Polysubstituted nitrogen-containing heteroaromatic compound, and preparation method and application thereof

Abstract

The present invention relates to a preparation method of a polysubstituted nitrogen-containing heteroaromatic compound. The polysubstituted nitrogen-containing heteroaromatic compound has a structurerepresented by general formula (I) or (II). The method concretely comprises the following specific steps: a transition metal catalyst, a 2,2'-bipyridine ligand and a solvent are added into a reactionvessel, and are uniformly mixed, a raw material A and a raw material B are added, the obtained mixture is sufficiently reacted at room temperature, a precursor of a raw material C or a raw material Dor a raw material D is added, and then the obtained mixture is sufficiently reacted at -10-150 DEG C to obtain the polysubstituted nitrogen-containing heteroaromatic compound. The method is characterized in that the nitrogen-containing heteroaromatic compound is prepared from alkenyl azide, isonitrile and an alkyne compound through a one-pot process under the action of the transition metal catalyst. The reaction involved in the method of the invention has very good tolerance and universality to functional groups, can be used for synthesizing various polysubstituted aminopyridines and aminoisoquinolines without strict anhydrous anaerobic conditions, and is very simple to operate.

Description

technical field

[0001] The invention relates to the field of organic synthesis, in particular to a multi-substituted nitrogen-containing aromatic heterocyclic compound and its preparation method and application. Background technique

[0002] Fluorescent molecular labeling detection technology is an efficient and fast detection method in biological detection and small molecule detection. Due to the difference in the fluorescence emission wavelength of each marker, different substances and different sites can be simultaneously labeled to achieve high throughput. Therefore, it is particularly important for the development of more fluorescently labeled molecules and the development of synthetic methods. Aminopyridine has a high fluorescence conversion rate (=0.6), and the advantages of simple and stable molecular structure. The light conversion rate can be further improved by modifying its structure with functional groups, and its absorption and emission wavelengths can be adjus...

Examples

Embodiment 1

[0050] This embodiment provides a new compound 2-tert-butylamino-6-phenylpyridine-3,4-dicarboxylic acid ethyl ester, its molecular formula is: C 21 h 26 N 2 o 4 , whose structure is:

[0051]

[0052] The compound is synthesized through the following specific steps:

[0053] Add {Rh(COD)Cl}2 (2mg, 0.0038mmol) and 2,2'-bipyridine (1mg, 0.0075mmol), 1,4-dioxane (2ml) in sequence to a 5ml reaction tube, and stir for 5min Afterwards, (1-azidovinyl)benzene (22mg, 0.15mmol) and tert-butylisonitrile (13mg, 17uL, 0.2mmol) were added using a syringe, and reacted at room temperature for 5h. After the reaction was complete, diethyl butynoate (51mg, 48uL, 0.3mmol) was added with a syringe, heated to 120°C for 5h, and TLC detected the complete reaction. The solvent was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 40 mg of a yellow-green solid with a yield of 71%.

[...

Embodiment 2

[0061] Prepare brand-new compound C according to the method described in Example 1 22 h 28 N 2 o 4, the product yield is 60%; the compound structural formula is:

[0062]

[0063] Characterization data for the obtained compounds include:

[0064] 1 H NMR (400MHz, CDCl 3 )δ7.99–7.91(m,3H),7.32–7.21(m,2H),6.94(s,1H),4.42–4.23(m,4H),2.41(s,3H),1.56(s,9H) ,1.42–1.30(m,6H).

[0065] 13 C NMR(101MHz,cdcl3)δ169.17,167.10,159.30,157.88,145.90,140.25,135.79,129.51,127.32,105.53,100.73,61.80,61.36,51.82,29.32,21.52,144.167

[0066] IR (neat) 2954.64, 1737.67, 1686.74, 1558.48, 1369.89, 1289.68, 1182.11, 1044.46.

[0067] HRMS(ESI+)calcd for C 22 h 29 N 2 o 4 :385.2127,found:385.2108.

Embodiment 3

[0069] Prepare brand-new compound C according to the method described in Example 1 22 h 28 N 2 o 4 , the product yield is 68%; the compound structural formula is:

[0070]

[0071] Characterization data for the obtained compounds include:

[0072] 1 H NMR (400MHz, CDCl 3 )δ7.97(s,1H),7.89–7.83(m,2H),7.39–7.33(m,1H),7.25(d,J=6.4Hz,1H),6.96(s,1H),4.36(q ,J=7.2Hz,2H),4.30(q,J=7.2Hz,2H),2.43(s,3H),1.56(s,9H),1.38(t,J=7.2Hz,3H),1.34(t ,3H).

[0073] 13 C NMR (75MHz, CDCl3) δ169.12, 167.09, 159.45, 157.85, 145.89, 138.52, 138.28, 130.77, 128.68, 128.05, 124.59, 105.88, 101.00, 61.80, 61.39, 51.812, 24.14, 29.3

[0074] IR (neat) 2917.53, 1737.76, 1686.83, 1559.92, 1369.89, 1255.88, 1229.12, 1178.37.

[0075] HRMS(ESI+)calcd for C 22 h 29 N 2 o 4 :385.2127,found:385.2112.

technical field

[0001] The invention relates to the field of organic synthesis, in particular to a multi-substituted nitrogen-containing aromatic heterocyclic compound and its preparation method and application. Background technique

[0002] Fluorescent molecular labeling detection technology is an efficient and fast detection method in biological detection and small molecule detection. Due to the difference in the fluorescence emission wavelength of each marker, different substances and different sites can be simultaneously labeled to achieve high throughput. Therefore, it is particularly important for the development of more fluorescently labeled molecules and the development of synthetic methods. Aminopyridine has a high fluorescence conversion rate (=0.6), and the advantages of simple and stable molecular structure. The light conversion rate can be further improved by modifying its structure with functional groups, and its absorption and emission wavelengths can be adjus...

Examples

Embodiment 1

[0050] This embodiment provides a new compound 2-tert-butylamino-6-phenylpyridine-3,4-dicarboxylic acid ethyl ester, its molecular formula is: C 21 h 26 N 2 o 4 , whose structure is:

[0051]

[0052] The compound is synthesized through the following specific steps:

[0053] Add {Rh(COD)Cl}2 (2mg, 0.0038mmol) and 2,2'-bipyridine (1mg, 0.0075mmol), 1,4-dioxane (2ml) in sequence to a 5ml reaction tube, and stir for 5min Afterwards, (1-azidovinyl)benzene (22mg, 0.15mmol) and tert-butylisonitrile (13mg, 17uL, 0.2mmol) were added using a syringe, and reacted at room temperature for 5h. After the reaction was complete, diethyl butynoate (51mg, 48uL, 0.3mmol) was added with a syringe, heated to 120°C for 5h, and TLC detected the complete reaction. The solvent was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 40 mg of a yellow-green solid with a yield of 71%.

[...

Embodiment 2

[0061] Prepare brand-new compound C according to the method described in Example 1 22 h 28 N 2 o 4, the product yield is 60%; the compound structural formula is:

[0062]

[0063] Characterization data for the obtained compounds include:

[0064] 1 H NMR (400MHz, CDCl 3 )δ7.99–7.91(m,3H),7.32–7.21(m,2H),6.94(s,1H),4.42–4.23(m,4H),2.41(s,3H),1.56(s,9H) ,1.42–1.30(m,6H).

[0065] 13 C NMR(101MHz,cdcl3)δ169.17,167.10,159.30,157.88,145.90,140.25,135.79,129.51,127.32,105.53,100.73,61.80,61.36,51.82,29.32,21.52,144.167

[0066] IR (neat) 2954.64, 1737.67, 1686.74, 1558.48, 1369.89, 1289.68, 1182.11, 1044.46.

[0067] HRMS(ESI+)calcd for C 22 h 29 N 2 o 4 :385.2127,found:385.2108.

Embodiment 3

[0069] Prepare brand-new compound C according to the method described in Example 1 22 h 28 N 2 o 4 , the product yield is 68%; the compound structural formula is:

[0070]

[0071] Characterization data for the obtained compounds include:

[0072] 1 H NMR (400MHz, CDCl 3 )δ7.97(s,1H),7.89–7.83(m,2H),7.39–7.33(m,1H),7.25(d,J=6.4Hz,1H),6.96(s,1H),4.36(q ,J=7.2Hz,2H),4.30(q,J=7.2Hz,2H),2.43(s,3H),1.56(s,9H),1.38(t,J=7.2Hz,3H),1.34(t ,3H).

[0073] 13 C NMR (75MHz, CDCl3) δ169.12, 167.09, 159.45, 157.85, 145.89, 138.52, 138.28, 130.77, 128.68, 128.05, 124.59, 105.88, 101.00, 61.80, 61.39, 51.812, 24.14, 29.3

[0074] IR (neat) 2917.53, 1737.76, 1686.83, 1559.92, 1369.89, 1255.88, 1229.12, 1178.37.

[0075] HRMS(ESI+)calcd for C 22 h 29 N 2 o 4 :385.2127,found:385.2112.

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