CN111019016B - Synthesis method of sugammadex impurity - Google Patents
Synthesis method of sugammadex impurity Download PDFInfo
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- CN111019016B CN111019016B CN201911404653.5A CN201911404653A CN111019016B CN 111019016 B CN111019016 B CN 111019016B CN 201911404653 A CN201911404653 A CN 201911404653A CN 111019016 B CN111019016 B CN 111019016B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
The invention relates to the technical field of new synthesis methods of known compounds, and particularly discloses a synthesis method of sugammadex sodium impurity, which comprises the following steps of: (3.5-4.5): (7.5-8.5) reacting octa- (6-bromo-6-deoxy) -gamma-cyclodextrin and 3-mercaptopropionic acid with alkali at 40-50 ℃ for 14-20h, and refining by pulp washing, recrystallization and the like to obtain the impurity of sugammadex sodium. The impurity purity of the sugammadex sodium prepared by the method reaches more than 99 percent, and the sugammadex sodium can be used as a reference substance for quality research.
Description
Technical Field
The invention relates to the technical field of new synthesis methods of known compounds, in particular to a synthesis method of sugammadex sodium impurity.
Background
Sugammadex sodium: chemical name: octa-6-per-deoxy-6-per (2-carboxyethyl) thio- γ -cyclodextrin sodium salt, english: su γ dex, trade name: bridion, Shugammadex was first discovered by Organon Biosciences, Inc., which was purchased by Schering-Plough, Inc. in 2007. In 2009 pioneer Baoya was combined with Merck (Merck). Sugammadex sodium is currently owned and sold by merck.
In 2008, the FDA worries about possible allergic reactions, and schlegelian sodium glucosate by the company of rejuvenescence is on the market; in late 2009, sugammadex sodium was approved for sale in europe; the merck corporation soon began to set up 11 clinical medicine centers in china, starting a phase three clinical study of sugammadex sodium in china. The sugammadex sodium is used for reversing the action of a neuromuscular blocking drug rocuronium bromide or vecuronium bromide which is conventionally used, and can immediately reverse the action of rocuronium bromide which is conventionally used by adults and the action of rocuronium bromide which is conventionally used by children and teenagers (2-17 years old). Sugammadex sodium is the first and only Selective Relaxation Binding Agent (SRBA), the first major drug development in the field of narcotics over 20 years, and is known as a milestone muscle relaxation antagonist.
The mechanism of sulgammadex muscle relaxation antagonism is: the sugammadex sodium chelates free rocuronium bromide molecules in plasma, so that the concentration of the plasma free rocuronium bromide is reduced sharply, a concentration gradient is formed between an effect chamber (at a neuromuscular junction) and a central chamber (plasma), and the rocuronium bromide molecules in the effect chamber are transported to the central chamber rapidly along the concentration difference, so that the concentration of the rocuronium bromide in the effect chamber is reduced rapidly, and the rocuronium bromide bound with a nicotinic acetylcholine receptor at the neuromuscular junction is dissociated rapidly, thereby reversing the muscle relaxation effect of the rocuronium bromide. The antagonism of sugammadex sodium against muscle relaxants is highly selective. Because the inner cavity of the antagonist has complementarity with rocuronium bromide molecules, the antagonist for the steroid muscle relaxant rocuronium bromide selectively has good antagonistic action on the similar drug vecuronium bromide, and has no antagonistic action on the benzylisoquinoline non-depolarized muscle relaxants (such as atracurium) and depolarized muscle relaxants (such as succinylcholine).
Sugammadex sodium (sodium sugammadex), with chemical name of octa-6-fully deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt and molecular formula of C72H104Na8O48S8U.S. chemical abstracts accession number CAS: 343306-71-8, the structural formula is:
the original patent US6670340B1 discloses a preparation method of sugammadex sodium, which is prepared by reacting 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydride and DMF, wherein the molar ratio of 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin, 3-mercaptopropionic acid and sodium hydride is 1: 10: 22.
the sugammadex sodium is unstable to oxygen due to the existence of thioether bonds on the molecular structure of the sugammadex sodium, is easy to be oxidized to form a series of oxidation impurities and disulfide impurities such as sulfoxide, sulfone, disulfide and the like in the purification process, different substituted products are generated in the reaction process of synthesizing the sugammadex sodium, the sugammadex sodium product is obtained if 8 sites of bromine in the octa- (6-bromo-6-deoxy) -gamma-cyclodextrin are completely substituted, and the substance with 7 sites of bromine substituted in the octa- (6-bromo-6-deoxy) -gamma-cyclodextrin is the impurity to be researched, 7 sites of iodine substituted substances are mentioned in the original patent, but the content of the impurity is extremely low, and the synthesis method of the impurity is not available in the published literature.
Disclosure of Invention
Aiming at the technical blank existing in the prior art, the invention aims to provide a compound with the following structural formula: c69H100BrNa7O46S7A preparation method of sugammadex sodium impurity.
The reaction route of the sugammadex sodium impurity of the invention is as follows:
specifically, the preparation method of the sugammadex sodium impurity comprises the following steps:
(1) preparation of crude sugammadex impurity:
adding solvent A, adding 3-mercaptopropionic acid, adding alkali in batches, and dropwise adding a mixture of eight- (6-bromo-6-deoxy) -gamma-cyclodextrin and the solvent A at room temperature under the protection of nitrogen, wherein the molar ratio of the eight- (6-bromo-6-deoxy) -gamma-cyclodextrin to the 3-mercaptopropionic acid to the alkali is 1: (3.5-4.5): (7.5-8.5), preferably in a ratio of 1: 4: 8, heating to 40-50 ℃ after finishing dropping, reacting for 14-20h, cooling to 0-10 ℃ after finishing the reaction, and performing suction filtration to obtain an impurity crude product;
preferably, the solvent A is selected from one or more of dimethyl sulfoxide, N-dimethylacetamide, N-dimethylformamide, 1, 4-dioxane and toluene.
Preferably, the base is selected from one or more of sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
(2) Refining
Pulping the impurity crude product with absolute ethyl alcohol, filtering, dissolving the filter cake with purified water, dripping a solvent B, crystallizing, filtering, repeatedly recrystallizing at least once, and drying to obtain white powder, namely the impurity of the sugammadex sodium.
Further, the solvent B selected in each recrystallization step may be the same or different.
Preferably, the solvent B is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetonitrile and acetone.
Preferably, the ratio of the crude impurity to the absolute ethyl alcohol is 1 g: (5-10) mL.
Preferably, the ratio of the filter cake to purified water is 1 g: (1-10) mL, more preferably, in a ratio of 1 g: 3 mL; purifying water: the volume ratio of the solvent B is 1: (1-10), more preferably, the volume ratio is 1: 3.
preferably, the number of recrystallization times is 2 to 5 times in total.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the purity of the sugammadex sodium impurity obtained by the preparation method reaches over 99 percent, and the impurity can be used as a reference substance for quality research.
Drawings
FIG. 1 is an HPLC plot of the sugammadex sodium impurity of example 4;
FIG. 2 shows the impurities of sugammadex sodium of example 41A map of HNMR;
FIG. 3 shows the impurities of sugammadex sodium of example 413Graph of CNMR.
Detailed Description
The applicants will now further describe the synthesis of the present invention in detail with reference to specific examples, but it should be understood that the following examples are only illustrative and not intended to limit the scope of the invention as claimed in the claims.
In the following examples, octa- (6-bromo-6-deoxy) -gamma-cyclodextrin reference Supermolecular chemistry, 2000,12, P221-224, was prepared, and all other reagents were commercially available.
Example 1: a method for synthesizing impurities of sugammadex sodium comprises the following steps:
(1) substitution
Adding 50mL of N, N-dimethylformamide into a 250mL three-necked bottle at room temperature under the protection of nitrogen, adding 1.2g of 3-mercaptopropionic acid, adding 0.89g of 60% sodium hydride solid in four batches, dropwise adding a mixture of 5g of octa- (6-bromo-6-deoxy) -gamma-cyclodextrin and 50mL of N, N-dimethylformamide, heating to 40-50 ℃ after dropwise adding, reacting for 16 hours, cooling to 0-10 ℃ after the reaction is finished, and performing suction filtration to obtain 21.3g of white solid which is an impurity crude product.
(2) Refining
Pulping the crude impurity with 128mL of absolute ethyl alcohol (volume of absolute ethyl alcohol: weight of crude impurity is 6 mL: 1g) for 2h, filtering, dissolving the filter cake with purified water (volume: weight of filter cake is 3 mL: 1g), dropwise adding N, N-dimethylformamide (volume: weight of filter cake is 9 mL: 1g), crystallizing at 20-30 ℃, filtering, dissolving the filter cake with purified water (volume: weight of filter cake is 3 mL: 1g), dropwise adding absolute methanol (volume: weight of filter cake is 9 mL: 1g), crystallizing at 20-30 ℃, filtering, and drying in a hot air circulation oven at 90 ℃ for 12h to obtain 2.8g of white powder with purity of 99.2% and yield of 47%.
Example 2: a method for synthesizing impurities of sugammadex sodium comprises the following steps:
(1) substitution
Adding 50mL of dimethyl sulfoxide into a 250mL three-necked bottle at room temperature under the protection of nitrogen, adding 1.2g of 3-mercaptopropionic acid, adding 0.89g of 60% sodium hydride solid in four batches, dropwise adding a mixed solution of 5g of octa- (6-bromo-6-deoxy) -gamma-cyclodextrin and 50mL of dimethyl sulfoxide, heating to 40-50 ℃ after dropwise adding, reacting for 16 hours, cooling to 0-10 ℃ after the reaction is finished, and performing suction filtration to obtain 22.4g of white solid.
(2) Refining
Pulping the crude impurity product for 2h by using 134mL of absolute ethyl alcohol (volume of the absolute ethyl alcohol: weight of the crude impurity product is 6 mL: 1g), filtering, dissolving a filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding N, N-dimethylformamide (volume: weight of the filter cake is 12 mL: 1g), crystallizing at 20-30 ℃, filtering, dissolving the filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding absolute methanol (volume: weight of the filter cake is 12 mL: 1g), crystallizing at 20-30 ℃, filtering, and drying in a hot air circulation oven at 90 ℃ for 12h to obtain 3.2g of white powder, the purity is 98.4%, and the yield is 54%.
Example 3: a method for synthesizing impurities of sugammadex sodium comprises the following steps:
(1) substitution
Adding 50mL LN, N-dimethylformamide into a 250mL three-necked bottle at room temperature under the protection of nitrogen, adding 1.2g of 3-mercaptopropionic acid, dropwise adding 4g of 30 wt% sodium methoxide solution, dropwise adding a mixed solution of 5g of octa- (6-bromo-6-deoxy) -gamma-cyclodextrin and 50mL LN, N-dimethylformamide, heating to 40-50 ℃ after dropwise adding, reacting for 16 hours, cooling to 0-10 ℃ after the reaction is finished, and performing suction filtration to obtain 20.2g of white solid.
(2) Refining
Pulping the crude impurity product for 2h by using 121mL of absolute ethyl alcohol (volume of the absolute ethyl alcohol: weight of the crude impurity product is 6 mL: 1g), filtering, dissolving a filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding dimethyl sulfoxide (volume: weight of the filter cake is 6 mL: 1g), crystallizing at 20-30 ℃, filtering, dissolving the filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding absolute methanol (volume: weight of the filter cake is 6 mL: 1g), crystallizing at 20-30 ℃, filtering, and drying in a hot air circulation oven at 90 ℃ for 12h to obtain 2.6g of white powder, wherein the purity is 99.3%, and the yield is 44%.
Example 4: a method for synthesizing impurities of sugammadex sodium comprises the following steps:
(1) substitution
Adding 50mLN, N-dimethylformamide into a 250mL three-necked flask at room temperature under the protection of nitrogen, adding 1.2g of 3-mercaptopropionic acid, adding 0.89g of 60% sodium hydride solid in four batches, dropwise adding a mixed solution of 5g of octa- (6-bromo-6-deoxy) -gamma-cyclodextrin and 50mLN, N-dimethylformamide, heating to 60-70 ℃ after dropwise adding, reacting for 16 hours, cooling to 10-20 ℃ after the reaction is finished, and performing suction filtration to obtain 21.8g of white solid.
(2) Refining
Pulping the crude impurity product for 2h by using 131mL of absolute ethyl alcohol (volume of the absolute ethyl alcohol: weight of the crude impurity product is 6 mL: 1g), filtering, dissolving a filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding methanol (volume: weight of the filter cake is 9 mL: 1g), crystallizing at 20-30 ℃, filtering, dissolving the filter cake by using purified water (volume: weight of the filter cake is 3 mL: 1g), dropwise adding acetone (volume: weight of the filter cake is 9 mL: 1g), cooling to 0-10 ℃, crystallizing, filtering, and drying in a hot air circulation oven at 90 ℃ for 12h to obtain 3.0g of white powder, wherein the purity is 98.8%, and the yield is 51%.
Claims (4)
1. A synthesis method of sugammadex impurity, wherein the molecular formula of the sugammadex impurity is C69H100BrNa7O46S7，Structural formula is
The method is characterized by comprising the following steps:
(1) preparation of crude sugammadex impurity:
adding a solvent into a reaction container at room temperature under the protection of nitrogen, adding 3-mercaptopropionic acid, adding a base in batches, and adding a mixture of eight- (6-bromo-6-deoxy) -gamma-cyclodextrin and the solvent dropwise, wherein the molar ratio of the eight- (6-bromo-6-deoxy) -gamma-cyclodextrin to the 3-mercaptopropionic acid to the base is 1: (3.5-4.5): (7.5-8.5), heating to 40-50 ℃ after finishing dropping, reacting for 14-20h, cooling to 0-10 ℃ after the reaction is finished, and performing suction filtration to obtain an impurity crude product; the solvent in the step (1) is one or more selected from dimethyl sulfoxide, N-dimethylacetamide, N-dimethylformamide, 1, 4-dioxane and toluene; the alkali is selected from one or more of sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide;
(2) refining
Pulping the crude product of the impurities by using absolute ethyl alcohol, filtering, dissolving a filter cake by using purified water, dripping a solvent, crystallizing, filtering, repeatedly recrystallizing at least once, and drying to obtain white powder, namely the impurity of the sugammadex sodium; in the step (2): the solvent is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetonitrile and acetone; the ratio of the crude impurity product to absolute ethyl alcohol is 1 g: (5-10) mL; the ratio of the filter cake to the purified water is 1 g: (1-10) mL; the purified water: the volume ratio of the solvent is 1: (1-10).
2. The method for synthesizing sugammadex sodium impurity according to claim 1, wherein said octa- (6-bromo-6-deoxy) - γ -cyclodextrin, 3-mercaptopropionic acid and base are present in a molar ratio of 1: 4: 8.
3. the synthesis method of sugammadex sodium impurity according to claim 1, wherein in step (2): the ratio of the filter cake to the purified water is 1 g: 3 mL; the purified water: the volume ratio of the solvent is 1: 3.
4. the method for synthesizing sugammadex sodium impurity according to claim 1, wherein said number of recrystallizations is 2-5 times in total.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1188428C (en) * | 1999-11-29 | 2005-02-09 | 阿克佐诺贝尔公司 | 6-mercapto-cyclodextrin derivs.: resersal agent for drug-induced neuromuscular block |
| CN106749771A (en) * | 2015-11-23 | 2017-05-31 | 成都渊源生物科技有限公司 | A kind of easypro more glucose sodium preparation method of high-purity |
| CN109879986A (en) * | 2019-03-13 | 2019-06-14 | 陈文辉 | A method of preparing relax more glucose sodium and its intermediate |
| CN110105469A (en) * | 2019-06-12 | 2019-08-09 | 常州亚邦制药有限公司 | The easypro more glucose sodium impurity and preparation method thereof of one kind |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
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- 2019-12-30 CN CN201911404653.5A patent/CN111019016B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1188428C (en) * | 1999-11-29 | 2005-02-09 | 阿克佐诺贝尔公司 | 6-mercapto-cyclodextrin derivs.: resersal agent for drug-induced neuromuscular block |
| CN106749771A (en) * | 2015-11-23 | 2017-05-31 | 成都渊源生物科技有限公司 | A kind of easypro more glucose sodium preparation method of high-purity |
| CN109879986A (en) * | 2019-03-13 | 2019-06-14 | 陈文辉 | A method of preparing relax more glucose sodium and its intermediate |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
| CN110105469A (en) * | 2019-06-12 | 2019-08-09 | 常州亚邦制药有限公司 | The easypro more glucose sodium impurity and preparation method thereof of one kind |
Non-Patent Citations (1)
| Title |
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| "An Improved Synthesis of Per(6-Deoxyhalo) Cyclodextrins Using N-Halosuccinimides—Triphenylphosphine in Dimethylformamide ";Kazimierz Chmurski等;《Supramolecular Chemistry》;20060923;第12卷;第221-224页 * |
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