A key impurity of netupitant and a preparation method thereof

Abstract

The application relates to the technical field of pharmaceutical chemistry, and particularly discloses a key impurity of netupitant and a preparation method thereof. The preparation method of the key impurity of netupitant is as follows: netupitant is placed in a dichloromethane medium, stirred, heated and refluxed, and the netupitant and the dichloromethane are reacted. The structure of the netupitant contains an N-methyl piperazine ring, and a chloromethyl group is connected to a tertiary amine nitrogen of the ring. The reaction generates a chloromethylated quaternary ammonium salt, which is the key impurity of the netupitant. The impurity belongs to an impurity possibly generated in a preparation route of the netupitant. The application discloses reaction conditions for generating the key impurity of the netupitant, and provides a reference for quality control of the netupitant.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry technology, and specifically discloses a key impurity of netupitant and its preparation method. Background Technology

[0002] Nettopitan is a selective antagonist of substance P / neurokine 1 (NK1) receptors and is one of the active ingredients in the combination drug nettopitan-palonosetron capsules, used to prevent chemotherapy-induced nausea and vomiting.

[0003] The current mainstream synthetic routes for netotipant are as follows: Route 1: Reference: J. Org. Chem. 2006, 71, 2000-2008. The synthetic route is as follows:

[0004] This route uses 6-chloro-nicotinic acid as the starting material, which undergoes a substitution reaction with o-tolyl magnesium chloride to generate 6-chloro-4-o-tolylnicotinic acid. Then, it reacts sequentially with thionyl chloride and ammonia to generate 6-chloro-4-o-tolylnicotinamide, which then condenses with N-methylpiperazine to generate 6-(4-methylpiperazin-1-yl)-4-o-tolylnicotinamide. This condensation is then carried out under the action of NBS (N-bromosuccinimide) and sodium methoxide to generate N-methoxyyl-6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-amine, which is then reduced by red aluminum to generate N-methyl-6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-amine. Finally, it undergoes a condensation reaction with 2-(3,5-bis(trifluorotolyl)-2-methylpropionyl chloride to generate the product netupitant.

[0005] Route 2: References: Chinese patent application number CN201810922093.1, the synthetic route is as follows:

[0006] This route uses N-tert-butyl-6-chloro-4-o-tolylnicotinamide as the starting material, which is condensed with N-methylpiperazine to generate N-tert-butyl-6-(4-methylpiperazin-1-yl)-4-o-tolylnicotinamide. Then, it is detert-butylated with methanesulfonic acid to obtain 6-(4-methylpiperazin-1-yl)-4-o-tolylnicotinamide, which is then rearranged under the action of NBS (N-bromosuccinimide) and sodium methoxide to form N-methoxyyl-6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-amine. After reduction with red aluminum, it generates N-methyl-6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-amine, which finally undergoes a condensation reaction with 2-(3,5-bis(trifluorotolyl)-2-methyl-propionyl chloride to generate the product netupitant.

[0007] The synthesis of netutipant generally employs coupling and condensation reactions to construct the product, with dichloromethane often used as a solvent or in post-processing. Netutipant and dichloromethane may react under certain conditions. To maintain the safety and efficacy of netutipant, analyzing whether the dichloromethane used in its synthesis reacts with netutipant to generate impurities is crucial for the quality control of netutipant. Summary of the Invention

[0008] To maintain the safety and efficacy of netupitant, this application tested whether netupitant reacted with dichloromethane, and the results proved that a reaction occurred. The protocol of this application is as follows.

[0009] In the first aspect, this application proposes a key impurity for netotipant and adopts the following technical solution.

[0010] A key impurity for netutrapane, the structural formula of which is shown in Formula 1 below: .

[0011] By adopting the above technical solution, this application presents for the first time the key impurity information of netutopeptide. Structural analysis and QSAR prediction revealed that this impurity contains a warning result, and the QSAR software assessment is positive, posing a significant risk to the safety and efficacy of the product. Further investigation of this impurity is needed to ensure the safety and efficacy of the drug.

[0012] Secondly, this application proposes a method for preparing key impurities of netotipant, and adopts the following technical solution.

[0013] A method for preparing a key impurity of netutrapane involves reacting netutrapane and dichloromethane to obtain the key impurity, as shown in the following reaction formula: .

[0014] By adopting the above technical solution, this application clarifies that netupitant can react with dichloromethane under certain conditions, and the tertiary amine nitrogen on the N-methylpiperazine ring of netupitant is quaternized with a chloromethyl group.

[0015] A preferred embodiment of the preparation method for the key impurity of netutopeptide is that the mass ratio of netutopeptide to dichloromethane is (5g~10g):(50mL~100mL).

[0016] By adopting the above technical solution, excess dichloromethane will convert more netupitan into a critical impurity.

[0017] A preferred embodiment of the method for preparing the key impurity of netupitant is that the reaction is carried out under stirred reflux conditions.

[0018] By adopting the above technical solution, it is beneficial to convert more netupitant into key impurities.

[0019] A preferred embodiment of the method for preparing the key impurity of netupitant is that the reaction is carried out under normal pressure.

[0020] By adopting the above technical solution, the reaction conditions are mild, and it can be concluded that netupitant and dichloromethane can react under normal pressure.

[0021] A preferred embodiment of the method for preparing the key impurity of netupitant is that the reflux time of the reaction is 2-24 h.

[0022] By adopting the above technical solution, netupitant and dichloromethane gradually react to generate key impurities.

[0023] A preferred embodiment of the method for preparing the key impurity of netupitant is that the reflux time of the reaction is 12-24 h.

[0024] By adopting the above technical solution, the reaction of netopitant and dichloromethane produces a high yield of key impurities.

[0025] A preferred embodiment of the preparation method of the key impurity of netutopeptide is as follows: after the reaction, dichloromethane is evaporated by vacuum distillation while maintaining the temperature of the reaction solution at 30-40°C to obtain a concentrated solution. The concentrated solution is then separated by chromatographic column chromatography to obtain a pure solution. The pure solution is then concentrated and lyophilized to obtain the key impurity of netutopeptide.

[0026] By adopting the above technical solution, the purified product was obtained by separating it using conventional purification methods.

[0027] In summary, the key impurities of netupitant and their preparation method disclosed in this application have the following beneficial effects: Through experiments, it was found that netupitant and dichloromethane undergo an alkylation reaction to generate chloromethylated quaternary ammonium salt impurities, providing a reference for the quality control of netupitant. Attached Figure Description

[0028] Figure 1 The NMR spectrum of the key impurities of netupitant prepared in Example 1.

[0029] Figure 2 The mass spectrum is of the key impurities of netupitant prepared in Example 1. Detailed Implementation

[0030] The technical solutions in the embodiments are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the following embodiments without creative effort are within the scope of protection of this application.

[0031] Example 1: Synthesis of chloromethylated impurities Add 5g netupitant (molecular weight 578.592, 8.642 mmol) and 50ml dichloromethane (molecular weight 84.933, density 1.325 g / cm³) to a 250ml three-necked flask. 3 The sample (66.25 g, 780 mmol) was stirred and heated to reflux under normal pressure, and the reaction was maintained at this temperature for 2 hours. The mixture was then concentrated under reduced pressure using a rotary evaporator at 30-40°C. The concentrate was separated using a preparative liquid chromatography-diagnostic DAC100 (automated column chromatography purification equipment). The pure solution was collected, concentrated, and lyophilized to obtain the target impurity (i.e., the key impurity of netupitant), weighing 0.38 g, with a yield of 6.63% and a purity of 98.3%. The product was confirmed by NMR and mass spectrometry; see attached [details]. Figure 1 and Figure 2 The map.

[0032] Example 2: Synthesis of chloromethylated impurities Add 7.5 g netupitant (molecular weight 578.592, 12.963 mmol) and 75 ml dichloromethane (molecular weight 84.933, density 1.325 g / cm³) to a 250 ml three-necked flask. 3 The sample (99.375 g, 1170 mmol) was stirred and heated to reflux under normal pressure and kept at that temperature for 12 hours. It was then concentrated using a rotary evaporator at a concentration temperature of 30-40℃. The concentrate was separated using a preparative liquid chromatography DAC100. The pure solution was collected, concentrated, and lyophilized to obtain the target impurity, weighing 0.91 g, with a yield of 10.58% and a purity of 98.7%.

[0033] Example 3: Synthesis of chloromethylated impurities Add 10g (molecular weight 578.592, 17.283 mmol) of netupitant and 100ml of dichloromethane (molecular weight 84.933, density 1.325 g / cm³) to a 250ml three-necked flask. 3The sample (132.5 g, 1560 mmol) was stirred and heated to reflux under normal pressure and kept at that temperature for 24 hours. It was then concentrated using a rotary evaporator at a concentration temperature of 30-40℃. The concentrate was separated using a preparative liquid chromatography DAC100. The pure solution was collected, concentrated, and lyophilized to obtain the target impurity, weighing 1.23 g, with a yield of 10.73% and a purity of 98.6%.

[0034] Characterization analysis The structure of the compound (a key impurity of netupitant) was determined by nuclear magnetic resonance (NMR). 1 Characterization and determination were performed using 1H NMR and mass spectrometry (MS).

[0035] 1 The 1H NMR spectrometer was a BRUKER AVANCE III HD 400MHz NMR spectrometer. The solvent was deuterated chloroform, and the internal standard was tetramethylsilane (TMS). Chemical shifts (δ) are given in parts per million (ppm).

[0036] The LC-MS instrument was an Aglient 6545 Q-TOF (USA). The mass spectrometry test conditions were positive ion mode, ES-API ionization source, and scan range of 10³ m / z to 1000 m / z.

[0037] The product from Example 1 was tested, and the resulting NMR spectrum is as follows: Figure 1 As shown, the mass spectrum is as follows Figure 2 As shown.

[0038] I. In the NMR spectrum: (1) There is a singlet at ~6.13ppm, and the sum of the integrals is 2H, which are the two H on the chloromethyl (-CH2Cl), proving that the chloromethyl has been successfully connected.

[0039] (2) There is a singlet at ~3.47 ppm, the integral of which is approximately equal to 3H. This is the quaternary ammonium methyl (N + The characteristic signal of -CH3). Compared with the corresponding tertiary aminomethyl group in the raw material netupitant, this signal shifts significantly to the lower field (left) due to its positive charge, indicating the formation of a quaternary ammonium salt.

[0040] (3) Multiple sets of peaks were observed in the 6.62–8.01 ppm region, which are complex signals from aromatic hydrogens such as benzene ring and pyridine ring. These peaks were largely preserved, indicating that the parent nucleus structure had not undergone any destructive changes.

[0041] (4) The region of 3.61–4.21 ppm corresponds to 8 H signals on the piperazine ring.

[0042] (5) The 1.25–2.30 ppm region corresponds to the four methyl H signals near the benzene ring and acyl group.

[0043] The NMR spectrum perfectly matches the structure of the chloromethylated quaternary ammonium salt impurity (i.e., the key impurity of netupitant), with key characteristic peaks (-CH2Cl and N) present. + -CH3) is clear and correct.

[0044] II. In the mass spectrum: (1) The main peak is located at m / z 627.2376. The molecular weight of netutopeptide is known to be 578.592, and the molecular formula of netutopeptide is C 30 H 32 F6N4O, a chloromethyl (-CH2Cl) group with the highest molecular weight. 35 The calculated CL is 48.97, and the sum of the molecular weights of netupitant and chloromethyl is 627.562. However, through precise calculation of CL... 31 H 34 The molecular weight of ClF6N4O is 627.2325, which matches the main peak, proving that the netutropitan molecule is linked to a chloromethyl group, yielding the chloromethylated quaternary ammonium salt of netutropitan, formula 1, with the molecular formula C. 31 H 34 ClF6N4O.

[0045] from Figure 1 and Figure 2 It can be seen that the proton nuclear magnetic resonance spectrum of the obtained product (NMR spectrum) 1 The H NMR signal was clear with no obvious impurity peaks, and the high-resolution mass spectrometry (HRMS) showed a single molecular ion peak, indicating that the product had high chemical purity. This confirmed that the netutopeptide molecule was linked to a chloromethyl group, resulting in the chloromethylated quaternary ammonium salt of netutopeptide of Formula 1.

[0046] This application provides for the first time the structure and preparation method of the finished product impurity generated from netupitant and dichloromethane. The method described in this application can prepare high-purity netupitant key impurities as shown in Formula I, which is beneficial for the study of key process impurities in the synthesis of netupitant, fills a gap in the research on process impurities, and provides a basis for the quality control of netupitant.

[0047] Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A key impurity of netupitant, characterized in that, The structural formula of the key impurity of netotipant is as follows: Formula 1: 。 2. A method for preparing the key impurity of netupitant as described in claim 1, characterized in that, The key impurity of netutrapane is obtained by reacting a mixture of netutrapane and dichloromethane, as shown in the following reaction formula: 。 3. The method for preparing key impurities of netupitant according to claim 2, characterized in that, The mass ratio of netopitane to dichloromethane is (5g~10g): (50mL~100mL).

4. The method for preparing key impurities of netupitant according to claim 2, characterized in that, The reaction was carried out under stirred reflux conditions.

5. The method for preparing key impurities of netupitant according to claim 4, characterized in that, The reaction takes place under normal pressure.

6. The method for preparing key impurities of netupitant according to claim 5, characterized in that, The reflux time for this reaction is 2 to 24 hours.

7. The method for preparing the key impurity of netupitant according to claim 6, characterized in that, The reflux time for this reaction is 12-24 hours.

8. The method for preparing key impurities of netupitant according to claim 2, characterized in that, After the reaction, the dichloromethane was evaporated by vacuum distillation at a temperature of 30-40°C to obtain a concentrated solution. The concentrated solution was then separated by chromatographic column chromatography to obtain a pure solution. The pure solution was then concentrated and lyophilized to obtain the key impurities of netutopeptide.

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