Preparation method of deuterated chemical
阅读说明：本技术 一种氘代化学品的制备方法 (Preparation method of deuterated chemical ) 是由 苏陈良 张兵 邱春天 李瑛� 于 2019-12-05 设计创作，主要内容包括：本发明公开一种氘代化学品的制备方法,其包括步骤：卤代烃类化合物在电场、催化剂共同催化作用下,与氘源进行脱卤加氘反应,得到氘代化学品；其中所述氘源为氘水、氘代醇类化合物、氘代酸类化合物中的一种或多种。本发明以环保、廉价的氘水或氘代试剂来代替氘气作为氘源,在电催化的作用下实现在温和的条件下对卤代烃类化合物的定点选择性氘化反应。本方法较传统的氘化反应具有更高的选择性、更温和的反应条件以及更经济适用性,适合用于大规模氘代化学品生产。(The invention discloses a preparation method of a deuterated chemical, which comprises the following steps: under the combined catalysis of an electric field and a catalyst, the halogenated hydrocarbon compound and a deuterium source are subjected to dehalogenation and deuterium addition reaction to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound. The invention uses environment-friendly and cheap deuterium water or a deuterium substitute reagent to replace deuterium gas as a deuterium source, and realizes site-specific selective deuteration reaction on halogenated hydrocarbon compounds under the action of electrocatalysis under mild conditions. Compared with the traditional deuteration reaction, the method has higher selectivity, milder reaction conditions and more economic applicability, and is suitable for large-scale production of deuterated chemicals.)
1. A preparation method of a deuterated chemical is characterized by comprising the following steps: under the combined catalysis of an electric field and a catalyst, the halogenated hydrocarbon compound and a deuterium source are subjected to dehalogenation and deuterium addition reaction to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound.
2. The method of claim 1, further comprising: adding a halogenated hydrocarbon compound, a catalyst, a deuterium source and a solvent into a reaction bottle, placing an electrode into the reaction bottle, and introducing voltage to perform dehalogenation and deuterium addition reaction at the reaction temperature of between room temperature and 80 ℃ in an inert gas atmosphere to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound.
3. The method of claim 1 or 2, wherein the deuterated alcohol compound is deuterated methanol, deuterated ethanol, deuterated propanol or deuterated isopropanol.
4. The method of claim 1 or 2, wherein the deuterated acid compound is deuterated formic acid or deuterated acetic acid.
5. The method of preparing a deuterated chemical according to claim 1 or 2, wherein the catalyst is a homogeneous catalyst or a heterogeneous catalyst;
the homogeneous catalyst is palladium acetate, palladium acetylacetonate, palladium chloride or platinum chloride;
the heterogeneous catalyst is palladium carbon or palladium aluminum oxide.
6. The method of claim 2, wherein the voltage is 0-10V.
7. The method of claim 6, wherein the voltage is 2.5-5V.
8. The method of claim 1 or 2, wherein the molar ratio of the deuterium source to the halogenated hydrocarbon is greater than 1.
9. The method of claim 2, wherein the electrode is a platinum electrode, a graphite electrode, a glassy carbon electrode, a transition metal oxide electrode, a transition metal sulfide electrode, or a transition metal carbide electrode.
10. The method for preparing a deuterated chemical as recited in claim 1 or 2, wherein the structure of the halogenated hydrocarbon compound is represented by formula (I),
wherein X is F, Cl, Br, I, R1、R2And R3Each independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said alkyl, alkenyl and alkynyl are substituted with a substituent selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -, and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R2And R3And the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, which is substituted with 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C,C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy and C1-4Substituted with a haloalkyl;
or R1、R2And R3Each independently is hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl; said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said C1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl is substituted by 0, 1,2 or 3 substituents selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R3And R4、R2And R4Together with the carbon atom to which they are attached form C3-10Carbocyclic ring or 3-to 10-membered heterocyclic ring, said C3-10The carbocycle and the 3-10 membered heterocycle may be substituted by 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxyAmino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical, C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, methyl, ethyl, n-propyl, t-butyl, methoxy, ethoxy, trifluoromethyl and difluoromethyl.
Technical Field
The invention relates to the field of preparing chemicals by electrocatalysis, in particular to a preparation method of a deuterated chemical.
Background
The deuterated chemicals are special compounds and have important application in the fields of reaction mechanism research, dynamics, drug metabolism, biological structure determination and the like. Heavy isotopes of hydrogen (deuterium or tritium) are typically introduced into target compounds by multi-step synthesis. The hydrogen deuterium exchange reaction commonly used today is a very attractive strategy, however this process faces huge challenges. On one hand, deuterium is often used as a deuterium source in the hydrogen-deuterium exchange reaction, and most processes involve conditions of high temperature, high pressure, strong acid and strong base, so that the reaction equipment is also required to be high; on the other hand, the selectivity of the hydrogen-deuterium exchange reaction is difficult to control, and the fixed-point deuteration on the number of deuterium atoms and key sites of the deuteration product is difficult to realize. Thus, existing deuteration strategies and techniques are in need of further improvement and development.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, the present invention aims to provide a method for preparing a deuterated chemical, which aims to solve the problems of the prior deuterium addition reaction that deuterium gas is required, high temperature and high pressure conditions are required, and selectivity is not high.
The technical scheme of the invention is as follows:
a preparation method of a deuterated chemical comprises the following steps: under the combined catalysis of an electric field and a catalyst, the halogenated hydrocarbon compound and a deuterium source are subjected to dehalogenation and deuterium addition reaction to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound.
Further, the method specifically comprises the following steps: adding a halogenated hydrocarbon compound, a catalyst, a deuterium source and a solvent into a reaction bottle, placing an electrode into the reaction bottle, and introducing voltage to perform dehalogenation and deuterium addition reaction at the reaction temperature of between room temperature and 80 ℃ in an inert gas atmosphere to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound.
Further, the deuterated alcohol compound is deuterated methanol, deuterated ethanol, deuterated propanol or deuterated isopropanol.
Further, the deuterated acid compound is deuterated formic acid or deuterated acetic acid.
Further, the catalyst is a homogeneous catalyst or a heterogeneous catalyst;
the homogeneous catalyst is palladium acetate, palladium acetylacetonate, palladium chloride or platinum chloride;
the heterogeneous catalyst is palladium carbon or palladium aluminum oxide.
Further, the voltage is 0-10V.
Further, the voltage is 2.5-5V.
Further, the molar ratio of the deuterium source to the halogenated hydrocarbon compound is greater than 1.
Further, the electrode is a platinum electrode, a graphite electrode, a glassy carbon electrode, a transition metal oxide electrode, a transition metal sulfide electrode, or a transition metal carbide electrode.
Further, the structure of the halogenated hydrocarbon compound is shown as a formula (I),
wherein X is F, Cl, Br, I, R1、R2And R3Each independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said alkyl, alkenyl and alkynyl are substituted with a substituent selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -, and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R2And R3And the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, which is substituted with 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy and C1-4Substituted with a haloalkyl;
or R1、R2And R3Each independently is hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl; said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said C1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl is substituted by 0, 1,2 or 3 substituents selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R3And R4、R2And R4Together with the carbon atom to which they are attached form C3-10Carbocyclic ring or 3-to 10-membered heterocyclic ring, said C3-10The carbocycle and the 3-10 membered heterocycle may be substituted by 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical, C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, methyl, ethyl, n-propyl, t-butyl, methoxy, ethoxy, trifluoromethyl and difluoromethyl.
Has the advantages that: the invention uses green and cheap deuterium water or deuterium reagent to replace deuterium gas as a deuterium source, realizes the fixed-point selective dehalogenation and deuterium addition reaction of halogenated hydrocarbon to synthesize the high-added-value deuterium chemical by using the electrocatalysis technology at normal temperature and normal pressure, and solves the problems of the existing deuterium addition reaction scheme that the deuterium gas is used, the reaction condition is harsh, the selectivity is low and the like. Because the reaction condition is milder, the new method can deuterate a series of chemicals, has the advantages of controllable and adjustable deuteration sites and number and the like, can reduce the preparation cost of the deuterated chemicals, and can be widely applied to reaction mechanism research, dynamics research, drug metabolism calibration, biomolecule marking and the like.
Drawings
FIG. 1 is a high resolution mass spectrum of deuterated acetophenone of example 1.
FIG. 2 is a high resolution mass spectrum of deuterated acetophenone from example 2.
FIG. 3 is a high resolution mass spectrum of deuterated acetophenone of example 3.
Figure 4 is the nuclear magnetic spectrum of the deuterated coumarin obtained from example 4.
FIG. 5 is the nuclear magnetic spectrum of deuterated non-nilamin of the product of example 5.
Detailed Description
The present invention provides a method for preparing a deuterated chemical, and the present invention is further described in detail below in order to make the objects, technical schemes, and effects of the present invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a preparation method of a deuterated chemical, which comprises the following steps: under the combined catalysis of an electric field and a catalyst, the halogenated hydrocarbon compound and a deuterium source are subjected to dehalogenation and deuterium addition reaction to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound.
In the embodiment, green and cheap deuterium water or a deuterium reagent is used as a deuterium source to replace deuterium gas, the fixed-point selective dehalogenation and deuterium addition reaction of the halogenated hydrocarbon is realized at normal temperature and normal pressure by using an electro-catalytic technology to synthesize the deuterium chemical, and specifically, a deuterium intermediate with high activity is generated by using electrolytic deuterium water or the deuterium reagent, and the selective deuteration of a specific site in the halogenated hydrocarbon compound is realized by combining a carbon-halogen bond dehalogenation and deuterium addition technology. Aims to solve the problems that deuterium gas needs to be used in the existing deuterium adding reaction, the reaction conditions are harsh (harsh conditions such as high temperature, high pressure and the like), the selectivity is not high and the like. Because the reaction condition is milder, the new method of the embodiment can deuterate a series of chemicals, has the advantages of controllable and adjustable deuteration sites and number and the like, can reduce the preparation cost of the deuterated chemicals, and can be widely applied to reaction mechanism research, dynamics research, drug metabolism calibration, biomolecule marking and the like. By utilizing the novel method, a series of deuterated chemicals with high added values can be obtained, the reaction requirement energy consumption is low, the product selectivity is high, the separation is simple, the pollutant emission is less, the requirements of green industry and national energy-saving and emission-reduction policies are met, and the industrial application prospect is wide.
The site-directed deuteration technique of this example has higher selectivity and deuteration efficiency relative to hydrogen-deuterium exchange catalysis. By selecting different voltages, controlled deuteration of different functional groups and sites can be achieved, and thus can be a more desirable deuteration strategy.
In one embodiment, the method for preparing a deuterated chemical specifically comprises the following steps: adding a halogenated hydrocarbon compound, a catalyst, a deuterium source and a solvent into a reaction bottle, placing an electrode into the reaction bottle, and introducing voltage to perform dehalogenation and deuterium addition reaction at the reaction temperature of between room temperature and 80 ℃ in an inert gas atmosphere to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water, a deuterated alcohol compound and a deuterated acid compound. Note that the "room temperature" generally means a room temperature of 18 ℃ to 35 ℃, or 20 ℃ to 30 ℃. Further in one embodiment, the reaction temperature is room temperature.
Further in one embodiment, the deuterated alcohol compound is deuterated methanol, deuterated ethanol, deuterated propanol or deuterated isopropanol, etc.; further, in one embodiment, the deuterated acid compound is deuterated formic acid, deuterated acetic acid or the like.
In one embodiment, the solvent is one or more of organic solvents such as acetonitrile, acetone, nitrogen-nitrogen dimethyl formamide and the like; further in one embodiment, the solvent is acetonitrile.
In one embodiment, the catalyst is a homogeneous catalyst or a heterogeneous catalyst; the homogeneous catalyst is palladium acetate, palladium acetylacetonate, palladium chloride or platinum chloride and the like, but is not limited thereto; the heterogeneous catalyst is palladium carbon or palladium alumina, etc., but is not limited thereto. Further in one embodiment, the homogeneous catalyst is palladium acetylacetonate in view of coordination; the heterogeneous catalyst is palladium on carbon in consideration of cost, reaction efficiency and stability.
In one embodiment, the voltage is 0-10V. Further in one embodiment, to overcome the reaction energy barrier and reduce the occurrence of side reactions, the voltage is 2.5-5V.
In one embodiment, the reaction concentration of the halogenated hydrocarbon compound is 10 to 1000mmol/L in consideration of solubility and reaction rate; considering the efficiency of substitution of the halogen by the deuterium source, the molar ratio of the deuterium source to the halogenated hydrocarbon compound is greater than 1.
In one embodiment, the electrode is a platinum (Pt) electrode, a graphite electrode, a glassy carbon electrode, a transition metal oxide electrode, a transition metal sulfide electrode, a transition metal carbide electrode, or the like, but is not limited thereto. Further in one embodiment, the electrode is a graphite electrode, taking into account cost and processing.
In one embodiment, the structure of the halogenated hydrocarbon compound is shown as formula (I),
wherein X is F, Cl, Br, I, R1、R2And R3Each independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said alkyl, alkenyl and alkynyl are substituted with a substituent selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -, and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R2And R3And the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, which is substituted with 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo (═ O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, mercapto, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-C (═ O) -O-, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy and C1-4Substituted with a haloalkyl;
or R1、R2And R3Each independently is hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl; said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5RaSubstitution; or said C1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl is substituted by 0, 1,2 or 3 substituents selected from the group consisting of-O-, -S-, -NH-, -C (═ O) -, -S (═ O) -and-S (═ O)2-a group substitution; or R1And R2、R1And R3、R3And R4、R2And R4Together with the carbon atom to which they are attached form C3-10Carbocyclic ring or 3-to 10-membered heterocyclic ring, said C3-10The carbocycle and the 3-10 membered heterocycle may be substituted by 0, 1,2,3,4 or 5RbSubstitution;
each Ra、RbAnd RcIndependently hydrogen, oxo (═ O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, mercapto, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; the hydroxyl, amino, mercapto and C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical, C1-4Alkyl radical, C1-4alkyl-C (═ O) -, C1-4alkyl-C (═ O) -O-, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently substituted with 0, 1,2,3,4 or 5 substituents selected from hydrogen, oxo (═ O), fluoro, chloro, bromo, iodo, hydroxy, amino, mercapto, nitro, cyano, methyl, ethyl, n-propyl, t-butyl, methoxy, ethoxy, trifluoromethyl and difluoromethyl.
"carbocyclic" in this embodiment refers to a non-aromatic carbocyclic ring system containing 3 to 14 ring carbon atoms that is saturated or contains one or more units of unsaturation. In some embodiments, the number of carbon atoms is 3 to 12; in other embodiments, the number of carbon atoms is from 3 to 10; in other embodiments, the number of carbon atoms is from 3 to 8; in other embodiments, the number of carbon atoms is from 3 to 6; in other embodiments, the number of carbon atoms is from 5 to 6; in other embodiments, the number of carbon atoms is from 5 to 8. In other embodiments, the number of carbon atoms is from 6 to 8. Such "carbocycle" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocycle may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the atom groups or points of attachment are on the carbocycle. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system contains two rings that share 2 contiguous ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridging carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.
"Heterocyclyl" and "heterocycle" in this embodiment are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms, and wherein the ring system has one or more attachment points to the rest of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, as well as polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-12 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 3 ring atoms; in other embodimentsIn (1), the heterocyclic group is a ring system composed of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.
Examples of heterocyclyl groups include, but are not limited to: the heterocyclic group may be a carbon-based or heteroatom group. "Heterocyclyl" also includes groups formed by the fusion of heterocyclic groups with saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepinyl, oxepinyl, azepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienoalkyl, dithienyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1, 1-dioxothiomorpholinyl; examples of the group in which the carbon atom on the ring is substituted with an oxo (═ O) group include, but are not limited to, pyrimidinedione group, 1,2, 4-thiadiazol-5 (4H) -one group, 1,2, 4-oxadiazol-5 (4H) -one group, 1H-1,2, 4-triazol-5 (4H) -one group and the like; examples in which the carbon atom on the ring is substituted with an ═ S group include, but are not limited to, 1,2, 4-oxadiazol-5 (4H) -thioketo, 1,3, 4-oxadiazol-2 (3H) -thioketo, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described in the examples herein.
"aryl" in this embodiment means a monocyclic, bicyclic, and tricyclic carbon ring system containing 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 carbon atoms in the ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.
"heteroaryl" in this embodiment denotes monocyclic, bicyclic, and tricyclic ring systems containing 5 to 16 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. In some embodiments, heteroaryl is 5-14 atoms consisting of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-12 atoms inclusive of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-8 atoms inclusive of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-7 atoms consisting of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-6 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, or dibenzothienyl, and the like. The heteroaryl group is optionally substituted with one or more substituents described in the examples herein.
The present invention is further illustrated by the following specific examples.
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