CN104844732A - Preparation method for sugammadex sodium - Google Patents
Preparation method for sugammadex sodium Download PDFInfo
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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 the preparation method of the easypro more glucose sodium of a kind of short of money dose of flesh pine.
Background technology
Relax more glucose sodium: chemical name: complete (2-carboxy ethyl) the thio-y-cvclodextrin sodium salt of the full deoxidation of 6--6-, English: Su γ dex, trade(brand)name: Bridion, the more glucose sodium that relaxes is found by Organon Biosciences company the earliest, and within 2007, Organon company is purchased by Schering Plough company (Schering-Plough).Schering Ploughs in 2009 and Merck (Merck) merge.The more glucose sodium that relaxes at present is that Merck has and sells.
FDA in 2008 worries to cause anaphylaxis, rejects the easypro more glucose sodium application for quotation of Schering Plough; The end of the year 2009, more glucose sodium granted listing in Europe of relaxing; Hen Kuai Merck & Co., Inc. starts to set up 11 Clinical Medical Centers in China, starts easypro more glucose sodium in the three phases clinical study of China.
Easypro more glucose sodium, for reversing neuromuscular blocking drug Zemuron or the vecuronium bromide effect of conventional use, can reverse the used Zemuron effect of adult, conventional reverse Children and teenager (2 ~ 17 years old) used Zemuron effect immediately.The more glucose sodium that relaxes is that first and unique selectivity relaxes bonding agent (selective relaxant binding agent, SRBA), is first, narcotic field significant pharmaceutical progress over 20 years, is described as the loose antagonist of landmark flesh.
The mechanism of easypro more glucose sodium flesh pine antagonism is: relax more glucose sodium chelating sequestered Zemuron molecule in blood plasma, plasma free type Zemuron concentration is sharply declined, a concentration gradient is formed between effect compartment (neuromuscular junction) and central compartment (blood plasma), thus make to be in effect compartment Zemuron molecule be transported to central compartment rapidly along concentration difference, this makes the Zemuron concentration of effect compartment decline rapidly, the Zemuron be combined with the nicotine-like acetylcholinergic receptor of neuromuscular junction dissociates out rapidly, thus the Muscle relaxation of Zemuron has been reversed.The more antagonism of glucose sodium to muscle relaxant that relax has high selectivity.Because its inner chamber has complementarity with Zemuron molecule, therefore optionally antagonism steroid muscle relaxant Zemuron, also good antagonistic action is had to similar drugs vecuronium bromide, and to benzyl iloquinoline derivative non-depolarizing muscular relaxant (as atracurium etc.) and depolarizing relaxant (sux-cert) without antagonistic action.
The more glucose sodium that relaxes is open in US Patent No. 6670340 by Akzo Nobel, and in US6670340, preparation technology is as follows:
Thereafter in patent WO2012/025937A1, more glucose sodium preparation technology of relaxing is improved by Davuluri, improves as follows:
Two kinds of route key intermediates are different, but final step is all use 3-thiohydracrylic acid, sodium hydride and halo cyclodextrin (iodo, chloro or bromo cyclodextrin) to react in DMF system.But there is following problem in this reaction in actual mechanical process:
1, sodium hydride is high risk material, and producing a large amount of hydrogen after feeding intake also is flammable explosive gas, and sodium hydride dispersion is kept in mineral oil simultaneously, introduces a large amount of unknown impuritie can to reaction, affect the finished product purity;
2, this reaction requires anhydrous, but anhydrous condition implements very complicated to the cyclodextrin class of molecule with cavity, and micro-moisture is mixed into reaction can be caused occurring in product that 7 replace or 6 replacements, and this impurity replaced less than 8 is extremely difficult to be separated, and affects product purity;
3, sodium hydride is in DMF, very easily occurs that gel phenomenon causes reaction vessel edge to be stirred dispersion, makes reaction uneven;
4, after the reaction of DMF organic solvent system terminates, need the precipitation process of ethanol, consume a large amount of ethanol, and after ethanol mixes with DMF, two kinds of organic solvents all cannot recovery.
When above two kinds of preparation technologies synthesize on a small scale in laboratory, Problems existing can be ignored, but after expanding preparative-scale further, it is more outstanding that above defect just can show, thus affects the finished product quality and increase cost, is not suitable for scale operation.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method amplifying the easypro more glucose sodium produced simple to operate, easy, adopt halo γ-cyclodextrin and vinylformic acid or esters of acrylic acid or sodium acrylate as reactant, cause sulfydryl-alkene click-reaction by using illumination or initiator and prepare high purity at aqueous phase and to relax more glucose sodium.Operating environment is gentle, and improves yield, and the finished product are relaxed, and more glucose sodium purifying process is more simple.
Technical scheme of the present invention is as follows:
A preparation method for easypro more glucose sodium, comprises step as follows:
(1) halo γ-cyclodextrin is dissolved in N, in dinethylformamide, then thiocarbamide is added, the mass ratio of described halo γ-cyclodextrin and thiocarbamide is: 1:1.5 ~ 4, be heated to 70-90 DEG C, stir lower reaction 10 ~ 12 hours, concentration of reaction solution is separated out to solid sediment, solid sediment to be added in the aqueous sodium hydroxide solution of concentration 0.2 ~ 0.3mol/L at 70-90 DEG C stirring reaction 0.5 ~ 3 hour, adjust ph to 2 ~ 3 after concentrated, alcohol settling obtains throw out, and throw out washs, recrystallization, obtained sulfydryl γ-cyclodextrin;
(2) the sulfydryl γ-cyclodextrin that step (1) is obtained and vinylformic acid or acrylate or vinylformic acid sodium salt mixing and stirring in aqueous, then UV-irradiation 1-24 hour at 10-20 DEG C, obtains reaction solution; The addition of vinylformic acid, acrylate or acrylate is 8-21 times of mercapto-cyclodextrin molar weight;
(3) regulate more than reacting liquid pH value to 8, be then concentrated into specific conductivity by nanofiltration membrane constant, obtain the treatment solution after nanofiltration, after the treatment solution drying after nanofiltration, must relax more glucose sodium.
The present invention is preferred, described halo cyclodextrin is the full deoxidation of 6--6-perhalogeno-γ-cyclodextrin, further preferably, described γ-cyclodextrin is the full deoxidation of 6--6-periodo-γ-cyclodextrin, the full deoxidation of 6--6-perbromo-γ-cyclodextrin or the full deoxidation of 6--6-perchloro-γ-cyclodextrin.
The full deoxidation of 6--6-perhalogeno-γ-cyclodextrin can be obtained by γ-cyclodextrin halogenation, preparation method's reference literature Methodsfor Selective Modifications of Cyclodextrins, Chem.Rev.1998,98,1977-1996.
Preferably, the mass ratio of described halo γ-cyclodextrin and thiocarbamide is: 1:1.8 ~ 2.5.
The present invention is preferred, and in step (1), concentration of reaction solution to solid precipitation is separated out as first concentrating under reduced pressure reaction solution to reaction solution volume is 1/4 ~ 1/2 of DMF volume, and the ethanol then adding concentrated solution volume 6 ~ 9 times precipitates.
The present invention is preferred, and step (1), every gram of solid sediment adds 0.2 ~ 0.3mol/L aqueous sodium hydroxide solution 50-100ml.
The present invention is preferred, in step (1), and salt acid for adjusting pH value to 2 ~ 3 of working concentration 30-35wt%.
The present invention is preferred, and in step (1), alcohol settling is that the ethanol adding reaction solution volume 6 ~ 9 times in the reaction solution after adjust ph precipitates.
The present invention is preferred, step (2) medium ultraviolet rayed time 10-20 hour, and throw out washs, and recrystallization carries out washing 2 ~ 3 times for being added in frozen water by throw out, then in 10 times of quality pure water, carries out recrystallization.
The present invention is preferred, and the addition of vinylformic acid, acrylate or acrylate is 18-20 times of sulfydryl γ-cyclodextrin molar weight.
The present invention is preferred, and described acrylate is methyl acrylate, ethyl propenoate.
The present invention is preferred, and described acrylate is sodium acrylate.
The present invention is preferred, uses the NaOH of 1 ~ 2mol/L to regulate reaction solution to pH value to 9 ~ 10 in step (3).
The present invention is preferred, and in step (3), nanofiltration membrane is use the nanofiltration membrane that molecular weight cut-off is 100-1500MWCO.
The present invention is preferred, and constant to specific conductivity in step (3), specific conductivity constant range is 5000-8000 μ S/cm.
The present invention take γ-cyclodextrin as starting point, through halo, sulfhydrylation, the obtained more glucose sodium that relaxes of sulfydryl-alkene click-reaction, also halo γ-cyclodextrin can be directly adopted to be starting point, through sulfhydrylation, sulfydryl-alkene click-reaction obtains, although the present invention take γ-cyclodextrin as the more former technique of starting point take γ-cyclodextrin as starting point, through halo, the preparation of thiohydracrylic acidization two step, although add a step, click-reaction of the present invention is introduced and is made actually operating more simple, and ultimate yield is also higher.And the product yield that preparation method's thiohydracrylic acidization disclosed in US Patent No. 6670340 obtains is only 43%, the product yield that method disclosed in WO2012/025937A1 obtains is 60%, preparation method of the present invention, sulfhydrylation step yield is 93%, sulfydryl-alkene click-reaction step yield 90%, total recovery 84%, far above existing preparation technology.The preparation of mercapto-cyclodextrin of the present invention, does not need to use alkali to activate, only thiocarbamide need be used to react, introduce without other impurity.Particularly when using halo γ-cyclodextrin for starting raw material, this step is moisture insensitive to system, on a small quantity the moisture reduction that can not cause substitution value.
Preparation method of the present invention first by the thiocarbamide of halo γ-cyclodextrin and 1.5 ~ 3 quality at N, mix in dinethylformamide, through reacting obtained sulfydryl γ-cyclodextrin, then sulfydryl γ-cyclodextrin and 8-20 times of molar weight vinylformic acid or acrylate or sodium acrylate are in 10-100 times of mass aqueous solution, room temperature or stirring in water bath, UV illumination reaction 1-24 hour; Slowly with NaOH regulation system pH value to more than 8; This step have employed now comparatively ripe sulfydryl-end alkene clicking chemistry, by the splicing of junior unit, completes the chemosynthesis of varied molecule fast and reliablely, simply obtains molecular diversity efficiently by click-reaction.
The equation of its reaction is as follows:
Vinylformic acid and vinylformic acid sodium salt, inherently can dissolve each other with water, sulfydryl γ-cyclodextrin also favorable solubility in water.Although acrylate is slightly soluble in water, after the stirring that feeds intake, solution also has no obvious layering in uniform state, may be help it to be dispersed in water by sulfydryl γ-cyclodextrin at the solubilising of aqueous phase.Reaction solution nanofiltration membrane removes small molecules.Real reaction process should close to 100% with sulfydryl γ-cyclodextrin calculated yield, but final step yield 90%.Yield losses mainly occurs in nanofiltration process, may be that still have a small amount of aperture comparatively large, cause removing in small molecules process, a small amount of product also runs off thereupon due in the distribution of nanofiltration membrane molecular weight cut-off not complete set.Nanofiltration process control, use vinylformic acid and sodium acrylate reaction time, direct-detection filtrate specific conductivity 150 μ scm-1 or trapped fluid specific conductivity constant time.When using propionic acid olefin(e) acid ester, specific conductivity also needs beyond detecting to use chloroform extraction, is aided with vapor detection method, to determine that impurity removal is clean.
Product is obtained the step of solid from aqueous phase separation, a lot of mode can be adopted.But should be specifically noted that the more glucose sodium that relaxes has sulfide based structural, the treating processes with oxidisability can destroy product, causes purity to decline.
Beneficial effect
1, the present invention by change security more by force, more environmental protection, more efficient sulfydryl-end alkene click-reaction replace traditional sulfydryl halogen substiuted in existing technique to react preparing target product, change original route to need to use high risk material sodium hydride, and at N, the easy gelation of reaction system and the easy drawback occurring low substitution product in dinethylformamide, operating environment is gentle, and improve yield, and make the relax purifying process of more glucose sodium of the finished product more simple.Greatly be better than now commonly using preparation technology, prepare on a large scale for the more glucose sodium that relaxes and have laid a good foundation.
Embodiment
Below in conjunction with embodiment, the present invention will be further described,
The raw material used in embodiment:
The full deoxidation of 6--6-perchloro-γ-cyclodextrin source, reference literature Methods for Selective Modificationsof Cyclodextrins, the method for Chem.Rev.1998,98,1977-1996 obtains.
Thiocarbamide, Chemical Reagent Co., Ltd., Sinopharm Group, analytical pure;
DMF, Laiyang Shandong Province chemical plant, analytical pure;
Vinylformic acid is originated, Tianjin Development Zone Le Tai Chemical Co., Ltd., analytical pure;
Methyl acrylate, Tianjin Development Zone Le Tai Chemical Co., Ltd., analytical pure;
Sodium acrylate, Tianjin Kermel Chemical Reagent Co., Ltd., analytical pure.
Embodiment 1
A kind of more glucose sodium preparation method of relaxing, comprises step as follows:
(1) the full deoxidation of 6--6-perchloro-γ-cyclodextrin 20g (13.9mmol) and thiocarbamide 42g (556mmol) are joined in DMF 600ml, stir lower 90 DEG C of reactions 12 hours; First concentrating under reduced pressure reaction solution is 1/4 of DMF volume to reaction solution volume, and the ethanol then adding concentrated solution volume 8 times precipitates.Gained solid sediment adds in the aqueous sodium hydroxide solution 750ml of concentration 0.25mol/L in 90 DEG C of stirring reactions 2 hours, obtain mixed reaction solution, concentrating under reduced pressure liquid volume is to 1/4 of mixed reaction solution volume, pH to 2 is adjusted with the hydrochloric acid of 35wt%, the ethanol adding reaction solution volume 8 times in the reaction solution after adjust ph precipitates, throw out washs with frozen water, then recrystallization in 10 times of quality pure water, the obtained full mercapto-y-cyclodextrin 18.4g of the full deoxidation of white solid 6--6-, yield 93%.(m/z＝1426m+H+,1448m+Na+)。
(2) the full mercapto-y-cyclodextrin 15g (10.5mmol) of the full deoxidation of 6--6-will be obtained and vinylformic acid 12.2g (168mmol) adds in 600ml water after stirring and dissolving, at 20 DEG C, with ultra violet lamp, continue stirring reaction 6 hours;
(3) in step (2) gained reaction solution, the NaOH of 2mol/L is added, adjust ph to 9;
Use the nanofiltration membrane treatment reaction solution that molecular weight cut-off is 1000MWCO, constant to specific conductivity 7000 μ S/cm;
Decompression rotary evaporation removes moisture, and obtain white solid, vacuum 60 DEG C of dried overnight, 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),3.92-3.97(m,8H),4.04-4.06(m,8H)，5.19(m,8H)ppm。
Embodiment 2
A kind of more glucose sodium preparation method of relaxing, comprises step as follows:
(1) the full deoxidation of 6--6-perchloro-γ-cyclodextrin 20g (13.9mmol) and thiocarbamide 42g (556mmol) are joined in DMF 600ml, stir lower 90 DEG C of reactions 12 hours; First concentrating under reduced pressure reaction solution is 1/4 of DMF volume to reaction solution volume, and the ethanol then adding concentrated solution volume 6 times precipitates.Gained solid sediment adds in the aqueous sodium hydroxide solution 750ml of concentration 0.25mol/L in 90 DEG C of stirring reactions 2 hours, obtain mixed reaction solution, concentrating under reduced pressure liquid volume is to 1/4 of mixed reaction solution volume, pH to 2 is adjusted with the hydrochloric acid of 35wt%, the ethanol adding reaction solution volume 6 times in the reaction solution after adjust ph precipitates, and throw out washs with frozen water, then recrystallization in 10 times of quality pure water, the obtained full mercapto-y-cyclodextrin 23g of the full deoxidation of white solid 6--6-
(2) the full mercapto-y-cyclodextrin 15g (10.5mmol) of the full deoxidation of 6--6-will be obtained and methyl acrylate 15mL adds 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 to being solid state;
(4) solid dissolves with 1M NaOH 500mL, refluxes 2 hours;
(5) the nanofiltration membrane treatment reaction solution that molecular weight cut-off is 1000MWCO is used, constant to specific conductivity 6000 μ S/cm;
(6) rotary evaporation that reduces pressure removes moisture, and obtain white solid, vacuum 60 DEG C of dried overnight, must relax more glucose sodium product 16.0.
Embodiment 3
With the more glucose sodium preparation method of relaxing described in embodiment 1, difference is:
In step (1), the full deoxidation of 6--6-periodo-γ-cyclodextrin 24g and thiocarbamide 42g joins N, in dinethylformamide 600ml, be heated to 85 DEG C, stir lower reaction 12 hours, first concentrating under reduced pressure reaction solution is N to reaction solution volume, 1/4 of dinethylformamide volume, the ethanol then adding concentrated solution volume 9 times precipitates.Gained solid sediment adds in the aqueous sodium hydroxide solution 750ml of concentration 0.2mol/L in 85 DEG C of stirring reactions 2 hours, obtain mixed reaction solution, concentrating under reduced pressure liquid volume is to 1/4 of mixed reaction solution volume, pH to 2 is adjusted with the hydrochloric acid of 30wt%, the ethanol adding reaction solution volume 9 times in the reaction solution after adjust ph precipitates, throw out washs with frozen water, then recrystallization in 10 times of quality pure water, the obtained full mercapto-y-cyclodextrin of the full deoxidation of white solid 6--6-.
Embodiment 4
With the more glucose sodium preparation method of relaxing described in embodiment 1, difference is:
Step (2), adds in 600ml water after stirring and dissolving by the full deoxidation of obtained 6--6-full mercapto-y-cyclodextrin 15g and sodium acrylate 13g, water-bath temperature control less than 20 DEG C, with ultra violet lamp, continues stirring reaction 3 hours.
Final white solid relaxes more glucose sodium 17.9g, yield 85%.
Claims (10)
1. a preparation method for easypro more glucose sodium, comprises step as follows:
(1) halo γ-cyclodextrin is dissolved in N, in dinethylformamide, then thiocarbamide is added, the mass ratio of described halo γ-cyclodextrin and thiocarbamide is: 1:1.5 ~ 3, be heated to 70-90 DEG C, stir lower reaction 10 ~ 12 hours, concentration of reaction solution is separated out to solid sediment, solid sediment to be added in the aqueous sodium hydroxide solution of concentration 0.2 ~ 0.3mol/L at 70-90 DEG C stirring reaction 0.5 ~ 3 hour, adjust ph to 2 ~ 3 after concentrated, alcohol settling obtains throw out, and throw out washs, recrystallization, obtained sulfydryl γ-cyclodextrin;
(2) the sulfydryl γ-cyclodextrin that step (1) is obtained and the aqueous solution of vinylformic acid or acrylate or vinylformic acid sodium salt stir, and then UV-irradiation 1-24 hour at 10-20 DEG C, obtains reaction solution; The addition of vinylformic acid, acrylate or acrylate is 8-21 times of mercapto-cyclodextrin molar weight;
(3) regulate more than reacting liquid pH value to 8, be then concentrated into specific conductivity by nanofiltration membrane constant, obtain the treatment solution after nanofiltration, after the treatment solution drying after nanofiltration, must relax more glucose sodium.
2. more glucose sodium preparation method of relaxing according to claim 1, it is characterized in that, described halo γ-cyclodextrin is the full deoxidation of 6--6-perhalogeno-γ-cyclodextrin.
3. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, described γ-cyclodextrin is the full deoxidation of 6--6-periodo-γ-cyclodextrin, the full deoxidation of 6--6-perbromo-γ-cyclodextrin or the full deoxidation of 6--6-perchloro-γ-cyclodextrin.
4. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, the mass ratio of described halo γ-cyclodextrin and thiocarbamide is: 1:1.8 ~ 2.5.
5. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, in step (1), concentration of reaction solution to solid precipitation is separated out as first concentrating under reduced pressure reaction solution to reaction solution volume is N, 1/4 ~ 1/2 of dinethylformamide volume, the ethanol then adding concentrated solution volume 6 ~ 9 times precipitates.
6. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, step (1), every gram of solid sediment adds 0.2 ~ 0.3mol/L aqueous sodium hydroxide solution 50-100ml.
7. the preparation method of easypro more glucose sodium according to claim 1, is characterized in that, in step (1), and salt acid for adjusting pH value to 2 ~ 3 of working concentration 30-35wt%; Alcohol settling is that the ethanol adding reaction solution volume 6 ~ 9 times in the reaction solution after adjust ph precipitates.
8. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, step (2) medium ultraviolet rayed time 10-20 hour, throw out washs, recrystallization carries out washing 2 ~ 3 times for being added in frozen water by throw out, then in 10 times of quality pure water, carries out recrystallization.
9. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, the addition of vinylformic acid or acrylate or vinylformic acid sodium salt is 18-20 times of sulfydryl γ-cyclodextrin molar weight, described acrylate is methyl acrylate, ethyl propenoate, and described acrylate is sodium acrylate.
10. the preparation method of easypro more glucose sodium according to claim 1, it is characterized in that, the NaOH of 1 ~ 2mol/L is used to regulate reaction solution to pH value to 9 ~ 10 in step (3), nanofiltration membrane is use the nanofiltration membrane that molecular weight cut-off is 100-1500MWCO, and specific conductivity constant range is 5000-8000 μ S/cm.
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