CN104844732B - Preparation method for sugammadex sodium - Google Patents
Preparation method for sugammadex sodium Download PDFInfo
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- CN104844732B CN104844732B CN201510142126.7A CN201510142126A CN104844732B CN 104844732 B CN104844732 B CN 104844732B CN 201510142126 A CN201510142126 A CN 201510142126A CN 104844732 B CN104844732 B CN 104844732B
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Abstract
The invention relates to a preparation method for a muscle relaxing antagonistic agent sugammadex sodium. The preparation method comprises the following steps: preparing sulfydryl gamma-cyclodextrin by taking halogenated gamma-cyclodextrin and thiourea as reactants; then, initiating sulfydryl-alkene click reaction by illuminating or using an initiator on sulfydryl gamma-cyclodextrin with acrylic acid or acrylic esters or sodium acrylate so as to prepare high-purity sugammadex sodium in a water phase. According to the preparation method for the sugammadex sodium, the the operation environment is gentle, the yield is increased, and the purifying process for the final product sugammadex sodium is simpler.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, specifically a kind of short of money dose of flesh pine is relaxed the preparation method of more glucose sodium.
Background technology
Relax more glucose sodium：Chemical name：Complete (2- carboxy ethyls) the thio-y-cvclodextrin sodium salts of the full deoxidation -6- of 6-, English：Su
γ dex, trade name：Bridion, relax more glucose sodium earliest by Organon Biosciences companies find, 2007
Organon companies are purchased by Schering Plough company (Schering-Plough).Schering Plough in 2009 is closed with Merck (Merck)
And.At present easypro more glucose sodium possesses for Merck and sells.
FDA in 2008 worries that anaphylaxiss may be caused, and rejects the easypro more glucose sodium application for quotation of Schering Plough；2009
Bottom, the more glucose sodium that relaxes is in European granted listing；Quickly Merck ＆ Co., Inc. starts to set up 11 Clinical Medical Centers in China, starts and relaxes
Three phases clinical research of the more glucose sodium in China.
The more glucose sodium that relaxes is used to reverse conventional use of neuromuscular blocking drug Rocuronium Bromide or vecuronium bromide effect, can stand
Reverse the used Rocuronium Bromide effect of adult, the used Rocuronium Bromide of conventional reverse Children and teenager (2～17 years old)
Effect.The more glucose sodium that relaxes is lax bonding agent (the selective relaxant binding of first and unique selectivity
Agent, SRBA), it is first, anesthetics field significant pharmaceutical progress over 20 years, it is described as landmark flesh pine antagonist.
Relax more glucose sodium flesh pine antagonism mechanism be：The more glucose sodium that relaxes chelates sequestered Rocuronium Bromide point in blood plasma
Son, makes plasma free type Rocuronium Bromide concentration drastically decline, effect compartment (neuromuscular junction) and central compartment (blood plasma) it
Between formed a Concentraton gradient so that the Rocuronium Bromide molecule in effect compartment is transported to rapidly central authorities along concentration difference
Room, this causes the Rocuronium Bromide concentration of effect compartment to decline rapidly, ties with the nicotine-like acetylcholinergic receptor of neuromuscular junction
The rapid separate out of Rocuronium Bromide of conjunction, thus reversed the Muscle relaxation of Rocuronium Bromide.More glucose sodium relax to the short of money of muscle relaxant
Anti- is with high selectivity.Because its inner chamber has complementarity, therefore selective antagonism steroidal with Rocuronium Bromide molecule
Class muscle relaxant Rocuronium Bromide, also has good antagonism to similar drugs vecuronium bromide, and to benzyl iloquinoline derivative non depolarization
Muscle relaxant (such as atracurium) and depolarizing relaxant (succinylcholine) are without antagonism.
Relax more glucose sodium by Akzo Nobel disclosed in United States Patent (USP) US6670340, preparation technology is such as in US6670340
Under：
Thereafter by Davuluri more glucose sodium preparation technology of relaxing is improved in patent WO2012/025937A1,
Improve as follows：
Two kinds of route key intermediates are different, but final step is all to use 3- mercaptopropionic acids, sodium hydride and halo ring paste
Smart (iodo, chloro or bromo cyclodextrin) reacts in DMF system.But the reaction is in actual mechanical process
In there is problems with：
1st, sodium hydride is high risk material, and it is also flammable explosive gas that a large amount of hydrogen are produced after feeding intake, while sodium hydride
Distributed and saved can introduce a large amount of unknown impurities in mineral oil to reaction, affect final products purity；
2nd, the reaction require it is anhydrous, but anhydrous condition to cavity cyclodextrin class of molecule implement it is extremely complex,
Micro-moisture is mixed into reaction can cause occur 7 replacements or 6 replacements in product, this impurity extremely difficult separation substituted less than 8, affect
Product purity；
3rd, gel phenomenon occurs in DMF, easily in sodium hydride causes the reaction vessel edge cannot be by
Dispersed with stirring, makes reaction uneven；
4th, after the reaction of DMF organic solvent system terminates, the precipitation process of ethanol is needed, consumes a large amount of
Ethanol, and after ethanol mixes with DMF, two kinds of organic solvents all cannot recovery.
When laboratory synthesizes on a small scale, the problem for existing can be ignored both the above preparation technology, but further expand
After big preparative-scale, what disadvantages described above will be showed more projects, and so as to affecting final products quality and increasing cost, is not suitable for
Large-scale production.
The content of the invention
For the deficiencies in the prior art, the present invention provides a kind of system of the easypro more glucose sodium for amplifying production simple to operate, easy
Preparation Method, using halo gamma-cyclodextrin and acrylic acid or esters of acrylic acid or sodium acrylate as reactant, by using illumination
Or initiator causes sulfydryl-alkene click-reaction mutually to prepare the easypro more glucose sodium of high-purity in water.Operating environment is gentle, and improves
Yield, and make the easypro more glucose sodium purifying process of final products more simple.
Technical scheme is as follows：
A kind of preparation method of the more glucose sodium that relaxes, including step is as follows：
(1) halo gamma-cyclodextrin is dissolved in DMF, is subsequently adding thiourea, the halo γ-ring
Dextrin is with the mass ratio of thiourea：1:1.5～4,70-90 DEG C is heated to, stirring is lower to react 10～12 hours, and concentration of reaction solution is extremely
Solid sediment separate out, by solid sediment add 0.2～0.3mol/L of concentration sodium hydrate aqueous solution at 70-90 DEG C
Stirring reaction 0.5～3 hour, adjusts pH value to 2～3 after concentration, ethanol precipitation obtains precipitate, precipitate washing, recrystallization, system
Obtain sulfydryl gamma-cyclodextrin；
(2) sulfydryl gamma-cyclodextrin obtained in step (1) and acrylic acid or acrylate or acrylic acid sodium salt is in aqueous
Mixing and stirring, then the ultraviolet light 1-24 hour at 10-20 DEG C, obtains reactant liquor；Acrylic acid, acrylate or propylene
The addition of hydrochlorate is 8-21 times of mercapto-cyclodextrin mole；
(3) reacting liquid pH value is adjusted to more than 8, be then concentrated into that electrical conductivity is constant by NF membrane, obtain the place after nanofiltration
Reason liquid, after the treatment fluid after nanofiltration is dried, obtains final product the more glucose sodium that relaxes.
Currently preferred, described halo cyclodextrin is the full deoxidation -6- perhalogenos-gamma-cyclodextrins of 6-, further excellent
Choosing, described gamma-cyclodextrin be the full deoxidation -6- periodos-gamma-cyclodextrins of 6-, the full deoxidation -6- perbromo-s-gamma-cyclodextrins of 6- or
Full deoxidation -6- perchloro-s-the gamma-cyclodextrins of 6-.
6- is complete, and deoxidation -6- perhalogenos-gamma-cyclodextrin can be obtained by gamma-cyclodextrin halogenation, preparation method reference literature
Methods for Selective Modifications of Cyclodextrins,Chem.Rev.1998,98,1977-
1996。
Preferably, the halo gamma-cyclodextrin is with the mass ratio of thiourea：1:1.8～2.5.
Currently preferred, it is first concentrating under reduced pressure reactant liquor to anti-that concentration of reaction solution to solid precipitation is separated out in step (1)
Liquid product is answered to be the 1/4～1/2 of DMF volume, the ethanol for being subsequently adding 6～9 times of the volume of concentrate is sunk
Form sediment.
Currently preferred, step (1), every gram of solid sediment adds 0.2～0.3mol/L sodium hydrate aqueous solution 50-
100ml。
It is currently preferred, in step (1), the salt acid for adjusting pH value of concentration 30-35wt% to 2～3.
Currently preferred, ethanol precipitation is that reactant liquor volume 6 is added in the reactant liquor adjusted after pH value in step (1)
～9 times of ethanol is precipitated.
It is currently preferred, ultraviolet light time 10-20 hours in step (2), precipitate washing, recrystallization is will be heavy
Starch is added in frozen water and carries out washing 2～3 times, and recrystallization is then carried out in 10 times of quality pure water.
Currently preferred, the addition of acrylic acid, acrylate or acrylates is sulfydryl gamma-cyclodextrin mole
18-20 times.
Currently preferred, described acrylate is acrylic acid methyl ester., ethyl acrylate.
Currently preferred, described acrylates are sodium acrylate.
Currently preferred, the NaOH of 1～2mol/L adjusts reactant liquor to pH value to 9～10 used in step (3).
Currently preferred, NF membrane is the NF membrane using molecular cut off for 100-1500MWCO in step (3).
Currently preferred, constant to electrical conductivity in step (3), electrical conductivity constant range is 5000-8000 μ S/cm.
The present invention is obtained easypro more glucose with gamma-cyclodextrin as starting point through halo, sulfhydrylation, sulfydryl-alkene click-reaction
Sodium, it is also possible to directly adopt halo gamma-cyclodextrin for starting point, through sulfhydrylation, sulfydryl-alkene click-reaction is obtained, although this
It is bright with gamma-cyclodextrin as the more former technique of starting point with gamma-cyclodextrin as starting point, through halo, the step of mercaptopropionic acidization two prepare, although
A step is increased, but click-reaction of the present invention is introduced and makes practical operation more simple, and ultimate yield is also higher.And United States Patent (USP)
Product yield obtained in preparation method mercaptopropionic acid disclosed in US6670340 is only disclosed in 43%, WO2012/025937A1
Product yield obtained in method is 60%, the preparation method of the present invention, and sulfhydrylation step yield 93%, click on anti-by sulfydryl-alkene
Answer step yield 90%, total recovery 84%, far above existing preparation technology.The preparation of the mercapto-cyclodextrin of the present invention, is not required to
To be activated using alkali, only need to be reacted using thiourea, be introduced without other impurities.Particularly using halo gamma-cyclodextrin
For initiation material when, the step is aqueous to system insensitive, a small amount of aqueous reduction for being not result in substitution value.
The preparation method of the present invention is first by the thiourea of halo gamma-cyclodextrin and 1.5～3 mass in N, N- dimethyl formyls
Mix homogeneously in amine, reacted prepared sulfydryl gamma-cyclodextrin, then sulfydryl gamma-cyclodextrin and 8-20 times of mole acrylic acid or
In 10-100 times of mass aqueous solution, reaction 1-24 is little for room temperature or stirring in water bath, UV illumination for acrylate or sodium acrylate
When；Slowly with NaOH regulation system pH value to more than 8；The step employs now more ripe sulfydryl-end alkene clicking chemistry,
By the splicing of junior unit, the chemosynthesis of varied molecule are completed with carrying out fast and reliable, come simple high by click-reaction
Effect ground obtains molecular diversity.
The equation of its reaction is as follows：
Acrylic acid and acrylic acid sodium salt, inherently can dissolve each other with water, and also dissolubility is good in water for sulfydryl gamma-cyclodextrin
It is good.Although acrylate is slightly soluble in water, but after the stirring that feeds intake, solution also has no substantially layering in uniform state, it may be possible to by
Sulfydryl gamma-cyclodextrin helps it to be dispersed in water in the solubilising power of water phase.Reactant liquor removes small molecule with NF membrane.It is actual anti-
Answer process with sulfydryl gamma-cyclodextrin calculated yield should close 100%, but final step yield 90%.Yield losses mainly occur
In nanofiltration process, it may be possible in due to the distribution of nanofiltration retaining molecular weight not complete set, still have a small amount of aperture larger, cause to take off
During except small molecule, a small amount of product is also lost in therewith.Nanofiltration process is controlled, when being reacted using acrylic acid and sodium acrylate,
Direct detection filter liquor electrical conductivity is in 150 μ scm-1 or constant trapped fluid electrical conductivity.When using propanoic acid olefin(e) acid ester, electricity
Also need to use chloroform extraction beyond conductance detection, be aided with gas phase detection method, to determine that impurity removal is clean.
By product from aqueous phase separation obtain solid the step of, can be with using many modes.But should be specifically noted that the more glucose that relaxes
Sodium has sulfide based structural, and the processing procedure with oxidisability can destroy product, causes purity to decline.
Beneficial effect
1st, the present invention replaces existing work by changing higher, more environmentally friendly, the more efficient sulfydryl of safety-end alkene click-reaction
Traditional sulfydryl halogen substiuted reacts to prepare target product in skill, and changing original route needs to be hydrogenated using high risk material
Sodium, and the easy gelation of reaction system and the drawbacks of easily there is low substitution product in DMF, operating environment temperature
With, and yield is improve, and make the purifying process of the easypro more glucose sodium of final products more simple.It is significantly better than now to commonly use and prepares
Technique, is that easypro more glucose sodium on a large scale have laid a good foundation by preparation.
Specific embodiment
With reference to embodiment, the present invention will be further described,
Raw material used in embodiment：
Full deoxidation -6- the perchloro-s of 6--gamma-cyclodextrin source, reference literature Methods for Selective
The method of Modifications of Cyclodextrins, Chem.Rev.1998,98,1977-1996 is obtained.
Thiourea, Chemical Reagent Co., Ltd., Sinopharm Group analyzes pure；
DMF, Laiyang Shandong Province chemical plant is analyzed pure；
Acrylic acid is originated, Tianjin Development Zone Le Tai Chemical Co., Ltd.s, is analyzed pure；
Acrylic acid methyl ester., Tianjin Development Zone Le Tai Chemical Co., Ltd.s analyze pure；
Sodium acrylate, Tianjin Kermel Chemical Reagent Co., Ltd. analyzes pure.
Embodiment 1
The easypro more glucose sodium preparation method of one kind, including step is as follows：
(1) the full deoxidation -6- perchloro-s of 6--gamma-cyclodextrin 20g (13.9mmol) and thiourea 42g (556mmol) is added to
In DMF 600ml, stir lower 90 DEG C and react 12 hours；First concentrating under reduced pressure reactant liquor to reactant liquor volume is N,
The 1/4 of dinethylformamide volume, the ethanol for being subsequently adding 8 times of the volume of concentrate is precipitated.Gained solid sediment adds
Enter in the sodium hydrate aqueous solution 750ml of concentration 0.25mol/L in 90 DEG C of stirring reactions 2 hours, obtain mixed reaction solution, reduce pressure dense
Contracting liquid volume adjusts pH to 2 to the 1/4 of mixed reaction solution volume with the hydrochloric acid of 35wt%, in the reactant liquor adjusted after pH value
The ethanol for adding 8 times of reactant liquor volume is precipitated, and precipitate is washed with frozen water, then the recrystallization in 10 times of quality pure water,
The full mercapto-y-cyclodextrin 18.4g of the full deoxidation -6- of prepared white solid 6-, yield 93%.(m/z=1426m+H+, 1448m+Na
+)。
(2) by the full mercapto-y-cyclodextrin 15g (10.5mmol) of the full deoxidation -6- of prepared 6- and acrylic acid 12.2g
(168mmol) add in 600ml water after stirring and dissolving, at 20 DEG C, with ultra violet lamp, continue stirring reaction 6 hours；
(3) NaOH of 2mol/L is added in step (2) gained reactant liquor, pH value is adjusted to 9；
It is constant to the μ S/cm of electrical conductivity 7000 using the nanofiltration membrane treatment reactant liquor that molecular cut off is 1000MWCO；
Decompression rotary evaporation removing moisture, obtains white solid, and 60 DEG C of vacuum is dried overnight, and must relax more glucose sodium product
18.9g, yield 90%.1HNMR(D2O):2.47-2.51(m,16H),2.84-2.88(m,16H),3.01-3.03(t,8H),
(m, the 8H) ppm of 3.92-3.97 (m, 8H), 4.04-4.06 (m, 8H), 5.19.
Embodiment 2
The easypro more glucose sodium preparation method of one kind, including step is as follows：
(1) the full deoxidation -6- perchloro-s of 6--gamma-cyclodextrin 20g (13.9mmol) and thiourea 42g (556mmol) is added to
In DMF 600ml, stir lower 90 DEG C and react 12 hours；First concentrating under reduced pressure reactant liquor to reactant liquor volume is N,
The 1/4 of dinethylformamide volume, the ethanol for being subsequently adding 6 times of the volume of concentrate is precipitated.Gained solid sediment adds
Enter in the sodium hydrate aqueous solution 750ml of concentration 0.25mol/L in 90 DEG C of stirring reactions 2 hours, obtain mixed reaction solution, reduce pressure dense
Contracting liquid volume adjusts pH to 2 to the 1/4 of mixed reaction solution volume with the hydrochloric acid of 35wt%, in the reactant liquor adjusted after pH value
The ethanol for adding 6 times of reactant liquor volume is precipitated, and precipitate is washed with frozen water, then the recrystallization in 10 times of quality pure water,
The full mercapto-y-cyclodextrin 23g of the full deoxidation -6- of prepared white solid 6-,
(2) the full mercapto-y-cyclodextrin 15g (10.5mmol) of the full deoxidation -6- of prepared 6- and acrylic acid methyl ester. 15mL are added
In 600ml water after stirring and dissolving, at 20 DEG C, with ultra violet lamp, continue stirring reaction 3 hours；
Less than (3) 40 DEG C vacuum rotary steam concentration of reaction solution are in solid, shaped；
(4) solid is flowed back 2 hours with 1M NaOH 500mL dissolvings；
(5) it is constant to the μ S/cm of electrical conductivity 6000 using the nanofiltration membrane treatment reactant liquor that molecular cut off is 1000MWCO；
(6) reduce pressure rotary evaporation removing moisture, obtains white solid, and 60 DEG C of vacuum is dried overnight, and must relax more glucose sodium product
16.0。
Embodiment 3
With the easypro more glucose sodium preparation method described in embodiment 1, difference is：
Full deoxidation -6- periodos-gamma-cyclodextrin the 24g of 6- and thiourea 42g is added to N, N- dimethyl formyls in step (1)
In amine 600ml, 85 DEG C are heated to, the lower reaction of stirring 12 hours, first concentrating under reduced pressure reactant liquor to reactant liquor volume is N, N- diformazans
The 1/4 of base Methanamide volume, the ethanol for being subsequently adding 9 times of the volume of concentrate is precipitated.Gained solid sediment adds concentration
In 85 DEG C of stirring reactions 2 hours in the sodium hydrate aqueous solution 750ml of 0.2mol/L, mixed reaction solution, concentrating under reduced pressure liquid are obtained
Volume adjusts pH to 2 to the 1/4 of mixed reaction solution volume with the hydrochloric acid of 30wt%, adds in the reactant liquor adjusted after pH value anti-
The ethanol that liquid accumulates 9 times is answered to be precipitated, with frozen water washing, then the recrystallization in 10 times of quality pure water, is obtained white precipitate
The full mercapto-y-cyclodextrins of the full deoxidation -6- of color solid 6-.
Embodiment 4
With the easypro more glucose sodium preparation method described in embodiment 1, difference is：
Step (2), by the full mercapto-y-cyclodextrin 15g of the full deoxidation -6- of prepared 6- and sodium acrylate 13g 600ml water is added
After middle stirring and dissolving, below 20 DEG C of water-bath temperature control, with ultra violet lamp, continue stirring reaction 3 hours.
It is final to obtain the easypro more glucose sodium 17.9g of white solid, yield 85%.
Claims (8)
1. a kind of preparation method of the more glucose sodium that relaxes, including step is as follows：
(1) halo gamma-cyclodextrin is dissolved in DMF, is subsequently adding thiourea, the halo γ-ring paste
Essence is with the mass ratio of thiourea：1:1.5～3,70-90 DEG C is heated to, stirring is lower to react 10～12 hours, first concentrating under reduced pressure reaction
Liquid to reactant liquor volume is the 1/4～1/2 of DMF volume, is subsequently adding the ethanol of 6～9 times of the volume of concentrate
Carry out being precipitated to solid sediment precipitation, solid sediment is added in the sodium hydrate aqueous solution of 0.2～0.3mol/L of concentration
Stirring reaction 0.5～3 hour at 70-90 DEG C, adjusts pH value to 2～3 after concentration, ethanol precipitation obtains precipitate, and precipitate is washed
Wash, recrystallization, sulfydryl gamma-cyclodextrin is obtained；
(2) sulfydryl gamma-cyclodextrin is stirred with the aqueous solution of acrylic acid or acrylate or acrylic acid sodium salt obtained in step (1)
Mix uniform, then the ultraviolet light 1-24 hour at 10-20 DEG C, obtains reactant liquor；Acrylic acid, acrylate or acrylic acid sodium salt
Addition be 8-21 times of mercapto-cyclodextrin mole；
(3) reacting liquid pH value is adjusted to more than 8, is then concentrated into that electrical conductivity is constant by NF membrane, obtain the treatment fluid after nanofiltration,
After treatment fluid after nanofiltration is dried, the more glucose sodium that relaxes is obtained final product.
2. more glucose sodium preparation method of relaxing according to claim 1, it is characterised in that described halo gamma-cyclodextrin is
Full deoxidation -6- perhalogenos-the gamma-cyclodextrins of 6-.
3. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that described gamma-cyclodextrin be 6-
Full deoxidation -6- periodos-gamma-cyclodextrin, the full deoxidation -6- perbromo-s-gamma-cyclodextrins of 6- or the full deoxidation -6- perchloro-s-γ of 6- -
Cyclodextrin.
4. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that the halo gamma-cyclodextrin with
The mass ratio of thiourea is：1:1.8～2.5.
5. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that step (1), every gram of solid precipitation
Thing adds 0.2～0.3mol/L sodium hydrate aqueous solution 50-100ml.
6. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that in step (1), concentration
The salt acid for adjusting pH value of 30-35wt% is to 2～3；Ethanol precipitation is that reactant liquor volume 6 is added in the reactant liquor adjusted after pH value
～9 times of ethanol is precipitated.
7. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that step（1）Middle precipitate washing,
Recrystallization is precipitate to be added in frozen water to carry out washing 2～3 times, and recrystallization, step are then carried out in 10 times of quality pure water
(2) ultraviolet light time 10-20 hours in.
8. it is according to claim 1 relax more glucose sodium preparation method, it is characterised in that acrylic acid or acrylate or third
The addition of olefin(e) acid sodium salt is 18-20 times of sulfydryl gamma-cyclodextrin mole, described acrylate be acrylic acid methyl ester., third
Olefin(e) acid ethyl ester, described acrylic acid sodium salt is sodium acrylate.
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| WO2017089978A1 (en) | 2015-11-25 | 2017-06-01 | Fresenius Kabi Antiinfectives S.R.L. | Crystalline forms of per-chloro-gamma-cyclodextrines |
| CN108290964B (en) * | 2015-11-25 | 2021-07-09 | 费森尤斯卡比依普莎姆有限责任公司 | Improved process for the preparation of sugammadex and intermediates thereof |
| WO2017163165A1 (en) | 2016-03-22 | 2017-09-28 | Fresenius Kabi Anti-Infectives S.r.l. | An improved process for the preparation of sugammadex |
| JP6692941B2 (en) * | 2016-06-29 | 2020-05-27 | 北京叡創康泰医薬研究院有限公司Ｂｅｉｊｉｎｇ Ｃｒｅａｔｒｏｎ Ｉｎｓｔｉｔｕｔｅ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｒｅｓｅａｒｃｈ Ｃｏ．， Ｌｔｄ． | Method for manufacturing and purifying sugammadex |
| US10526422B2 (en) | 2016-06-29 | 2020-01-07 | Beijing Creatron Institute Of Pharmaceutical Research Co., Ltd. | Process for preparation and purification of Sugammades sodium |
| CN107778383B (en) * | 2016-08-24 | 2020-03-10 | 王炳永 | Refining method of sugammadex sodium |
| CN108929390A (en) * | 2017-05-23 | 2018-12-04 | 合肥博思科创医药科技有限公司 | A kind of method that microwave reaction synthesizes the more glucose sodium that relaxes |
| CN109021148B (en) * | 2017-06-08 | 2020-11-10 | 天津科伦药物研究有限公司 | Method for preparing sugammadex sodium |
| CN112724280A (en) * | 2017-06-08 | 2021-04-30 | 天津科伦药物研究有限公司 | Method for purifying sugammadex sodium |
| CN107325203B (en) * | 2017-07-07 | 2019-09-24 | 中国大冢制药有限公司 | A kind of gamma-cyclodextrin modifier and its preparation method and application |
| CN107325204B (en) * | 2017-07-07 | 2019-09-24 | 中国大冢制药有限公司 | A kind of preparation method for the more glucose sodium that relaxes |
| TWI703163B (en) * | 2017-08-23 | 2020-09-01 | 台耀化學股份有限公司 | Method for preparing sugammadex sodium and crystalline form thereof |
| CN107686530B (en) * | 2017-10-16 | 2019-09-13 | 河北坤安药业有限公司 | A kind of synthetic method for the more glucose sodium that relaxes |
| CN110156917B (en) * | 2018-02-10 | 2021-07-16 | 合肥博思科创医药科技有限公司 | Method for preparing sugammadex sodium by applying polymer-loaded trivalent phosphine compound |
| CN110144019B (en) * | 2018-02-10 | 2021-03-23 | 合肥博思科创医药科技有限公司 | Refining and purifying method of sugammadex sodium crude product |
| KR102054228B1 (en) * | 2018-05-28 | 2019-12-10 | 연성정밀화학(주) | Process for Preparing Sugammadex Sodium |
| CN110615858B (en) * | 2018-06-20 | 2023-10-20 | 鲁南制药集团股份有限公司 | Preparation method of sodium sugammadex intermediate |
| CN110615860A (en) * | 2018-06-20 | 2019-12-27 | 江苏恒瑞医药股份有限公司 | Method for purifying sugammadex sodium |
| CN111518228B (en) * | 2019-02-01 | 2022-08-05 | 鲁南制药集团股份有限公司 | Preparation method of sugammadex sodium |
| CN112830981A (en) * | 2019-11-22 | 2021-05-25 | 北京泰德制药股份有限公司 | Intermediate of sugammadex sodium and preparation method thereof |
| CN111574642B (en) * | 2020-06-23 | 2021-03-19 | 湖南如虹制药有限公司 | Purification method of sugammadex sodium |
| CN115433293B (en) * | 2022-09-13 | 2023-08-18 | 苏州弘森药业股份有限公司 | Preparation method of sodium gluconate |
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