CN108034012A - The synthetic method of the Bifunctionalized beta cyclodextrin derivative of 6A, 6D- - Google Patents

Abstract

The invention discloses a synthesis method of 6A, 6D-difunctionalized β-cyclodextrin derivatives, which comprises the following steps: 1) in anhydrous DMF, in the presence of NaH, 6A, 6D-dideoxy-6A, 6D-diiodo-β-cyclodextrin (1) reacts with 1-thioper-O-acetyl-β-D-galactose by stirring; 2) removes the solvent, and then treats it with NaOMe to obtain β-cyclodextrin Derivatives (2). The present invention provides a synthesis method of galactosyl and lactosyl-modified galactosyl and lactosyl-modified 6A, 6D-bifunctionalized β-cyclodextrin derivatives. The method is simple and easy to operate and has high yield. Lactosyl and lactosyl-modified 6A, 6D‑difunctionalized β-cyclodextrin derivatives are used as drug carriers, which can improve the targeting ability, solubility and stability of liver cancer drugs, and have potential application value.

Description

Synthesis of 6A, 6D-bifunctionalized β-cyclodextrin derivatives

technical field

The present invention relates to the technical field of carbohydrate synthesis, and relates to a method for synthesizing conjugated 6A, 6D-difunctionalized β-cyclodextrin derivatives, more specifically, to the synthesis of 6A-galactosyl-6D-lactosyl-β-cyclodextrin resolve resolution.

Background technique

At present, during chemotherapy, there is a problem of non-specific targeting of tumors in tumor therapy, which is caused by poor response of patients to chemotherapy regimens and severe systemic toxicity. The main reason for this result is due to the low therapeutic index of these drugs and also due to the low bioavailability of the drugs in tumor cells. Therefore, it is necessary to find ways to increase the tumor-targeting ability of anticancer drugs, improve their absorption and transport mode and stability in vivo, and reduce systemic adverse reactions while improving their effectiveness. Usually these goals are achieved by conjugating the drug to the carrier by physical or chemical methods.

The main purpose of designing and synthesizing drug carriers targeting cancer cells is to improve the systemic water solubility and stability of drugs, thereby improving the efficacy and safety of cancer drugs. Cyclodextrins - cyclic carbohydrates with a hydrophilic outer surface and a lipophilic cavity, are water soluble and biocompatible, and are well documented for their use as drug carriers. Their intrinsic ability to incorporate drug molecules into their hydrophobic cavities through non-covalent interactions has aroused a great research boom in the field of targeted drug delivery. When a drug is partially or fully contained in the host lumen as a guest molecule, an clathrate is usually formed, a property that helps improve drug solubility in aqueous media and reduces drug exposure to in the degradation mechanism.

Linear oligosaccharides are involved in many remarkable physiological and pathological recognition phenomena on cell membrane surfaces, such as cell-cell interactions, cell-bacteria or cell-virus adhesion, cell proliferation or cell differentiation. D-galactose has a high affinity for lectins and galactose receptors (asialoglycoprotein receptors) present on hepatocytes. It is expected that if galactose-related oligosaccharide moieties are chemically linked to β-cyclodextrin and the resulting compound is used as a drug carrier targeting liver cancer cells, then these linked molecules can further increase the targeting efficacy, water solubility and stability of the drug.

Monofunctionalized cyclodextrin derivatives have been widely studied as potential drug carriers for cancer therapy, and various hydrophilic and hydrophobic ionic cyclodextrin derivatives have been developed and utilized as drug carriers to improve the efficacy of drugs. However, there are no related reports on the use of modified double-conjugated β-cyclodextrins as site carriers.

Therefore, it is necessary to find more efficient methods for the synthesis of 6A,6D-difunctionalized β-cyclodextrin derivatives.

Contents of the invention

The purpose of the present invention is to provide a synthesis method of 6A, 6D-bifunctionalized β-cyclodextrin derivatives modified by galactosyl and lactosyl groups. The method is simple and easy to operate, and the yield is high. The 6A, 6D-bifunctional The β-cyclodextrin derivatives are used as drug carriers, which can improve the targeting ability, solubility and stability of liver cancer drugs.

In order to solve the above-mentioned technical problems, the technical solution adopted in the present invention is: a method for synthesizing 6A, 6D-difunctionalized β-cyclodextrin derivatives, comprising the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose carries out stirring reaction;

2) Removal of the solvent, followed by treatment with NaOMe to obtain the β-cyclodextrin derivative (2).

Preferably, the equivalent ratio of 6A, 6D-dideoxy-6A, 6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1: 1-3:1-3:0.5.

More preferably, the equivalent ratio of 6A, 6D-dideoxy-6A, 6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1 :2.5:2.5:0.5.

Preferably, in step 1), the stirring speed of the stirring reaction is 100-300r/min, and the stirring time is 1.5-4h. More preferably, in step 1), the stirring speed of the stirring reaction is 250r/min, and the stirring time is 2h.

Preferably, in step 2), the temperature of NaOMe treatment is 20-30°C, and the treatment time is 2-3h. More preferably, in step 2), the temperature of NaOMe treatment is 25°C, and the treatment time is 2.5h.

Preferably, the yield of the β-cyclodextrin derivative (2) is 68-75%.

The beneficial effects of the present invention are: the present invention provides a synthesis method of galactosyl and lactosyl-modified galactosyl and lactosyl-modified 6A, 6D-bifunctionalized β-cyclodextrin derivatives, which is simple and easy to operate, The yield is high, and the 6A, 6D-bifunctionalized β-cyclodextrin derivative modified by galactosyl and lactosyl is used as a drug carrier, which can improve the targeting ability, solubility and stability of liver cancer drugs, and has potential applications value.

Detailed ways

The synthesis method of the 6A, 6D-difunctionalized β-cyclodextrin derivative of the present invention mainly follows the following equation:

Example 1

6A, the synthetic method of 6D-difunctionalization β-cyclodextrin derivative, comprises the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose was stirred and reacted, wherein, the stirring speed of the stirring reaction was 100r/min, and the stirring time was 4h;

2) The solvent was removed, and then treated with NaOMe at 20° C. for 3 h to obtain the β-cyclodextrin derivative (2) in a yield of 68%.

Among them, the mass ratio of 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1:1 :2.5:0.5.

Example 2

6A, the synthetic method of 6D-difunctionalization β-cyclodextrin derivative, comprises the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose was stirred and reacted, wherein, the stirring speed of the stirring reaction was 150r/min, and the stirring time was 3h;

2) The solvent was removed, and then treated with NaOMe at 23° C. for 2 h to obtain the β-cyclodextrin derivative (2) in a yield of 70%.

Among them, the equivalent ratio of 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1:2 :2.5:0.5.

Example 3

6A, the synthetic method of 6D-difunctionalization β-cyclodextrin derivative, comprises the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose was stirred and reacted, wherein, the stirring speed of the stirring reaction was 200r/min, and the stirring time was 2h;

2) The solvent was removed, and then treated with NaOMe at 30° C. for 2 h to obtain the β-cyclodextrin derivative (2) in a yield of 75%.

Among them, the equivalent ratio of 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1:2.5 :2.5:0.5.

Example 4

6A, the synthetic method of 6D-difunctionalization β-cyclodextrin derivative, comprises the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose was stirred and reacted, wherein, the stirring speed of the stirring reaction was 250r/min, and the stirring time was 1.5h;

2) The solvent was removed, and then treated with NaOMe at 30° C. for 3 h to obtain the β-cyclodextrin derivative (2) in a yield of 72%.

Among them, the equivalent ratio of 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1:2 :2:0.5.

Example 5

6A, the synthetic method of 6D-difunctionalization β-cyclodextrin derivative, comprises the following steps:

1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose was stirred and reacted, wherein, the stirring speed of the stirring reaction was 300r/min, and the stirring time was 1.5h;

2) The solvent was removed, and then treated with NaOMe at 30° C. for 3 h to obtain the β-cyclodextrin derivative (2) in a yield of 73%.

Among them, the equivalent ratio of 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β-D-galactose and NaOMe is 1:3 :3:0.5.

Claims (6)

1. a 6A, a synthetic method of 6D-bifunctionalized β-cyclodextrin derivative, is characterized in that, comprises the following steps: 1) Mix 6A,6D-dideoxy-6A,6D-diiodo-β-cyclodextrin (1) with 1-thioper-O-acetyl-β- D-galactose carries out stirring reaction; 2) Removal of the solvent, followed by treatment with NaOMe to obtain the β-cyclodextrin derivative (2). 2. The synthetic method according to claim 1, characterized in that, 6A, 6D-dideoxy-6A, 6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β The equivalent ratio of -D-galactose and NaOMe is 1:1-3:1-3:0.5. 3. The synthetic method according to claim 1, characterized in that, 6A, 6D-dideoxy-6A, 6D-diiodo-β-cyclodextrin, NaH, 1-thioper-O-acetyl-β The equivalent ratio of -D-galactose and NaOMe is 1:2.5:2.5:0.5. 4. The synthetic method according to claim 1, characterized in that, in step 1), the stirring speed of the stirring reaction is 100-300r/min, and the stirring time is 1.5-4h. 5. The synthesis method according to claim 1, characterized in that, in step 2), the temperature of NaOMe treatment is 20-30°C, and the treatment time is 2-3h. 6. The synthesis method according to claim 1, characterized in that the yield of the β-cyclodextrin derivative (2) is 68-75%.