CN111303093A - Preparation method of methylnaltrexone bromide impurity - Google Patents
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- IFGIYSGOEZJNBE-LHJYHSJWSA-N (3s,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one;bromide Chemical compound [Br-].C([N@@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 IFGIYSGOEZJNBE-LHJYHSJWSA-N 0.000 title claims abstract description 37
- 229960002834 methylnaltrexone bromide Drugs 0.000 title claims abstract description 36
- 239000012535 impurity Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000012670 alkaline solution Substances 0.000 claims abstract description 6
- 238000004237 preparative chromatography Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- UHNSRFWQBVXBSK-UHFFFAOYSA-N methanol;2,2,2-trifluoroacetic acid Chemical compound OC.OC(=O)C(F)(F)F UHNSRFWQBVXBSK-UHFFFAOYSA-N 0.000 claims description 8
- 238000012856 packing Methods 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000007983 Tris buffer Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000012043 crude product Substances 0.000 description 12
- 238000000746 purification Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- LYINKTVZUSKQEQ-UHFFFAOYSA-N furan-3-one Chemical compound O=C1COC=C1 LYINKTVZUSKQEQ-UHFFFAOYSA-N 0.000 description 7
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000006105 Hofmann reaction Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 206010010774 Constipation Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 239000002623 mu opiate receptor antagonist Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
The invention relates to a preparation method of methylnaltrexone bromide impurity, the impurity has a structure shown in formula (I),
the method comprises the following steps: (1) adding methylnaltrexone bromide into an alkaline solution, wherein the concentration of the methylnaltrexone bromide is 0.01-0.1 g/ml; (2) adjusting the temperature to 100-126 ℃; (3) purifying by preparative chromatography and concentrating. The method is simple to operate, short in reaction time, and capable of directly taking the product with purity of more than 95% as a reference substance to carry out qualitative and quantitative research on methylnaltrexone bromide impurities, so that the product quality is more effectively controlled.
Description
Technical Field
The invention relates to a preparation method of methylnaltrexone bromide impurity. Belongs to the technical field of pharmaceutical chemical synthesis.
Background
Methylnaltrexone bromide was the first selective peripheral mu opioid receptor antagonist to be marketed. Opioids have found widespread clinical use in the relief of pain through specific interaction with the mu opioid receptors of the brain and spinal cord in the central nervous system. However, mu opioid drugs can act on mu opioid receptors outside the central nervous system (e.g., in the gastrointestinal tract) to cause nausea, constipation, and other adverse reactions. As a quaternary ammonium compound, methylnaltrexone bromide is limited in its ability to cross the blood brain barrier. This property allows methyhaaltrexone bromide to act as a peripheral mu opioid receptor antagonist in some tissues (e.g., the gastrointestinal tract), thereby reducing the constipation effects of the opioid without affecting the central nervous system mediated analgesic effects of the opioid.
The structure of methylnaltrexone bromide is as follows:
the methylnaltrexone bromide Hofmann impurity is one of the main impurities of methylnaltrexone bromide, and the chemical name of the methylnaltrexone bromide Hofmann impurity is as follows: (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one, of the formula:
disclosure of Invention
The invention aims to provide a preparation method of methylnaltrexone bromide impurity, which is simple to operate, short in reaction time and high in product purity of more than 95%, and can be directly used as a reference substance for qualitative and quantitative research on the methylnaltrexone bromide impurity, so that the product quality is more effectively controlled.
The technical scheme of the invention is as follows:
a process for the preparation of methylnaltrexone bromide impurity having the formula shown in formula (I):
the method comprises the following steps:
step 1: adding methylnaltrexone bromide into an alkaline solution, wherein the concentration of the methylnaltrexone bromide is 0.01-0.1 g/ml;
step 2: adjusting the temperature of the reaction solution in the step 1 to be 100-126 ℃;
and step 3: and (3) purifying the reaction liquid obtained in the step (2) by preparative chromatography, and concentrating to obtain a product shown in the formula (I).
According to the present invention, the alkaline solution in step 1 is preferably a sodium hydroxide solution, a sodium carbonate solution, or a tris solution, and more preferably a sodium hydroxide solution;
preferably, the concentration of the methylnaltrexone bromide in the step 1 is 0.02-0.05 g/ml;
according to the invention, the reaction temperature in the step 2 is preferably 120-122 ℃;
according to the present invention, preferably, the chromatographic conditions in the step 3 are:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; the detection wavelength is 280 nm.
The principle of the invention is as follows:
the methylnaltrexone bromide is sensitive under the environmental conditions of high temperature, air, high pH and the like, and the quaternary ammonium salt structure of the methylnaltrexone bromide is easy to generate Hofmann reaction to generate tertiary amine structure impurities under the high-temperature or high-pH environment.
In the research process, the invention discovers that the proper concentration of methylnaltrexone bromide solution can improve the purity of the Hofmann impurity of methylnaltrexone bromide, and the high-concentration methylnaltrexone bromide forms intramolecular salt with low solubility in alkaline solution, so that the Hofmann reaction selectivity is poor, and the impurity purity is reduced. The proper temperature is beneficial to obtaining high-purity impurities, the temperature is too low and too high, and the purity of the impurities is reduced due to poor selectivity of Hofmann reaction. Purification by preparative chromatography can further improve the purity of impurities.
Drawings
FIG. 1: column chromatography separation and purification diagram
Detailed Description
The invention discloses a preparation method of a methylnaltrexone bromide Hofmann impurity, and a person skilled in the art can appropriately improve process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The reagents used in the present invention are all commercially available.
Example 1
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Dissolving methylnaltrexone bromide 1g with water 100ml, stirring and dissolving, adjusting pH to 10 with 10% sodium hydroxide solution, placing in an autoclave, heating to 121 ℃ for reaction for about 6 hours, extracting the reaction solution with ethyl acetate, washing the ethyl acetate layer with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and removing the solvent by reduced pressure evaporation to obtain a crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; the wavelength was measured at 280nm, see FIG. 1, and the sample fractions were collected and combined, lyophilized to give a gray powder solid. HPLC purity: 97.5 percent.
1H-NMR(500NHz,DMSO-d6)δ9.12(s,1H)、δ6.61(dd,2H)、δ6.31(dd，J＝9.5,1H)、δ5.61(dd，J＝9.5,1H)、δ5.04(s,1H)、δ2.95(dt,J＝12.0,1H)、δ2.78～2.81(m,4H)、δ2.63(s,3H)、δ2.50(s,1H)、δ2.11(dt,J＝12.0,1H)、δ1.99～2.01(m,3H)、δ1.38(m,1H)、δ0.74(m,1H)、δ0.16(m,2H)、δ0.46～0.48(m,2H)。
13C-NMR(500NHz,DMSO-d6)δ210.48(1C)、δ145.06(1C)、δ142.25(1C)、δ136.42～136.35(1C)、δ127.29～127.21(1C)、δ122.53～122.43(1C)、δ124.60(1C)、δ120.53～120.47(1C)、δ118.58(1C)、δ92.21～92.02(1C)、δ75.64～75.55(1C)、δ61.07～60.87(1C)、δ52.29(1C)、δ55.49(1C)、δ40.74～40.44(1C)、δ35.98～35.85(1C)、δ34.09(1C)、δ28.86～28.68(1C)、δ6.49～6.43(1C)、δ5.02(1C)、δ4.83～4.75(1C)。MS[M+H+]:356.2。
Example 2
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Dissolving methylnaltrexone bromide 1g with water 100ml, stirring and dissolving, adjusting pH to 10 with 10% sodium hydroxide solution, placing in an autoclave, heating to 126 deg.C, reacting for about 3 hours, extracting the reaction solution with ethyl acetate, washing the ethyl acetate layer with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and removing the solvent by reduced pressure evaporation to obtain the crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; detecting the wavelength at 280nm, collecting sample component solutions, combining, and freeze-drying to obtain a gray powder solid. HPLC purity: 95.6 percent.
Example 3
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Dissolving methylnaltrexone bromide 1g with water 50ml, stirring to dissolve, adjusting pH to 10 with 10% sodium carbonate solution, placing in an autoclave, heating to 120 deg.C, reacting for about 10 hours, extracting the reaction solution with ethyl acetate, washing the ethyl acetate layer with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and removing the solvent by reduced pressure evaporation to obtain the crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; detecting the wavelength at 280nm, collecting sample component solutions, combining, and freeze-drying to obtain a gray powder solid. HPLC purity: 98.9 percent.
Example 4
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Dissolving methylnaltrexone bromide 1g with water 50ml, stirring and dissolving, adjusting pH to 10 with 1mol/L tris solution, placing in an autoclave, heating to 100 ℃ for reaction for about 10 hours, extracting the reaction solution with ethyl acetate, washing the ethyl acetate layer with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to remove the solvent to obtain a crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; detecting the wavelength at 280nm, collecting sample component solutions, combining, and freeze-drying to obtain a gray powder solid. HPLC purity: 95.3 percent.
Comparative example 1
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Stirring 1g of methylnaltrexone bromide with 10ml of water, adjusting the pH value to 14 by using 10% sodium hydroxide solution, clarifying and then turbidity the solution, placing the solution in an autoclave, heating the solution to 121 ℃ for reaction for about 10 hours, extracting the reaction solution by using ethyl acetate, washing an ethyl acetate layer by using saturated sodium chloride solution, drying the ethyl acetate layer by using anhydrous sodium sulfate, and removing the solvent by reduced pressure evaporation to obtain a crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; detecting the wavelength at 280nm, collecting sample component solutions, combining, and freeze-drying to obtain a gray powder solid. HPLC purity: and (5) 55.3%.
Comparative example 2
Synthesis of (3aR,9aR,9bS) -9b- [2- [ (cyclopropylmethyl) methylamino ] ethyl ] -1,3a,9a,9 b-tetrahydro-5, 9 a-dihydroxyphenanthro [4,5-bcd ] furan-3 (2H) -one
Stirring 1g of methylnaltrexone bromide with 5ml of water, adjusting the pH value to 14 by using 10% sodium hydroxide solution, clarifying and then turbidity the solution, heating and refluxing for reaction for about 10 hours, extracting the reaction solution by using ethyl acetate, washing an ethyl acetate layer by using saturated sodium chloride solution, drying the ethyl acetate layer by using anhydrous sodium sulfate, and removing the solvent by reduced pressure evaporation to obtain a crude product.
And (3) performing column chromatography separation and purification on the crude product:
the chromatographic conditions are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; detecting the wavelength at 280nm, collecting sample component solutions, combining, and freeze-drying to obtain a gray powder solid. HPLC purity: 55.8 percent.
Claims (5)
1. A preparation method of methylnaltrexone bromide impurity is characterized by comprising the following steps:
step 1: adding methylnaltrexone bromide into an alkaline solution, wherein the concentration of the methylnaltrexone bromide is 0.01-0.1 g/ml;
step 2: adjusting the temperature of the reaction solution in the step 1 to be 100-126 ℃;
and step 3: purifying the reaction liquid obtained in the step 2 by preparative chromatography, and concentrating to obtain methylnaltrexone bromide impurity;
the structural formula of the methylnaltrexone bromide impurity is as follows:
2. the method of claim 1, wherein: the alkaline solution in the step 1 is sodium hydroxide solution, sodium carbonate solution and tris solution.
3. The method of claim 1, wherein: the concentration of the methylnaltrexone bromide in the step 1 is 0.02-0.05 g/ml.
4. The method of claim 1, wherein: the reaction temperature in the step 2 is 120-122 ℃.
5. The method of claim 1, wherein: the chromatographic conditions in step 3 are as follows:
the chromatographic packing is C18 silica gel; the mobile phase A is 0.1% trifluoroacetic acid aqueous solution, the mobile phase B is 0.1% trifluoroacetic acid methanol solution, and a gradient elution mode is adopted, wherein the gradient mode is as follows: 0 minute to 10 minutes, the mobile phase A is 85 percent to 70 percent (V/V), and the mobile phase B is 15 percent to 30 percent (V/V); the mobile phase A is linearly reduced to 70-40% (V/V) and the mobile phase B is linearly increased to 30-60% (V/V) in 10-20 minutes; the time is 20-25 minutes, the mobile phase A is 40-0% (V/V), and the mobile phase B is 60-100% (V/V). The flow rate is 20 ml/min; the detection wavelength is 280 nm.
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Application publication date: 20200619 |