CN110590973B

CN110590973B - Cyclodextrin derivatives and process for producing the same

Info

Publication number: CN110590973B
Application number: CN201911032672.XA
Authority: CN
Inventors: 王计奎
Original assignee: Huaibei Yunduan Culture Media Co ltd
Current assignee: Huaibei yunduan culture media Co.,Ltd.
Priority date: 2019-10-28
Filing date: 2019-10-28
Publication date: 2021-11-05
Anticipated expiration: 2039-10-28
Also published as: CN110590973A

Abstract

Discloses a cyclodextrin derivative and a preparation method thereof, wherein the structural formula of the derivative is shown as a formula 2. In addition, a preparation method of the cyclodextrin derivative is also disclosed, and the method comprises the following steps: obtaining a compound of formula 1; reacting the compound of formula 1 with (R) - β -methyl- γ -butyrolactone in the presence of a base and a solvent. The cyclodextrin derivative can be used as a phase transfer catalyst for catalyzing asymmetric synthesis reaction of amygdalic acid, and has the advantages of mild reaction conditions, strong stereoselectivity and high yield.

Description

Cyclodextrin derivatives and process for producing the same

Technical Field

The invention belongs to the technical field of organic compounds, relates to a cyclodextrin derivative and a preparation method thereof, and particularly relates to a beta-cyclodextrin derivative and a preparation method thereof.

Background

Cyclodextrin is a product obtained by degrading amylose under the action of cyclodextrin glucosyltransferase, and is formed by cyclic connection of a plurality of D-glucopyranose units, which is also called as cyclopolyglucose. Has the characteristics of external hydrophilicity and internal hydrophobicity. This leads to the extensive use of betacyclodextrin in the fields of drug stability enhancement, solubility enhancement, bioavailability improvement, toxic side effects reduction, chiral resolution, complex catalysis and the like.

Over the last two thirty years, cyclodextrins have been used as simple organic macromolecules, forming host-guest inclusion complexes through intermolecular interactions with a wide variety of substances. The properties are widely applied to various fields such as bionic chemistry, catalysis, organic synthesis and the like. In addition, cyclodextrins also have broad application prospects in the solubilization, modification and molecular packaging of drugs, flavors and flavoring agents. Among the cyclodextrin family, the most common cyclodextrins are alpha, beta and gamma cyclodextrins, corresponding to 6-8D-glucopyranose units, respectively.

Taking beta-cyclodextrin as an example, seven glucopyranose units are connected to form a cone-cylinder structure, the C1 carbon atom on the D-glucopyranose unit of the beta-cyclodextrin is connected with the C4 carbon atom on the adjacent D-glucopyranose unit end to end through alpha-glycosidic bond, and the C2, C3 and C6 carbon atoms all have hydroxyl groups. Except that the hydroxyl group on the carbon atom of C6 is a primary hydroxyl group, and the hydroxyl groups on the carbon atoms of C2 and C3 are secondary hydroxyl groups.

The cyclodextrin molecule structure is not easy to deform and has good rigidity due to the hydrogen bond band formed in the molecule, and organic reactants and the like can be included in the hydrophobic cavity, so that the solubility of the cyclodextrin molecule in water is changed, and the reaction environment of the molecule can be influenced through charge action and space effect. In recent years it has been found that cyclodextrins and their derivatives have a preferred effect in the regioselective and stereoselective invention in promoting organic reactions. In the reactions, cyclodextrin and derivatives thereof are often used as phase transfer catalysts and applied to organic reactions in a water phase, but the cyclodextrin is limited in application due to poor solubility in organic solvents, limited hydrophobic regions and catalytic activity.

As typical reactions of regioselectivity and stereoselectivity, the synthesis and resolution of mandelic acid are organic reactions of great interest. The optical active mandelic acid has good biological decomposability and is an important intermediate for synthesizing a plurality of chiral drugs. For example, R-mandelic acid is used as side chain modifier of cephalosporin series antibiotic hydroxybenzyltetrazole. In addition, chiral mandelic acid is an important racemate resolution reagent.

However, at present, chemical resolution is still used as the main means for preparing chiral mandelic acid in industry, but due to the high price of resolution reagent or the need of multiple recrystallization to obtain chiral mandelic acid with high optical purity, the production cost is high, and the wide application of chiral mandelic acid in pharmaceutical industry is limited.

To alter this situation, Guaitong et al (journal of the Chinese pharmaceutical industry, 2007,38(7), P484-488) studied the biological asymmetric catalysis of the synthesis of (R) -mandelic acid from phenylacetic acid. The original strain candida ca.3 with high conversion activity to the substrate acetophenone acid is obtained by primary screening of 38 strains. Further ultraviolet and microwave mutagenesis to obtain mutant strain Ca.3.37.48 with high conversion rate and high enantioselectivity. In the transformation culture, the conditions of initial substrate concentration of 30mmol/L, pH 7.0.0 and temperature of 32 ℃ were selected, the yield of (R) -mandelic acid was 86.5%, and the enantiomeric excess was 99.5%. The reaction has the characteristics of mild reaction conditions, strong stereoselectivity and less pollution, but the problems that how to extract the single enantiomer with single activity, select and breed efficient and specific microbial strains and improve the self stability of the microbial strains are all urgently needed to be solved at present.

Schoenkle et al (Liaoning chemical engineering, 2007,36(2), P78-79) selectively synthesize o-hydroxyacetophenone through Fries rearrangement reaction by utilizing the enveloping effect of beta-cyclodextrin on a substrate. The experimental result shows that the selectivity of the rearrangement reaction can be improved by adding the beta-cyclodextrin, so that the yield of the o-hydroxyacetophenone reaches 44.6 percent. However, the catalytic reaction of β -cyclodextrin described above achieves high regioselectivity, but the reaction stereoselectivity is poor, being essentially a racemic mixture. In addition, the yield of the reaction is not high.

Therefore, a synthesis method with strong stereoselectivity and high yield is urgently needed to be found.

Disclosure of Invention

The invention aims to provide a cyclodextrin derivative and a preparation method thereof, the cyclodextrin derivative can be used as a phase transfer catalyst for catalyzing asymmetric synthesis reaction of amygdalic acid, the reaction condition is mild, the stereoselectivity is strong, and the yield is high.

In one aspect, the present invention provides a cyclodextrin derivative having the formula:

wherein n is 6-8.

The cyclodextrin derivative according to the present invention, wherein n is 6.

The cyclodextrin derivative according to the present invention, wherein n is 7.

The cyclodextrin derivative according to the present invention, wherein n is 8.

In a specific embodiment, in the case where n ═ 7, the structural formula of the cyclodextrin derivative is as follows:

in another aspect, the present invention provides a method for preparing the above cyclodextrin derivative, which comprises: obtaining the compound of formula 1

Reacting the compound of formula 1 with (R) - β -methyl- γ -butyrolactone in the presence of a base and a solvent.

The process according to the invention, wherein the compound of formula 1 is obtained by a process as described in Carbohydrate Research,187, (1989), 203-221 of Kenichi Takeo.

The preparation method of the invention, wherein n is 7. The starting material was identified as n-7 in inventive example 1.

The preparation method of the invention, wherein the alkali is NaH.

The preparation method of the invention, wherein the solvent is DMF.

The preparation method provided by the invention is characterized in that the reaction temperature is 70-80 ℃.

The preparation method provided by the invention is characterized in that the reaction time is 36-96 h.

The inventor finds that when the cyclodextrin derivative obtained according to the invention and the quaternary ammonium salt are used according to a certain proportion, the cyclodextrin derivative is used for catalyzing asymmetric synthesis reaction of the amygdalic acid, the reaction condition is mild, the stereoselectivity is strong, the amygdalic acid mainly comprising (R) -amygdalic acid is mainly obtained, and the yield is high. That is, the present invention further provides the use of the above cyclodextrin derivative for catalyzing an asymmetric synthesis reaction of mandelic acid.

Without wishing to be bound by any theory, the cyclodextrin derivatives of the invention, in addition to providing a hydrophobic cavity, also provide a negatively charged stereoselective inductive group at position C6, which can form an inclusion complex with quaternary ammonium salts or be attracted together by charge interactions, which in turn stabilize with chloroform by electrostatic interactions, which effects favor the formation of (R) -amygdalic acid, resulting in a product with high stereoselectivity and, at the same time, higher yields.

The materials, compounds, compositions and components of the present invention may be used in, or may be used in combination with, the methods and compositions of the present invention, or may be used in the practice of the methods and in the preparation of the compositions, or as products resulting from the methods. It is to be understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each and every collective combination and permutation of these compounds may not be explicitly made, each is specifically contemplated and described herein. For example, if an extraction aid component is disclosed and discussed, and a number of alternative solid state forms of that component are discussed, each and every combination and permutation of the possible reference aid components and solid state forms is specifically contemplated unless specifically indicated to the contrary. This concept applies to all aspects of the invention, including but not limited to steps in methods of making and using the disclosed compositions. Thus, if there are a plurality of additional steps that can be performed it is understood that each of these additional steps can be performed by any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:

it must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include both one and more than one (i.e., two, including two) unless the context clearly dictates otherwise. Thus, for example, reference to "the base" can include a single base, or a mixture of two or more bases, and the like.

Unless otherwise indicated, the numerical ranges in this disclosure are approximate and thus may include values outside of the stated ranges. The numerical ranges may be stated herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the numerical ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

Reference in the specification and concluding claims to parts by weight of a particular element or component in a composition or article refers to the weight relationship between that element or component and any other elements or components in the composition or article, expressed as parts by weight.

Unless specifically indicated to the contrary, or implied by the context or customary practice in the art, all parts and percentages referred to herein are by weight and the weight percentages of a component are based on the total weight of the composition or product in which it is included.

References to "comprising," "including," "having," and similar terms in this specification are not intended to exclude the presence of any optional components, steps or procedures, whether or not any optional components, steps or procedures are specifically disclosed. In order to avoid any doubt, all methods claimed through use of the term "comprising" may include one or more additional steps, apparatus parts or components and/or materials unless stated to the contrary. In contrast, the term "consisting of … …" excludes any component, step, or procedure not specifically recited or recited. Unless otherwise specified, the term "or" refers to the listed members individually as well as in any combination.

Furthermore, the contents of any referenced patent or non-patent document in this application are incorporated by reference in their entirety, especially with respect to definitions disclosed in the art (where not inconsistent with any definitions specifically provided herein) and general knowledge.

Detailed Description

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and/or methods described and claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for.

Unless otherwise indicated, parts are parts by weight, temperatures are in degrees Celsius or at ambient temperature, and pressures are at or near atmospheric. There are many variations and combinations of reaction conditions (e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges) and conditions that can be used to optimize the purity and yield of the product obtained by the process. Only reasonable routine experimentation will be required to optimize such process conditions.

Example 1

12.5g of Compound 1(5.21mmol) are added to 500mL of anhydrous NMF under nitrogen.

3.50g NaH (0.145mol) was added and stirred for 3 hours. To the reaction mixture was added 0.55g NaI (3.6mmol), followed by dropwise addition via syringe of a solution of (R) - β -methyl- γ -butyrolactone (11g, 109.6mmol) dissolved in DMF. Heat to 75 ℃ and stir for 48 h. Excess NaH was degraded by slow addition of methanol. The solvent was removed by rotary evaporation under reduced pressure and the resulting brown solid was dried in vacuo. Ultrafiltering with MWCO 1000 filter membrane, and concentrating to obtain brown solidDrying in vacuum. Washed 3 times with dry acetone to give compound 2 as an off-white solid (3.6g, 69%).¹H NMR(600MHz,d6-DMSO):6.9-7.3(7*10H),5.12(d,7*1H),4.94(d,7*1H),4.59(d,7*1H),4.52(d,7*1H),4.43(d,7*1H),3.72-4.03(m,7*4H),3.2-3.5(m,7*4H),2.13(m,7*2H),1.54(t,7*1H),1.02(m,7*3H).¹³C NMR(150MHz,d6-DMSO):178.2,138.9,137.2,129.4,129.5,129.1,128.2,98.1,97.8,81.4,79.2,78.6,75.5,73.4,72.1,52.5,27.9,20.6,12.4.

Examples 2-1 to 2-5

4.3g of chloroform, 0.025mol of benzaldehyde, the dispersion/solution of the cyclodextrin derivative (compound 2) in the amount shown in Table 1 and a quaternary ammonium salt were precisely weighed, charged into a three-necked flask equipped with a magnetic stirrer, a dropping funnel and a thermometer, and mixed well. Stirring at 50 deg.C for 15 min. Then, 8mL of an aqueous solution containing 5g of sodium hydroxide was added dropwise from a dropping funnel to carry out the reaction with continuous stirring. After the addition, the temperature is maintained at 50 ℃ for continuous reaction for 8h, and after the reaction is finished, a proper amount of water is added to dissolve the precipitate formed by the reaction. The solution was adjusted to pH 3 with 1M dilute hydrochloric acid and then extracted 3 times with 20mL of diethyl ether. Combining the extracts, drying with anhydrous sodium sulfate, volatilizing to dryness, analyzing the residual precipitate with high performance chromatography, and separating with column chromatography on silica gel with acetone/petroleum ether (boiling range 60-90 deg.C) at volume ratio of 1:2 as eluent to obtain (R) -amygdalic acid as main component and benzoic acid as impurity.

The reaction yield was determined by HPLC, and the chromatographic conditions were as follows: column Varian C18 column (4.6 mm. times.250 mm, 5 μm); mobile phase 50mmol/L phosphate buffer-methanol (90: 10); the detection wavelength is 226 nm; the flow rate is 1 ml/min; the column temperature was 25 ℃.

Enantiomeric excess was determined according to the method of Guotai apple et al (journal of the Chinese pharmaceutical industry, 2007,38(7), P484-488).

TABLE 1

Comparative examples C1 and C2

Replacement of compound 2 in examples 2-1 and 2-2 with β -cyclodextrin and compound 1, respectively, gave comparative examples C1 and C2, respectively. The results are shown in Table 2.

TABLE 2

As can be seen from tables 1 and 2, when the cyclodextrin derivative obtained according to the present invention and the quaternary ammonium salt are used in a certain ratio, the reaction conditions are mild, the stereoselectivity is strong, the amygdalic acid mainly comprising (R) -amygdalic acid is mainly obtained, and the yield is high.

According to the invention, through the structural improvement of cyclodextrin, especially the combined use of cyclodextrin and quaternary ammonium salt, the stereoselectivity and yield of the asymmetric synthesis reaction of (R) -amygdalic acid are unexpectedly improved; the fact that the cyclodextrin derivatives used according to the invention produce a synergistic effect with quaternary ammonium salts is also well demonstrated in the examples in comparison with comparative examples C1 and C2.

Various modifications and variations can be made in the compounds, compositions, and methods described herein. Other aspects of the compounds, compositions, and methods described herein will be apparent from consideration of the specification and practice of the disclosed compounds, compositions, and methods. It is intended that the specification and examples be considered as exemplary.

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims

1. A cyclodextrin derivative having the formula:

formula 2;

wherein n = 6-8.

2. The cyclodextrin derivative of claim 1, wherein n = 6.

3. The cyclodextrin derivative of claim 1, wherein n = 7.

4. The cyclodextrin derivative of claim 1, wherein n = 8.

5. A process for preparing a cyclodextrin derivative of any one of claims 1-4, comprising: obtaining the compound of formula 1

Formula 1;

6. The method of claim 5, wherein n = 7.

7. The method of claim 5, wherein the base is NaH.

8. The method of claim 5, wherein the solvent is NMF.

9. The production method according to claim 5, wherein the reaction temperature of the reaction is 70 to 80 ℃.

10. The method of claim 5, wherein the reaction time is 36-96 h.