WO2020015659A1 - 罗库溴铵粗品的精制方法 - Google Patents

罗库溴铵粗品的精制方法 Download PDF

Info

Publication number
WO2020015659A1
WO2020015659A1 PCT/CN2019/096224 CN2019096224W WO2020015659A1 WO 2020015659 A1 WO2020015659 A1 WO 2020015659A1 CN 2019096224 W CN2019096224 W CN 2019096224W WO 2020015659 A1 WO2020015659 A1 WO 2020015659A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
rocuronium bromide
crude
drying
ether
Prior art date
Application number
PCT/CN2019/096224
Other languages
English (en)
French (fr)
Inventor
王加旺
Original Assignee
济南高德医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 济南高德医药科技有限公司 filed Critical 济南高德医药科技有限公司
Priority to JP2021525354A priority Critical patent/JP7279900B2/ja
Priority to EP19838199.8A priority patent/EP3819304B1/en
Priority to US17/261,281 priority patent/US11466049B2/en
Publication of WO2020015659A1 publication Critical patent/WO2020015659A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps

Definitions

  • the invention relates to the field of medicine, in particular to a method for refining crude rocuronium bromide.
  • Rocuronium injection is a muscle relaxant widely used clinically.
  • the residual solvent in the drug substance must be less than a certain content in order to qualify for medicinal use.
  • the content of methylene chloride in the second class of solvents should not be higher than 600 ppm
  • acetonitrile should not be higher than 410 ppm
  • methanol should not be higher than 3000 ppm.
  • the three types of solvents such as ether, methyl acetate, ethyl acetate, and acetone should not be higher than 5000 ppm.
  • Organic solvents are inevitably used in the preparation of rocuronium bromide, and the residual solvents used as raw materials of rocuronium bromide for pharmaceutical use must meet these requirements.
  • the present application provides a method for refining a crude rocuronium bromide, by which a high-quality rocuronium bromide refined product with a residual solvent that satisfies medical requirements can be obtained.
  • rocuronium bromide generally uses epiandrostenone as the starting material, and most of them require 7-9 steps of chemical reaction to complete.
  • epiandrostenone For specific operating procedures, please refer to the documents US20060058275A1, US4894369, US20050159398, CN201180045999.6, CN201610028808.X, CN200710092747.4, Recorded in GB2445764. It can be seen from all the published literatures that although the synthesis reaction in the first few steps may be different, the last step is to use the rocuronium intermediate "monoester" (CAS No.
  • the solvent used in the reaction is generally a dipolar aprotic solvent, such as dichloromethane, acetonitrile, etc .; the reaction temperature is 10 to 40 ° C, and the reaction time is 5 to 24 hours. Those skilled in the art can adjust the experimental parameters according to the actual situation, such as material ratio, reaction temperature, time and so on.
  • rocuronium bromide crude the amount of rocuronium bromide that exceeds the requirements as API (API) is called "rocuronium bromide crude", which can refer to rocuronium bromide containing too much solvent.
  • the ammonium solid material can also be rocuronium bromide slurry or paste containing too much solvent, and it can also refer to the reaction solution in the last step of the rocuronium bromide synthesis process.
  • the first is to use a solution of rocuronium bromide (the solvent is a non-polar dipolar proton solvent such as dichloromethane, acetonitrile, and acetone).
  • Rocuronium bromide solid was obtained by antisolvent crystallization with diethyl ether as an anti-solvent.
  • the main residual solvent contained in the crude rocuronium bromide was diethyl ether, and then vacuum drying was performed to reduce the ether to meet the pharmaceutical standards.
  • Another method is to mix and crystallize the rocuronium bromide solution and the anti-solvent to obtain the crude rocuronium bromide, then dissolve the solid in a large amount of water, and reduce the residual solvent by freeze-drying.
  • the anti-solvent used in the second method can also use other safer solvents with higher boiling points. For example: ethyl acetate, butyl acetate, hexane, heptane, methyl tert-butyl ether, etc.
  • the first method mentioned above is to crystallize the crude product with an anti-solvent and dry it under vacuum.
  • diethyl ether can be used as the anti-solvent.
  • Other solvents will not work.
  • the boiling point of diethyl ether is only 36 ° C
  • the rocuronium bromide is precipitated with diethyl ether as an anti-solvent
  • the ether and rocuronium molecules will combine to form a solvate.
  • vacuum drying it must be dried for a long time (usually more than 5 days, or even 10 days or more) under the conditions of high vacuum above 37 ° C to barely make the residual ether reach the pharmaceutical standard requirement of 5000ppm or less.
  • a serious disadvantage of using ether is that it is very flammable and explosive. Therefore, although diethyl ether is not absolutely prohibited in the production of APIs, it is generally used only when the amount is not large and no other solvents are available. However, if rocuronium bromide is produced by antisolvent crystallization with ether, the amount of ether is very large. For example, the production of 10 kg of rocuronium bromide usually requires 1100L or more ether, so there is a serious safety hazard in the production process; The used rocuronium bromide raw materials need to be carried out in a closed clean area according to GMP requirements, which further increases the degree of danger. For projects with a relatively large amount of ether, the management department often does not approve the construction in consideration of safety issues, especially under the current stricter EHS (environmental protection, safety, health) requirements.
  • EHS environmental protection, safety, health
  • solvents with slightly higher boiling points that can be used in the production of rocuronium bromide, such as dichloromethane, n-hexane, methyl acetate, ethyl acetate, butyl acetate, isopropyl
  • the conventional vacuum drying method cannot remove it to meet the medicinal level; if the final step in the production process of rocuronium bromide
  • the solvent used is methyl tert-butyl ether and ethyl acetate.
  • the solvent in the crude rocuronium bromide can be removed by the freeze-drying method as described in the documents CN200710092747.4, GB2445764, US20060058275A1 to meet pharmaceutical standards, the residual solvent is removed by the freeze-drying method to obtain the rocuronium bromide in rocuronium bromide.
  • Impurity C is generally relatively large and difficult to control below 0.1%. It is generally close to the upper limit of 0.2% required by the standard, and it will exceed 0.2% if it is not careful, exceeding EP8.0 (European Pharmacopeia 8.0, European Pharmacopoeia, Eighth Edition). The upper limit of the standard (0.2%).
  • rocuronium bromide is an acetate, which is easy to hydrolyze in the presence of water.
  • the crude rocuronium bromide In the freeze-drying operation, the crude rocuronium bromide must first be dissolved in a large amount of water. The amount of impurity C will increase due to hydrolysis. Big.
  • the freeze-drying method has high energy consumption, large space occupied by equipment, and large equipment investment. Under the same production scale, the investment in freeze-drying equipment exceeds the cost of implementing this application by 10 times.
  • the present application provides a method for refining a crude rocuronium bromide, which method comprises using a vacuum microwave drying method or a fluidized drying method to remove the residual solvent in the crude rocuronium bromide, so as to meet the medical requirements.
  • This method not only overcomes the difficulties mentioned above, but also has simple operation, environmental protection, low cost and significant effect.
  • the method includes using a solvent a to replace the residual solvent in the crude rocuronium bromide with vacuum microwave drying of the crude rocuronium bromide containing the a solvent.
  • the method includes: mixing a solvent and a crude rocuronium bromide into a rocuronium bromide-containing liquid, and the liquid is solidified by vacuum microwave (vacuum Microwave curing), and then continue to vacuum microwave drying and / or use other drying methods to make the solvent and moisture reach a level that meets medical requirements.
  • vacuum microwave vacuum Microwave curing
  • the vacuum microwave curing described in the text means that the vacuum microwave is carried out to a certain degree, and the liquid material to be processed is formed into a solid due to the evaporation of the solvent.
  • the residual solvent in the rocuronium bromide sample is generally relatively large and does not meet the requirements of pharmaceutical standards.
  • vacuum microwave drying and / or other drying methods should be used for processing.
  • the a solvent is a polar solvent with strong microwave absorption capability. It may further be selected from C 1 ⁇ C 4 monohydric alcohols, one or more C monobasic acids, acetone, methyl ethyl ketone, tetrahydrofuran and water of 1 ⁇ C 3.
  • the a solvent that can be implemented is not limited to this. Those skilled in the art can select or try other feasible solvents while using the present invention according to the disclosure of this application. It should be known that this simple solvent exploration is based on the routine of the present invention. The choice should also be included in the protection scope of this application.
  • the solvent is a monohydric alcohol selected from C 1 ⁇ C 3, and C of one or more monobasic acids 1 ⁇ C 3 as acetone, methyl ethyl ketone, tetrahydrofuran and water.
  • the solvent is a selected from one or more of methanol, ethanol, isopropanol, C 1 ⁇ C 3 one yuan acid, acetone, tetrahydrofuran and water.
  • the solvent is a selected from one or more of methanol, ethanol, C monobasic acids 1 ⁇ C 3 as acetone, methyl ethyl ketone, tetrahydrofuran and water; or, in certain embodiments, The a solvent is selected from one or more of methanol, C 1 to C 3 monobasic acid, acetone, and water; or, in some embodiments, the a solvent is selected from C 1 to C 3 monohydric alcohol Or formic acid, acetic acid, acetone, and water; or, in certain embodiments, the a solvent is selected from one or more of methanol, ethanol, formic acid, acetic acid, propionic acid, acetone, and water Or, in certain embodiments, the a solvent is selected from one or more of methanol, ethanol, isopropanol, formic acid, acetic acid, acetone, and water; or, in certain embodiments, the a The solvent is selected from one or more of methanol,
  • rocuronium bromide is easily hydrolyzed and unstable in the presence of water, which can be stabilized by adding acetic acid.
  • acetic acid due to the relatively high boiling point of acetic acid, it is difficult to remove, and it will inevitably remain in the product. . Therefore, the amount of appropriate acetic acid must be controlled to ensure that the acetic acid content in the final refined rocuronium bromide product does not exceed the 5% (mass percentage, w / w: that is, the upper limit of the USP38 (United States States Pharmacopoeia 38) standard) 100g of Roku API contains acetic acid within 5g) or other special requirements.
  • the amount of the acetic acid added may exceed 5% (V / V), but generally does not exceed the solvent a. 8% (V / V) of the total amount to further control the content of acetic acid in the final product does not exceed 5% (W / W) of the upper limit of the USP standard.
  • the vacuum degree of the vacuum microwave is -0.01 to -0.1Mpa, or further -0.01 to -0.099Mpa, further -0.01 to -0.08Mpa, further -0.01 to -0.07Mpa, further -0.01 to -0.06Mpa, or further -0.06 to -0.1Mpa, further -0.06 to -0.099Mpa, further -0.06 to -0.09Mpa, further -0.06 to -0.089Mpa, further -0.06 to -0.08Mpa, further -0.06 to -0.079Mpa, further -0.06- to -0.07Mpa, or further -0.07 to -0.01Mpa, further -0.07 to -0.099Mpa , Further -0.07 to -0.09Mpa, further -0.07 to -0.089Mpa, further -0.07 to -0.089Mpa, further -0.07 to
  • the temperature of the vacuum microwave is 10 to 60 ° C, for example, it may be 10 ° C, 15 ° C, 20 ° C, 25 ° C, 30 ° C, 35 ° C, 40 ° C. , 45 ° C, 50 ° C, 55 ° C, or 60 ° C, or further 10 to 50 ° C, 20 to 50 ° C, or 10 to 40 ° C or 20 to 40 ° C, or 30 to 40 ° C, or even more It is 25 to 36 ° C.
  • the temperature range described in the embodiments of the present application, such as 43 ° C or lower, 40 ° C or lower, or 36 ° C or lower, is applicable to the definition of temperature herein.
  • the other drying method may be a drying method generally used by those skilled in the art, or may be selected from one or more of a reduced-pressure (vacuum) drying method, an air-flow drying method, and a fluidized drying method. But it is not limited to this, it should be known to those skilled in the art that based on the disclosure of this application, the ability to select other drying methods based on the methods of this application.
  • the air-blast drying method described in this article is to place solid materials in a sealed device capable of inlet and outlet, maintaining a certain temperature inside the device, allowing air or inert gas to enter and flow out of the device.
  • the solid materials are placed in the tray of the vacuum oven shelf, and a certain temperature is maintained to allow air or inert gas to enter and exit the oven.
  • inert gas is better, especially when the moisture content of the material is high, air may be used. Can cause oxidation and discoloration of the product.
  • the method includes: mixing a solvent and a crude rocuronium bromide into a rocuronium bromide-containing liquid, and the liquid is solidified by vacuum microwave (vacuum Microwave curing), and then continue to vacuum microwave drying and / or use air-flow drying to process the solvent and moisture to a level that meets medical requirements.
  • vacuum microwave vacuum Microwave curing
  • the vacuum drying can be continued under aeration to remove moisture.
  • the crude rocuronium bromide may be vacuum-treated in a vacuum drying box.
  • the vacuum microwave is performed to a certain degree, and the crude rocuronium bromide will solidify. At this time, the crude solid rocuronium bromide still contains residual solvents and moisture. If it fails to meet the requirements of pharmaceutical standards, it can continue to perform vacuum microwave drying. It can also use air-flow drying, vacuum drying, fluidized drying, or a combination of these methods.
  • the air-blast drying method described here is to place solid materials in a sealed device capable of inlet and outlet, and maintain a certain temperature in the device to allow gas to enter and flow out of the device. For example, the solid material is placed in a tray on a vacuum oven shelf, and a certain temperature is maintained to allow air or inert gas to enter and exit the oven.
  • the liquid obtained by mixing the crude rocuronium bromide and the microwave-absorbent solvent a can be processed in a short time by vacuum microwave treatment (for example, in some embodiments, for 10 to 25 minutes, further to 10 ⁇ 20min, such as 10min, 12min, 14min, 15min, 16min, 17min, 18min, 19min, 20min, 23min, 25min, any temperature range between any two of these temperatures), lower temperature (such as some implementations 10 to 60 ° C. in the embodiment, or 20 to 40 ° C. in some embodiments, or 25 to 36 ° C. in some embodiments) to solidify. Then continue to use vacuum microwave to make its solvent meet the pharmaceutical standards. After the solid is obtained, it can also be combined with other drying methods (such as one or more of air-flow blowing, vacuum drying, and fluidized drying methods), so that the residual solvent contained in it can meet the standards of the drug substance.
  • other drying methods such as one or more of air-flow blowing, vacuum drying, and fluidized drying methods
  • the temperature used for other drying methods cannot exceed 60 ° C, generally does not exceed 43 ° C, and further does not exceed 36 ° C.
  • the solid obtained after the vacuum microwave curing can be moved into a small vacuum drying box (such as DZF-6050 vacuum drying box) for subsequent air-flow drying with the belt; if the production scale is relatively large, it can be used
  • the industrially larger vacuum drying box or double cone rotary dryer is used for air-flow drying. During the drying process, keep the box (material) at a certain temperature (generally 26 ⁇ 43 ° C). Blow the belt with nitrogen, argon, carbon dioxide or air. It can also be vacuum dried or used in combination.
  • the effect of removing solvents can be increased by maintaining a certain humidity of the material or system.
  • the power of the vacuum microwave can be adjusted according to the amount of the material to be dried, the suction rate of the air pump during the drying process and / or its ultimate vacuum degree, and the conditions of the drying process.
  • high power is generally required in the early stage of the drying process due to the high solvent content
  • low power is generally required in the late stage of the drying process due to the low solvent content.
  • the power of the microwave when 200 grams of materials are dried at one time, the power of the microwave is changed from 300 to 800W; when 6 to 8kg of materials are dried at one time, the power of the microwave is changed from 1000 to 20,000W.
  • the method includes fluid drying the crude rocuronium bromide with diethyl ether as a main residual solvent.
  • the crude rocuronium bromide with diethyl ether as the main residual solvent described herein is the crude rocuronium bromide with diethyl ether as the main residual solvent or is processed so that the crude rocuronium bromide as defined above becomes the main residual solvent with diethyl ether.
  • Rocuronium crude is the crude rocuronium bromide with diethyl ether as the main residual solvent or is processed so that the crude rocuronium bromide as defined above becomes the main residual solvent with diethyl ether.
  • Diethyl ether as the main residual solvent described herein means that the content of diethyl ether as the residual solvent exceeds the standard to be used, and other residual solvents have passed or are nearly qualified; for example, if the residual solvents are diethyl ether and dichloromethane, according to ICH ( The International Council for Harmonization (Guidelines for the International Coordination Meeting of Technical Requirements for the Registration of Human Drugs) Guidelines.
  • the amount of ether should not be higher than 5000 ppm, and the amount of dichloromethane should be not higher than 600 ppm.
  • the ether described here is the main residual solvent.
  • the amount is higher than 5000 ppm, and may even be 100 times higher than this value, that is, 500,000 ppm, and the amount of methylene chloride is lower than 600 ppm or close to 600 ppm, such as 610 ppm or 620 ppm.
  • the crude rocuronium bromide using ether as the main residual solvent described in the present application is an antisolvent crystallization method such that the crude rocuronium bromide as defined above becomes The crude rocuronium bromide with diethyl ether as the main residual solvent.
  • the method comprises subjecting the crude rocuronium bromide to anti-solvent crystallization to the main residual solvent contained in the crude rocuronium bromide as ether, followed by fluid drying.
  • the antisolvent crystallization method includes dissolving the crude rocuronium bromide in solvent b to prepare a crude rocuronium bromide solution, and preparing the crude rocuronium bromide solution by mixing it with the solvent c. Rocuronium crude solid.
  • the solvent b is a dipolar aprotic solvent; further, the solvent b is a solvent capable of dissolving rocuronium bromide. Further, the solvent b is selected from the group consisting of methylene chloride, acetonitrile, acetone, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), and N, N-dimethylacetamide. One or more. Further, the solvent b is selected from one or more of dichloromethane, acetonitrile, acetone, and DMSO. Further dichloromethane.
  • the solvent c is an anti-solvent, and is further a solvent insoluble or slightly soluble with rocuronium bromide; further, the solvent c is ether or non-ether Solvent; further, the non-ether solvent is selected from the group consisting of isopropyl ether, methyl tert-butyl ether, methyl acetate, ethyl acetate, butyl acetate, propyl acetate, cyclohexane, n-hexane, and n-heptane Further, the non-ether solvent is selected from one or more of methyl tert-butyl ether, methyl acetate, ethyl acetate, and n-hexane; further, the non-ether solvent It is methyl tert-butyl ether, methyl acetate, ethyl acetate or n-hexane.
  • the method includes dissolving the crude rocuronium bromide in solvent b to prepare a crude rocuronium bromide solution, and mixing the crude rocuronium bromide solution and the solvent c.
  • Rocuronium crude solid was prepared and then fluidized to dryness.
  • the solvent c is diethyl ether
  • the method includes dissolving the crude rocuronium bromide in solvent b to prepare a crude rocuronium bromide solution, and the crude rocuronium bromide solution and the solvent. c.
  • the crude solid rocuronium bromide was mixed and then fluidized to dryness.
  • the ether in the crude rocuronium bromide can be relatively easily removed by the fluid drying method, but it is difficult to remove other solvents (such as ethyl acetate, methyl acetate) in the crude rocuronium bromide. , N-hexane, methyl tert-butyl ether, etc.).
  • the solvent c is non-ether
  • the method includes dissolving the crude rocuronium bromide in the solvent b to prepare a crude rocuronium bromide solution, and the crude rocuronium bromide solution and Solvent c was mixed to prepare a crude solid rocuronium bromide. The solid was washed with diethyl ether and then fluidized to dryness.
  • the fluidized drying described in the present application is also referred to as boiling drying; the equipment used is a fluidized bed dryer (such as XF series boiling dryers XF10, XF20, XF30, etc.), vibrating flow Fluidized bed dryer (such as ZLG series vibrating fluidized bed dryer) and so on.
  • a fluidized bed dryer such as XF series boiling dryers XF10, XF20, XF30, etc.
  • vibrating flow Fluidized bed dryer such as ZLG series vibrating fluidized bed dryer
  • the material particles are turned up and down in the air flow, mixed and collided, and fully contacted, and the drying efficiency is very high.
  • the gas passing through the material is removed by bag dust removal or cyclone separator to recover the entrained dust and leave; dried qualified products overflow from the discharge port.
  • the gas used in the present application when performing fluidized drying may be an inert gas (such as nitrogen, carbon dioxide, argon) or air.
  • the temperature used for the drying is 15 to 70 ° C.
  • it may be 15 ° C, 20 ° C, 25 ° C, 30 ° C, 35 ° C, 40 ° C, 45 ° C. , 50 ° C, 55 ° C, 60, 65 ° C, or 70 ° C; further 15 to 60 ° C, still more 15 to 50 ° C or 25 to 50 ° C, and still more 30 to 37 ° C.
  • the flow velocity of the gas stream in the fluidized drying method is not particularly required, but it is preferably large enough to keep the materials in a sufficient fluidized state, so that the materials and the gas can be fully contacted, so that the materials frictionally collide with each other. So that the solvent is taken away as soon as possible. Low air velocity will greatly extend the solvent removal time.
  • a non-ether solvent c is used (the selection of the non-ether solvent is as described above, for example, ethyl acetate, methyl acetate, n-hexane, Methyl tert-butyl ether, etc.) as a reverse crystallization solvent, it is difficult to remove these high-boiling solvents c in the subsequent use of fluid drying to make them meet the medical requirements; therefore, these high-boiling solvents c must be washed with ether Subsequent fluid drying is performed.
  • the solvent c is non-ether
  • the method includes dissolving the crude rocuronium bromide in the solvent b to prepare the crude rocuronium bromide.
  • Solution, the crude rocuronium bromide solution and the solvent c are mixed to prepare a crude rocuronium bromide solid, and then a solvent and the crude rocuronium bromide solid are mixed into a liquid containing rocuronium bromide, and the liquid is subjected to vacuum microwave dry.
  • the non-ether solvent can be reduced to a certain extent by concentration under reduced pressure or gas blowing before vacuum microwave.
  • the method includes dissolving the crude rocuronium bromide in solvent b to prepare a crude rocuronium bromide solution, and mixing the crude rocuronium bromide solution and the solvent c to prepare rocuronium bromide.
  • the crude solid is then mixed with the solvent a and the crude rocuronium bromide to form a liquid containing rocuronium bromide.
  • the liquid is solidified by vacuum microwave.
  • the vacuum microwave drying and / or other drying methods are used to treat the liquid. Solvents and moisture reach levels that meet medicinal requirements.
  • the non-ether solvent can be reduced to a certain extent by concentration under reduced pressure or gas blowing before vacuum microwave.
  • the solvent a may be selected from the group consisting of methanol, ethanol, water, isopropanol, butanol, acetone, methyl ethyl ketone, tetrahydrofuran, and formic acid. Or more of acetic acid, propionic acid, and further selected from one or more of methanol, acetic acid, formic acid, water, and acetone.
  • rocuronium bromide is easily hydrolyzed and unstable in the presence of water, which can be stabilized by adding acetic acid.
  • acetic acid due to the relatively high boiling point of acetic acid, it is difficult to remove, and it will inevitably remain in the product. . Therefore, the amount of appropriate acetic acid must be controlled to ensure that the acetic acid content in the final refined rocuronium bromide product does not exceed the 5% (mass percentage, w / w: that is, the upper limit of the USP38 (United States States Pharmacopoeia 38) standard) 100g of Roku API contains acetic acid within 5g) or other special requirements.
  • the amount of the acetic acid added may exceed 5% (V / V), but generally does not exceed the solvent a. 8% (V / V) of the total amount to further control the content of acetic acid in the final product does not exceed 5% (W / W) of the upper limit of the USP standard.
  • the vacuum microwave is performed to a certain degree, and the crude rocuronium bromide will solidify. At this time, the crude solid rocuronium bromide still contains residual solvents and moisture. If it fails to meet the requirements of pharmaceutical standards, it can continue to perform vacuum microwave drying. It can also use air-flow drying, vacuum drying, fluidized drying, or a combination of these methods.
  • the air-blast drying method described here is to place solid materials in a sealed device capable of inlet and outlet, and maintain a certain temperature in the device to allow gas to enter and flow out of the device. For example, the solid material is placed in a tray on a vacuum oven shelf, and a certain temperature is maintained to allow air or inert gas to enter and exit the oven.
  • the liquid obtained by mixing the crude rocuronium bromide and the microwave-absorbent solvent a can be processed in a short time by vacuum microwave treatment (for example, in some embodiments, for 10 to 25 minutes, further for 10 ⁇ 20min, for example, 10min, 12min, 14min, 15min, 16min, 17min, 18min, 19min, 20min, 23min, or 25min), lower temperature (such as 10 ⁇ 60 °C in some embodiments, or (20 to 40 ° C in some embodiments, or 25 to 36 ° C in other embodiments) to solidify.
  • vacuum microwave to make its solvent meet the pharmaceutical standards.
  • it can also be combined with other drying methods (such as air-flow blowing, vacuum drying, fluidized drying) to make the residual solvent contained in it meet the standard of the drug substance.
  • the temperature used for other drying methods cannot exceed 60 ° C, generally does not exceed 43 ° C, and further does not exceed 36 ° C.
  • the solid obtained after the vacuum microwave curing can be moved into a small vacuum drying box (such as DZF-6050 vacuum drying box) for subsequent air-flow drying with the belt; if the production scale is relatively large, it can be used
  • the industrially larger vacuum drying box or double cone rotary dryer is used for air-flow drying. During the drying process, keep the box (material) at a certain temperature (generally 26 ⁇ 43 ° C). Blow the belt with nitrogen, argon, carbon dioxide or air. It can also be vacuum dried or used in combination.
  • the effect of removing solvents can be increased by maintaining a certain humidity of the material or system.
  • the vacuum degree of vacuum microwave drying and the temperature of vacuum microwave drying may be as described above, for example, the vacuum degree of vacuum microwave drying is -0.01 to -0.1Mpa, or in some embodiments, it is further -0.06. ⁇ -0.1Mpa, or -0.08 ⁇ -0.099Mpa in some embodiments; for example, in some embodiments, the temperature of vacuum microwave drying may be 10 ⁇ 60 ° C, or in some embodiments, it is further 20 to 60 ° C, or further 20 to 40 ° C in other embodiments, or 30 to 40 ° C in still other embodiments, or 25 to 36 ° C in still other embodiments.
  • the power of the vacuum microwave can be adjusted according to the amount of the material to be dried, the suction rate of the air pump during the drying process and / or its ultimate vacuum degree, and the conditions of the drying process.
  • high power is generally required in the early stage of the drying process due to the high solvent content
  • low power is generally required in the late stage of the drying process due to the low solvent content.
  • the power of the microwave when 200 grams of materials are dried at one time, the power of the microwave is changed from 300 to 800W; when 6 to 8kg of materials are dried at one time, the power of the microwave is changed from 1000 to 20,000W.
  • the refining method of the present application does not substantially destroy the structure of the rocuronium molecule during the process of removing the residual solvent.
  • the related substances in the finished rocuronium bromide obtained after the vacuum microwave drying method operation and subsequent drying treatment of the present application are generally relatively low; in the present application
  • the content of impurity A is found to decrease after the refining is completed.
  • the related substances can meet EP8.0 (European Pharmacopoeia 8th Edition) and / or USP38 (United States Pharmacopoeia 38th Edition)
  • EP8.0 European Pharmacopoeia 8th Edition
  • USP38 United States Pharmacopoeia 38th Edition
  • the required high-quality rocuronium bromide (finished product) in most cases the relevant substance can reach less than 0.1%, and the total content of known and unknown impurities generally does not exceed 0.4%; the main product rocuronium bromide content is in accordance with US standards
  • the detection can generally reach more than 99.0% (the American standard is 98-102%); other indicators are also very good and meet the pharmaceutical standards.
  • the preparation of crude rocuronium bromide in the following examples can be performed with reference to the methods described in US20060058275A1, CN101381390A or US4894369 or modified methods; for the detection of impurities, content and acetic acid, refer to the rocuronium bromide standard in USP38; residual solvents For the detection method, refer to US20060058275A1; the Karl Fischer method is used for moisture detection.
  • the relevant substances are: A ⁇ 0.2%, B ⁇ 0.3%, C ⁇ 0.3%; D ⁇ 0.1%, E ⁇ 0.1%, F ⁇ 0.1%, G ⁇ 0.1%, H ⁇ 0.1%, total impurity ⁇ 1.5%, acetic acid ⁇ 5%, content 98 ⁇ 102%
  • the residual solvents are dichloromethane ⁇ 600ppm, acetonitrile ⁇ 410ppm, ethanol ⁇ 5000ppm, methanol ⁇ 3000ppm, methyl tert-butyl ether ⁇ 5000ppm, and ethyl acetate ⁇ 5000ppm.
  • Rocuronium bromide crude 500 g of rocuronium intermediate monoester, 2.25L of dichloromethane, and 600mL of 3-bromopropene are stirred at room temperature for 16 hours. After filtering the reaction mixture, add 1.75L of dichloromethane to dilute After mixing with 25L of methyl tert-butyl ether under vigorous stirring, a white precipitate was precipitated, and stirring was continued for 20 minutes. The precipitate was filtered off, re-dissolved with 3.5L of dichloromethane, and 25L of methyl tertiary was added under stirring. In butyl ether, the precipitate was filtered off and washed with methyl tert-butyl ether to obtain a crude rocuronium bromide.
  • Refining crude rocuronium bromide first vacuum the above rocuronium bromide in a vacuum drying box for 3 to 5 hours, then transfer it to a 2L single-necked flask, and then add 680ml of methanol and 100ml of water to the bottle Nitrogen and 30ml of acetic acid were bubbled to dissolve, added to a microwave tray, and placed in a microwave vacuum dryer for vacuum microwave drying. The temperature was controlled below 43 ° C and the vacuum was -0.08 to -0.096Mpa for about 16 minutes to obtain a solid. . Then control the temperature to not exceed 43 ° C, and the vacuum degree to be higher than -0.096Mpa for 50-60min.
  • follow-up monitoring of the residual solvent and moisture content of the material take out the material after qualified, and obtain the finished product of rocuronium bromide.
  • Refining the crude rocuronium bromide first evacuate the crude rocuronium bromide in a vacuum drying box for 30 minutes, then transfer it to a 2L single-necked flask, add 560ml of methanol to the bottle, and use a glass A carbon dioxide gas was bubbled into the duct to mix and dissolve the solid to form a homogeneous liquid. After adding 60 ml of water, continue aeration for about 1 hour. Pour the liquid in the bottle into a microwave vacuum tray and put it in a microwave vacuum dryer to control the temperature. When the temperature is below 36 ° C and the vacuum degree is -0.08 to -0.096Mpa, the reaction is performed for about 20 to 23 minutes to obtain a solid.
  • Detection moisture content 2.1%; residual solvent content: methanol 2090ppm, acetonitrile: not detected; methyl tert-butyl ether 2350ppm, dichloromethane 330ppm; related substances: A 0.06%, C0.09%, F0.05%, G0.02%, H0.04%, B, D, E were not detected, the total impurities were 0.36% (the upper limit of the qualified standard is 1.5%); the content (by anhydrous) was 99.3%.
  • Refining crude rocuronium bromide Add the crude rocuronium bromide to a 2L single-necked flask, add 480ml of methanol and 100ml of water to the bottle, and dissolve the solid to form a homogeneous liquid by bubbling carbon dioxide and stirring. Then pour the liquid Put it into the microwave vacuum tray, put it into the microwave vacuum dryer, control the temperature below 40 ° C, and the vacuum degree at -0.08 ⁇ -0.096Mpa for about 16 ⁇ 19min to obtain a solid, and then continue the vacuum microwave action for 4 ⁇ 6 minutes .
  • Detection 3.3% moisture content; residual solvent content: 1200ppm methanol, acetonitrile: not detected; 960ppm methyl tert-butyl ether; 360ppm dichloromethane; related substances: A 0.08%, C 0.13%, F0.05%, G0 .03%, H0.04%, B, D, E are not detected, the total impurities are 0.43% (the upper limit of the qualified standard is 1.5%); the content (calculated as anhydrous) is 99.6%.
  • Purification of crude rocuronium bromide Add 600ml of methanol to the crude rocuronium bromide, concentrate and remove 400ml of methanol at no higher than 27 ° C, then add 250ml of methanol, 90ml of water, 30ml of acetic acid, mix well, add the microwave tray In the process, the material tray is put into a microwave vacuum dryer, and the temperature is controlled below 43 ° C, and the vacuum degree is -0.08 to -0.098Mpa, and the reaction is performed for about 15 to 20 minutes to obtain a solid.
  • Detection water content of 3.5%; residual solvent content: methanol 1900ppm, methylene chloride 60ppm; ethyl acetate, 960ppm, methyl tert-butyl ether 830ppm, acetic acid 4.6%; related substances: A0.06%, C0.1%, F0.08%, G0.04%, H0.05%, B, D, E are not detected, the total amount of impurities is 0.39% (the upper limit of the qualified standard is 1.5%); the content (excluding acetic acid and moisture) is 99.5%.
  • Rocuronium bromide intermediate monoester 400g dissolved in 3600mL of dichloromethane, 150ml of allyl bromide, 8g of chitin, and nitrogen-protected, stirred at 30-34 ° C for 23-25 hours, the reaction solution was filtered, and the filtrate After concentrating to a viscous state under reduced pressure below 26 degrees, then add 400ml of dichloromethane to concentrate to a foamy state, add 530ml of methanol, weigh the bottle and the total weight of the materials, and concentrate under reduced pressure at a temperature not higher than 28 ° C.
  • Detection 3.2% moisture content; residual solvent content: 1600ppm of methanol, 360ppm of dichloromethane, 4.1% of acetic acid; HPLC detection: related substances: A 0.08%, C 0.1%, F0.08%, G0.03%, H0.04 %, B, D, E are not detected, the total amount of impurities is 0.39% (the upper limit of the qualified standard is 1.5%); the content (after deducting water) is 99.6%.
  • Rocuronium bromide intermediate monoester 400g dissolved by adding 3600mL of dichloromethane, 200ml of allyl bromide, 8g of chitin, and under nitrogen protection, the reaction was stirred at 30 ⁇ 34 °C for 22 ⁇ 24 hours, the reaction solution was filtered, and the filtrate After concentrating to a foamy state under reduced pressure, 3600 ml of dichloromethane was added to dissolve the foamy solid, and then the dissolved solution was added to 36 L of ether, stirred for 20 minutes, the solid was filtered off, the solid was transferred to a vacuum drying box, and evacuated at room temperature for 2 hours. Then, a powdery solid is obtained. This solid is transferred to an ebullating bed dryer.
  • the aeration temperature is set to 36 ° C.
  • the gas passes through the sulfuric acid absorption device and enters the system to keep the material in a fluidized state. After 24 hours, the residual solvent is detected by gas chromatography. If the residual solvent is unsatisfactory, continue to dry until it is qualified; when the residual solvent is qualified, collect and determine its content, related substances and moisture.
  • Test results 3300ppm diethyl ether, 320ppm dichloromethane; related substances: Impurity A0.13%, Impurity C0.07%, Impurity F0.1%, Impurities G, D, E, H, B are all less than 0.05%; Moisture 2.3% ; The total amount of impurities is 0.61%; the content of main components (as anhydrous) is 99.0%.
  • a powdery solid was obtained.
  • the demi-meter solid is moved into a boiling fluidized bed dryer, the aeration temperature is set to 36 ° C, and the gas passes through the sulfuric acid absorption device and enters the system to keep the material in a fluidized state.
  • the residual solvent is detected by gas chromatography. If the residual solvent is unsatisfactory, continue to dry until it is qualified; when the residual solvent is qualified, collect and determine its content, residual solvents and moisture of related substances.
  • Test results methyl tert-butyl ether 4600ppm, diethyl ether 2000ppm, dichloromethane 320ppm; related substances: impurities A0.13%, impurities C0.08%, impurities F0.09%, impurities G, D, E, H, B Both are less than 0.05%, the total amount of impurities is 0.69%, the water content is 2.2%, and the main component content (calculated as anhydrous) is 99.3%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

精制罗库溴铵粗品的方法，该方法包括使用真空微波干燥法或者流化干燥法除去罗库溴铵粗品中的残留溶剂，使其符合药用要求。该方法能够得到高质量的罗库溴铵，使罗库溴铵的规模化工业生产容易实现；同时能够避免或减少易燃易爆溶剂乙醚的使用；另外，所用设备投资小，设备占用空间小。

Description

罗库溴铵粗品的精制方法 技术领域
本发明涉及医药领域，具体涉及罗库溴铵粗品的精制方法。
背景技术
罗库溴铵注射剂是一种临床上广泛使用的肌肉松弛剂。按ICH(The International Council for Harmonization,人用药品注册技术要求国际协调会议)指南要求，原料药中残留溶剂必须低于一定的含量才能符合药用。如：二类溶剂二氯甲烷含量应不高于600ppm，乙腈应不高于410ppm，甲醇不高于3000ppm；乙醚、乙酸甲酯、乙酸乙酯、丙酮等三类溶剂需不高于5000ppm。罗库溴铵制备过程中不可避免用到有机溶剂，作为药用的罗库溴铵原料中的残留溶剂必须达到这些要求。
发明内容
本申请提供了罗库溴铵粗品的精制方法，通过该方法能够得到残留溶剂满足药用要求且高品质的罗库溴铵精制品。
罗库溴铵的合成一般以表雄酮为起始原料，大多需要7～9步化学反应完成，具体操作工艺可参照文献US20060058275A1、US4894369、US20050159398、CN201180045999.6、CN201610028808.X、CN200710092747.4、GB2445764中的记载。从目前所有公开的文献可以看出，尽管前几步合成反应可能不同，但最后一步都是用罗库溴铵中间体“单酯”(CAS No.119302-24-8,(2β,3α,5α,16β,17β)-17-乙酰氧基-3-羟基-2-(4-吗啉基)-16-(1-吡咯烷基)雄甾烷))和3-溴丙烯发生季铵化成盐反应来实现的，反应方程式表示如下：
Figure PCTCN2019096224-appb-000001
反应所用溶剂一般为偶极非质子溶剂，如二氯甲烷、乙腈等；反应温度为10～40℃，反应时间为5～24小时。本领域技术人员可根据实际情况调整实验参数，比如物料配比、反应温度、时间等。
本申请把在罗库溴铵原料药制备过程中，含有溶剂量超过作为原料药(API)要求的罗库溴铵称为“罗库溴铵粗品”，可以指含有溶剂过多的罗库溴铵固体物料，也可以是含有溶剂太多的罗库溴铵浆状物或膏状物，还可以指罗库溴铵合成过程中最后一步的反应液。
虽然罗库溴铵注射液已在临床上应用20多年了，罗库溴铵原料药的合成工艺有大量的文献报道，例如上述提到的文献，但迄今为止，罗库溴铵原料的工业化生产还有一定的困难，现有的生产工艺仍然存在缺陷。一个主要的原因是罗库溴铵分子和其制造过程中所用的溶剂容易形成溶剂化物，而该溶剂化物中的溶剂和罗库溴铵分子结合很牢固，必须用很高的温度才能使溶剂化物中的溶剂离开罗库溴铵分子；但罗库溴铵对热敏感，温度稍高就很容易分解，所以除去罗库溴铵粗品中的溶剂使其符合药用标准迄今仍为一大难题。
解决该问题的现有技术方法主要有两个：一是将罗库溴铵的溶液(溶剂为二氯甲烷、乙腈、丙酮等非极性偶极质子溶剂)，用易燃易爆低沸点的乙醚为反溶剂进行反溶剂析晶法得到罗库溴铵固体，这种情况下得到的罗库溴铵粗品含有的主要残留溶剂为乙醚，然后进行真空干燥使乙醚降低达到符合药用标准。另外一个方法是，将罗库溴铵溶液和反溶剂混合析晶得到罗库溴铵粗品后，将固体溶解在大量的水中，通过冷冻干燥方法达到降低残留溶剂的目的。第二种方法中所用的反溶剂除乙醚之外，还可以用较为安全的、沸点较高的其他溶剂。如：乙酸乙酯、乙酸丁酯、己烷、庚 烷、甲基叔丁基醚等。
上述的第一个方法是用反溶剂析晶得粗品后用真空干燥，这种情况下只能用乙醚作为反溶剂，其他溶剂都不行。尽管乙醚的沸点只有36℃，但从以乙醚为反溶剂析出罗库溴铵后，乙醚和罗库溴铵分子会结合成溶剂化物。采用真空干燥，必须在37℃以上，真空度很高的条件下长时间(一般需要5天以上，甚至10天或更长时间)干燥才能勉强使残留的乙醚达到药用标准5000ppm以下的要求。与此同时，在该条件下罗库溴铵很容易分解，杂质会明显升高，所以用这种方法处理得到的罗库溴铵即使杂质合格，其含量一般都比较大；并且如果温度控制不好，稍微高一点，或者时间稍长一点，杂质量将会升高到不能接受的程度。
使用乙醚还存在的严重的缺点是，乙醚非常易燃易爆。所以尽管乙醚在原料药生产中没有绝对禁止使用，但一般只是在使用量不大、且没有别的可用的溶剂情况下才使用。而如果用乙醚通过反溶剂结晶法生产罗库溴铵，乙醚的使用量很大，如生产10kg罗库溴铵通常需要乙醚1100L或更多，所以生产过程存在严重的安全隐患；另外，符合药用的罗库溴铵原料按GMP要求需在密闭的洁净区中进行，这又进一步加大危险程度。对于使用乙醚量比较大的项目，管理部门考虑到安全问题常常不批准建设，特别是在目前EHS(环保、安全、健康)要求越来越严格的情况下。
根据文献US20060058275A1和发明人前期的研究结果，沸点稍高的、能够用在罗库溴铵生产过程中的溶剂，如二氯甲烷、正己烷、乙酸甲酯、乙酸乙酯、乙酸丁酯、异丁基乙酯、甲基叔丁基醚等和罗库溴铵结合成溶剂化物后，常规的真空干燥方法并不能将其去除达到符合药用水平；若罗库溴铵生产过程中最后步骤中所用的溶剂为甲基叔丁基醚、乙酸乙酯，所得罗库溴铵粗品中将含有甲基叔丁基醚、乙酸乙酯残留溶剂，这种粗品在80℃，真空度-0.098Mpa的条件下16小时后，其中甲基叔丁基醚、乙酸乙酯含量仍大大超过标准上限5000ppm，有时甚至超过100倍，达到500000ppm以上；在此条件下继续干燥12小时，甲基叔丁基醚、乙酸乙酯的含量基本上没有降低。
上述提到的第二个方法中，可以用沸点较高、安全性较高的其他溶剂 (如：乙酸乙酯、乙酸丁酯、甲基叔丁基醚等)作为反溶剂来把罗库溴铵固体从溶液中析出，然后用冷冻干燥除去残留罗库溴铵铵中的这些相对安全的、高沸点的溶剂。虽然通过冷冻干燥方法如文献CN200710092747.4、GB2445764、US20060058275A1中所述的，可以除去罗库溴铵粗品中的溶剂使其符合药用标准，但冷冻干燥方法去除残留溶剂得到罗库溴铵中的杂质C一般都比较大，很难控制在0.1％以下，一般都会接近标准要求的上限0.2％，稍不小心就会超过0.2％，超过EP8.0(European Pharmacopeia 8.0，欧洲药典，第八版)标准的上限(0.2％)。这是因为罗库溴铵是一种乙酸酯，有水存在时很容易水解，而冻干操作中首先必须把罗库溴铵粗品溶解在大量的水中，杂质C的量会因水解而增大。除此之外，冷冻干燥法能耗高，设备占的空间大，设备投资大，在同样生产规模情况下，冻干设备投资超过实施本申请的成本10倍。
因此，就目前而言，除去罗库溴铵粗品中所含的溶剂使最后的产品中含有的残留溶剂达到作为药物使用可接受范围有相当大的难度，是罗库溴铵原料制造中的一个难点。也就是说，得到上述的“罗库溴铵粗品”后，除去其中的溶剂使其达到符合药用的罗库溴铵原料有很大难度。
基于此，本申请提供了精制罗库溴铵粗品的方法，该方法包括使用真空微波干燥法或者流化干燥法除去罗库溴铵粗品中的残留溶剂，使其符合药用要求。该方法不但克服了如上所述的难点，而且操作简单、环保，成本低，效果显著。
进一步地，在本申请的一个或多个实施方式中，所述方法包括使用a溶剂替换罗库溴铵粗品中的残留溶剂后对含有a溶剂的罗库溴铵粗品进行真空微波干燥。
进一步地，在本申请的一个或多个实施方式中，所述方法包括：用a溶剂和罗库溴铵粗品混合成含罗库溴铵的液体，将该液体通过真空微波达到固化状态(真空微波固化)，然后继续真空微波干燥和/或使用其他干燥方法进行处理使其溶剂和水分达到符合药用要求的水平。
文本所述的真空微波固化指真空微波进行到一定程度，被处理的液体物料因溶剂蒸发而形成固体。一开始固化时罗库溴铵样品中残留溶剂一般 都比较大，不符合药用标准的要求，这时需要继续真空微波干燥和/或使用其他干燥方法进行处理。
进一步地，所述a溶剂为吸收微波能力强的极性溶剂。可进一步地选自C 1～C 4的一元醇、C 1～C 3的一元酸、丙酮、丁酮、四氢呋喃和水中的一种或多种。当然可实施的a溶剂并不限于此，本领域技术人员可根据本申请的公开在使用本发明的同时选择或尝试其他可行的溶剂，应当知晓，这种简单的溶剂探索是基于本发明的常规选择，也应包含在本申请的保护范围内。
在某些实施方式中，本申请所述a溶剂选自C 1～C 3的一元醇、C 1～C 3的一元酸、丙酮、丁酮、四氢呋喃和水中的一种或多种。
在某些实施方式中，所述a溶剂选自甲醇、乙醇、异丙醇、C 1～C 3的一元酸、丙酮、丁酮、四氢呋喃和水中的一种或多种。
在某些实施方式中，所述a溶剂选自甲醇、乙醇、C 1～C 3的一元酸、丙酮、丁酮、四氢呋喃和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、C 1～C 3的一元酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自C 1～C 3的一元醇、甲酸、乙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、乙醇、甲酸、乙酸、丙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、乙醇、异丙醇、甲酸、乙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、乙醇、甲酸、乙酸和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、甲酸、乙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、甲酸、乙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、乙醇、乙酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、甲酸、丙酮和水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、甲酸、水中的一种或多种；或者，在某些实施方式中，所述a溶剂选自甲醇、乙酸、水中的一种或多种；或者，在某些实施方式中，所述a溶剂为甲醇、乙醇、甲醇和水(甲醇/水或甲醇-水)、乙醇和水(乙醇/水或 乙醇-水)、甲醇和水和乙酸(甲醇/水/乙酸或甲醇-水-乙酸)、或乙醇和水和乙酸(乙醇/水/乙酸或乙醇-水-乙酸)。
进一步地，在某些实施方式中，当有水存在时，罗库溴铵容易水解不稳定，可以通过加入乙酸使其稳定，但由于乙酸沸点比较高，难以除去，最后难免会留到产品里。所以必须控制适当乙酸的量，以保证最终精制得到的罗库溴铵产品中的乙酸含量不超过USP38(United States Pharmacopoeia 38，美国药典38)标准上限的5％(质量百分比，w/w：即100g罗库原料药里含乙酸在5g以内)或其他特殊的要求。
进一步地，在本申请的某些实施方式中，考虑到乙酸加入后，在后续的处理过程中要挥发掉一部分，乙酸加入的量可以超过5％(V/V)，但一般不超过溶剂a的总量的8％(V/V)，以进一步控制最后产品中乙酸的含量不超过USP标准上限的5％(W/W)。
进一步地，在本申请的一个或多个实施方式中，所述真空微波的真空度为-0.01～-0.1Mpa，或进一步为-0.01～-0.099Mpa、进一步为-0.01～-0.08Mpa、进一步为-0.01～-0.07Mpa、进一步为-0.01～-0.06Mpa，或者进一步为-0.06～-0.1Mpa、进一步为-0.06～-0.099Mpa、进一步为-0.06～-0.09Mpa、进一步为-0.06～-0.089Mpa、进一步为-0.06～-0.08Mpa、进一步为-0.06～-0.079Mpa、进一步为-0.06-～-0.07Mpa，或者进一步为-0.07～-0.01Mpa、进一步为-0.07～-0.099Mpa、进一步为-0.07～-0.09Mpa、进一步为-0.07～-0.089Mpa、进一步为-0.07～-0.08Mpa，或者更进一步为-0.08～-0.099Mpa(比如，可以是-0.08～-0.096Mpa，或者-0.08～-0.098Mpa)、进一步为-0.08～-0.09Mpa、进一步为-0.08～-0.089Mpa、进一步为-0.08～-0.085Mpa。
进一步地，在本申请的一个或多个实施方式中，所述真空微波的温度为10～60℃，比如可以为10℃、15℃、20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃或60℃，或者进一步为10～50℃、20～50℃，或者进一步为10～40℃或者20～40℃，或者进一步为30～40℃，或者更进一步为25～36℃。本申请实施方式中所述的比如43℃以下、40℃以下或36℃以下的温度范围适用此处对温度的定义。
进一步地，所述其他干燥方法可以为本领域技术人员通常采用的干燥方法，或者可以选自减压(真空)干燥法、气流吹带干燥法和流化干燥法中的一种或多种，但并不限于此，应当知晓本领域普通技术人员有基于本申请的公开，根据本申请的方法选择其他干燥方法的能力。
本文所述的气流吹带干燥法就是将固体物料放在一个能够进气和出气的密封的设备里，维持设备内有一定的温度，让空气或惰性气体进入和流出设备。例如，将固体物料放在真空烘箱层板上的料盘里，维持一定的温度，让空气或惰性气体进出烘箱，一般用惰性气体较好，特别是物料的含水量较高时，用空气可能会使产品氧化变色。
进一步地，在本申请的一个或多个实施方式中，所述方法包括：用a溶剂和罗库溴铵粗品混合成含罗库溴铵的液体，将该液体通过真空微波达到固化状态(真空微波固化)，然后继续真空微波干燥和/或使用气流吹带干燥法进行处理使其溶剂和水分达到符合药用要求的水平。
进一步地，在某些实施方式中，当残留溶剂达到药用要求后，可在不通气的状况下继续真空干燥以除去水分。
进一步地，在某些实施方式中，在真空微波干燥之前，可先将罗库溴铵粗品在真空干燥箱中进行抽真空处理。
进一步地，在本申请的一个或多个实施方式中，真空微波进行到一定程度，罗库溴铵粗品会发生固化，此时的罗库溴铵粗品固体中仍然包含有残留溶剂及水分，若达不到药用标准的要求则可以继续进行真空微波干燥也可以选用气流吹带干燥法、真空干燥干燥、流化干燥法，或综合利用此类方法。这里所述的气流吹带干燥法就是将固体物料放在一个能够进气和出气的密封的设备里，维持设备内有一定的温度，让气体进入和流出设备。例如，将固体物料放在真空烘箱层板上的料盘里，维持一定的温度，让空气或惰性气体进出烘箱。
根据本申请的实施方式，罗库溴铵粗品和吸收微波强的溶剂a混合所得的液体，通过真空微波处理可以在很短的时间内(比如在某些实施方式中进行10～25min，进一步为10～20min，比如可以是10min、12min、14min、15min、16min、17min、18min、19min、20min、23min、25min这些温度 任意两两之间的温度范围)、较低的温度下(比如某些实施方式中的10～60℃，或者在一些实施方式中的20～40℃，或者又一些实施方式中的25～36℃)固化成固体。然后继续用真空微波作用使其溶剂符合药用标准。得到固体后也可以结合其他的干燥方式处理(如：气流吹带、真空干燥、流化干燥法中的一种或多种)，使其中含有的残留溶剂达到符合原料药的标准。
进一步地，在本申请的某些实施方式中，真空微波固化后若使用其他干燥方法，则其他干燥方法所用温度不能超过60℃，一般不超过43℃，进一步不超过36℃。
进一步地，若生产规模不太大，可以将真空微波固化后得到的固体移入小型真空干燥箱(比如DZF-6050型真空干燥箱)进行后面的气流吹带干燥；若生产规模比较大，可以用工业上比较大的真空干燥箱或双锥回旋干燥机进行气流吹带干燥。干燥过程中保持箱内(物料)有一定的温度(一般26～43℃)，通入氮气、氩气、二氧化碳或空气气流吹带，也可以用真空干燥，或联合两种方法使用。在本申请的某些实施方式中，可以通过维持物料或体系有一定的湿度来增加去除溶剂的效果。
根据本申请的实施方式，真空微波的功率可以根据被干燥物料的量、干燥过程中的抽气泵的抽气速率和/或其极限真空度以及干燥过程的情况来调整。一般而言，本申请的某些实施方式，干燥过程的前期由于含溶剂多，一般需要大功率，到干燥后期，由于溶剂含量低一般需要较小的功率。
根据本申请的一个或多个实施方式，一次干燥200克物料，微波的功率变化在300～800W；一次干燥6～8kg物料，微波功率的变化在1000～20000W。
在本申请的一个或多个实施方式中，所述方法包括对乙醚为主要残留溶剂的罗库溴铵粗品进行流化干燥。
本申请所述的乙醚为主要残留溶剂的罗库溴铵粗品为以乙醚为主要残留溶剂的罗库溴铵粗品或者经处理使得如上定义的罗库溴铵粗品变成以乙醚为主要残留溶剂的罗库溴铵粗品。
本文所述的以乙醚为主要残留溶剂是指乙醚作为残留溶剂的含量超 过要用标准，其他残留溶剂已经合格或者接近合格；举例说明，比如所含残留溶剂为乙醚和二氯甲烷，根据ICH(The International Council for Harmonization,人用药品注册技术要求国际协调会议)指南，乙醚的量应不高于5000ppm，二氯甲烷应不高于600ppm，则此处所述的乙醚为主要残留溶剂则为乙醚的量高于5000ppm，甚至可能高于该值100倍，即500000ppm，而二氯甲烷的量低于600ppm或者接近600ppm，比如该值为610ppm或620ppm。
进一步地，在本申请的一个或多个实施方式中，本申请所述的以乙醚为主要残留溶剂的罗库溴铵粗品为经反溶剂结晶法使得如上定义的罗库溴铵粗品变为以乙醚为主要残留溶剂的罗库溴铵粗品。
在本申请的某些实施方式中，所述方法包括将罗库溴铵粗品通过反溶剂结晶法使罗库溴铵粗品中含有的主要残留溶剂为乙醚，然后进行流化干燥。
在本申请的某些实施方式中，所述反溶剂结晶法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备获得罗库溴铵粗品固体。
进一步地，在本申请的一个或多个实施方式中，所述溶剂b为偶极非质子溶剂；进一步地，所述溶剂b为可以溶解罗库溴铵的溶剂。进一步地，所述溶剂b选自二氯甲烷、乙腈、丙酮、二甲基亚砜(DMSO)、N,N-二甲基甲酰胺(DMF)和N,N-二甲基乙酰胺中的一种或多种。进一步地，所述溶剂b选自二氯甲烷、乙腈、丙酮和DMSO中的一种或多种。进一步为二氯甲烷。
进一步地，在本申请的一个或多个实施方式中，所述溶剂c为反溶剂，进一步为与罗库溴铵不溶或微溶的溶剂；更进一步地，所述溶剂c为乙醚或非乙醚溶剂；进一步地，所述非乙醚溶剂选自异丙醚、甲基叔丁基醚、乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸丙酯、环己烷、正己烷、正庚烷中的一种或多种；进一步地，所述非乙醚溶剂选自甲基叔丁基醚、乙酸甲酯、乙酸乙酯和正己烷中的一种或多种；进一步地，所述非乙醚溶剂为甲基叔丁基醚、乙酸甲酯、乙酸乙酯或正己烷。
进一步地，在本申请的一个或多个实施方式中，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后进行流化干燥。
进一步地，在某些实施方式中，所述溶剂c为乙醚，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后进行流化干燥。
进一步地，在实施本申请时，用流化干燥法可以比较容易地除去罗库溴铵粗品中的乙醚，但很难除去罗库溴铵粗品中的其他溶剂(比如乙酸乙酯，乙酸甲酯，正己烷、甲基叔丁基醚等)。所以若实施本申请，但考虑到乙醚的危险性而用上述的其他溶剂c作反溶剂制备罗库溴铵粗品固体时，可以在滤出这些高沸点反溶剂(溶剂c)析出的固体后，用乙醚洗涤，使流化干燥前罗库溴铵粗品中含的主要溶剂为乙醚，其他溶剂接近或达到符合药用标准的上限水平。这样可以减少乙醚的用量。
进一步地，在某些实施方式中，所述溶剂c为非乙醚，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，用乙醚洗涤该固体，然后进行流化干燥。
在本申请的一个或多个实施方式中，本申请所述的流化干燥也称沸腾干燥；所用的设备有沸腾床干燥机(比如XF系列沸腾干燥机XF10、XF20、XF30等)，振动流化床干燥机(比如ZLG系列振动流化床干燥机)等。在这种干燥方法中，将物料(一般是粉状或细颗粒状)放在能够通气的微孔板上，气体从孔板的下部以一定的流速通过孔板，使物料吹起成流化或沸腾状态，物料颗粒在气流中上下翻动，混合和碰撞，充分接触，其干燥效率很高。穿过物料的气体，经布袋除尘或旋风分离器回收所夹带的粉尘后离去；干燥合格产品，从出料口溢出。
进一步地，在一个或多个实施方式中，本申请在实施流化干燥时所用的气体，可以是惰性气体(如氮气、二氧化碳、氩气)或空气。
进一步地，若是空气，一般需要干燥、净化处理。含水量太高的气流和固体(如粉状)罗库溴铵物料接触后，不仅会使罗库溴铵水解，而且可 能结块、使干燥效果不好。干燥、净化处理可以让空气通过浓硫酸洗气瓶、碱石灰塔等。进一步地，在本申请的一个或多个实施方式中，上述干燥所用的温度为15～70℃，例如，可以是15℃、20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60、65℃或70℃；进一步为15～60℃，更进一步为15～50℃或者25～50℃，再进一步为30～37℃。
在本申请中，流化干燥法中的气流的流速没有特别要求，但最好是足够大以保持物料处于充分的流化状态，这样可以保证物料和气体充分接触，使物料之间互相摩擦撞击以使溶剂被尽快带走。低的气流速度将大大延长除溶剂的时间。
如上所述，在本申请的一个或多个实施方式中，若用非乙醚的溶剂c(非乙醚溶剂的选择如上所述，举例而言，比如，乙酸乙酯、乙酸甲酯、正己烷、甲基叔丁基醚等)作为反结晶溶剂，后续使用流化干燥法很难除去这些高沸点的溶剂c使其符合药用要求；因此必须再用乙醚洗涤将这些高沸点溶剂c洗去后再进行后续的流化干燥。
进一步地，作为另一种选择，在本申请的一个或多个实施方式中，所述溶剂c为非乙醚，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后用a溶剂和该罗库溴铵粗品固体混合成含罗库溴铵的液体，对该液体进行真空微波干燥。在某些实施方式中，可以先通过减压浓缩或气体吹带使非乙醚溶剂降低到一定程度后再进行真空微波。
进一步地，在某些实施方式中，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后用a溶剂和该罗库溴铵粗品固体混合成含罗库溴铵的液体，将该液体通过真空微波达到固化状态，继续真空微波干燥和/或使用其他干燥方法进行处理使其溶剂和水分达到符合药用要求的水平。在某些实施方式中，可以先通过减压浓缩或气体吹带使非乙醚溶剂降低到一定程度后再进行真空微波。
进一步地，所述溶剂a的选择如上所述，例如在本申请的某些实施方式中，溶剂a可以选自甲醇、乙醇、水、异丙醇、丁醇、丙酮、丁酮、四 氢呋喃、甲酸、乙酸和丙酸中的一种或多种，进一步可以选自甲醇、乙酸、甲酸、水和丙酮中的一种或多种。
进一步地，在某些实施方式中，当有水存在时，罗库溴铵容易水解不稳定，可以通过加入乙酸使其稳定，但由于乙酸沸点比较高，难以除去，最后难免会留到产品里。所以必须控制适当乙酸的量，以保证最终精制得到的罗库溴铵产品中的乙酸含量不超过USP38(United States Pharmacopoeia 38，美国药典38)标准上限的5％(质量百分比，w/w：即100g罗库原料药里含乙酸在5g以内)或其他特殊的要求。
进一步地，在本申请的某些实施方式中，考虑到乙酸加入后，在后续的处理过程中要挥发掉一部分，乙酸加入的量可以超过5％(V/V)，但一般不超过溶剂a的总量的8％(V/V)，以进一步控制最后产品中乙酸的含量不超过USP标准上限的5％(W/W)。
进一步地，在本申请的一个或多个实施方式中，真空微波进行到一定程度，罗库溴铵粗品会发生固化，此时的罗库溴铵粗品固体中仍然包含有残留溶剂及水分，若达不到药用标准的要求则可以继续进行真空微波干燥也可以选用气流吹带干燥法、真空干燥干燥、流化干燥法，或综合利用此类方法。这里所述的气流吹带干燥法就是将固体物料放在一个能够进气和出气的密封的设备里，维持设备内有一定的温度，让气体进入和流出设备。例如，将固体物料放在真空烘箱层板上的料盘里，维持一定的温度，让空气或惰性气体进出烘箱。
根据本申请的实施方式，罗库溴铵粗品和吸收微波强的溶剂a混合所得的液体，通过真空微波处理可以在很短的时间内(比如在某些实施方式中进行10～25min，进一步为10～20min，比如可以是10min、12min、14min、15min、16min、17min、18min、19min、20min、23min或25min)、较低的温度下(比如某些实施方式中的10～60℃，或者在一些实施方式中的20～40℃，或者又一些实施方式中的25～36℃)固化成固体。然后继续用真空微波作用使其溶剂符合药用标准。得到固体后也可以结合其他的干燥方式处理(如：气流吹带、真空干燥、流化干燥法)，使其中含有的残留溶剂达到符合原料药的标准。
进一步地，在本申请的某些实施方式中，真空微波固化后若使用其他干燥方法，则其他干燥方法所用温度不能超过60℃，一般不超过43℃，进一步不超过36℃。
进一步地，若生产规模不太大，可以将真空微波固化后得到的固体移入小型真空干燥箱(比如DZF-6050型真空干燥箱)进行后面的气流吹带干燥；若生产规模比较大，可以用工业上比较大的真空干燥箱或双锥回旋干燥机进行气流吹带干燥。干燥过程中保持箱内(物料)有一定的温度(一般26～43℃)，通入氮气、氩气、二氧化碳或空气气流吹带，也可以用真空干燥，或联合两种方法使用。在本申请的某些实施方式中，可以通过维持物料或体系有一定的湿度来增加去除溶剂的效果。
本申请的某些实施方式中，真空微波干燥的真空度和真空微波干燥的温度可以如上所述，比如真空微波干燥的真空度-0.01～-0.1Mpa，或者又一些实施方式中进一步为-0.06～-0.1Mpa，或者在一些实施方式中进一步为-0.08～-0.099Mpa；比如，在某些实施方式中，真空微波干燥的温度可以为10～60℃，或者在有一些实施方式中进一步为20～60℃，或者在另一些实施方式中进一步为20～40℃，或者在又一些实施方式中进一步为30～40℃，或者在又一些实施方式中更进一步为25～36℃。
根据本申请的实施方式，真空微波的功率可以根据被干燥物料的量、干燥过程中的抽气泵的抽气速率和/或其极限真空度以及干燥过程的情况来调整。一般而言，本申请的某些实施方式，干燥过程的前期由于含溶剂多，一般需要大功率，到干燥后期，由于溶剂含量低一般需要较小的功率。
根据本申请的一个或多个实施方式，一次干燥200克物料，微波的功率变化在300～800W；一次干燥6～8kg物料，微波功率的变化在1000～20000W。
本申请的精制方法在去除残留溶剂的处理过程中基本上不破坏罗库溴铵分子的结构。在罗库溴铵粗品中有关物质含量不高的情况下，通过本申请的真空微波干燥法操作及后续的干燥处理后得到的罗库溴铵成品中的有关物质一般都比较低；在本申请的某些实施方式中，杂质A的含量被发现在精制结束后会降低。
根据本申请的方法精制罗库溴铵粗品，可以得到有关物质(已知杂质)及其含量、残留溶剂含量符合EP8.0(欧洲药典第8版)和/或USP38(美国药典第38版)的要求的高品质罗库溴铵(成品)，大多数情况下有关物质可以达到0.1％以下，已知和未知杂质的总含量一般不超过0.4％；主产物罗库溴铵的含量按美国标准检测一般能达到99.0％以上(美国标准是98～102％)；其他指标也都很好，满足药用标准。
用本申请的方法能够得到高质量的罗库溴铵，使罗库溴铵的规模化工业生产容易实现；同时能够避免或减少易燃易爆溶剂乙醚的使用；另外，所用设备投资小，设备占用空间小。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。
下述实施例1～7仅作为示例性实施例，其目的是使本领域技术人员可以更为清晰的了解本申请的技术方案，但是，应当明确的是，本申请给出的是一种全新的方法，其具有指导作用，根据本申请的公开，以与下述实施方式相同或相似的手段根据本申请的发明内容中提及的或与本申请所提及内容相似的、相关的或本领域技术人员常用的溶剂或操作或参数，或以上内容的各种结合方式组合或仅针对某一项或多项替换或替换后再进行组合的方式得到的实施方式均属于本申请的保护范围。此外，如前所述，本申请提出的是全新的方法，该方法具有指导作用，因此，应当理解本申请的申请人无法以穷尽的方式列举本申请的所有实施方式。
下述实施例中制备罗库溴铵粗品可以参照US20060058275A1、CN101381390A或US4894369中所述的方法或修饰后的方法进行；杂质、含量及乙酸的检测方法参见USP38中罗库溴铵的标准；残留溶剂检测方法 参考US20060058275A1；水分检测用卡尔费休法。
其中，USP38以及ICH的指导原则要求如下：
按罗库溴铵USP38的标准，有关物质为：A≤0.2％，B≤0.3％,C≤0.3％；D≤0.1％,E≤0.1％,F≤0.1％,G≤0.1％,H≤0.1％，杂质总量≤1.5％,；乙酸≤5％；含量98～102％
按ICH原则要求残留溶剂二氯甲烷≤600ppm，乙腈≤410ppm，乙醇≤5000ppm，甲醇≤3000ppm，甲基叔丁基醚≤5000ppm，乙酸乙酯≤5000ppm。
实施例1
罗库溴铵粗品：将罗库溴铵中间体单酯500g、二氯甲烷2.25L，3-溴丙烯600mL混合，室温下搅拌16小时，然后将反应混合物过滤后，加入1.75L二氯甲烷稀释后，在剧烈搅拌下和25L甲基叔丁基醚混合中，析出白色沉淀，继续搅拌20分钟，滤出沉淀物，用3.5L二氯甲烷重新溶解后，在搅拌下加入大25L甲基叔丁基醚中，滤出沉淀并用甲基叔丁基醚洗涤沉淀，即得罗库溴铵粗品。
罗库溴铵粗品的精制：先将上述的罗库溴铵粗品在真空干燥箱中抽真空3～5小时，然后将其转移到2L的单口烧瓶中，再向瓶中加入680ml甲醇、100ml水和30ml乙酸通入氮气鼓泡溶解后，加入微波料盘中，放进微波真空干燥机进行真空微波干燥，控制温度在43℃以下、真空度在-0.08～-0.096Mpa作用约16min，得到固体。然后控制温度不超过43℃，真空度高于-0.096Mpa继续作用50-60min。跟踪监测物料的残留溶剂及水分的含量，合格后取出物料，即得罗库溴铵成品。
检测：水分2.6％；残留溶剂含量：甲醇2800ppm，二氯甲烷，60ppm；甲基叔丁基醚2960ppm，乙酸4.6％；有关物质:A 0.11％，C 0.10％，F0.07％，G0.03％，H0.05％，B、D、E未检出，总杂质0.4％(合格标准上限是1.5％)，含量(扣除乙酸和水后)99.1％
实施例2
罗库溴铵粗品制备：将罗库溴铵中间体单酯500g、乙腈2L、3-溴丙 烯600ml混合，室温下搅拌8小时。将反应混合物过滤后所得的滤液，滤液用2L二氯甲烷稀释后，在剧烈搅拌下和25L甲基叔丁基醚混合中，析出白色沉淀，继续搅拌20分钟，滤出沉淀物，用3.5L二氯甲烷重新溶解后，在搅拌下加入大25L甲基叔丁基醚中，滤出沉淀并用甲基叔丁基醚洗涤沉淀，即得罗库溴铵粗品。
罗库溴铵粗品的精制：先将上述的罗库溴铵粗品在真空干燥箱中抽真空30分钟后，将其转移到2L的单口烧瓶中，再向瓶中加入560ml甲醇，用一根玻璃导管通入二氧化碳气体鼓泡混合使固体溶解形成均相液体，加入水60ml，继续通气1小时后左右，将瓶中液体倒入微波真空的料盘中，放进微波真空干燥机中，控制温度在36℃以下、真空度在-0.08～-0.096Mpa作用约20～23min，得到固体。
将固体转移至真空干燥箱中，设置箱内温度为34～37℃，通入二氧化碳气体吹带24小时后，取样检测残留溶剂，当残留溶剂甲醇不高于3000ppm后，停止通气；将真空干燥箱接上真空泵抽真空(真空度高于-0.095Mpa)继续干燥(箱内放入五氧化二磷)，约6小时后取出物料。即得罗库溴铵成品。
检测：水分含量2.1％；残留溶剂含量：甲醇2090ppm，乙腈：未检测到；甲基叔丁基醚2350ppm，二氯甲烷330ppm；有关物质:A 0.06％，C0.09％，F0.05％，G0.02％，H0.04％，B、D、E未检出，总杂质0.36％(合格标准上限是1.5％)；含量(按无水计)99.3％。
实施例3
罗库溴铵粗品制备：将罗库溴铵中间体单酯500克、乙腈2L，3-溴丙烯600mL混合，室温下搅拌8小时。将反应混合物过滤后所得的滤液，滤液用2L二氯甲烷稀释后，在剧烈搅拌下和25L甲基叔丁基醚混合中，析出白色沉淀，继续搅拌20分钟，滤出沉淀物，用3.5L二氯甲烷重新溶解后，在搅拌下加入大25L甲基叔丁基醚中，滤出沉淀并用甲基叔丁基醚洗涤沉淀，即得罗库溴铵粗品。
罗库溴铵粗品的精制：将罗库溴铵粗品加入2L的单口烧瓶中，向瓶 中加入480ml甲醇和100ml水混合物，通过二氧化碳鼓泡、搅拌使固体溶解形成均匀液体，然后将该液体倒入微波真空的料盘中，放进微波真空干燥机中，控制温度在40℃以下、真空度在-0.08～-0.096Mpa作用约16～19min，得到固体，然后继续真空微波作用4～6分钟。
将固体转移至真空干燥箱中，设置箱内温度为34～36℃，通入二氧化碳吹带24小时后，取样检测残留溶剂，当残留溶剂甲醇不高于3000ppm后，停止通气，在真空干燥箱里放入五氧化二磷，抽真空(真空度高于-0.096Mpa)继续干燥，监测水分含量，当水分含量小于4.0％时，取出物料，即得罗库溴铵成品。
检测：水分含量3.3％；残留溶剂含量：甲醇1200ppm，乙腈：未检测到；甲基叔丁基醚960ppm；二氯甲烷360ppm；有关物质:A 0.08％，C 0.13％，F0.05％，G0.03％，H0.04％，B、D、E未检出，总杂质0.43％(合格标准上限是1.5％)；含量(按无水计)99.6％。
实施例4
罗库溴铵粗品制备：将罗库溴铵中间体单酯500g、二氯甲烷2L，3-溴丙烯600mL混合，室温搅拌16小时。将反应液过滤，滤液加入1L二氯甲烷后，在剧烈搅拌下和25L甲基叔丁基醚混合中，析出白色沉淀，继续搅拌20分钟，滤出沉淀物，用3.5L二氯甲烷重新溶解后，然后在剧烈搅拌下慢慢加入20L乙酸乙酯-甲基叔丁基醚(V:V＝1:10)混合溶剂，析出白色沉淀，过滤并混合溶剂沉淀，即得罗库溴铵粗品。
罗库溴铵粗品的精制：向罗库溴铵粗品里加入600ml甲醇，在不高于27℃浓缩除去400ml甲醇，然后补加250ml甲醇、90ml水、30ml乙酸，混匀后，加入微波料盘中，将料盘放进微波真空干燥机，控制温度在43℃以下、真空度在-0.08～-0.098Mpa作用约15～20min，得到固体。
将固体转移至真空干燥箱中，设置温度为36℃，通入氮气吹带24小时后，取样检测残留溶剂，当残留溶剂甲醇含量不高于5000ppm后，停止通气，将真空干燥箱放入五氧化二磷，接上真空泵抽真空继续干燥6小时后，取样检测残留溶剂及水分，若不合格，继续真空干燥3-5小时，直至 合格。然后取出物料，粉碎，过50～60目筛孔，即得罗库溴铵成品。
检测：水分含量3.5％；残留溶剂含量：甲醇1900ppm，二氯甲烷60ppm；乙酸乙酯，960ppm，甲基叔丁基醚830ppm，乙酸4.6％；有关物质:A0.06％，C0.1％，F0.08％，G0.04％，H0.05％，B、D、E未检出，杂质总量0.39％(合格标准上限是1.5％)；含量(扣除乙酸和水分)99.5％。
实施例5
罗库溴铵中间体单酯400g，加二氯甲烷3600mL溶解，加烯丙基溴150ml，加8g克甲壳质，氮气保护下，30～34℃反应搅拌23～25小时，反应液过滤，滤液在26度以下减压浓缩至粘稠状后，然后再加二氯甲烷400ml浓缩至泡沫状，加入甲醇530ml，称取瓶及其中物料总重量，在不高于28℃温度下减压浓缩去掉约290g，然后加230ml甲醇-水-乙酸(V/V/V＝4:4:1)，混匀后，加入微波料盘中，将料盘放进微波真空干燥机，控制温度在43℃以下、真空度在-0.08～-0.098Mpa作用约15～20min，得到固体。
将固体转移至真空干燥箱中，设置箱内温度为33～36℃，通入氮气和二氧化碳(V/V＝1：6，吹带24小时后，取样检测残留溶剂，当残留溶剂甲醇不高于3000ppm后，停止通气，在真空干燥箱里放入五氧化二磷，抽真空(真空度高于-0.096Mpa)继续干燥，监测水分含量，当水分含量小于4.0％时，取出物料，即得罗库溴铵成品。
检测：水分含量3.2％；残留溶剂含量：甲醇1600ppm，二氯甲烷360ppm，乙酸4.1％；HPLC检测：有关物质:A 0.08％，C 0.1％，F0.08％，G0.03％，H0.04％，B、D、E未检出，杂质总量0.39％(合格标准上限是1.5％)；含量(扣除水后)99.6％。
实施例6
罗库溴铵中间体单酯400g，加二氯甲烷3600mL溶解，加烯丙基溴200ml，加8克甲壳质，氮气保护下，30～34℃反应搅拌22～24小时，反应液过滤，滤液减压浓缩至泡沫状后，加入3600ml二氯甲烷将泡沫状固体 溶解，然后将溶解液加入到36L乙醚中，搅拌20分，滤出固体，将固体移入真空干燥箱中，室温抽气2小时，然后得到粉末状固体，将此固体移入沸腾床干燥机，设置通气的温度为36℃，气体通过硫酸吸收装置后进入系统，保持物料处于流化状态。24小时后用气相色谱检测残留溶剂，若残留溶剂不合格，继续干燥直至合格为止；当残留溶剂合格后，收料并测定其含量、有关物质及水分。
检测结果：乙醚3300ppm，二氯甲烷320ppm；有关物质：杂质A0.13％，杂质C0.07％，杂质F0.1％，杂质G、D、E、H、B都小于0.05％；水分2.3％；杂质总量0.61％；主成分含量(按无水计)99.0％。
实施例7
罗库溴铵中间体单酯400g，加二氯甲烷3600mL溶解，加烯丙基溴200ml，加4克甲壳质，氮气保护下，31～35℃反应搅拌22～24小时，反应液过滤，滤液减压浓缩至泡沫状后，加入3600ml二氯甲烷溶解，然后加入36L甲基叔丁基醚中，搅拌20分，滤出固体，用乙醚打浆洗涤3～4次，将固体移入真空干燥箱中，室温抽气2小时，然后得到粉末状固体。将分米状固体移入沸腾流化床干燥机，设置通气的温度为36℃，气体通过硫酸吸收装置后进入系统，保持物料处于流化状态。24小时后用气相色谱检测残留溶剂，若残留溶剂不合格，继续干燥直至合格为止；当残留溶剂合格后，收料并测定其含量、有关物质残留溶剂及水分。
检测结果：甲基叔丁基醚4600ppm，乙醚2000ppm，二氯甲烷320ppm；有关物质：杂质A0.13％，杂质C0.08％，杂质F0.09％，杂质G、D、E、H、B都小于0.05％，杂质总量0.69％；水分2.2％；主成分含量(按无水计)99.3％。

Claims (10)

  1. 一种精制罗库溴铵粗品方法，所述方法包括使用真空微波干燥法或者流化干燥法除去罗库溴铵粗品中的残留溶剂，使其符合药用要求。
  2. 根据权利要求1所述的方法，其特征在于，所述方法包括使用a溶剂替换罗库溴铵粗品中的残留溶剂后对含有a溶剂的罗库溴铵粗品进行真空微波干燥。
  3. 根据权利要求1或2所述的方法，其特征在于，所述方法包括：用a溶剂和罗库溴铵粗品混合成含罗库溴铵的液体，将该液体通过真空微波达到固化状态，继续真空微波干燥和/或使用其他干燥方法进行处理使其溶剂和水分达到符合药用要求的水平。
  4. 根据权利要求1所述的方法，其特征在于，所述方法包括对主要含有乙醚的罗库溴铵粗品进行流化干燥；
    进一步地，所述主要含有乙醚的罗库溴铵粗品为以乙醚为主要残留溶剂的罗库溴铵粗品或者经处理使得乙醚为主要残留溶剂的罗库溴铵粗品；
    进一步地，所述主要含有乙醚的罗库溴铵粗品为经反溶剂结晶法使得乙醚为主要残留溶剂的罗库溴铵粗品；
    进一步地，所述方法包括将罗库溴铵粗品通过反溶剂结晶法使罗库溴铵粗品中含有的主要残留溶剂为乙醚，然后进行流化干燥；
  5. 根据权利要求4所述的方法，其特征在于，所述反溶剂结晶法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体；
    进一步地，所述溶剂b为偶极非质子溶剂；
    进一步地，所述溶剂b为可以溶解罗库溴铵的溶剂
    进一步地，所述溶剂b选自二氯甲烷、乙腈、丙酮、二甲基亚砜(DMSO)、N,N-二甲基甲酰胺(DMF)和N,N-二甲基乙酰胺中的一种或多种；
    进一步地，所述溶剂b选自二氯甲烷、乙腈、丙酮和DMSO中的一种或多种；进一步为二氯甲烷；
    进一步地，所述溶剂c为反溶剂，进一步为与罗库溴铵不溶或微溶的溶剂；
    进一步地，所述溶剂c为乙醚或非乙醚溶剂；
    进一步地，所述溶剂c为非乙醚，选自异丙醚、甲基叔丁基醚、乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸丙酯、环己烷、正己烷、正庚烷中的一种或多种；
    进一步地，所述溶剂c为非乙醚，选自甲基叔丁基醚、乙酸甲酯、乙酸乙酯和正己烷中的一种或多种；
    进一步地，所述溶剂c为非乙醚、为甲基叔丁基醚、乙酸甲酯、乙酸乙酯或正己烷。
  6. 根据权利要求1、4或5所述的方法，其特征在于，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后进行流化干燥；
    进一步地，所述溶剂c为乙醚，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后进行流化干燥；
    进一步地，所述溶剂c为非乙醚时，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，用乙醚洗涤该固体，然后进行流化干燥。
  7. 根据权利要求1至6中任一项所述的方法，其特征在于，所述流化干燥所用的气体选自空气、氩气、氮气和二氧化碳气体中的一种或多种；
    进一步为空气、氩气、氮气或二氧化碳气体；
    进一步地，所述气体在和罗库溴铵固体接触前需经干燥处理；
    进一步地，所述干燥所用进风温度为15～60℃，进一步为25～45℃，更进一步为30～37℃。
  8. 根据权利要求6所述的方法，其特征在于，所述溶剂c为非乙醚时，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备罗库溴铵粗品固体，然后用a溶剂和该罗库溴铵粗品固体混合成含罗库溴铵的液体，对该液体进行真空微波干燥；
    进一步地，所述方法包括将罗库溴铵粗品溶解在b溶剂中制备罗库溴铵粗品溶液，将该罗库溴铵粗品溶液和溶剂c混合制备获得罗库溴铵粗品固体，然后用a溶剂和该罗库溴铵粗品固体混合成含罗库溴铵的液体，将该液体通过真空微波达到固化状态，继续真空微波干燥和/或使用其他干燥方法进行处理使其溶剂和水分达到符合药用要求的水平。
  9. 根据权利要求2或8所述的方法，其特征在于，所述a溶剂为吸收微波能力强的极性溶剂；
    进一步地，所述a溶剂选自C 1～C 4的一元醇、C 1～C 3的一元酸、丙酮、丁酮、四氢呋喃和水中的一种或多种；
    进一步地，所述a溶剂选自甲醇、乙醇、甲酸、乙酸、丙酮和水中的一种或多种；
    进一步地，所述a溶剂为甲醇、乙醇、甲醇和水、乙醇和水、甲醇和水和乙酸、或乙醇和水和乙酸。
    进一步地，所述真空微波的真空度为-0.01～-0.1Mpa，进一步为-0.06～-0.1Mpa，进一步为-0.08～-0.099Mpa；
    进一步地，所述真空微波的温度为10～60℃，进一步为10～50℃，进一步为10～40℃，进一步为20～40℃，进一步为30～40℃，更进一步为25～36℃；
    进一步地，所述其他干燥方法为本领域技术人员通常采用的干燥方法，或者可以选自减压(真空)干燥法、气流吹带干燥法和流化干燥法中的一种或多种。
  10. 根据权利要求1至7中任一项所述的方法精制后得到符合药用标准的罗库溴铵。
PCT/CN2019/096224 2018-07-20 2019-07-16 罗库溴铵粗品的精制方法 WO2020015659A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2021525354A JP7279900B2 (ja) 2018-07-20 2019-07-16 粗製臭化ロクロニウムの精製方法
EP19838199.8A EP3819304B1 (en) 2018-07-20 2019-07-16 Method for refining crude rocuronium bromide
US17/261,281 US11466049B2 (en) 2018-07-20 2019-07-16 Method for purifying crude rocuronium bromide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810804763.XA CN110734468B (zh) 2018-07-20 2018-07-20 罗库溴铵粗品的精制方法
CN201810804763.X 2018-07-20

Publications (1)

Publication Number Publication Date
WO2020015659A1 true WO2020015659A1 (zh) 2020-01-23

Family

ID=69164278

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/096224 WO2020015659A1 (zh) 2018-07-20 2019-07-16 罗库溴铵粗品的精制方法

Country Status (5)

Country Link
US (1) US11466049B2 (zh)
EP (1) EP3819304B1 (zh)
JP (1) JP7279900B2 (zh)
CN (1) CN110734468B (zh)
WO (1) WO2020015659A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113368115B (zh) * 2020-12-24 2022-09-20 上海药坦药物研究开发有限公司 一种罗库溴铵的药物组合物以及罗库溴铵的精制方法
US20230310749A1 (en) * 2022-04-05 2023-10-05 Hikma Pharmaceuticals Usa Inc. Rocuronium bromide prefilled syringe

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894369A (en) 1987-04-14 1990-01-16 Akzo N.V. Novel 2β-morpholino-androstane derivatives
US20050159398A1 (en) 2004-01-15 2005-07-21 Eliezer Adar Processes for the preparation of rocuronium bromide and intermediates thereof
US20060058275A1 (en) 2004-07-15 2006-03-16 Oded Friedman Processes for preparing stabilized, highly pure rocuronium bromide
GB2445764A (en) 2007-01-22 2008-07-23 Surfcontrol Plc Resource access filtering system and database structure for use therewith
CN101381390A (zh) 2007-09-05 2009-03-11 王加旺 溴铵类肌肉松弛剂的合成方法
CN101993470A (zh) * 2009-08-27 2011-03-30 济南诺和诺泰生物制药有限公司 一种制备高纯度罗库溴铵的工艺
EP2703408A1 (en) * 2011-04-25 2014-03-05 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for purifying rocuronium bromide

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7974892B2 (en) 2004-06-23 2011-07-05 Concur Technologies, Inc. System and method for expense management
US20060058276A1 (en) * 2004-07-15 2006-03-16 Oded Friedman Processes for the preparation and purification of rocuronium bromide
CN101397329B (zh) 2007-09-25 2011-04-27 重庆人本药物研究院 罗库溴铵结晶水合物的制备方法
ES2593502T3 (es) 2011-01-26 2016-12-09 Zhejiang Huahai Pharmaceutical Co., Ltd Método de preparación de rocuronio
CN103435674B (zh) * 2013-09-09 2015-05-06 山东新华制药股份有限公司 高纯度、高稳定性罗库溴铵的制备方法
CN103435675B (zh) * 2013-09-25 2015-05-13 宜昌人福药业有限责任公司 一种甾类肌松药的精制方法
CN204115430U (zh) * 2014-07-18 2015-01-21 陈长清 一种高效连续真空微波干燥机
CN105566433A (zh) 2016-01-15 2016-05-11 安徽悦康凯悦制药有限公司 一种罗库溴铵的生产工艺
CN107312055A (zh) * 2017-06-08 2017-11-03 江苏正大清江制药有限公司 一种罗库溴铵新的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894369A (en) 1987-04-14 1990-01-16 Akzo N.V. Novel 2β-morpholino-androstane derivatives
US20050159398A1 (en) 2004-01-15 2005-07-21 Eliezer Adar Processes for the preparation of rocuronium bromide and intermediates thereof
US20060058275A1 (en) 2004-07-15 2006-03-16 Oded Friedman Processes for preparing stabilized, highly pure rocuronium bromide
GB2445764A (en) 2007-01-22 2008-07-23 Surfcontrol Plc Resource access filtering system and database structure for use therewith
CN101381390A (zh) 2007-09-05 2009-03-11 王加旺 溴铵类肌肉松弛剂的合成方法
CN101993470A (zh) * 2009-08-27 2011-03-30 济南诺和诺泰生物制药有限公司 一种制备高纯度罗库溴铵的工艺
EP2703408A1 (en) * 2011-04-25 2014-03-05 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for purifying rocuronium bromide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3819304A4
ZHANG SHOUSHAN : "Microwave . . Vacuum Dryer", PHARMACEUTICAL FACTORY WORKSHOP, 31 October 2005 (2005-10-31), pages 1325 - 1328, XP009525592, ISBN: 7-5047-1824-7 *

Also Published As

Publication number Publication date
US20210261601A1 (en) 2021-08-26
EP3819304A1 (en) 2021-05-12
US11466049B2 (en) 2022-10-11
EP3819304A4 (en) 2021-08-25
EP3819304B1 (en) 2024-10-30
JP2021534225A (ja) 2021-12-09
CN110734468A (zh) 2020-01-31
CN110734468B (zh) 2021-04-16
JP7279900B2 (ja) 2023-05-23

Similar Documents

Publication Publication Date Title
WO2020015659A1 (zh) 罗库溴铵粗品的精制方法
Li et al. Preparation of uniform prednisolone microcrystals by a controlled microprecipitation method
SG185003A1 (en) A process for particle processing of active pharmaceutical ingredients
CN113214128B (zh) 一种小粒径的过氧化苯甲酰的制备方法
DE2415556C3 (de) Verfahren zur Herstellung von mit Glyoxal behandelten hochmolekularen Substanzen
Shen et al. Preparation of chitosan microparticles with diverse molecular weights using supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer
US20220362167A1 (en) Water-dispersible cannabidiol product and preparation method therefor
JP2001288201A (ja) セルロースエーテルの、酸触媒を作用させる、加水分解解重合方法
JP2883911B2 (ja) 水溶性酢酸セルロース及びその製造方法
US20140142293A1 (en) Method for Producing Purified Low-Substituted Hydroxypropyl Cellulose
CN100441196C (zh) 一种制备微粉化阿奇霉素的方法
CN103588846B (zh) 一种丙酸氟替卡松微粒的制备方法及其用途
CN104161729A (zh) 炎琥宁特种超细粉体制剂及其制备方法
CN107998998B (zh) 一种氧化还原响应性微球及制备和降解方法
CN108864069A (zh) 一种利伐沙班微粒及其制备方法与应用
CN106268730B (zh) 脱硝催化剂载体二氧化钛的制备方法
CN105832694A (zh) 一种青霉素类药物胶囊及其制法
KR100469195B1 (ko) 저치환도 히드록시프로필 셀룰로오즈 입자의 형성 방법
CN109970664B (zh) 吡嗪酰胺与富马酸的共晶产品及其超声波-微波耦合制备方法
CN110101668B (zh) 一种吉非替尼复合微粒的制备方法
CN108409821A (zh) 一种醋酸甲地孕酮纳米结晶的制备方法及醋酸甲地孕酮
CN113368115B (zh) 一种罗库溴铵的药物组合物以及罗库溴铵的精制方法
EP1056782A1 (de) Verfahren zur herstellung von gefällten stärkeestern
JPH09176208A (ja) 包接化合物およびその製法
CN114671964A (zh) 一种制备聚乙烯醇的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19838199

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021525354

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE