Central control detection method of electrolytic reaction for synthesizing muscone precursor
By screening the chromatographic column and mobile phase, combined with the terminal absorption detection method, the problem of detection in the electrolytic reaction of synthetic musk ketone precursors is solved, and the rapid and accurate detection of raw materials and products is achieved, the reaction process is monitored, and costs and uncertainties are reduced.
Patent Information
- Application Number
- CN202510023273.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-07
- Publication Date
- 2025-04-11
AI Technical Summary
The prior art lacks effective central control detection methods to monitor the electrolytic reaction of synthetic musk ketone precursors, which makes it difficult to accurately monitor the selectivity, progress and end time of the reaction, increasing the cost and uncertainty of the reaction.
By screening the chromatographic column, mobile phase, elution gradient and detection wavelength, using the terminal absorption of the compound, rapid, efficient and accurate detection of monomethyl dodecanediate, monomethyl β-methylglutarate and dimethyl 3-methylpentasenediate was achieved.
Accurate detection of raw materials and products during Kolbe electrolysis is achieved, the reaction process can be monitored, the accuracy and simplicity of detection are improved, and the operation difficulty and cost are reduced.
Smart Images
Figure BDA0005232011680000021 
Figure BDA0005232011680000031 
Figure BDA0005232011680000041
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of compound detection and relates to a central control detection method for an electrolytic reaction of a synthetic musk ketone precursor. Background Art
[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.
[0003] 3-Methylpentadecanedioic acid dimethyl ester is a precursor compound for synthesizing musk ketone (hereinafter referred to as product), which is generated by Kolbe electrolysis of monomethyl dodecanedioate (raw material 1) and monomethyl β-methylglutarate (raw material 2). In the electrochemical cross-coupling reaction, the active free radical intermediates can easily be freely combined, and the central control detection method is particularly important for monitoring the selectivity, progress and end time of the reaction. At present, there is no quality control method for detecting the electrolyte, which invisibly increases the cost of the reaction and the uncertainty of the reaction.
[0004] No matter raw material 1, raw material 2 or product, they are all straight-chain acids or esters. At present, there are very few detection methods for compounds of straight-chain acids or esters, mainly because: it does not have a long conjugated system, the shorter the conjugated system, the less the degree of delocalization of electrons in the molecule, and the corresponding reduction in the absorption wavelength, which not only increases the difficulty for the detection method of this type of compound, but also is full of challenges. In the previous study of the synthesis of dimethyl 3-methylpentadecanedioate, the present invention used high-performance liquid chromatography for detection in order to obtain the conversion rate and selectivity of each raw material after the reaction; however, the chromatogram baseline obtained by the method is poor, the background peaks are many and very mixed, and extremely complex spectrogram processing and special integration methods are required to quantitatively analyze each raw material and product in the reacted material, which is extremely difficult to operate; at the same time, in the Kolbe electrolysis process, there are a large number of free radical intermediates, which also affect the accuracy of its detection in the Kolbe electrolysis process. Therefore, it is a difficult point in this field to realize the central control detection of the electrolytic reaction of the synthesis of musk ketone precursor. Summary of the invention
[0005] In order to overcome the shortcomings of the prior art, the purpose of the present invention is to provide a central control detection method for the electrolytic reaction of synthesizing a musk ketone precursor. The present invention achieves rapid, efficient and accurate detection of raw material 1, raw material 2 and products by screening chromatographic columns, mobile phases, elution gradients and detection wavelengths and utilizing the terminal absorption of compounds, thereby being able to be used for monitoring the reaction progress of raw material 1 and raw material 2 in preparing products through Kolbe electrolysis.
[0006] In order to achieve the above object, the technical solution of the present invention is:
[0007] In a first aspect, a method for in-process control detection of an electrolytic reaction for synthesizing a musk ketone precursor is provided, wherein the electrolyte in the process of preparing 3-methylpentadecanedioic acid dimethyl ester by Kolbe electrolysis of monomethyl dodecanedioate and monomethyl β-methylglutarate is used as a sample to be tested, and the sample to be tested is subjected to high performance liquid chromatography detection;
[0008] In the HPLC detection, an aqueous solution containing 0.08-0.12% by mass of phosphoric acid is used as mobile phase A, acetonitrile is used as mobile phase B, octadecylsilane bonded silica gel is used as filler in the chromatographic column, the detection wavelength is 219-221 nm, and the elution procedure is shown in the following table:
[0009]
[0010]
[0011] Since the dodecanedioic acid monomethyl ester (raw material 1), β-methylglutaric acid monomethyl ester (raw material 2) and 3-methylpentadecanedioic acid dimethyl ester (product) to be detected by the present invention are all straight-chain acids or esters, it is difficult to detect by conventional chromatography, so the present invention, at the beginning of the study, adopts the method of terminal absorption (detection wavelength is 228nm) to try detection. In the detection process, raw materials 1 and 2 all contain carboxyl groups, which are easily ionized, so it is necessary to add acidic substances in the mobile phase to prevent carboxylic acids from ionizing into ionic forms, to ensure that the substances exist in the form of molecules, to obtain good sharp peaks in the chromatogram, thereby ensuring the accurate detection of raw materials 1 and 2. When the chromatography is detected, formic acid can prevent tailing, and formic acid can change the peak shape for acidic compounds. If liquid chromatography-mass spectrometry is used, the protonation ability can also be improved, so formic acid is first selected to be added in the mobile phase. However, it is found in actual detection that formic acid has background absorption and is used in large amounts, resulting in poor baselines, many background peaks and disorder, and there are problems recorded in the background technology of the present invention.
[0012] In subsequent studies, the present invention unexpectedly discovered that selecting phosphoric acid instead of formic acid can better solve the problems of baseline and background peaks, but there are problems such as obvious bulging of the product peak and inability to separate the raw material 1 and adjacent impurity peaks. To this end, the present invention further improved the elution procedure and the chromatographic column, so that most of the peaks can be better separated by baseline, but the unknown impurity peaks and adjacent peaks did not meet the requirements of baseline separation. Therefore, the present invention further changed the detection wavelength to 219-221nm, so as to achieve better peak shapes for each peak, and the separation degree and tailing factor of each peak meet the requirements, thereby realizing the central control detection of the electrolytic reaction of the synthesized musk ketone precursor.
[0013] In some embodiments, the electrolyte is frozen at -25 to -15°C, filtered, and then detected by high performance liquid chromatography.
[0014] In some embodiments, the sample to be tested is diluted with an electrolyte solvent, and then frozen at -25 to -15°C, filtered, and then detected by high performance liquid chromatography.
[0015] In some embodiments, the chromatography column is Agilent 5HC C18(2) 250×4.6 mm, 5 μm.
[0016] In some embodiments, during high performance liquid chromatography detection, the flow rate of the mobile phase is 0.8-1.2 ml / min.
[0017] In some embodiments, during HPLC detection, the column temperature is 25-35°C.
[0018] In some embodiments, during high performance liquid chromatography detection, the injection volume is 9-11 μl.
[0019] On the other hand, an in-process control detection method for the electrolytic reaction of the above-mentioned synthetic musk ketone precursor is used in quality monitoring during the production of 3-methylpentadecanedioic acid dimethyl ester by Kolbe electrolysis of monomethyl dodecanedioate and monomethyl β-methylglutarate.
[0020] In a third aspect, a central control detection kit for an electrolytic reaction of synthesizing a musk ketone precursor comprises:
[0021] Phosphoric acid and water: used to prepare an aqueous solution of phosphoric acid with a mass percentage of 0.08-0.12% as mobile phase A; and,
[0022] Acetonitrile: used as mobile phase B; and,
[0023] Instructions for use: used to record the use conditions of the central control detection kit, which include: the chromatographic column uses octadecylsilane bonded silica gel as a filler, the detection wavelength is 219-221nm, and the elution procedure is shown in the following table:
[0024]
[0025]
[0026] In some embodiments, the instruction manual is also used to record the pretreatment process of the sample to be tested, and the pretreatment process includes: placing the electrolyte in a freezing process at -25 to -15°C.
[0027] In some embodiments, the use conditions also include: during detection, the chromatographic column selected is Agilent 5HC C18(2) 250×4.6 mm, 5 μm.
[0028] In some embodiments, the use conditions further include: during detection, the flow rate of the mobile phase is 0.8 to 1.2 ml / min.
[0029] In some embodiments, the use conditions further include: during detection, the column temperature is 25-35°C.
[0030] In some embodiments, the use conditions further include: during detection, the injection volume is 9 to 11 μl.
[0031] The beneficial effects of the present invention are:
[0032] On the basis of using a formic acid aqueous solution and a formic acid acetonitrile solution as a mobile phase, phosphoric acid is used in the mobile phase to replace formic acid, thereby solving the problems of poor baseline, multiple and messy background peaks, etc. when using terminal absorption to detect raw materials 1 and raw materials 2 in the electrolyte of preparing products by Kolbe electrolysis; by optimizing the elution program and the chromatographic column, the problems of obvious bulging of product peaks caused by the introduction of phosphoric acid, and the inability to separate raw materials 1 and adjacent impurity peaks, etc., are solved; by optimizing the detection wavelength, the problem that the unknown impurity peaks and adjacent peaks that do not meet the requirement of baseline separation after the mobile phase, the elution program and the chromatographic column are determined can be further solved; by matching the mobile phase, the elution program, the chromatographic column and the detection wavelength, the peak shape of the detection is better, the separation degree and the tailing factor both meet the requirements, and the terminal absorption detection of raw materials 1, raw materials 2 and products in the Kolbe electrolysis process can be realized.
[0033] Experiments have shown that the linear relationships of the standard curves produced by the central control detection method provided by the present invention are all good, and the concentrations of raw material 1, raw material 2, and product in the electrolytic reaction solution can be detected and determined, and the conversion rate and yield of the reactants can be calculated. The operation is simple and fast, and the measurement results are accurate and reliable, and the process of preparing 3-methylpentadecanedioic acid dimethyl ester by Kolbe electrolysis can be monitored. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.
[0035] Figure 1 It is the chromatogram of Example 1 of the present invention;
[0036] Figure 2 It is the chromatogram of Example 2 of the present invention;
[0037] Figure 3It is the chromatogram of Example 3 of the present invention;
[0038] Figure 4 It is the chromatogram of Example 4 of the present invention;
[0039] Figure 5 It is the chromatogram of Example 5 of the present invention;
[0040] Figure 6 is the molar concentration standard curve of raw material 1 in Example 6 of the present invention;
[0041] Figure 7 The mass concentration standard curve of raw material 1 in Example 6 of the present invention;
[0042] Figure 8 is the molar concentration standard curve of raw material 2 in Example 6 of the present invention;
[0043] Fig. 9 The mass concentration standard curve of raw material 2 of Example 6 of the present invention;
[0044] Fig.10 is the molar concentration standard curve of the product of Example 6 of the present invention;
[0045] Fig.11 This is the mass concentration standard curve of the product of Example 6 of the present invention. DETAILED DESCRIPTION
[0046] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.
[0047] In the following examples, monomethyl dodecanedioate is referred to as raw material 1, monomethyl β-methylglutarate is referred to as raw material 2, and dimethyl 3-methylpentadecanedioate is referred to as product.
[0048] Example 1
[0049] Sample preparation:
[0050] Preparation of system suitability solution: Take 0.5g of raw material 1, 0.35g of raw material 2, and 0.45g of product, put them into the same 10ml volumetric flask, dissolve and dilute to the scale with methanol, shake well, and obtain.
[0051] The system suitability solution was used as the sample for HPLC detection.
[0052] Chromatographic conditions: octadecylsilane bonded silica gel as filler (ZORBAX SB-C18250×4.6mm, 5μm), 0.1% formic acid aqueous solution as mobile phase A and 0.1% formic acid acetonitrile as mobile phase B, linear gradient elution according to Table 1; flow rate 1.0 ml per minute; column temperature 30°C; detection wavelength 228 nm; injection volume 10μl.
[0053] Table 1 Linear gradient elution program
[0054]
[0055] The method described in this example is the method used by the present invention to detect raw material 1, raw material 2 and product in previous research. The results are as follows Figure 1 As shown, the method provided in this embodiment has a poor baseline, many background peaks, and is very messy. A special integration method of blank deduction is required to ensure a relatively flat baseline, which increases the difficulty of operation.
[0056] The main reason is that formic acid has background absorption and the amount of formic acid used is relatively large. It is planned to change the mobile phase to 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B for investigation, so Example 2 is carried out.
[0057] Example 2
[0058] Sample preparation:
[0059] Preparation of system suitability solution: Take 0.5g of raw material 1, 0.35g of raw material 2, and 0.45g of product, put them into the same 10ml volumetric flask, dissolve and dilute to the scale with methanol, shake well, and obtain.
[0060] The system suitability solution was used as the sample for HPLC detection.
[0061] Chromatographic conditions: octadecylsilane bonded silica gel as filler (ZORBAX SB-C18250×4.6mm, 5μm), 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, linear gradient elution according to Table 2; flow rate 1.0 ml per minute; column temperature 30°C; detection wavelength 228 nm; injection volume 10μl.
[0062] Table 2 Linear gradient elution program
[0063]
[0064] The results are as follows Figure 2 As shown, under this method, the product peak has an obvious bulge, and the raw material 1 and the adjacent impurity peaks cannot be separated.
[0065] Example 3
[0066] Sample preparation:
[0067] Preparation of system suitability solution: Take 0.5g of raw material 1, 0.35g of raw material 2, and 0.45g of product, put them into the same 10ml volumetric flask, dissolve and dilute to the scale with methanol, shake well, and obtain.
[0068] The system suitability solution was used as the sample for HPLC detection.
[0069] Chromatographic conditions: Octylsilane bonded silica gel was used as filler (ZORBAX SB-C8
[0070] 250×4.6mm, 5μm), with 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, linear gradient elution was performed according to Table 3; the flow rate was 1.0ml per minute; the column temperature was 30°C; the detection wavelength was 228nm; the injection volume was 10μl.
[0071] Table 3 Linear gradient elution program
[0072]
[0073] The results are as follows Figure 3 As shown, under this method, the product is not baseline-separated from adjacent peaks.
[0074] Example 4
[0075] Sample preparation:
[0076] Preparation of system suitability solution: Take 0.5g of raw material 1, 0.35g of raw material 2, and 0.45g of product, put them into the same 10ml volumetric flask, dissolve and dilute to the scale with methanol, shake well, and obtain.
[0077] The system suitability solution was used as the sample for HPLC detection.
[0078] Chromatographic conditions: octadecylsilane bonded silica gel as filler (Agilent 5HC C18(2) 250×4.6 mm, 5 μm), 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, linear gradient elution according to Table 4; flow rate 1.0 ml per minute; column temperature 30°C; detection wavelength 228 nm; injection volume 10 μl.
[0079] Table 4 Linear gradient elution program
[0080]
[0081] The results are as follows Figure 4 As shown, compared with Example 3, under this method, the high carbon column is replaced to remove the unknown impurities, and the remaining peaks are baseline separated, but the unknown impurity peak is not baseline separated from the adjacent peaks at this wavelength.
[0082] Example 5
[0083] Sample preparation:
[0084] Preparation of system suitability solution: Take 0.5g of raw material 1, 0.35g of raw material 2, and 0.45g of product, put them into the same 10ml volumetric flask, dissolve and dilute to the scale with methanol, shake well, and obtain.
[0085] The system suitability solution was used as the sample for HPLC detection.
[0086] Chromatographic conditions: Octadecylsilane bonded silica gel was used as filler (Agilent 5HC C18(2)
[0087] 250×4.6mm, 5μm), with 0.1% phosphoric acid aqueous solution as mobile phase A and acetonitrile as mobile phase B, linear gradient elution was performed according to Table 5; the flow rate was 1.0ml per minute; the column temperature was 30°C; the detection wavelength was 220nm; the injection volume was 10μl.
[0088] Table 5 Linear gradient elution program
[0089]
[0090] The results are as follows Figure 5 As shown, under this condition, the peak shape of each peak is good, and the separation and tailing factor of each peak meet the requirements.
[0091] Example 6
[0092] Preparation of blank solution (diluent): chromatographic methanol
[0093] Preparation of sample solution: ① Take 3-5 ml of the control sample from the electrolytic reaction solution, freeze it in the freezer (-20°C) for 10 minutes, and filter it with a 0.45μm organic filter membrane.
[0094] ② Take about 5 ml of the final reaction solution sample and put it into a 10 ml volumetric flask, accurately weigh it, dissolve it with methanol and dilute it to the scale, place it in the freezer (-20°C) of the refrigerator and freeze it for 10 minutes, and filter it with a 0.45μm organic filter membrane to obtain it.
[0095] The chromatographic conditions of Example 5 were used to perform high performance liquid chromatography on the samples of this example.
[0096] The standard curve of raw material 1 detected is shown in Table 6 and Figure 6 , 7 The standard curve of the raw material 2 detected is shown in Table 7 and Figure 8 , 9 The standard curve of the raw material 2 detected is shown in Table 8 and Fig.10 ,11 shown.
[0097] Table 6
[0098]
[0099]
[0100] Table 7
[0101]
[0102] Table 8
[0103]
[0104]
[0105] The results show that the linear relationship of each standard curve after adopting the chromatographic conditions of Example 5 is good, which can be used to detect the concentrations of raw material 1, raw material 2, and product in the electrolytic reaction solution, and then the conversion rate and yield of the reactants can be calculated. The operation is simple and fast, and the measurement results are accurate and reliable.
[0106] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for in-process control detection of an electrolytic reaction for synthesizing a musk ketone precursor, characterized in that: The electrolyte in the process of preparing 3-methylpentadecanedioic acid dimethyl ester by Kolbe electrolysis of monomethyl dodecanedioate and monomethyl β-methylglutarate is used as a sample to be tested, and the sample to be tested is subjected to high performance liquid chromatography detection; In the HPLC detection, an aqueous solution containing 0.08-0.12% by mass of phosphoric acid is used as mobile phase A, acetonitrile is used as mobile phase B, octadecylsilane bonded silica gel is used as filler in the chromatographic column, the detection wavelength is 219-221 nm, and the elution procedure is shown in the following table:
2. The in-process control detection method for the electrolytic reaction of the synthetic musk ketone precursor according to claim 1, characterized in that: The electrolyte was frozen at -25 to -15°C, filtered, and then detected by high performance liquid chromatography.
3. The in-process control detection method for the electrolytic reaction of the synthetic musk ketone precursor according to claim 1, characterized in that: The sample to be tested is diluted with the solvent of the electrolyte, and then placed in a freezing treatment at -25 to -15°C, filtered, and then tested by high performance liquid chromatography.
4. The in-process control detection method for the electrolytic reaction of the synthetic musk ketone precursor according to claim 1, characterized in that: The chromatographic column is Agilent 5HC C18(2) 250×4.6 mm, 5 μm.
5. The in-process control detection method for the electrolytic reaction of the synthetic musk ketone precursor according to claim 1, characterized in that: During HPLC detection, the flow rate of the mobile phase is 0.8-1.2 ml / min; Or, for HPLC detection, the column temperature is 25-35°C; Or, for HPLC detection, the injection volume is 9 to 11 μl.
6. Application of the in-process control detection method for the electrolytic reaction of the synthetic musk ketone precursor according to claim 1 in the quality monitoring of the process of producing 3-methylpentadecanedioic acid dimethyl ester by Kolbe electrolysis of monomethyl dodecanedioate and monomethyl β-methylglutarate.
7. A central control detection kit for electrolytic reaction of synthesizing musk ketone precursor, characterized in that: include: Phosphoric acid and water: used to prepare an aqueous solution of 0.08-0.12% by mass of phosphoric acid as mobile phase A; and, Acetonitrile: used as mobile phase B; and, Instructions for use: used to record the use conditions of the central control detection kit, which include: the chromatographic column uses octadecylsilane bonded silica gel as a filler, the detection wavelength is 219-221nm, and the elution procedure is shown in the following table:
8. The central control detection kit for the electrolytic reaction of synthesizing a musk ketone precursor as claimed in claim 7, characterized in that: The instruction manual is also used to record the pretreatment process of the sample to be tested, and the pretreatment process includes: placing the electrolyte in a freezing process at a temperature of -25 to -15°C.
9. The central control detection kit for the electrolytic reaction of synthesizing a musk ketone precursor according to claim 7, characterized in that: The use conditions also include: during detection, the chromatographic column selected is Agilent 5HC C18 (2) 250×4.6 mm, 5 μm.
10. The central control detection kit for electrolytic reaction of synthesizing musk ketone precursor according to claim 7, characterized in that: The use conditions also include: during detection, the flow rate of the mobile phase is 0.8 to 1.2 ml / min; Or, the use conditions also include: during detection, the column temperature is 25 to 35°C; Alternatively, the use conditions further include: during detection, the injection volume is 9 to 11 μl.