Process for the 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 selectively alkylating cyclodextrins to produce hexakis(2,6-di-O-alkyl)-α-cyclodextrins, heptakis(2,6-di-O-alkyl)-β-cyclodextrins, and octakis(2,6-di-O-alkyl)-γ-cyclodextrins.

Description

[Technical Field]

[0001] 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 selectively partially alkylating cyclodextrins to produce hexakis(2,6-di-O-alkyl)-α-cyclodextrins, heptakis(2,6-di-O-alkyl)-β-cyclodextrins, and octakis(2,6-di-O-alkyl)-γ-cyclodextrins. [Background technology]

[0002] Cyclodextrins (CDs) are a group of cyclic oligosaccharides obtained from the enzymatic conversion of starch by the action of the enzyme cyclodextrin glycosyltransferase, produced, for example, by the bacterium Bacillus macerans. There are various methods for the generation of cyclodextrin glycosyltransferase and the production and isolation of cyclodextrins. Cyclodextrins are cyclic molecules containing six to eight α-D-glucopyranose units linked by α-linkages at the 1,4 position, similar to amylose. As a result of this cyclic arrangement, the molecules are characterized by having neither reducing nor non-reducing end groups. Molecules containing six α-D-glucopyranose units are commonly known as α-cyclodextrins or cyclohexaamyloses, molecules containing seven α-D-glucopyranose units are commonly known as β-cyclodextrins or cycloheptaamyloses, and molecules containing eight α-D-glucopyranose units are known as γ-cyclodextrins or cyclooctaamyloses. References to "cyclodextrin" herein are intended to include these forms of cyclodextrin, as well as molecules with oligomerization levels greater than eight. As a result of the cyclic arrangement and conformation of the α-D-glucopyranose units, free rotation about the glycosidic bond is restricted, and cyclodextrins exist as cone-shaped molecules, with the primary hydroxyl groups located at the small end of the cone and the secondary hydroxyl groups located at the large opening of the cone. The cavity is lined with glycosidic oxygen atoms together with hydrogen atoms from C3 and C5, resulting in a relatively lipophilic cavity but a hydrophilic outer surface.

[0003] As a result of the two distinct domains of different polarity and the change in solvent structure that occurs upon complexation, cyclodextrins have the ability to form inclusion complexes with the hydrophobic portions of various organic molecules or polymers. The formation of cyclodextrin inclusion complexes with molecules is called the host-guest phenomenon. These unique properties of cyclodextrins have led to their commercial use in agriculture, water treatment, household products, and drug delivery systems. The application of cyclodextrins in the pharmaceutical field has led to time-release microencapsulation of various drugs, improved stability, and improved water solubility.

[0004] Cyclodextrins are generally known to improve the dissolution rate of drugs. However, because the complexes formed are also stable in aqueous solution, the improvement in solubility is accompanied by an increase in the saturation solubility of the drug. Unfortunately, β-cyclodextrin, which forms the most stable complexes with most drugs, has the lowest water solubility, making it impossible to obtain a solution of the drug complexed with it at therapeutic concentrations. This is thought to be due to the crystalline structure of β-cyclodextrin itself.

[0005] Despite their pharmaceutical usefulness, cyclodextrins also have limitations. Clinical use of natural cyclodextrins is limited to oral and topical administration forms due to the nephrotoxicity of cyclodextrins when they enter the body without being metabolized. Because mammalian enzymes are specific for the degradation of linear starch molecules, cyclodextrins remain largely unmetabolized and accumulate in the proximal tubule cells due to their recycling and reabsorption.

[0006] Underivatized cyclodextrins are crystalline solids that, when concentrated in renal tissue, form crystals and cause necrotic damage to cells. Despite forming water-soluble inclusion complexes, crystalline cyclodextrin drug complexes limit their usefulness for oral or sublingual administration. Alkylated Cyclodextrin

[0007] To overcome the above drawbacks, it is known to chemically modify cyclodextrins to adjust their properties. The introduction of methyl groups may lead to derivatives with high solubility. In addition to non-selective derivatization techniques, selective substitution patterns are also preferred, which lead to single compounds that can be well characterized. Nonselective alkylation reaction

[0008] The first attempt to prepare methylated cyclodextrins was made by Irvine, Pringsheim, and MacDonald (Irvine, JC, Pringsheim, H., MacDonald, J. Chem. Soc., 125, 942 (1924)). They used methyl sulfate as an alkylating agent in sodium hydroxide solution. According to Muskat's method (Muskat, I.: J. Am. Chem. Soc., 56, 693 and 2449 (1934)), the methylation of α- and β-cyclodextrins proceeded in liquid ammonia in the presence of metallic sodium and methyl iodide.

[0009] Ionel Ciucán and Francis Kerek (Carbohydrate Research Volume 131, Issue 2, 15 August 1984, Pages 209-217 "A Simple and Rapid Method for the Permethylation of Carbohydrates") discovered that methyl iodide is the most effective methylating agent for per-O-methylation. They applied methyl iodide in the presence of a solid base (e.g., NaOH, KOH, or a K-tert-BuOH / NaOH mixture) in a polar aprotic solvent.

[0010] Regardless of the type of sugar, permethylation is typically performed with alkyl halides (e.g., methyl iodide). The reaction can be performed in short reaction times (usually 6-7 minutes) with excellent yields (98±2%). This method was first described by Hakomori, and is therefore also known as the Hakomori methylation (S. Hakomori, J. Biochem. (Tokyo), 55 (1964) 205-208). Hakomori also used sodium hydride in addition to methyl iodide. NaH base was found to be preferable compared to potassium tert-butoxide. The latter is safer but does not provide sufficient yields (Lindberg, Methods Enzymol., 28 (1972) 178-195. es J. Finne, T. Krusius, H. Rauvala, Carbohydr. Res., 80 (1980) 336-339).

[0011] Similarly, rapid methylation can be achieved using Na in liquid ammonia in the presence of methyl iodide, but selectivity may not be achieved, and as a result, the subject 2,6 methylation may not be achieved.

[0012] In the methylation reaction by 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 solvent. Although little regioselectivity was observed, this method was successfully applied to permethylated sugars (J.S. Brimacombe, B.D. Jones, M. Stacey, J.J. Willard "Alkylation of carbohydrates using sodium hydride" - Carbohydrate Research Volume 2, Issue 2, June 1966, Pages 167-169).

[0013] JPEG2025536835000002.jpg29170

[0014] Complete methylation of hexakis(6-azido)-α-CD (instead of native α-CD) was achieved by treatment with crystalline sodium hydride and methyl iodide in DMF, which gave the hexakis(2,3)-di-O-methyl derivative in quantitative yield after deprotection (Boger et al. Helvetica Chimica Acta - Vol. 61, Fasc. 6, 2190(1978)), but this method requires an azide protecting group strategy (i.e., a multi-step synthetic strategy) to obtain selective methylation.

[0015] Cui Yanli Mao's patented technology (University of Zhejiang, CN1709918, and J Chem Technol Biotechnol. 2010; 85: 248-251) describes a synthetic method that results in stochastic substitution patterns of methylated β-cyclodextrins. The process is based on the reaction of β-cyclodextrin, alkali metal hydroxides, and methylating agents (including methyl chloride, methyl bromide, and methyl iodide) under high pressure, applying a mixture temperature of 60-130°C, a reaction pressure of 6-14 bar, and a reaction time of 2-9 hours.

[0016] Therefore, it can be concluded that alkyl halides are directly used for the permethylation and nonselective partial alkylation of cyclodextrins. Selective partial alkylation

[0017] For partial and selective methylation, dimethyl sulfate (Me2SO4) and methyl carbonate have mostly been used in dipolar aprotic solvents in the presence of a suitable base. In the presence of a strong base (NaH, Na, liquid NH3), the alkylation is rapid but not selective. The only known method to achieve adequate selectivity is to use a barium base.

[0018] Casu et al. (Casu, B., Reggiani, M., Gallo, GG, Vigevani, A.: Tetrahedron, 24, 803 (1968)) applied the Kuhn method (Kuhn, R., Trischmann, H., Low, I.: Angew. Chem., 67, 32 (1955) and Kuhn, R., Baer, ​​HH, Seeliger, A.: Ann., 611, 236 (1958)) to the methylation of α- and β-cyclodextrins using Me2SO4 and BaO in a 1:1 mixture of DMF and DMSO, achieving regioselective alkylation.

[0019] Later, Tanimoto et al. demonstrated that Szejtli's method was not universal for all three natural cyclodextrins; methylation of γ-CD primarily gave octakis(2,3,6-tri-O-methyl)-γ-cyclodextrin, with no detectable partially selectively methylated octakis(2,6-di-O-methyl)-γ-cyclodextrin. Szejtli's method also yielded hexakis(2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl)-β-cyclodextrin and several minor hypermethylated homologs. (T. Tanimoto et al. Chem. Pharm. Bull. 38(2) 318-322 (1990)).

[0020] JPEG2025536835000004.jpg34170

[0021] Boger et al. prepared hexakis(2,6-di-O-methyl)-α-cyclodextrin using α-cyclodextrin dissolved in DMSO and DMF. Methylation with dimethyl sulfate was performed using a mixture of barium hydroxide (Ba(OH)2·8H2O) and carbonate-free barium oxide (Boger et al. Helvetica Chimica Acta - Vol. 61, Fasc. 6, 2190(1978)).

[0022] According to Hungarian Patent HU 180580, methylation of the 2,6-positions was carried out in aqueous medium with dimethyl sulfate in the presence of sodium hydroxide (this step was repeated twice). The drawback of this method was that the required product could not be prepared in a single technical step. [Brief explanation of the drawings]

[0023] [Figure 1] 1 shows an HPLC chromatogram of heptakis(2,6-di-O-methyl) β-cyclodextrin prepared according to Example 5. [Figure 2] 1 shows the NMR spectrum of heptakis(2,6-di-O-methyl) β-cyclodextrin prepared according to Example 5. [Figure 3] 1 shows an HPLC chromatogram of heptakis(2,6-di-O-methyl) β-cyclodextrin prepared according to Example 8. [Figure 4] 1 shows the NMR spectrum of heptakis(2,6-di-O-methyl) β-cyclodextrin prepared according to Example 8. [Figure 5] 1 shows the HPLC chromatogram of randomly methylated β-cyclodextrin prepared according to Example 3 compared to the HPLC chromatogram of heptakis(2,6-di-O-methyl) β-cyclodextrin prepared according to Example 8. [Figure 6] 1 shows the NMR spectrum of randomly methylated β-cyclodextrin prepared according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0024] The preferred embodiments of the process disclosed herein are provided by way of example and are not intended to limit the scope of the present disclosure. Surprisingly, it has been found that partial alkylation of cyclodextrins, essentially yielding products in which all 2- and 6-positions of α-, β-, and γ-cyclodextrins are substituted, respectively, can be achieved by a process in which alkylation is carried out 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 without the use of protecting groups (i.e., a one-step synthesis) in a solvent mixture consisting essentially of water and dimethyl sulfoxide (DMSO) in the presence of an alkali metal hydroxide or alcoholate. The performance and selectivity of the reaction using this solvent mixture have been found to be superior to other aprotic solvent mixtures containing N,N-dimethylformamide (DMF), which are commonly used in synthetic methods applied to carbohydrate chemistry.

[0025] The present invention is based on the use of an appropriate base / catalyst combination that can distinguish between hydroxyl groups at different positions in the cyclodextrin ring due to their different pK values. The pK difference between primary and secondary hydroxyl groups alone cannot distinguish between hydroxyl groups at the 2- and 3-positions, respectively. The use of BaO or Ba(OH)2 bases results in selective alkylation of the 2- and 6-positions due to complexation of the hydroxyl groups with the Ba ion resulting from steric hindrance. The presence of DMF is not known in the art to adversely affect this selectivity, reducing the yield of the selectively substituted 2,6-alkylated species. The typical impurities present in DMF, dimethylamine (DMA) and formic acid, are expected to result from both the acid and the base, particularly from the alkylation reaction (Liu, J. et al. Journal of Molecular Structure Vol. 654, Issues 1-3, 215-221 and Burrows, A. et al. Cryst Eng Comm, 2005, 7(89), 548-550). The presence of DMA is undesirable for pharmaceutical applications of the subject selectively alkylated cyclodextrins. This is because DMA can be nitrosated under mildly acidic conditions to produce dimethylnitrosamine, a known carcinogen (Questions and answers on "Information on nitrosamines for marketing authorization holders EMA / CHMP / 428592 / 2019 Rev. 1"). To control nitrosamines in selectively alkylated cyclodextrins, the FDA limit test (https: / / www.fda.gov / media / 124025 / download) was applied according to Example 1. This method allows for quantification of nitrosamines at levels of 0.05 ppm.

[0026] DMA in selectively alkylated cyclodextrins was measured by a GC-headspace chromatography method applied to this compound (AR Deshpande et al. Eurasian J Anal Chem 2012;7(1):43-48).

[0027] It was also surprisingly found that, among the suitable methyl halides, methyl iodide can effectively lower the freezing point of DMSO to a temperature range (below +5°C) where enhanced ion selectivity is observed.

[0028] Even more surprisingly, the yield enhancements achieved by the present invention have been found to allow isolation of selectively alkylated cyclodextrins using only solvent-based precipitation, without the need for thermal recrystallization, a technically undesirable additional step in previously disclosed processes (e.g., crude products synthesized from dimethyl sulfate in a mixture of DMF and / or DMSO according to Examples 5-6).

[0029] The barium content of the crude reaction mixture was reduced by extraction with dichloromethane and acetic acid, which was added to the mixture at low temperature. Two immiscible phases formed, and the organic layer was washed several times with water and sodium bicarbonate solution. The resulting organic layer was concentrated under vacuum. The product was precipitated from the concentrated solution by the addition of diisopropyl ether.

[0030] A further advantage of the process according to the invention is that, due to the appropriate selection of the precipitation solvent, the residual impurities (i.e., barium catalyst and residual alkylating agent) in the resulting product are low in quantity. The barium level is maximum at 30 ppm, which is relevant for the most important pharmaceutical products as listed on page 26 of the ICH guideline Q3 (March 28, 2019).

[0031] Example 1 Nitrosamine Impurity Analysis by GC-MS / MS Equipment and Facilities Gas chromatography system equipped with a quadrupole mass spectrometer detector and a headspace autosampler DB-Wax GC column, 30m x 0.25mm, 0.5µm, or equivalent Analytical Balance Shaking mechanical shaker Vortex mixer 20mL headspace vial HS Vial Cap with Teflon / Silicone Septa solvent Dimethyl sulfoxide (DMSO), > 99.5% Standard Stock Solutions N-nitrosodimethylamine (NDMA): 1 mg / mL (in MeOH) N-nitrosodimethylamine-d6 labeling (NDMA d6): 1 mg / mL (in MeOH) Preparation of standard solutions Internal standard solution (NDMA d6): Using a 1000 μL pipettor, 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. Add DMSO to make 100 mL and mix thoroughly to give a concentration of 10 μg / mL. Cyclodextrin sample preparation Accurately weigh 500 mg of 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, then immediately cap and tighten the vial. Mix the sample solution using a vortex mixer. GC / MS-HS Parameters Instrument: Agilent 7890B GC equipped with Agilent 5977A MSD and Agilent 7697A HS autosampler Column: DB-WAX, 30m x 0.25mm, 0.5μm Inlet temperature: 220℃ Column flow rate: 1 mL / min Split ratio 5:1 Oven program: 70°C for 4 minutes; 20°C / min to 240°C, hold for 3.5 minutes. GC runtime: 16 minutes. GC cycle time: 24 minutes. HS autosampler parameters Oven temperature: 120℃ Loop temperature: 125℃ Transfer line temperature: 130℃ Vial equilibration time: 15 minutes Injection time: 1.0 minutes Vial size: 20 mL vial Shaking: Level 9 (250 shakes / min) Filling pressure: 15 psi Loop size: 1 mL MS parameters MS source temperature: 230℃ Quadrupole temperature: 150℃ Measurement type: SIM Gain factor 5 Solvent delay: 6.0 min.

[0032] Example 2 HPLC analysis of alkylated cyclodextrin derivatives Device: Agilent 1260 Quaternary Pump System Agilent 1100 Series Thermostatted Column Compartment Agilent 2-Way / 6-Port Switch Valve Agilent 1260 Series Thermostatic Autosampler Agilent 1200 DAD detector Agilent 1260 Refractive Index Detector Agilent OpenLAB CDS ChemStation Rev. C.01.07 SR3 Column: Kinetex C18 (Phenomenex) In-house code: KIN1 (batch number: 5569-110) and KIN7 (batch number: 5569-0217). Column length: 100 mm Inner diameter: 4.6mm Particle size: 2.6μm Guard:SecurityGuard Cartridge C18 4x3.0mm ID (Phenomenex). Column temperature: 30℃ Mobile phase: Isopropanol (IPA) 70mL Methanol 410mL Water 520mL Flow rate: 0.5mL / min. RI detector temperature: 40℃ Sample volume: 10 μl Sample concentration: 8mg / mL Downtime: 45 minutes Integrator: area

[0033] Example 3 Preparation of methyl-s-cyclodextrin using methyl iodide (random alkylation) Dissolve 113.5 g (0.1 mol) of s-cyclodextrin in 800 mL of dimethyl sulfoxide. Add 280 mL (4.5 mol) of methyl iodide to the reaction mixture while stirring at room temperature. Dissolve 123 g (3.08 mol) of sodium hydroxide in 113 mL of water. Add the sodium hydroxide solution dropwise to the stirred reaction mixture at a steady rate over a period of 3 hours, maintaining the temperature below 30°C. After the addition of the sodium hydroxide solution, stir the reaction mixture at room temperature for approximately 2 more hours to obtain the desired degree of substitution. After 30 minutes, dilute the mixture with sodium chloride solution and extract with ethyl acetate. Wash the organic layer several times with sodium chloride and sodium sulfate solutions and dry over anhydrous sodium sulfate. The resulting solution is dried under vacuum. Figure 5 shows a comparison of the chromatogram of the resulting product with that of the selectively alkylated analog, heptakis(2,6-di-O-methyl)-β-cyclodextrin. Figure 6 shows the NMR spectrum.

[0034] Obtained white amorphous product: 118.5 g Residual solvent: 1.0(m / m)% Heptakis(2,6-di-O-methyl)-β-cyclodextrin content: Not detected

[0035] Example 4 Preparation of methyl-s-cyclodextrin using methyl bromide (random alkylation) Dissolve 113.5 g (0.1 mol) of s-cyclodextrin in 800 mL of a 50-50 vol% solvent mixture of DMF and DMSO. Cool the solution to -2 °C, and add 248 mL (4.5 mol) of methyl bromide (boiling point +4 °C) to the stirring reaction mixture. Dissolve 123 g (3.08 mol) of sodium hydroxide in 113 mL of water. Over a period of 3 hours, add the sodium hydroxide solution dropwise to the stirring reaction mixture at a steady rate while maintaining the temperature at -2 °C. After the addition of the sodium hydroxide solution, stir the reaction mixture at -2 °C for approximately 2 more hours to obtain the desired degree of substitution. Add water to the mixture, and heat to 5 °C to hydrolyze any unreacted methyl bromide. After 30 minutes, dilute the mixture with sodium chloride solution and extract with ethyl acetate. Wash the organic layer several times with sodium chloride solution and sodium sulfate solution and dry over anhydrous sodium sulfate. Dry the resulting solution under vacuum.

[0036] Obtained white amorphous product: 117.0 g Residual solvent: 1.5(m / m)% Heptakis(2,6-di-O-methyl)-β-cyclodextrin content Undetected N-nitrosodimethylamine content 1.3 ppm DMA content 0.8ppm

[0037] Example 5 Preparation of heptakis(2,6-di-O-methyl)-s-cyclodextrin using dimethyl sulfate (I) Dissolve 113.5 g (0.1 mol) of s-cyclodextrin in 800 mL of DMSO. Add 333 mL (3.5 mol) of dimethyl sulfate to the solution and cool to -2 °C. After reaching the specified temperature, add 110 g (0.35 mol) of barium hydroxide octahydrate to the reaction mixture under stirring. Stirring is continued 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. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 3 hours, while maintaining the temperature at -2 °C. After the addition of the sodium hydroxide solution, stir the reaction mixture at -2 °C for approximately another 2 hours to obtain 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 extract with ethyl acetate. The organic layer is washed several times with sodium chloride solution and sodium sulfate solution, and dried over anhydrous sodium sulfate. The resulting solution is concentrated under vacuum. The product is obtained from the concentrated solution by adding diisopropyl ether and n-hexane. The resulting solid is dried.

[0038] Obtained white crystalline product: 118.5g Residual solvent: 1(m / m)%

[0039] To reduce the residual solvent content, 118.5 g of heptakis(2,6-di-O-methyl)-β-cyclodextrin was first dissolved in cold water and then heated to 90°C under stirring. Upon heating, the pure product crystallized from the mixture. It was filtered at 90°C and then dried. The HPLC chromatogram of the material is shown in Figure 1, and the corresponding NMR spectrum is shown in Figure 2.

[0040] Obtained white crystalline heptakis(2,6-di-O-methyl)-β-cyclodextrin: 82.5g Yield: 62% Barium content (ICP-MS): 150ppm Residual dimethyl sulfate content (GC-MS): 20ppm

[0041] Example 6 Preparation of heptakis(2,6-di-O-methyl)-s-cyclodextrin using dimethyl sulfate (II) Dissolve 113.5 g (0.1 mol) of s-cyclodextrin in 800 mL of a 50-50 vol% solvent mixture of DMF and DMSO. Add 333 mL (3.5 mol) of dimethyl sulfate to the solution and cool to -2 °C. After reaching the specified temperature, add 110 g (0.35 mol) of barium hydroxide octahydrate to the reaction mixture under stirring. Stirring is continued 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. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 3 hours, while maintaining the temperature at -2 °C. After the addition of the sodium hydroxide solution, stir the reaction mixture at -2 °C for approximately another 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 extract with ethyl acetate. The organic layer is washed several times with sodium chloride solution and sodium sulfate solution, and dried over anhydrous sodium sulfate. The resulting solution is concentrated under vacuum. The product is obtained from the concentrated solution by adding diisopropyl ether and n-hexane.

[0042] Obtained white crystalline product: 118.5g Residual solvent: 1(m / m)%

[0043] To reduce the residual solvent content, 118.5 g of heptakis(2,6-di-O-methyl)-β-cyclodextrin is first dissolved in cold water and then heated to 90°C under stirring. Upon heating, the pure product crystallizes from the mixture. It is filtered at 90°C and then dried.

[0044] Obtained white crystalline heptakis(2,6-di-O-methyl)-β-cyclodextrin: 82.5g Yield: 62% Barium content (ICP-MS): 160ppm Residual dimethyl sulfate content (GC-MS): 25ppm N-nitrosodimethylamine content 1.4 ppm DMA content 0.9ppm

[0045] Example 7 Preparation of hexakis(2,6-di-O-methyl)-α-cyclodextrin using methyl bromide Dissolve 136.2 g (0.14 mol) of α-cyclodextrin in 925 mL of DMSO. Add 304 mL (5.51 mol) of methyl bromide at a temperature of -20 °C to the solution so that the resulting mixture attains a temperature of -6 °C. After the specified temperature is reached, add 265.0 g (0.84 mol) of barium hydroxide octahydrate in portions to the reaction mixture under stirring. Dissolve 152.4 g (3.81 mol) of sodium hydroxide in 194 mL of water. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 1 hour, while maintaining the temperature at -4 °C. After the addition, stir the reaction mixture at -4 °C for 1 hour. Add 250 mL of tetrahydrofuran to the mixture. Continue stirring at -4 °C for 5.5 hours. Heat the reaction mixture to 5 °C within 30 minutes. 610 mL of water is added to the mixture and stirring is continued for 10 minutes at 5°C. 820 mL of dichloromethane is added to the mixture. 360 mL of acetic acid is added. The two phases are separated and the organic layer is washed several times with water and sodium bicarbonate solution. The organic layer obtained is concentrated under vacuum. The product is precipitated from the concentrated solution by adding diisopropyl ether. The product obtained is recrystallized from water and dried.

[0046] Obtained white crystalline hexakis(2,6-di-O-methyl)-α-cyclodextrin: 139.0g Yield: 87% Barium content (ICP-MS): 5 ppm Residual methyl bromide content (GC-MS): 0.9 ppm N-nitrosodimethylamine content <0.05ppm DMA content <0.03ppm

[0047] Example 8 Preparation of heptakis(2,6-di-O-methyl)-s-cyclodextrin using methyl iodide 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 the solution at 15°C and cool to -6°C. After reaching the specified temperature, add 309.5 g (0.98 mol) of barium hydroxide octahydrate in portions to the reaction mixture under stirring. Dissolve 178 g (4.45 mol) of sodium hydroxide in 194 mL of water. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring 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. 610 mL of water is added to the mixture and stirring is continued at 20°C for 10 minutes. 820 mL of dichloromethane is added to the mixture, which is then cooled to 10°C. 360 mL of acetic acid is added. The two phases are separated, and the organic layer is washed several times with water and sodium bicarbonate solution. The resulting organic layer is concentrated under vacuum. The product is precipitated from the concentrated solution by the addition of diisopropyl ether. The resulting product is recrystallized from water and dried. The HPLC chromatogram of the material is shown in Figure 3, and the corresponding NMR spectrum is shown in Figure 4.

[0048] Obtained white crystalline heptakis(2,6-di-O-methyl)-β-cyclodextrin: 162.1g Yield: 87% Barium content (ICP-MS): 4 ppm Residual methyl iodide content (GC-MS): 0.9 ppm N-nitrosodimethylamine content <0.05ppm DMA content <0.03ppm

[0049] Example 9 Preparation of Octakis(2,6-di-O-methyl)-γ-cyclodextrin Using Methyl Iodide 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 the solution at 15°C and cool to -6°C. After reaching the specified temperature, add 353.3 g (1.12 mol) of barium hydroxide octahydrate in portions to the reaction mixture under stirring. Dissolve 203.2 g (5.08 mol) of sodium hydroxide in 194 mL of water. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 1 hour, 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. 610 mL of water is added to the mixture and stirring is continued for 10 minutes at 20°C. 820 mL of dichloromethane is added to the mixture, which is then cooled to 10°C. 360 mL of acetic acid is added. The two phases are separated and the organic layer is washed several times with water and sodium bicarbonate solution. The organic layer obtained is concentrated under vacuum. The product is precipitated from the concentrated solution by the addition of diisopropyl ether. The product obtained is recrystallized from water and dried.

[0050] Obtained white crystalline octakis(2,6-di-O-methyl)-γ-cyclodextrin: 185.3g Yield: 87% Barium content (ICP-MS): 3 ppm Residual methyl iodide content (GC-MS): 0.8 ppm N-nitrosodimethylamine content <0.05ppm DMA content <0.03ppm

[0051] Example 10 Preparation of hexakis(2,6-di-n-butyl)-α-cyclodextrin using n-butyl iodide Dissolve 136.2 g (0.14 mol) of α-cyclodextrin in 925 mL of DMSO. Add 640 mL (5.62 mol) of n-butyl iodide to the solution at 15°C and cool to -6°C. After reaching the specified temperature, add 265.3 g (0.84 mol) of barium hydroxide octahydrate in portions to the reaction mixture under stirring. Dissolve 152.6 g (3.82 mol) of sodium hydroxide in 194 mL of water. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 1 hour, 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. 610 mL of water is added to the mixture and stirring is continued for 10 minutes at 20°C. 820 mL of dichloromethane is added to the mixture, which is then cooled to 10°C. 360 mL of acetic acid is added. The two phases are separated and the organic layer is washed several times with water and sodium bicarbonate solution. The organic layer obtained is concentrated under vacuum. The product is precipitated from the concentrated solution by adding diisopropyl ether. The product obtained is dried.

[0052] Obtained white crystalline hexakis(2,6-di-On-butyl)-α-cyclodextrin: 0.125mol Yield: 89% Barium content (ICP-MS): 4 ppm Residual n-butyl iodide content (GC-MS): 0.9ppm N-nitrosodimethylamine content <0.05ppm DMA content <0.03ppm

[0053] Example 11 Preparation of hexakis(2,6-di-Ot-butyl)-α-cyclodextrin using t-butyl chloride Dissolve 136.2 g (0.14 mol) of α-cyclodextrin in 925 mL of DMSO. Add 598 mL (5.49 mol) of t-butyl chloride (boiling point +51°C) to the solution at 15°C and cool to -6°C. After reaching the specified temperature, add 265.3 g (0.84 mol) of barium hydroxide octahydrate in several portions to the reaction mixture under stirring. Dissolve 152.6 g (3.81 mol) of sodium hydroxide in 194 mL of water. Add the sodium hydroxide solution dropwise to the reaction mixture under stirring at a steady rate over 1 hour, 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. 610 mL of water is added to the mixture and stirring is continued for 10 minutes at 20°C. 820 mL of dichloromethane is added to the mixture, which is then cooled to 10°C. 360 mL of acetic acid is added. The two phases are separated and the organic layer is washed several times with water and sodium bicarbonate solution. The organic layer obtained is concentrated under vacuum. The product is precipitated from the concentrated solution by adding diisopropyl ether. The product obtained is dried.

[0054] Obtained white crystalline hexakis(2,6-di-Ot-butyl)-α-cyclodextrin: 0.122mol Yield: 87% Barium content (ICP-MS): 5 ppm Residual t-butyl chloride content (GC-MS): 0.9ppm N-nitrosodimethylamine content <0.05ppm DMA content <0.03ppm

Claims

1. A process for selective partial alkylation of cyclodextrins at the 2- and 6-positions using C1-4 alkyl halides in a single step.

2. 10. The process of claim 1, wherein the alkylation is carried out in the presence of a barium-containing catalyst.

3. 3. The process according to claim 1, wherein an alkali metal hydroxide or alcoholate is applied as the base.

4. 4. The process of any one of claims 1 to 3, wherein the reaction solvent comprises greater than 50% dimethyl sulfoxide.

5. 5. The process according to any one of claims 1 to 4, wherein the selective alkylation of the cyclodextrin is carried out with an alkyl iodide.

6. 5. The process according to any one of claims 1 to 4, characterized in that the selective alkylation of the cyclodextrin is carried out with a methyl halide.

7. 6. The process according to claim 1, wherein the barium-containing catalyst used is barium oxide or barium hydroxide.

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

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

10. 10. The 2,6-di-O-alkylated cyclodextrin of claim 9, wherein the product contains less than 0.5 ppm of nitrosamine impurities.

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

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

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

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

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

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

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

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