CN111777617A - Refining method of methylnaltrexone bromide - Google Patents
Refining method of methylnaltrexone bromide Download PDFInfo
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- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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Abstract
The invention provides a refining method of methylnaltrexone bromide. The refining method of methylnaltrexone bromide comprises two recrystallization steps, and hydrobromic acid is added into a solvent for the first recrystallization, wherein the mass ratio of methylnaltrexone bromide to hydrobromic acid is 1: (0.02-0.06). The refining method of methylnaltrexone bromide provided by the invention comprises the steps of two-time recrystallization, wherein the two-time recrystallization can respectively remove impurities in a targeted manner, the impurity content in the crude methylnaltrexone bromide can be obviously reduced through the cooperation of the two-time recrystallization, and the purity of the refined methylnaltrexone bromide is improved. In addition, in the two recrystallization steps, the concentration of iron ions in the solution containing the methylnaltrexone bromide is controlled to be less than or equal to 10ppm, so that the impurity content in the crude methylnaltrexone bromide can be obviously reduced, and the invention provides a key process control condition for refining the methylnaltrexone bromide.
Description
Technical Field
The invention relates to the field of chemical drug synthesis, in particular to a refining method of methylnaltrexone bromide.
Background
Methylnaltrexone bromide, known by the chemical name (R) -17-cyclopropylmethyl-4, 5 a-epoxy-3, 14-dihydroxy-17-methyl-6-oxomorphinan bromide, is a mu opioid receptor antagonist developed by the united states Wyeth Pharmaceuticals, inc. The canadian health department in 4 months of 2008 and the FDA in the united states respectively approve methylnaltrexone bromide (Relistor) to be marketed for treating opioid-induced constipation (OIC). The chemical structural formula of methylnaltrexone bromide is as follows:
methyhaaltrexone bromide belongs to derivatives of morphinones, and is generally synthesized by taking naltrexone hydrochloride as a raw material through steps of hydroxyl protection, methylation, deprotection and the like, and the synthesized crude methyhaaltrexone bromide usually contains the following impurities: (17RS) -17- (cyclopropylmethyl) -4,5 α -epoxy-14-hydroxy-17-methyl-3-methoxy-6-oxomorphinan bromide (impurity 1), (17S) -cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-17-methyl-6-oxomorphinan bromide (impurity 2), (17, 17 'R) -dicyclopropylmethyl-4, 4', 5,5 'α -diepoxy-3, 3', 14,14 '-tetrahydroxy-17, 17' -dimethyl-6, 6 '-dioxo-2, 2' -bimorphinan bromide (impurity 3) having the following chemical structure:
the synthesized methylnaltrexone bromide needs to be refined to obtain the chemical raw material medicine with higher purity. At present, recrystallization is mainly adopted for refining methylnaltrexone bromide, for example, chinese patent literature (CN103626782A) provides a refining method for crude methylnaltrexone bromide: using methylnaltrexone bromide with C1-C3The solvent of alcohol and water is recrystallized. Further, for example, chinese patent document (CN102558189A) discloses a method for purifying methylnaltrexone bromide, which comprises separating and purifying methylnaltrexone bromide by reverse-phase silica gel column chromatography, and recrystallizing and purifying the crude methylnaltrexone bromide with methanol, water and solvent before or after the reverse-phase silica gel column chromatography. The reverse phase silica gel column chromatography has the defects of large solvent consumption and difficult post-treatmentThe problem is that after the crude methylnaltrexone bromide is recrystallized and purified only by using a solvent of alcohol and water, the content of impurities in the product is still high.
Disclosure of Invention
Therefore, the technical problems to be solved by the invention are to overcome the defects of large solvent consumption and difficult post-treatment caused by reverse silica gel column chromatography in the refining process of methylnaltrexone bromide and high impurity content in the recrystallization purification process of methylnaltrexone bromide by using the solvent of alcohol and water, thereby providing a refining method of methylnaltrexone bromide.
The invention provides a refining method of methylnaltrexone bromide, which comprises two recrystallization steps, wherein hydrobromic acid is added into a solvent for the first recrystallization, and the mass ratio of the methylnaltrexone bromide to the hydrobromic acid is 1: (0.02-0.06).
Further, the first recrystallization includes:
dissolving methylnaltrexone bromide to be refined in a solvent to obtain methylnaltrexone bromide solution;
dropwise adding hydrobromic acid into the methylnaltrexone bromide solution and refluxing;
and (3) cooling and crystallizing the solution obtained by refluxing, collecting solids, washing and drying in sequence.
Further, the first recrystallization also comprises the steps of adding active carbon into the methylnaltrexone bromide solution, refluxing and hot filtering, wherein the using amount of the active carbon is 0.5-1.5% of the mass of the methylnaltrexone bromide to be refined, and refluxing to be clear.
Further, the second recrystallization comprises:
dissolving methylnaltrexone bromide obtained by primary recrystallization in a solvent to obtain methylnaltrexone bromide solution;
and sequentially cooling and crystallizing the methylnaltrexone bromide solution, collecting solids, washing and drying.
Further, the solvents used for the two recrystallizations each comprise a solvent having a volume ratio of 1: (3-4) water and alcohol, wherein the mass-to-volume ratio of the methylnaltrexone bromide to the alcohol is 1: (3-10), wherein the alcohol is at least one of methanol, ethanol, n-propanol or isopropanol.
Further, in the two recrystallization steps, the crystallization temperature is 0-5 ℃, the crystallization time is 2-3h, and the precipitated crystals are dried under reduced pressure under the conditions of 60-70 ℃ and the pressure less than or equal to 0.09 MPa.
Further, in the two recrystallization steps, the concentration of iron ions in the solution containing the methylnaltrexone bromide is controlled to be less than or equal to 10 ppm.
Further, the synthesis steps of the methylnaltrexone bromide are as follows:
taking naltrexone hydrochloride as a starting material, and carrying out acetylation reaction on the naltrexone hydrochloride and acetic anhydride to obtain an intermediate 1;
the intermediate 1 and methyl bromide are subjected to methylation reaction to obtain an intermediate 2;
the intermediate 2 and hydrobromic acid are subjected to deprotection reaction to obtain methylnaltrexone bromide,
further, in the step of synthesizing the intermediate 1, the acetylation reaction is performed under the condition of toluene and sodium hydroxide, wherein the molar ratio of naltrexone hydrochloride, acetic anhydride and sodium hydroxide is 1: (1-1.4): (2.0-2.1) and the reaction temperature is below 30 ℃.
Further, in the step of synthesizing the intermediate 2 and methylnaltrexone bromide, dissolving the intermediate 1 in an N-methylpyrrolidone solvent containing methyl bromide to react, dropwise adding hydrobromic acid after the reaction is finished, and adding methanol to precipitate a solid after the reaction is finished to obtain methylnaltrexone bromide, wherein the molar ratio of the intermediate 1 to the methyl bromide to the hydrobromic acid is 1: (2-5): (1-1.2); the mass-to-volume ratio of the intermediate 1 to the methanol is 1: (3-6).
The technical scheme of the invention has the following advantages:
1. the refining method of methylnaltrexone bromide provided by the invention comprises two recrystallization steps, and hydrobromic acid is added into a solvent for the first recrystallization, wherein the mass ratio of methylnaltrexone bromide to hydrobromic acid is 1: (0.02-0.06). Hydrobromic acid is added in the first recrystallization step, so that impurity 1 in the crude methylnaltrexone bromide product can be removed more conveniently. And (3) by adopting a twice recrystallization method, wherein the first recrystallization mainly and specifically removes the impurity 1 and the impurity 2 in the crude methylnaltrexone bromide, and the second recrystallization is carried out on the methylnaltrexone bromide obtained by the first recrystallization, so that the impurity 2 and the impurity 3 in the crude methylnaltrexone bromide are mainly and specifically removed. The two-time recrystallization can respectively remove impurities in a targeted manner, the impurity content in the crude methylnaltrexone bromide product can be obviously reduced through the cooperation of the two-time recrystallization, and the purity of the refined methylnaltrexone bromide product is improved. The two-time recrystallization process is adopted, so that the problems of large solvent consumption and difficult post-treatment caused by reverse silica gel column chromatography are solved, and the refining method of methylnaltrexone bromide is convenient to operate and suitable for large-scale popularization and application.
2. According to the refining method of methylnaltrexone bromide, provided by the invention, in the step of twice recrystallization, the concentration of iron ions in the solution containing methylnaltrexone bromide is controlled to be less than or equal to 10 ppm. The applicant has found for the first time that the content of impurity 3 is related to the concentration of iron ions in the solution containing methylnaltrexone bromide during the recrystallization. The iron ions may be introduced from the solvent used in the recrystallization process, from a line carrying the solvent, or due to other materials added during the recrystallization process. The method for controlling the concentration of the iron ions can be to control the content of the iron ions in a solvent or other substances added into a recrystallization system of the methylnaltrexone bromide, or to detect that a metal ion complexing agent is added to reduce the concentration of the iron ions when the concentration of the iron ions in a solution containing the methylnaltrexone bromide in the recrystallization system exceeds a standard. The content of impurity 3 in the crude methylnaltrexone bromide product can be obviously reduced by controlling the concentration of iron ions in the solution containing methylnaltrexone bromide to be less than or equal to 10ppm in the recrystallization process. The invention provides key process control conditions for refining methylnaltrexone bromide.
3. The refining method of methylnaltrexone bromide provided by the invention further comprises the steps of adding activated carbon, refluxing and hot filtering for the first recrystallization. The active carbon is added for reflux, so that the crude methylnaltrexone bromide can be decolorized, the clarity of the refined methylnaltrexone bromide product is effectively improved, impurities are removed, and the refined methylnaltrexone bromide can be used for preparing methylnaltrexone bromide preparations.
4. According to the refining method of methyhaaltrexone bromide provided by the invention, naltrexone hydrochloride is used as an initial raw material, and acetylation reaction is carried out on naltrexone bromide and acetic anhydride to protect hydroxyl groups, compared with the method that tert-butyldimethylsilyl chloride is used as a protective agent, the method is beneficial to purifying subsequent products, impurities generated by tert-butyldimethylsilyl chloride have a certain dissolving amount in subsequent reaction solvents, and the purification is difficult, and the problem is solved by using acetic anhydride as the protective agent.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
Reagent and instrument sources
Reagent:
naltrexone hydrochloride (Sanofi); toluene (medium petroleum gas Jilin stand); acetic anhydride and hydrobromic acid (Shanghai Vocko Biotechnology, Inc.); methyl bromide (Liandong dead sea Bromide, Inc.); n-methylpyrrolidone (coastal energy-rich chemical company); activated carbon (shanghai activated carbon plant); methanol (Tangshangming chemical Co., Ltd.); ferric chloride solution (1M, alatin); phenanthroline (alatin).
The instrument comprises the following steps:
an electric stirrer (ASONE); glassware (shanghai grain steam glassware, ltd); HPLC (agilent 1260); an ultraviolet-visible spectrophotometer (agilent cary 3500).
The method for detecting the concentration of iron ions in a solution in the following examples and experimental examples is as follows:
accurately measuring 0.9mL of ferric trichloride solution in a 10mL volumetric flask, and shaking up after constant volume by using deionized water. Precisely measuring 1.0mL in a 50mL volumetric flask, and shaking up after constant volume by using deionized water to obtain a standard iron solution.
Respectively adding 1mL of 10% hydroxylamine hydrochloride solution (v/v) into a 50mL volumetric flask, adding a corresponding amount of standard iron solution, shaking uniformly, standing for 2min, adding 1.5mL of 0.15% o-phenanthroline solution (v/v) and 3mL of sodium acetate solution (1M) to obtain an iron ion solution with the concentration of 0-60ppm, and drawing a standard curve at 510nm by a spectrophotometry.
Taking 4.0mL of a reaction solution sample into a 10mL volumetric flask, adding 1mL of 10% hydroxylamine hydrochloride solution, adding a corresponding amount of standard iron solution, shaking uniformly, standing for 2min, adding 1.5mL of 0.15% phenanthroline solution and 3mL of sodium acetate solution (1M), diluting with deionized water to a constant volume, and calculating the content of iron ions according to a standard curve.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or apparatus used are all conventional products commercially available, including but not limited to those used in the examples of the present application.
Example 1
The preparation method of methylnaltrexone bromide comprises the following steps:
(1) weighing 100.0g (0.26mol) of naltrexone hydrochloride, adding the naltrexone hydrochloride into a reaction bottle, stirring uniformly, weighing 433.0g (500mL) of toluene, adding the toluene into the reaction bottle, controlling the reaction temperature to be less than or equal to 30 ℃, dropwise adding 21.2g (0.53mol) of 10 wt% sodium hydroxide solution, stirring for 30min, dropwise adding 27.0g (0.265mol) of acetic anhydride, after 1h of reaction, monitoring the completion of TLC reaction (the starting material is not speckled), adjusting the pH value to 11.7 by using sodium hydroxide, layering the mixed solution, extracting the water phase by using toluene, collecting the toluene layer, and distilling to obtain an intermediate 1, namely an oily substance;
(2) adding 107.7g of oily matter (0.26mol) obtained in the step (1) into 205g (226mL) of N-methylpyrrolidone solution containing 24.1 percent (0.52mol) of methyl bromide for dissolving, cooling the solution to-15 ℃, slowly heating the solution to 60 ℃, keeping the temperature for reaction for 12 hours, monitoring the reaction by HPLC to be complete, dropwise adding 53.0g (0.26mol HBr) of 40 wt% hydrobromic acid solution, heating the solution to 80 ℃ after the dropwise adding is finished, reacting for 3 hours, monitoring the reaction by HPLC to be finished, cooling to 55 ℃, dropwise adding 228.0g (325mL) of methanol, slowly cooling to 0-5 ℃, crystallizing for 2 hours, and collecting solid to obtain crude methyl naltrexone bromide.
Example 2
The preparation method of methylnaltrexone bromide comprises the following steps:
(1) weighing 100.0g (0.2646mol) of naltrexone hydrochloride, adding the naltrexone hydrochloride into a reaction bottle, stirring the naltrexone hydrochloride uniformly, weighing 433.0g (500mL) of toluene, adding the toluene into the reaction bottle, controlling the reaction temperature to be less than or equal to 30 ℃, dropwise adding 22.5g (0.56mol) of 10 wt% sodium hydroxide solution, stirring the mixture for 30min, dropwise adding 38.0g (0.372mol) of acetic anhydride, after reacting for 1h, monitoring the completion of the TLC reaction (the starting material is not speckled), adjusting the pH value to 11.0 by using sodium hydroxide, layering the mixed solution, extracting the water phase by using toluene, collecting the toluene layer, and distilling the toluene layer to obtain an intermediate 1.
(2) Adding 107.7g of oily matter (0.26mol) obtained in the step (1) into 513g (565mL) of N-methylpyrrolidone solution containing 24.1 percent (1.3mol) of methyl bromide for dissolving, cooling the solution to-15 ℃, slowly heating the solution to 60 ℃, keeping the temperature for reaction for 12 hours, monitoring the reaction by HPLC to be complete, dropwise adding 64.0g (0.316 mol) of 40 wt% hydrobromic acid solution, heating the solution to 80 ℃ after the dropwise adding is finished, reacting for 3 hours, cooling the solution to 55 ℃, dropwise adding 515.0g (650mL) of methanol after the HPLC monitoring reaction is finished, slowly cooling the solution to 0-5 ℃, and after 2 hours of crystallization, collecting solid to obtain crude methylnaltrexone bromide. The obtained product has the following structural characteristics:
HPLC-MS characteristic peaks: m/z356.2 of [ M + H-Br]+Molecular ion Peak and [ M-Br + Na ] of M/z388.2]+Molecular ion peaks.
The IR data table is shown in Table 1:
TABLE 1IR data sheet
1The H-NMR data are shown in Table 2:
TABLE 21H-NMR data sheet
Example 3
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: adding 80.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 80mL of purified water and 190.0g (240mL) of methanol, heating and refluxing for 20min until the system is clear (the clear solution in the example indicates that the solution is clear), detecting the iron ion concentration in the solution (the detection result indicates that the solution is not detected), adding 2g of activated carbon into the solution, refluxing for 30min, filtering while the solution is hot, dropwise adding 4g (1.6g HBr) of 40 wt% hydrobromic acid solution into the solution, refluxing for 30min until the system is clear, detecting the iron ion concentration in the solution again (the detection result indicates that the solution is not detected), cooling the solution in an ice water bath to 0-5 ℃, stirring and crystallizing for 2h, performing suction filtration, washing the solid with methanol, drying under reduced pressure of below 60-70 ℃ and-0.09 MPa for 6h to obtain refined methylnaltrexone bromide 1 with the yield of 92%;
(2) and (3) secondary recrystallization: adding 70g (70mL) of purified water and 167g (210mL) of methanol into 170.6 g of refined methyhaaltrexone bromide obtained in the step (1), heating and refluxing for 20min until the system is clear, detecting the concentration of iron ions in the solution (the detection result is that the iron ions are not detected), filtering while the solution is hot, cooling the solution in an ice water bath to 0-5 ℃, stirring and crystallizing for 2h, carrying out suction filtration, washing the solid with methanol, drying the solid at 60-70 ℃ under reduced pressure of-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2, wherein the yield is 89 percent
Example 4
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: adding purified water 200mL and methanol 634.0g (800mL) into 80.0g of methylnaltrexone bromide crude product obtained by the preparation method of example 2, heating and refluxing for 20min until the system is clear, detecting the iron ion concentration in the solution (the detection result is that the iron ion concentration is not detected), adding 2g of activated carbon into the solution, refluxing for 30min, filtering while the solution is hot, dropwise adding 40 wt% hydrobromic acid solution 12.0g (4.8g HBr), refluxing for 30min until the system is clear, detecting the iron ion concentration in the solution again (the detection result is that the iron ion concentration is not detected), cooling the solution in an ice water bath to 0-5 ℃, stirring and crystallizing for 2h, performing suction filtration, washing the solid with methanol, and drying under reduced pressure of 60-70 ℃ and-0.09 MPa for 6h to obtain refined methylnaltrexone bromide 1 with the yield of 88%;
(2) and (3) secondary recrystallization: adding 162mL of purified water and 515g (650mL) of methanol into 165 g of refined methylnaltrexone bromide obtained in the step (1), heating and refluxing for 20min until the system is clear, detecting the concentration of iron ions in the solution (the detection result is that the iron ions are not detected), filtering while hot, cooling to 0-5 ℃ in an ice water bath, stirring and crystallizing for 2h, carrying out suction filtration, washing the solid with methanol, and drying under reduced pressure below 0.09MPa at 60-70 ℃ for 6h to obtain refined methylnaltrexone bromide 2 with the yield of 85%.
Example 5
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 15.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 15.0g (15mL) of purified water and 36g (45mL) of methanol are added, heating and refluxing are carried out for 20min until the system is clear, the concentration of iron ions in the solution is detected (the detection result is that the iron ions are not detected), the solution is filtered while hot, 0.75g (0.3g HBr) of 40 wt% hydrobromic acid solution is dripped into the solution, the solution is refluxed for 30min until the system is clear, the concentration of iron ions in the solution is detected again (the detection result is that the iron ions are not detected), the solution is added into an ice water bath to be cooled to 0-5 ℃, the solution is stirred and crystallized for 2h, the solution is filtered, the solid is washed by methanol, and is dried under reduced pressure of below 0.09MPa and 60-70 ℃ for 6h to obtain a refined methylnaltre;
(2) and (3) secondary recrystallization: adding 10mL of purified water and 9.7g (30mL) of methanol into 110 g of the refined methyhaaltrexone bromide obtained in the step (1), heating and refluxing for 20min until the system is clear, detecting the concentration of iron ions in the solution (the detection result is that the iron ions are not detected), filtering while the solution is hot, cooling to 0-5 ℃ in an ice water bath, stirring and crystallizing for 2h, carrying out suction filtration, washing the solid with methanol, drying under reduced pressure of below 0.09MPa at 60-70 ℃ for 6h to obtain refined methyhaaltrexone bromide 2, wherein the yield is 88%.
Example 6
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 10.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 10mL of purified water and 24g (30mL) of methanol are added, 0.35g of ferric trichloride solution (100ppm) is added to simulate the condition that the solution contains iron ions, the mixture is heated and refluxed for 20min until the system is clear, the concentration of the iron ions in the solution is detected (the detection result is 1.05ppm), 0.25g of activated carbon is added into the solution and refluxed for 30min, the solution is filtered while hot, 1.0g (0.4g HBr) of 40 wt% hydrobromic acid solution is dripped into the solution, the solution is refluxed for 30min until the system is clear, the concentration of the iron ions in the solution is detected again (the detection result is 1.1ppm), the ice water bath is cooled to 0-5 ℃, crystals are crystallized by stirring for 2h, the filtration is carried out, the solid is washed by the methanol, and is dried under reduced pressure for 6h at 60-70 ℃ and below 0.09MPa to obtain refined methylnaltrexone bromide 1, and;
(2) and (3) secondary recrystallization: and (2) adding 5g (5mL) of purified water and 12.0g (15mL) of methanol into 15.0g of the refined methyhaaltrexone bromide obtained in the step (1), adding 0.18g of ferric trichloride solution (100ppm) to simulate the condition that the solution contains iron ions, heating and refluxing for 20min until the system is clear, detecting the concentration of the iron ions in the solution (the detection result is 1.2ppm), filtering while hot, cooling to 0-5 ℃ in an ice water bath, stirring for crystallization for 2h, carrying out suction filtration, washing the solid with methanol, drying under reduced pressure at the temperature of 60-70 ℃ and the pressure of-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2 with the yield of 89%.
Example 7
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 10.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 10mL of purified water and 24g (30mL) of methanol are added, 1.85g of ferric trichloride solution (100ppm) is added under the condition that the simulated solution contains iron ions, the mixture is heated and refluxed for 20min until the system is clear, the concentration of the iron ions in the solution is detected (the detection result is 5.5ppm), 0.25g of activated carbon is added into the solution and refluxed for 30min, the solution is filtered while hot, 1.0g (0.4g HBr) of 40 wt% hydrobromic acid solution is dripped into the solution, the solution is refluxed for 30min until the system is clear, the concentration of the iron ions in the solution is detected again (the detection result is 5.4ppm), the ice water bath is cooled to 0-5 ℃, the crystals are crystallized by stirring for 2h, the filtration is carried out, the solid is washed by the methanol, and is dried under reduced pressure for 6h under the temperature of 60-70 ℃ and the MPa of less than 0.09MPa, so as;
(2) and (3) secondary recrystallization: and (2) adding 5g (5mL) of purified water and 12.0g (15mL) of methanol into 15.0g of the refined methyhaaltrexone bromide obtained in the step (1), adding 0.88g of ferric trichloride solution (100ppm) to simulate the condition that the solution contains iron ions, heating and refluxing for 20min until the system is clear, detecting the concentration of the iron ions in the solution (the detection result is 5.7ppm), filtering while hot, cooling to 0-5 ℃ in an ice water bath, stirring for crystallization for 2h, carrying out suction filtration, washing the solid with methanol, drying under reduced pressure below 60-70 ℃ and-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2 with the yield of 85%.
Example 8
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 10.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 10mL of purified water and 24g (30mL) of methanol are added, 3.5g of ferric trichloride solution (100ppm) is added to simulate the condition that the solution contains iron ions, the mixture is heated and refluxed for 20min until the system is clear, the concentration of the iron ions in the solution is detected (the detection result is 10.2ppm), 0.25g of activated carbon is added into the solution and refluxed for 30min, the solution is filtered while hot, 1.0g (0.4g HBr) of 40 wt% hydrobromic acid solution is dripped into the solution, the solution is refluxed for 30min until the system is clear, the concentration of the iron ions in the solution is detected again (the detection result is 10.2ppm), the ice water bath is cooled to 0-5 ℃, the crystals are crystallized by stirring for 2h, the filtration is carried out, the solid is washed by the methanol, and is dried under reduced pressure for 6h at 60-70 ℃ and-0.09 MPa to obtain refined methylnaltrexone bromide 1;
(2) and (3) secondary recrystallization: and (2) adding 5g (5mL) of purified water and 12.0g (15mL) of methanol into 15.0g of the refined methyhaaltrexone bromide obtained in the step (1), adding 1.4g of ferric trichloride solution (100ppm) to simulate the condition that the solution contains iron ions, heating and refluxing for 20min until the system is clear, detecting the concentration of the iron ions in the solution (the detection result is 9.6ppm), filtering while hot, cooling to 0-5 ℃ in an ice water bath, stirring for crystallization for 2h, carrying out suction filtration, washing the solid with methanol, drying under reduced pressure at 60-70 ℃ and below-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2 with the yield of 89%.
Example 9
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 10.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 10mL of purified water and 24g (30mL) of methanol are added, 7.0g of ferric trichloride solution (100ppm) is added under the condition that the simulated solution contains iron ions, the mixture is heated and refluxed for 20min until the system is clear, the concentration of the iron ions in the solution is detected (the detection result is 20.8ppm), 0.25g of activated carbon is added into the solution and refluxed for 30min, the solution is filtered while hot, 1.0g (0.4g HBr) of 40 wt% hydrobromic acid solution is dripped into the solution, the solution is refluxed for 30min until the system is clear, the concentration of the iron ions in the solution is detected again (the detection result is 20.8ppm), the ice water bath is cooled to 0-5 ℃, crystals are precipitated by stirring for 2h, the filtration is carried out, the solid is washed by the methanol, and is dried under the reduced pressure of below 0.09MPa at the temperature of 60-70 ℃ for 6h to obtain the refined methylnaltrexone;
(2) and (3) secondary recrystallization: and (2) adding 5g (5mL) of purified water and 12.0g (15mL) of methanol into 15.0g of the refined methyhaaltrexone bromide obtained in the step (1), adding 3.0g (100ppm) of ferric trichloride solution to simulate the condition that the solution contains iron ions, heating and refluxing for 20min until the system is clear, detecting the concentration of the iron ions in the solution (the detection result is 20.4ppm), filtering while hot, cooling to 0-5 ℃ in an ice water bath, stirring for crystallization for 2h, carrying out suction filtration, washing the solid with methanol, and drying under reduced pressure at the temperature of 60-70 ℃ and the pressure of-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2 with the yield of 80%.
Comparative example 1
The refining method of methylnaltrexone bromide comprises the following steps:
(1) primary recrystallization: 15.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2 is added with 15.0g (15mL) and 36g (45mL) of methanol, the mixture is heated and refluxed for 20min until the system is clear, the concentration of iron ions in the solution is detected (the detection result is that the iron ions are not detected), 0.38g of activated carbon is added into the solution and refluxed for 30min, the solution is filtered while hot, the temperature is reduced to 0-5 ℃ in an ice water bath, the mixture is stirred and crystallized for 2h, the solution is filtered, the solid is washed by methanol and dried under reduced pressure below 0.09MPa for 6h at 60-70 ℃ to obtain refined methylnaltrexone bromide 1 with the yield of 90 percent;
(2) and (3) secondary recrystallization: adding purified water 5g (5mL) and methanol 12.0g (15mL) into 15g of refined methyhaaltrexone bromide obtained in the step (1), heating and refluxing for 20min until the system is clear, detecting the concentration of iron ions in the solution (the detection result is that the iron ions are not detected), filtering while the solution is hot, cooling the solution in an ice water bath to 0-5 ℃, stirring and crystallizing for 2h, carrying out suction filtration, washing the solid with methanol, drying the solid at 60-70 ℃ under reduced pressure of-0.09 MPa for 6h to obtain refined methyhaaltrexone bromide 2, wherein the yield is 89%.
Comparative example 2
The refining method of methylnaltrexone bromide comprises the following steps:
5.0g of crude methylnaltrexone bromide obtained by the preparation method of example 2, 5g (5mL) of purified water and 12.0g (15mL) of methanol are added, heating and refluxing are carried out for 20min until the system is clear, the concentration of iron ions in the solution is detected (the detection result is that the iron ions are not detected), 0.125g of activated carbon is added into the system, after refluxing for 30min, the filtration is carried out while the system is hot, 0.25g (0.1g HBr) of 40 wt% hydrobromic acid solution is dripped into the system, refluxing is carried out for 30min until the system is clear, the concentration of iron ions in the solution is detected again (the detection result is that the iron ions are not detected), the temperature is reduced to 0-5 ℃ through an ice water bath, the crystallization is carried out for 2h by stirring, the filtration is carried out, the solid is washed by the methanol, and is dried under reduced pressure of below 60-70 ℃ and-.
Comparative example 3
5g of crude methylnaltrexone bromide refined product obtained by the preparation method of example 2 is added with 5mL of purified water and 12g (15mL) of methanol, heated and refluxed for 20min until the system is clear, the concentration of iron ions in the solution is detected (the detection result is that the iron ions are not detected), the solution is filtered while the solution is hot, the temperature is reduced to 0-5 ℃ in an ice water bath, stirred and crystallized for 2h, filtered, the solid is washed by methanol, and dried under reduced pressure below 0.09MPa at 60-70 ℃ for 6h to obtain the refined methylnaltrexone bromide product with the yield of 93%.
Examples of the experiments
Impurity content detection and purity detection were performed on the methyhaaltrexone bromide refined products finally obtained by the methyhaaltrexone bromide refining methods provided in examples 3-9 and comparative examples 1-3, according to the following chromatographic methods:
mobile phase A: water-methanol-trifluoroacetic acid (95:5:0.1)
Mobile phase B: water-methanol-trifluoroacetic acid (35:65:0.1)
Gradient elution conditions:
detection wavelength: 225nm
Flow rate: 1.5mL/min
Sample introduction amount: 20 μ L
Column temperature: 30 deg.C
The sample preparation method comprises the following steps: and (4) operating in dark, and preparing the product into a 2mg/mL solution by using 0.025mol/L sodium dihydrogen phosphate solution-methanol (volume ratio is 7:3) as a test solution. A1% test solution (v/v) was prepared as a control solution.
Sample detection: respectively and precisely measuring 20 mul of sample solution to be tested and 20 mul of reference solution to be injected and measured, and calculating the impurity content and purity according to a self-reference method.
The results are shown in Table 3.
TABLE 3 impurity content and purity of refined methyhaaltrexone bromide
As shown in table 3, the impurity content of the refined methyhaaltrexone bromide obtained in examples 3-9 is significantly reduced and the purity is significantly improved compared with the crude methyhaaltrexone bromide before refining. Compared with example 3, the reflux step of adding hydrobromic acid solution is omitted in comparative example 1, the content of impurity 1 is obviously increased (0.03% → 0.14%), and it is proved that the addition of hydrobromic acid in the first recrystallization step is more favorable for removing impurity 1 in the crude methylnaltrexone bromide. Comparative example 2 and example 3 omitted the second recrystallization step, the content of impurity 1 was slightly increased, and the content of both impurity 2 and impurity 3 was significantly increased (ND → 0.24%, 0.03% → 0.09%), demonstrating that the second recrystallization was primarily directed to removing impurity 2 and impurity 3 from the crude methylnaltrexone bromide. Comparative example 3 omits the first recrystallization step compared to example 3, the content of impurity 3 is slightly increased, and the content of both impurity 1 and impurity 2 is significantly increased (0.03% → 0.15%, ND → 0.20%), demonstrating that the first recrystallization is mainly directed to removing impurity 1 and impurity 2 from the crude methylnaltrexone bromide. Example 5 compared to example 3, which omitted the reflux step of adding activated carbon, the content of impurities 1 and 3 was slightly increased, demonstrating that the addition of activated carbon facilitates further purification of methylnaltrexone bromide. From the experimental data of examples 6-9, it can be seen that when the concentration of iron ions in the solution containing methylnaltrexone bromide is less than or equal to 10ppm, the content of impurity 3 is 0.03% -0.07%, and the limit requirement of impurity 3 is satisfied (< 0.1%), while when the concentration of iron ions exceeds 10ppm, the content of impurity 3 is obviously increased, reaching 0.44%, and the limit requirement is obviously exceeded. The result proves that the content of impurity 3 in the crude methylnaltrexone bromide product can be obviously reduced by controlling the concentration of iron ions in the solution containing methylnaltrexone bromide to be less than or equal to 10ppm in the recrystallization process.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. A refining method of methylnaltrexone bromide is characterized by comprising two recrystallization steps, and adding hydrobromic acid into a solvent for the first recrystallization, wherein the mass ratio of the methylnaltrexone bromide to the hydrobromic acid is 1: (0.02-0.06).
2. The method of purifying methylnaltrexone bromide according to claim 1, wherein the first recrystallization includes:
dissolving methylnaltrexone bromide to be refined in a solvent to obtain methylnaltrexone bromide solution;
dropwise adding hydrobromic acid into the methylnaltrexone bromide solution and refluxing;
and (3) cooling and crystallizing the solution obtained by refluxing, collecting solids, washing and drying in sequence.
3. The method for refining methylnaltrexone bromide according to claim 2, characterized in that the first recrystallization further comprises the steps of adding activated carbon to the methylnaltrexone bromide solution, refluxing, and hot filtering.
4. The refining method of methylnaltrexone bromide according to any one of claims 1 to 3, characterized in that the second recrystallization comprises:
dissolving methylnaltrexone bromide obtained by primary recrystallization in a solvent to obtain methylnaltrexone bromide solution;
and sequentially cooling and crystallizing the methylnaltrexone bromide solution, collecting solids, washing and drying.
5. The refining method of methylnaltrexone bromide according to any one of claims 1 to 4, characterized in that the solvents used for the two recrystallizations each comprise a solvent having a volume ratio of 1: (3-4) water and alcohol, wherein the mass-to-volume ratio of the methylnaltrexone bromide to the alcohol is 1: (3-10), wherein the alcohol is at least one of methanol, ethanol, n-propanol or isopropanol.
6. The method of purifying methylnaltrexone bromide according to any one of claims 1 to 5, wherein in the two recrystallization steps, the crystallization temperature is 0 to 5 ℃ and the precipitated crystals are dried under reduced pressure at 60 to 70 ℃ and a pressure of 0.09MPa or less.
7. The method of purifying methylnaltrexone bromide according to any one of claims 1 to 6, wherein the concentration of iron ions in the solution containing methylnaltrexone bromide is controlled to 10ppm or less in the two recrystallization steps.
8. The method for purifying methylnaltrexone bromide according to any one of claims 1 to 7, characterized in that the step of synthesizing methylnaltrexone bromide is as follows:
taking naltrexone hydrochloride as a starting material, and carrying out acetylation reaction on the naltrexone hydrochloride and acetic anhydride to obtain an intermediate 1;
the intermediate 1 and methyl bromide are subjected to methylation reaction to obtain an intermediate 2;
the intermediate 2 and hydrobromic acid are subjected to deprotection reaction to obtain methylnaltrexone bromide,
9. the method for refining methylnaltrexone bromide according to claim 8, wherein in the step of synthesizing the intermediate 1, the acetylation reaction is carried out under the conditions of toluene and sodium hydroxide, wherein the molar ratio of naltrexone hydrochloride, acetic anhydride, and sodium hydroxide is 1: (1-1.4): (2.0-2.1) and the reaction temperature is below 30 ℃.
10. The refining method of methylnaltrexone bromide according to claim 8 or 9, characterized in that in the step of synthesizing the intermediate 2 and methylnaltrexone bromide, the intermediate 1 is dissolved in an N-methylpyrrolidone solvent containing methyl bromide to react, hydrobromic acid is added dropwise after the reaction is completed, and methanol is added to precipitate a solid after the reaction is completed, so that methylnaltrexone bromide is obtained, wherein the molar ratio of the intermediate 1 to the methyl bromide to the hydrobromic acid is 1: (2-5): (1-1.2); the mass-to-volume ratio of the intermediate 1 to the methanol is 1: (3-6).
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