Macrocyclic lactam compound using diaryl ether as skeleton, and preparation method thereof

A technology of macrocyclic lactam and diaryl ether, which is applied in the field of macrocyclic lactam compounds, can solve the problems of difficult chemical synthesis, complex structure, and long cycle, and achieve mild process conditions, simple operation, and cheap reagents Effect

Inactive Publication Date: 2018-01-05
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although macrocyclic natural products have high biological activity, generally spe

Method used

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  • Macrocyclic lactam compound using diaryl ether as skeleton, and preparation method thereof
  • Macrocyclic lactam compound using diaryl ether as skeleton, and preparation method thereof
  • Macrocyclic lactam compound using diaryl ether as skeleton, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1) Synthesis of Compound 1

[0043] a) Synthesis of Compound 15

[0044] 10.0 g of 3-methoxyphenol (80.6 mmol), 14.8 g of ethyl 4-iodobenzoate (53.7 mmol), 3.07 g of cuprous iodide (16.1 mmol), 52.5 g of cesium carbonate (161 mmol ) and 5.54 g of 2-(dimethylamino)acetic acid (53.7 mmol) were dissolved in 120 ml of 1,4-dioxane, the reaction mixture was stirred at 80°C for 15 hours, concentrated, the organic solvent was removed, and 60 ml of water was added , extracted with dichloromethane (150 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and purified on a silica gel column (petroleum ether: ethyl acetate (volume ratio) = 1:0 to 10:1) to obtain yellow oil 15 (9.10 g, yield: 62.3 %). ESI-MS m / z : 273.0 [M+1] + .

[0045] b) Synthesis of Compound 16

[0046]4.00 g of compound 15 (15.0 mmol) was dissolved in 50 ml of dichloromethane, cooled to minus 78°C, and 4.25 ml of boron tribromide (44.1 mmol) was added. After the ...

Embodiment 2

[0066]

[0067] 2) Synthesis of Compound 2

[0068] Dissolve 35 mg of compound 24 (74 μmol) and 31 μl of triethylamine (0.22 mmol) in 5 mL of dichloromethane, and then add 8.0 μl of cyclopropylformyl chloride (89 μmol). The reaction was stirred at 20°C for 1 hour, concentrated, added with 20 mL of water, and extracted with dichloromethane (40 mL×2). The organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by high performance liquid chromatography to obtain 8.5 mg of white solid compound 2 (yield: 22.8%). ESI-MS m / z : 506.1 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.45-8.33 (m, 1H), 8.04-7.93 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H),7.22-7.14 (m, 2H), 6.86-6.79 (m, 1H), 6.37-6.22 (m, 1H), 4.53-4.17 (m, 3H),4.15-3.94 (m, 1H ), 3.79-3.55 (m, 2H), 3.43-3.35 (m, 1H), 3.25-2.88 (m, 3H),2.85-2.72 (m, 1H), 2.27-1.87 (m, 3H), 1.86-1.58 (m, 1H), 1.58-1.32 (m, 4H), 1.31-1.06 (m, 5H), 0.81-0.62 (m, 4H).

Embodiment 3

[0070]

[0071] 3) Synthesis of compound 3

[0072] Dissolve 35 mg of compound 24 (74 μmol) and 31 μl of triethylamine (0.22 mmol) in 5 mL of dichloromethane, and add 8.1 μl of cyclopropylformyl chloride (89 μmol). The reaction was stirred at 20°C for 1 hour, concentrated, added with 20 mL of water, and extracted with dichloromethane (40 mL×2). The organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by high-performance liquid chromatography to obtain 6.1 mg of white solid compound 3 (yield: 16.2%). ESI-MS m / z : 532.1 [M+23] + . 1 H NMR (400 MHz, DMSO- d 6) δ8.45-8.30 (m, 1H), 8.05-7.92 (m, 2H), 7.31-7.26 (m, 1H), 7.21-7.16 (m, 2H), 6.86-6.78 (m, 1H), 6.66- 6.55 (m, 1H), 6.54-6.46 (m, 0.3H), 6.27-6.24 (m, 0.7H), 4.50-4.40 (m, 0.7H), 4.16-4.30 (m, 1.3H), 4.17-4.00 (m, 3H), 3.85-3.55 (m, 3H), 3.45-3.35 (m, 1H), 3.28-3.26 (m, 4H), 3.26-3.05 (m, 3H), 2.88-2.75 (m, 1H) , 2.45-2.03 (m, 2H), 1.55-1.45 (m, 1H), 1.40-1.15 (m, 6H). 1 H NMR (400 ...

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Abstract

The invention relates to a macrocyclic lactam compound with a diaryl ether as a skeleton and a preparation method thereof, and mainly solves the technical problem that currently there are few macrocyclic lactam compounds with a diaryl ether as a skeleton. The technical scheme of the present invention: a macrocyclic lactam compound with a diaryl ether as a skeleton is characterized in that it has the following structural formula: R1 and R2 are alkyl, cycloalkyl, aryl or alkyl with heteroatoms and One of the substituents of aryl.

Description

technical field [0001] The invention relates to a macrocyclic lactam compound with a diaryl ether as a skeleton and a preparation method thereof. Background technique [0002] Macrocyclic natural products usually have various biological activities and play an important role in the development of new drugs, especially in anti-infection, anti-cancer, and other therapeutic fields ( Future Med. Chem. , 2012, 4 ,1409; J. Med. Chem. , 2014, 57 , 278). At present, there are a certain number of macrocyclic drugs on the market, mainly derived from natural products with complex structures. Cyclic peptides and macrolides are the two main classes. It is worth mentioning that macrocyclic antibiotics are the most successful class of macrocyclic drugs. Representative macrocyclic antibiotics include erythromycin, vancomycin, telavancin, daptomycin, rifampicin, spiramycin and so on. Followed by macrocyclic antineoplastic drugs, such as actinomycin D (dactinomycin), epothilone B, ixab...

Claims

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Application Information

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IPC IPC(8): C07D498/08
Inventor 赵正邬思春刘晓雷万双谊王丽娟
Owner 上海药明康德新药开发有限公司
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