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Method for preparing deuterated aromatic organic compound

A technology of aromatic compounds and compounds, applied in the preparation of organic compounds, organic chemical methods, and hydrocarbon production from halogen-containing organic compounds, etc., can solve the problems of harsh reaction conditions and poor compatibility

Active Publication Date: 2017-07-07
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although these known methods can effectively synthesize corresponding deuterated aromatic compounds from a wide range of halogenated aromatic compounds, there are obvious deficiencies, such as the general need to use toxic tin hydrogen reagents or expensive transition metals (Pd, Ni, Rh, etc.), deuterated solvents (such as THF-d 5 , 10g / $375, Aldrich or other deuterated reagents such as Bu 3 SnD, NaBD 4 etc.), the reaction conditions are harsh (such as the use of flammable metal reagents at -78 ° C), and the synthesis of target compounds with high selectivity and high deuteration rate is still a big challenge, especially for transition metal-catalyzed reactions. Poor compatibility of unsaturated functional groups such as bonds

Method used

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  • Method for preparing deuterated aromatic organic compound
  • Method for preparing deuterated aromatic organic compound
  • Method for preparing deuterated aromatic organic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Research on alkali metal salts and deuterated solvents using 5-bromo-N-methylindole as a standard substrate dehalogenation reaction:

[0043]

[0044]

[0045] Among them, MA represents alkali metal salt, [CH 3 (H)SiO] n Represents polymethylhydrogensiloxane, equiv refers to the equivalent, deuterated solvent represents a deuterated reagent or a mixture of a deuterated reagent and a conventional solvent, and the volume is 1 mL. Among them, CD 3 CN is deuterated acetonitrile, THF is tetrahydrofuran, Et 2 O is diethyl ether, DME is dimethylethylene ether, MTBE is methyl tert-butyl ether, DMSO-d 6 is deuterated dimethyl sulfoxide. When using a mixed solvent, the molar ratio of the deuterated reagent to the raw material should be ≥1:1, preferably 5:1.

Embodiment 2

[0046] Embodiment 2: Preparation of 5-deuterium-N-methylindole and its gram-level reaction

[0047]

[0048] Dissolve 105 mg of 5-bromo-N-methylindole (0.5 mmol) and 70.15 mg of potassium methoxide (1 mmol) in 1 mL of deuterated acetonitrile, add 200 μL of hexamethyldisilane (1 mmol) dropwise to the mixture, and stir at room temperature Reaction 3h. After the reaction was complete, add 10 mL of water to quench, extract with 30 mL of diethyl ether three times, collect the organic phase, and remove the solvent under reduced pressure. Separation and purification by column chromatography, the eluent is petroleum ether: ethyl acetate = 20:1 (v / v), to obtain 57 mg of 5-deuterium-N-methylindole (pale yellow liquid, yield 87%). 1 H NMR (400MHz, CDCl3) δ=7.72(s,1H),7.43–7.36(m,1H),7.32(s,1H),7.14–7.08(m,1H),6.57(d,J=2.9Hz, 1H), 3.83(s, 3H). GC-MS (EI+): 132.1.

[0049] 2.1 g of 5-bromo-N-methylindole (10 mmol) and 1.403 g of potassium methylate (20 mmol) were dissolved in a mixe...

Embodiment 3

[0050] Embodiment 3: the preparation of 5-deuterium-N-methylindole under mixed solvent

[0051]

[0052] Dissolve 105 mg of 5-bromo-N-methylindole (0.5 mmol) and 70.15 mg of potassium methoxide (1 mmol) in a mixture of 130 μL of deuterated acetonitrile (2.5 mmol) and 870 μL of tetrahydrofuran, and add 200 μL of hexamethanol dropwise to the mixture Base disilane (1mmol), stirred at room temperature for 3h. After the reaction was complete, add 10 mL of water to quench, extract with 30 mL of diethyl ether three times, collect the organic phase, and remove the solvent under reduced pressure. Separation and purification by column chromatography, the eluent is petroleum ether: ethyl acetate = 20:1 (v / v), to obtain 48 mg of 5-deuterium-N-methylindole (pale yellow liquid, yield 73%). 1 H NMR (400MHz, CDCl3) δ=7.72(s,1H),7.43–7.36(m,1H),7.32(s,1H),7.14–7.08(m,1H),6.57(d,J=2.9Hz, 1H), 3.83(s, 3H). GC-MS (EI+): 132.1.

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Abstract

The invention provides a method for preparing a deuterated aromatic organic compound. The method comprises the following steps: firstly, dissolving a halogenated aromatic compound and an alkali metal salt MA into a deuterated solvent or a mixed solvent of the deuterated solvent and a common solvent, dropping an organic silicon reagent, performing stirring reaction at minus 40 DEG C to 150 DEG C, and performing separation purification after reaction, thereby obtaining the deuterated aromatic organic compound. By adopting the method, the deuterated aromatic organic compound can be efficiently, economically and environment-friendly prepared without participation of a transition metal or a metallic tin reagent, and the deuteration rate of the prepared deuterated product is greater than 95%. The method is gentle in condition, good in substrate universality and high in yield, and the prepared deuterated compound can be widely applied to fields of medicine chemistry and organic chemistry.

Description

technical field [0001] The invention relates to a preparation method of deuterated aromatic organic compounds, belonging to the field of organic synthesis. Background technique [0002] Deuterated compounds are due to their mass spectrometry (MS), nuclear magnetic resonance spectrum ( 2 H NMR) and electron spin resonance spectroscopy (ESR) show unique signals, and are widely used in the labeling of reaction intermediates, biological metabolism analysis, natural product biosynthesis verification, pesticide residue detection and pollution source tracking [a) Pieniaszek, H.J.; Mayersohn, M.; Adams, M.P.; Reinhart, R.J.; Barrett, J.S.J. Clin. .;Ju,W.D.J.Pharm.Sci.1999,88,568.c)Gani,D.;Young,D.W.J.Chem.Soc.,Chem.Commun.1983,576.d)Gani,D.;Hitchcock,P.B.;Young,D.W.J. Chem. Soc., Chem. Commun. 1983, 898.]. Especially in the development of generic drugs, all generic drugs need to use deuterated compounds for consistency evaluation. In addition, due to the difference in bond energ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08C07D333/54C07B59/00C07C41/24C07C43/20C07C201/12C07C205/37C07D215/06C07D295/023C07D295/033C07D209/86C07D213/74C07D213/16C07D213/127C07J1/00C07D209/60C07D495/04C07D263/56C07D471/04C07D241/42C07F7/18C07C43/166C07C45/65C07C47/277C07C43/178C07C43/174C07C1/26C07C13/567C07C331/28C07D301/00C07D303/23C07C231/12C07C235/06C07C205/29C07C15/02C07C315/04C07C317/14C07C303/30C07C309/65C07C209/74C07C211/48C07D333/08C07D209/38C07D213/38C07C43/184C07H9/04C07H1/00C07C213/08C07C217/10C07C217/60C07D405/12C07D401/12C07D239/94C07D471/08
Inventor 刘文博王欣钟大猷
Owner WUHAN UNIV
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