WO2017084401A1 - 舒更葡糖钠的制备及纯化方法 - Google Patents

舒更葡糖钠的制备及纯化方法 Download PDF

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WO2017084401A1
WO2017084401A1 PCT/CN2016/095985 CN2016095985W WO2017084401A1 WO 2017084401 A1 WO2017084401 A1 WO 2017084401A1 CN 2016095985 W CN2016095985 W CN 2016095985W WO 2017084401 A1 WO2017084401 A1 WO 2017084401A1
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sgmd
crude
sodium
cyclodextrin
acetone
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PCT/CN2016/095985
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English (en)
French (fr)
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贾慧娟
陈岩
刘祥伟
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北京睿创康泰医药研究院有限公司
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Priority to US15/544,226 priority Critical patent/US20180016359A1/en
Priority to EP16865579.3A priority patent/EP3421503B1/en
Priority to JP2018569124A priority patent/JP6692941B2/ja
Publication of WO2017084401A1 publication Critical patent/WO2017084401A1/zh
Priority to US15/909,824 priority patent/US10526422B2/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention belongs to the field of drug synthesis, and relates to the preparation of raw materials and intermediates, in particular to a method for preparing and purifying a drug and an intermediate of a sodium sulphate.
  • Sodium Glucosamine (English name: Sugammadex, abbreviated SGMD in this article) was first discovered by Organon Biosciences. In 2003, Organon was acquired by Schering-Plough. In 2009, Schering-Plough merged with Merck. Merck eventually has Sodium Glucosamine. Sodium Glucosamine and Injection were approved for sale in Europe at the end of 2009. The trade name is Bridion; in 2010, it was approved by Japan PMDA; in December 2015, it was approved by the US FDA. Currently, Shugen Glucosamine Injection has been marketed in more than 50 countries around the world. The Dutch Eugenin Sodium Glucosamine Injection was approved by the Chinese CFDA in 2015 for clinical trials in China.
  • Sodium Glucosamine is the world's first and only selective relaxant binding agent (SRBA), the first major drug advance in the field of anesthesia in the past 20 years.
  • the mechanism of action of sodium sulphate is that sedative sodium gluconate chelate free radical rocuronium in plasma, causing a sharp drop in plasma free rocuronium concentration in the effect chamber (neuromuscular junction) and A concentration gradient is formed between the central chambers (plasma), so that the rocuronium bromide molecules in the effect chamber are rapidly transported to the central chamber along the concentration difference, which causes the concentration of rocuronium in the effect chamber to rapidly decrease, and the neuromuscular
  • the nicotinic acetylcholine receptor-bound rocuronium bromide at the linker rapidly liberated, thereby reversing the muscle relaxant effect of rocuronium.
  • the antagonism of sodium succinate on muscle relaxants is highly selective. Because its inner cavity is complementary to rocuronium, it selectively antagonizes the steroidal muscle relaxant rocuronium, which also has good antagonistic effect on the similar drug vecuronium, and benzylisoquinoline. Non-depolarizing muscle relaxants (such as atracurium, etc.) and depolarizing muscle relaxants (succinylcholine) have no antagonistic effect.
  • Sodium Glucosamine is a ⁇ -cyclodextrin derivative with 8 glucopyranose
  • the ring structure has a hydrophilic outer edge and a hydrophobic inner cavity.
  • the chemical name of Sodium Glucosamine is: 6-perdeoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt, the structural formula is as follows:
  • Patent CN1188428C (is a family patent of EP1259550B1)
  • the preparation route reported in this patent is as follows: starting from ⁇ -cyclodextrin, the intermediate 6-perdeoxy-6-periodo- ⁇ -cyclodextrin is obtained by substitution with iodine and triphenylphosphine, and the intermediate is The 3-mercaptopropionic acid is obtained by a nucleophilic substitution reaction to obtain a crude sodium succinate, and the macroporous resin is used to remove impurities and dialysis to obtain a final qualified sodium sulphate product.
  • This patent involves cooling the mixture during the process of obtaining the intermediate, adding sodium methoxide to the mixture, and stirring the mixture before pouring into methanol and evaporating to dryness.
  • Patent WO2012025937 and WO2014125501 are identical to Patent WO2012025937 and WO2014125501:
  • this route uses phosphorus pentachloride in the preparation of sodium succinate intermediate 6-deoxy-oxy-6-periodo- ⁇ -cyclodextrin (SGMD-1). (P-pentabromide) in place of triphenylphosphine and iodine, the resulting intermediate is 6-perdeoxy-6-perchloro(bromo)- ⁇ -cyclodextrin, which is passed through with 3-mercaptopropionic acid. The nucleophilic substitution reaction gives a crude product of saponin sodium, which is then refined to obtain a finished product of saponin.
  • WO2012025937 uses ethanol to the reaction solution to precipitate sodium sulphate (unreacted SGMD-1 is also precipitated), filtered, and the solid passes through the silica gel. Purification was carried out by column chromatography on a Sephadex column G-25.
  • the second step of WO2014125501 is carried out by recrystallization from methanol, ethanol, acetonitrile and water. Before recrystallization, it is mentioned that the activated carbon is decolorized first.
  • the present invention relates to a process for the industrial production which is inexpensive and inexpensive to prepare and purify sodium sulphate.
  • the method comprises reacting ⁇ -cyclodextrin (SM1) with iodine and triphenylphosphine in an organic solvent to provide intermediate-1 (abbreviated as: SGMD-1), ie 6 - Total deoxy-6-periodo- ⁇ -cyclodextrin, which is recrystallized and reacted with 3-mercaptopropionic acid (SM2) under basic conditions in an organic solvent to give 6-all deoxy-6-
  • SM1 ⁇ -cyclodextrin
  • SGMD-1 intermediate-1
  • ie 6 - Total deoxy-6-periodo- ⁇ -cyclodextrin which is recrystallized and reacted with 3-mercaptopropionic acid (SM2) under basic conditions in an organic solvent to give 6-all deoxy-6-
  • SM2 3-mercaptopropionic acid
  • stainless product of SGMD the crude SGMD is adsorbed by an adsorbent, and recrystallized to obtain a finished product of saponin
  • ⁇ -cyclodextrin (SM1) is reacted with iodine and triphenylphosphine in an organic solvent to obtain intermediate 6-perdeoxy-6-periodo- ⁇ -cyclodextrin (SGMD-1);
  • the crude SGMD-1 is recrystallized
  • the crude SGMD was adsorbed by an adsorbent and then recrystallized.
  • the organic solvent is N,N-dimethylformamide.
  • the process route prepared is as follows:
  • the ratio of acetone to SM1 charge is from 30:1 to 150:1, preferably from 35:1 to 140:1, from 40:1 to 130:1, 45:1.
  • 120:1, 50:1 to 110:1, 50:1 to 100:1 is most preferably 60:1 to 100:1.
  • the method is characterized in that the obtained SGMD-1 is directly added to acetone and then recrystallized before the preparation of the crude SGMD, wherein the solvent for recrystallization is N,N-dimethyl Formamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol or acetone or a mixed solvent of these two solvents, preferably acetone/DMF mixed solvent, acetone/DMSO mixed solvent, or methanol /DMF and ethanol / DMF mixed solvent, the most preferred mixed solvent is acetone / DMF mixed solvent, the mixed solvent ratio (V / V) is 1:0.3 ⁇ 1:2.5, preferably the ratio is 1:0.4 ⁇ 1:2.4 , 1:0.5 to 1:23, 1:0.6 to 1:2.2, 1:0.7 to 1:2.1, and the most preferable ratio is 1:0.8 to 1:2.0.
  • the solvent for recrystallization is N,N-dimethyl Formamide (DMF), dimethyl sulfoxide (DM
  • the process is characterized in that the molar ratio of intermediate-1 (SGMD-1) to mercaptopropionic acid (SM2) is from 1:8 to 1:25, preferably 1:9 to 1
  • the ratio of 24, 1:10 to 1:22, 1:11 to 1:21, and the most preferable molar ratio is 1:12 to 1:20.
  • the process is characterized in that the molar ratio of intermediate-1 (SGMD-1) to sodium hydride is from 1:10 to 1:50, preferably from 1:12 to 1:48,1 : 15 to 1:45, 1:17 to 1:42, 1:18 to 1:40, and the most preferable molar ratio is 1:22 to 1:40.
  • the molar ratio of intermediate-1 (SGMD-1) to sodium hydride is from 1:10 to 1:50, preferably from 1:12 to 1:48,1 : 15 to 1:45, 1:17 to 1:42, 1:18 to 1:40, and the most preferable molar ratio is 1:22 to 1:40.
  • the method is characterized in that the reagent for recrystallization of SGMD is: ethanol, water, methanol and isopropanol, or a mixture of methanol, ethanol and water, preferably a mixed solvent of methanol/water. Or a mixed solvent of ethanol/water.
  • the method is characterized in that the adsorbent is selected from the group consisting of activated carbon, silica gel, macroporous resin, alumina (basic alumina or neutral alumina), molecular sieves, zeolites, or the like a group consisting of a mixture of three adsorbents.
  • the preferred adsorbent is alumina and activated carbon, and alumina and activated carbon may be used singly or in combination.
  • the method is characterized in that the mass ratio of the crude SGMD to the adsorbent is from 1:0.1 to 1:2.5, preferably from 1:0.1 to 1:2.3, from 1:0.1 to 1:2.1,1 From 0.2 to 1:2.0, from 1:0.2 to 1:1.8, most preferably from 1:0.2 to 1:1.5.
  • the present invention removes the by-product triphenyl oxygen which is produced in large quantities by the reaction of ⁇ -cyclodextrin with iodine and triphenylphosphine in the prior art by recrystallization of the prepared SGMD-1.
  • the effect of phosphorus on the subsequent reaction but also avoids the evaporation of a large amount of high-boiling solvent DMF, simplifies the process, improves the quality of SGMD-1, and uses the adsorbent to adsorb, remove and recrystallize impurities in the crude SGMD.
  • Figure 1 1 H-NMR of Intermediate-1: 6-perdeoxy-6-periodo- ⁇ -cyclodextrin;
  • Figure 3 1 H-NMR of sodium succinate: 6-perdeoxy-6-per(2-carboxyethyl)thio- ⁇ -cyclodextrin sodium salt;
  • Figure 4 Sodium glucomannan: 6-perdeoxy-6-per(2-carboxyethyl) thio- ⁇ -cyclodextrin sodium salt High resolution mass spectrometry;
  • Figure 5 Analytical spectrum of related substances of the finished product of sodium succinate obtained by the method of the present invention
  • FIG. 7 Analytical spectrum of related substances of the listed product Bridon 2ml (batch number: S217P);
  • Figure 8 Analytical profile of the substance related to the injection of Bridon 5ml (batch number: S502P).
  • N,N-dimethylformamide (DMF) was added to a 1 L three-necked flask, and 36.16 g of triphenylphosphine was added while stirring, and dissolved by stirring at room temperature.
  • a solution of N,N-dimethylformamide iodine (36.63 g of iodine dissolved in 45 g of N,N-dimethylformamide) was added dropwise, and the temperature was controlled at 20 to 30 ° C, and the heat retention reaction was about 30. In minutes, 12 g of ⁇ -cyclodextrin was added. The reaction system was started to warm to 70 ° C, and the reaction was allowed to stand (about 24 hours) until the starting reaction was complete (HPLC monitoring).
  • the reaction system was cooled to 20 ° C, and under a temperature of 20 to 30 ° C, a methanol solution of sodium methoxide was added dropwise to the above reaction system (8.74 g of sodium methoxide was added to 48 g of methanol to form a suspension). After the completion of the dropwise addition, the temperature is controlled at 20 to 30 ° C, and the mixture is kept warm for about 2 hours. 995g of acetone was added to the above reaction solution, a large amount of solid was precipitated in the solution, and the mixture was stirred at a temperature of 20 to 30 ° C for 2 hours, and filtered under reduced pressure. The filter cake was rinsed with acetone 20 g, and air dried at 45 to 50 ° C. ⁇ 13 hours.
  • the white powder was obtained in an amount of 14.09 g, and the yield range was 69.5%.
  • N,N-dimethylformamide (DMF) was added to a 5 L three-necked flask, and 36.16 g of triphenylphosphine was added thereto with stirring, and dissolved by stirring at room temperature.
  • a solution of iodine in N,N-dimethylformamide (36.63 g of iodine dissolved in 45 g of N,N-dimethylformamide) was added dropwise, and the temperature was controlled at 20 to 30 ° C. For 30 minutes, 12 g of ⁇ -cyclodextrin was added. reaction system The temperature was raised to 70 ° C and the reaction was allowed to proceed (about 24 hours) until the starting reaction was complete (HPLC monitoring).
  • the reaction system was cooled to 20 ° C, and under a temperature of 20 to 30 ° C, a methanol solution of sodium methoxide was added dropwise to the above reaction system (8.74 g of sodium methoxide was added to 48 g of methanol to form a suspension). After the completion of the dropwise addition, the temperature is controlled at 20 to 30 ° C, and the mixture is kept warm for about 2 hours. 948g of acetone was added to the solution in the reaction solution to form a solid. The mixture was stirred at a temperature of 20 to 30 ° C for 2 hours, and filtered under reduced pressure. The filter cake was rinsed with acetone 20 g, and dried at 45 to 50 ° C for 8 to 13 hours.
  • N,N-dimethylformamide (DMF) was added to a 1 L three-necked flask, and 36.16 g of triphenylphosphine was added thereto with stirring, and dissolved by stirring at room temperature.
  • a solution of iodine in N,N-dimethylformamide (36.63 g of iodine dissolved in 45 g of N,N-dimethylformamide) was added dropwise, and the temperature was controlled at 20 to 30 ° C. For 30 minutes, 12 g of ⁇ -cyclodextrin was added. The reaction system was started to warm to 70 ° C, and the reaction was allowed to stand (about 24 hours) until the starting reaction was complete (HPLC monitoring).
  • the reaction system was cooled to 20 ° C, and under a temperature of 20 to 30 ° C, a methanol solution of sodium methoxide was added dropwise to the above reaction system (8.74 g of sodium methoxide was added to 48 g of methanol to form a suspension). After the completion of the dropwise addition, the temperature is controlled at 20 to 30 ° C, and the mixture is kept warm for about 2 hours. Add 398g of acetone to the solution in the reaction solution to form a solid. Under the condition of temperature control 20 ⁇ 30°C, stir for 2 hours, vacuum filter under vacuum, filter cake with 20g of acetone, and dry at 45 ⁇ 50°C (vacuum/blast). ⁇ 13 hours.
  • N,N-dimethylformamide DMF
  • triphenylphosphine triphenylphosphine
  • the reaction system was cooled to 20 ° C, and under a temperature of 20 to 30 ° C, a methanol solution of sodium methoxide was added dropwise to the above reaction system (874 g of sodium methoxide was added to 4.8 kg of methanol to form a suspension). After the completion of the dropwise addition, the temperature is controlled at 20 to 30 ° C, and the mixture is kept warm for about 2 hours. 49.9 kg of acetone was added to the solution in the reaction solution to form a solid. Under the condition of temperature control at 20-30 ° C, the mixture was stirred for 2 hours, filtered under reduced pressure, and the filter cake was rinsed with acetone 2.0 kg, and dried at 45-50 ° C for 8-13. hour.
  • the white powder was obtained in an amount of 1.77 kg, and the yield range was 87.9%.
  • Example 5 Sodium glucomannan crude: Synthesis of crude 6-deoxy-oxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • the temperature was controlled at 20 to 30 ° C, 96 g of purified water was added to the reaction system, stirred for 30 minutes, filtered, rinsed with 20 g of acetone, and the temperature was controlled at 45 ⁇ 2 ° C, and dried by air for 12 to 15 hours to obtain a crude product: 8.81 g. Yield: 88.1%.
  • Example 6 Sodium glucomannan crude: 6-total deoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin Synthesis of crude sodium salt
  • Example 7 Crude sodium sulphate crude: Synthesis of crude 6-deoxy-oxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 8 Crude sodium gluconate: Synthesis of crude 6-deoxy-oxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 9 Crude sodium sulphate crude: Synthesis of crude 6-deoxy-oxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 10 Sodium glucomannan crude: Synthesis of crude 6-deoxy-oxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 11 Sodium gluconate: 6-perdeoxy-6-per(2-carboxyethyl) thio- ⁇ -cyclodextrin sodium salt Refinement
  • the detection results of the sodium sulphate impurity prepared according to this example are shown in the corresponding data of the SG11 row in the attached table, and the normalized content of the main component is 98.842%, and the number of detected impurities is lower than that allowed by the listed preparation. At the maximum, the amount of each impurity detected is lower than the limit of the corresponding impurity control in the marketed formulation.
  • the data is shown in Schedule 1.
  • Example 12 Sodium glucomannan: Purification of 6-perdeoxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • 50 g of crude saponin sodium was added to a mixed solution of 150 g of purified water and 150 g of ethanol.
  • 10 g of activated carbon and 50 g of basic alumina were added and stirred for 30 minutes, and filtered, 50 g of purified water was washed, and the filter cake was purged with nitrogen.
  • the lower filtrate is controlled at a temperature of 50-55 ° C, and 200 g of ethanol is added dropwise. After the dropwise addition is completed, the temperature is slowly lowered, the temperature is controlled at 25 to 30 ° C (crystallization temperature), and the crystallization is stirred for 0.5 hours (crystallization time), and the filter cake is 150 g.
  • the ethanol was rinsed once, and the obtained solid was dried at 60 to 65 ° C for 24 hours to obtain 27.8 g of a white powdery solid. Yield range: 55.6%.
  • the results of the detection of the sodium sulphate impurity prepared according to this example are shown in the corresponding data of the SG12 row in Table 1, and the normalized content of the main component is 98.488%.
  • the number of detected impurities is lower than that of the marketed preparation, and the content of each impurity detected is lower than the limit of the corresponding impurity control in the marketed preparation.
  • Example 13 Sodium glucomannan: 6-perdeoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium Salt refining
  • the results of the detection of the sodium sulphate impurity prepared according to this example are shown in the corresponding data of the SG13 row in the attached Table 1, and the normalized content of the main component is 98.734%.
  • the number of detected impurities is lower than that of the marketed preparation, and the content of each impurity detected is lower than the limit of the corresponding impurity control in the marketed preparation.
  • Example 14 Sodium Glucosamine: Purification of 6-Deoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • the results of the detection of the sodium sulphate impurity prepared according to this example are shown in the corresponding data of the SG14 line in the attached Table 1, and the normalized content of the main component is 98.790%.
  • the number of detected impurities is lower than that of the marketed preparation, and the content of each impurity detected is lower than the limit of the corresponding impurity control in the marketed preparation.
  • Example 15 Sodium glucomannan: Purification of 6-perdeoxy-6-per(2-carboxylic acid ethyl)thio- ⁇ -cyclodextrin sodium salt.
  • Example 16 Sodium glucomannan: Purification of 6-perdeoxy-6-per(2-carboxylic acid ethyl)thio- ⁇ -cyclodextrin sodium salt.
  • Example 17 Sodium Glucosamine: Purification of 6-Deoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 18 sodium succinate: 6-perdeoxy-6-per(2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt Refinement
  • 50 g of crude saponin sodium was added to a mixed solution of 150 g of purified water and 100 g of methanol.
  • 20 g of activated carbon and 40 g of neutral alumina were added, stirred for 30 minutes, filtered, and 50 g of purified water was washed to wash the filter cake with nitrogen.
  • the temperature of the filtrate under protection is controlled at 50-55 ° C, and 200 g of methanol is added dropwise. After the dropwise addition is completed, the temperature is slowly lowered, the temperature is controlled at 25 to 30 ° C (crystallization temperature), and the crystallization is stirred for 0.5 hours (crystallization time), and the filter cake is used for filtration.
  • Example 19 Sodium Glucosamine: Purification of 6-Deoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • Example 20 Sodium glucomannan: Purification of 6-perdeoxy-6-per(2-carboxylic acid ethyl)thio- ⁇ -cyclodextrin sodium salt
  • Example 21 Sodium Glucosamine: Purification of 6-Deoxy-6-all (2-carboxylic acid ethyl) thio- ⁇ -cyclodextrin sodium salt
  • the results of the detection of the sodium sulphate impurity prepared according to this example are shown in the corresponding data of the SG21 line in the attached Table 1, and the normalized content of the main component is 98.916%.
  • the number of detected impurities is lower than that of the marketed preparation, and the content of each impurity detected is lower than the limit of the corresponding impurity control in the marketed preparation.
  • the impurities produced during the preparation of sodium sulphate have similar chemical structure and similar polarity to the sodium sulphate.
  • the ultraviolet absorption of these impurities is basically the same as or similar to the target active ingredient. Therefore, the process is optimized early in the impurity.
  • the area preparation method and the impurity content of the finished product of the saponin prepared in Examples 11 to 21 were calculated by the area normalization method.
  • test preparation solution (Bridion): Precision measurement of the marketed preparation (Bridion was purchased from Japan MSD Co., Ltd., batch numbers: S217P, S502P and R501G, concentration: 100 mg/ml), about 1.0 ml, In a 50 ml volumetric flask, the purified water was quantitatively diluted to prepare a solution containing about 2.0 mg per 1 ml, and the test solution was supplied as a marketed preparation.
  • the positioning of impurities and principal components is carried out with relative retention times.
  • the peaks with relative retention times of 0.88 and 1.00 are Org48302 and Sodium glucosinolate, respectively.
  • the above analysis results are shown in the table below.
  • the normalized content of the two main components in the three batches of the marketed preparations was about 97.0%, and the number of impurities detected was more than the number of impurities detected in the finished product of the sodium sulphate prepared by the present invention, and the three batches were listed.
  • the detection spectrum of the substance related to the preparation is shown in Fig. 6 to Fig. 8 respectively.

Abstract

涉及制备6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的方法，包括：将γ-环糊精(SM1)与碘和三苯基膦在有机溶剂中反应，得到中间体6-全脱氧-6-全碘代-γ-环糊精(SGMD-1)；向反应液中加入甲醇钠的甲醇溶液，不经过减压蒸馏，直接加入丙酮，析出固体，过滤，得到SGMD-1粗品；将所述SGMD-1粗品进行重结晶；将获得的重结晶中间体(SGMD-1)与3-巯基丙酸(SM2)在碱性条件(例如氢化钠)下反应，得到6-全脱氧-6-全(2-羧基乙基)硫代-γ-环糊精钠盐粗品(SGMD粗品)；将所述SGMD粗品经吸附剂吸附，然后重结晶。

Description

舒更葡糖钠的制备及纯化方法 技术领域
本发明属于药物合成领域，涉及原料药与中间体的制备，特别涉及一种舒更葡糖钠原料药及中间体的制备及纯化方法。
背景技术
舒更葡糖钠(英文名：Sugammadex，在本文中缩写为SGMD)最早由Organon Biosciences公司发现，2007年Organon公司被先灵葆雅公司(Schering-Plough)收购，2009年先灵葆雅与默克(Merck)合并，默克公司最终拥有舒更葡糖钠。舒更葡糖钠及注射液于2009年底在欧洲获批上市，商品名为布瑞亭(Bridion)；2010年被日本PMDA批准上市；2015年12月被美国FDA批准上市。目前，舒更葡糖钠注射液已经在全球50多个国家上市。荷兰欧加农的舒更葡糖钠注射液已于2015年获得中国CFDA批准在中国进行临床试验。
舒更葡糖钠是全球首个和唯一的选择性松弛结合剂(selective relaxant binding agent，SRBA)，是20年来***领域第一个重大药物进展。舒更葡糖钠的作用机理在于：舒更葡糖钠在血浆中螯合游离型罗库溴铵分子，使血浆游离型罗库溴铵浓度急剧下降，在效应室(神经肌肉接头处)和中央室(血浆)之间形成一个浓度梯度，从而使处于效应室的的罗库溴铵分子顺着浓度差迅速转运到中央室，这使得效应室的罗库溴铵浓度迅速下降，与神经肌肉接头处的烟碱样乙酰胆碱受体结合的罗库溴铵迅速游离出来，因而逆转了罗库溴铵的肌松作用。
舒更葡糖钠对肌松药的拮抗是具有高度选择性的。由于其内腔同罗库溴铵分子具有互补性，因此选择性的拮抗甾体类肌松药罗库溴铵，对同类药物维库溴铵也有良好的拮抗作用，而对苄异喹啉类非去极化肌松药(如阿曲库铵等)及去极化肌松药(琥珀胆碱)无拮抗作用。
舒更葡糖钠是一种γ-环糊精衍生物，具有由8个吡喃葡萄糖构成的 环状结构，其外缘亲水而内腔疏水。舒更葡糖钠的化学名称为：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐，结构式如下：
Figure PCTCN2016095985-appb-000001
由于舒更葡糖钠本身的超分子结构，分子极性大，水溶性很好，制备过程产生的杂质也和舒更葡糖钠分子具有相似的极性和溶解性，这给后续的精制工艺带来非常大的难度。目前，现有技术关于舒更葡糖钠的制备及纯化工艺如下：
1.专利CN1188428C(为EP1259550B1的同族专利)
这是原研公司的专利。
该专利报道的制备路线为：从γ-环糊精出发，经过与碘、三苯基膦的取代得到中间体6-全脱氧-6-全碘代-γ-环糊精，该中间体与3-巯基丙酸通过亲核取代反应得到舒更葡糖钠粗品，再经过大孔树脂除去杂质及渗析得到最终合格的舒更葡糖钠成品。该专利在获得中间体过程中，涉及冷却混合物，向混合物中加入甲醇钠，在倾入甲醇中并蒸发至干燥之前搅拌混合物。
2.专利WO2012025937与WO2014125501：
与专利CN1188428C报道的路线相比，该路线(WO2014125501)在制备舒更葡糖钠中间体6-全脱氧-6-全碘代-γ-环糊精(SGMD-1)时采用五氯化磷(五溴化磷)替代三苯基磷和碘，最终生成的中间体为6-全脱氧-6-全氯(溴)代-γ-环糊精，该中间体与3-巯基丙酸通过亲核取代反应得到舒更葡糖钠粗品，再经过精制得到舒更葡糖钠成品。
WO2012025937中的制备工艺与WO2014125501的相同，均采用了卤代化磷来替换CN1188428C专利中的三苯基磷，同时在中间体-1反应结束 后需要蒸除高沸点的溶剂DMF。在第二步制备舒更葡糖钠(SGMD)粗品时，WO2012025937采用向反应液中加乙醇，使舒更葡糖钠析出(未反应的SGMD-1也会析出)，过滤，固体再通过硅胶柱层析、葡聚糖凝胶柱G-25进行纯化。WO2014125501的第二步采用的甲醇、乙醇、乙腈和水进行重结晶，在进行重结晶前，提到先加活性炭脱色。
发明内容
本发明涉及适用于工业化生产的、成本低廉制备及纯化舒更葡糖钠的方法。
在本发明的实施方案中，所述方法包括将γ-环糊精(SM1)与碘和三苯基膦在有机溶剂中反应，得到中间体-1(简写为：SGMD-1)，即6-全脱氧-6-全碘代-γ-环糊精，该中间体经过重结晶后与3-巯基丙酸(SM2)在碱性条件下在有机溶剂中反应得到6-全脱氧-6-全(2-羧基乙基)硫代-γ-环糊精钠盐(SGMD粗品)，SGMD粗品经吸附剂吸附、重结晶得到舒更葡糖钠成品。
在本发明的实施方案中，提供制备6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的方法，包括：
将γ-环糊精(SM1)与碘和三苯基膦在有机溶剂中反应，得到中间体6-全脱氧-6-全碘代-γ-环糊精(SGMD-1)；
向反应液中加入甲醇钠的甲醇溶液，不经过减压蒸馏，直接加入丙酮，析出固体，过滤，得到SGMD-1粗品；
将所述SGMD-1粗品进行重结晶；
将获得的重结晶中间体(SGMD-1)与3-巯基丙酸(SM2)在碱性条件(例如氢化钠)下反应，得到6-全脱氧-6-全(2-羧基乙基)硫代-γ-环糊精钠盐粗品(SGMD粗品)；
将所述SGMD粗品经吸附剂吸附，然后重结晶。
在本发明的实施方案中，所述有机溶剂是N，N-二甲基甲酰胺。
在本发明的实施方案中，制备的工艺路线如下：
Figure PCTCN2016095985-appb-000002
在本发明的实施方案中，丙酮与SM1投料量投料比(V/W)为30∶1～150∶1，优选35∶1～140∶1，40∶1～130∶1，45∶1～120∶1，50∶1～110∶1，50∶1～100∶1最优选60∶1～100∶1。
在本发明的实施方案中，所述方法的特征在于：在制备SGMD粗品之前，将获得的SGMD-1直接加丙酮析出，然后进行重结晶，其中重结晶的溶剂为N，N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、甲醇，乙醇，异丙醇或丙酮或这其中两种溶剂的混合溶剂，优选为丙酮/DMF混合溶剂、丙酮/DMSO混合溶剂、或甲醇/DMF及乙醇/DMF的混合溶剂，最优选的混合溶剂为丙酮/DMF的混合溶剂，混合溶剂比例(V/V)为1∶0.3～1∶2.5，优选比例为1∶0.4～1∶2.4，1∶0.5～1∶23，1∶0.6～1∶2.2，1∶0.7～1∶2.1，最优选的比例为1∶0.8～1∶2.0。
在本发明的实施方案中，所述方法的特征在于：中间体-1(SGMD-1)与巯基丙酸(SM2)的投料摩尔比为1∶8～1∶25，优选1∶9～1∶24，1∶10～1∶22，1∶11～1∶21，最优选的投料摩尔比为1∶12～1∶20。
在本发明的实施方案中，所述方法的特征在于：中间体-1(SGMD-1)与氢化钠的投料摩尔比为1∶10～1∶50，优选1∶12～1∶48，1∶15～1∶45，1∶17～1∶42，1∶18～1∶40，最优选的摩尔投料比为1∶22～1∶40。
在本发明的实施方案中，所述方法的特征在于：用于SGMD重结晶的试剂为：乙醇，水，甲醇及异丙醇，或甲醇、乙醇与水的混合物，优选甲醇/水的混合溶剂或乙醇/水的混合溶剂。
在本发明的实施方案中，所述方法的特征在于：所述吸附剂选自由活性炭、硅胶、大孔树脂、氧化铝(碱性氧化铝或中性氧化铝)，分子筛、沸石，或上述2～3种吸附剂的混合物组成的组。优选的吸附剂为氧化铝及活性炭，氧化铝和活性炭可以单独使用，也可以混合使用。
在本发明的实施方案中，所述方法的特征在于：SGMD粗品与吸附剂的质量比为1∶0.1～1∶2.5，优选1∶0.1～1∶2.3，1∶0.1～1∶2.1，1∶0.2～1∶2.0，1∶0.2～1∶1.8，最优选1∶0.2～1∶1.5。
本发明相对于现有技术而言，通过对制备的SGMD-1进行重结晶，去除了现有技术中γ-环糊精与碘和三苯基膦反应所大量产生的副产物三苯基氧磷对后续反应的影响，同时也避免了蒸除大量高沸点溶剂DMF，简化了工艺，提高了SGMD-1的质量，而且使用吸附剂对SGMD粗品中的杂质进行吸附、去除及重结晶，用简单、经济、可控的工艺制备出符合药用需求的舒更葡糖钠原料药，不引入新的毒理、安全性未知的杂质，质量更可控，并且所制备的原料药在质量上不低于目前上市品的质量。
附图说明
附图1：中间体-1：6-全脱氧-6-全碘代-γ-环糊精的1H-NMR；
附图2：中间体-1：6-全脱氧-6-全碘代-γ-环糊精高分辨质谱；
附图3：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的1H-NMR；
附图4：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的 高分辨质谱；
附图5：使用本发明的方法制备得到的舒更葡糖钠成品有关物质分析谱图；
附图6：上市品Bridon 5ml(批号：R501G)注射液有关物质分析谱图；
附图7：上市品Bridon 2ml(批号：S217P)注射液有关物质分析谱图；
附图8：上市品Bridon 5ml(批号：S502P)注射液有关物质分析谱图。
具体实施方式
为了进一步对本发明进行说明，下面将通过具体实施例进行说明，但是以下的实施例对本发明的保护范围不构成任何限制。
实施例1：中间体-1(SGMD-1)：6-全脱氧-6-全碘代-γ-环糊精的合成
氮气保护下，向1L的三口瓶中加入170g N，N-二甲基甲酰胺(DMF)，搅拌的同时加入36.16g三苯基膦，室温搅拌溶解。向上述反应体系中滴加N，N-二甲基甲酰胺碘溶液(将36.63g碘溶于45g的N，N-二甲基甲酰胺中)，控温20～30℃，保温反应约30分钟，加入γ-环糊精12g。反应体系开始升温至70℃，保温反应(约24小时)至原料反应完全(HPLC监控)。
反应体系降温至20℃，控温20～30℃条件下，向上述反应体系中滴加甲醇钠的甲醇溶液(将8.74g甲醇钠加入到48g甲醇中形成悬浊液)。滴加完成后，控温20～30℃，保温搅拌约2小时。向上述反应液中加入995g丙酮，溶液中有大量固体析出，控温20～30℃条件下，搅拌2小时，减压抽滤，滤饼用丙酮20g淋洗，45～50℃鼓风干燥8～13小时。
将所得固体控温50℃条件下溶于170g DMF和丙酮的混合溶液(丙酮/DMF＝1∶0.8，V/V)中，保温搅拌约60分钟，将体系降温至20～30℃，继续搅拌、析晶、过滤，丙酮32g淋洗。45～50℃(真空/鼓风)干燥8～13小时。得到类白色粉末14.09g，收率范围：69.5％。
实施例2：中间体-1(SGMD-1)：6-全脱氧-6-全碘代-γ-环糊精的合成
氮气保护，向5L的三口瓶中加入227g N，N-二甲基甲酰胺(DMF)，搅拌下加入36.16g三苯基膦，室温搅拌溶解。向上述反应体系中滴加碘的N，N-二甲基甲酰胺溶液(将36.63g碘溶于45g的N，N-二甲基甲酰胺中)，控温20～30℃，保温反应约30分钟，加入γ-环糊精12g。反应体系 开始升温至70℃，保温反应(约24小时)至原料反应完全(HPLC监控)。
反应体系降温至20℃，控温20～30℃条件下，向上述反应体系中滴加甲醇钠的甲醇溶液(将8.74g甲醇钠加入到48g甲醇中形成悬浊液)。滴加完成后，控温20～30℃，保温搅拌约2小时。将948g丙酮加入反应液中溶液中形成固体，控温20～30℃条件下，搅拌2小时，减压抽滤，滤饼用丙酮20g淋洗，45～50℃鼓风干燥8～13小时。
将所得固体控温50℃条件下溶于270g DMF和丙酮的混合溶液(丙酮-DMF＝1：1.5，V/V)中，保温搅拌约60分钟，降至20～30℃，过滤，丙酮32g淋洗。45～50℃(真空/鼓风)干燥8～13小时。得到类白色粉末18.72g，收率范围：93.0％。1H-NMR(400Mz，DMSO-d6)δ：5.990～5.972(m，16H)，5.042～5.034(d，J＝3.2Hz，8H)，3.841～3.818(m，8H)，3.619(m，16H)，3.448～3.423(m，8H)，3.340～3.292(m，8H)(详见附图1)；ESI-HRMS谱图显示SGMD-1分子离子峰m/z＝2176.6386[M+H]1，其加合峰m/z＝2198.6249[M+Na+H]+，所对应的分子量与提供的结构式理论计算值(2175.6354)相符。绝对误差为0.48ppm，在高分辨质谱误差范围之内，(详见附图2)。
实施例3：中间体-1(SGMD-1)：6-全脱氧-6-全碘代-γ-环糊精的合成
氮气保护，向1L的三口瓶中加入159g N，N-二甲基甲酰胺(DMF)，搅拌下加入36.16g三苯基膦，室温搅拌溶解。向上述反应体系中滴加碘的N，N-二甲基甲酰胺溶液(将36.63g碘溶于45g的N，N-二甲基甲酰胺中)，控温20～30℃，保温反应约30分钟，加入γ-环糊精12g。反应体系开始升温至70℃，保温反应(约24小时)至原料反应完全(HPLC监控)。
反应体系降温至20℃，控温20～30℃条件下，向上述反应体系中滴加甲醇钠的甲醇溶液(将8.74g甲醇钠加入到48g甲醇中形成悬浊液)。滴加完成后，控温20～30℃，保温搅拌约2小时。到398g丙酮加入反应液中溶液中形成固体，控温20～30℃条件下，搅拌2小时，减压抽滤，滤饼用丙酮20g淋洗，45～50℃(真空/鼓风)干燥8～13小时。
将所得固体控温50℃条件下溶于270g DMF和丙酮的混合溶液(丙酮-DMF＝1.0∶2.0，V/V)中，保温搅拌约60分钟，降至20～30℃，析晶，过滤，丙酮32g淋洗。45～50℃鼓风干燥8～13小时。得到类白色粉末17.51 g，收率范围：87.0％。
实施例4：中间体-1(SGMD-1)：6-全脱氧-6-全碘代-γ-环糊精的合成
氮气保护，向50L的反应釜中加入13.2kg N，N-二甲基甲酰胺(DMF)，搅拌下加入3.6kg三苯基膦，室温搅拌溶解。向上述反应体系中滴加碘的N，N-二甲基甲酰胺溶液(将3.67kg碘溶于4.5kg的N，N-二甲基甲酰胺中)，控温20～30℃，保温反应约30分钟，加入γ-环糊精1.2kg。反应体系开始升温至70℃，保温反应(约24小时)至原料反应完全(HPLC监控)。
反应体系降温至20℃，控温20～30℃条件下，向上述反应体系中滴加甲醇钠的甲醇溶液(将874g甲醇钠加入到4.8kg甲醇中形成悬浊液)。滴加完成后，控温20～30℃，保温搅拌约2小时。到49.9kg丙酮加入反应液中溶液中形成固体，控温20～30℃条件下，搅拌2小时，减压抽滤，滤饼用丙酮2.0kg淋洗，45～50℃鼓风干燥8～13小时。
将所得固体控温50℃条件下溶于2.6kg DMF和丙酮的混合溶液(丙酮-DMF＝1.0∶0.8，V/V)中，保温搅拌约60分钟，降至20～30℃，析晶，过滤，丙酮3.2kg淋洗。45～50℃(真空/鼓风)干燥8～13小时。得到类白色粉末1.77kg，收率范围：87.9％。
实施例5：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐粗品的合成
氮气保护下，向1L的三口瓶中依次加入200g N，N-二甲基甲酰胺，5.76g巯基丙酸(SM2)。反应体系降温至0～5℃，加入氢化钠7.38g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将10g SGMD-1溶于66.2g的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料反应完全。
控温20～30℃，向反应体系加入96g纯化水，搅拌30分钟，过滤，以20g丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：8.81g。收率：88.1％。
实施例6：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精 钠盐粗品的合成
氮气保护，向1L的三口瓶中依次加入200g N，N-二甲基甲酰胺，9.64g巯基丙酸(SM2)。反应体系降温至0～5℃，加入氢化钠7.38g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将10g SGMD-1溶于66.2g的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料反应完全。
控温20～30℃，向反应体系加入96g纯化水，搅拌30分钟，过滤，以20g丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：8.91g。收率：84.1％。
实施例7：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐粗品的合成
氮气保护，向1L的三口瓶中依次加入200g N，N-二甲基甲酰胺，8.64g巯基丙酸(SM2)。反应体系降温至0～5℃，加入氢化钠6.42g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将10g SGMD-1溶于66.2的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料反应完全。
控温20～30℃，向反应体系加入96g纯化水，搅拌30分钟，过滤，以20g丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：9.02g。收率：90.2％。
实施例8：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐粗品的合成
氮气保护，向1L的三口瓶中依次加入200g N，N-二甲基甲酰胺，8.64g巯基丙酸(SM2)。反应体系降温至0～5℃，加入氢化钠4.41g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将10g SGMD-1溶于66.2g的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料 反应完全。
控温20～30℃，向反应体系加入96g纯化水，搅拌30分钟，过滤，以20g丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：9.34g。收率：93.4％。
实施例9：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐粗品的合成
氮气保护，向50L的反应釜中依次加入15.88kg N，N-二甲基甲酰胺，1.05kg巯基丙酸(SGMD-SM2)。反应体系降温至0～5℃，加入氢化钠7.38g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将1.2kg SGMD-1溶于7.94kg的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料反应完全。
控温20～30℃，向反应体系加入3.84kg纯化水，搅拌30分钟，过滤，以7.8kg丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：1.1kg。收率：91.7％。
实施例10：舒更葡糖钠粗品：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐粗品的合成
氮气保护，向1L的三口瓶中依次加入200g N，N-二甲基甲酰胺，5.76g巯基丙酸(SM2)。反应体系降温至0～5℃，加入氢化钠4.06g，充分搅拌30分钟，向上述反应体系中滴加SGMD-1的N，N-二甲基甲酰胺溶液(将10g SGMD-1溶于66.2g的N，N-二甲基甲酰胺)，滴加时间：20～40分钟。滴加完成后，反应体系升温至70℃～75℃，保温反应(约12小时)至原料反应完全。
控温20～30℃，向反应体系加入96g纯化水，搅拌30分钟，过滤，以20g丙酮淋洗，控温45±2℃，鼓风干燥12～15小时，得粗品：8.91g。收率：89.1％。
实施例11：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐 的精制
将上述制备的舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入活性炭75g搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得30.5g白色粉末状固体。收率：61.0％。1H-NMR(400Mz，D2O)δ：5.123～5.133(d，J＝4Hz，8H)，3.982～4.006(m，8H)，3.864～3.911(m，8H)，3.555～3.615(m，16H)，3.052～3.087(m，8H)，2.921～2.956(m，8H)，2.778～2.815(m，16H)，2.408～2.451(m，16H)(详见附图3)；ESI-HRMS谱图显示分子离子峰：1999.41432[M-H]-，舒更葡糖钠分子离子峰的理论计算值为：1999.40159[M-H]-，绝对误差为6.36ppm，符合高分辨质谱误差范围，实测值与理论值相符，(详见附图4)。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG11行对应的数据，其主成分归一化含量为：98.842％，检出的杂质个数低于上市制剂允许控制的最大限度，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。数据见附表1。
实施例12：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品50g加入到纯化水150g与乙醇150g的混合溶液中，50℃条件下，加入活性炭10g和碱性氧化铝50g搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加乙醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用150g乙醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得27.8g白色粉末状固体。收率范围：55.6％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG12行对应的数据，其主成分归一化含量为：98.488％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例13：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠 盐的精制
将舒更葡糖钠粗品50g加入到150g纯化水和150g乙醇中，50℃条件下，加入碱性氧化铝75g搅拌30分钟，过滤，乙醇50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加乙醇400g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用150g乙醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得23.6g白色粉末状固体。收率范围：47.2％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG13行对应的数据，其主成分归一化含量为：98.734％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例14：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入碱性氧化铝60g搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得35.1g白色粉末状固体。收率范围：70.2％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG14行对应的数据，其主成分归一化含量为：98.790％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例15：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制。
将舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入活性炭40g搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24 小时，得31.6g白色粉末状固体。收率范围：63.2％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG15行对应的数据，其主成分归一化含量为：98.884％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例16：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制。
将舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入10g活性炭和65g中性氧化铝，搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得34.5g白色粉末状固体。收率范围：69.0％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG16行对应的数据，其主成分归一化含量为：98.833％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例17：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入活性炭10g，搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得36.2g白色粉末状固体。收率范围：72.4％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG17行对应的数据，其主成分归一化含量为：98.878％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例18：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐 的精制
将舒更葡糖钠粗品50g加入到纯化水150g与甲醇100g的混合溶液中，50℃条件下，加入20g活性炭和40g中性氧化铝，搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用100g甲醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得33.4g白色粉末状固体。收率范围：66.8％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG18行对应的数据，其主成分归一化含量为：98.783％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例19：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品50g加入到纯化水150g与乙醇150g的混合溶液中，50℃条件下，加入中性氧化铝25g搅拌30分钟，过滤，纯化水50g洗涤滤饼，氮气保护下滤液控温50～55℃，滴加乙醇200g，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用150g乙醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得43.3g白色粉末状固体。收率范围：86.6％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG19行对应的数据，其主成分归一化含量为：99.269％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例20：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品1.5kg加入到纯化水4.5kg与甲醇3kg的混合溶液中，50℃条件下，加入活性炭300g和750g中性氧化铝，搅拌30分钟，过滤，纯化水1.5kg洗涤滤饼，氮气保护下滤液控温50～55℃，滴加甲醇6kg，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用3kg甲醇淋洗一次，所得固体于60～65℃， 鼓风干燥24小时，得0.95kg白色粉末状固体。收率范围：63.3％，杂质检测谱图见附图5(其检测参见“舒更葡糖钠及上市制剂(Bridion)杂质分析”部分)。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG20行对应的数据，其主成分归一化含量为：98.796％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
实施例21：舒更葡糖钠：6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的精制
将舒更葡糖钠粗品1.5kg加入到纯化水4.5kg与乙醇4.5kg的混合溶液中，50℃条件下，加入活性炭150g和中性氧化铝2.25kg，搅拌30分钟，过滤，纯化水1.5kg洗涤滤饼，氮气保护下滤液控温50～55℃，滴加乙醇9kg，滴加完毕，缓慢降温，控制温度25～30℃(析晶温度)，搅拌析晶0.5小时(析晶时间)，过滤，滤饼用3kg乙醇淋洗一次，所得固体于60～65℃，鼓风干燥24小时，得1.08kg白色粉末状固体。收率范围：72.0％。按照该实施例制备的舒更葡糖钠杂质检测结果见附表1中SG21行对应的数据，其主成分归一化含量为：98.916％。检出的杂质个数低于上市制剂，检出的各杂质含量均低于上市制剂中对应杂质控制的限度。
舒更葡糖钠及上市制剂(Bridion)杂质分析
舒更葡糖钠制备过程中产生的杂质与舒更葡糖钠具有相似化学结构和相似的极性，这些杂质的紫外吸收情况与目标活性成分基本相同或相近，因此，工艺优化早期，在杂质对照品不能获得的情况下，参考2015年版中国药典，采用面积归一化法计算上市制剂和实施例11～21制备的舒更葡糖钠成品的杂质含量。
样品配制：
供试品溶液的制备
(1)制备舒更葡糖钠供试品溶液：取上述实施例11～21制备的舒更葡糖钠原料药适量，精密称定，置10ml容量瓶中，加适量纯化水定量稀释制成每1ml约含舒更葡糖钠2.0mg的溶液，摇匀，作为舒更葡糖钠供试品溶 液(分别简写为SG11、SG12、SG13、SG14、SG15、SG16、SG17、SG18、SG19、SG20和SG21)。
(2)上市制剂(Bridion)供试品溶液的制备：精密量取上市制剂(Bridion购自日本MSD株式会社，批号分别为：S217P、S502P和R501G，浓度：100mg/ml)约1.0ml，置50ml容量瓶中，加纯化水定量稀释制成每1ml约含2.0mg的溶液，作为上市制剂供试品溶液。
样品分析：
采用Agilentl260高效液相色谱仪(购自安捷仑科技，紫外检测器、配柱温箱和自动进样器)，采用反相色谱体系进行梯度洗脱(照高效液相色谱法(中国药典2015年版四部通则0512)试验，用十八烷基硅烷键合硅胶为填充剂；以25mM磷酸二氢钠溶液(磷酸调节pH至3.0)-乙腈(83：20，V/V)为流动相A，以乙腈为流动相B，按下表进行梯度洗脱；检测波长为200nm；流速为0.5ml/min；柱温为40℃。梯度洗脱表如下：
T(min) 0 5 15 22 27 32 37 42 42.01 52
B(％) 0 0 2 8 25 50 70 70 0 0
A(％) 100 100 98 92 75 50 30 30 100 100
用相对保留时间进行杂质和主成分的定位。在本发明制备的舒更葡糖钠供试品溶液和上市制剂(Bridion)供试品溶液的液相色谱图中，相对保留时间为0.88和1.00的峰分别为Org48302和舒更葡糖钠主成分峰，其中48302也为其中的一个主成分。上述分析结果见下表。三批上市制剂中两主成分归一化含量约为97.0％，且检出的杂质个数多于本发明制备的舒更葡糖钠成品中检出的杂质个数，三个批次的上市制剂有关物质检测谱图分别见附图6～附图8。
需要说明的是在本发明中提及的所有文献在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，以上所述的是本发明的具体实施例及所运用的技术原理，在阅读了本发明的内容后，本领域技术人员可以对本发明做各种改动或修改而不背离本发明的精神与范围，这些等价形式同样落在本发明的范围内。
表1不同制备工艺制备的舒更葡糖钠杂质谱对比分析
Figure PCTCN2016095985-appb-000003
注：未知杂质归一化含量低于0.05％的杂质忽略不计。

Claims (10)

  1. 制备6-全脱氧-6-全(2-羧酸乙基)硫代-γ-环糊精钠盐的方法，包括：
    将γ-环糊精(SM1)与碘和三苯基膦在有机溶剂中反应，得到中间体6-全脱氧-6-全碘代-γ-环糊精(SGMD-1)；
    向反应液中加入甲醇钠的甲醇溶液，不经过减压蒸馏，直接加入丙酮，析出固体，过滤，得到SGMD-1粗品；
    将所述SGMD-1粗品进行重结晶；
    将获得的重结晶中间体(SGMD-1)与3-巯基丙酸(SM2)在碱性条件(例如氢化钠)下反应，得到6-全脱氧-6-全(2-羧基乙基)硫代-γ-环糊精钠盐粗品(SGMD粗品)；
    将所述SGMD粗品经吸附剂吸附，然后重结晶。
  2. 权利要求1的方法，其特征在于，所述有机溶剂是N，N-二甲基甲酰胺。
  3. 权利要求1或2的方法，其特征在于，丙酮与SM1投料量投料比(V/W)为30∶1～150∶1，优选35∶1～140∶1，40∶1～130∶1，45∶1～120∶1，50∶1～110∶1，50∶1～100∶1最优选60∶1～100∶1。
  4. 权利要求1-2任一项的方法，其特征在于，用于将SGMD-1粗品进行重结晶的溶剂为N，N-二甲基甲酰胺、二甲基亚砜(DMSO)、甲醇，乙醇，异丙醇或丙酮或这其中两种溶剂的混合溶剂，优选为丙酮/N，N-二甲基甲酰胺混合溶剂、丙酮/DMSO混合溶剂、或甲醇/N，N-二甲基甲酰胺及乙醇/N，N-二甲基甲酰胺的混合溶剂，最优选的混合溶剂为丙酮/N，N-二甲基甲酰胺的混合溶剂。
  5. 权利要求4的方法，其特征在于，丙酮/N，N-二甲基甲酰胺的混合溶剂比例(V/V)为1∶0.3～1∶2.5，优选比例为1∶0.4～1∶2.4，1∶0.5～1∶2.3，1∶0.6～1∶2.2， 1∶0.7～1∶2.1，最优选的比例为1∶0.8～1∶2.0。
  6. 权利要求1-5任一项的方法，其特征在于，SGMD-1与巯基丙酸(SM2)的投料摩尔比为1∶8～1∶25，优选1∶9～1∶24，1∶10～1∶22，1∶11～1∶21，最优选的投料摩尔比为1∶12～1∶20。
  7. 权利要求1-6任一项的方法，其特征在于：SGMD-1与氢化钠的投料摩尔比为1∶10～1∶50，优选1∶12～1∶48，1∶15～1∶45，1∶17～1∶42及1∶18～1∶40，最优选的投料摩尔比为1∶20～1∶40。
  8. 权利要求1-7任一项的方法，其特征在于：用于SGMD粗品重结晶的试剂为：乙醇，水，甲醇或异丙醇，或这些溶剂与水的混合溶剂，优选甲醇/水或乙醇/水的混合溶剂。
  9. 权利要求1-8任一项的方法，其特征在于：吸附剂选自有活性炭、硅胶、大孔树脂、氧化铝、分子筛和沸石组成的组，优选选自由氧化铝和活性炭或其组合组成的组，优选地，所述氧化铝是碱性氧化铝或中性氧化铝。
  10. 权利要求1-9任一项的方法，其特征在于：SGMD粗品与吸附剂的质量比为1∶0.1～1∶2.5，优选1∶0.1～1∶2.3，1∶0.1～1∶2.1，1∶0.2～1∶2.0及1∶0.2～1∶1.8，最优选1∶0.2～1∶1.5。
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