A preparation method of sugammadex sodium intermediate

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a sodium sugammadex intermediate compound. The invention uses compound II as a raw material to generate compound I under the action of triphenyl phosphite iodomethane; the process uses triphenyl phosphite iodomethane as an iodine reagent to carry out the reaction, which can effectively avoid the ring-opening degradation of raw material γ-cyclodextrin and product fully iodinated γ-cyclodextrin caused by HI generated during the reaction of single iodine, and the reaction is more mild, economical and environmentally friendly, and has a high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a key intermediate of sugammadex sodium. Background Art

[0002] Sugammadex Sodium, chemical name is octa-6-deoxy-6-per(2-carboxyethyl)thio-γ-cyclodextrin sodium salt, CAS number: 343306-79-6, specific structural formula is as follows:

[0003]

[0004] Sugammadex sodium is a new type of muscle relaxant reversal agent, first developed by Organon of the Netherlands. In 2007, Organon was acquired by Schering-Plough. In 2009, Schering-Plough merged with Merck. Currently, Merck owns and sells Sugammadex sodium. Sugammadex sodium was approved for marketing by the European Medicines Agency (EMEA) in 2008 and the U.S. Food and Drug Administration (FDA) in December 2015. The trade name is It is used to reverse the blocking effects of the commonly used neuromuscular blocking drugs rocuronium bromide (ROC) or vecuronium bromide. It can immediately reverse the effects of rocuronium bromide used in adults and routinely reverse the neuromuscular blocking (NMB) effects induced by rocuronium bromide used in children and adolescents (2 to 17 years old).

[0005] Sugammadex sodium is the first and only selective relaxant binding agent (SRBA), the first major drug development in the field of anesthetics in 20 years, and is known as a milestone muscle relaxant antagonist. Its chemical structure is surrounded by 8 glucose molecules, and the hydroxyl group on the sixth carbon position of each glucose molecule in natural γ-cyclodextrin is replaced by hydroxythioester, which deepens the inner cavity of the molecule and can accommodate steroid muscle relaxant molecules, while benzylisoquinoline muscle relaxant molecules with too large molecular volume cannot be encapsulated by sugammadex. At the same time, sugammadex sodium combines with the positively charged quaternary ammonium molecules of steroidal muscle relaxants through the negatively charged carboxyl bond to form a 1:1 stable and strong inactive complex, thereby effectively reducing the blood concentration of free muscle relaxants, forming a concentration gradient between the effect chamber (neuromuscular junction) and the central chamber (plasma), so that the muscle relaxant molecules in the effect chamber are rapidly transported to the central chamber along the concentration gradient difference, and the concentration in the effect chamber is rapidly reduced, thereby reducing the binding of muscle relaxants to nicotinic receptors and reversing the muscle relaxant effect, and it is not affected by pH and temperature.

[0006] The original company's patents WO0140316 (EP99309558.7, CN1402737A) and USRE44733E (US6670340) first disclosed the structure and preparation method of sugammadex sodium. This method uses γ-cyclodextrin as the starting material and passes through a C 6 The fully activated cyclodextrin derivative intermediate (shown in Formula I) reacts with 3-mercaptopropionic acid under alkaline conditions to obtain the target product. The leaving group R in the key intermediate structure after activation can be a leaving group of a halogen (Cl, Br or I), a sulfate or sulfonate functional group, such as toluenesulfonate, naphthalenesulfonate or trifluorotoluenesulfonate.

[0007]

[0008] At present, there are many methods for preparing sodium sugammadex or its intermediates disclosed. In addition to the preparation methods of related intermediates disclosed in CN104844732A, CN110615859A, and J.Med.Chem., 2002, 45, 1806-1816, which use octa-6-perdeoxy-6-perthiol-γ-cyclodextrin as an intermediate to prepare the target product, the existing processes are improved and optimized on the basis of the original research process, such as patents EP2609120B1 (EP2609120A4, ES2551585T3), US9120876B2, US9879096B2, US2016009827A1, US20140221641, WO2012025937A1, WO2014125501A1 (EP2956486A1) using PX 5 or PX 3 The corresponding octa-6-perdeoxy-6-perhalogenated-γ-cyclodextrin is obtained by the reaction.

[0009] Patents CN105273095A, CN107849157A, CN107849157A (WO2016194001A1), TWI668236B, US10385142B2, US10494450B2, US2018171033A1, US20180208683A1, WO2016194001A1, WO2016194001(EP3303413A1, IN201727007741), and WO2019102009A1 use one or more of thionyl chloride, oxalyl chloride, triphosgene, or methanesulfonyl chloride to prepare octa-6-deoxy-6-perchloro-γ-cyclodextrin.

[0010] Patents WO2017144734A2, CN109879986A, CN109988256A, US10233263B1 (US2019062459A1), US2019185589A1, WO2019236436A1, WO2019159191A1 and literature J.Med.Chem., 2002, 45, 1806-1816, Optimization of the synthesis process of sugammadex sodium. Chinese Modern Applied Pharmacy, 2016, 33(4), 431-433, Optimization of the synthesis process of sugammadex sodium. Chemistry and Bioengineering, 2019, 36(7): 54-58 use Br 2 , NBS, DDH, N-bromophthalimide, CBrCl 3 , BBr 3 , pyridinium tribromide, CBr 4 Octadecyl-6-perdeoxy-6-perbromo-γ-cyclodextrin can be prepared by using one or more of the following reagents: tetrabutylammonium bromide, trimethylphenylammonium tribromide.

[0011] Patents EP3421503A1, US2018016359A1 and document Chem. Asian J., 2011, 6, 2390-2399 utilize elemental iodine reaction to prepare octa-6-deoxy-6-periodinated-γ-cyclodextrin.

[0012] Literature: Optimization of the synthetic process of sodium sugammadex. 2019, 50(5), 511-513. Octa-6-deoxy-6-toluenesulfonyl-γ-cyclodextrin was prepared using p-toluenesulfonyl chloride.

[0013] In general, the preparation method of sugammadex sodium is mainly to generate octa-6-deoxy-6-perhalogenated-γ-cyclodextrin through a halogenation reaction of γ-cyclodextrin and then further react to synthesize the target product. However, due to the difference in the activity of the leaving group and the post-treatment separation of the leaving group, the purification method of the target product is different, resulting in a greater application prospect of the octa-6-deoxy-6-periodinated-γ-cyclodextrin intermediate (shown in Formula II).

[0014]

[0015] At present, there are two methods for preparing octa-6-deoxy-6-periodine-γ-cyclodextrin intermediates:

[0016] 1. Patent US6670340 discloses a method for preparing iodine by reacting iodine in DMF.

[0017] 2. Patents EP3421503A1, US2018016359A1 and document Chem. Asian J., 2011, 6, 2390-2399 provide an improved method, namely a method of preparing by reacting elemental iodine in DMF in the presence of triphenylphosphine.

[0018] However, the above scheme has the following disadvantages: since γ-cyclodextrin is a closed-loop structure composed of 8 glucose units connected by α-1,4-glycosidic bonds, the corresponding α-1,4-glycosidic bonds themselves are acetal structures that are unstable under strong acidic conditions and are easily degraded by ring opening. At the same time, a large amount of HI (the pH of the reaction system is less than 1) exists in the reaction liquid of the periodinated γ-cyclodextrin intermediate obtained after the γ-cyclodextrin reaction, which causes the degradation of γ-cyclodextrin and octa-6-deoxy-6-periodinated-γ-cyclodextrin, resulting in a large amount of impurities in the crude product, making it difficult to purify and having a low yield.

[0019] Summarizing the many problems existing in the existing technology, exploring a process route for compound I (eight-6-deoxy-6-periodinated-γ-cyclodextrin) with low production cost, mild reaction, easy operation and control, high yield and purity, and more suitable for industrialization is still a problem that needs to be solved at present. Summary of the invention

[0020] In view of the problems of low conversion rate and large amount of impurities generated in the current process of preparing sugammadex sodium intermediate compound I (octa-6-perdeoxy-6-periodinated-γ-cyclodextrin), the present invention aims to provide a method for industrially producing sugammadex sodium intermediate with simple operation, mild reaction conditions, high product yield and low production cost.

[0021] The specific technical solutions of the present invention are as follows:

[0022] A method for preparing a sodium sugammadex intermediate, characterized in that compound II, i.e., γ-cyclodextrin, reacts in a solvent to generate compound I, and the synthesis route is as follows:

[0023]

[0024] A method for preparing a sugammadex sodium intermediate as shown in formula (I), comprising the following steps:

[0025] Under the protection of inert gas, compound II (γ-cyclodextrin), triphenyl phosphite iodomethane [(PhO) 3 P + -CH 3 I - ] Add solvent A, wait for the solution to become clear, control the temperature until the reaction is complete, filter, cool the filtrate to room temperature, concentrate under reduced pressure, adjust the pH with alkali to crystallize, filter after complete crystallization, and obtain the crude product by recrystallization to obtain the target product Compound I.

[0026] Preferably, the solvent A is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination thereof, wherein N,N-dimethylformamide is preferred.

[0027] Preferably, the mass volume ratio of the compound II to the solvent A is 1:8-20, g / mL, preferably 1:15, g / mL.

[0028] Preferably, the molar ratio of the compound II to triphenyl phosphite iodomethane is 1:8.8-20.0, preferably 1:16.0.

[0029] Preferably, the reaction temperature is 15-50°C, preferably 20-25°C.

[0030] Preferably, in the reduced pressure concentration, the volume of the filtrate after concentration is 1 / 5 to 1 / 3 of the volume of the reaction solution.

[0031] Preferably, the base used to adjust the pH includes an inorganic base or an organic base, wherein the inorganic base includes but is not limited to one or a combination of sodium hydroxide, potassium hydroxide, and barium hydroxide; the organic base includes but is not limited to one or a combination of sodium methoxide, sodium ethoxide, sodium isopropoxide, and sodium tert-butoxide, and the organic base can be a dilute solution or a saturated solution of the base or its corresponding alcohol, wherein a sodium methoxide / methanol solution is preferred.

[0032] Preferably, the adjusted pH is between 9 and 12, with a preferred pH being 10.

[0033] In a preferred embodiment of the present invention, the recrystallization operation is as follows: after the crude product is dissolved with solvent A, solvent B is added for crystallization, the crystallization is stirred until it is completely completed, filtered, and the filter cake is vacuum dried to obtain the target compound I.

[0034] Preferably, the solvent B is a mixed solvent of an organic solvent and purified water, preferably one of methanol / purified water, ethanol / purified water, isopropanol / purified water, tert-butanol / purified water, acetone / purified water, tetrahydrofuran / purified water, 1,4-dioxane / purified water, and acetonitrile / purified water, and more preferably methanol / purified water.

[0035] Preferably, the volume ratio of the organic solvent to purified water in the solvent B is 0.5-5:1, preferably 2:1.

[0036] Preferably, the volume ratio of the solvent B to the solvent A is 1 to 5:1, preferably 2:1.

[0037] Preferably, the inert gas is one of nitrogen and argon, among which argon is preferred.

[0038] Beneficial effects achieved by the present invention:

[0039] 1. The present invention provides a method for preparing a sugammadex sodium intermediate.

[0040] 2. The prepared product has high yield and high purity, low production cost, simple and time-saving operation and high safety. DETAILED DESCRIPTION

[0041] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection required by the present invention.

[0042] In the following examples, triphenyl phosphite iodomethane [(PhO) 3 P + -CH 3 I - ] The sources are commercially available or can be prepared with reference to existing technologies. Other processes and methods not described in detail are conventional methods known in the art. The reagents used without indicating the sources and specifications are all commercially available analytical grade or chemically pure.

[0043] Example 1

[0044] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (361.78 g, 0.80 mol) were added to N, N-dimethylformamide (1000 mL). After the solution was clarified, the temperature was controlled at 20-25 ° C for reaction. After the reaction was completed, the filtrate was filtered and cooled to room temperature. The volume was concentrated under reduced pressure to 1 / 3 of the volume of the reaction solution, and the pH was adjusted to 10 with a saturated solution of sodium methoxide / methanol. The mixture was stirred until complete crystallization. The obtained filter cake was dissolved in N, N-dimethylformamide (250 mL), and methanol / purified water (V 甲醇 :V 纯化水 =2:1, 500 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 95.5% and a purity of 99.89%.

[0045] Example 2

[0046] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (198.98 g, 0.44 mol) were added to N, N-dimethylacetamide (1000 mL). After the solution was clarified, the temperature was controlled at 15-20 ° C for reaction. After the reaction was completed, the filtrate was filtered and cooled to room temperature. The volume was concentrated under reduced pressure to 1 / 4 of the volume of the reaction solution. The pH was adjusted to 10 with a saturated solution of 4M sodium hydroxide, and stirred until complete crystallization. The obtained filter cake N, N-dimethylacetamide (250 mL) was dissolved and filtered. The filtrate was dropwise added with ethanol / purified water (V 乙醇 :V 纯化水 =0.5:1, 500 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 92.3% and a purity of 99.75%.

[0047] Example 3

[0048] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (452.22 g, 1.0 mol) were added to N-methylpyrrolidone (1000 mL). After the solution was clarified, the temperature was controlled at 45-50 ° C. After the reaction was completed, the filtrate was cooled to room temperature and concentrated under reduced pressure to 1 / 3 of the volume of the reaction solution. The pH was adjusted to 10 with a saturated solution of 4M barium hydroxide and stirred until complete crystallization. The obtained filter cake was dissolved in N-methylpyrrolidone (250 mL), filtered, and the filtrate was dropwise added with isopropanol / purified water (V 异丙醇 :V 纯化水 =5:1, 500 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 93.8% and a purity of 99.55%.

[0049] Example 4

[0050] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (169.58 g, 0.375 mol) were added to dimethyl sulfoxide (1000 mL). After the solution was clarified, the temperature was controlled at 10-15 ° C for reaction. After the reaction was completed, the filtrate was filtered and cooled to room temperature. The volume was concentrated under reduced pressure to 1 / 3 of the volume of the reaction solution. The pH was adjusted to 10 with a saturated solution of 4M barium hydroxide. The mixture was stirred until complete crystallization. The obtained filter cake was dissolved in dimethyl sulfoxide (250 mL), filtered, and the filtrate was dropwise added with acetone / purified water (V 丙酮 :V 纯化水 =2:1, 500 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 86.8% and a purity of 99.25%.

[0051] Example 5

[0052] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (497.45 g, 1.1 mol) were added to N, N-dimethylformamide (1000 mL). After the solution was clarified, the temperature was controlled at 50-55 ° C for reaction. After the reaction was completed, the filtrate was filtered and cooled to room temperature. The volume was concentrated under reduced pressure to 1 / 3 of the volume of the reaction solution. The pH was adjusted to 10 with a saturated solution of 4M sodium tert-butoxide, and stirred until complete crystallization. The obtained filter cake was dissolved in N, N-dimethylformamide (250 mL), filtered, and the filtrate was added dropwise with tetrahydrofuran / purified water (V 四氢呋喃 :V 纯化水 =4:1, 500 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 84.2% and a purity of 98.95%.

[0053] Example 6

[0054] Under argon protection, compound II (64.86 g, 0.05 mol) and triphenyl phosphite iodomethane (361.78 g, 0.80 mol) were added to N, N-dimethylformamide (1000 mL). After the solution was clarified, the temperature was controlled at 20-25 ° C for reaction. After the reaction was completed, the filtrate was cooled to room temperature and concentrated under reduced pressure to 1 / 3 of the volume of the reaction solution. The pH was adjusted to 9 with 4M sodium isopropoxide and stirred until complete crystallization. The obtained filter cake was dissolved in N, N-dimethylformamide (200 mL), filtered, and the filtrate was dropwise added with 1,4-dioxane / purified water (V 二氧六环 :V 纯化水 =2:1, 1000 mL) for crystallization, continue stirring until the crystallization is completely completed, filter, and vacuum dry the filter cake to obtain the target compound I with a yield of 85.5% and a purity of 98.89%.

[0055] Comparative Example

[0056] Take phosphorus triiodide (658.75g, 1.6mol), control the temperature at 0-5℃ and add it to N,N-dimethylformamide (400mL). After the addition is completed, control the temperature at 20-25℃ and stir for 1 hour. Under nitrogen protection, control the temperature at 5-10℃ and add γ-cyclodextrin (64.86g, 0.05mol) in N,N-dimethylformamide (500mL) dropwise. After the addition is completed, control the temperature at 65-70℃ and stir for 14 hours. After the reaction is completed, cool the reaction solution to 20-25℃ and then reduce the pressure N,N-dimethylformamide was evaporated, purified water (200 mL) was added to the concentrate to dilute it, sodium hydroxide solution was added dropwise at a temperature of 5-10°C to adjust the pH to 8, the temperature was controlled at 20-25°C and stirred for 1 hour, the filter cake was filtered with suction, and the filter cake was washed with purified water to obtain a crude compound I; the crude compound I was diluted with purified water (300 mL), the temperature was controlled at 20-25°C and stirred for 1 hour, the suspension was filtered with suction, and the filter cake was dried at 55-60°C for 12 hours to obtain a finished compound I with a yield of 85% and a purity of 95.54%.

Claims

1. A method for preparing a sugammadex sodium intermediate, characterized in that: Compound II is reacted in a solvent to prepare compound I. The synthetic route is as follows: ， Specifically, the method comprises the following steps: under the protection of an inert gas, adding compound II and triphenyl phosphite iodomethane to solvent A, waiting for the solution to become clear, controlling the temperature until the reaction is completed, filtering, cooling the filtrate to room temperature, concentrating under reduced pressure, adjusting the pH with an alkali for crystallization, filtering after complete crystallization, and recrystallizing the obtained crude product to obtain the target product compound I; wherein the molar ratio of compound II to triphenyl phosphite iodomethane is 1:8.8-20.0; and the reaction temperature is 15-50°C.

2. The preparation method according to claim 1, characterized in that: The solvent A is selected from N , N -dimethylformamide, N , N -Dimethylacetamide, N -Methyl pyrrolidone, dimethyl sulfoxide or a combination thereof.

3. The preparation method according to claim 1, characterized in that: The mass volume ratio of the compound II to the solvent A is 1:8~20g / mL.

4. The preparation method according to claim 1, characterized in that: The base used to adjust the pH includes an inorganic base or an organic base.

5. The preparation method according to claim 4, characterized in that: The inorganic base is one of sodium hydroxide, potassium hydroxide, and barium hydroxide or a combination thereof; the organic base is one of sodium methoxide, sodium ethoxide, sodium isopropoxide, and sodium tert-butoxide or a combination thereof.

6. The preparation method according to claim 1, characterized in that: The pH is adjusted to 9-12.

7. The preparation method according to claim 1, characterized in that: The recrystallization operation is as follows: the crude product is dissolved in solvent A, and then solvent B is added for crystallization. After the crystallization is completed, the filter is filtered and the filter cake is vacuum dried to obtain the target product compound I.

8. The preparation method according to claim 7, characterized in that: The solvent B is a mixed solvent of an organic solvent and purified water.

9. The preparation method according to claim 8, characterized in that: The mixed solvent is one of methanol / purified water, ethanol / purified water, isopropanol / purified water, tert-butyl alcohol / purified water, acetone / purified water, tetrahydrofuran / purified water, 1,4-dioxane / purified water and acetonitrile / purified water.

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