WO1994002516A1

WO1994002516A1 - Method of producing partially methylated cyclodextrines and compounds obtained

Info

Publication number: WO1994002516A1
Application number: PCT/FR1993/000730
Authority: WO
Inventors: Jacek Ropenga; André DERATANI; Jean-François LETAVERNIER; Didier Majou
Original assignee: Orsan
Priority date: 1992-07-17
Filing date: 1993-07-16
Publication date: 1994-02-03
Also published as: FR2693728B1; FR2693728A1; EP0650499A1

Abstract

A method of preparing partially methylated cyclodextrines in an aqueous medium from a cyclodextrine such as alpha-cyclodextrine, beta-cyclodextrine or gamma-cyclodextrine, or from a salt of said cyclodextrines, which is reacted with dimethyl sulphate and a base, preferably an alkaline metal hydroxide, is characterised in that the methylation reaction is carried out in the presence additionally of at least one substance having an affinity for the cyclodextrine cavity, such that an inclusion complex with the said substance may form during the methylation reaction. Partially methylated cyclodextrines obtained by this method are also disclosed.

Description

Process for the production of partially methylated cyclodextrins and compounds obtained

The present invention relates to a process for the production of partially methylated cyclodextrins, as well as the partially methylated cyclodextrins resulting from this process.

The cyclodextrin molecules (hereinafter referred to by the abbreviation "CD") are composed of glucose units (6 for alpha-CD, 7 for beta-CD and 8 for gamma-CD) linked in such a way that 'they form a cage capable of including a wide variety of hydrophobic compounds. DCs can also give rise to intermolecular interactions leading to a modification of the solubility of the molecules invited in solution and, in the solid state, to effects on their crystalline state (amorphization or modification of the crystalline system). This property has been taken advantage of in numerous applications in fields as varied as the food industry, cosmetology, the pharmaceutical and chemical industries.

One of the limitations of CD applications, and mainly beta-CD, results from their low solubility in water: at 25 ° C it reaches 127 g / 1 for alpha-CD, 18.8 g / 1 for beta-CD and 236 g / 1 for gamma-CD.

This is why there is an increasing use of highly soluble CD derivatives allowing, inter alia, the solubilization and in general the inclusion of compounds which are insoluble in water by the formation of a complex of inclusion soluble or by intermolecular interaction or by the combination of the two above-mentioned effects. The presence of hydroxyl groups on the CD molecules has made it possible to develop CD derivatives having improved solubility. Indeed, CD are polyfunctional molecules having three types of alcohol functions: a primary alcohol function by glucose unit (position 6) and two secondary alcohol functions by glucose unit (positions 2 and 3), which represents for beta-CD 21 alcohol functions likely to react.

Among the CD derivatives, the partially methylated CDs have a markedly improved solubility in water compared to the original CDs. In addition, partially methylated CDs retain the inclusion properties of native CDs and, in some cases, improve them.

REPLACEMENT SHEET Thus, at 25 ° C, the following solubilities in water are noted:

- 550 g / liter of solution for heptakis - (2,6 - di - O - methyl) - beta-CD. But its solubility and that of its complexes decreases when the temperature increases. - 300 g / liter of solution for heptakis - (2,3,6 - tri - O - methyl) - beta-CD.

But its solubility decreases when the temperature increases. Furthermore, due to the substitution of all the positions, there is a decrease in the inclusion capacity and the affinity for certain host molecules, and this despite the strengthening of the hydrophobic character of the cavity. - of the order of 1330 g / liter of water for the methylated derivatives of beta-CD having an average degree of methylation of the hydroxyl groups from 53 to 64% for position 2, from 38 to 51% for position 3 and from 70 to 100% for position 6 (US Patent 4,746,734). The average solubility of these derivatives increases with increasing temperature. - of the order of 100 g / liter of water for methylated beta-CD derivatives having an average degree of methylation per beta-CD molecule comprised mainly between 8 and 11 of the 21 available sites that this molecule contains (Patent JP 62 220501).

Several possibilities for CD methylation are known to date. Depending on the synthesis used, different products are obtained:

- The permethylated derivative (for example heptakis (2,3,6 - tri - O - methyl) -beta-CD) results from an exhaustive methylation of all the positions. It can be obtained in an anhydrous solvent (dimethylformamide or dimethylsulfoxide) by reaction between CD and dimethyl sulfate in the presence of a strong base, such as sodium hydroxide in solid sprayed form [for example, Tetrahedron, 24, 803 -821, (1968)].

- the methyl derivative specifically in positions 2 and 6, which are the most reactive positions (for example, heptakis - (2,6 - di - O - methyl) - beta-CD): it is obtained in a dimethylformamide mixture -dimethylsulfoxide, by reaction between beta-CD and dimethyl sulfate in the presence of barium oxide and hydroxide according to a conventional method of modification of polysaccharides [for example, Chem. Ber., 96, 284-287, (1963)]. These two methods have the drawback of using solvents with a high boiling point which it is then difficult to remove.

- partially methylated derivatives in all positions in the glucose units with either at least 90% in position 2, 25-35% in position 3 and at least 95% in position 6 (EP patent No. 193850), or 53 -64% in position 2, 38-51% in position 3 and 70-100% in position 6 (US patent 4,746,734). According to US Patent 4,746,734, they are obtained by reaction of a cyclodextrin with dimethyl sulphate in concentrated aqueous sodium hydroxide. This reaction requires more than 30 equivalent parts of dimethyl sulfate (and preferably from 100 to 200 to ensure satisfactory methylation), more than 30 equivalent parts of alkali metal hydroxide (such as sodium hydroxide) and maintaining the concentration reactants beyond

10% by weight. These derivatives have the advantage of having greater solubility in water at 25 ° C than the previous ones: 1330 g / liter of water against 300 g / liter of solution and 550 g / liter of solution respectively for the derivative permethylated and the methylated derivative specifically in positions 2 and 6. - partially methylated derivatives having an average degree of methylation per beta-CD molecule mainly between 8 and 11. According to patent JP62220501, they are obtained by reaction of a beta -CD with dimethyl sulfate in basic aqueous solution. However, these last two processes are difficult to control industrially. Indeed, the presence of water in the reaction medium results in a strong hydrolysis of dimethyl sulfate. However, this hydrolysis leads to the formation of an abundant, rigid and very stable foam which prevents heat exchanges and mass transfers from establishing properly and can cause the reaction to runaway by accumulation of the reactants. This is highlighted in Comparative Example 16. Therefore, because of this phenomenon, the methylation reaction must be carried out very slowly. This product gives a product consisting of a mixture of derivatives of different degrees of substitution with a very broad composition ranging from 11 methyl substituents to 18 per molecule of CD. Furthermore, it is very difficult to obtain repeatability and reproducibility of the syntheses, that is to say to regularly produce the same partially methylated derivatives.

We have now found a process for preparing a family of partially methylated CDs in position 2, 3 and 6 which does not have the drawbacks described above. More specifically, it is a process for preparing partially methylated CD in an aqueous medium from a CD such as alpha-CD, beta-CD or gamma-CD, or a salt of said CD which is reacted with dimethyl sulphate and a base, preferably an alkali metal hydroxide, characterized in that the methylation reaction is carried out in the presence also of at least one substance having an affinity with the cavity CDs such that an inclusion complex with said substance can form during the methylation reaction.

It is well known that the formation of inclusion complexes with DCs can modify the properties of the molecules included. Thus, it is believed that dimethyl sulfate forms an inclusion complex with the DCs and that this complexation facilitates its hydrolysis resulting in an abundant production of foam in the processes prior to the present invention. We have now surprisingly found that CD (and more particularly alpha-CD, beta-CD and gamma-CD) can be methylated in a basic, or even strongly basic, aqueous medium without producing foam by introducing in the reaction medium a substance competing with dimethyl sulfate for the formation of the inclusion complex.

In the following description, this substance will be designated by the term "competitor". Thanks to the process according to the invention, the hydrolysis of dimethyl sulfate is limited, and consequently, the formation of foam which, in the past, made control of the process difficult. Therefore, a better course of the reaction is made possible without the need for special monitoring. Another important advantage of the invention lies in the reproducibility of the process which, therefore, regularly, and in a controlled manner, produces the same partially methylated derivatives. Also, it should be noted that the process according to the invention makes it possible to avoid the use of organic solvents such as dimethyl formamide and dimethyl sulfoxide which are generally difficult to remove and whose presence, even in trace amounts, is incompatible in many applications, even prohibited by the regulations according to the applications.

Another advantage of using the competitor lies in the fact that it is suitable for the preparation of partially methylated CD derivatives of various degrees of methylation: it is therefore not limited to the preparation of partially methylated CD described in the present description and is also suitable for the preparation of derivatives of lower degree of methylation.

The partially methylated CDs resulting from the process according to the invention will be particularly useful for solubilizing in organic or aqueous media organic compounds which are insoluble or poorly soluble in these media in the form of inclusion complexes, or to dissolve by intermolecular interaction or by the combination of the two aforementioned effects. In fact, the partially methylated CDs obtained according to the invention are very suitable for the preparation of aqueous or organic solutions, or of medicinal, cosmetic, chemical, agro-food or other compositions. The inclusion complexes formed with partially methylated DCs according to the invention are also useful:

- In organic or aqueous media with a view in particular to improving the extraction of compounds by chemical or physical means (for example ultrafiltration), chemical reactivity, catalysis, sharing between immiscible phases; - or as an emulsifying agent or modifier of the physical state (amorphous, anti-aggregating, ...).

Molecules such as ethers such as tetrahydrofuran, chlorinated derivatives such as methylene chloride, alcohols such as ethanol or isopropanol or any other molecule having a good affinity with the CD cavity can be used as competitors.

The greater the competitor's affinity with the CD cavity, the more stable the inclusion complex and the smaller the amount of competitor necessary to avoid the foaming phenomenon. The quantity of competitor introduced into the reaction medium is such that the molar ratio of competitor to the CD is preferably at least equal to 1. In the case where the competitor is a compound immiscible with water, a proportion of competitor such as this does not cause the methylated derivatives to be subtracted from the aqueous phase by extraction during the reaction, which would have the effect of limiting the degree of methylation.

The competitor can be introduced, by successive or continuous additions:

- before the introduction of the methylating agent,

- or after the introduction of the methylating agent,

- and, at the latest, as soon as an abundant foam appears. The process according to the invention is more particularly useful for the methylation of

CD using dimethyl sulphate and a base when the reaction medium comprises non-negligible quantities of water.

Also, the process according to the invention is suitable for the methylation reaction when it is carried out directly on the CD salt: this reaction consists in reacting the CD with the alkali metal hydroxide, then drying the salt obtained, for example by atomization, finally react this salt directly with dimethyl sulfate. Despite the drying operation, there is often a small amount of water in the reaction medium which can cause hydrolysis of dimethyl sulfate. The water present in the reaction medium may also have been added to facilitate the progress of the methylation reaction. According to the invention, by the presence of the competitor, the loss of dimethyl sulfate is prevented by hydrolysis.

As indicated above, the base used in the process according to the invention is preferably an alkali metal hydroxide such as soda or potash. According to another preference, the process is carried out with a mass concentration of alkali metal hydroxide of between 30 and 50%. More preferably, a mass concentration of alkali metal hydroxide of between 30 and 35% is chosen to obtain an average methylation of at least two-thirds of the hydroxyl functions.

To obtain derivatives in which the degrees of methylation per unit of glucose are predominantly greater than or equal to 2, the amount of dimethyl sulfate is chosen to be greater than two thirds of the equivalent parts based on the hydroxyl functions of the CD. In the case of beta-CD, it is preferably chosen to be less than 105 equivalent parts based on the hydroxyl functions of the CD, and more preferably between 30 and 60 equivalent parts based on the hydroxyl functions of the CD.

Preferably, to facilitate the methylation reaction, in particular when the amount of dimethyl sulfate is greater than 70 equivalent parts based on the CD, an emulsifier is added to the reaction medium. As emulsifier, a partially methylated CD is advantageously chosen, and more preferably that which must be produced during methylation.

Advantageously, a molar ratio of dimethyl sulfate to the alkali metal hydroxide greater than 0.9 is provided. Preferably, this ratio is between 1 and 1, 1 (inclusive), and more preferably between 1 and 1.02 (inclusive).

The process according to the invention can be carried out between 0 and 60 ° C and, preferably, between 4 and 40 ° C. Below 4 ° C, the rate of methylation is reduced too much and dimethyl sulfate accumulates in the reaction mixture. More preferably, to limit the rate of hydrolysis of dimethyl and the consumption of significant quantities of this reagent by hydrolysis, the reaction temperature is maintained less than or equal to 10 ° C, and even better, between 5 and 8 ° C.

In accordance with a preferred embodiment of the process according to the invention, the methylation reaction of alpha-CD, beta-CD or gamma-CD is carried out under the following conditions:

- a competitor's molar ratio on CD at least equal to 1;

- A mass concentration of alkali metal hydroxide of between 30 and 50% and preferably between 30 and 35%; - an amount of dimethyl sulfate added gradually, greater than two thirds of the equivalent parts based on the hydroxyl functions of the CDs. In the case of methylation of beta-CD, this amount is preferably chosen to be less than 105 equivalent parts based on the hydroxyl functions of beta-CD, and preferably between 30 and 60 equivalent parts based on the hydroxyl functions of beta-CD;

- a molar ratio - dimethyl sulphate on alkali metal hydroxide - of between 0.9 and 1.1, preferably between 1 and 1.1 (inclusive), more preferably between 1 and 1.02 (inclusive);

- a reaction temperature below 10 ° C, which is preferably between 4 and 10 ° C, more preferably between 5 and 8 ° C;

Thanks to this preferred variant of the process according to the invention, partially methylated CD having a higher solubility in water are obtained than those of the known methyl derivatives of CD.

Another advantage of this preferred variant lies in the fact that it leads to a mixture whose composition has a relatively narrow distribution of derivatives of different molar mass.

In the following description, the abbreviation "PMCD" will denote the partially methylated CDs resulting from the process according to the invention. The isomers in molecular mass of which each PMCD is made up can be a homogeneous substitution corresponding to a regular distribution of the same number of methyl groups on each glucose unit or correspond to an uneven distribution, so that the CD nuclei are formed from unsubstituted glucose units and others substituted with one, two or three methyl groups.

Each PMCD is characterized by a narrow distribution of derivatives of different molecular mass which it comprises, by at most two spots when it is analyzed by thin layer chromatography on silica "G" using an eluent composed of a mixture of chloroform, methanol 90: 10 (V / V) and the fact that at least 40% of the derivatives constituting each PMCD, measured using a mass spectrometer in electrospray mode, have a predominantly equal degree of methylation at 2 per glucose unit.

When the methylation process according to the invention is carried out with unsalted CDs, the resulting PMCDs have a methylation rate of the hydroxyl functions varying from 68 to 72% depending on the operating conditions.

In the specific case of beta-CD, a distribution of the composition in derivatives containing from 11 to 21 substitutions is observed with a predominance of two derivatives so that at least 40% of the PMCD derivatives have a degree of methylation of 14, and At least 70% of the PMCD derivatives have a degree of methylation of 14 and 15 and at least 80% of the PMCD derivatives have a degree of methylation of 14, 15 or 16.

If higher degrees of methylation are desired, remethylation of the

Previous PMCD can be performed, for example, according to the procedure of Example 7. In the specific case of beta-CD, we then obtained PMCD including

At least 20% of the derivatives have a degree of methylation of 16, and at least 40% of the derivatives have a degree of methylation of 15 and 16.

The physico-chemical properties, and in particular the solubilizing effect of PMCDs of higher degrees of methylation thus obtained are close to the PMCDs resulting from the process according to the invention. This is why they can be advantageously used in the same industrial sectors as PMCD. Among the aforementioned PMCDs, the applicant has highlighted PMCDs resulting from the preferred embodiment of the method according to the invention (hereinafter designated PMCD ^ which have a high ability to make organic molecules little or not soluble in water. Water-soluble PMCD _! are characterized in that they have a degree of methylation of the hydroxyl groups from 73 to 78% for position 2, from 43 to 51% for position 3 and from 75 to 81% for position 6.

PMCD _! according to the invention are advantageous in more than one way:

- in particular, we have shown that the complexing capacity of PMCD ₁ derivatives ₍ methylated in more than 14 positions, appears to be higher than that of dimethyl-CD, for example in the case of phenylalanine (see Example 11).

- Their capacity to form inclusion complexes is higher than that of known partially methylated CDs such as the methylated CDs of French patent 2,484,252 in the complexation of hydrocortisone

(example 1, page 10 of this French patent).

- Their solubility in water is significantly improved by comparison with known products. It is indeed, at 22 ° C, of the order of 710 g / liter of solution (or 1500 g added to 1 liter of water) or even higher. In addition, the solubility of PMCDi according to the invention increases with temperature to reach values of at least 3000 g added to 1 liter of water at 70 ° C: this was demonstrated in Example 8, table I.

- PMCD _j are found to be very soluble in usual solvents, unlike native CDs or certain derivatives such as hydroxypropyl-CDs: this was notably demonstrated in Example 8, Table II.

The PMCDs according to the invention are identified:

- by mass spectrometry in electrospray ionization mode which makes it possible to define the distribution of the composition in derivatives of different molar mass and their rate of methylation. Mass spectrometry in mode of electrospray ionization is a recent technique in usual applications and the general operating conditions have been described in particular by:

- C.-K. Meng, C.N. Me Ewen, B.S. Larsen Rapid Commun. Mass Spec. 4 ^ 5 (1990) 147-150

- B. Ganem J. Am. Chem. Soc. 113 (1990) 6294-6296

- A. Van Dorsselaer, F. Bifsch, B. Green, S. Jarvis, P. Leparge, R. Bischoff, H.V. J. Kolbe, and C. Roitsch Biomed. About. Mass Spec. 19 (1990) 692-704. This technique, unlike the usual operating modes in mass spectrometry, makes it possible to avoid fragmentation: this gives access to molecular ions of fragile molecules of high mass. Under certain conditions, it is also possible to obtain multi-charged ions whose presence confirms the mass of the original mono-charged ions. As was shown very recently by J.W. Metzger, M. Jung. D. Schmatzing, E.

Bayer and V. Shurig Carbohydr. Res. 222 (1991) 23-35, this method makes it possible to obtain the molar mass distribution of the CD derivatives. The Applicant has applied this characterization method not only to define partially methylated CD but also, and this in an original way, to highlight the inclusion compounds obtained between partially methylated CD and model guest molecules such as dodecylamine, l hydrocortisone or phenylalanine. Dodecylamine reacts quantitatively with PMCD. The spectra obtained have excellent readability (without interference with traces of ions possibly present such as sodium ions). This feature was used to determine the distribution of the molar masses of PMCDs obtained by the process according to the invention. Furthermore, it has been shown that the inclusion is in no way limited to an optimum for derivatives having 14 methyl substituents (otherwise called dimethyl-CD), the compounds 15, 16 and 17 methyls having at least equal effectiveness in the case of dodecylamine and hydrocortisone and even greater in the case of phenylalanine.

- by their solubility in water, according to the "OECD Guidelines for the testing of chemicals", in the article "Solubility in water, flask method", reference n ° 105 of 12 May 1981.

- By measuring the methylation percentage of positions 2, 3 and 6 of each glucose unit according to the reductive cleavage method described in Example 15. It can be noted that a single spot is obtained by thin layer chromatography (mixture of chloroform eluent) , methanol 90:10 (V / V) when the composition of the final product does not contain derivatives of degree of substitution less than 2 per glucose unit, corresponding in the case of beta-CD to derivatives having at least 14 methyl substituents per molecule. Additional spots appear when derivatives having less than 14 methyl substituents per molecule are in sufficient proportions; thus, a second spot is observed when the mixture contains derivatives having 13 methyl substituents per molecule and a third and fourth spots are due. the presence of derivatives having respectively 12 and 11 methylated substituents per molecule. PMCD present in analysis thermal changes of state weak, variable according to the samples and of delicate interpretation. The decomposition of these mixtures, which generally occurs at high temperature, is much more satisfactory repeatability and justifies the characterization using thermogravimetry. The PMCDs produced by the method according to the invention have a decomposition temperature measured by TGA (Thermal Gravimetry Analysis, i.e. Gravimetric thermal analysis) of 375 ° C ± 10 ° C.

The invention will now be illustrated through:

- examples which follow, given by way of illustration and not limitation, and - Figures 1 to 9 and 12 to 14, representing the measurement of the compositions exemplified as derivatives of different molar mass by means of mass spectra in electrospray mode of the complexes of inclusion of dodecylamine in the PMCDs of Examples 1 to 9 and 12 to 14.

- Figure 10 corresponding to the mass spectrum in electrospray mode of the inclusion complex of dodecylamine in the PMCD of Example 7 (see text Example 11).

FIG. 11 corresponding to the mass spectrum in electrospray mode of the inclusion complex of phenylalanine in the PMCD of Example 8

(see text example 11).

Example 1

A suspension of 160 g of beta-CD (Ringdex-B, Ringdex) in 300 ml of water is added to a solution of 282 g of NaOH in 272 ml of water maintained at 10 ° C. After complete dissolution of the beta-CD, 40 ml of tetrahydrofuran (THF) are added. Then, 675 ml of dimethyl sulphate and 110 ml of THF are added in small fractions over a period of 8 to 10 hours. The temperature of the medium is strictly maintained at a temperature between 5 and 8 ° C throughout the duration of the addition. Then the reaction is allowed to take place at room temperature overnight. At the end of the reaction, the unreacted dimethyl sulfate is decomposed by the addition of 20 ml of 20% ammonia. After one hour, the pH of the medium is neutralized by the addition of an aqueous solution of hydrochloric acid. THF is evaporated in vacuo. 800 ml of water are then added and the solution is extracted twice with 500 ml of methylene chloride. The organic phase, washed with water and dried over anhydrous sodium sulfate, is evaporated to dryness. The residue taken up in water is treated with activated carbon at 80 ° C. under vacuum. After filtration, the product (166.5 g) is dried by atomization or lyophilization. The characteristics of the product obtained are as follows:

- The thin layer chromatography on silica of the product eluted with a chloroform, methanol 90: 10 mixture (V / V) gives only one spot (Rf = 0.63). - Rotary power at 25 ° C = + 158.5 ° (C = 10g / l, water).

- Solubility in water 20 ° C = 1420 g for 1 liter of water.

- Average degree of methylation = 70.5% (14.8 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 57.7% of the derivatives have 14 substitutions (M = 1331), 26% of the derivatives have

15 substitutions (M = 1345) and 8.1% have 16 substitutions (M = 1359); see figure 1.

- inclusion capacity: it is shown in FIG. 1 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 1:

• 1516.98 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1529.84 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl). • 1545.05 - peak M + 1 corresponding to the inclusion of dodecylamine

(M = 185) in the molar mass derivative 1359 (16 methyl).

Example 2

A suspension of 80 g of beta-CD (Ringdex-B, Ringdex) in 150 ml of water is added to a solution of 296 g of NaOH in 450 ml of water maintained at 10 ° C. After complete dissolution of the beta-CD, 150 ml of THF and 1.2 g of partially methylated beta-CD, such as that obtained in Example 1, are added. Then, 700 ml of dimethyl sulfate are added in small portions during a period of 8 to 10 hours while strictly maintaining the temperature of the medium at a temperature between 5 and 8 ° C. The reaction mixture is then treated as in Example 1. 73.8 g of product are obtained. The product characteristics are as follows: - The thin layer chromatography on silica of the product eluted with a chloroform, methanol 90:10 mixture (N / N) gives only one spot (Rf =

0.63).

- Rotary power at 25 ° C = + 157.5 ° (C = 10 g / 1, water).

- solubility in water, 20 ° C = 1520 g for 1 liter of water. - Average methylation rate = 71.6% (15 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 51.3% of the derivatives have 14 substitutions (M = 1331), 31.1% of the derivatives have 15 substitutions (M = 1345 ) and 8.7% have 16 substitutions (M = 1359); see figure 2. - inclusion capacity: it is shown in figure 2 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 2:

• 1515.74 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl). • 1529.46 - peak M corresponding to the inclusion of dodecylamine

(M = 185) in the derivative of molar mass 1345 (15 methyl).

• 1544.74 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1359 (16 methyl).

Example 3

A suspension of 80 g of beta-CD (Ringdex-B, Ringdex) in 150 ml of water is added to a solution of 220 g of ΝaOH in 296 ml of water maintained at 10 ° C. After complete dissolution of the beta -CD, 150 ml of THF and 1.0 g of partially methylated beta-CD such as that obtained in Example 1. Then, 505 ml of dimethyl sulphate are added in small fractions over a period of 8 to 10 hours while strictly maintaining the temperature of the medium at a temperature between 5 and 8 ° C. The reaction mixture is then treated as in Example 1. 70.0 g of product are obtained.

The product features are as follows:

- The thin layer chromatography on silica of the product eluted with a chloroform, methanol 90: 10 mixture (V / V) gives only one spot (Rf = 0.63).

- Rotary power at 25 ° C = + 158.7 ° (C = 10 g / 1, water).

- solubility in water at 20 ° C = 1690 g for 1 liter of water.

- Average methylation rate = 71% (14.9 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 58.1% of the derivatives have 14 substitutions (M = 1331), 27.8% of the derivatives have 15 substitutions (M = 1345 ) and 7% have 16 substitutions (M = 1359); see figure 3.

- inclusion capacity: it is shown in FIG. 3 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to Example 3:

• 1516.29 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1529.96 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl). • 1545.36 - peak M + 1 corresponding to the inclusion of dodecylamine

(M = 185) in the molar mass derivative 1359 (16 methyl). Example 4

A suspension of 40 g of beta-CD (Ringdex-B, Ringdex) in 75 ml of water is added to a solution of 70.5 g of NaOH in 68 ml of water maintained at 10 ° C. After complete dissolution of the beta-CD, 168 ml of dimethyl sulphate are added in small fractions over a period of 8 to 10 hours while strictly maintaining the temperature of the medium at a temperature of between 5 and 8 ° C. 5 ml of methylene chloride (CH2CI2) are added when an abundant foam appears. The reaction mixture is then treated as in Example 1. 38.4 g of product are obtained. The product features are as follows:

- The thin layer chromatography on silica of the product eluted with a chloroform, methanol 90: 10 mixture (V / V) gives two spots (Rf = 0.63 and 0.48).

- Rotary power at 25 ° C = + 163 ° (C = 10 g / 1, water).

- solubility in water at 20 ° C = 1610 g for 1 liter of water. - Average methylation rate = 69.2% (14.5 substituted hydroxyl functions) determined by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 57% of the derivatives have 14 substitutions (M = 1331), 15.9% of the derivatives have 15 substitutions (M = 1345) and 11.8% have 16 substitutions (M = 1359); see figure 4.

- inclusion capacity: it is shown in FIG. 4 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 4:

• 1516.84 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1530.78 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl).

• 1544.46 - peak M coπespondant to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1359 (16 methyl). Exe ple 5

A suspension of 80 g of beta-CD (Ringdex-B, Ringdex) in 100 ml of water is added to a solution of 82 g of NaOH in 65 ml of water maintained at 10 ° C. After complete dissolution of the beta-CD, 10 ml of THF are added. Then 193 ml of dimethyl sulphate and 40 ml of THF are added in small fractions over a period of 8 to 10 hours while strictly maintaining the temperature of the medium at a temperature between 5 and 8 ° C. The reaction mixture is then treated as in Example 1. 70.4 g of product are obtained. The product features are as follows:

- The thin layer chromatography on silica of the product eluted with a chloroform, ethanol mixture 90: 10 (V / V) gives two spots (Rf = 0.63 and 0.48).

- Rotary power at 25 ° C = + 161.0 ° (C = 10 g / 1, water).

- solubility in water at 20 ° C = 1500 g for 1 liter of water. ^" - Average methylation rate = 68.7% (14.4 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 66.8% of the derivatives have 14 substitutions (M = 1331), 21.4% of the derivatives have 15 substitutions (M = 1345) and 5.0% have 16 substitutions (M = 1359); see Figure 5.

- inclusion capacity: it is shown in FIG. 5 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to Example 5:

• 1516.79 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1530.76 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl).

• 1543.75 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1359 (16 methyl). Example 6

512 g of beta-CD (Ringdex-B, Ringdex) are slowly dissolved in an aqueous sodium hydroxide solution (336 g of NaOH in 1818 ml of water). The sodium salt of beta-CD (beta-CD-Na) is then recovered by spray drying (170 ° C). To a suspension containing 20 g of beta-CD-Na in 30 ml of THF, 30 ml of dimethyl sulfate are added. The mixture is left under stirring for 70 min. Two 2.5 ml fractions of water are then added at room temperature with stirring at 30 min intervals. The reaction mixture is then heated at 55 ° C for 15 min. Left for 1 hour at room temperature, it is then treated as in Example 1. 10.8 g of methyl derivative of beta-CD are obtained. The product features are as follows:

- The thin layer chromatography on silica of the product eluted with a chloroform, methanol 90: 10 mixture (N / V) gives several spots including two spots (Rf = 0.63 and 0.48).

- Rotary power at 25 ° C = + 156.5 ° (C = 10 g / 1, water).

- solubility in water at 20 ° C = 1490 g for 1 liter of water.

- Average methylation rate = 64.3% (13.5 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 29.5% of the derivatives have 14 substitutions (M = 1331), 6.9% of the derivatives have 15 substitutions (M = 1345 ) and 3.0% have 16 substitutions (M = 1359); see figure 6.

- inclusion capacity: it is shown in FIG. 6 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 6:

• 1474.93 - peak M 4- 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1289 (11 methyl). • 1488, 10 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1303 (12 methyl).

• 1502.20 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1317 (13 methyl). • 1515.86 - peak M corresponding to the inclusion of dodecylamine

(M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1530.21 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl).

Example 7

40 g of methyl beta-CD derivative from Example 5 and having several TLC spots are dissolved in a solution of 26 g of NaOH in 39 ml of water maintained at 10 ° C. Then, 60 ml of dimethyl sulphate and 30 ml of THF are added in small fractions over a period of approximately 2 hours while strictly maintaining the temperature of the medium at a temperature between 5 and 8 ° C. The reaction mixture is then treated as in Example 1. 33 g of product are obtained. The product characteristics are as follows: - The thin layer chromatography on silica of the product eluted with a chloroform, methanol mixture 90: 10 (V / V) gives only one spot (Rf = 0.63).

- Rotary power at 25 ° C = + 161.0 ° (C = 10 g / 1, water).

- solubility in water, at 20 ° C = 1440 g for 1 liter of water. - Average methylation rate = 77.1% (16.2 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 29.5% of the derivatives have 15 substitutions (M = 1345), 33.2% of the derivatives have 16 substitutions (M = 1359) and 16.2% have 17 substitutions (M = 1373); see figure 7. - inclusion capacity: it is shown in FIG. 7 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 7:

• 1516.17 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1531.44 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl). • 1543.87 - peak M corresponding to the inclusion of dodecylamine

(M = 185) in the molar mass derivative 1359 (16 methyl).

• 1557.91 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1373 (17 methyl).

• 1573.30 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1387 (18 methyl).

Example 8

A suspension of 40 g beta-CD (Ringdex-B, Ringdex) in 75 ml of water is added to a solution of 70.5 NaOH in 68 ml of water maintained at 10 ° C. After complete dissolution of the beta-CD, 168 ml of dimethyl sulphate are added in small fractions over a period of 8 to 9 hours while strictly maintaining the temperature of the medium at a temperature of between 5 and 8 ° C. 14 ml of isopropanol are poured into the medium as soon as the foam begins to appear. The reaction mixture is then treated as in Example 1, using ethyl acetate as the extraction solvent. 40.3 g of product are obtained. The product features are as follows:

- rotary power at 25 ° C = + 159 ° (C = 10 g / 1, water);

- solubility in water at 20 ° C = 1560 g for 1 liter of water.

- solubility in water as a function of temperature: as can be seen in table I below, it increases with temperature.

solubility in usual solvents (Table II):

Solvent Ethanol Acetone Chloroform Ethylene glycol

Solubility in g 65.7 71 45 37

PMCD / 100 g solution

average methylation rate = 71.6% (15 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the composition in derivatives of different molar mass is defined: 50.8% of the derivatives have 14 substitutions (M = 1331), 21.4% of the derivatives have 15 substitutions (M = 1345 ) and 11.8% have 16 substitutions (M = 1359); see figure 8. • inclusion capacity: it is shown in FIG. 8 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 8: • 1516.36 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1529.77 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl). • 1545.05 - peak M + 1 corresponding to the inclusion of dodecylamine

(M = 185) in the molar mass derivative 1359 (16 methyl).

Example 9

A suspension of 40 g of beta-CD (Ringdex-B, Ringdex) treated under the same conditions as Example 8 by substituting the 14 ml of isopropanol with 15 ml of ethanol gives 37.6 g of a product of which the characteristics are as follows:

- Rotating power = + 160 ° (c = 10 g / 1, water)

- solubility in water at 20 ° C = 1690 g for 1 liter of water.

- Average methylation rate = 70.7% (14.8 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the distribution of the derivative composition of different molar mass is defined: 54.8% of the derivatives have 14 substitutions (M = 1331), 25% of the derivatives have 15 substitutions (M = 1345) and 8.5% have 16 substitutions (M = 1359); see figure 9.

- inclusion capacity: it is shown in FIG. 9 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine (M = 185) by the PMCD prepared according to example 9:

• 1516.54 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl). • 1530.95 - peak M + 1 corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl).

• 1544.43 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1359 (16 methyl).

Example 10

According to a usual method well known to those skilled in the art, an inclusion complex is prepared from the PMCDs of Example 8 and hydrocortisone. The solubility of hydrocortisone was measured at 20 ° C. after stirring for 3 h in a solution containing the PMCDs prepared according to example 8. The results are collated in the following table:

An increase in the solubility of hydrocortisone is observed of approximately 53 times compared with its solubility in water in a solution of 100 g / liter of PMCD solution.

Example 11

Figures 10 and 11 show the ability of PMCDs prepared according to Examples 7 and 8 respectively, to form inclusion complexes. These are mass spectra in electrospray mode performed on the complex formed between these PMCDs and dodecylamine (Figure 10) and phenylalanine (Figure 11). The inclusion complexes were prepared by following a procedure well known to those skilled in the art. FIG. 10 shows, using the dodecylamine used as a “guest” model molecule, that the capacity for inclusion of dodecylamine by PMCDs prepared according to example 10 is not limited to dimethyl CD (derivatives with 14 substituents methylated) and that all the other compounds constituting the mixture participate with an efficiency at least equal to the complexation. It may be noted, moreover, that the complexation of dodecylamine is quantitative (almost total disappearance of the peaks corresponding to the free PMCDs situated between 1300 and 1400); this is consistent with the fact that dodecylamine is commonly used for the determination of cyclodextrins by potentiometry (D. Jezequel, University thesis. Pierre and Marie Curie University, 26.11.91).

Figure 11 shows the inclusion complex with phenylalanine (peaks 1497-1525) under conditions where PMCD is in excess (peaks 1325-1360). It is remarkable to note that the derivatives with a degree of substitution greater than 14 have a proportionally greater affinity for phenylalanine than dimethyl-CD. The massif centered around 1420 corresponds to the inclusion of a guest molecule phenylalanine in two molecules of PMCD (doubly charged ions).

Example 12

To a suspension of 232 g of beta-CD (Ringdex B, Ringdex) in 170 ml of water are added 409 g of NaOH in 30% solution and 110 g of NaOH in pellets. After complete dissolution of the beta-CD, 50 ml of dimethyl sulphate are added and then 35 ml of isopropanol 1 hour later. 518 ml of dimethyl sulphate are then added in small portions over a period of 4 hours while maintaining the temperature of the medium between 5 and 30 ° C. The reaction mixture is then left to react at room temperature overnight. At the end of the reaction, the unreacted dimethyl sulfate is decomposed by 50 ml of 20% ammonia. After 1 hour, the pH of the medium is neutralized by the addition of a 50% aqueous solution of sulfuric acid. The solution is extracted twice with 450 ml of ethyl acetate. The organic phase is washed with water and evaporated to dryness. The residue taken up in water is treated with activated carbon at 80 ° C. under vacuum. After filtration, the product (150 g) is dried by atomization or lyophilization. The characteristics of the product obtained are as follows:

- TLC: thin layer chromatography on silica of the product eluted with a chloroform: methanol mixture, 90:10 (v / v) gives two spots of Rf = 0.63 and 0.48. - Average degree of methylation = 67.9% (14.3 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the composition is defined as follows: 9.6% of the derivatives have 13 substituents (M = 1317), 63.5% of the derivatives have 14 substituents (M = 1331) and 20% derivatives have 15 substituents (M = 1345); see figure 12. - Decomposition temperature = 371 ° C.

- Inclusion capacity: it is shown in FIG. 12 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine by PMCD prepared according to example 12:

• 1502.15 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1317 (13 methyl).

• 1516.15 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1331 (14 methyl).

• 1530.15 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1345 (15 methyl).

EXAMPLE 13 Methylation of Alpha CD

To a suspension of 30 g of alpha-CD (Ringdex A, Ringdex) in 80 ml of water are added 40 g of NaOH in pellets. After complete dissolution of the alpha-CD, 7 ml of dimethyl sulphate are added, then 4 ml of isopropanol 1 hour later. 89 ml of dimethyl sulphate are then added in small fractions over a period of 8 to 10 hours, strictly keeping the temperature of the medium between 5 and 7.5 ° C. The reaction mixture is then left to react at room temperature overnight. At the end of the reaction, the dimethyl sulfate having not reacted is decomposed by 4 ml of 20% ammonia. After 1 hour, the pH of the medium is neutralized by the addition of a 50% aqueous solution of sulfuric acid. The solution is extracted 3 times with 50 ml of ethyl acetate. The organic phase is washed with water and evaporated to dryness. The residue taken up in water is treated with activated carbon at 80 ° C. under vacuum. After filtration, the product (23.5 g) is dried by atomization or lyophilization.

The characteristics of the product obtained are as follows:

- TLC: the thin layer chromatography on silica of the product eluted with a chloroform: methanol mixture, 90: 10 (v / v) gives only one spot of

Rf = 0.82.

- Average degree of methylation = 68.2% (12.7 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the composition is defined as follows: 5.8% of the derivatives have 12 substituents, 66.3% of the derivatives have 13 substituents, 21.9% of the derivatives have 14 substituents and 6, 0% of the derivatives have 15 substituents; see figure 13.

- Decomposition temperature = 373 ° C.

- Inclusion capacity: it is shown in FIG. 13 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine by PMCD prepared according to example 13:

• 1312.37 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1127 (11 methyl).

• 1326.37 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1141 (12 methyl). • 1340.31 - peak M corresponding to the inclusion of dodecylamine

(M = 185) in the derivative of molar mass 1155 (13 methyl). EXAMPLE 14 Methylation of Gamma-CD

To a suspension of 30 g of gamma-CD (Ringdex C, Ringdex) in 80 ml of water are added 40 g of NaOH in pellets. After complete dissolution of the gamma-CD, 5 ml of dimethyl sulphate are added and then 4 ml of isopropanol 1 hour later. 90 ml of dimethyl sulphate are then added in small fractions over a period of 8 to 10 hours, strictly keeping the temperature of the medium between 5 and 7.5 ° C. The reaction mixture is then left to react at room temperature overnight. At the end of the reaction, the unreacted dimethyl sulfate is decomposed with 4 ml of 20% ammonia. After 1 hour, the pH of the medium is neutralized by the addition of a 50% aqueous solution of sulfuric acid. The solution is extracted 3 times with 50 ml of ethyl acetate. The organic phase is washed with water and evaporated to dryness. The residue taken up in water is treated with activated carbon at 80 ° C. under vacuum. After filtration, the product (26.4 g) is dried by atomization or lyophilization.

The characteristics of the product obtained are as follows:

- TLC: the thin layer chromatography on silica of the product eluted with a chloroform: methanol mixture, 90:10 (v / v) gives only one spot of Rf = 0.79.

- Average methylation degree = 72.3% (17.3 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the composition is defined as follows: 27.2% of the derivatives have 16 substituents, 31.2% of the derivatives have 17 substituents, 19.8% of the derivatives have 18 substituents and 11, 6% of the derivatives have 19 substituents; see figure 13.

- Decomposition temperature = 365 ° C.

- Inclusion capacity: it is shown in FIG. 14 which represents a mass spectrum in electrospray mode of the inclusion complex of dodecylamine by PMCD prepared according to example 14: • 1705.83 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1521 (16 methyl).

• 1719.89 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1535 (17 methyl). • 1733.89 - peak M corresponding to the inclusion of dodecylamine

(M = 185) in the derivative of molar mass 1549 (18 methyl).

• 1747.83 - peak M corresponding to the inclusion of dodecylamine (M = 185) in the derivative of molar mass 1563 (19 methyl).

EXAMPLE 15 Methylation Position

Description of the reductive cleavage technique.

5.00 mg of PMCD from Example 8 is dissolved in a mixture containing

0.090 ml of CH ₂ C1 ₂ , 0.063 ml of triethylamine and 0.040 ml of trimethylsilyl trifluoromethanesulfonate and left to react at room temperature for 16 hours. The medium is then concentrated by evaporation under a stream of nitrogen without heating. The residue is taken up in a mixture of 0.25 ml of pyridine and 0.25 ml of bis (trimethylsilyl) -trifluoroacetamide containing 1% of trimethyl-chlorosilane and heated at 70 ° C. for 1 h 30 min. After reaction, the mixture is left at room temperature for 30 min. 0.5 ml of hexane are then added to the solution.

All of these reactions must be carried out in the absence of moisture. This is why, the preparation of the sample is carried out in a bottle set with 2 ml and the reagents withdrawn with syringes are introduced through the septum. The analysis conditions are as follows: injection of 1 microliter of the preceding solution on a capillary column of gas chromatography, the characteristics of which are as follows: length 30 meters, diameter 0.32 mm, phase 5% diphenyl, 80% dimethylpolysiloxane. The temperature conditions are: 200 ° C injector, 240 ° C detector, 120 ° C oven for 5 minutes and then a temperature rise of 5 ° C per minute to 200 ° C. The different peaks obtained were identified by mass spectrometry in electronic impact and chemical ionization mode and correspond to the glucose units tri-substituted in 2, 3, 6, di-substituted in 2, 6 and 3, 6, and mono-substituted in position 6 and 2.

From the integration of the different peaks, we can define methylation percentages for each position. We obtain, for a PMCD from Example 8:

- position 2 = 75.50% ± 2.50

- position 3 = 47.00% ± 4.00

- position 6 = 78.00% ± 3.00

Example 16

To 10.3 g of beta-CD (Ringdex B, Ringdex) dissolved in 45 ml of 40% NaOH are added 43.5 ml of dimethyl sulphate in small fractions while maintaining the temperature of the medium between 25 and 40 ° C. After pouring 15 ml of dimethyl sulphate, a rigid foam appears and the temperature of the reaction mixture rises to 40 ° C., which makes it necessary to drastically slow down the addition of dimethyl sulphate which then requires a period of 20 hours. The reaction mixture is then left to react at room temperature overnight. At the end of the reaction, the unreacted dimethyl sulfate is decomposed by the addition of 120 ml of 20% ammonia for 6 hours. The medium is then neutralized. The solution is extracted twice with 200 ml of chloroform. The organic phase is washed with water and evaporated to dryness. The residue taken up in water is dried by lyophilization (13 g). The characteristics of the product obtained are as follows: - TLC: four spots (Rf = 0.63; 0.48; 0.34; 0.23). - Average methylation degree = 67.1% (14.1 substituted hydroxyl functions); by mass spectrometry in electrospray mode, the composition is defined as follows: 1.3% of the derivatives have 11 substituents, 4.4% of the derivatives have 12 substituents, 15.5% of the derivatives have 13 substituents, 49, 2% of the derivatives have 14 substituents, 21.9% of the derivatives have 15 substituents, 5.3% of the derivatives have 16 substituents, 1.7% of the derivatives have 17 substituents and 0.5% of the derivatives have 18 substituents.

Claims

1 / Process for the preparation of partially methylated cyclodextrins in an aqueous medium from a cyclodextrin such as alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin or a salt of these cyclodextrins, which are reacted with dimethyl sulphate and a base, preferably an alkali metal hydroxide, characterized in that the methylation reaction is carried out in the presence also of at least one substance having an affinity with the cavity of the cyclodextrins such as a complex of inclusion with said substance may be formed during the methylation reaction.

2 / A method according to claim 1, characterized in that the substance having an affinity with the cavity of the cyclodextrins (or competitor) is chosen from ethers such as tetrahydrofuran, chlorinated derivatives such as methylene chloride, alcohols such as ethanol or isopropanol or any other molecule having a good affinity with the cyclodextrin cavity.

3 / A method according to claim 1 or 2, characterized in that the molar ratio of competitor on the cyclodextrin is at least equal to 1.

4 / Method according to one of claims 1 to 3, characterized in that an alkali metal hydroxide is used as the base.

5 / A method according to claim 4, characterized in that a mass concentration of alkali metal hydroxide of between 30 and 50% is used. 6 / A method according to claim 5, characterized in that a mass concentration of alkali metal hydroxide of between 30 and 35% is used.

11 Method according to one of claims 1 to 6, characterized in that the amount of dimethyl sulfate is greater than two thirds of the equivalent parts based on the hydroxyl functions of the cyclodextrin.

8 / A method according to one of claims 1 to 7, characterized in that the molar ratio of dimethyl sulfate on the alkali metal hydroxide is greater than 0.9.

9 / A method according to claim 8, characterized in that the molar ratio of dimethyl sulfate on the alkali metal hydroxide is between 1 and 1.1 (inclusive).

10 / A method according to claim 9, characterized in that the molar ratio of dimethyl sulfate to the alkali metal hydroxide is between 1 and 1.02 (inclusive).

11 / Method according to one of claims 1 to 10, characterized in that the reaction temperature is between 0 and 60 ° C.

12 / A method according to claim 11, characterized in that the reaction temperature is between 4 and 40 ° C.

13 / A method according to claim 12, characterized in that the reaction temperature is between 4 and 10 ° C. 4 / A method according to claim 13, characterized in that the reaction temperature is between 5 and 8 ° C.

5 / Method according to one of claims 1 to 4, characterized in that the methylation reaction of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or a salt of these cyclodextrins is set in works under the following conditions:

- a competitor's molar ratio on CD at least equal to 1;

- A mass concentration of alkali metal hydroxide of between 30 and 50% and preferably between 30 and 35%;

- an amount of dimethyl sulfate added gradually, greater than two thirds of the equivalent parts based on the hydroxyl functions of the cyclodextrin or its salt;

- A molar ratio - dimethyl sulphate on alkali metal hydroxide- of between 0.9 and 1.1, preferably between 1 and 1.1, more preferably between 1.0 and 1.02;

- A reaction temperature below 10 ° C, preferably between 4 and 10 ° C, more preferably between 5 and 8 ° C.

16 / A method according to one of claims 1 to 15 characterized in that the amount of dimethyl sulfate is chosen to be less than 105 equivalent parts based on the hydroxyl functions of cyclodextrin, when the latter is beta-cyclodextrin.

17 / A method according to claim 16, characterized in that the amount of dimethyl sulfate is between 30 and 60 equivalent parts based on the hydroxyl functions of beta-cyclodextrin. 18 / A method according to one of claims 1 to 17, characterized in that the partially methylated cyclodextrins, obtained at the end of the methylation reaction according to claims 1 to 16, are again subjected to a methylation reaction in order to d '' obtain partially or fully methylated cyclodextrins having a higher degree of methylation.

19 / Partially methylated cyclodextrins obtained by the process according to one of claims 1 to 18.

20 / Partially methylated cyclodextrins (PMCD _j ) characterized in that they have a degree of methylation of the hydroxyl groups of:

- 73 to 78% for position 2,

- 43 to 51% for position 3,

- 75 to 81% for position 6.

21 / Partially methylated beta-cyclodextrins characterized in that they are composed of at least 20% of PMCD derivatives having an average degree of methylation of 16 and 40% at least of PMCD derivatives having an average degree of methylation of 15 and 16.

22 / Inclusion complexes soluble in water of organic compounds insoluble or poorly soluble in water with partially methylated cyclodextrins, obtained by means of the process according to one of claims 1 to 18 or defined in claims 20 and 21 .

23 / Aqueous solutions of inclusion complexes soluble in water according to claim 22. / Inclusion complexes soluble in organic medium formed from organic compounds and partially methylated cyclodextrins obtained by means of the process according to one of claims 1 to 18 or defined in claims 20 and 21.

/ Organic solutions of inclusion complexes according to claim 24.

/ Medicinal, cosmetic, chemical, food-processing or other preparations, characterized in that they contain soluble inclusion complexes in aqueous or organic media according to claim 22.

/ Application of partially methylated cyclodextrins obtained by the process according to one of claims 1 to 18 or in accordance with claims 20 and 21 in organic or aqueous media:

- to improve:

- the extraction of compounds by chemical or physical means;

- chemical reactivity;

- catalysis; - sharing between immiscible phases;

- or as an emulsifying agent.