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Preparation method of o-position deuterated benzoic acid compound

A technology of deuterated benzoic acid and compounds, which is applied in the field of synthesis of deuterated compounds, can solve the problems of low deuterated rate of reaction, difficult production and supply, low deuterated rate of ortho-deuterated o-toluic acid, etc. Achieve the effect of good economy, wide application and high selectivity

Active Publication Date: 2018-06-22
ZHEJIANG UNIV
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Problems solved by technology

[0011] The deuteration rate of ortho-deuterated o-toluic acid obtained by this method is also relatively low, only 69%, and the catalyst used is a complex of rhenium carbonyl. Obtained by the reaction of carbon monoxide and rhenium oxide, involving highly toxic, flammable and explosive carbon monoxide gas, not suitable for industrial production
[0012] The synthetic method of the benzoic acid compound of existing ortho-deuterated mainly is to use transitional metal complex as catalyzer, and deuterated reagent is made the source of deuterium to react, but reaction deuterated rate is generally not high, and all there is catalyst expensive, Shortcomings such as difficulty in production and supply

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  • Preparation method of o-position deuterated benzoic acid compound
  • Preparation method of o-position deuterated benzoic acid compound
  • Preparation method of o-position deuterated benzoic acid compound

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Embodiment 1-1

[0057] The preparation method of embodiment 1-1,6-deuterium-2-methylbenzoic acid (m1), carries out the following steps successively:

[0058] 1) Weigh 0.1312g (0.5mmol, 1.0eq.) of 8-aminoquinoline o-toluic acid amide, 0.0224g (0.1mmol, 0.2eq.) of palladium acetate and 2mL of heavy water in a sealed tube. After sealing Reaction in an oil bath at 140°C for 48h.

[0059] 2), after the reaction solution obtained in step 1) was cooled to room temperature, 15mL of water was added, and ethyl acetate (3×20mL) was added for extraction, the organic phases were combined, washed with saturated brine (30mL), and then washed with anhydrous sodium sulfate 4g was dried, concentrated under reduced pressure by a rotary evaporator, the concentration temperature was 30-40°C, the vacuum degree was not lower than -0.07MPa, and concentrated until there was no obvious droplet dripping to obtain a concentrate;

[0060] 3), the concentrate obtained in step 2) is separated and purified by silica gel ch...

Embodiment 1-2

[0069] Example 1-2, changing the 140°C locking reaction to 120°C locking reaction, the rest is the same as Example 1-1, and the deuteration rate is 81%.

[0070] Example 1-3, changing the 140°C locking reaction to 160°C locking reaction, the rest is the same as Example 1-1, and the deuteration rate is 96%.

[0071] Example 1-4, changing the 140°C locking reaction to a reflux device reflux reaction, the rest is the same as Example 1-1, and the deuteration rate is 96%.

Embodiment 1-5

[0072] Example 1-5, change 0.2eq. palladium acetate to 0.1eq., the rest are the same as Example 1-1, the deuteration rate is 91%.

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Abstract

The invention discloses a preparation method of an o-position deuterated benzoic acid compound. The preparation method sequentially comprises the following steps: carrying out an oil bath reaction on8-aminoquinoline substituted benzoic acid amide used as a raw material under a sealing state at a temperature of 120-160 DEG C for 24-72 hours in the presence of a deuterated reagent and a palladium catalyst, cooling the obtained reaction liquid to room temperature, carrying out extraction, washing the obtained organic layer, and carrying out drying and concentration; carrying out silica gel column chromatography on the obtained concentrate; carrying out an oil bath reaction on the obtained deuterated intermediate in a sulfuric acid water solution at 120+ / -20 DEG C until a TLC detection reaction is completed; cooling the obtained reaction solution to room temperature, carrying out extraction, washing the obtained ether layer, and carrying out drying, suction filtration and concentration toobtain the o-position deuterated benzoic acid compound. The o-position deuterated benzoic acid compound prepared by adopting the method provided by the invention has the technical advantages of highyield, good selectivity and good economical efficiency.

Description

technical field [0001] The invention belongs to a synthesis method of a deuterated compound, in particular to a preparation method of an ortho-deuterated benzoic acid compound. Background technique [0002] Deuterium reaction has a wide range of applications in the pharmaceutical industry. First of all, due to the characteristic radioactive absorption of the isotope-labeled drug by deuteration reaction, specific β-nuclear detectors can be used to detect and track the position, quantity and transformation of the drug in the body. Theoretical research in science and other related disciplines provides an effective and reliable experimental basis. Secondly, in exploring the mechanism of some organic reactions, the deuterium atom can be tracked by deuterating the hydrogen at a specific position in the reactant, which can be used as a basis to explain some difficult-to-study organic chemical reaction mechanisms (Thomas G et al., Using Deuterium in Drug Discovery: Leaving the Lab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/40C07C51/06C07C63/04C07C63/06C07C65/21C07B59/00
CPCC07B59/001C07B59/002C07B2200/05C07C51/06C07D215/40C07C63/04C07C63/06C07C65/21
Inventor 章国林赵冬红罗浩帆俞永平
Owner ZHEJIANG UNIV
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