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Macrocyclic lactam compound containing rigid biaryl skeleton, and preparation method thereof

A macrocyclic lactam and compound technology, applied in the field of macrocyclic lactam compounds, can solve the problems of long cycle, difficult chemical synthesis, complex structure, etc., and achieves the effects of mild process conditions, simple operation and cheap reagents

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 speaking, their structures are complex, chemical synthesis is difficult and the cycle is long

Method used

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  • Macrocyclic lactam compound containing rigid biaryl skeleton, and preparation method thereof
  • Macrocyclic lactam compound containing rigid biaryl skeleton, and preparation method thereof
  • Macrocyclic lactam compound containing rigid biaryl skeleton, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Synthesis of Compound 1

[0047] a) Synthesis of Compound 16

[0048]Add 8.00 g of 3-hydroxymethylpiperazine carbonate tert-butyl carbonate (37.0 mmol) to a solution containing 80 mL of 1,4-dioxane, 80 mL of water and 11.8 g of sodium carbonate (111 mmol) at 0 °C The mixed solution was then added with 4.90 g of allyl chloroformate (40.7 mmol), and then warmed to room temperature and stirred for 16 hours. Add 70 ml of water to the reaction solution, and extract with ethyl acetate (200 ml×3). 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) = 20:1 to 3:1) to obtain 10.0 g of white oil 16 (yield: 90.0%) . 1 H NMR (400 MHz, CDCl 3 ) δ 5.97-5.90 (m, 1H), 5.32-5.20 (m, 2H), 4.60 (d, J = 5.2 Hz, 2H), 4.31-4.13 (m, 2H),4.02-3.84 (m, 2H), 3.63 (br.s., 2H),3.12-2.85 (m, 3H), 2.85-2.64 (m, 1H), 1.46 (s, 9H).

[0049] b) Synthesis of Compound 17

[0050] ...

Embodiment 2

[0068]

[0069] 2) Synthesis of Compound 2

[0070] Dissolve 35.0 mg of compound 25 (75.3 μmol) and 31 μl of triethylamine (0.23 mmol) in 4 ml of dichloromethane, add 7.0 μl of cyclopropylformyl chloride (77 μmol) at 0 °C, The reaction was stirred at 20°C for 1 hour. Add 20 ml of water and extract with dichloromethane (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 6.9 mg of compound 2 as a white solid (yield: 21.5%). ESI-MS m / z : 497.1 [M+H] + .

Embodiment 3

[0072]

[0073] 3) Synthesis of compound 3

[0074] Dissolve 30.0 mg of compound 25 (64.5 μmol) and 27 μl of triethylamine (0.19 mmol) in 4 ml of dichloromethane, and add 7.1 μl of 2-methoxyacetyl chloride (77 μmol ), and the reaction was stirred at 20 °C for 1 h. Add 20 ml of water and extract with dichloromethane (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 14.5 mg of white solid compound 3 (yield: 44.9%). ESI-MS m / z : 501.1 [M+H] + .

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Abstract

The invention relates to a macrocyclic lactam compound containing a rigid biaryl skeleton and a preparation method thereof, and mainly solves the technical problem that currently there are few macrocyclic lactam compounds containing a rigid biaryl skeleton linked by carbon-nitrogen bonds. The technical scheme of the present invention: the macrocyclic lactam compound containing rigid biaryl skeleton is characterized in that it has the following general structural formula: R1 and R2 are alkyl, cycloalkyl, aryl or alkyl are connected with heteroatom and aromatic One of the substituents of the group.

Description

technical field [0001] The invention relates to a macrocyclic lactam compound containing a rigid biaryl 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 ( Molecules , 2013, 18 , 6230; 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, ixabepilo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
Inventor 邬思春汪琛万双谊王丽娟
Owner 上海药明康德新药开发有限公司
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