CN115433293B - Preparation method of sodium gluconate - Google Patents
Preparation method of sodium gluconate Download PDFInfo
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- CN115433293B CN115433293B CN202211110226.8A CN202211110226A CN115433293B CN 115433293 B CN115433293 B CN 115433293B CN 202211110226 A CN202211110226 A CN 202211110226A CN 115433293 B CN115433293 B CN 115433293B
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Abstract
The invention relates to a preparation method of sodium gluconate. The preparation method comprises the following specific steps: dissolving the dried 6-deoxidized-6-perhalogenated-gamma-cyclodextrin in an organic solvent, adding a sulfur source, and heating for reaction to obtain a solid substance 1; dissolving the solid substance 1 obtained in the step (1) in a strong alkaline water solution for reaction to obtain a solid substance 2; mixing the solid substance 2 obtained in the step (2) with acrylic acid or acrylic ester, and carrying out illumination reaction in stages to obtain the sodium suger; the reaction is carried out in stages and is specifically divided into three stages, namely, the first stage: reacting for 1-2 h at 0-10 ℃; and a second stage: reacting for 1h to 15h at the temperature of between 10 and 20 ℃; and a third stage: reacting for 1-5 h at 20-30 ℃. The preparation method disclosed by the invention is simple in process, safe in production, low in raw material cost and high in product yield.
Description
Technical Field
The invention belongs to the technical field of polysaccharide preparation, and particularly relates to a preparation method of sodium sugammadex.
Background
Sodium supreme glucose (SugammadexSodiumInjection), chemical name: 6-perdeoxy-6-per (2-carboxyethyl) thio- γ -cyclodextrin sodium salt, english name: su gamma dex, under the trade name Bristin (Brition), is the first and only specific binding neuromuscular blocking antagonist worldwide developed by the company moxadong. It is a modified chemical book gamma-cyclodextrin that antagonizes the neuromuscular blockade induced by rocuronium or vecuronium by forming a complex with the neuromuscular blocking drug rocuronium or vecuronium in plasma, thereby reducing the amount of neuromuscular blocking drug that binds to nicotinic receptors at the neuromuscular junction. The sodium sulmore plays a role in the molecular structure of the gamma-cyclodextrin, can form a compound with rocuronium bromide, and reduces the concentration of free medicine in blood, thereby reversing the neuromuscular blocking effect of the rocuronium bromide.
The FDA was concerned about the possibility of causing allergic reactions in 2008, reject the first application of the Liriose Shu sodium gluconate; at the end of 2009, sodium supreme was marketed in europe; very soon the merck company began setting up 11 clinical centers in china, starting a three-phase clinical study of sodium sulmore gluconate in china.
Antagonism of the muscle relaxant by sodium diglucose is highly selective. Because the inner cavity of the drug has complementarity with rocuronium bromide molecules, the selective antagonism steroid muscle relaxant rocuronium bromide has good antagonism on similar drugs of vecuronium bromide, but has no antagonism on benzyl isoquinoline non-depolarizing muscle relaxants (such as atracurium, etc.) and depolarizing muscle relaxants (succinylcholine).
The earliest publication of sodium sugammadex in patent US6670340 discloses that gamma-cyclodextrin is used as a starting material to generate perhalogenated gamma-cyclodextrin through substitution with triphenylphosphine and halogen, and then the perhalogenated gamma-cyclodextrin and mercaptopropionic acid are used for generating a target product under the action of sodium hydride, and the preparation method comprises the following steps of: the preparation method comprises the steps of using gamma-cyclodextrin as a starting material, generating perhalogenated gamma-cyclodextrin through substitution with triphenylphosphine and halogen, and generating a target product with mercaptopropionic acid under the action of sodium hydride, wherein the following steps are shown:
the reaction route is short, but the process operation is difficult to control, wherein the activity of the reactant is strong, the perhalogenated gamma-cyclodextrin and thiourea are difficult to completely replace, the intermediate impurities are more, and the intermediate impurities are very difficult to remove, in addition, the long-time high-temperature reaction of the replacing step is extremely easy to cause degradation of the starting materials, the reaction efficiency is influenced, the quality and the yield of the product are finally lower,
disclosure of Invention
Therefore, the invention aims to solve the technical problems of low yield, difficult control of reaction conditions, difficult purification and the like of the sodium gluconate preparation process in the prior art.
In order to solve the technical problems, the invention provides a preparation method of sodium sugammadex. The preparation method disclosed by the invention is simple in process, safe in production, low in raw material cost and high in product yield.
The invention aims to provide a preparation method of sodium sugammadex, which comprises the following steps:
(1) Dissolving the dried 6-deoxidized-6-perhalogenated-gamma-cyclodextrin in an organic solvent, adding a sulfur source, and heating for reaction to obtain a solid substance 1;
(2) Dissolving the solid substance 1 obtained in the step (1) in an aqueous solution of strong alkali to react to obtain a solid substance 2;
(3) Mixing the solid substance 2 obtained in the step (2) with acrylic acid or acrylic ester, and carrying out reaction in stages to obtain the sodium suger; the reaction is carried out in stages and is specifically divided into three stages, namely, the first stage: reacting for 1-2 h at 0-10 ℃; and a second stage: reacting for 1-15 h at the temperature of 10-20 ℃; and a third stage: reacting for 1-5 h at 20-30 ℃.
In one embodiment of the present invention, in step (1), the organic solvent is one or more selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, N-dimethylacetamide, tetrahydrofuran and formamide.
In one embodiment of the present invention, in step (1), the 6-deoxy-6-perhalogenated γ -cyclodextrin is selected from one or more of 6-deoxy-6-perchloro- γ -cyclodextrin, 6-deoxy-6-perfluoro- γ -cyclodextrin, 6-deoxy-6-perbrominated- γ -cyclodextrin, or 6-deoxy-6-periodate- γ -cyclodextrin.
In one embodiment of the present invention, in step (1), the 6-deoxy-6-perhalo- γ -cyclodextrin is prepared by the following method:
s1, dissolving beta-cyclodextrin and imidazole compounds in an organic solvent, adding aryl or alkyl sulfonyl chloride under the protection of inert gas, stirring for reaction, and distilling the reaction solution under reduced pressure to remove the reaction solvent after the reaction is finished to obtain a reactant 1;
s2, redissolving the reactant 1 in the step S1 in water, regulating the reactant to be alkaline by using an alkaline regulator, continuously stirring, filtering, collecting precipitate, and washing by using a cleaning agent to obtain a primary product;
s3, recrystallizing the initial product obtained in the step S2 in a mixed solvent to obtain the 6-deoxy-6-perhalogeno-gamma-cyclodextrin.
In one embodiment of the present invention, in step S1, the imidazole compound is selected from one or more of imidazole, benzimidazole, dimethylimidazole and diethyltetramethylimidazole.
In one embodiment of the present invention, in step S1, the molar ratio of the β -cyclodextrin, the imidazole-based compound and the aryl or alkylsulfonyl chloride is 1:10-15:10-15.
In one embodiment of the present invention, in step S1, the aryl or alkyl sulfonyl chloride is selected from one or more of benzenesulfonyl chloride, methylsulfonyl chloride, or p-toluenesulfonyl chloride.
In one embodiment of the present invention, in step S1, the inert gas is selected from nitrogen and/or argon.
In one embodiment of the present invention, in step S1, the reaction temperature is 80 ℃ to 100 ℃ and the reaction time is 5h to 10h.
In one embodiment of the present invention, in step S2, the alkaline modifier is selected from one or more of strong sodium oxide, potassium hydroxide, and ammonia.
In one embodiment of the present invention, in step S2, the alkaline pH ranges from 8 to 11.
In one embodiment of the present invention, in step S2, the cleaning agent is selected from one or more of water, acetone, and methanol.
In one embodiment of the present invention, in step S3, the mixed solvent is selected from DMF-H 2 O, tetrahydrofuran-H 2 O or DMSO-H 2 O。
In one embodiment of the invention, in step (1), the sulfur source is selected from the group consisting of thio urea.
In one embodiment of the invention, in step (1), the molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is from 1:1 to 5.
In one embodiment of the present invention, in step (1), the heating reaction conditions: the temperature is 50-60 ℃ and the reaction time is 15-20 h.
In one embodiment of the invention, in step (2), the strong base is selected from sodium hydroxide or potassium hydroxide.
In one embodiment of the invention, in the step (2), the reaction temperature is 40-65 ℃ and the reaction time is 20min-2h.
In one embodiment of the invention, in step (2), the concentration of the aqueous strong base is from 0.5mol/L to 2mol/L.
In one embodiment of the present invention, in step (3), the reaction is a photoreaction and the light source is ultraviolet light.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the preparation method solves the problems of difficult control of the preparation process of the sodium sulmore gluconate, low product quality and yield and the like in the prior art, and compared with the existing preparation method of the sodium sulmore gluconate, the preparation method provided by the invention has the advantages that the reaction quality is obviously improved, and the product yield can reach 93%. Low cost, simple operation, high reaction efficiency and convenient industrialized production.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
The reagents used in the present invention are all commercially available.
Example 1
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-iodo-gamma-cyclodextrin is prepared by:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:10:10;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 50 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 75mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 1h at 5 ℃; and a second stage: reacting for 15h at 10 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 10. And the reaction solution is treated by a nanofiltration membrane, and the conductivity is regulated to 6500 mu S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore in 93% yield.
Example 2
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-iodo-gamma-cyclodextrin is prepared by:
s1, dissolving 2g of beta-cyclodextrin and dimethyl imidazole in 80mL of tetrahydrofuran, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the p-toluenesulfonyl chloride is 1:10:15;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 8.5 by using an alkaline regulator potassium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-acetone for three times in sequence to obtain an initial product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (3:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 60mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 60 ℃ for 20h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to thiourea is 1:5);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 100mol of methyl acrylate, and carrying out ultraviolet light illumination reaction in stages, wherein in the first stage: reacting for 2 hours at 0 ℃; and a second stage: reacting for 5 hours at 15 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 9.5. And the reaction solution is treated by a nanofiltration membrane, and the conductivity is regulated to 6500 mu S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore in 91% yield.
Example 3
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-chloro-gamma-cyclodextrin is prepared by the following method:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding methylsulfonyl chloride under the protection of argon inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:15:10;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 10 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing four times by using a cleaning agent water-methanol-acetone in sequence to obtain a primary product;
s3, putting the initial product obtained in the step S2 into a mixed solvent DMF-H 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 3g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 55 ℃ for 20h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 6mol of the solid substance 2 obtained in the step (2) with 80mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 1h at 5 ℃; and a second stage: reacting for 15h at 10 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 8. And the reaction solution was treated with a nanofiltration membrane, and the conductivity was adjusted to 7000. Mu.S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore gluconate in 89% yield.
Example 4
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-fluoro-gamma-cyclodextrin is prepared by the following method:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:15:15;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(3) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 50 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 2mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 75mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 1h at 5 ℃; and a second stage: reacting for 15h at 10 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 10. And the reaction solution was treated with a nanofiltration membrane, and the conductivity was adjusted to 7000. Mu.S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium digluconate in a yield of 90%.
Example 5
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-bromo-gamma-cyclodextrin is prepared by the following method:
s1, dissolving 4.5g of beta-cyclodextrin and diethyl tetramethylimidazole in 100ml of LDMSO, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:10:15;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (4:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2.5g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 60 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:4);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 75mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 1h at 10 ℃; and a second stage: reacting for 15 hours at 15 ℃; and a third stage: reacting for 5 hours at 25 ℃ to obtain a reaction solution; 1mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 8.5. And the reaction solution was treated with a nanofiltration membrane, and the conductivity was adjusted to 7000. Mu.S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore gluconate in 89% yield.
Example 6
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-iodo-gamma-cyclodextrin is prepared by:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:10:10;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 50 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 75mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 1h at 5 ℃; and a second stage: reacting for 15h at 10 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 10. And the reaction solution is treated by a nanofiltration membrane, and the conductivity is regulated to 6500 mu S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore in 91% yield.
Example 7
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-iodo-gamma-cyclodextrin is prepared by:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:10:10;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 50 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 100mol of acrylic acid, and carrying out a photoreaction in stages, wherein in the first stage: reacting for 2 hours at the temperature of 5 ℃; and a second stage: reacting for 15h at 10 ℃; and a third stage: reacting for 5 hours at 20 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 10. And the reaction solution is treated by a nanofiltration membrane, and the conductivity is regulated to 6500 mu S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore in 88% yield.
Comparative example 1 (in contrast to example 1, the difference is that the photoreaction is not performed in stages)
The invention provides a preparation method of sodium sugammadex, which comprises the following specific experiments:
(1) The 6-deoxy-6-iodo-gamma-cyclodextrin is prepared by:
s1, dissolving 2g of beta-cyclodextrin and imidazole in 80mL of DMF, adding benzenesulfonyl chloride under the protection of nitrogen inert gas, stirring for reaction, and after the reaction is finished, distilling the reaction solution under reduced pressure to remove a reaction solvent to obtain a reactant 1; wherein, the mol ratio of the beta-cyclodextrin, the imidazole and the benzenesulfonyl chloride is 1:10:10;
s2, redissolving the reactant 1 obtained in the step S1 in water, regulating the pH value to 9 by using an alkaline regulator sodium hydroxide aqueous solution, continuously stirring, filtering, collecting precipitate, and washing the precipitate with a cleaning agent water-methanol for three times in sequence to obtain a primary product;
s3, mixing the initial product obtained in the step S2 with tetrahydrofuran-H as a mixed solvent 2 Recrystallizing in O (2:1, v/v), purifying, and drying to obtain the 6-deoxy-6-perhalo-gamma-cyclodextrin.
(2) 2g of dried 6-deoxy-6-perhalo-gamma-cyclodextrin is dissolved in 100mL of DMF as an organic solvent, thiourea is added, and the mixture is stirred and heated to 50 ℃ for 15h to obtain a solid substance 1; (molar ratio of 6-deoxy-6-perhalo-gamma-cyclodextrin to sulfur source is 1:2);
(3) Dissolving the solid substance 1 obtained in the step (1) in 0.5mol/L sodium hydroxide aqueous solution for reaction to obtain a solid substance 2;
(4) Mixing 5mol of the solid substance 2 obtained in the step (2) with 75mol of acrylic acid, and carrying out illumination reaction in stages, wherein the reaction is carried out for 25 hours at 10 ℃ to obtain a reaction solution; 2mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to 10. And the reaction solution is treated by a nanofiltration membrane, and the conductivity is regulated to 6500 mu S/cm. The reaction solvent was removed by rotary evaporation to give a white solid which was dried in vacuo to give sodium sulmore in 85% yield.
As is clear from the above example 1 and comparative example 1, the method provided by the invention performs the reaction in stages, and can realize more efficient reaction, so that the reaction yield is as high as 93%. The reason for this is probably that the reaction between the raw materials can be made more efficient by proceeding in stages.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (10)
1. A method for preparing sodium sugammadex, which is characterized by comprising the following steps:
(1) Dissolving the dried 6-deoxidized-6-perhalogenated-gamma-cyclodextrin in an organic solvent, adding a sulfur source, and heating for reaction to obtain a solid substance 1; the sulfur source is selected from thio urea;
(2) Dissolving the solid substance 1 obtained in the step (1) in an aqueous solution of strong alkali to react to obtain a solid substance 2;
(3) Mixing the solid substance 2 obtained in the step (2) with acrylic acid or acrylic ester, and carrying out illumination reaction in stages to obtain the sodium suger; the reaction is carried out in stages and is specifically divided into three stages, namely, the first stage: reacting for 1-2 h at 0-10 ℃; and a second stage: reacting for 1h to 15h at the temperature of between 10 and 20 ℃; and a third stage: reacting for 1-5 h at 20-30 ℃.
2. The method of claim 1, wherein in step (1), the 6-deoxy-6-perhalogenated γ -cyclodextrin is selected from one or more of 6-deoxy-6-perchloro- γ -cyclodextrin, 6-deoxy-6-perfluoro- γ -cyclodextrin, 6-deoxy-6-perbromo- γ -cyclodextrin, or 6-deoxy-6-periodate- γ -cyclodextrin.
3. The method of claim 1, wherein in step (1), the 6-deoxy-6-perhalo- γ -cyclodextrin is prepared by:
s1, dissolving beta-cyclodextrin and imidazole compounds in an organic solvent, adding aryl or alkyl sulfonyl chloride under the protection of inert gas, stirring for reaction, and distilling the reaction solution under reduced pressure to remove the reaction solvent after the reaction is finished to obtain a reactant 1;
s2, redissolving the reactant 1 in the step S1 in water, regulating the reactant to be alkaline by using an alkaline regulator, continuously stirring, filtering, collecting precipitate, and washing by using a cleaning agent to obtain a primary product;
s3, recrystallizing the initial product obtained in the step S2 in a mixed solvent to obtain the 6-deoxy-6-perhalogeno-gamma-cyclodextrin.
4. A method according to claim 3, wherein in step S1, the imidazole compound is selected from one or more of imidazole, benzimidazole, dimethylimidazole and diethyltetramethylimidazole.
5. A process according to claim 3, wherein in step S1, the molar ratio of β -cyclodextrin, imidazole compound and aryl or alkylsulfonyl chloride is 1:10-15:10-15.
6. A method according to claim 3, wherein in step S1, the aryl or alkylsulfonyl chloride is selected from one or more of benzenesulfonyl chloride, methylsulfonyl chloride or p-toluenesulfonyl chloride.
7. The method according to claim 3, wherein in step S2, the alkaline regulator is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide and aqueous ammonia.
8. The method of claim 1, wherein in step (1), the molar ratio of 6-deoxy-6-perhalo- γ -cyclodextrin to sulfur source is 1:1-5.
9. The method of claim 1, wherein in step (2), the strong base is selected from sodium hydroxide or potassium hydroxide.
10. The process according to claim 1, wherein in the step (2), the concentration of the aqueous alkali solution is 0.5 to 2mol/L.
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| CN104844732A (en) * | 2015-03-27 | 2015-08-19 | 山东滨州智源生物科技有限公司 | Preparation method for sugammadex sodium |
| CN112430423A (en) * | 2020-11-16 | 2021-03-02 | 西北工业大学 | Preparation method of brush-shaped organic silicon-based self-cleaning anti-icing coating |
| 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 |
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| CN104844732A (en) * | 2015-03-27 | 2015-08-19 | 山东滨州智源生物科技有限公司 | Preparation method for 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 |
| CN112430423A (en) * | 2020-11-16 | 2021-03-02 | 西北工业大学 | Preparation method of brush-shaped organic silicon-based self-cleaning anti-icing coating |
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