Difluoromethylated paclitaxel and preparation method thereof

Abstract

The invention relates to the technical field of paclitaxel, and particularly discloses difluoromethylated paclitaxel and a preparation method thereof. The invention relates to difluoromethylated paclitaxel. The difluoromethylated paclitaxel comprises direct difluoromethylated paclitaxel and deoxidized difluoromethylated paclitaxel. The difluoromethylated paclitaxel provided by the invention can be used in clinical drugs, and has the advantages of improved drug utilization rate, high selectivity, high target cell pertinence and the like. In addition, the preparation method has the advantages of mild reaction conditions, high yield, wide substrate applicability and the like.

Description

Technical Field

[0001] The present application relates to the technical field of paclitaxel, and more specifically, to a difluoromethylated paclitaxel and a preparation method thereof. Background Art

[0002] Paclitaxel is a powerful anti-tumor drug, and its main effects and functions include: 1. Anti-cancer activity: Paclitaxel can interfere with the cell division process, causing cancer cells to be unable to form spindles normally, thereby preventing cell division. This mechanism makes paclitaxel an effective chemotherapy drug for the treatment of a variety of cancers, such as breast cancer, lung cancer, ovarian cancer, and gastric cancer. 2. Broad-spectrum anti-cancer: Due to its unique anti-cancer mechanism, paclitaxel can have an effect on many types of tumor cells, which makes it widely used in combination chemotherapy regimens. 3. Targeted therapy: In some cases, paclitaxel may be used in combination with other targeted drugs to improve efficacy and reduce side effects. 4. Treatment progress: The clinical application of paclitaxel continues to expand, including the treatment of relapsed or refractory cancer, as well as its use in neoadjuvant chemotherapy and adjuvant chemotherapy. However, the selectivity of paclitaxel and its targeting of target cells need to be improved. Summary of the invention

[0003] In order to improve the selectivity of paclitaxel and its targeting to target cells, the present application provides a difluoromethylated paclitaxel and a preparation method thereof, which adopts the following technical scheme:

[0004] In a first aspect, the present application provides a difluoromethylated paclitaxel, wherein the difluoromethylated paclitaxel is directly difluoromethylated paclitaxel, and the chemical structure of the directly difluoromethylated paclitaxel is as follows:

[0005]

[0006] By adopting the above technical scheme, difluoromethyl is an important fluorine-containing group. When it is introduced into drug molecules, the fat solubility of target molecules can be improved, and the permeability of drugs to cell membranes can be improved, thereby improving the utilization rate of drugs and the ability of drugs to reach target cells. Moreover, difluoromethyl, as an electron-withdrawing group, can improve the metabolic stability of drug molecules. Difluoromethyl is very similar to hydroxyl (OH) and amino (NH) in acidity and alkalinity and electrical properties. Therefore, difluoromethyl is prone to interactions such as intramolecular and intermolecular hydrogen bonds, which can well increase the fat solubility and metabolic stability of drug molecules. Introducing difluoromethyl into paclitaxel can show special advantages in improving the special selectivity and biological metabolic stability of drugs.

[0007] Optionally, the difluoromethyl group in the direct difluoromethyl paclitaxel is provided by TMSCF2Br.

[0008] By adopting the above technical scheme, TMSCF2Br can generate a difluorocarbene intermediate under the action of a base, and react mildly with paclitaxel to achieve difluoromethylation of paclitaxel.

[0009] Optionally, the difluoromethylated paclitaxel is deoxydifluoromethylated paclitaxel, and the chemical structure of the deoxydifluoromethylated paclitaxel is as follows:

[0010]

[0011] Optionally, the difluoromethyl group in the deoxydifluoromethylated paclitaxel is provided by Zn(CF2H)2.

[0012] By adopting the above technical scheme, a difluoromethyl metal reagent is used to difluoromethylate paclitaxel, which is beneficial to the difluoromethylation reaction.

[0013] In a second aspect, the present application provides a method for preparing difluoromethylated paclitaxel, using the following technical solution:

[0014] A preparation method of difluoromethylated paclitaxel comprises the following steps: adding TMSCF2Br and a weak base to water, activating the weak base to obtain an activation solution; adding paclitaxel to DCM to obtain a paclitaxel solution, mixing the paclitaxel solution and the activation solution, reacting at room temperature, and separating to obtain difluoromethylated paclitaxel. The reaction mechanism is as follows:

[0015]

[0016] By adopting the above technical scheme, TMSCF2Br is used as a difluorocarbene precursor, and a difluorocarbene intermediate is generated under the action of a base, and the latter reacts with an alkyl alcohol to obtain a difluoromethylated product. The reaction conditions of this transformation are mild, the yield is high, the substrate applicability is good, and it has good application prospects.

[0017] Optionally, the weak base is selected from KOAc or KH2F.

[0018] By adopting the above technical scheme, the reaction uses KOAc or KHF2 as the activation reagent of TMSCF2Br and is carried out under the two-phase conditions of DCM and H2O. The substrate adaptability is high, so that the reaction obtains a higher yield.

[0019] Optionally, a method for preparing difluoromethylated paclitaxel comprises the following steps: mixing paclitaxel with an organic solvent, adding ethyl chloroformate and ultrasonically mixing, adding an organic base, separating, washing, and obtaining esterified paclitaxel; mixing esterified paclitaxel, Zn(CF2H)2, and DMPU, adding a catalyst B, reacting at 40°C for 24h, separating, and obtaining deoxydifluoromethylated paclitaxel, and the reaction mechanism is as follows:

[0020]

[0021] By adopting the above technical solution, the hydroxyl group of paclitaxel is converted into an ester group, and Zn(CF2H)2 is used as a nucleophilic difluoromethyl reagent to achieve deoxydifluoromethylation of paclitaxel under the action of a copper catalyst. The conversion has a high yield and excellent spatial selectivity, and can maintain the molecular configuration of paclitaxel to the maximum extent, thereby ensuring or enhancing the biological activity of the drug.

[0022] Optionally, the catalyst B is selected from transition metals, and the transition metal includes CuI.

[0023] By adopting the above technical scheme, the difluoromethyl zinc reagent is used in combination with a copper-based catalyst to catalyze the reaction of difluoromethyl and esterified paclitaxel, and under the action of the copper-based catalyst, the substrate has a better expansion range, good reaction regioselectivity and better yield.

[0024] Optionally, the added amount of the catalyst B is 10-20%.

[0025] In summary, this application has the following beneficial effects:

[0026] 1. In the present application, paclitaxel is difluoromethylated. Difluoromethyl is an important fluorine-containing group. When introduced into drug molecules, the fat solubility of target molecules can be improved, and the permeability of drugs to cell membranes can be improved, thereby improving the utilization rate of drugs and the ability of drugs to reach target cells. Moreover, difluoromethyl, as an electron-withdrawing group, can improve the metabolic stability of drug molecules. Difluoromethyl is very similar to hydroxyl (OH) and amino (NH) in acid-base and electrical properties. Therefore, difluoromethyl is prone to interactions such as intramolecular and intermolecular hydrogen bonds, which can well increase the fat solubility and metabolic stability of drug molecules. Introducing difluoromethyl into paclitaxel can show special advantages in improving the special selectivity and biological metabolic stability of drugs.

[0027] 2. In this application, TMSCF2Br is used as a difluorocarbene precursor to generate a difluorocarbene intermediate under the action of a base, and the latter reacts with an alkyl alcohol to obtain a difluoromethylated product. The reaction conditions of this transformation are mild, the yield is high, the substrate applicability is good, and it has good application prospects.

[0028] 3. In the present application, the hydroxyl group of paclitaxel is converted into an ester group, and Zn(CF2H)2 is used as a nucleophilic difluoromethyl reagent to achieve deoxydifluoromethylation of paclitaxel under the action of a copper catalyst. The conversion has a high yield and excellent spatial selectivity, and can maintain the molecular configuration of paclitaxel to the maximum extent, thereby ensuring or enhancing the biological activity of the drug. DETAILED DESCRIPTION

[0029] The present application is further described in detail below with reference to the embodiments.

[0030] Example

[0031] Example 1

[0032] In one aspect, the present application provides a difluoromethylated paclitaxel, wherein the difluoromethylated paclitaxel is directly difluoromethylated paclitaxel, and the chemical structure of the difluoromethylated paclitaxel is as follows:

[0033]

[0034] On the other hand, the present application provides a method for preparing difluoromethylated paclitaxel, comprising the following steps: adding TMSCF2Br and a weak base to water, activating the weak base to obtain an activation solution; adding paclitaxel to DCM to obtain a paclitaxel solution, mixing the paclitaxel solution and the activation solution, reacting at room temperature, and separating to obtain direct difluoromethylated paclitaxel.

[0035] The weak base is KOAc or KH2F. Specifically, the weak base in this embodiment is KOAc.

[0036] The specific reaction mechanism is as follows:

[0037]

[0038] Example 2

[0039] In one aspect, the present application provides a difluoromethylated paclitaxel, wherein the difluoromethylated paclitaxel is directly difluoromethylated paclitaxel, and the chemical structure of the difluoromethylated paclitaxel is as follows:

[0040]

[0041] On the other hand, the present application provides a method for preparing difluoromethylated paclitaxel, comprising the following steps: adding TMSCF2Br and a weak base to water, activating the weak base to obtain an activation solution; adding paclitaxel to DCM to obtain a paclitaxel solution, mixing the paclitaxel solution and the activation solution, reacting at room temperature, and separating to obtain direct difluoromethylated paclitaxel.

[0042] The weak base is KOAc or KH2F. Specifically, the weak base in this embodiment is KH2F.

[0043] The specific reaction mechanism is as follows:

[0044]

[0045] In summary, the introduction of difluoromethyl into paclitaxel in Example 1-2 can show special advantages in improving the special selectivity and biological metabolic stability of the drug; preferably, TMSCF2Br is used as a difluorocarbene precursor to produce a difluorocarbene intermediate under the action of a base, and the latter reacts with an alkyl alcohol to obtain a difluoromethylated product. The reaction conditions of this transformation are mild, the yield is high, the substrate applicability is good, and it has good application prospects.

[0046] Example 3

[0047] On the one hand, the present application provides a difluoromethylated paclitaxel, wherein the difluoromethylated paclitaxel is deoxydifluoromethylated paclitaxel, and the chemical structure of the difluoromethylated paclitaxel is as follows:

[0048]

[0049] On the other hand, the present application provides a method for preparing difluoromethylated paclitaxel, comprising the following steps: mixing paclitaxel with water, adding acetic acid for ultrasonic mixing, adding catalyst A, separating, washing, and obtaining esterified paclitaxel; mixing esterified paclitaxel, Zn(CF2H)2 and DMPU, adding catalyst B, reacting at 40°C for 24 hours, separating, and obtaining deoxydifluoromethylated paclitaxel.

[0050] The catalyst A is DAMP, the catalyst B is CuI, and the addition amount of the catalyst B is 10 mol%.

[0051] The specific reaction mechanism is as follows:

[0052]

[0053] Example 4

[0054] On the one hand, the present application provides a difluoromethylated paclitaxel, wherein the difluoromethylated paclitaxel is deoxydifluoromethylated paclitaxel, and the chemical structure of the difluoromethylated paclitaxel is as follows:

[0055]

[0056] On the other hand, the present application provides a method for preparing difluoromethylated paclitaxel, comprising the following steps: mixing paclitaxel with an organic solvent, adding ethyl chloroformate for ultrasonic mixing, adding an organic base, separating, washing, and obtaining esterified paclitaxel; mixing esterified paclitaxel, Zn(CF2H)2, and DMPU, adding a catalyst B, reacting at 40°C for 24 hours, separating, and obtaining deoxydifluoromethylated paclitaxel.

[0057] The catalyst A is DAMP, the catalyst B is CuI, and the addition amount of the catalyst B is 20 mol%.

[0058] The specific reaction mechanism is as follows:

[0059]

[0060] In summary, in Examples 3-4, it is preferred that the difluoromethyl zinc reagent is used in combination with a copper-based catalyst to catalyze the reaction of difluoromethyl with esterified paclitaxel, and under the action of the copper-based catalyst, the substrate has a better expansion range, good reaction regioselectivity, and a better yield; and the difluoromethyl zinc reagent has better stability, can stably achieve functionalization on paclitaxel, maintain the molecular configuration of paclitaxel, and improve the drug activity of paclitaxel.

[0061] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A difluoromethylated paclitaxel, characterized in that: The difluoromethylated paclitaxel is directly difluoromethylated paclitaxel, and the chemical structure of the directly difluoromethylated paclitaxel is as follows:

2. The difluoromethylated paclitaxel according to claim 1, characterized in that: The difluoromethyl group in the direct difluoromethyl paclitaxel is provided by TMSCF2Br.

3. A difluoromethylated paclitaxel according to claim 2, characterized in that: The difluoromethylated paclitaxel is deoxydifluoromethylated paclitaxel, and the chemical structural formula of the deoxydifluoromethylated paclitaxel is as follows:

4. The difluoromethylated paclitaxel according to claim 3, characterized in that: The difluoromethyl group in the deoxydifluoromethylated paclitaxel is provided by Zn(CF2H)2.

5. A method for preparing difluoromethylated paclitaxel according to any one of claims 1 to 2, characterized in that: The following steps are involved: TMSCF2Br and a weak base are added to water for weak base activation to obtain an activation solution; paclitaxel is added to DCM to obtain a paclitaxel solution, the paclitaxel solution and the activation solution are mixed, reacted at room temperature, and separated to obtain difluoromethylated paclitaxel. The reaction mechanism is as follows:

6. The method for preparing difluoromethylated paclitaxel according to claim 5, characterized in that: The weak base is selected from KOAc or KH2F.

7. A method for preparing difluoromethylated paclitaxel according to any one of claims 3 to 4, characterized in that: The method comprises the following steps: mixing paclitaxel with an organic solvent, adding ethyl chloroformate and ultrasonically mixing, adding an organic base, washing, and separating to obtain esterified paclitaxel; mixing esterified paclitaxel, Zn(CF2H)2, and DMPU, adding a catalyst B, reacting at 40°C for 24 hours, and separating to obtain deoxydifluoromethylated paclitaxel. The reaction mechanism is as follows:

8. The method for preparing difluoromethylated paclitaxel according to claim 7, characterized in that: The catalyst B is selected from transition metals, and the transition metals include CuI.

9. The method for preparing difluoromethylated paclitaxel according to claim 7, characterized in that: The addition amount of the catalyst B is 10-20%.

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