Preparation method of pecuronium bromide impurity C
The method for preparing impurity C in pipecuronium bromide solves the problem of insufficient impurity control in the existing technology, and achieves the acquisition of high-purity impurity C, which can be used for quality control and safety assurance of pipecuronium bromide.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-04
- Publication Date
- 2026-03-10
AI Technical Summary
The lack of existing technology for preparing impurity C in pipecuronium bromide makes it difficult to effectively control the quality and safety of pipecuronium bromide.
Pipercuronium bromide impurity C was prepared by using 2α,3α,16α,17α-bisepoxy-17β-acetoxy-5αandrostane as the starting material and through a series of steps including reaction with N-methylpiperazine, reduction with sodium borohydride, reaction with methyl bromide and esterification.
Impurity C of pipecuronium bromide with a purity of over 95% was prepared and can be used as a reference standard for the quality control of pipecuronium bromide, ensuring the quality and safety of the drug.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a preparation method of impurity C of pipecuronium bromide, and belongs to the field of medicines. BACKGROUND
[0002] Pipecuronium bromide is a long-acting non-depolarizing muscle relaxant of steroid, which is mainly used for muscle relaxation in the process of general anesthesia, and is mostly used for surgical anesthesia with a time of more than 40 minutes, especially for cardiovascular or non-cardiovascular surgery of patients with cardiovascular diseases. Pipecuronium bromide is widely used in clinical practice due to its good muscle relaxation effect, long duration, no cardiovascular side effects, and safe and reliable pharmacological effect. The chemical name of pipecuronium bromide is 4,4'-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)androstane-2,16-ylidene]bis(1,1-dimethylpiperazinyl) dibromide, CAS: 52212-02-9, molecular formula C 35 H 62 Br2N4O4, molecular weight: 762.7, and its structure is shown as formula I:
[0003]
[0004] At present, there are many reports on the preparation method of pipecuronium bromide. For example, CN101035801, West China Journal of Pharmacy, 2009, 24 (1): 049-051, Chinese Journal of Pharmaceutical Chemistry, 2008, 18, 2, 115-118, etc. disclose the synthesis method of pipecuronium bromide. 5α-androst-2-ene-17-ketone is used as a raw material, and six steps of reactions including esterification of isopropyl acrylate, cyclization of m-chloroperbenzoic acid, ring opening of N-methylpiperazine, reduction of sodium borohydride, esterification of acetic anhydride, and double quaternary ammonium saltification of bromomethane are performed to obtain pipecuronium bromide.
[0005] In the process of drug development, the research and control of impurities are important links of risk control in drug development, key elements of drug safety guarantee, and one of the core contents of drug quality control, which runs through the whole process of drug research. Whether the impurities in the drug can be reasonably and effectively controlled is directly related to the controllability and safety of the quality of the drug.
[0006] In the preparation process of pipecuronium bromide, various process impurities are easily produced, which may have adverse effects on the quality of pipecuronium bromide and the safety of drug use. Among them, impurity C (shown as formula II) is an impurity produced due to incomplete double quaternary ammonium saltification of bromomethane in the preparation process of pipecuronium bromide. The impurity is also a degradation impurity of pipecuronium bromide, which is easily produced in the storage or placement of pipecuronium bromide.
[0007]
[0008] At present, there is no report on the preparation method of the impurity C of pipecuronium bromide at home and abroad. In order to better control the quality of pipecuronium bromide, it is urgent to study the impurity C of pipecuronium bromide, and to prepare the impurity C with qualified purity as a control sample, so as to better control the quality of pipecuronium bromide and ensure the quality of pipecuronium bromide. SUMMARY
[0009] The technical scheme of the present application provides a preparation method of the impurity C of pipecuronium bromide.
[0010] The present application provides a preparation method of the impurity C of pipecuronium bromide, which is prepared from 2α, 3α, 16α, 17α-bis-epoxidized-17β-acetyloxy-5α-androstane as a starting material, and the synthesis process route is as follows:
[0011]
[0012] Further, it comprises the following steps:
[0013] a. Preparation of intermediate 1: 2α, 3α, 16α, 17α-bis-epoxidized-17β-acetyloxy-5α-androstane as a starting material, and N-methylpiperazine is reacted to prepare intermediate 1;
[0014] b. Preparation of intermediate 2: Intermediate 1 is reduced by sodium borohydride to obtain intermediate 2;
[0015] c. Preparation of intermediate 3: Intermediate 2 is reacted with bromomethane to obtain intermediate 3;
[0016] d. Preparation of intermediate 4: Intermediate 3 is reacted with N-methylpiperazine to obtain intermediate 4;
[0017] e. Esterification reaction to obtain the impurity C of pipecuronium bromide;
[0018] Preferably, in step a, the reaction time is 0.5-2 hours, more preferably 0.5-1.5 hours. When the reaction time of step a is greater than 2 hours, the yield of intermediate 1 will decrease. In step a, 2α, 3α, 16α, 17α-bis-epoxidized-17β-acetyloxy-5α-androstane and N-methylpiperazine are added to water, stirred under reflux conditions for 0.5-2 hours, and the reaction solution is concentrated under reduced pressure to obtain intermediate 1; the molar ratio of 2α, 3α, 16α, 17α-bis-epoxidized-17β-acetyloxy-5α-androstane to N-methylpiperazine is 1:2-11; preferably the molar ratio is 1:5-10.3; the mass / volume ratio of 2α, 3α, 16α, 17α-bis-epoxidized-17β-acetyloxy-5α-androstane to water is 1:5-10 g / mL.
[0019] In step b, the preparation method of intermediate 2 is:
[0020] Intermediate 1 was dissolved in organic solvent a, sodium borohydride was added, and the mixture was stirred to react. After the reaction was completed, a mixture of water and organic solvent b was added, the mixture was separated, and the organic layer was concentrated under reduced pressure. The concentrate was added to organic solvent c and stirred, filtered, and the filter cake was dried under reduced pressure to obtain intermediate 2.
[0021] The mass-to-volume ratio of intermediate 1 to organic solvent a is 1:5-10 g / mL; the molar ratio of intermediate 1 to sodium borohydride is 1:1.5-6, preferably 1:3-4; during the addition of sodium borohydride, the reaction system temperature is controlled below 25°C, preferably below 20°C; the stirring reaction temperature is 0-5°C, and the stirring reaction time is 1-5 hours; the volume ratio of water to organic solvent b in the mixed solvent is 1:1-3; the mass-to-volume ratio of intermediate 1 to the mixed solvent is 1:5-15 g / mL; the mass-to-volume ratio of intermediate 1 to organic solvent c is 1:2-5 g / mL.
[0022] The organic solvents a, b, and c are independently selected from any one or a combination of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, and acetonitrile.
[0023] The preparation method of intermediate 3 includes the following steps:
[0024] Intermediate 2 is added to an organic solvent, methyl bromide is added, the mixture is stirred and reacted, filtered, and the filter cake is dried to obtain intermediate 3; the mass-to-volume ratio of intermediate 2 to organic solvent is 1:5-15 g / mL; the organic solvent is selected from acetonitrile; the molar ratio of intermediate 2 to methyl bromide is 1:1-5, preferably 1:1.5-3.
[0025] The preparation method of intermediate 4 includes the following steps:
[0026] Intermediate 3 and N-methylpiperazine were added to water and stirred under reflux. The reaction solution was concentrated under reduced pressure. The concentrate was added to an organic solvent and stirred. The mixture was filtered and the filter cake was dried under reduced pressure to obtain intermediate 4.
[0027] The molar ratio of intermediate 3 to N-methylpiperazine is 1:2-15, preferably 1:5-11;
[0028] The mass-to-volume ratio of intermediate 3 to water is 1:3-10 g / mL, preferably 1:6-10 g / mL;
[0029] The mass-to-volume ratio of intermediate 3 to organic solvent is 1:2-5 g / mL; the organic solvent is selected from acetonitrile.
[0030] The esterification reaction described in step e includes the following steps:
[0031] Intermediate 4, acetic acid, and acetic anhydride were added to a reaction flask and reacted at room temperature. After the reaction was complete, water and organic solvent were added to adjust the pH of the system to 8-9. The mixture was separated into layers, and the organic layer was concentrated under reduced pressure. The concentrate was dried under reduced pressure to obtain pipecuronium bromide impurity C.
[0032] The molar ratio of intermediate 4 to acetic acid is 1:10 to 20, preferably 1:12 to 17;
[0033] The molar ratio of intermediate 4 to acetic anhydride is 1:10 to 25, preferably 1:15 to 21;
[0034] The mass-to-volume ratio of intermediate 4 to water is 1:5-15 g / mL;
[0035] The mass-to-volume ratio of intermediate 4 to organic solvent is 1:10-20 g / mL;
[0036] The organic solvent is selected from any one or a combination of toluene, ethyl acetate, dichloromethane, chloroform, and n-butanol.
[0037] The beneficial effects of this invention are:
[0038] This invention provides an effective method for preparing impurity C in pipecuronium bromide, achieving a purity of over 95%, which can be used as a reference standard for the quality control of pipecuronium bromide. This invention effectively addresses the shortcomings of existing technologies in controlling this impurity, providing a guarantee for further quality control of pipecuronium bromide raw materials or formulations.
[0039] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.
[0040] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation
[0041] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.
[0042] Example 1: Preparation method of pipecuronium bromide impurity C of the present invention
[0043] 1. Preparation of intermediate 1:
[0044] 30.00 g of 2α,3α,16α,17α-bisepoxy-17β-acetoxy-5αandrostane (1.0 eq), 220 ml of water, and 90.00 g of N-methylpiperazine (10.3 eq) were added to a reaction flask. The mixture was heated to reflux and stirred for 1.5 h. The reaction solution was then concentrated under reduced pressure at 60 °C to obtain 38.56 g of a light yellow oil.
[0045] 2. Preparation of intermediate 2:
[0046] 38.00 g (1.0 eq) of intermediate 1 was dissolved in 300 ml of methanol, stirred and cooled to -1 °C, and 15.00 g (4.0 eq) of sodium borohydride was added in batches, with the system temperature controlled below 20 °C during the addition. After the addition was complete, the mixture was stirred at 0 °C for 2 h until the reactants were basically completely reacted. 200 ml of water and 200 ml of dichloromethane were added and the mixture was separated. The organic layer was concentrated to dryness under reduced pressure at 50 °C to obtain 31.82 g of a light yellow oil. This oil was added to 100 ml of acetonitrile and stirred to disperse, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the filter cake was dried under reduced pressure at 60 °C to obtain 8.23 g of intermediate 2.
[0047] 3. Preparation of intermediate 3:
[0048] Add 3.80 g of intermediate 2 (1.0 eq) to 40 ml of acetonitrile and stir at 5 °C until dissolved. Add 2.80 g of bromomethane (3.0 eq) and stir for 30 min. A white solid precipitates. Filter the mixture and dry the filter cake under reduced pressure at 55 °C to obtain 2.82 g of intermediate 3.
[0049] 4. Preparation of impurity intermediate 4:
[0050] 2.50 g of intermediate 3 (1.0 eq), 15 ml of water, and 7.00 g of N-methylpiperazine (11.0 eq) were added to a reaction flask and stirred until heated. The mixture was refluxed at 138 °C for 2 h until the reactants were basically completely reacted. The reaction solution was concentrated under reduced pressure at 60 °C to obtain a light yellow oil. The oil was added to 10 ml of acetonitrile and stirred to disperse. A white solid precipitated out. The solid was filtered, and the filter cake was dried under reduced pressure at 55 °C to obtain 2.20 g of intermediate 4.
[0051] 5. Preparation of pipecuronium bromide impurity C:
[0052] 1.70 g of intermediate 4 (1.0 eq), 3.8 ml of acetic acid (17.0 eq), and 7.7 ml of acetic anhydride (21.0 eq) were added to a reaction flask and stirred overnight at room temperature until the reactants were basically completely reacted. 17 ml of water and 30 ml of dichloromethane were added and stirred. The pH of the system was adjusted to 9 with ammonia water, and the layers were separated. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate by stirring. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dried under reduced pressure to obtain 0.97 g of pipecuronium bromide impurity C.
[0053] HPLC analysis showed that the purity of pipecuronium bromide impurity C was 95.82%.
[0054] The impurity C of pipecuronium bromide was analyzed using nuclear magnetic resonance spectroscopy, and its proton and carbon NMR spectra were obtained. The results are as follows:
[0055] 1 H NMR (400MHz, CDCl3), δ=5.247~5.254(t, 1H); 4.764~4.788(d, 1H); 3.492~3.694(s / t, 10H); 3.185~3.253(m, 1H); 2.800~2 .954(t / m, 9H); 2.274~2.438(s / t, 10H); 2.066(s, 3H); 1.152~1.983(m, 15H); 0.720~1.022(m, 4H); 1.925~1.947(s / m, 9H).
[0056] 13 C NMR (400MHz, CDCl3), δ=170.432~170.455, 81.619, 69.470, 63.620, 62.464~62.681, 55.337, 54.660, 51.612, 50.801, 48.102, 45.730 , 45.122, 42.810, 40.438, 37.934, 36.096, 33.606~33.762, 31.838, 29.718, 27.322, 25.434, 21.346~21.566, 20.495, 13.270, 12.737.
[0057] Comparative Example 1: Preparation of Pipercuronium Bromide Impurity C
[0058] Weigh 50 mg of pipecuronium bromide and place it in a 5 ml volumetric flask. Add 1.0 ml of 3% hydrogen peroxide solution, shake to dissolve, mix well, seal, and place in a 40°C water bath for 1 hour. Testing showed that the amount of pipecuronium bromide impurity C produced under these conditions was 0.1–0.2%, making it impossible to obtain a pipecuronium bromide impurity C reference standard via this method. The pipecuronium bromide impurity C of this invention is a degradation impurity, and theoretically, it can be obtained through a degradation reaction. However, experiments have shown that the amount of impurity C produced through degradation reactions is very small, making it impossible to prepare a reference standard using this method.
[0059] Preparation of intermediate 1 in Comparative Example 2
[0060] 30.00 g of 2α,3α,16α,17α-bisepoxy-17β-acetoxy-5α-androstane (1.0 eq), 220 ml of water, and 90.00 g of N-methylpiperazine (10.3 eq) were added to a reaction flask. The mixture was heated to reflux and stirred for 4 h. The reaction solution was then concentrated under reduced pressure at 60 °C to obtain a concentrate. Analysis showed that the concentrate contained 3.947% intermediate 1.
[0061] If the reaction time exceeds 4 hours, it is impossible to obtain intermediate 1 with a high content. It should be controlled within 2 hours, preferably within 1.5 hours. The longer the time, the more substances with open rings will be produced.
[0062] In summary, this invention provides a method for preparing pipecuronium bromide impurities and their uses. The pipecuronium bromide impurity C prepared by this invention has high purity and can be used as a reference standard for the quality detection of pipecuronium bromide.
Claims
1. A process for the preparation of piperidolate impurity C, characterized by: It is prepared from 2α, 3α, 16α, 17α-bisepoxidized-17β-acetoxy-5α-androstan as starting material, and the synthetic process route is as follows:
2. The method of preparing piperidolate Impurity C according to claim 1, characterized by: It comprises the following steps: a. Preparation of intermediate 1: 2α, 3α, 16α, 17α-bisepoxidized-17β-acetoxy-5α-androstan as starting material, and N-methylpiperazine is reacted to prepare intermediate 1; b. Preparation of intermediate 2: Intermediate 1 is reduced by sodium borohydride to obtain intermediate 2; c. Preparation of intermediate 3: Intermediate 2 is reacted with bromomethane to obtain intermediate 3; d. Preparation of intermediate 4: Intermediate 3 is reacted with N-methylpiperazine to obtain intermediate 4; e. Esterification reaction to obtain pirenzepine bromide impurity C; Preferably, in step a, the reaction time is 0.5-2 hours, more preferably 0.5-1.5 hours.
3. The method of preparing piperidolate Impurity C according to claim 2, wherein: In step a, 2α, 3α, 16α, 17α-bisepoxidized-17β-acetoxy-5α-androstan and N-methylpiperazine are added to water, and stirred under reflux conditions for 0.5-2 hours. The reaction solution is concentrated under reduced pressure to obtain intermediate 1. The molar ratio of 2α, 3α, 16α, 17α-bisepoxidized-17β-acetoxy-5α-androstan to N-methylpiperazine is 1:2-11, preferably 1:5-10.
3. The mass-volume ratio of 2α, 3α, 16α, 17α-bisepoxidized-17β-acetoxy-5α-androstan to water is 1:5-10 g / mL.
4. The process for preparing piperidolate Impurity C according to claim 2, characterized by: The preparation method of intermediate 2 in step b is as follows: Intermediate 1 is dissolved in organic solvent a, sodium borohydride is added, and stirred to react. After the reaction is completed, a mixed solvent of water and organic solvent b is added, and the mixture is separated. The organic layer is concentrated under reduced pressure, and the obtained concentrate is stirred with organic solvent c, filtered, and the filter cake is dried under reduced pressure to obtain intermediate 2. The mass-volume ratio of intermediate 1 to organic solvent a is 1:5-10 g / mL. The molar ratio of intermediate 1 to sodium borohydride is 1:1.5-6, preferably 1:3-4. During the addition of sodium borohydride, the temperature of the reaction system is controlled below 25°C, preferably below 20°C. The stirring reaction temperature is 0-5°C, and the stirring reaction time is 1-5 hours. The volume ratio of water to organic solvent b in the mixed solvent is 1:1-3. The mass-volume ratio of intermediate 1 to the mixed solvent is 1:5-15 g / mL. The mass-volume ratio of intermediate 1 to organic solvent c is 1:2-5 g / mL. The organic solvents a, b and c are independently selected from any one or a combination of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate and acetonitrile.
5. The method of preparing piperidolate Impurity C according to claim 2, wherein: The preparation method of intermediate 3 comprises the following steps: Intermediate 2 is added to an organic solvent, bromomethane is added, and stirred to react. After filtration, the filter cake is dried to obtain intermediate 3. The mass-volume ratio of intermediate 2 to the organic solvent is 1:5-15 g / mL. The organic solvent is selected from acetonitrile. The molar ratio of intermediate 2 to bromomethane is 1:1-5, preferably 1:1.5-3.
6. The preparation method of pirenzepine bromide impurity C according to claim 2. The preparation method of the intermediate 4 comprises the following steps: The intermediate 3 and N-methylpiperazine are added into water, and stirred under reflux condition; the reaction solution is concentrated under reduced pressure; the concentrate is added into an organic solvent and stirred; filtration is performed; the filter cake is dried under reduced pressure to obtain the intermediate 4; The molar ratio of the intermediate 3 to N-methylpiperazine is 1:2-15, preferably 1:5-11; The mass-volume ratio of the intermediate 3 to water is 1:3-10 g / mL, preferably 1:6-10 g / mL; The mass-volume ratio of the intermediate 3 to the organic solvent is 1:2-5 g / mL; the organic solvent is selected from acetonitrile.
7. The method of preparing piperidolate Impurity C according to claim 2, wherein: The esterification reaction in the e step comprises the following steps: The intermediate 4, acetic acid and acetic anhydride are added into a reaction bottle, and reacted at room temperature; after the reaction is completed, water and an organic solvent are added, the pH of the system is adjusted to 8-9, and the layers are separated; the organic layer is concentrated under reduced pressure; the concentrate is dried under reduced pressure to obtain the piperidolate bromide impurity C; The molar ratio of the intermediate 4 to acetic acid is 1:10-20, preferably 1:12-17; The molar ratio of the intermediate 4 to acetic anhydride is 1:10-25, preferably 1:15-21; The mass-volume ratio of the intermediate 4 to water is 1:5-15 g / mL; The mass-volume ratio of the intermediate 4 to the organic solvent is 1:10-20 g / mL; The organic solvent is selected from any one or a combination of toluene, ethyl acetate, dichloromethane, chloroform and n-butanol.