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Synthesis method of 1,3-benzodiazepine compounds and antitumor activity

A technology for benzodiazepines and a synthesis method, which is applied in the directions of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of single product structure, difficult to obtain raw materials, low atom economy and the like, and achieves simple synthesis process and raw materials. Inexpensive and readily available raw materials

Active Publication Date: 2021-01-05
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At the same time, some reliable methods have been developed for the synthesis of 1,3-benzodiazepines, but these methods often have problems such as difficult access to raw materials, long synthetic routes, single product structures, and low atom economy.

Method used

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  • Synthesis method of 1,3-benzodiazepine compounds and antitumor activity
  • Synthesis method of 1,3-benzodiazepine compounds and antitumor activity
  • Synthesis method of 1,3-benzodiazepine compounds and antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] Add compound 1a, solvent, catalyst, additive and compound 2a to a 15mL reaction bottle in sequence, cover with a stopper and seal it, place it in an oil bath to heat up and stir for reaction. After the reaction was completed, it was cooled to room temperature, filtered with suction, spin-dried, and separated through a silica gel column (petroleum ether / ethyl acetate=300 / 1) to obtain product 3a as a yellow solid.

[0030] A series of results were obtained by changing reaction conditions such as catalyst, additive, organic solvent, equivalent ratio between reactants and reaction temperature, as shown in Table 1.

[0031] Synthesis of 3a under different conditions in table 1 a

[0032]

[0033]

Embodiment 2

[0035]

[0036] To a 15mL reaction flask, add 1a (53mg, 0.3mmol), methanol (1mL), dichloro(pentamethylcyclopentadienyl) rhodium (III) dimer (5.6mg, 0.009mmol), acetic acid Copper monohydrate (15mg, 0.075mmol) and compound 2a (72.8mg, 0.36mmol) were capped and sealed, and placed in an oil bath at 90°C and stirred for 5h. After the reaction, cooled to room temperature, suction filtered, spin-dried, and separated by silica gel column (petroleum ether / ethyl acetate=300 / 1) to obtain yellow solid product 3a (68.4 mg, 72%). The characterization data of this compound are: 1 H NMR (400MHz, CDCl 3 )δ1.27(s,9H),1.60(s,3H),1.68(s,3H),7.09-7.15(m,2H),7.21(td,J 1 =8.0Hz,J 2 =2.0Hz,1H),7.29-7.35(m,4H),7.93-7.95(m,2H). 13 C NMR (100MHz, CDCl 3 )δ19.8, 21.5, 28.4, 39.7, 125.7, 127.0, 127.7, 128.1, 128.7, 128.9, 129.9, 130.7, 131.4, 131.8, 135.7, 145.3, 165.1, 172.1. HRMS calcd for C 22 h 25 N 2 :317.2012[M+H] + ,found: 317.2012.

Embodiment 3

[0038] According to the method and steps of embodiment 2a,b , by changing reactant 1 and reactant 2, a series of 1,3-benzodiazepine compounds 3a-3z and 3aa-3qq were synthesized, the specific results are as follows:

[0039]

[0040]

[0041] a Reaction conditions: 1 (0.3mmol), 2 (0.36mmol), [RhCp*Cl 2 ] 2 (3mol%), Cu(OAc) 2 ·H 2 O (25mol%), MeOH (1mL), 90°C, 5h; b Separation yield; c With AgOAc (25mol%) and NaHCO 3 (0.3mmol) instead of Cu(OAc) 2 ·H 2 O (25mol%), 10h.

[0042] ________________________________________________________________

[0043] Representative product characterization data are as follows:

[0044] 2-(tert-Butyl)-7-methyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3b)

[0045] Yellow oil (66.4mg, 67%). 1 H NMR (400MHz, CDCl 3 )δ1.33(s,9H),1.66(s,3H),1.75(s,3H),2.33(s,3H),6.96(s,1H),7.09(dd,J 1 =8.4Hz,J 2 =1.6Hz,1H),7.29(d,J=8.0Hz,1H),7.38-7.43(m,3H),8.02(dd,J 1 =8.0Hz,J 2 =2.0Hz,2H). 13 C NMR (150MHz, CDCl 3 )δ19.8,21.1,...

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Abstract

The invention discloses 1,3-benzodiazepine compounds with anticancer activity and a synthesis method thereof, and belongs to the technical field of drug development. The structural general formula ofthe 1,3-benzodiazepine compounds is shown in the specification; and the synthesis method comprises the following steps: mixing N-aryl amidine 1, propargyl alcohol ester compounds 2, a rhodium or ruthenium catalyst, an additive and an organic solvent, and performing heating and reacting to obtain the 1, 3-benzodiazepine compounds 3. The synthesis method disclosed by the invention has the advantagesof simple and easily available raw materials, simplicity and convenience in operation, mild conditions, wide substrate application range and the like, and the compounds have remarkable inhibitory activity on cancer cells such as HeLa or Ramos and are potential candidate drug molecular structures.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and drug discovery, and specifically relates to a synthesis method and anticancer activity of 1,3-benzodiazepine compounds. Background technique [0002] As we all know, a variety of 1,3-benzodiazepines have significant anticancer, analgesic and antidepressant drug activities, and have been widely used in clinical practice, making important contributions to ensuring life and health and improving quality of life , but the existing 1,3-benzodiazepine activity studies are actually clinically applied, and there are not many drugs that have been successfully marketed. [0003] Therefore, research and develop anti-cancer drug candidates of new 1,3-benzodiazepine compounds, find better activity than existing drugs, and then carry out structural modification, so as to screen out more potential drug molecular structures Still very much to look forward to. [0004] At the same time, some reliabl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/04A61P35/00
CPCC07D243/04A61P35/00
Inventor 范学森周倩婷宋霞张新迎姜玉钦赵杰
Owner HENAN NORMAL UNIV
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