 4mg/ml test solution) and the results of the reproducibility test were shown in Table 6 under the chromatographic conditions of the method for detecting isomers in 4- (3-fluorobenzyloxy) benzaldehyde described in example 1. As can be seen from Table 6, the test results of 6 test solutions are substantially consistent, which indicates that the test method provided by the present application has good repeatability.
TABLE 6 repeatability results
Example 6 solution stability
The test solution prepared in example 5 was allowed to stand for 0h, 2h, 4h, 8h, 12h, and 24h, respectively, and then the test was performed by gas chromatography, the specific conditions of which were as described in example 1, and the test results are shown in table 7 below.
TABLE 7 solution stability results
EXAMPLE 7 durability
A4- (3-fluorobenzyloxy) benzaldehyde sample is precisely weighed and prepared into a test solution with the concentration of 4mg/ml by using acetonitrile.
Adjusting the temperature of a sample inlet: the sample solution prepared as described above was measured by gas chromatography with the injection port temperature set to 175 deg.C, 180 deg.C or 185 deg.C, respectively, and the other conditions of the gas chromatography were the same as those of example 1, and the degree of separation was recorded, and the results are shown in Table 8 below. As can be seen from Table 8, the temperature of the fine adjustment injection port has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the invention has good durability.
TABLE 8 injection port temperature adjustment
| Composition (I) | 180℃ | 175℃ | 185℃ |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.37 | 47.53 | 47.38 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.70 | 1.76 | 1.69 |
Adjusting the flow rate: the sample solution prepared as described above was measured by gas chromatography at flow rates of 1.0ml/min, 0.9ml/min or 1.1ml/min, respectively, under the same other conditions as in example 1, and the degrees of separation were recorded, and the results are shown in table 9 below. As can be seen from Table 9, the fine-tuning flow rate has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the invention has good durability.
TABLE 9 flow Rate adjustment
| Composition (I) | 1.0ml/min | 0.9ml/min | 1.1ml/min |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 36.740 | 43.300 | 42.572 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.499 | 1.762 | 1.667 |
Initial temperature adjustment: the sample solution prepared as described above was measured by gas chromatography at an initial temperature of 50 c, 48 c or 52 c, respectively, and the other conditions of the gas chromatography were the same as those of example 1, and the degrees of separation were recorded, and the results are shown in table 10 below. As can be seen from Table 10, the fine-tuning initial temperature has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the invention has good durability.
TABLE 10 initial temperature adjustment
| Composition (I) | 50℃ | 48℃ | 52℃ |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.37 | 46.29 | 48.92 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.70 | 1.71 | 1.78 |
Adjusting the split ratio: the sample solution prepared as described above was measured by gas chromatography with the split ratio set to 3:1, 2:1 or 4:1, respectively, and the other conditions of the gas chromatography were the same as those of example 1, and the degrees of separation were recorded, and the results are shown in table 11 below. As can be seen from table 11, the fine tuning split ratio has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the present invention has good durability.
TABLE 11 Split ratio adjustment
| Composition (I) | 3:1 | 2:1 | 4:1 |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.37 | 40.63 | 53.84 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.70 | 1.49 | 1.93 |
Adjusting the heating rate: the sample solution prepared as described above was measured by gas chromatography, the temperature increase rate was set to 30 ℃/min, 28 ℃/min or 32 ℃/min, respectively, other conditions of the gas chromatography were the same as those of example 1, and the degrees of separation thereof were recorded, and the results are shown in table 12 below. As can be seen from Table 12, the fine-tuning temperature-raising rate has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the invention has good durability.
TABLE 12 ramp rate adjustment
| Composition (I) | 30℃/ |
28℃/ |
32℃/min |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.37 | 47.39 | 48.22 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.70 | 1.72 | 1.73 |
Adjusting the temperature of the detector: the sample solution prepared as described above was measured by gas chromatography, the detector temperature was set to 230 c, 225 c or 235 c, respectively, and the other conditions of the gas chromatography were the same as those of example 1, and the degree of separation was recorded, and the results are shown in table 13 below. As can be seen from Table 13, the temperature of the fine tuning detector has no influence on the detection of the test sample, and the separation degree between the components meets the requirement, which indicates that the detection method provided by the invention has good durability.
TABLE 13 Detector temperature adjustment
| Composition (I) | 230℃ | 225℃ | 235℃ |
| Solvent (acetonitrile) | N/A | N/A | N/A |
| 4- (3-Fluorobenzyloxy) benzaldehyde | 47.37 | 47.22 | 47.42 |
| 4- (4-Fluorobenzyloxy) benzaldehyde | 1.70 | 1.70 | 1.72 |
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the invention is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (10)
1. A method for detecting isomers in 4- (3-fluorobenzyloxy) benzaldehyde is characterized by comprising the following steps: the detection method comprises the following steps:
step one, preparing a test solution and a reference solution;
preparing a reference substance solution: preparing a 4- (4-fluorobenzyloxy) benzaldehyde reference substance into a reference substance solution by using a solvent;
preparing a test solution: preparing a 4- (3-fluorobenzyloxy) benzaldehyde sample into a test solution by using a solvent, wherein the 4- (3-fluorobenzyloxy) benzaldehyde sample is a 4- (3-fluorobenzyloxy) benzaldehyde bulk drug;
step two, detecting the test solution and the reference solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography are as follows:
the stationary liquid of the chromatographic column is 2, 3-di-O-methyl-6-tert-butylsilyl modified beta-cyclodextrin, the detector is a hydrogen flame ionization detector, the temperature of the detector is 225-235 ℃, the initial temperature is 48-52 ℃, the temperature is increased to 180 ℃ at the temperature increase rate of 28-32 ℃/min, the temperature is kept for 35min, and the temperature of a sample inlet is 175-185 ℃.
2. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein: the carrier gas is nitrogen, the flow rate is 0.9 ml/min-1.1 ml/min, and the split ratio is 2-4: 1.
3. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 2, wherein: the flow rate is 1ml/min, and the split ratio is 3: 1.
4. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein the method comprises: the detector temperature was 230 ℃.
5. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein: the initial temperature is 50 ℃, the temperature is increased to 180 ℃ at the heating rate of 30 ℃/min, the temperature is kept for 35min, and the temperature of a sample inlet is 180 ℃.
6. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein the method comprises: the specification of the chromatographic column is 30m × 0.25mm × 0.12 μm.
7. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 6, wherein: the model of the chromatographic column is B-DM.
8. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein the method comprises: the sample amount is 1-3 mul.
9. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to claim 1, wherein: the concentration of the test solution is 3mg/ml to 5 mg/ml; and/or
The concentration of the reference substance solution is 7 mu g/ml-9 mu g/ml.
10. The method for detecting an isomer in 4- (3-fluorobenzyloxy) benzaldehyde according to any one of claims 1 to 9, wherein: the solvent is acetonitrile.
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| BRPI0820657A2 (en) * | 2007-12-11 | 2015-06-16 | Newron Pharm Spa | Process for the production of high purity 2- [4- (3- or 2-fluorobenzyloxy) benzylamino] propanamides |
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| CN103284984A (en) * | 2006-06-19 | 2013-09-11 | 纽朗制药有限公司 | Process for the production of 2-[4-(3- and 2-flu0r0benzyl0xy)benzylamin0]propanamides |
| CN107271600A (en) * | 2017-07-28 | 2017-10-20 | 成都百裕制药股份有限公司 | The detection method of isomer impurities content in a kind of 4 (3 fluorine benzyloxy) benzaldehydes |
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