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N,N'-asymmetric diayl substitution urea compound and preparation method and purpose thereof

A compound, asymmetric technology, applied in the N field, can solve the problems of generating by-products and decreasing yield, and achieve the effect of improving yield

Inactive Publication Date: 2013-06-05
TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when triphosgene is used as a reactant, theoretically one mole of triphosgene can be decomposed into three moles of phosgene, so in conventional reactions, one-third of the mole of triphosgene is often used to react with amines to prepare urea compounds, which leads to In the reaction of triphosgene with some substrate amines, the yield decreases
And if the reaction conditions are not well controlled, it is easy to generate by-products in the reaction when triphosgene is used instead of phosgene

Method used

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  • N,N'-asymmetric diayl substitution urea compound and preparation method and purpose thereof
  • N,N'-asymmetric diayl substitution urea compound and preparation method and purpose thereof
  • N,N'-asymmetric diayl substitution urea compound and preparation method and purpose thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0070] Step 1. Preparation of NDM-1 substrate stock solution

[0071] Imipenem monohydrate (Imipenem monohydrate, purchased from Sigma Company) was dissolved in 50 mM HEPES (purchased from BioBasic Company) to prepare a 10 mM substrate stock solution for future use.

[0072] Step 2. Treatment of Compounds

[0073] Compound in 95%DMSO+5%ddH 2 O, and prepared to a solution with a concentration of 100mM, and then placed the prepared compound solution in a 1.5ml ep tube, and stored it at 4°C for use.

[0074] Step 3. Preparation of NDM-1 protein buffer

[0075] NDM-1 (provided by the MDC protein purification group of our laboratory, the preparation method refers to Yu Guo, Jing Wang et al., A structural view of the antibiotic degradation enzyme NDM-1 from a superbug. Protein & Cell, 2011, 2(5): 384 -394) was dissolved in protein buffer (pH=6.8), and was prepared into 50nM NDM-1 protein buffer, wherein the protein buffer contained 50mM HEPES, 5μM ZnCl 2 (purchased from BioBasic...

Embodiment 1

[0088] The preparation of embodiment 11-phenyl-3-naphthyl urea

[0089]

[0090] Triphosgene (10 mmol) dissolved in 20 ml dichloromethane was added dropwise to 1-aminonaphthalene (10 mmol) dissolved in 20 ml dichloromethane, then triethylamine (3 ml) dissolved in 10 ml dichloromethane was added dropwise , stirred at room temperature for 30 minutes; the solution was transferred to a rotary evaporator, and evaporated to dryness, the residue was dissolved in 20ml of dichloromethane, and aniline (10mmol) dissolved in 20ml of dichloromethane was added, and the mixture was refluxed for 30min; the solution was transferred to a rotary evaporator In the evaporator, the obtained residue was dissolved with 30ml of acetone, and 30ml of water was added, and the precipitate was filtered with suction and washed with water-acetone (1:1, 4×5ml) to obtain the product. The yield was 88%. Gray powder, M.P. 223-224°C. 1 H NMR (400MHz, DMSO-d6, δin ppm): 9.07(s, 1H), 8.78(s, 1H), 8.14(d, J=8.4...

Embodiment 2

[0091] Preparation of Example 21-(4-tert-butylphenyl)-3-(1-naphthyl)urea

[0092]

[0093] The aniline in Example 1 is replaced with p-tert-butylaniline, and all the other steps are the same as in Example 1. The yield was 88%. Gray powder, M.P. 239-241°C. 1 H NMR (400MHz, DMSO-d6, δinppm): 8.99(s, 1H), 8.74(s, 1H), 8.14(d, J=8.4Hz, 1H), 8.04(d, J=8.4Hz, 1H), 7.95(d, J=7.8Hz, 1H), 7.60(m, 3H), 7.50(t, J=7.8Hz, 1H), 7.43(d, J=9Hz, 2H), 7.33(d, J=9Hz, 2H), 1.29(s, 9H); ESI-MS m / z: 319.20 ([M+H + ]).

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Abstract

The invention relates to N,N'-asymmetric diayl substitution urea compound of a general formula (I). A and B independently represent aryl, one-substitution or multi-substitution aryl, miscellaneous aryl and one-substitution or multi-substitution miscellaneous aryl. R1 and R2 independently represent hydrogen or C1-C8 alkyl or C1-C8 alkoxy or aromatic alkoxy or acyl or non-aromatic heterocycle substitution group or halogen or nitryl or trifluoromethyl or cyan. The invention further relates to a preparation method of the compound, active component medicine composition of the compound and application of the compound in preparing medicine for restraining new delhi metallo beta-lactamase (NDM-1) drug-resistant bacteria.

Description

technical field [0001] The invention relates to an N, N'-disubstituted urea compound, a preparation method and application of the compound. Background technique [0002] In the 1950s and 1960s, known as the "golden age" of antibiotics, about 7 million people died of infectious diseases worldwide every year, and this figure rose to 20 million by 1999. The main reason for the increase in the fatality rate is the difficulty in medication brought by drug-resistant bacteria. [0003] At present, the problem of bacterial resistance has become very serious. In developed countries, 5% to 10% of hospitalized patients have one or more infections. There are about 2 million patients with nosocomial infection in the United States every year, 90,000 people die, and the economic loss reaches 4.5 billion to 5.7 billion US dollars. In developing countries, the risk of nosocomial infection is 2 to 20 times higher than in developed countries. The incidence rate of nosocomial infection in o...

Claims

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Application Information

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IPC IPC(8): C07C275/28C07C275/30C07C275/38C07D295/135C07D213/75A61K31/17A61K31/44A61K31/5375A61P31/04
Inventor 杨诚路支超刘伟陈卫强傅晟张炜程
Owner TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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