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Deuterated compound synthesis method

A deuterated compound and synthetic method technology, applied in the field of isotope labeling chemical synthesis, can solve the problems of harsh reaction conditions, flammable and explosive, expensive deuterium sources, etc., and achieve good substrate applicability, easy availability, and high-efficiency multi-deuterium effect of modernization

Active Publication Date: 2019-01-25
HUAZHONG UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] For the above deficiencies or improvement needs of the prior art, the object of the present invention is to provide a synthetic method of deuterated compounds, wherein through the reaction process of its key reduction deuterated reaction, the type and proportion of each raw material used, The research and improvement of the corresponding reaction conditions can effectively solve the problems of harsh reaction conditions and expensive, toxic or flammable and explosive deuterium sources in the preparation process of deuterated compounds compared with the existing technology.

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preparation example Construction

[0034] In general, the synthetic method of the deuterated compound provided by the invention specifically comprises the following steps:

[0035] (1) Halogenated compound shown in formula (I), sulfide shown in formula (II), promotor, alkali and deuterated solvent are mixed, and the amount of the substance of described sulfide (formula (II)) is described Halogenated compound (formula (I)) more than twice (that is, the ratio of the amount of sulfide and halogenated compound is greater than or equal to 2:1), the amount of the substance of the base is the amount of the halogenated compound (Formula (I)) is more than double (ie, the ratio of the amount of the base to the halogenated compound is greater than or equal to 1:1), and a mixed system of reaction raw materials is obtained.

[0036] The reaction process of the above-mentioned method is as follows, wherein, the halogenated compound shown in formula (I) produces the free radical shown in formula (IV) under dehalogenation reac...

Embodiment 1

[0049] Embodiment 1: the synthesis of compound 1a

[0050]

[0051] a), weigh iodo compound 1 (30mg), bismuth trioxide (0.4mg, 1mol%), p-toluenethiol (p-toluenethiol, 55.2mg, 5equiv) in a 10mL reaction flask, and then Add acetonitrile (1.5ml), heavy water (1.5ml) and 2,6-lutidine (51.3μL, 5equiv), react under 1W blue LED light irradiation, and stop the reaction after iodo compound 1 is consumed (16h ). Extracted three times with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, separated and purified by column chromatography to obtain compound 1a (18.1 mg), the yield was 96%, and the deuterated rate was 97%.

[0052] b), iodo compound 1 (20mg), Pepto Bismol (containing C 7 h 5 BiO 4 ) (4.3mg, 5mol%) and p-methylthiophenol (36.8mg, 5equiv) were weighed in a 10mL reaction flask, and then acetonitrile (1.0ml), heavy water (1.0ml) and 2,6-dimethyl Basepyridine (34.2 μL, 5...

Embodiment 2

[0058] Embodiment 2: the synthesis of compound 2a

[0059]

[0060] a), weigh iodo compound 2 (30mg), bismuth trioxide (0.4mg, 1mol%), and p-methylthiophenol (53.8mg, 5equiv) in a 10mL reaction flask, and then add acetonitrile (1.5 ml), heavy water (1.5ml) and N,N-diisopropylethylamine (75.5μL, 5equiv) were reacted under 1W blue LED light irradiation, and the reaction was terminated after iodo compound 2 was consumed (9h). Extracted three times with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, separated and purified by column chromatography to obtain compound 2a (18.0 mg), the yield was 94%, and the deuterated rate was 97%.

[0061] b), weigh iodo compound 2 (30mg), bismuth trioxide (0.4mg, 1mol%), and p-methylthiophenol (53.8mg, 5equiv) in a 10mL reaction flask, and then add acetonitrile (1.5 ml), heavy water (1.5ml) and 2,6-lutidine (50.0μL, 5equiv), react under 1W b...

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Abstract

The invention discloses a deuterated compound synthesis method, which comprises: carrying out a mixing reaction on a halogenated compound represented by a formula (I), a sulfide represented by a formula (II), a promoter, an alkali and a deuteration solvent to obtain a reduced deuterated product represented by a formula (III), wherein the reaction equation of the reaction is defined in the specification, R<1>, R<2>, R<3> and R<4> respectively are at least one selected from alkyl, aryl, acyl, hydrogen atom and deuterium atom, and X is at least one selected from iodine, bromine and chlorine. According to the present invention, the deuteration marking of the compound is efficiently achieved by using the common heavy water and the deuterated alcohol as the deuterium source through the simple reduction reaction, such that the use of expensive, toxic, flammable and explosive deuterium source reagents is not required compared with the prior art. The formulas I, II and III are defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of isotope labeling chemical synthesis, and more specifically relates to a method for synthesizing a deuterated compound. Background technique [0002] Deuterium (D)-labeled compounds have been widely used in many scientific fields such as organic chemistry, organometallic chemistry, spectroscopy, and pharmacy. Specifically, in the field of organic chemistry, the isotope labeling method is used to study the mechanism of the reaction; in the field of metal organics, deuterium-labeled compounds are used to prepare new metal materials; in terms of spectroscopy, deuterium-labeled compounds can be used as internal standard substances; The drug is modified with deuterium to change the metabolism process of the drug in vivo, and then obtain a drug with better efficacy. In view of the wide application of deuterated compounds, the preparation of deuterated compounds is particularly important. At present, deuterated...

Claims

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Application Information

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IPC IPC(8): C07B59/00C07D205/04C07D207/16C07D209/08C07D295/205C07D307/00C07D309/30C07D451/02C07H1/00C07H9/04C07H15/18C07J1/00C07J71/00C07D493/04
CPCC07B59/002C07B59/005C07B59/007C07B2200/05C07D205/04C07D207/16C07D209/08C07D295/205C07D307/00C07D309/30C07D451/02C07D493/04C07H1/00C07H9/04C07H15/18C07J1/00C07J71/0005
Inventor 万谦曾静孟令奎陈薇王浩赵祥
Owner HUAZHONG UNIV OF SCI & TECH
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