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(+/-)-ferruginol analogs and preparation method thereof, and applications of (+/-)-ferruginol analogs in preparation of antibacterial drugs

A technology of milopineol and its analogues, which is applied in the field of preparation of antibacterial drugs, and can solve problems such as raw materials and ligands are difficult to obtain, difficult to purify, and low in content

Active Publication Date: 2018-10-09
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The antibacterial activity of natural tricyclic diterpene phenolic compound (+)-melopineol has been confirmed, but the natural melopineol extracted from plants often has a small content and is difficult to purify
There are many problems in the existing method of synthesizing mirocinol such as route is longer, and productive rate is lower, or raw material used, ligand are difficult to obtain, and the price is expensive, and the (±)-milocinol synthetic method reported in the literature , such as in 2004, the Shanta S.Bhar group used citral as a raw material to synthesize (±)-melopineol (J.Org.Chem.2004,69,8935-8937) through 11 steps of reactions, one of which used dangerous reagents Sodium cyanide; In 1957, King et al. used 2,2,6-trimethylcyclohexanone as a raw material to fully synthesize (±)-melopine phenol (J.Chem.Soc.1957,573-577.), which prepared The productive rate of an important intermediate is only less than 20%, therefore, has greatly limited the biological activity research to miloconol and its analogues

Method used

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  • (+/-)-ferruginol analogs and preparation method thereof, and applications of (+/-)-ferruginol analogs in preparation of antibacterial drugs
  • (+/-)-ferruginol analogs and preparation method thereof, and applications of (+/-)-ferruginol analogs in preparation of antibacterial drugs
  • (+/-)-ferruginol analogs and preparation method thereof, and applications of (+/-)-ferruginol analogs in preparation of antibacterial drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0355] Embodiment 1: the preparation of (±)-melopineol analog shown in formula (6b), (6d), (7b), (10b), (10-1b), (12a)

[0356]

[0357] The structures of the (±)-mirospinol analogues shown in formulas (6b), (6d), (7b), (10b), (10-1b), (12a) are as follows:

[0358]

[0359] Preparation of (±)-meloconol analogs shown in formula (6b): Compound 1 (1g, 3.65mmol) was dissolved in anhydrous DCM (30mL), DMAP (222.9mg, 1.82mmol) was added, and B Acid anhydride (1.028mL, 10.95mmol), react at room temperature for 3 hours, add water (30mL), adjust pH to neutral with 2M HCl, extract with DCM (20mLx3), combine organic phases, wash with saturated brine (30mL), anhydrous sodium sulfate After drying, concentration, and silica gel column chromatography (PE:EA=20:1), compound 2 (white solid, 1.1 g, 95%) was obtained. 1 H NMR (400MHz, CDCl 3 )δ6.97(d, J=8.4Hz, 1H), 6.77(s, 1H), 6.68(d, J=8.4Hz, 1H), 4.55(dd, J=11.2, 4.0Hz, 1H), 3.77( s,3H),2.91(dd,J=16.4,6.0Hz,1H),2.84-2.75(m,1H),2.27(...

Embodiment 2

[0377] Embodiment 2: the preparation of (±)-melopineol analog shown in formula (15):

[0378]

[0379] Compound 1 (7.8g, 28.6mmol) was dissolved in anhydrous DCM (200mL), under nitrogen protection, when the system was cooled to 0°C, BBr was added dropwise 3 (7.54mL, 71mmol), react at 0°C for 0.5 hours. Add water (150mL), extract with DCM (50mLx3), combine the organic phases, wash with saturated brine (100mL), dry over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (PE:EA=1000:1) to obtain compound 13 ( White solid, 5.64 g, 90.7%). 1 H NMR (400MHz, CDCl 3 )δ6.97(d,J=8.4Hz,1H),6.80(s,1H),6.68(d,J=8.4Hz,1H),5.62–5.58(m,1H),5.48(d,J=10.0 Hz,1H),3.78(s,3H),2.88–2.72(m,2H),2.52-2.46(m,1H),2.12(d,J=16.8Hz,1H),1.86-1.83(d,J= 11.7Hz, 1H), 1.69–1.61(m, 2H), 1.25(s, 3H), 1.04(s, 3H), 0.98(s, 3H).

[0380] Compound 13 (5 g, 19 mmol) was dissolved in anhydrous methanol (200 mL), protected under nitrogen, added 15% Pd\C (750 mg), replaced with hy...

Embodiment 3

[0382] Embodiment 3: the preparation of (±)-mirospinol analog shown in formula (19a), (19b), (19c), (19d), (19e):

[0383]

[0384] The structures of (±)-melopineol analogs shown in formulas (19a), (19b), (19c), (19d), (19e) are as follows:

[0385]

[0386] POCl 3 (16mL) was placed in a single-necked bottle under nitrogen protection. When the system was cooled to 0°C, DMF (9.56mL, 1.368mmol) was added dropwise, stirred at 0°C for 1 hour, and compound 14 (800mg, 3.1mmol) was added dropwise in CHCl 3 (7mL) solution, heated and refluxed for 12 hours, cooled and added water (100mL), extracted with DCM (40mLx3), combined organic phases, washed with saturated brine (60mL), dried over anhydrous sodium sulfate, concentrated, silica gel column chromatography (PE: EA=100:1), to obtain compound 16a (yellow solid, 672 mg, 75.8%). 1 H NMR (500MHz, CDCl 3 )δ10.37(s,1H),7.50(s,1H),6.85(s,1H),3.89(d,J=5.1Hz,3H),2.94-2.90(m,1H),2.83–2.76(m ,1H),2.26(d,J=12.5Hz,1H),1.91–1.87(m,1H),1....

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Abstract

The present invention discloses (+ / -)-ferruginol analogs represented by formulas (I) and (II), and a preparation method thereof, wherein a tricyclic diterpene analog (1) is used as a raw material, andesterification, acylation, oxidation, reduction, dehydroxylation, deprotection, dehydration, halogenation, demethylation and other reactions are performed to obtain the (+ / -)-ferruginol analogs represented by the formulas (I) and (II). The invention further discloses a total synthesis method of (+ / -)-ferruginol, wherein a compound (16b) as a raw material and a Grignard reagent are subjected to aGrignard reaction, and a dehydroxylation reaction and a demethylation reaction are performed to obtain the (+ / -)-ferruginol. According to the present invention, the prepared (+ / -)-ferruginol analogs represented by the formulas (I) and (II) have significant antibacterial activity and can be potentially used for the preparation of antibacterial drugs. The formulas (I) and (II) are defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a (±)-melopineol analogue, its preparation method and its application in the preparation of antibacterial drugs. Background technique [0002] In today's society, the overuse of antibiotics has spawned many resistant strains, and bacterial resistance is considered to be a serious threat to human health. Staphylococcus aureus is a Gram-positive spherical bacterium. It is one of the most popular pathogens for nosocomial and community infections, and can cause suppuration, otitis media, sepsis, enteritis, sinusitis, osteomyelitis, pneumonia and even sepsis and other diseases after infection. Staphylococcus aureus includes drug-resistant and non-resistant bacteria, such as non-resistant Newman strains, drug-resistant NRS-1 strains (aminoglycoside antibiotics and tetracycline-resistant Staphylococcus aureus), drug-resistant NRS-70 stra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/83C07C45/64C07C37/20C07C37/00C07C39/17C07C39/23C07C39/42C07C201/08C07C205/25C07C213/02C07C215/88C07C49/747A61P31/04
CPCC07C39/17C07C39/23C07C39/42C07C49/747C07C49/83C07C205/25C07C215/88Y02A50/30
Inventor 汤杰肖春梅杨财广杨腾倪腾凤仇文卫姚垠青王李婷
Owner EAST CHINA NORMAL UNIV