Zopiclone process impurity and preparation method thereof
By stirring the reaction of 4-methylpiperazine-1-formyl chloride hydrochloride and DMAP at room temperature, unknown impurities in the zopiclon process were prepared and confirmed, and the problems of impurity structure confirmation and high purity preparation in the prior art were solved, and high-purity impurity samples or standards were provided, which improved the quality control of zopiclon raw materials.
Patent Information
- Application Number
- CN202510196560.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-21
- Publication Date
- 2025-06-06
AI Technical Summary
During the synthesis of zopiclon, an unknown impurity was found, and the prior art was difficult to confirm its structure and provide a high purity preparation method, which affected the quality control of zopiclon raw materials.
The reaction of 4-methylpiperazine-1-formyl chloride hydrochloride and DMAP in dichloromethane or a mixed solvent was stirred at room temperature, and the new Zopiclon process impurities were prepared by filtration.
The structure confirmation of impurities in the zopiclon process is achieved, and a preparation method with simple operation, low cost and high purity is provided, providing high-purity impurity samples or standard products for the process research and quality control of zopiclon.
Smart Images
Figure CN120097906A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical chemistry, relates to the study of impurities in a zopiclone process, and particularly relates to a new zopiclone process impurity and a preparation method thereof. Background Art
[0002] Zopiclone, chemical name: 6-(5-chloropyridin-2-yl)-7-[(4-methylpiperazin-1-yl)carbonyloxy]-5,6-dihydropyrrolo[3.4-b]pyrazin-5-one, is a third-generation sedative hypnotic developed by Rhono-PouleneRorer, France, for the treatment of sleep disorders.
[0003]
[0004] At present, the commonly used synthesis method of zopiclone is: zopiclone alcohol and 4-methylpiperazine-1-carbonyl chloride hydrochloride are prepared under the catalysis of 4-dimethylaminopyridine (DMAP). In the process of zopiclone synthesis, the research and control of impurities is one of the key research points of technicians at present.
[0005] When using the above method to study the synthesis of zopiclone, the technicians conducted a liquid phase analysis on the reaction solution after the reaction and found a large unknown impurity at a retention time of about 180 minutes. In order to ensure the quality of the zopiclone API, it is necessary to confirm the structure of the impurity and provide a preparation method for the impurity. Summary of the invention
[0006] In view of the deficiencies in the prior art, the purpose of the present invention is to provide a new zopiclone process impurity; another purpose of the present invention is to provide a method for preparing the zopiclone process impurity; the present invention confirms the structure of the new impurity, and the provided synthesis method is simple to operate, low in cost, and high in purity, providing high-purity impurity samples or standards for process research and quality control of zopiclone.
[0007] The present invention is achieved through the following technical solutions:
[0008] A zopiclone process impurity, the structure of which is shown below:
[0009]
[0010] A further improvement of the present invention is:
[0011] A method for preparing a zopiclone process impurity comprises the following steps: stirring 4-methylpiperazine-1-carbonyl chloride hydrochloride and DMAP in a reaction solvent at room temperature, filtering after the reaction is completed, beating the filter cake with a purification solvent, suction filtering, and drying to obtain the impurity.
[0012] The reaction equation is as follows:
[0013]
[0014] A further improvement of the present invention is:
[0015] The reaction solvent is one of dichloromethane, chloroform or tetrachloromethane, or a mixture of two or more thereof.
[0016] Furthermore, the purification solvent is one or a mixture of two or more of ethyl acetate, propyl acetate or isopropyl acetate.
[0017] Furthermore, the molar ratio of the 4-methylpiperazine-1-carbonyl chloride hydrochloride to DMAP is 1:1-2.
[0018] Furthermore, the stirring reaction time is 4 to 6 hours.
[0019] Furthermore, the mass ratio of the filter cake to the purification solvent is 1:5-10.
[0020] Furthermore, the drying is reduced pressure drying, the drying temperature is 40 to 60° C., and the drying time is 4 to 8 hours.
[0021] The beneficial effects of the present invention are:
[0022] The present invention discovers a new zopiclone process impurity and confirms its structure; the present invention also provides a method for preparing the impurity. The preparation method of the present invention is simple to operate, low in cost, and high in purity, and provides a high-purity impurity sample or standard for process research and quality control of zopiclone. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 is the HPLC chromatogram of the zopiclone reaction solution;
[0024] Figure 2 HPLC chromatogram of the impurities prepared in Example 1;
[0025] Figure 3 HPLC chromatogram of impurities obtained in the embodiment using the HPLC method for detecting the zopiclone reaction solution;
[0026] Figure 4 This is the mass spectrum of the impurity prepared in Example 1;
[0027] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the impurity prepared in Example 1;
[0028] Figure 6 The impurities prepared in Example 1 1 Magnified H NMR spectrum. DETAILED DESCRIPTION
[0029] The present invention is described in detail below in conjunction with specific embodiments.
[0030] Example 1: Confirmation of impurities
[0031] The synthesis of zopiclone is carried out by using the existing process: zopiclone alcohol and 4-methylpiperazine-1-carbonyl chloride hydrochloride are used to synthesize zopiclone under the catalytic condition of 4-dimethylaminopyridine (DMAP), and the equation is as follows:
[0032]
[0033] An unknown impurity peak with a normalized content of 46.58% to 48.29% (retention time of about 180 minutes) was found in multiple batches of reaction solutions, as shown in Table 1 and Figure 1 shown.
[0034] Table 1 Zopiclone reaction solution HPLC results
[0035]
[0036] The technicians analyzed the reaction raw materials and the retention time of impurities and determined the possible structure of the impurities to be:
[0037]
[0038] In order to verify the above speculation, the technicians designed a synthetic route for the impurities, as follows:
[0039]
[0040] The specific preparation process is:
[0041] Dissolve 4-methylpiperazine-1-carbonyl chloride hydrochloride (11.3 g, 0.057 mol) in 130.0 g of dichloromethane, stir, add DMAP (7.5 g, 0.06 mol), the system becomes turbid, then clears up, solid precipitates after 1 hour, continue stirring for 4 hours, filter by suction, beat the filter cake with 100.0 g of ethyl acetate for 30 minutes, filter by suction, and dry under reduced pressure at 50°C for 6 hours to obtain 15.0 g of solid (white powder, purity: 99.93%).
[0042] The purity of the solid prepared above is determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). The specific process of the new preparation is as follows:
[0043] Solvent acetonitrile-solution A (take 8.1 g of sodium dodecyl sulfate and 2.1 g of sodium dihydrogen phosphate, add water to dissolve and dilute to 1000 ml) (1000:1000), adjust the pH value to 4.0 with phosphoric acid.
[0044] Take an appropriate amount of the product for test solution, weigh it accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing about 1 mg per 1 ml.
[0045] Chromatographic conditions: octylsilane bonded silica gel as filler (Welch Ultimate LPC8, 250 mm × 4.6 mm, 5 μm or chromatographic column with equivalent performance); [acetonitrile-solution A (take 8.1 g of sodium dodecyl sulfate and 2.1 g of sodium dihydrogen phosphate, dissolve in water and dilute to 1000 ml) (800:1000), adjust the pH to 4.0 with phosphoric acid] as mobile phase; flow rate is 1.5 ml per minute; detection wavelength is 300 nm; column temperature is 35°C; injection volume is 20 l.
[0046] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram of the test solution to 1.5 times the retention time of the main peak.
[0047] The limit is calculated by peak area normalization method, and the main peak content shall not be less than 98%.
[0048] The above method was used to determine (the results are as follows Figure 2 The purity of the prepared compound was 99.93%.
[0049] The obtained impurity compounds were detected by high performance liquid chromatography using the same detection method as the zopiclone reaction solution, and the obtained chromatogram was as follows: Figure 3 ,contrast Figure 3 and Figure 1 The retention time of the prepared compound was consistent with the impurity peak retention time of about 180 minutes in the zopiclone reaction solution, which preliminarily confirmed the speculation on the impurity structure.
[0050] (1) The prepared compound is subjected to mass spectrometry (MS) detection, and the mass spectrometry conditions are:
[0051] Instrument: Agilent 1200 / 6220 liquid chromatography-mass spectrometer
[0052] Solvent: Methanol
[0053] Ionization method: ESI (+)
[0054] The mass spectrum measured is as follows Figure 3 The results are shown in Table 2:
[0055] Table 2 Mass spectrometry results
[0056] Mass-to-charge ratio (m / z) Theoretical accurate molecular weight Remark 249.1709 249.1710 <![CDATA[[C 13 H 21 N 4 O] + ]]>
[0057] Depend on Figure 3 It can be seen that the molecular ion peak corresponding to the sample is 249.1709, which is the base peak in the spectrum. + The theoretical value of the mass-to-charge ratio is 249.1710. Since the structure is a quaternary ammonium salt, in the positive ion mode, the mass-to-charge ratio is the mass-to-charge ratio of the cation part. The molecular formula after adding chloride ions is C 13 H 21 C1N 4 O, the mass-to-charge ratio of the molecule is 284.1404. The molecular weight of this product is an even number, and the molecule should contain no nitrogen atoms or an even number of N atoms, and the molecule contains 4 nitrogen atoms. The above results are consistent with the inferred structure.
[0058] (2) The prepared compound was subjected to nuclear magnetic resonance detection under the following nuclear magnetic resonance conditions:
[0059] Instrument: BRUKERAV-400 NMR instrument
[0060] Solvent: DMSO-d 6
[0061] Temperature: 303K
[0062] Internal standard: TMS
[0063] The hydrogen spectrum and the enlarged hydrogen spectrum of the sample are shown in Figure 4 , 5 ;
[0064] Combined with the test sample preparation process, a preliminary analysis of the hydrogen spectrum of the obtained product showed that the sample was a mixture. After careful comparison, it was found that they were actually two resonance formulas.
[0065]
[0066] According to calculations, the chemical shifts of hydrogen atoms on C2 and C4, C1 and C5 in resonance formula 1 are higher than those of hydrogen atoms on C4 and C6, C1 and C3 in the corresponding resonance formula 2. In resonance formula 1, there are two double peaks in the low field region (δ is 8.44, 7.14), and the coupling constants are both 8.0Hz, indicating that this is a typical ab peak. Combined with the starting materials, it can be easily identified.
[0067]
[0068] There are two peaks with an integral of 4H at δ 3.50 and 2.58, corresponding to the hydrogen atoms on the four methylene groups in piperazine. There is a single peak at δ 3.30, with an integral of 6H. It is the hydrogen atoms on the two methyl groups of C8 and C9. There is a single peak at δ 2.31, with an integral of 3H, corresponding to the N-CH 3 The assignment of all signals is shown in Table 3.
[0069] Table 3 Hydrogen spectrum measurement results of resonance formula 1 in samples
[0070] Chemical shift (ppm) Number of protons Peak shape Attribution Remark 8.44 2H d Pyridine J = 8.0 Hz, C2 and C4 7.14 2H d Pyridine J = 8.0 Hz, C1 and C5 3.50 4H s <![CDATA[CH 2 ]]> C13 and C17 3.30 6H s <![CDATA[CH 3 ]]> C8 and C9 2.58 4H s <![CDATA[CH 2 ]]> C14 and C16 2.31 3H s <![CDATA[CH 3 ]]> C18
[0071] In resonance formula 2, there are also two double peaks in the low field region (δ is 8.20, 6.94), the coupling constant is 8.0 Hz, and the integral is 1H. Considering the integral values at δ of 3.34, 3.15, 2.78, and 2.48 in the spectrum, we believe that these peaks correspond to the structure of resonance formula 2. The attribution of all signals is shown in Table 4. The ratio of the amount of substance of resonance formula 1 and resonance formula 2 is about 2:1. This shows that resonance formula 1 accounts for a higher proportion and is more stable.
[0072] Table 4 Hydrogen spectrum measurement results of resonance formula 2 in samples
[0073] Chemical shift (ppm) Number of protons Peak shape Attribution Remark 8.20 2H d Pyridine J = 8.0 Hz, C4 and C6 6.94 2H d Pyridine J = 8.0 Hz, C1 and C3 3.34 4H s <![CDATA[CH 2 ]]> C13 and C17 3.15 6H s <![CDATA[CH 3 ]]> C9 and C10 2.78 4H s <![CDATA[CH 2 ]]> C14 and C16 2.48 3H s <![CDATA[CH 3 ]]> C18
[0074] After analysis and calculation, the conclusions are as follows
[0075] 1) In positive ion mode, the molecular ion peak corresponding to the sample is 249.1709, which is the base peak in the spectrum. This product [M-Cl] + The theoretical value of the mass-to-charge ratio is 249.1710, and the obtained mass-to-charge ratio is the mass-to-charge ratio of the cation part, which is consistent with the target molecule data.
[0076] 2) The NMR hydrogen spectrum of the sample has two double peaks in the low field region (δ is 8.44, 7.14), and the coupling constant is 8.0Hz, indicating that this is a typical ab peak. Combined with the starting material, it can be easily identified. There are two more double peaks in the low field region (δ is 8.20, 6.94), the coupling constant is 8.0Hz, and the integral is 1H. Comprehensive consideration shows that the spectrum is a balance of resonance formula 1 and resonance formula 2. The specific values and attributions are shown in Tables 2 and 3 respectively. According to the integral values of the two groups of peaks in the low field region (δ is 8.44, 7.14 and δ is 8.20, 6.94), it can be calculated that the proportion of the two is 2:1, which means that the proportion of resonance formula 1 is twice that of resonance formula 2.
[0077] In summary, combined with the synthetic route of the experimental samples, the structure of the product is:
[0078]
[0079] Example 2: Synthesis of impurities
[0080] Dissolve 4-methylpiperazine-1-carbonyl chloride hydrochloride (11.3 g, 0.057 mol) in 130.0 g of chloroform, stir, add DMAP (10.25 g, 0.084 mol), the system becomes turbid, then clears up, solid precipitates after 1 hour, continue stirring for 4 hours, filter by suction, beat the filter cake with 100.0 g of propyl acetate for 30 minutes, filter by suction, and dry under reduced pressure at 50°C for 6 hours to obtain 15.6 g of solid (white powder, purity: 99.75%).
[0081] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A zopiclone process impurity, characterized in that: The structure is shown below:
2. The method for preparing zopiclone process impurities according to claim 1, characterized in that: The following steps are involved: At room temperature, 4-methylpiperazine-1-carbonyl chloride hydrochloride and DMAP are stirred in a reaction solvent for reaction. After the reaction is completed, the mixture is filtered. The filter cake is slurried with a purification solvent, filtered, and dried to obtain the impurities.
3. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The reaction solvent is one of dichloromethane, chloroform or tetrachloromethane, or a mixture of two or more thereof.
4. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The purification solvent is one or a mixture of two or more of ethyl acetate, propyl acetate or isopropyl acetate.
5. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The molar ratio of the 4-methylpiperazine-1-carbonyl chloride hydrochloride to DMAP is 1:1-2.
6. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The stirring reaction time is 4 to 6 hours.
7. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The mass ratio of the filter cake to the purification solvent is 1:5-10.
8. The method for preparing zopiclone process impurities according to claim 2, characterized in that: The drying is reduced pressure drying, the drying temperature is 40-60° C., and the drying time is 4-8 hours.