Dihydroartemisinin-containing carboxy phenol/ester phenol/amido phenol conjugate as well as synthesis method and application thereof

Abstract

The invention discloses a dihydroartemisinin-containing carboxy phenol / ester phenol / amido phenol conjugate. The conjugate or a racemate, stereoisomer and tautomer thereof and a pharmaceutically acceptable salt of the conjugate have a structural general formula as shown in a formula I, wherein n is equal to 2 or 3, X is an alkoxyl, a hydroxyl, an amino group or -O(CH2)b-DHA, Y is -H or an alkoxyl,Z is an alkenyl and an alkyl or has no groups, b is equal to 2 or 3, and DHA represents for dihydroartemisinin. The invention further discloses a synthesis method of the dihydroartemisinin-containingcarboxy phenol / ester phenol / amido phenol conjugate and an application of the conjugate as a drug for resisting to tuberculosis and diabetes mellitus, reducing blood fat and inhibiting interleukin-17.

Description

technical field

[0001] The invention relates to the technical field of chemistry and medicine, in particular to a dihydroartemisinin-containing carboxyl phenol / ester phenol / amide phenol conjugate, a synthesis method and an application. Background technique

[0002] Artemisinin is a terpenoid compound found in the plant Artemisia annua, which is a colorless needle-like crystal. Dihydroartemisinin (DHA) is the first-generation derivative of artemisinin. It not only has a unique structure, but also shows better pharmaceutical properties than artemisinin. It is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, the research on DHA continues. At present, it mainly focuses on the design and synthesis of new derivatives of DHA, and the exploration of new activities of old molecules or new molecules of DHA. So far, many new derivatives of DHA have been synthesized, and some artemisinin derivatives have been used in clinical trials...

Examples

Embodiment 1

[0032] Embodiment 1, the preparation of dihydroartemisinin-containing carboxyl phenol conjugate

[0033] (1) The preparation method of intermediate IM1 is as follows:

[0034]

[0035] Add dihydroartemisinin, diethyl ether and bromoalcohol, and add boron trifluoride-diethyl ether (BF 3 .Et 2 O), under stirring reaction 5 ~ 20h, after the completion of the reaction, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with ethyl acetate (EA), the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Drying, suction filtration, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product, which was recrystallized with petroleum ether-EA mixed solvent to obtain intermediate IM1.

[0036] (2) DHA and carboxyl-containing phenol conjugates, we use TM5 to represent in this application, and its preparation method is as follows:

[0037]

[0038] Into a 1...

Embodiment 2

[0039] Example 2, Preparation of dihydroartemisinin-containing carboxyl phenol conjugates TM5-1~TM5-11

[0040] According to the preparation method described in Example 1, when n=2 or 3, Y is -H or -OMe, and Z is -(CH 2 )- m Or -CH=CH-, X is -OH or -O(CH 2 ) b -DHA, m=0, 1 or 2, b=2 or 3, prepared a series of products TM5-1~TM5-11, the respective reaction conditions, output, product yield, product melting point are shown in Table 1.

[0041] Table 1 Experimental results of synthesis of TM5 series compounds

[0042]

[0043]

Embodiment 3

[0044] Example 3, Preparation of dihydroartemisinin-containing ester group / amidophenol conjugate

[0045]

[0046] In a 100mL round bottom flask, add ester group / amidophenol B2 (1.2mmol), DMF 2mL, K 2 CO 3 (2.5mmol) and IM1 (1mmol), stirred and reacted in a water bath at 45-80°C, and monitored the progress of the reaction by TLC. After the reaction is complete, add 20mL of water and 15mL of EA, adjust the pH to about 7 with 1N HCl, continue to stir for 5min, separate the layers, extract the aqueous layer with 10mL of EA, combine the organic phases, wash with 1NNaOH (5mL×2), and wash with water (20mL×2) . Anhydrous Na 2 SO 4 Dry, filter with suction, remove EA by rotary evaporation under reduced pressure, and obtain the product TM6 by column chromatography.

technical field

[0001] The invention relates to the technical field of chemistry and medicine, in particular to a dihydroartemisinin-containing carboxyl phenol / ester phenol / amide phenol conjugate, a synthesis method and an application. Background technique

[0002] Artemisinin is a terpenoid compound found in the plant Artemisia annua, which is a colorless needle-like crystal. Dihydroartemisinin (DHA) is the first-generation derivative of artemisinin. It not only has a unique structure, but also shows better pharmaceutical properties than artemisinin. It is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, the research on DHA continues. At present, it mainly focuses on the design and synthesis of new derivatives of DHA, and the exploration of new activities of old molecules or new molecules of DHA. So far, many new derivatives of DHA have been synthesized, and some artemisinin derivatives have been used in clinical trials...

Examples

Embodiment 1

[0032] Embodiment 1, the preparation of dihydroartemisinin-containing carboxyl phenol conjugate

[0033] (1) The preparation method of intermediate IM1 is as follows:

[0034]

[0035] Add dihydroartemisinin, diethyl ether and bromoalcohol, and add boron trifluoride-diethyl ether (BF 3 .Et 2 O), under stirring reaction 5 ~ 20h, after the completion of the reaction, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with ethyl acetate (EA), the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Drying, suction filtration, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product, which was recrystallized with petroleum ether-EA mixed solvent to obtain intermediate IM1.

[0036] (2) DHA and carboxyl-containing phenol conjugates, we use TM5 to represent in this application, and its preparation method is as follows:

[0037]

[0038] Into a 1...

Embodiment 2

[0039] Example 2, Preparation of dihydroartemisinin-containing carboxyl phenol conjugates TM5-1~TM5-11

[0040] According to the preparation method described in Example 1, when n=2 or 3, Y is -H or -OMe, and Z is -(CH 2 )- m Or -CH=CH-, X is -OH or -O(CH 2 ) b -DHA, m=0, 1 or 2, b=2 or 3, prepared a series of products TM5-1~TM5-11, the respective reaction conditions, output, product yield, product melting point are shown in Table 1.

[0041] Table 1 Experimental results of synthesis of TM5 series compounds

[0042]

[0043]

Embodiment 3

[0044] Example 3, Preparation of dihydroartemisinin-containing ester group / amidophenol conjugate

[0045]

[0046] In a 100mL round bottom flask, add ester group / amidophenol B2 (1.2mmol), DMF 2mL, K 2 CO 3 (2.5mmol) and IM1 (1mmol), stirred and reacted in a water bath at 45-80°C, and monitored the progress of the reaction by TLC. After the reaction is complete, add 20mL of water and 15mL of EA, adjust the pH to about 7 with 1N HCl, continue to stir for 5min, separate the layers, extract the aqueous layer with 10mL of EA, combine the organic phases, wash with 1NNaOH (5mL×2), and wash with water (20mL×2) . Anhydrous Na 2 SO 4 Dry, filter with suction, remove EA by rotary evaporation under reduced pressure, and obtain the product TM6 by column chromatography.

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