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Method for preparing deuterated five-membered aromatic heterocyclic compound under catalysis of silver

A technology for aromatic heterocycles and compounds, applied in the field of chemical synthesis, can solve the problems of inability to apply the final stage of drug development, poor functional group compatibility, and high production costs, and achieve the effects of being suitable for large-scale production, high compatibility, and stable deuteration rate.

Inactive Publication Date: 2019-08-23
NANJING UNIV OF TECH
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Problems solved by technology

At present, the reported methods for synthesizing deuterated aromatic five-membered heterocyclic compounds have the following disadvantages: First, they need to be prepared under high temperature and pressure or strong acid and strong alkali conditions, and their functional group compatibility is poor, so they cannot be applied to the final stage of drug development ( Org. Lett. 2004, 2071-2073); Second, the use of expensive deuterated reagents as solvents results in higher production costs ( Angew. Chem. Int. Ed. 2014, 734-737); Third, when the aromatic heterocycle has a substituent, the electronic effect of the substituent has a great influence on the deuterium rate, and the deuterium rate can fluctuate between 30% and 95%, which cannot satisfy Requirements for the deuterium rate in the field of drug research and development ( Chem. Eur. J. 2009, 10397-10404)

Method used

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  • Method for preparing deuterated five-membered aromatic heterocyclic compound under catalysis of silver
  • Method for preparing deuterated five-membered aromatic heterocyclic compound under catalysis of silver
  • Method for preparing deuterated five-membered aromatic heterocyclic compound under catalysis of silver

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1: deuterated saconazole

[0021] Silver reagent (0.3 mmol), phosphine ligand (0.3 mmol), deuterated water (0.4 g, 20 mmol), saconazole (0.39 g, 1 mmol) and dimethyl sulfoxide ( 5 mL). 40 o After C reacted for 12 hours, a saturated ammonium chloride solution was added to quench the reaction, the mixed solution was extracted with dichloromethane, the organic phase was combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain deuterated saconazole with a yield of 85%. . The deuterium substitution rate is 91%. 1 H NMR: δ 7.50 (s, 1 H), 7.46 (d, J = 2.4Hz, 1 H), 7.36 (d, J = 3.2 Hz, 1 H), 7.32 (d, J = 2.4 Hz, 1 H) , 7.08 (d, J =4.8 Hz, 0.09 H), 7.05 (s, 1 H), 6.91 (s, 1 H), 6.78 (s, 1 H), 4.97 (d, J =6.4 Hz, 1 H) , 4.53 (d, J = 9.6 Hz, 1 H), 4.28 (d, J = 9.6 Hz, 1 H), 4.20 (d, J = 12.0 Hz, 1 H), 4.04 (d, J = 12.0 Hz, 1 H); 13 C NMR: 157.85, 126.97, 118.92, 93.06, 61.72.

Embodiment 2

[0022] Embodiment 2: deuterated ticlopidine

[0023] Add silver reagent (0.3 mmol), phosphine ligand (0.3 mmol), deuterated water (0.4 g, 20 mmol), ticlopidine (0.26 g, 1 mmol) and dimethyl sulfoxide into a 10 mL three-necked flask in sequence (5 mL). 40 o After C reacted for 12 hours, a saturated ammonium chloride solution was added to quench the reaction, the mixed solution was extracted with dichloromethane, the organic phase was combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain deuterated ticlopidine with a yield of 95 %. The deuterium substitution rate is 91%. 1 H NMR: δ 7.52 (d, J = 9.6 Hz, 1 H), 7.40 (d, J = 12.0 Hz, 1 H), 7.22 ~ 7.32 (m, 2 H), 7.20 (d, J = 6.4 Hz, 0.09 H), 6.72 (s, 1 H), 3.74 (s, 1 H), 3.52 (s, 1 H), 2.71 ~ 2.82 (m, 4 H); 13 C NMR: 157.85, 126.97, 118.92, 93.06, 61.72.

Embodiment 3

[0024] Embodiment 3: deuterated phenylthiazine

[0025] Into a 10 mL three-necked flask, silver reagent (0.3 mmol), phosphine ligand (0.3 mmol), deuterated water (0.4 g, 20 mmol), thiothiazine (0.28 g, 1 mmol) and dimethyl sulfoxide ( 5 mL). 40 o After C reacted for 12 hours, a saturated ammonium chloride solution was added to quench the reaction, the mixed solution was extracted with dichloromethane, the organic phase was combined, the organic solvent was concentrated, and the product was further purified by column chromatography to obtain deuterated phenylthiazine with a yield of 75%. . The deuterium substitution rate is 91%. 1 H NMR: δ 7.05 ~ 7.35 (m, 4 H), 7.20 (d, J= 6.4 Hz, 0.09 H), 6.83 (s, 1 H), 3.28 ~ 3.50 (m, 2 H), 2.85 ~ 2.97 (m , 2 H),2.52 ~ 2.72 (m, 4 H), 2.25 ~ 2.44 (m, 2 H), 2.22 (s, 3 H); 13 C NMR: 157.85, 126.97, 118.92, 93.06, 61.72.

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Abstract

The invention belongs to the field of chemical synthesis, and concretely relates to a method for preparing a deuterated five-membered aromatic heterocyclic compound through a silver-catalyzed hydrogen-deuterium exchange reaction. Cheap deuterium oxide used as a deuteration reagent and dimethyl sulfoxide used as a solvent are subjected to the silver-catalyzed hydrogen-deuterium exchange reaction under a stirring condition at 25-120 DEG C to exchange hydrogen in the five-membered aromatic heterocycle with deuterium in order to conveniently synthesize the deuterated five-membered aromatic heterocyclic compound. The method has the advantages of mild conditions, avoiding of expensive transition metals and deuteration reagents in the reaction process, reduction of the production cost, and suitableness for large-scale production. The deuteration rate of the deuterated aromatic heterocyclic compound reaches 90% or more, the substrate application range is wide, and the compound can be applied to fields of organic photoelectric materials and medicinal pesticides.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a silver-catalyzed hydrogen-deuterium exchange reaction for preparing deuterated five-membered aromatic heterocyclic compounds. Background technique [0002] Deuterium is an isotope of hydrogen consisting of a neutron and a proton with twice the mass of a hydrogen atom. Due to the influence of mass effect, carbon-deuterium bond has shorter bond length, higher bond energy and lower vibration energy than carbon-hydrogen bond. Therefore, deuterated compounds are widely used in the fields of life, environment and NMR identification of organic matter. Especially in the field of pharmaceutical design, deuterium has a unique role: after the hydrogen in the drug molecule is replaced by deuterium, the metabolic stability of the drug molecule can be improved without changing the targeting of the drug molecule. Through deuterium modification, some drugs that have been abandoned due to me...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D495/04C07D409/04C07D277/56C07D277/62C07D333/54C07D333/08C07D333/16C07D333/38C07B59/00
CPCC07D409/12C07D495/04C07D409/04C07D277/56C07D277/62C07D333/54C07D333/08C07D333/16C07D333/38C07B59/002C07B2200/05
Inventor 张宏海李恩赐胡光棋朱玉杏沈康杭晓春
Owner NANJING UNIV OF TECH
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