Preparation method of deuterated aromatic compound

A technology for aromatic compounds and compounds, applied in the field of preparation of deuterated aromatic compounds, can solve the problems of low deuterated rate, low product yield, poor selectivity and the like

Pending Publication Date: 2022-03-01
TIANJIN JIKUN MEDICAL TECH CO LTD
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Problems solved by technology

At present, the hydrogen-deuterium exchange reaction that has been reported is catalyzed by Ir and Fe. Although this met

Method used

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  • Preparation method of deuterated aromatic compound
  • Preparation method of deuterated aromatic compound
  • Preparation method of deuterated aromatic compound

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[0029] The invention provides a kind of preparation method of deuterated aromatic compound, comprises the following steps:

[0030] Mix aryl boronic acid, photocatalyst, Lewis base catalyst, mercaptan catalyst, deuterated water and organic solvent, and perform deboronated deuterated reaction under visible light irradiation condition to obtain deuterated aromatic compound.

[0031] In the present invention, the photocatalyst is preferably Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 , the specific structure is as follows:

[0032]

[0033] In the present invention, the Lewis base catalyst preferably includes one or more of quinuclidine, quinuclidin-3-ol, triethylamine, triphenylphosphine and 4-dimethylaminopyridine; the sulfur Alcohol catalysts preferably include substituted or unsubstituted thiophenols, C 4 ~C 16 One or more of the alkylthiols, the substituted thiophenol is preferably alkylthiophenol, more preferably p-methylthiophenol, p-tert-butylthiophenol or p-isopropyl Thioph...

Embodiment 1

[0061] Embodiment 1: Synthesis of 2-methyl-2-(phenoxy-4-d) ethyl propionate:

[0062] Weigh 0.2mmol (4-((1-ethoxy-2-methyl-1-oxopropan-2-yl) oxy)phenyl) boronic acid, 0.004mmol photocatalyst Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 , 0.04mmol quinuclidin-3-ol, 0.08mmol tert-butyl mercaptan in an 8mL reaction bottle, then add 1mL deuterated chloroform, 1mL deuterated water, blow argon gas into the reaction bottle for 30s, and use 470nm blue light at 36W React under irradiation for 24 hours, spin off the solvent, and the resulting crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a white solid with a yield of 85% and a melting point of 124-125°C. 1 HNMR (400MHz, CDCl 3 )δ7.25(d, J=8.4Hz, 2H), 6.87(d, J=8.4Hz, 2H), 4.26(q, J=7.2Hz, 2H), 1.62(s, 6H), 1.26(t, J=7.2Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ174.4, 155.5, 129.1, 121.8 (t, J=24.5Hz), 119.1, 79.0, 61.4, 25.4, 14.1. HRMS (EI-FTMS) m / z: [M] + ·Calcd for C 12 h 15 do 3 209.116...

Embodiment 2

[0063] Embodiment 2: the synthesis of tyrosine-4-d:

[0064] Weigh 0.2mmol (4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronic acid, 0.004mmol photocatalyst Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 , 0.04mmol quinuclidin-3-ol, 0.08mmol tert-butyl mercaptan in 8mL reaction bottle, then add 1mL deuterated chloroform solution, 1mL deuterated water, blow argon gas into the reaction bottle for 30s, at 36W at 470nm The reaction was performed under blue light irradiation for 24 hours, and the solvent was spun off. The obtained crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a white solid with a yield of 62% and a melting point of 187-188°C. 1 HNMR (400MHz, CDCl 3 )δ7.28(d, J=7.2Hz, 2H), 7.12(d, J=7.2Hz, 2H), 5.00(d, J=7.2Hz, 1H), 4.59(dd, J=13.6, 6.0Hz, 1H), 3.71(s, 3H), 3.08(qd, J=13.6, 6.0Hz, 2H), 1.42(s, 9H). 13 C NMR (100MHz, CDCl 3 )δ172.4, 155.1, 136.0, 129.3, 128.6, 128.5, 127.8 (t, J = 23.5Hz), 127.1, 80....

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Abstract

The invention relates to the technical field of fine chemicals, and provides a preparation method of a deuterated aromatic compound. The method comprises the following steps: mixing arylboronic acid, a photocatalyst, a Lewis base catalyst, a mercaptan catalyst, deuterated water and an organic solvent, and carrying out deboration deuteration reaction under a visible light irradiation condition to obtain the deuterated aromatic compound. According to the method, the deboration deuteration reaction of arylboronic acid is synergistically catalyzed by adopting visible light, Lewis alkali and mercaptan, the deuterated aromatic compound can be obtained in one step, the deuteration rate is high, the selectivity is good, and the product yield is high; by adopting the method disclosed by the invention, deuterated modification of complex arylboronic acid molecules and drugs can be realized. The result of the embodiment shows that the yield of the deuterated aromatic compound prepared by the preparation method provided by the invention can reach 90%.

Description

technical field [0001] The invention relates to the technical field of fine chemicals, in particular to a preparation method of deuterated aromatic compounds. Background technique [0002] Deuterium as a labeling technique has important applications in the study of reaction mechanism, drug absorption, distribution, metabolism and excretion (ADME) research, nuclear magnetic resonance spectroscopy and mass spectrometry research. In recent years, studies have found that the introduction of deuterium atoms into drug molecules can enhance the metabolic and pharmacokinetic properties of the drug while maintaining its basic pharmacological activity, which has led to the rapid development of deuterium in the field of drugs. [0003] Aromatic compounds are ubiquitous in organic synthesis, and the introduction of deuterium atoms into aromatic rings is of great significance for the study of deuterated drug molecules. The most commonly used method for the synthesis of deuterated aromat...

Claims

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Application Information

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IPC IPC(8): C07C41/18
CPCC07C41/18C07D309/12C07D319/18C07C1/321C07C17/35C07C319/20C07C231/12C07C209/68C07D209/08C07D209/86C07D333/76C07J1/0059C07C213/08C07C217/16C07B59/001C07B59/002C07B2200/05C07C2602/08C07C2603/18C07C2603/24C07C2603/26C07C2603/94C07C2531/22C07C43/205C07C43/225C07C43/2055C07C15/14C07C15/24C07C15/30C07C15/28C07C13/567C07C13/72C07C25/18C07C25/22C07C43/202C07C321/28C07C233/07C07C211/54
Inventor 杨诚汪清民杨光董建洋周红刚
Owner TIANJIN JIKUN MEDICAL TECH CO LTD
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