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A glycosyl ligand of calixanthamycin A and its intermediate and preparation method

A xanthomycin and glycosyl technology, applied in the field of chemical drug synthesis, can solve the problem that there are no reports related to chemical synthesis of calixanthomycin A glycosyl ligands, the high oxidation state is complex, and there is no chemical synthesis of calixanthene. Mycin A, etc.

Active Publication Date: 2021-02-26
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] As a new polycyclic xanthone natural product, calixanthamycin A has broad application prospects, but due to its high oxidation state and complex six-ring structure, calixanthamycin A has not yet been chemically synthesized Related reports on karixanthenycin A
[0005] The present inventors have found that if the glycosyl ligand of kalixanthamycin A is first synthesized Then only one step of glycosylation is needed to synthesize calixanthamycin A, but there is no related report on calixanthamycin A glycosyl ligand, and there is no chemical synthesis of calixanthamycin A glycosyl ligand. Body related reports

Method used

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  • A glycosyl ligand of calixanthamycin A and its intermediate and preparation method
  • A glycosyl ligand of calixanthamycin A and its intermediate and preparation method
  • A glycosyl ligand of calixanthamycin A and its intermediate and preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Embodiment 1: the preparation of formula 10 compound

[0131] Step a: Preparation of the compound of formula 10-2:

[0132]

[0133] Dissolve the compound of formula 10-1 (10.0g, 49.2mmol) in acetone (120ml), add potassium carbonate (10.2g, 73.9mmol), tetrabutylammonium fluoride (182mg, 0.49mmol), stir and mix well, add Allyl bromide (5.1ml, 59.1mmol) was then reacted at 55°C for 12 hours to end the reaction, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, concentrated, and the residue was column chromatographed (5% ethyl acetate / petroleum ether) to obtain the compound of formula 10-2 (11.77 g, yield 98%), Rf=0.54 (10% ethyl acetate / petroleum ether).

[0134] Tested: 1 H NMR (500MHz, Chloroform-d) δ7.14(d, J=2.9Hz, 1H), 6.85(d, J=8.9Hz, 1H), 6.80(d, J=8.9Hz, 1H), 6.07(m ,1H),5.48(dq,J=17.2,1.6Hz,1H),5.31(d,J=10.6Hz,1H),4.55(d,J=3.7Hz,2H),3.76(s,3H);

[0135] 13 C NMR (125MHz, CDCl3) δ154.3, 149.3, 133.1, 118.9, 117.6, 115....

Embodiment 2

[0175] Embodiment 2: the preparation of formula 11 compound

[0176] Step A: Preparation of compound of formula 11-2:

[0177]

[0178] The formula 11-1 compound (7.20g, 30.9mmol, 1.0equiv.) was dissolved in 60ml of DMF, potassium carbonate (6.40g, 46.3mmol, 1.5equiv.) and benzyl bromide (4.0ml, 34.0mmol, 1.1equiv.) were added .), react at room temperature for 2 hours, finish the reaction, add 20ml of distilled water to quench the reaction, extract three times with ethyl acetate (30ml), combine the organic phases, wash the organic phases with distilled water for 3 times, and wash with saturated sodium chloride solution for 1 time , dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (5% ethyl acetate / petroleum ether) to obtain the compound of formula 11-2 (8.97g, yield 90%), Rf=0.57 ( 10% ethyl acetate / petroleum ether).

[0179] Tested: 1 H NMR (400MHz, CDCl3) δ10.04(s, 1H), 7.43(d, J=3.1Hz, 1H), 7.42–7.34(m...

Embodiment 3

[0203] Embodiment 3: the preparation of formula 7 compound

[0204]

[0205] Formula 10 compound (1.52g, 5.05mmol, 1.0equiv.) and formula 11 compound (2.70g, 6.56mmol, 1.3equiv.) are dissolved in the mixed solvent of the DMF of 40ml and the triethylamine of 8ml, then add Ph( PPh3) 4 (577mg, 0.5mmol, 0.1equiv.) and CuI (95.3mg, 0.5mmol, 0.1equiv.), after the addition, under the protection of nitrogen, reacted at 95°C for 10.5 hours, ended the reaction, and lowered the temperature of the reaction system to room temperature, with 10ml saturated NH 4 Cl aqueous solution quenched reaction, extracted three times with ethyl acetate (40ml), combined organic phase, organic phase was washed twice with distilled water and saturated saline, dried, filtered, and concentrated to obtain formula 7 compound (2.50g, yield 78%).

[0206] Tested: 1 H NMR (500MHz, Chloroform-d) δ7.58–7.49(m,2H),7.32(q,J=6.2Hz,3H),6.85(s,1H),6.66(d,J=3.0Hz,1H) ,6.57(d,J=2.9Hz,1H),5.14(s,2H),4.52(ddd,J=11.6,6...

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Abstract

The invention discloses cali xanthene mycin A glycosyl ligand and intermediates and a preparation method thereof. The chemical construction of the cali xanthene mycin A glycosyl ligand is shown in formula 1, the preparation of the cali xanthene mycin A glycosyl ligand comprises step (2) or step (1)-(2) of the following synthetic route; the invention further discloses the intermediates of the calixanthene mycin A glycosyl ligand, the chemical constructions of the intermediates are shown in formula 2, formula 4, formula 5 and formula 7. The chemical synthesis of the cali xanthene mycin A glycosyl ligand is firstly achieved, the prepared cali xanthene mycin A glycosyl ligand can prepare cali xanthene mycin A through simple glycosylation, the practical value for achieving the chemical synthesis of the cali xanthene mycin A is extremely high.

Description

technical field [0001] The invention relates to a kalixanthamycin A glycosyl ligand, an intermediate and a preparation method thereof, and belongs to the technical field of chemical drug synthesis. Background technique [0002] Calixanthenone A is a polycyclic xanthone natural product, which was isolated from the culture medium of Streptomyces albus by Brady's research group using the amplified gene sequence of polyphenol natural products to introduce into Streptomyces albus , the natural product has a strong inhibitory activity on human colon cancer cells, with an IC50 value as low as 0.43nM (Hahk-Soo K.; Brady, S.; J.Am.Chem.S.2014,136,18111-18119 .), its chemical structure is as follows: [0003] [0004] As a new polycyclic xanthone natural product, calixanthamycin A has broad application prospects, but due to its high oxidation state and complex six-ring structure, calixanthamycin A has not yet been chemically synthesized Related reports of calixanthenycin A. [0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04C07D311/78C07D311/76C07F7/18
CPCC07D311/76C07D311/78C07D493/04C07F7/188C07F7/1892
Inventor 申艳芳代义华马飞霞高栓虎
Owner EAST CHINA NORMAL UNIV
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