A kind of refining method of methylnaltrexone bromide

Abstract

The present invention provides a method for refining methylnaltrexone bromide. The method for refining methylnaltrexone bromide includes the steps of two recrystallizations, and hydrobromic acid is added to the solvent for the first recrystallization, and the mass ratio of the methylnaltrexone bromide to hydrobromic acid is 1: (0.02-0.06). The method for refining methylnaltrexone bromide provided by the present invention includes the steps of two recrystallizations, and the two recrystallizations can be respectively targeted for impurity removal, and the impurity content in the crude product of methylnaltrexone bromide can be significantly reduced by the two recrystallizations, and the purity of the refined product of methylnaltrexone bromide can be improved. In addition, in the steps of two recrystallizations, the iron ion concentration in the solution containing methylnaltrexone bromide is controlled to be less than 10ppm, and the impurity content in the crude product of methylnaltrexone bromide can be significantly reduced, and the present invention proposes key process control conditions for the refining of methylnaltrexone bromide.

Description

Technical Field

[0001] The invention relates to the field of chemical drug synthesis, and in particular to a method for refining methylnaltrexone bromide. Background Art

[0002] Methylnaltrexone bromide, chemically known as (R)-17-cyclopropylmethyl-4,5a-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinan bromide, is a μ opioid receptor antagonist jointly developed by Wyeth Pharmaceuticals and Progenics Pharmaceuticals. In April 2008, Health Canada and the U.S. FDA approved the marketing of methylnaltrexone bromide injection (Relistor) for the treatment of opioid-induced constipation (OIC). The chemical structure of methylnaltrexone bromide is as follows:

[0003]

[0004] Methylnaltrexone bromide is a derivative of morphinone. It is generally synthesized from naltrexone hydrochloride as a raw material through steps such as hydroxyl protection, methylation, and deprotection. The crude methylnaltrexone bromide obtained by synthesis usually contains the following impurities: (17RS)-17-(cyclopropylmethyl)-4,5α-epoxy-14-hydroxy-17-methyl-3-methoxy-6-oxomorphinan bromide (impurity 1), (17S)-cyclopropylmethyl-4,5α-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'-dimorphinan bromide (impurity 3). The chemical structure is as follows:

[0005]

[0006] The synthesized methylnaltrexone bromide needs to be refined to obtain a chemical raw material with high purity. At present, the purification of methylnaltrexone bromide mainly adopts the recrystallization method. For example, Chinese patent document (CN103626782A) provides a method for refining crude methylnaltrexone bromide: methylnaltrexone bromide is treated with C 1 -C 3For example, Chinese patent document (CN102558189A) discloses a method for refining methylnaltrexone bromide, wherein methylnaltrexone bromide is separated and purified by reverse silica gel column chromatography, and the crude methylnaltrexone bromide is recrystallized and purified by methanol, water and solvent before or after reverse silica gel column chromatography. Reverse silica gel column chromatography has the problems of large solvent consumption and difficult post-processing, and after the crude methylnaltrexone bromide is recrystallized and purified by only alcohol and water solvent, the content of impurities in the product is still high. Summary of the invention

[0007] Therefore, the technical problem to be solved by the present invention is to overcome the defects of large amount of solvent used and difficult post-treatment when using reverse silica gel column chromatography for the purification of methylnaltrexone bromide, and high impurity content after recrystallization and purification of methylnaltrexone bromide using alcohol and water solvents, thereby providing a purification method for methylnaltrexone bromide.

[0008] The invention provides a method for refining methylnaltrexone bromide, comprising the steps of two recrystallizations, wherein hydrobromic acid is added to a solvent used for the first recrystallization, and the mass ratio of the methylnaltrexone bromide to the hydrobromic acid is 1:(0.02-0.06).

[0009] Further, the first recrystallization comprises:

[0010] dissolving the methylnaltrexone bromide to be purified in a solvent to obtain a methylnaltrexone bromide solution;

[0011] adding hydrobromic acid dropwise to the methylnaltrexone bromide solution and refluxing;

[0012] The solution obtained by reflux is cooled and crystallized, and the solid is collected, washed and dried in sequence.

[0013] Furthermore, the first recrystallization further comprises the steps of adding activated carbon to the methylnaltrexone bromide solution, refluxing, and hot filtering, wherein the amount of activated carbon is 0.5%-1.5% of the mass of the methylnaltrexone bromide to be purified, and refluxing until the solution becomes clear.

[0014] Further, the second recrystallization comprises:

[0015] dissolving the methylnaltrexone bromide obtained from the first recrystallization in a solvent to obtain a methylnaltrexone bromide solution;

[0016] The methylnaltrexone bromide solution is sequentially subjected to cooling, crystallization, solid collection, washing and drying.

[0017] Furthermore, the solvents used for the two recrystallizations include water and alcohol in a volume ratio of 1:(3-4), and the mass volume ratio of methylnaltrexone bromide to alcohol is 1:(3-10) in g / mL, and the alcohol is at least one of methanol, ethanol, n-propanol or isopropanol.

[0018] Furthermore, in the two recrystallization steps, the crystallization temperature is 0-5°C, the crystallization time is 2-3h, and the precipitated crystals are dried under reduced pressure at 60-70°C and a pressure of ≤0.09MPa.

[0019] Furthermore, in the two recrystallization steps, the iron ion concentration in the solution containing methylnaltrexone bromide is controlled to be ≤10 ppm.

[0020] Furthermore, the synthesis steps of methylnaltrexone bromide are as follows:

[0021] Using naltrexone hydrochloride as the starting material, an acetylation reaction was carried out with acetic anhydride to obtain intermediate 1;

[0022] The intermediate 1 undergoes a methylation reaction with methyl bromide to obtain intermediate 2;

[0023] The intermediate 2 undergoes a deprotection reaction with hydrobromic acid to obtain methylnaltrexone bromide.

[0024]

[0025] Furthermore, 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°C.

[0026] Furthermore, 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, and hydrobromic acid is added dropwise after the reaction is completed. After the reaction is completed, methanol is added to precipitate a solid to obtain methylnaltrexone bromide, wherein the molar ratio of the intermediate 1, methyl bromide and hydrobromic acid is 1:(2-5):(1-1.2); in terms of g / mL, the mass volume ratio of the intermediate 1 to methanol is 1:(3-6).

[0027] The technical solution of the present invention has the following advantages:

[0028] 1. The method for refining methylnaltrexone bromide provided by the present invention comprises the steps of two recrystallizations, and hydrobromic acid is added to the solvent used for the first recrystallization, and the mass ratio of the methylnaltrexone bromide to the hydrobromic acid is 1:(0.02-0.06). By adding hydrobromic acid in the step of the first recrystallization, it is more conducive to removing impurity 1 in the crude methylnaltrexone bromide. By adopting the method of two recrystallizations, the first recrystallization mainly removes impurities 1 and impurity 2 in the crude methylnaltrexone bromide, and the second recrystallization is performed on the methylnaltrexone bromide obtained by the first recrystallization, mainly removing impurities 2 and impurity 3 in the crude methylnaltrexone bromide. The two recrystallizations can remove impurities respectively and in a targeted manner, and the impurity content in the crude methylnaltrexone bromide can be significantly reduced by the combination of the two recrystallizations, and the purity of the refined methylnaltrexone bromide product can be improved. The two recrystallization processes are adopted to avoid the problems of large solvent consumption and difficult post-processing caused by the use of reverse silica gel column chromatography. The method for refining methylnaltrexone bromide provided by the present invention is easy to operate and suitable for large-scale promotion and application.

[0029] 2. The method for refining methylnaltrexone bromide provided by the present invention controls the iron ion concentration in the solution containing methylnaltrexone bromide to be ≤10ppm in the steps of two recrystallizations. The applicant first discovered that the content of impurity 3 is related to the iron ion concentration in the solution containing methylnaltrexone bromide during the recrystallization process. The iron ions may be introduced by the solvent used in the recrystallization process, by the pipeline for conveying the solvent, or by other substances added during the recrystallization process. The method for controlling the iron ion concentration may be to control the iron ion content in the solvent or other substances added to the methylnaltrexone bromide recrystallization system, or to detect when the iron ion concentration in the solution containing methylnaltrexone bromide in the recrystallization system exceeds the standard and add a metal ion complexing agent to reduce the iron ion concentration. By controlling the iron ion concentration in the solution containing methylnaltrexone bromide during the recrystallization process to be ≤10ppm, the content of impurity 3 in the crude methylnaltrexone bromide can be significantly reduced. The present invention proposes key process control conditions for the refining of methylnaltrexone bromide.

[0030] 3. The method for refining methylnaltrexone bromide provided by the present invention, wherein the first recrystallization further comprises the steps of adding activated carbon and refluxing and hot filtering. By adding activated carbon and refluxing, the crude methylnaltrexone bromide can be decolorized, the clarity of the refined methylnaltrexone bromide product can be effectively improved, and impurities can be removed, so that it can be used for the preparation of methylnaltrexone bromide preparations.

[0031] 4. The method for refining methylnaltrexone bromide provided by the present invention uses naltrexone hydrochloride as a starting material, and undergoes an acetylation reaction with acetic anhydride to protect the hydroxyl group. Compared with using tert-butyldimethylchlorosilane as a protective agent, it is beneficial to purify the subsequent product. The impurities generated by tert-butyldimethylchlorosilane itself have a certain solubility in the subsequent reaction solvent, making purification difficult. Using acetic anhydride as a protective agent solves this problem. DETAILED DESCRIPTION

[0032] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0033] Sources of reagents and instruments

[0034] Reagents:

[0035] Naltrexone hydrochloride (Sanofi); toluene (PetroChina Jilin Branch); acetic anhydride and hydrobromic acid (Shanghai Wokai Biotechnology Co., Ltd.); methyl bromide (Lianyungang Dead Sea Bromide Co., Ltd.); N-methylpyrrolidone (Binzhou Yuneng Chemical Co., Ltd.); activated carbon (Shanghai Activated Carbon Plant); methanol (Tangshan Mingfeng Chemical Co., Ltd.); ferric chloride solution (1M, Aladdin); o-phenanthroline (Aladdin).

[0036] instrument:

[0037] Electric stirrer (ASONE); glass instrument (Shanghai Heqi Glass Instrument Co., Ltd.); HPLC (Agilent 1260); UV-visible spectrophotometer (Agilent Cary 3500).

[0038] The method for detecting the iron ion concentration in the solution in the following embodiments and experimental examples is as follows:

[0039] Accurately measure 0.9 mL of ferric chloride solution into a 10 mL volumetric flask, dilute to volume with deionized water, and shake well. Accurately measure 1.0 mL into a 50 mL volumetric flask, dilute to volume with deionized water, and shake well as a standard iron solution.

[0040] In a 50mL volumetric flask, add 1mL of 10% hydroxylamine hydrochloride solution (v / v) and the corresponding amount of standard iron solution, shake well and let stand for 2 minutes, then add 1.5mL of 0.15% o-phenanthroline solution (v / v) and 3mL of sodium acetate solution (1M) to make an iron ion solution with a concentration of 0-60ppm, and draw a standard curve at 510nm by spectrophotometry.

[0041] Take 4.0mL of the reaction solution sample in a 10mL volumetric flask, add 1mL of 10% hydroxylamine hydrochloride solution, add the corresponding amount of standard iron solution, shake well and let stand for 2 minutes, then add 1.5mL of 0.15% o-phenanthroline solution and 3mL of sodium acetate solution (1M), make up to volume with deionized water, and calculate the iron ion content using the standard curve.

[0042] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the art can be used. The reagents or instruments used are all conventional products that can be purchased commercially, including but not limited to the reagents or instruments used in the examples of this application.

[0043] Example 1

[0044] The preparation method of methylnaltrexone bromide comprises the following steps:

[0045] (1) Weigh 100.0 g (0.26 mol) of naltrexone hydrochloride and add it to a reaction flask, stir evenly, weigh 433.0 g (500 mL) of toluene and add it to the reaction flask, control the reaction temperature to ≤30°C, dropwise add 21.2 g (0.53 mol) of 10 wt% sodium hydroxide solution, stir for 30 min, dropwise add 27.0 g (0.265 mol) of acetic anhydride, react for 1 h, monitor the reaction completion by TLC (no spots on the starting material), adjust the pH to 11.7 with sodium hydroxide, separate the mixed solution into layers, extract the aqueous phase with toluene, collect the toluene layer, and distill to obtain intermediate 1 as an oily substance;

[0046] (2) 107.7 g (0.26 mol) of the oil obtained in step (1) was added to 205 g (226 mL) of N-methylpyrrolidone solution containing methyl bromide (mass percentage 24.1%, (0.52 mol)) to dissolve, the solution was cooled to -15°C, then slowly heated to 60°C, and the temperature was maintained for 12 h. The reaction was completed by HPLC monitoring, and 53.0 g (0.26 mol HBr) of 40 wt% hydrobromic acid solution was added dropwise. After the addition was completed, the solution was heated to 80°C and reacted for 3 h. The reaction was completed by HPLC monitoring, and the temperature was cooled to 55°C. 228.0 g (325 mL) of methanol was added dropwise, and the temperature was slowly cooled to 0°C-5°C. After crystallization for 2 h, the solid was collected to obtain a crude product of methylnaltrexone bromide.

[0047] Example 2

[0048] The preparation method of methylnaltrexone bromide comprises the following steps:

[0049] (1) Weigh 100.0 g (0.2646 mol) of naltrexone hydrochloride and add it to a reaction flask, stir evenly, weigh 433.0 g (500 mL) of toluene and add it to the reaction flask, control the reaction temperature to ≤30° C., dropwise add 22.5 g (0.56 mol) of 10 wt % sodium hydroxide solution, stir for 30 min, dropwise add 38.0 g (0.372 mol) of acetic anhydride, react for 1 h, monitor the reaction completion by TLC (no spots on the starting material), adjust the pH to 11.0 with sodium hydroxide, separate the mixed solution into layers, extract the aqueous phase with toluene, collect the toluene layer, and distill to obtain intermediate 1 as an oily substance.

[0050] (2) 107.7 g of the oily substance (0.26 mol) obtained in step (1) was added to 513 g (565 mL) of N-methylpyrrolidone solution containing methyl bromide (mass percentage 24.1%, (1.3 mol)) to dissolve, the solution was cooled to -15°C, then slowly heated to 60°C, the temperature was maintained for 12 h, the reaction was completed by HPLC monitoring, 64.0 g (0.316 mol HBr) of 40 wt% hydrobromic acid solution was added dropwise, after the addition was completed, the solution was heated to 80°C, reacted for 3 h, HPLC monitoring of the reaction was completed, the temperature was cooled to 55°C, 515.0 g (650 mL) of methanol was added dropwise, the temperature was slowly cooled to 0°C-5°C, and after crystallization for 2 h, the solid was collected to obtain a crude product of methylnaltrexone bromide. The structural characteristics of the obtained product are as follows:

[0051] HPLC-MS characteristic peak: m / z 356.2 [M+H-Br] + Molecular ion peak and m / z 388.2 [M-Br+Na] + Molecular ion peak.

[0052] The IR data table is shown in Table 1:

[0053] Table 1 IR data sheet

[0054]

[0055] 1 The H-NMR data table is shown in Table 2:

[0056] Table 2 1 H-NMR data sheet

[0057]

[0058]

[0059] Example 3

[0060] The refining method of methylnaltrexone bromide comprises the following steps:

[0061] (1) First recrystallization: 80.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 80 mL of purified water and 190.0 g (240 mL) of methanol, and heated under reflux for 20 min until the system was clear (the clear solution in the example means that the solution was clear). The iron ion concentration in the solution was detected (the detection result was: not detected). 2 g of activated carbon was added to the solution and refluxed for 30 min. The solution was filtered while hot. 4 g of 40 wt % hydrobromic acid solution (1.6 g HBr) was added dropwise to the solution, and the solution was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: not detected). The solution was cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 92%;

[0062] (2) Second recrystallization: 70.6 g of the refined methylnaltrexone bromide 1 obtained in step (1) was added with 70 g (70 mL) of purified water and 167 g (210 mL) of methanol, and the mixture was heated under reflux for 20 min until the solution was clear. The iron ion concentration in the solution was detected (the detection result was: not detected), and the mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide 2, with a yield of 89%.

[0063] Example 4

[0064] The refining method of methylnaltrexone bromide comprises the following steps:

[0065] (1) First recrystallization: 80.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 200 mL of purified water and 634.0 g (800 mL) of methanol, and heated under reflux for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: not detected). 2 g of activated carbon was added to the solution and refluxed for 30 min. The solution was filtered while hot. 12.0 g (4.8 g HBr) of 40 wt % hydrobromic acid solution was added dropwise to the solution, and the solution was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: not detected). The solution was cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 88%;

[0066] (2) Second recrystallization: 165 g of the refined methylnaltrexone bromide obtained in step (1) was added with 162 mL of purified water and 515 g (650 mL) of methanol, and the mixture was heated under reflux for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: not detected), and the mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide 2 with a yield of 85%.

[0067] Example 5

[0068] The refining method of methylnaltrexone bromide comprises the following steps:

[0069] (1) First recrystallization: 15.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 15.0 g (15 mL) of purified water and 36 g (45 mL) of methanol, and the mixture was heated and refluxed for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: not detected). The mixture was filtered while hot, and 0.75 g (0.3 g HBr) of 40 wt % hydrobromic acid solution was added dropwise to the solution. The mixture was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: not detected). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred and crystallized for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 91%;

[0070] (2) Second recrystallization: 10 g of the refined methylnaltrexone bromide 1 obtained in step (1) was added with 10 mL of purified water and 9.7 g (30 mL) of methanol, and the mixture was heated under reflux for 20 min until the solution was clear. The iron ion concentration in the solution was detected (the detection result was: not detected), and the mixture was filtered while hot. The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide 2 with a yield of 88%.

[0071] Example 6

[0072] The refining method of methylnaltrexone bromide comprises the following steps:

[0073] (1) First recrystallization: 10.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 10 mL of purified water, 24 g (30 mL) of methanol, and 0.35 g of ferric chloride solution (100 ppm) to simulate the presence of iron ions in the solution. The mixture was heated and refluxed for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: 1.05 ppm). 0.25 g of activated carbon was added to the solution and refluxed for 30 min. The solution was filtered while hot. 1.0 g of 40 wt % hydrobromic acid solution (0.4 g HBr) was added dropwise to the solution. The mixture was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: 1.1 ppm). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred and crystallized for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 89%;

[0074] (2) Second recrystallization: 5.0 g of the refined methylnaltrexone bromide 1 obtained in step (1) was added with 5 g (5 mL) of purified water and 12.0 g (15 mL) of methanol, and 0.18 g of ferric chloride solution (100 ppm) was added to simulate the situation where the solution contained iron ions. The mixture was heated under reflux for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: 1.2 ppm). The mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide 2 with a yield of 89%.

[0075] Example 7

[0076] The refining method of methylnaltrexone bromide comprises the following steps:

[0077] (1) First recrystallization: 10.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 10 mL of purified water and 24 g (30 mL) of methanol, and 1.85 g of ferric chloride solution (100 ppm) was added to simulate the situation that the solution contained iron ions, and the mixture was heated and refluxed for 20 min until the system was clear, and the iron ion concentration in the solution was detected (the detection result was: 5.5 ppm). 0.25 g of activated carbon was added to the solution and refluxed for 30 min, and the solution was filtered while hot. 1.0 g of 40 wt % hydrobromic acid solution (0.4 g HBr) was added dropwise to the solution, and the mixture was refluxed for 30 min until the system was clear, and the iron ion concentration in the solution was detected again (the detection result was: 5.4 ppm). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred and crystallized for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 88%;

[0078] (2) Second recrystallization: 5.0 g of the refined methylnaltrexone bromide product 1 obtained in step (1) was added with 5 g (5 mL) of purified water, 12.0 g (15 mL) of methanol, and 0.88 g of ferric chloride solution (100 ppm) to simulate the presence of iron ions in the solution. The solution was heated under reflux for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: 5.7 ppm). The solution was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide product 2 with a yield of 85%.

[0079] Example 8

[0080] The refining method of methylnaltrexone bromide comprises the following steps:

[0081] (1) First recrystallization: 10.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 10 mL of purified water, 24 g (30 mL) of methanol, and 3.5 g of ferric chloride solution (100 ppm) to simulate the presence of iron ions in the solution. The mixture was heated and refluxed for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: 10.2 ppm). 0.25 g of activated carbon was added to the solution and refluxed for 30 min. The solution was filtered while hot. 1.0 g of 40 wt % hydrobromic acid solution (0.4 g HBr) was added dropwise to the solution. The mixture was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: 10.2 ppm). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 87%;

[0082] (2) Second recrystallization: 5.0 g of the refined methylnaltrexone bromide product 1 obtained in step (1) was added with 5 g (5 mL) of purified water, 12.0 g (15 mL) of methanol, and 1.4 g of ferric chloride solution (100 ppm) to simulate the presence of iron ions in the solution, and heated under reflux for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: 9.6 ppm), and the solution was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide product 2 with a yield of 89%.

[0083] Example 9

[0084] The refining method of methylnaltrexone bromide comprises the following steps:

[0085] (1) First recrystallization: 10.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 10 mL of purified water and 24 g (30 mL) of methanol, and 7.0 g of ferric chloride solution (100 ppm) was added to simulate the situation that the solution contained iron ions, and the mixture was heated and refluxed for 20 min until the system was clear, and the iron ion concentration in the solution was detected (the detection result was: 20.8 ppm). 0.25 g of activated carbon was added to the solution and refluxed for 30 min, and filtered while hot. 1.0 g of 40 wt % hydrobromic acid solution (0.4 g HBr) was added dropwise to the solution, and the mixture was refluxed for 30 min until the system was clear, and the iron ion concentration in the solution was detected again (the detection result was: 20.8 ppm). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred and crystallized for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide product 1 with a yield of 80.5%;

[0086] (2) Second recrystallization: 5.0 g of the refined methylnaltrexone bromide product 1 obtained in step (1) was added with 5 g (5 mL) of purified water, 12.0 g (15 mL) of methanol, and 3.0 g of ferric chloride solution (100 ppm) to simulate the situation where the solution contained iron ions. The mixture was heated under reflux for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: 20.4 ppm). The mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide product 2 with a yield of 80%.

[0087] Comparative Example 1

[0088] The refining method of methylnaltrexone bromide comprises the following steps:

[0089] (1) First recrystallization: 15.0 g (15 mL) and 36 g (45 mL) of methanol were added to 15.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2, and the mixture was heated and refluxed for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: not detected), 0.38 g of activated carbon was added to the solution, refluxed for 30 min, filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide 1 with a yield of 90%;

[0090] (2) Second recrystallization: 5 g (5 mL) of purified water and 12.0 g (15 mL) of methanol were added to the refined methylnaltrexone bromide product 1 obtained in step (1), and the mixture was heated under reflux for 20 min until the solution was clear. The iron ion concentration in the solution was detected (the detection result was: not detected), and the mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain the refined methylnaltrexone bromide product 2 with a yield of 89%.

[0091] Comparative Example 2

[0092] The refining method of methylnaltrexone bromide comprises the following steps:

[0093] 5.0 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 5 g (5 mL) of purified water and 12.0 g (15 mL) of methanol, and the mixture was heated and refluxed for 20 min until the system was clear. The iron ion concentration in the solution was detected (the detection result was: not detected). 0.125 g of activated carbon was added to the system and refluxed for 30 min. The mixture was filtered while hot. 0.25 g of 40 wt % hydrobromic acid solution (0.1 g HBr) was added dropwise to the system. The mixture was refluxed for 30 min until the system was clear. The iron ion concentration in the solution was detected again (the detection result was: not detected). The mixture was cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol. The solid was dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide with a yield of 88%.

[0094] Comparative Example 3

[0095] 5 g of the crude methylnaltrexone bromide obtained by the preparation method of Example 2 was added with 5 mL of purified water and 12 g (15 mL) of methanol, and the mixture was heated under reflux for 20 min until the system was dissolved. The iron ion concentration in the solution was detected (the detection result was: not detected), and the mixture was filtered while hot, cooled to 0° C.-5° C. in an ice-water bath, stirred for crystallization for 2 h, filtered, and the solid was washed with methanol, and dried under reduced pressure at 60° C.-70° C. and below -0.09 MPa for 6 h to obtain a refined methylnaltrexone bromide with a yield of 93%.

[0096] Experimental example

[0097] The refined methylnaltrexone bromide obtained by the methylnaltrexone bromide purification methods provided in Examples 3-9 and Comparative Examples 1-3 was tested for impurity content and purity by the following chromatographic method:

[0098] Mobile phase A: water-methanol-trifluoroacetic acid (95:5:0.1)

[0099] Mobile phase B: water-methanol-trifluoroacetic acid (35:65:0.1)

[0100] Gradient elution conditions:

[0101]

[0102]

[0103] Detection wavelength: 225nm

[0104] Flow rate: 1.5mL / min

[0105] Injection volume: 20 μL

[0106] Column temperature: 30°C

[0107] Sample preparation method: Protect from light, prepare a 2 mg / mL solution of this product with 0.025 mol / L sodium dihydrogen phosphate solution-methanol (volume ratio 7:3) as the test solution. Prepare a 1% test solution (v / v) as the control solution.

[0108] Sample testing: Accurately measure 20 μL of the test solution and the control solution for injection and determination, and calculate the impurity content and purity by the self-control method.

[0109] The test results are shown in Table 3.

[0110] Table 3 Impurity content and purity of methylnaltrexone bromide refined products

[0111]

[0112]

[0113] As shown in Table 3, the impurity content of the refined methylnaltrexone bromide obtained in Examples 3-9 was significantly reduced compared to the crude methylnaltrexone bromide before refining, and the purity was significantly improved. Compared with Example 3, Comparative Example 1 omitted the step of adding hydrobromic acid solution for reflux, and the content of impurity 1 was significantly increased (0.03%→0.14%), proving that adding hydrobromic acid in the first recrystallization step is more conducive to removing impurity 1 in the crude methylnaltrexone bromide. Compared with Example 3, Comparative Example 2 omitted the step of the second recrystallization, and the content of impurity 1 was slightly increased, and the contents of impurity 2 and impurity 3 were significantly increased (ND→0.24%, 0.03%→0.09%), proving that the second recrystallization mainly removes impurities 2 and impurity 3 in the crude methylnaltrexone bromide. Compared with Example 3, Comparative Example 3 omitted the step of the first recrystallization, and the content of impurity 3 increased slightly, and the contents of impurity 1 and impurity 2 increased significantly (0.03%→0.15%, ND→0.20%), proving that the first recrystallization mainly removes impurities 1 and impurity 2 in the crude methylnaltrexone bromide. Compared with Example 3, Example 5 omitted the step of adding activated carbon for reflux, and the contents of impurity 1 and impurity 3 increased slightly, proving that adding activated carbon is beneficial to the further purification of methylnaltrexone bromide. It can be seen from the experimental data of Examples 6-9 that when the iron ion concentration in the solution containing methylnaltrexone bromide is ≤10ppm, the content of impurity 3 is 0.03% to 0.07%, meeting the limit requirement of impurity 3 (<0.1%), and when the iron ion concentration exceeds 10ppm, the content of impurity 3 increases significantly, reaching 0.44%, which obviously exceeds the limit requirement. It is proved that by controlling the iron ion concentration in the solution containing methylnaltrexone bromide to ≤10ppm during the recrystallization process, the content of impurity 3 in the crude methylnaltrexone bromide can be significantly reduced.

[0114] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for refining methylnaltrexone bromide, It is characterized in that The method comprises the steps of two recrystallizations, and hydrobromic acid is added to the solvent used for the first recrystallization, and the mass ratio of methylnaltrexone bromide to hydrobromic acid is 1:(0.02-0.06); In the two recrystallization steps, when the iron ion concentration in the solution containing methylnaltrexone bromide exceeds 10 ppm, the iron ion concentration in the solution containing methylnaltrexone bromide needs to be controlled to be ≤ 10 ppm, and the iron ions are introduced by the solvent used in the recrystallization process, and / or introduced by the pipeline for conveying the solvent, and / or introduced by other raw materials added in the recrystallization process; The first recrystallization includes: dissolving the methylnaltrexone bromide to be purified in a solvent to obtain a methylnaltrexone bromide solution; adding hydrobromic acid dropwise to the methylnaltrexone bromide solution and refluxing; The refluxed solution is sequentially cooled for crystallization, solids are collected, washed and dried; The second recrystallization includes: dissolving the methylnaltrexone bromide obtained from the first recrystallization in a solvent to obtain a methylnaltrexone bromide solution; The methylnaltrexone bromide solution is sequentially subjected to cooling and crystallization, solid collection, washing and drying; The synthesis steps of the crude methylnaltrexone bromide are as follows: (1) Weigh 100.0 g of naltrexone hydrochloride and add it to a reaction flask, stir evenly, weigh 433.0 g of toluene and add it to the reaction flask, control the reaction temperature to ≤30° C., dropwise add 22.5 g of 10 wt % sodium hydroxide solution, stir for 30 min, dropwise add 38.0 g of acetic anhydride, react for 1 h, and after TLC monitoring, adjust the pH to 11.0 with sodium hydroxide after the reaction is complete. The mixed solution is separated, the aqueous phase is extracted with toluene, and the toluene layer is collected and distilled to obtain intermediate 1 as an oily substance; (2) 107.7 g of the oil obtained in step (1) was added to 513 g of a 24.1% by weight methyl bromide-containing N-methylpyrrolidone solution to dissolve, the solution was cooled to -15°C, then slowly heated to 60°C, and the temperature was maintained for 12 h. After the reaction was completed by HPLC monitoring, 64.0 g of a 40 wt% hydrobromic acid solution was added dropwise. After the addition was completed, the solution was heated to 80°C and reacted for 3 h. After the reaction was completed by HPLC monitoring, the solution was cooled to 55°C, 515.0 g of methanol was added dropwise, and the temperature was slowly cooled to 0°C-5°C. After crystallization for 2 h, the solid was collected to obtain a crude methylnaltrexone bromide.

2. The method for refining methylnaltrexone bromide according to claim 1, It is characterized in that The first recrystallization further comprises the steps of adding activated carbon to the methylnaltrexone bromide solution, refluxing, and hot filtering.

3. The method for refining methylnaltrexone bromide according to claim 1, It is characterized in that The solvents used for the two recrystallizations include water and alcohol in a volume ratio of 1:(3-4), and the mass volume ratio of the methylnaltrexone bromide to the alcohol is 1:(3-10) in g / mL, and the alcohol is at least one of methanol, ethanol, n-propanol or isopropanol.

4. The method for refining methylnaltrexone bromide according to claim 1, It is characterized in that In the two recrystallization steps, the crystallization temperature is 0-5°C, and the precipitated crystals are dried under reduced pressure at 60-70°C and a pressure of ≤0.09 MPa.

Images