Process for synthesis of selectively alkylated cyclodextrins

Abstract

The present invention generally relates to a process for the synthesis of selectively alkylated cyclodextrins. More specifically, the present invention relates to a process for the alkylation of cyclodextrins in a selective manner to produce hexakis (2, 6-di-O-alkyl)-alpha-cyclodextrin, heptakis (2, 6-di-O-alkyl)-beta-cyclodextrin, and octa (2, 6-di-O-alkyl)-gamma-cyclodextrin.

Description

Technical Field

[0001] The present invention generally relates to a method for synthesizing selectively alkylated cyclodextrins. More specifically, the present invention relates to a method for the partial alkylation of cyclodextrins in a selective manner to produce hexa(2,6-di-O-alkyl)-α-cyclodextrin, hepta(2,6-di-O-alkyl)-β-cyclodextrin, and octa(2,6-di-O-alkyl)-γ-cyclodextrin. Background Art

[0002] Cyclodextrins (CDs) are a class of cyclic oligosaccharides obtained by the enzymatic conversion of starch, for example, by cyclodextrin glycosyltransferase produced by Bacillus. There are various methods for the production of cyclodextrin glycosyltransferase and for the preparation and separation of cyclodextrins. Cyclodextrins are cyclic molecules containing six to eight α-D-glucopyranose units, similar to amylose, and these units are linked by α-bonds at the 1,4 positions. Due to this cyclic arrangement, the molecule is characterized by having neither a reducing end nor a non-reducing end. A molecule containing six α-D-glucopyranose units is commonly referred to as α-cyclodextrin or cyclohexasaccharide, a molecule containing seven α-D-glucopyranose units is commonly referred to as β-cyclodextrin or cycloheptasaccharide, and a molecule containing eight α-D-glucopyranose units is called γ-cyclodextrin or cyclooctasaccharide. When "cyclodextrin" is mentioned herein, it is intended to include cyclodextrins in the above forms as well as molecules with a degree of oligomerization exceeding 8. Due to the cyclic arrangement and conformation of the α-D-glucopyranose units, the free rotation of the glycosidic bond is limited, and cyclodextrins exist in the form of conical molecules, with primary hydroxyl groups at the small end of the cone and secondary hydroxyl groups at the large opening of the cone. The cavity is formed by the hydrogen atoms from C3 and C5 and the glycosidic oxygen atoms, thus forming a relatively lipophilic cavity, but the outer surface is hydrophilic.

[0003] Since cyclodextrins have two regions with different polarities and the solvent structure changes upon complexation, they are able to form inclusion complexes with the hydrophobic parts of various organic molecules or macromolecules. The phenomenon of cyclodextrins forming inclusion complexes with molecules is called the host-guest phenomenon. These unique properties of cyclodextrins have led to their commercial applications in agriculture, water treatment, household products, and drug delivery systems. The application of cyclodextrins in the pharmaceutical field has enabled the timed-release microencapsulation of drugs, improved stability, and increased the water solubility of various drugs.

[0004] Cyclodextrins are generally considered to be able to increase the dissolution rate of drugs. However, the formed complexes are also stable in aqueous solutions, so while the dissolution rate is increased, the saturated solubility of the drug also increases. Unfortunately, β-cyclodextrin, which forms the most stable complexes with most drugs, has the lowest water solubility, so the drugs complexed with it cannot dissolve at therapeutic concentrations. The reason for this phenomenon seems to be due to the crystal structure of β-cyclodextrin itself.

[0005] Although cyclodextrins have practical value in pharmaceuticals, they also have their limitations. Since cyclodextrins entering the human body without metabolism exhibit nephrotoxicity, in a clinical setting, the use of natural cyclodextrins is limited to oral and topical formulations. Due to the specificity of mammalian enzymes for the degradation of linear starch molecules, cyclodextrins remain largely unmetabolized and accumulate in proximal tubular cells due to their recycling and reabsorption.

[0006] Underivatized cyclodextrins are crystalline solids and form crystals after concentration in renal tissue, causing necrotic damage to cells. Although crystalline cyclodextrin drug complexes can form water-soluble cage complexes, their utility in oral and sublingual administration is limited.

[0007] Alkylated cyclodextrin

[0008] To overcome the above drawbacks, it is known that chemical modification of cyclodextrins can modulate their properties. Introducing methyl groups may generate derivatives of highly soluble substances. In addition to non-selective derivatization processes, selective substitution patterns are favorable for generating well-characterized single compounds.

[0009] Non-selective alkylation reaction

[0010] Irvine, Pringsheim, and MacDonald first attempted to prepare methylated cyclodextrins (Irvine, J.C., Pringsheim, H., MacDonald, J. Chem. Soc., 125, 942 (1924)), and they used methyl sulfate as an alkylating agent in sodium hydroxide solution. According to the method of Muskat (Muskat, I.: J. Am. Chem. Soc., 56, 693 and 2449 (1934)), α- and β-cyclodextrins were methylated in liquid ammonia in the presence of metallic sodium and methyl iodide.

[0011] Ionel Ciucanu and Francisc Kerek found (Carbohydrate Research, Volume 131, Issue 2, August 15, 1984, pages 209 - 217, "A Simple and Rapid Method for the Permethylation of Carbohydrates") that methyl iodide is the most effective methylating agent for complete O-methylation. They used methyl iodide in a polar aprotic solvent in the presence of a solid base (e.g., NaOH, KOH, or K-tert-BuOH / NaOH mixture).

[0012] Generally, regardless of the type of sugar, full methylation is carried out using an alkyl halide (e.g., methyl iodide). The reaction yield is high (98±2%) and the reaction time is short (usually 6 - 7 minutes). The method was first disclosed by Hakomori, so this methylation is also called Hakomori methylation (S. Hakomori, J. Biochem. (Tokyo), 55 (1964) 205 - 208.). Hakomori also used sodium hydride in addition to methyl iodide. Compared with potassium tert - butoxide, the base NaH has an advantage, although potassium tert - butoxide is safer, it cannot provide a sufficient yield (Lindberg, Methods Enzymol., 28 (1972) 178 - 195. and J. Finne, T. Krusius, H. Rauvala, Carbohydr. Res., 80 (1980) 336 - 339.).

[0013] Similarly, in liquid ammonia, in the presence of methyl iodide, rapid methylation can be achieved using sodium, but selectivity may not be achieved, so the subject 2,6 methylation cannot be achieved.

[0014] In the methylation reaction according to Brimacombe et al., NaH, methyl iodide and / or methyl bromide were used as alkylating agents, but the solid base was used in N,N - dimethylformamide (DMF) or N - methyl - 2 - pyrrolidone solvents. Almost no regioselectivity was observed, and the method was successfully applied to fully methylated sugars (S. Brimacombe, B.D. Jones, M. Stacey, J.J. Willard, “Alkylation of carbohydrates using sodium hydride” - Carbohydrate Research Vol. 2, No. 2, June 1966, pp. 167 - 169).

[0015] A partial, non - selective, random methylation method for cyclodextrins is described in patent US5710268 (Thomas Wimmer, Consortium Fur Elektrochemische Industrie GmbH, later renamed Wacker Chemie AG). The process is based on dissolving α -, β - or γ - cyclodextrin in a base, followed by adding chloromethane as an O - alkylating agent and adding additional base to react the cyclodextrin with the chloromethane O - alkylating agent in the base to form a reaction mixture.

[0016] Complete methylation was achieved by treating hexa(6-azido)-α-CD (instead of natural α-CD) with crystalline sodium hydride and methyl iodide in DMF, and after deprotection, the hexa(2,3)-di-O-methyl derivative was obtained in quantitative yield (Boger et al., Helvetica Chimica Acta - Vol. 61, Fasc. 6, 2190 (1978)), but this method requires the use of an azide protecting group strategy (i.e., a multi-step synthesis strategy) to achieve selective methylation.

[0017] The patented technology of Cui Yanli Mao (University of Zhejiang, CN1709918, also refer to J Chem Technol Biotechnol. 2010; 85:248 - 251) describes a synthesis method that can obtain a random substitution pattern of methylated β-cyclodextrin. This process is based on the reaction of β-cyclodextrin, alkali metal hydroxide, and methylating agents (including methyl chloride, methyl bromide, and methyl iodide) under high pressure and mixing at 60 - 130 °C, with a reaction pressure of 6 - 14 bar and a reaction time of 2 - 9 hours.

[0018] Therefore, it can be concluded that alkyl halides can be directly used for the complete methylation and non-selective partial alkylation of cyclodextrins.

[0019] Selective partial alkylation

[0020] For partial and selective methylation, dimethyl sulfate (Me2SO4) and methyl carbonate are mostly used in dipolar aprotic solvents in the presence of a suitable base. In the presence of strong bases (NaH, Na, liquid NH3), the alkylation reaction proceeds rapidly but not in a selective manner. The only method known to date to achieve sufficient selectivity is to use barium bases.

[0021] Casu et al. (Casu, B., Reggiani, M., Gallo, G.G., Vigevani, A.: Tetrahedron, 24, 803 (1968)) adopted the Kuhn method (Kuhn, R., Trischmann, H., Low, I.: Angew.Chem., 67, 32 (1955) and Kuhn, R., Baer, H.H., Seeliger, A.: Ann., 611, 236 (1958)), using Me2SO4 and BaO in a 1:1 mixture of DMF and DMSO to methylate α- and β-cyclodextrins, achieving regioselective alkylation.

[0022] Szejtli et al. reported the synthesis of hepta(2,6-di-O-methyl)-β-cyclodextrin in a β-cyclodextrin solution prepared with a 1:1 DMSO-DMF mixture containing equal amounts of BaO and Ba(OH)₂·8H₂O using dimethyl sulfate as the alkylating agent (Szejtli, J., Liptak, A., Jodal, I., Fugedi, P., Nanasi, P., Neszmelyi, A. Die Starke 32 165-169 (1980)). Subsequently, Tanimoto et al. demonstrated that Szejtli's method was not universal for all three natural cyclodextrins. The methylation of γ-CD mainly produced octa(2,3,6-tri-O-methyl)-γ-cyclodextrin, and the partially and selectively methylated octa(2,6-di-O-methyl)-γ-cyclodextrin could not be detected. Szejtli's method also produced hexa(2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl)-β-cyclodextrin and several minor over-methylated homologues (T. Tanimoto et al. Chem. Pharm. Bull 38(2), 318-322 (1990)).

[0023] The preparation of hepta(2,6-di-O-methyl)-β-cyclodextrin is described in US4542211 (Szejtli et al. Consortium für Elektrochemische Industrie GmbH, 1984), where selective methylated cyclodextrin is obtained by reacting β-cyclodextrin with dimethyl sulfate in an organic medium for methylation. 15 to 25 moles of dimethyl sulfate are used per 1 mole of β-cyclodextrin, and in the presence of an alkali metal hydroxide, the alkali metal hydroxide is used in at least an equimolar amount based on the amount of OH⁻ groups to be methylated; the reaction temperature is -10°C to 0°C.

[0024] Boger et al. prepared hexa(2,6-di-O-methyl)-α-cyclodextrin using α-cyclodextrin dissolved in DMSO and DMF. A mixture of barium hydroxide (Ba(OH)₂·8H₂O) and barium oxide free of carbonate was used with dimethyl sulfate for the methylation reaction (Boger et al., Helvetica Chimica Acta - Vol. 61, Fasc. 6, 2190 (1978)).

[0025] According to Hungarian patent HU180580, methylation at the 2,6 positions was carried out with dimethyl sulfate in an aqueous medium in the presence of sodium hydroxide, and this step was repeated twice. The disadvantage of this method is that the desired product cannot be prepared in a single process step. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1Show the HPLC chromatogram of hepta(2,6-di-O-methyl)β-cyclodextrin prepared according to Example 5.

[0027] Figure 2 Depict the NMR spectrum of hepta(2,6-di-O-methyl)β-cyclodextrin prepared according to Example 5.

[0028] Figure 3 Show the HPLC chromatogram of hepta(2,6-di-O-methyl)β-cyclodextrin prepared according to Example 8.

[0029] Figure 4 Depict the NMR spectrum of hepta(2,6-di-O-methyl)β-cyclodextrin prepared according to Example 8.

[0030] Figure 5 Show the HPLC chromatogram of randomly methylated β-cyclodextrin prepared according to Example 3 compared with hepta(2,6-di-O-methyl)β-cyclodextrin prepared according to Example 8.

[0031] Figure 6 Depict the NMR spectrum of randomly methylated β-cyclodextrin prepared according to Example 3. Detailed Description

[0032] Preferred embodiments of the methods disclosed herein are provided as examples and are not intended to limit the scope of the disclosure in any way. It has been surprisingly found that partial alkylation of cyclodextrins can substantially produce products substituted at the 2- and 6-positions in α-, β-, and γ-cyclodextrins, respectively. This partial alkylation can be achieved by a method of alkylation with a C1-4 alkyl halide in the presence of a barium-containing catalyst. An important aspect of the present invention is that the alkylation can be carried out in the presence of an alkali metal hydroxide or alkoxide without the use of protecting groups (i.e., one-step synthesis) in a solvent mixture consisting mainly of water and dimethyl sulfoxide (DMSO). It has been found that the performance and selectivity of the reaction using this solvent mixture are superior to other aprotic solvent mixtures containing N,N-dimethylformamide (DMF) commonly used in carbohydrate chemical synthesis methods.

[0033] The present invention is based on the use of a suitable base / catalyst combination that can distinguish based on the different pK values of the hydroxyl groups at different positions in the cyclodextrin ring. The pK difference between primary and secondary hydroxyl groups alone cannot distinguish the hydroxyl groups at the 2- and 3-positions separately. The use of BaO or Ba(OH)2 bases results in selective alkylation at the 2- and 6-positions due to the formation of complexes between Ba ions and hydroxyl groups and the resulting steric hindrance. In the prior art, it is not clear whether the presence of DMF will have an adverse effect on this selectivity and whether it will reduce the yield of the selectively substituted 2,6-alkylated product. It can be expected that typical impurities present in DMF, dimethylamine (DMA) and formic acid, will be generated under the action of acids and bases, especially after the alkylation reaction (Liu, J et al., Journal of Molecular Structure, Volume 654, Issues 1-3, 215-221; and Burrows, A. et al., Cryst Eng Comm, 2005, 7(89), 548-550). In the pharmaceutical applications of the subject selective alkylation of cyclodextrins, the presence of DMA is disadvantageous because DMA may undergo nitrosation under weak acid conditions to form dimethylnitrosamine, which is a known carcinogen (Questions and answers on "Information on nitrosamines for marketing authorization holders EMA / CHMP / 428592 / 2019 Rev.1). According to Example 1, a modified version of the FDA limit test (https: / / www.fda.gov / media / 124025 / download) was used to control nitrosamines in the selectively alkylated cyclodextrin. This method is capable of quantifying nitrosamines at the 0.05 ppm level.

[0034] The DMA in the selectively alkylated cyclodextrin was determined by GC-headspace chromatography modified for this compound (A.R. Deshpande et al., Eurasian J Anal Chem 2012; 7(l):43-48).

[0035] It was also surprisingly found that in a suitable methyl halide, methyl iodide can effectively lower the freezing point of DMSO to a certain temperature range (below +5 °C), within which the enhanced selectivity of Ba ions is manifested.

[0036] It was further unexpectedly found that the improved yield according to the present invention enables the separation of the selectively alkylated cyclodextrin without the need for thermal recrystallization - a technically disadvantageous additional step in the previously disclosed methods (e.g., the crude product synthesized from dimethyl sulfate in a mixture of DMF and / or DMSO according to Examples 5-6) - only a solvent-based precipitation method is required.

[0037] The barium content in the crude reaction mixture can be reduced by extraction with dichloromethane and acetic acid added to the crude reaction mixture at low temperature. Two immiscible phases are formed and the organic layer is washed several times with water and sodium bicarbonate solution. The resulting organic layer is concentrated in vacuo. The product is precipitated from the concentrated solution by addition of diisopropyl ether.

[0038] Another advantage of the method according to the invention is that due to the appropriate selection of the precipitation solvent, the amount of residual impurities (i.e., barium catalyst and residual alkylating agent) in the product formed is low. As stated in the ICH guideline Q3, page 26 (March 28, 2019), the barium content related to the most critical drug substance reaches a maximum at 30 ppm.

[0039] Example 1

[0040] Determination of nitrosamine impurities by GC-MS / MS

[0041] Instruments and equipment

[0042] Gas chromatography system equipped with a quadrupole mass detector and a headspace autosampler

[0043] DB-Wax GC column, 30 m x 0.25 mm, 0.5 μm, or equivalent

[0044] Analytical balance

[0045] Wrist-mounted mechanical shaker

[0046] Vortex mixer

[0047] 20 mL headspace vial

[0048] HP cap with Teflon / silicone septum

[0049] Solvents

[0050] Dimethyl sulfoxide (DMSO), >99.5%

[0051] Standard stock solutions

[0052] -N-Nitrosodimethylamine (NDMA): 1 mg / mL MeOH solution

[0053] -N-Nitrosodimethylamine-d6 labeled (NDMA d6): 1 mg / mL MeOH solution Standard preparation

[0054] Internal standard solution (NDMA d6):

[0055] Using a 1000 μL pipette, transfer 1 mL of the NDMA-d6 standard stock solution (1 mg / mL) into a 100 mL volumetric flask containing approximately 90 mL of DMSO.

[0056] Make up to 100 mL with DMSO and mix well to obtain a concentration of 10 μg / mL.

[0057] Sample preparation of cyclodextrin

[0058] Accurately weigh 500 mg of the test cyclodextrin into a 20 mL headspace vial. Add 4.5 mL of DMSO and 0.5 mL of the internal standard solution to the vial, immediately cover the vial cap and tighten it. Mix the sample solution using a vortex mixer.

[0059] GC / MS-HS parameters Instrument: Agilent 7890B GC, equipped with Agilent 5977A MSD and Agilent 7697A HS autosampler

[0060] Column: DB-WAX, 30 m × 0.25 mm, 0.5 μm

[0061] Inlet temperature: 220 °C

[0062] Column flow rate: 1 mL / min

[0063] Split ratio: 5:1

[0064] Oven program: Hold at 70 °C for 4 min; increase the temperature to 240 °C at a rate of 20 °C / min and hold for 3.5 min. GC run time is 16 min. GC cycle time: 24 min.

[0065] HS autosampler parameters Oven temperature: 120 °C

[0066] Loop temperature: 125 °C Transfer line temperature: 130 °C

[0067] Vial equilibration time: 15 min Injection time: 1.0 min Vial size: 20 mL vial

[0068] Oscillation: Level 9 (250 times / min) Fill pressure: 15 psi Loop size: 1 mL

[0069] MS parameters: MS source temperature: 230 °C Quad temperature: 150 °C

[0070] Acquisition type: SIM Gain factor 5 Solvent delay: 6.0 min

[0071] Example 2

[0072] HPLC Analysis of Alkylated Cyclodextrin Derivatives

[0073] Apparatus:

[0074] Agilent 1260 Quaterner Pumping System

[0075] Agilent 1100 Series Thermostatted Column Compartment

[0076] Agilent Bidirectional / Six-port Switching Valve

[0077] Agilent 1260 Series Thermostatted Autosampler

[0078] Agilent 1200 DAD Detector

[0079] Agilent 1260 Refractive Index Detector

[0080] Agilent OpenLAB CDS ChemStation Rev.C.01.07SR3

[0081] Column: Kinetex C18 (Phenomenex), internal codes: KIN1 (lot number: 5569 - 110) and KIN7 (lot number: 5569 - 0217).

[0082] Column length: 100 mm

[0083] Inner diameter: 4.6 mm

[0084] Particle size: 2.6 μm

[0085] Guard column: Security Guard Cartridge C18 4x3.0 mm ID (Phenomenex)

[0086] Column temperature: 30 °C

[0087] Mobile phase:

[0088] Isopropanol (IPA) 70 mL

[0089] Methanol 410 mL

[0090] Water 520 mL

[0091] Flow rate: 0.5 mL / min

[0092] RI detector temperature: 40 °C

[0093] Sample volume: 10 μl

[0094] Sample concentration: 8 mg / mL

[0095] Stop time: 45 min

[0096] Integrator: Area

[0097] Example 3

[0098] Preparation of methyl-β-cyclodextrin (random alkylation) using methyl iodide

[0099] Dissolve 113.5 g (0.1 mol) of β-cyclodextrin in 800 mL of dimethyl sulfoxide. At room temperature, with stirring, add 280 mL (4.5 mol) of methyl iodide to the reaction mixture. Dissolve 123 g (3.08 mol) of sodium hydroxide in 113 mL of water. Dropwise add the sodium hydroxide solution to the reaction mixture at a steady rate with stirring over 3 hours while maintaining the temperature below 30 °C. After adding the sodium hydroxide solution, stir the reaction mixture at room temperature for about 2 hours to achieve the desired degree of substitution. After 30 minutes, dilute the mixture with sodium chloride solution and then extract with ethyl acetate. Wash the organic layer several times with sodium chloride solution and sodium sulfate solution, and then dry over anhydrous sodium sulfate. Dry the resulting solution under vacuum. Figure 5 The chromatogram of the resulting product compared with the selectively alkylated analogue hepta(2,6-di-O-methyl)-β-cyclodextrin is depicted. Figure 6 The NMR spectrum is depicted.

[0100] Resulting white amorphous product: 118.5 g

[0101] Residual solvent: 1.0 (m / m) %

[0102] Content of hepta(2,6-di-O-methyl)-β-cyclodextrin: not detected

[0103] Example 4

[0104] Preparation of methyl-β-cyclodextrin (random alkylation) using methyl bromide

[0105] 113.5 g (0.1 mol) of β-cyclodextrin was dissolved in 800 mL of a 50-50 vol% solvent mixture of DMF and DMSO. The solution was cooled to -2 °C, and 248 mL (4.5 mol) of methyl bromide (b.p. +4 °C) was added to the reaction mixture with stirring. 123 g (3.08 mol) of sodium hydroxide was dissolved in 113 mL of water. The sodium hydroxide solution was added dropwise to the reaction mixture at a steady rate with stirring over 3 hours while maintaining the temperature at -2 °C. After the addition of the sodium hydroxide solution, the reaction mixture was stirred at -2 °C for about 2 hours to achieve the desired degree of substitution. Water was added to the mixture, and the mixture was heated to 5 °C to hydrolyze the unreacted methyl bromide. After 30 minutes, the mixture was diluted with sodium chloride solution and then extracted with ethyl acetate. The organic layer was washed several times with sodium chloride solution and sodium sulfate solution and then dried over anhydrous sodium sulfate. The resulting solution was dried in vacuo.

[0106] The resulting white amorphous product: 117.0 g

[0107] Residual solvent: 1.5 (m / m)%

[0108] Hepta(2,6-di-O-methyl)-β-cyclodextrin content: not detected

[0109] N-Nitrosodimethylamine content: 1.3 ppm

[0110] DMA content: 0.8 ppm

[0111] Example 5

[0112] Preparation of hepta(2,6-di-O-methyl)-β-cyclodextrin (I) using dimethyl sulfate

[0113] Dissolve 113.5 g (0.1 mol) of β-cyclodextrin in 800 mL of DMSO. Add 333 mL (3.5 mol) of dimethyl sulfate to the solution and cool the solution to -2 °C. After reaching the specified temperature, add 110 g (0.35 mol) of barium hydroxide octahydrate to the reaction mixture with stirring. Continue stirring at -2 °C for 1 hour until a clear solution is obtained. Dissolve 126 g (3.15 mol) of sodium hydroxide in 113 mL of water. Dropwise add the sodium hydroxide solution to the reaction mixture at a steady rate with stirring over 3 hours while maintaining the temperature at -2 °C. After adding the sodium hydroxide solution, stir the reaction mixture at -2 °C for about 2 hours to achieve the desired degree of substitution. Add water to the mixture and heat to 20 °C to hydrolyze the unreacted dimethyl sulfate. After 30 minutes, dilute the mixture with sodium chloride solution and then extract with ethyl acetate. Wash the organic layer several times with sodium chloride solution and sodium sulfate solution, and then dry with anhydrous sodium sulfate. Concentrate the resulting solution in vacuo. Add diisopropyl ether and n-hexane to the concentrated solution to obtain the product. Dry the resulting solid.

[0114] The resulting white crystalline product: 118.5 g

[0115] Residual solvent: 1 (m / m) %

[0116] To reduce the residual solvent content, first dissolve 118.5 g of hepta(2,6-di-O-methyl)-β-cyclodextrin in cold water and then heat to 90 °C with stirring. During heating, the pure product crystallizes out from the mixture; filter at 90 °C and then dry. The HPLC chromatogram of this substance is shown in Figure 1 and the corresponding NMR spectrum is shown in Figure 2 .

[0117] The resulting white crystalline hepta(2,6-di-O-methyl)-β-cyclodextrin: 82.5 g

[0118] Yield: 62%

[0119] Barium content (ICP-MS): 150 ppm

[0120] Residual dimethyl sulfate content (GC-MS): 20 ppm

[0121] Example 6

[0122] Preparation of hepta(2,6-di-O-methyl)-β-cyclodextrin (II) using dimethyl sulfate

[0123] 113.5 g (0.1 mol) of β-cyclodextrin was dissolved in 800 mL of a 50-50 vol% solvent mixture of DMF and DMSO. 333 mL (3.5 mol) of dimethyl sulfate was added to the solution, and the solution was cooled to -2 °C. After reaching the specified temperature, 110 g (0.35 mol) of barium hydroxide octahydrate was added to the reaction mixture with stirring. Stirring was continued at -2 °C for 1 hour until a clear solution was obtained. 126 g (3.15 mol) of sodium hydroxide was dissolved in 113 mL of water. The sodium hydroxide solution was added dropwise to the reaction mixture at a steady rate with stirring over 3 hours while maintaining the temperature at -2 °C. After adding the sodium hydroxide solution, the reaction mixture was stirred at -2 °C for about 2 hours to achieve the desired degree of substitution. Water was added to the mixture, and it was heated to 20 °C to hydrolyze the unreacted dimethyl sulfate. After 30 minutes, the mixture was diluted with sodium chloride solution and then extracted with ethyl acetate. The organic layer was washed several times with sodium chloride solution and sodium sulfate solution, and then dried over anhydrous sodium sulfate. The resulting solution was concentrated in vacuo. The product was obtained after adding diisopropyl ether and n-hexane to the concentrated solution.

[0124] The resulting white crystalline product: 118.5 g

[0125] Residual solvent: 1 (m / m)%

[0126] To reduce the residual solvent content, 118.5 g of hepta(2,6-di-O-methyl)-β-cyclodextrin was first dissolved in cold water and then heated to 90 °C with stirring. During heating, the pure product crystallized out from the mixture; it was filtered at 90 °C and then dried.

[0127] The resulting white crystalline hepta(2,6-di-O-methyl)-β-cyclodextrin: 82.5 g

[0128] Yield: 62%

[0129] Barium content (ICP-MS): 160 ppm

[0130] Residual dimethyl sulfate content (GC-MS): 25 ppm

[0131] N-Nitrosodimethylamine content: 1.4 ppm

[0132] DMA content: 0.9 ppm

[0133] Example 7

[0134] Preparation of hexa(2,6-di-O-methyl)-α-cyclodextrin using methyl bromide

[0135] 136.2 g (0.14 mol) of α-cyclodextrin was dissolved in 925 mL of DMSO. 304 mL (5.51 mol) of methyl bromide at -20 °C was added to the solution, and the temperature of the mixture reached -6 °C. After reaching the specified temperature, 265.0 g (0.84 mol) of barium hydroxide octahydrate was added to the reaction mixture in several portions with stirring. 152.4 g (3.81 mol) of sodium hydroxide was dissolved in 194 mL of water. The sodium hydroxide solution was added dropwise to the reaction mixture at a steady rate with stirring over 1 hour while maintaining the temperature at -4 °C. After addition, the reaction mixture was stirred at -4 °C for 1 hour. 250 mL of tetrahydrofuran was added to the mixture. Stirring was continued at -4 °C for 5.5 hours. The reaction mixture was heated to 5 °C over 30 minutes. 610 mL of water was added to the mixture, and stirring was continued at 5 °C for 10 minutes. 820 mL of dichloromethane was added to the mixture. 360 mL of acetic acid was added. The two phases were separated, and the organic layer was washed several times with water and sodium bicarbonate solution. The resulting organic layer was concentrated in vacuo. Diisopropyl ether was added to the concentrated solution to precipitate the product. The resulting product was recrystallized from water and dried.

[0136] The resulting white crystalline hexa(2,6-di-O-methyl)-α-cyclodextrin: 139.0 g

[0137] Yield: 87%

[0138] Barium content (ICP-MS): 5 ppm

[0139] Residual methyl bromide content (GC-MS): 0.9 ppm

[0140] N-Nitrosodimethylamine content: <0.05 ppm

[0141] DMA content: <0.03 ppm

[0142] Example 8

[0143] Preparation of hepta(2,6-di-O-methyl)-β-cyclodextrin using methyl iodide

[0144] Dissolve 158.9 g (0.14 mol) of β-cyclodextrin in 925 mL of DMSO. Add 400 mL (6.43 mol) of methyl iodide to this solution at 15 °C, and then cool the solution to -6 °C. After reaching the specified temperature, add 309.5 g (0.98 mol) of barium hydroxide octahydrate to the reaction mixture in several portions with stirring. Dissolve 178 g (4.45 mol) of sodium hydroxide in 194 mL of water. With stirring, add the sodium hydroxide solution dropwise to the reaction mixture at a steady rate over 1 hour while maintaining the temperature at -4 °C. After addition, heat the reaction mixture to 3 °C within 30 minutes and stir at 5 °C for 1 hour. Add 250 mL of tetrahydrofuran to the mixture. Continue stirring at 5 °C for 5.5 hours. Heat the reaction mixture to 20 °C within 30 minutes. Add 610 mL of water to the mixture and continue stirring at 20 °C for 10 minutes. Add 820 mL of dichloromethane to the mixture and then cool it to 10 °C. Add 360 mL of acetic acid. Separate the two phases and wash the organic layer several times with water and sodium bicarbonate solution. Concentrate the obtained organic layer in vacuo. Add diisopropyl ether to the concentrated solution to precipitate the product. Recrystallize the obtained product from water and dry it. The HPLC chromatogram of this substance is shown in Figure 3 and the corresponding NMR spectrum is shown in Figure 4 .

[0145] Obtained white crystalline hepta(2,6-di-O-methyl)-β-cyclodextrin: 162.1 g

[0146] Yield: 87%

[0147] Barium content (ICP-MS): 4 ppm

[0148] Residual methyl iodide content (GC-MS): 0.9 ppm

[0149] N-Nitrosodimethylamine content: <0.05 ppm

[0150] DMA content: <0.03 ppm

[0151] Example 9

[0152] Preparation of octa(2,6-di-O-methyl)-γ-cyclodextrin using methyl iodide

[0153] Dissolve 181.6 g (0.14 mol) of γ-cyclodextrin in 925 mL of DMSO (dimethyl sulfoxide). Add 457 mL (7.34 mol) of methyl iodide to this solution at 15 °C, and then cool the solution to -6 °C. After reaching the specified temperature, add 353.3 g (1.12 mol) of barium hydroxide octahydrate to the reaction mixture in several portions with stirring. Dissolve 203.2 g (5.08 mol) of sodium hydroxide in 194 mL of water. With stirring, add the sodium hydroxide solution dropwise to the reaction mixture at a steady rate within 1 hour while maintaining the temperature at -4 °C. After the addition, heat the reaction mixture to 3 °C within 30 minutes and stir at 5 °C for 1 hour. Add 250 mL of tetrahydrofuran to the mixture. Continue to stir at 5 °C for 5.5 hours. Heat the reaction mixture to 20 °C within 30 minutes. Add 610 mL of water to the mixture and continue to stir at 20 °C for 10 minutes. Add 820 mL of dichloromethane to the mixture and then cool it to 10 °C. Add 360 mL of acetic acid. Separate the two phases and wash the organic layer several times with water and sodium bicarbonate solution. Concentrate the obtained organic layer under vacuum. Add diisopropyl ether to the concentrated solution to precipitate the product. Recrystallize the obtained product from water and dry it.

[0154] The obtained white crystalline octakis(2,6-di-O-methyl)-γ-cyclodextrin: 185.3 g

[0155] Yield: 87%

[0156] Barium content (ICP-MS): 3 ppm

[0157] Residual methyl iodide content (GC-MS): 0.8 ppm

[0158] N-Nitrosodimethylamine content: <0.05 ppm

[0159] DMA content: <0.03 ppm

[0160] Example 10

[0161] Preparation of hexakis(2,6-di-O-butyl)-α-cyclodextrin using 1-iodobutane

[0162] Dissolve 136.2 g (0.14 mol) of α-cyclodextrin in 925 mL of DMSO. Add 640 mL (5.62 mol) of 1-iodobutane to the solution at 15 °C, and then cool the solution to -6 °C. After reaching the specified temperature, add 265.3 g (0.84 mol) of barium hydroxide octahydrate to the reaction mixture in several portions with stirring. Dissolve 152.6 g (3.82 mol) of sodium hydroxide in 194 mL of water. With stirring, add the sodium hydroxide solution dropwise to the reaction mixture at a steady rate over 1 hour while maintaining the temperature at -4 °C. After the addition, heat the reaction mixture to 3 °C within 30 minutes and stir at 5 °C for 1 hour. Add 250 mL of tetrahydrofuran to the mixture. Continue stirring at 5 °C for 5.5 hours. Heat the reaction mixture to 20 °C within 30 minutes. Add 610 mL of water to the mixture and continue stirring at 20 °C for 10 minutes. Add 820 mL of dichloromethane to the mixture and then cool it to 10 °C. Add 360 mL of acetic acid. Separate the two phases and wash the organic layer several times with water and sodium bicarbonate solution. Concentrate the resulting organic layer in vacuo. Add diisopropyl ether to the concentrated solution to precipitate the product. Dry the resulting product.

[0163] The resulting white crystalline hexa(2,6-di-O-butyl)-α-cyclodextrin: 0.125 mol

[0164] Yield: 89%

[0165] Barium content (ICP-MS): 4 ppm

[0166] Residual 1-iodobutane content (GC-MS): 0.9 ppm

[0167] N-Nitrosodimethylamine content: <0.05 ppm

[0168] DMA content: <0.03 ppm

[0169] Example 11

[0170] Preparation of hexa(2,6-di-O-tert-butyl)-α-cyclodextrin using tert-butyl chloride

[0171] 136.2 g (0.14 mol) of α-cyclodextrin was dissolved in 925 mL of DMSO. At 15 °C, 598 mL (5.49 mol) of tert-butyl chloride (b.p. +51 °C) was added to the solution, and then the solution was cooled to -6 °C. After reaching the specified temperature, 265.3 g (0.84 mol) of barium hydroxide octahydrate was added to the reaction mixture in several portions with stirring. 152.6 g (3.81 mol) of sodium hydroxide was dissolved in 194 mL of water. With stirring, the sodium hydroxide solution was added dropwise to the reaction mixture at a steady rate over 1 hour while maintaining the temperature at -4 °C. After the addition, the reaction mixture was heated to 3 °C within 30 minutes and stirred at 5 °C for 1 hour. 250 mL of tetrahydrofuran was added to the mixture. Stirring was continued at 5 °C for 5.5 hours. The reaction mixture was heated to 20 °C within 30 minutes. 610 mL of water was added to the mixture, and stirring was continued at 20 °C for 10 minutes. 820 mL of dichloromethane was added to the mixture, and then it was cooled to 10 °C. 360 mL of acetic acid was added. The two phases were separated, and the organic layer was washed several times with water and sodium bicarbonate solution. The resulting organic layer was concentrated in vacuo. Diisopropyl ether was added to the concentrated solution to precipitate the product. The resulting product was dried.

[0172] The resulting white crystalline hexa(2,6-di-O-tert-butyl)-α-cyclodextrin: 0.122 mol

[0173] Yield: 87%

[0174] Barium content (ICP-MS): 5 ppm

[0175] Residual tert-butyl chloride content (GC-MS): 0.9 ppm N-nitrosodimethylamine content: <0.05 ppm DMA content: <0.03 ppm.

Claims

1. A method for the selective partial alkylation of the 2- and 6-positions of cyclodextrin in a single step with a C1-4 alkyl halide.

2. The method according to claim 1, wherein The alkylation reaction is carried out in the presence of a barium-containing catalyst.

3. The method according to any one of claims 1 to 2, characterized in that, An alkali metal hydroxide or alkoxide is used as the base.

4. The method according to any one of claims 1 to 3, characterized in that, The reaction solvent contains more than 50% dimethyl sulfoxide.

5. The method according to any one of claims 1 to 4, characterized in that, The selective alkylation reaction of cyclodextrin is carried out using an alkyl iodide.

6. The method according to any one of claims 1 to 4, characterized in that The selective alkylation reaction of cyclodextrin is carried out using a methyl halide.

7. The method according to any one of claims 1 to 5, characterized in that, The barium-containing catalyst used is barium oxide or barium hydroxide.

8. The method according to any one of claims 1 to 6, characterized in that, The product is separated by precipitation with a suitable organic solvent.

9. 2,6-di - O - alkylated cyclodextrin, characterized in that, The product contains less than 1 ppm of nitrosamine impurities.

10. The 2,6-di-O-alkylated cyclodextrin according to claim 9, characterized in that, The product contains less than 0.5 ppm of nitrosamine impurities.

11. The 2,6-di-O-alkylated cyclodextrin according to claim 8, wherein, The product contains less than 0.1 ppm of nitrosamine impurities.

12. 2,6-di -O -alkylated cyclodextrin, characterized in that, The product contains less than 100 ppm of alkyl halide impurities.

13. The 2,6-di-O-alkylated cyclodextrin according to claim 11, wherein, The product contains less than 50 ppm of alkyl halide impurities.

14. The 2,6-di-O-alkylated cyclodextrin according to claim 11, wherein The product contains less than 10 ppm of alkyl halide impurities.

15. 2,6-di-O-alkylated cyclodextrin, characterized in that, The product contains less than 30 ppm of barium.

16. The 2,6-di-O-alkylated cyclodextrin according to claim 11, wherein, The product contains less than 20 ppm of barium.

17. The 2,6-di-O-alkylated cyclodextrin according to claim 11, wherein The product contains less than 10 ppm of barium.

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