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Preparation method of non-transition metal-catalyzed 2-halogenated pyridine compound

A halogenated pyridine and metal-catalyzed technology, which is applied in the field of preparation of pharmaceutical and chemical intermediates, can solve the problems of narrow substrate range, high reaction temperature, and harsh reaction conditions, and achieve great use value, social and economic benefits, and broad market prospects , the effect of easy access to raw materials

Inactive Publication Date: 2018-09-28
DALIAN UNIV OF TECH
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Problems solved by technology

There are many ways to prepare 2-halopyridine compounds, and there are two most classic methods, one is to use 2-hydroxypyridine and POCl 3 、CBr 4 The reaction, but the reaction conditions are relatively harsh, requiring a higher reaction temperature, so that the reaction is limited [J.Org. Chem., 2011, 76, 4149-4153; Tetrahedron Letters., 2012, 53, 647-677]
The second is to use pyridine nitrogen oxide as raw material and Cl 3 CCN, POBr 3 It is a halogen source, but the selectivity of this method is poor, making this type of reaction poorly applicable [Tetrahedron., 2016, 72, 4604-4607; Eur.J.Org.Chem., 2016, 1606-1611]
There are a lot of transition metal-catalyzed carboxylic acid decarboxylation and halogenation reactions, but there are more or less certain defects [J.Am.Chem.Soc.2012, 134, 4258-4263; J.Org.Chem., 2016 ,81,2794.J.Am.Chem.Soc.2017,134,11527-11536], such as: using noble metal catalyst palladium, silver, etc. or poisonous mercury catalyst, the reaction temperature is too high, the substrate range is narrow, only suitable for Aryl carboxylic acid etc.
And there is no report on the decarboxylation and halogenation of pyridinecarboxylic acid, so it is of great significance and potential application value to develop a transition metal-free catalytic system to realize the decarboxylation and chlorination of pyridine-2-carboxylic acid derivatives

Method used

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  • Preparation method of non-transition metal-catalyzed 2-halogenated pyridine compound
  • Preparation method of non-transition metal-catalyzed 2-halogenated pyridine compound
  • Preparation method of non-transition metal-catalyzed 2-halogenated pyridine compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis of 2-chloroquinoline (2a)

[0038]

[0039] Weigh quinoline-2-carboxylic acid (51.9mg, 0.3mmol), sodium carbonate (16.0mg, 0.15mmol), NaCl (26.3mg, 0.45mmol), tert-butyl hypochlorite (102μL, 0.9mmol) into 25mL Schlenk reaction flask, then add CH 2 Cl 2 (2 mL) was placed in an oil bath at 60°C for 5 h. After the reaction was completed, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent, and the silica gel column was used for separation. The yield of 2-chloroquinoline was 82%.

[0040] 1 H NMR (400MHz, CDCl 3 ):δ8.06(d, J=8.6Hz, 1H), 8.00(d, J=8.5Hz, 1H), 7.78(d, J=8.1Hz, 1H), 7.75–7.67(m, 1H), 7.53 (t,J=7.5Hz,1H),7.34(d,J=8.6Hz,1H); 13 C NMR (100MHz, CDCl 3 ): δ150.6, 147.9, 138.9, 130.6, 128.6, 127.6, 127.0, 126.8, 122.3.

Embodiment 2

[0041] Embodiment 2: Synthesis of 2-chloropyridine (2b)

[0042]

[0043]Weigh pyridine-2-carboxylic acid (36.9mg, 0.3mmol), potassium carbonate (4.2mg, 0.03mmol), NCS (60.1mg, 0.45mmol), tert-butyl hypochlorite (68μL, 0.6mmol) into 25mL of Schlenk reaction vial, then add CH 2 Cl 2 (2 mL) was placed in an oil bath at 150°C for 10 h. After the reaction, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent, and silica gel column separation was performed. The yield of 2-chloropyridine was 68%.

[0044] 1 H NMR (400MHz, CDCl3): δ8.40 (dd, J = 4.8, 1.8Hz, 1H), 7.66 (td, J = 7.7, 2.0 Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.23(ddd,J=7.3,4.9,0.7Hz,1H); 13 C NMR (100 MHz, CDCl3): δ151.61, 149.81, 138.69, 124.47, 122.23.

Embodiment 3

[0045] Embodiment 3: Synthesis of 2-chloro-3-phenylpyridine (2c)

[0046]

[0047] Weigh 3-phenylpyridine-2-carboxylic acid (56.7mg, 0.3mmol), sodium carbonate (32.0mg, 0.3mmol), NaCl (26.3mg, 0.45mmol), TBHP (102μL, 0.9mmol) into 25mL of Schlenk reaction bottle, then added THF (2 mL) and placed in an oil bath at 80°C for 20 h. After the reaction was completed, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent, and silica gel column separation was performed. The yield of 2-chloropyridine was 91%. 1 H NMR (400MHz, CDCl3): δ8.38(s, 1H), 7.80–7.57(m, 1H), 7.44(d, J=5.7Hz, 5H), 7.29(dd, J=11.4, 6.6Hz, 1H ); 13 C NMR (100MHz, CDCl 3 ): δ149.7, 148.4, 139.7, 137.5, 137.0, 129.3, 128.4, 122.6.

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Abstract

The invention provides a preparation method of a non-transition metal-catalyzed 2-halogenated pyridine compound. The 2-halogenated pyridine compound is an important component of many medicines and bioactive molecules and has important application in the fields of organic synthesis, medicinal chemistry and the like and wide market prospects. The invention relates to the preparation method of the non-transition metal-catalyzed 2-halogenated pyridine compound. According to the method, pyridine-2-carboxylic acid, derivatives of the pyridine-2-carboxylic acid, NaF, KF, CsF, TBAF, NaCl, KCl, CsCl, TBAC, NCS, NaBr, KBr, CsBr, Br2, TBAB, NBS, NaI, KI, CsI, I2 and NIS are used as raw materials, and under the presence of base and an accelerant and mild conditions, the 2-halogenated pyridine compoundis synthesized. The method has the advantages that the steps are simple, the raw materials are easy to obtain, the reaction conditions are mild and the like; the method has great use value and socialand economic benefits.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical chemical intermediate, in particular to a preparation method of a 2-halopyridine compound. Background technique [0002] 2-halopyridine compounds are not only important structural components of medicines, pesticides, dyes, functional materials, spices and natural products, but also important intermediates in organic synthesis. There are many ways to prepare 2-halopyridine compounds, and there are two most classic methods, one is to use 2-hydroxypyridine and POCl 3 、CBr 4 The reaction, but the reaction conditions are relatively harsh, requiring a higher reaction temperature, so that the reaction is limited [J.Org. Chem., 2011, 76, 4149-4153; Tetrahedron Letters., 2012, 53, 647-677]. The second is to use pyridine nitrogen oxide as raw material and Cl 3 CCN, POBr 3 It is a halogen source, but the selectivity of this method is poor, making this type of reaction poorly applicable [Tetrahe...

Claims

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Application Information

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IPC IPC(8): C07D215/18C07D213/61C07D213/80C07D213/803
CPCC07D213/61C07D213/80C07D213/803C07D215/18
Inventor 冯秀娟张西涛张海霞包明
Owner DALIAN UNIV OF TECH