A flexible lactam macrocyclic molecule and its preparation method

A technology of lactams and macrocyclic molecules, which is applied in the direction of organic active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, and can solve problems such as complex steps, low reaction yields, and many side reactions

Inactive Publication Date: 2016-05-25
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional synthesis of macrocycles is complex and requires a ring-closing reaction at an extremely low substrate concentration. The reaction time is long and there are many side reactions. The three-dimensional structure has a great influence, so there is still a lot of research space in the synthesis methodology

Method used

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  • A flexible lactam macrocyclic molecule and its preparation method
  • A flexible lactam macrocyclic molecule and its preparation method
  • A flexible lactam macrocyclic molecule and its preparation method

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preparation example Construction

[0043] Two, the preparation of raw material azidoacetic acid:

[0044] Reaction formula:

[0045]

[0046] Synthesis of Compound 10:

[0047] Dissolve 20.0 g of ethyl bromoacetate (120 mmol) in 20 mL of DMF in an ice-water bath, add sodium azide (12.5 g, 192 mmol) in batches, naturally rise to room temperature and react for 24 hours, then add saturated sodium carbonate solution, extract with ether three times, combine The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a colorless transparent liquid, which was dissolved in 60mL of methanol, added with 60mL of 1M sodium hydroxide solution, reacted at 40°C for 5 hours, and the methanol was spin-off with Wash the aqueous phase twice with ether, neutralize the aqueous phase with 2M hydrochloric acid solution to a pH of about 2, extract three times with ether, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and spin dry to obt...

Embodiment 1

[0061] The synthesis of embodiment 1 compound 1 and 2

[0062] Reaction formula:

[0063]

[0064] 1. Synthesis of intermediate 14:

[0065] The basic building block molecular material 9 (1.00g, 4.42mmol), HOBt (0.600g, 4.44mmol) and HBTU (2.50g, 6.60mmol) were dissolved in DMF (7mL), and DIEA (0.7mL, 4mmol) was added to react for 15min Add propargylamine (0.42mL, 0.361g, 6.63mmol) to react overnight at room temperature under nitrogen protection, add ethyl acetate to the reaction system, wash with 1% hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine successively, anhydrous sulfuric acid Na-dried, spin-dried, and subjected to column chromatography (CH 2 Cl 2 :CH 3 OH=15:1-10:1) to obtain product 14 (1.12 g, 4.26 mmol, 96%) as a pale yellow solid. 1 HNMR (400MHz, DMSO-d 6 ): δ11.10(s, 1H), 9.01(s, 1H), 8.42(t, 3 J(H,H)=8.0Hz,1H), 6.81(s,1H), 6.70(s,1H), 3.96(s,2H), 3.09(s,1H), 1.44(s,9H). 13 CNMR (100MHz, DMSO-d 6 ): δ171.6, 163.7,...

Embodiment 2

[0074] The synthesis of embodiment two compounds 3 and 4

[0075] Reaction formula:

[0076]

[0077] 1. Synthesis of intermediate 17:

[0078] 2.0 g of Boc-protected propargylamine 13 (12.9 mmol) and 1.3 g of azidoacetic acid 10 (12.9 mmol) were dissolved in 10 mL of THF, and 2 mL of water, CuCl (0.64 g, 6.5 mmol), N, N'- Dimethylethylenediamine (1.4mL, 114g, 12.9mmol), reacted at room temperature for 1 hour, added 2mL of 2M hydrochloric acid solution, added ethyl acetate, washed with 1% hydrochloric acid and saturated brine successively, dried over anhydrous sodium sulfate and spun Drying and freezing gave the product 17 as a white solid (3.0 g, 11.7 mmol, 91%). 1 HNMR (400MHz, acetone-d 6 ): δ11.91(br, 1H), 7.96(s, 1H), 6.50(s, 1H), 5.33(s, 2H), 4.36(s, 2H), 1.44(s, 9H). 13 CNMR (100MHz, acetone-d 6 ): δ168.8, 156.8, 124.9, 82.0, 79.1, 51.2, 36.7, 28.2. LRMS (ESI-IonTrap): m / z255.0 ([M-H] - , C 10 h 15 N 4 o 4 The theoretically calculated value is 255.1).

[0...

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Abstract

The present invention discloses a flexible lactam macrocycle molecule and a preparation method thereof, wherein the structure general formula is represented by a formula I, A is one selected from pyrrolyl, 1,4-dimethylene-1,2,3-triazolyl, phenyl, pyridyl, imidazolyl and N-methyl imidazolyl, R is H or -(CH2)nR', R' is one selected from amino, C1-C6 alkyl amino, C5-C7 aryl, C5-C10 heterocyclic aryl and C6-C10 arylamino, and n is an integer of 1-3. The flexible lactam macrocycle molecule preparation method adopts the half long-chain substrate containing the alkyne-azide bifunctional group to carry out intermolecular cyclization through the clicking reaction, is different from the traditional preparation method adopting the full long-chain precursor to carry out intramolecular ring closing, and has advantages of simple synthesis method, green, high efficiency and the like. The formula I is defined in the instruction.

Description

technical field [0001] The invention relates to lactam macrocyclic molecules, in particular to a class of flexible lactam macrocyclic molecules efficiently synthesized by click reaction. Background technique [0002] In the fields of chemistry, biology, and medicine, lactam macrocyclic molecules are a very active research focus, including vancomycin as an antibiotic (Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P.S. , Theartandscienceoftotalsynthesisatthedawnofthetwenty-firstcentury.AngewChemIntEdit2000, 39, (1), 44-122; Service, R.F., Raceformolecularsummits.Science1999, 285, (5425), 184-187.), and cyclic peptides and their derivatives are also a large class of lactams Class molecules. Studies have found that lactam macrocyclic molecules have unusual drug effects such as anticancer, antibacterial, and antiviral, and have a wide range of drug application prospects (Sarabia, F.; Chammaa, S.; Ruiz, A.S.; Ortiz, L.M.; Herrera,F.J.L.,Chemistryandbiologyofcyclicdepsip...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/22A61K31/4192A61P35/00A61P35/02
CPCC07D487/22
Inventor 张强崔晓杰谭伟陈瀚袁谷
Owner PEKING UNIV
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