CN113717099A - Bromination reaction method and application of nitrogen-containing heterocyclic compound - Google Patents
Bromination reaction method and application of nitrogen-containing heterocyclic compound Download PDFInfo
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a bromination reaction method and application of a nitrogen-containing heterocyclic compound, and relates to the technical field of organic synthesis. The method for bromination reaction of the nitrogen-containing heterocyclic compound comprises the following steps: reacting C-H activated nitrogenous heterocyclic benzyl quaternary ammonium salt with a bromization reagent in the presence of an additive; wherein the additive is at least one of organic acid and organic base; the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is at least one of N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenyl pyridine quaternary ammonium salt. Has the advantages of good yield, high selectivity and better atom economy, and is suitable for popularization and application. Bromo-product dibromoquinoline compounds or dibromopyridine compounds are further subjected to coupling reaction to obtain complex compound molecules and drug molecules with greater application potential.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a bromination reaction method and application of a nitrogen-containing heterocyclic compound.
Background
The brominated nitrogenous heterocyclic compound is widely used as an important structural skeleton in drug molecules and bioactive molecules. At present, the most common method is to use POBr as the raw material at high temperature using aminopyridine or quinoline3Or Br2A bromination reaction is carried out.
However, the conventional production method mainly depends on a substrate for regional control, and has side reactions such as debromination products and over-bromination.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a bromination reaction method and application of a nitrogen-containing heterocyclic compound, aims to directly introduce halogen bromine atoms into the nitrogen-containing heterocyclic compound in a C-H activation mode, and has the advantages of high yield and high atom economy.
The invention is realized by the following steps:
in a first aspect, the present invention provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, comprising:
reacting C-H activated nitrogenous heterocyclic benzyl quaternary ammonium salt with a bromization reagent in the presence of an additive;
wherein the additive is at least one of acid and alkali;
the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is at least one of N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenyl pyridine quaternary ammonium salt.
In a second aspect, the invention also provides the application of the method for bromination reaction of the nitrogen-containing heterocyclic compound in preparation of drug molecules or bioactive molecules;
preferably, the product obtained after the bromination reaction is subjected to a coupling reaction selected from at least one of Heck coupling, Sonogashira coupling, Stille coupling, Suzuki-Miyaura coupling and Ullmann coupling.
The invention has the following beneficial effects: the dibromo-substituted nitrogen-containing compound is obtained by taking C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt and a bromination reagent as reaction substrates and carrying out bromination reaction in the presence of organic acid or organic base. The bromination method in the embodiment of the invention has the advantages of good yield, high selectivity and good atom economy, and is suitable for popularization and application. Bromo-product dibromoquinoline compounds or dibromopyridine compounds are further subjected to coupling reaction to obtain complex compound molecules and drug molecules with greater application potential.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is the nuclear magnetic H spectrum of II-a in example 1;
FIG. 2 is the NMR H spectrum of II-b in example 2;
FIG. 3 is the NMR spectrum of II-b in example 2;
FIG. 4 is the nuclear magnetic H spectrum of II-c in example 3;
FIG. 5 is the NMR spectrum of II-C in example 3;
FIG. 6 is the II-d NMR spectrum of example 4;
FIG. 7 shows the II-d NMR spectrum of example 4.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which comprises the following steps: reacting C-H activated nitrogenous heterocyclic benzyl quaternary ammonium salt with a bromization reagent in the presence of an additive; wherein the additive is at least one of acid and alkali; the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is at least one of N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenyl pyridine quaternary ammonium salt.
Specifically, the nitrogen-containing compound may be activated with a benzyl bromide reagent or the like to obtain a corresponding quaternary ammonium salt and activate C — H, so that the bromination reaction can be promoted in the presence of an organic acid or an organic base, thereby increasing the yield of the product.
Specifically, the nitrogenous heterocyclic benzyl quaternary ammonium salt is obtained by activating a nitrogenous heterocyclic compound and benzyl bromide; the activation reaction temperature is 55-65 ℃, and the reaction time is 24-36 h. The step is the prior art, and the quaternary ammonium salt is obtained by activating benzyl bromide and the C-H is activated at the same time.
Further, the structural formula of the nitrogenous heterocyclic benzyl quaternary ammonium salt is as follows:
in the structural formula, R1Selected from any one of hydrogen, C1-C6 alkyl, halogen and quinoline ring, R1The number of the (B) is 1-3; r2The binding site of (a) is at least one of the remaining 5 unbound sites on the phenyl ring; r2Selected from any one of hydrogen, C1-C6 alkyl and halogen.
Specifically, the C1-C6 alkyl group may be a straight chain or branched chain alkyl group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. R1And R2The binding site of (b) is not limited, the benzylamine derivative may be mono-substituted or poly-substituted, and the substitution site may be ortho-position, meta-position or para-position. It is to be noted that, since alkenylation of the benzylamine derivative occurs at the ortho position, when the number of the substituent is plural, at leastOne ortho position is unsubstituted.
In some embodiments, the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is selected from at least one of the following compounds:
specifically, the nitrogen-containing heterocyclic benzyl quaternary ammonium salt can be one or more compounds, and the above compounds are all suitable for the bromination method in the embodiment of the invention. The nitrogen-containing compound has wide sources, is cheap and easy to obtain, and can obtain the corresponding benzyl quaternary ammonium salt derivative through one-step benzyl activation reaction.
Further, the bromization reagent is selected from at least one of bromization succinimide, dibromo hydantoin, 1,3, 5-tribromo-1, 3, 5-thiazine-2, 4, 6-trione; bromosuccinimide is preferred. The brominating reagent is preferably brominating succinimide, and the yield of the product can be further improved compared with other brominating reagents.
Specifically, the structural formula of bromosuccinimide is as follows:
in some embodiments, the molar ratio of the nitrogen-containing heterocyclic benzyl quaternary ammonium salt to the brominating agent is 1: 1.5-2.5; preferably 1: 1.8-2.2. Specifically, the molar ratio of the nitrogen-containing heterocyclic benzyl quaternary ammonium salt to the brominating agent may be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, or any value between the above adjacent ratio values. By controlling the dosage ratio of the reaction substrates, the reaction can be fully carried out, and the product yield is improved.
In some embodiments, the additive is an organic acid, and the yield of the product can be further improved by using the organic acid compared with the organic base, and the reaction mechanisms of the two may be different. Specifically, the additive is at least one selected from benzoic acid and 2-fluorobenzoic acid, and may be one or two.
Furthermore, the molar ratio of the additive to the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is 0.4-0.6:1, such as 0.4:1, 0.5:1, 0.6:1, and the like, the dosage of the additive has a large effect on improving the yield, if the dosage of the additive is too small, the yield is not ideal, and if the dosage of the additive is too large, the yield is not further improved. Controlling the amount of the additive within the range defined in the examples of the present invention enables higher yields and better selectivity.
Further, the nitrogenous heterocyclic benzyl quaternary ammonium salt and bromosuccinimide react in an organic solvent, wherein the organic solvent is at least one selected from 1, 2-dichloroethane, toluene and methyl tert-butyl ether; preferably, the organic solvent is 1, 2-dichloroethane. The inventor optimizes the organic solvent, and the product yield can be further improved by adopting 1, 2-dichloroethane as the solvent.
Further, the reaction temperature of the nitrogenous heterocyclic benzyl quaternary ammonium salt and the bromosuccinimide is 90-100 ℃, and the reaction time is 4-16 h. Specifically, the reaction temperature may be 90 ℃, 92 ℃, 94 ℃, 96 ℃, 98 ℃, 100 ℃ or the like, or may be any value between the above adjacent temperature values; the reaction time may be 4h, 6h, 8h, 10h, 12h, 14h, 16h, etc., or may be any value between the above adjacent time values.
It should be noted that, the inventors have optimized the reaction temperature, and if the reaction temperature is too low, the C — H activity may be low, resulting in low yield of the product; if the reaction temperature is too high, debenzylation is liable to occur and deactivation is liable to occur.
It should be added that the structural formula of the product obtained by the bromination method provided in the embodiment of the present invention is:
the embodiment of the invention also provides application of the bromination reaction method of the nitrogen-containing heterocyclic compound in preparation of drug molecules or bioactive molecules, and the product obtained after the reaction can be subjected to further coupling reaction to obtain complex compound molecules and drug molecules with greater application potential.
Specifically, the coupling reaction is selected from at least one of a Heck coupling, Sonogashira coupling, Stille coupling, Suzuki-Miyaura coupling, and Ullmann coupling.
The features and properties of the present invention are described in further detail below with reference to examples.
It should be noted that, in the following examples, the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is obtained by activating a nitrogen-containing heterocyclic compound with benzyl bromide; the activation reaction temperature is 60 ℃, and the reaction time is 30 h.
Example 1
This example provides a method for bromination of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25mL reaction tube in air, magnetons, N-benzyl-5-nitroquinoline quaternary ammonium salt I-a (0.1mmol,29.9mg), N-bromosuccinimide (0.2mmol,34.8mL), benzoic acid (0.05mmol,6.1mg), and dichloroethane (1.5mL) were added. Then, a rubber stopper was inserted, and the mixture was heated and stirred in an oil bath at 100 ℃ for 4 hours. After the reaction, the reaction system was cooled to room temperature, filtered through a glass sand funnel filled with diatomaceous earth, washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was evaporated under reduced pressure, 10mL of distilled water was added, then, 30mL of ethyl acetate was used for extraction in 3 portions, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, petroleum ether/ethyl acetate was selected as a mobile phase, and purification was performed by flash silica gel column chromatography to obtain 3, 4-dibromoquinoline II-a (white solid, yield 74%).
The characterization of 3, 4-dibromoquinoline II-a is shown in FIG. 1, which is as follows:
1H NMR(400MHz,Chloroform-d)δ8.93(s,1H),8.24(d,J＝2.2Hz,1H),7.97(d,J＝9.0Hz,1H),7.92(d,J＝2.2Hz,1H),7.81(dd,J＝9.0,2.2Hz,1H)。
example 2
This example provides a method for bromination of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25mL reaction tube in air, magneton, N-benzyl-2- (naphthyl-1-yl) pyridinium quaternary ammonium salt I-c (0.1mmol,37.5mg), N-bromosuccinimide (0.2mmol,34.8mL), p-fluorobenzoic acid (0.05mmol,6.1mg), dichloroethane (1.5mL) were added. Then, a rubber stopper was inserted, and the mixture was heated and stirred in an oil bath at 100 ℃ for 4 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered through a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then, extraction was carried out 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 3, 5-dibromo-6- (naphthyl-1-yl) pyridine II-b (white solid, yield 55%) was obtained by purification by flash silica gel column chromatography using petroleum ether/ethyl acetate as a mobile phase.
The characterization of 3, 5-dibromo-6- (naphthalen-1-yl) pyridine II-b is shown in FIGS. 2 and 3, in detail as follows:
white solid, melting point 85-87 ℃.
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.25(d,J＝2.0Hz,1H),7.94(ddt,J＝13.5,8.3,0.9Hz,2H),7.57(d,J＝1.2Hz,1H),7.54–7.36(m,4H)。
13C NMR(101MHz,Chloroform-d)δ157.1,149.1,142.6,136.4,133.6,130.8,129.4,128.5,127.0,126.6,126.1,125.1,122.2。
HRMS(ESI)m/z:calcd for C15H10Br2N+[M+Na]+:361.9175.found:361.9176。
Example 3
This example provides a method for bromination of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25mL reaction tube under air were added magnetons, N-benzyl-2-phenylpyridine quaternary ammonium salt I-d (0.1mmol,32.5mg), N-bromosuccinimide (0.2mmol,34.8mL), 2-fluorobenzoic acid (0.05mmol,7.0mg), and dichloroethane (1.5 mL). Then, a rubber stopper was inserted, and the mixture was heated and stirred in an oil bath at 100 ℃ for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered through a glass sand funnel filled with celite, washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then, 30mL of ethyl acetate was used for extraction in 3 portions, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 3, 5-dibromo-2-phenylpyridine II-c (white solid, yield 65%) was obtained by purification by flash silica gel column chromatography using petroleum ether/ethyl acetate as a mobile phase.
The characterization of 3, 5-dibromo-2-phenylpyridine compounds II-c is shown in fig. 4 and 5, in detail below:
white solid, melting point 90-92 ℃.
1H NMR(400MHz,Chloroform-d)δ8.68(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.74–7.61(m,2H),7.46(dd,J＝5.6,1.9Hz,3H)。
13C NMR(101MHz,Chloroform-d)δ156.69,149.09,143.12,138.49,129.21,129.09,128.10,119.83,118.78。
HRMS(ESI)m/z:calcd for C11H8Br2N+[M+Na]+:311.9018.found:311.9019。
Example 4
This example provides a method for bromination of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the preparation procedure was the same as in example 2, the yield was 34%, and the characterization of 3, 5-dibromo-2- (p-methyl) pyridine compounds II-d is shown in FIGS. 6 and 7, specifically as follows:
white solid, melting point 98-100 ℃.
1H NMR(400MHz,Chloroform-d)δ8.58(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.49(d,J＝8.1Hz,2H),7.34–7.05(m,2H),2.34(s,3H)。
13C NMR(101MHz,Chloroform-d)δ156.68,149.04,143.08,139.14,135.64,129.17,128.80,119.77,118.47,21.42。
HRMS(ESI)m/z:calcd for C12H10Br2N+[M+Na]+:325.9175.found:325.9177。
Example 5
This example provides a method for bromination of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the procedure was as in example 2, giving a yield of 55%, and the 3, 5-dibromo-2- (p-fluoromethyl) pyridine compounds II-f were characterized as follows:
white solid, melting point 105-.
1H NMR(400MHz,Chloroform-d)δ8.66(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.75–7.62(m,2H),7.15(t,J＝8.7Hz,2H)。
13C NMR(101MHz,Chloroform-d)δ163.18(d,J＝249.3Hz),155.6,149.1,143.2,134.5,131.3(d,J＝8.5Hz),119.7,118.9,115.2(d,J＝21.7Hz)。
HRMS(ESI)m/z:calcd for C11H7Br2FN+[M+Na]+:329.8924.found:329.8925。
Comparative example 1
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the N-bromosuccinimide is replaced by the same amount of dibromohydantoin.
The results showed a product yield of 30%.
Comparative example 2
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the N-bromosuccinimide is replaced by 1,3, 5-tribromo-1, 3, 5-thiazine-2, 4, 6-trione with the same quantity.
The results showed a product yield of 10%.
Comparative example 3
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: dichloroethane was replaced with an equal amount of acetone.
The results showed a product yield of 15%.
Comparative example 4
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: dichloroethane was replaced with an equal amount of methyl tert-butyl ether.
The results showed a product yield of 10%.
Comparative example 5
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: benzoic acid was replaced with an equal amount of KHF2。
The result showed that the product yield was 35%.
Comparative example 6
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: benzoic acid was replaced with an equal amount of NaSO3。
The results showed a product yield of 41%.
Comparative example 7
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 110 ℃.
The results showed a product yield of 60%.
Comparative example 8
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 90 ℃.
The results showed a product yield of 65%.
Comparative example 9
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 80 ℃.
The results showed a product yield of 55%.
Comparative example 10
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 60 ℃.
The results showed a product yield of 45%.
Comparative example 11
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 40 ℃.
The results showed a product yield of 40%.
Comparative example 12
This comparative example provides a process for bromination of a nitrogen-containing heterocyclic compound, which differs from example 1 only in that: the reaction temperature was 25 ℃.
The results showed a product yield of 25%.
In summary, the embodiments of the present invention provide a bromination reaction method and application of a nitrogen-containing heterocyclic compound, in which a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt and a bromination reagent are used as reaction substrates, and a bromination reaction is performed in the presence of an organic acid or an organic base to obtain a dibromo-substituted nitrogen-containing compound. The bromination method in the embodiment of the invention has the advantages of good yield, high selectivity and good atom economy, and is suitable for popularization and application. Further obtaining complex compound molecules with larger application potential and drug molecules through Heck coupling, Sonogashira coupling, Stille coupling, Suzuki-Miyaura coupling and Ullmann coupling reaction.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for bromination reaction of a nitrogen-containing heterocyclic compound is characterized by comprising the following steps:
reacting C-H activated nitrogenous heterocyclic benzyl quaternary ammonium salt with a bromization reagent in the presence of an additive;
wherein the additive is at least one of an acid and a base;
the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is at least one of N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenyl pyridine quaternary ammonium salt.
2. The method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 1, wherein said nitrogen-containing heterocyclic benzyl quaternary ammonium salt has the structural formula:
in the structural formula, R1Selected from any one of hydrogen, C1-C6 alkyl, halogen and quinoline ring, R1The number of the (B) is 1-3; r2Selected from any one of hydrogen, C1-C6 alkyl and halogen.
3. The method for bromination of a nitrogen-containing heterocyclic compound according to claim 2, wherein said nitrogen-containing heterocyclic benzyl quaternary ammonium salt is selected from at least one of the following compounds:
4. the method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 2, wherein said quaternary ammonium salt of nitrogen-containing heterocyclic benzyl is obtained by benzyl activation reaction of nitrogen-containing heterocyclic compound and benzyl bromide;
preferably, the solvent for benzyl activation reaction is acetone, the reaction temperature is 55-65 ℃, and the reaction time is 24-36 h.
5. The method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 1, wherein said bromination reagent is at least one selected from the group consisting of bromosuccinimide, dibromohydantoin, 1,3, 5-tribromo-1, 3, 5-thiazinan-2, 4, 6-trione; bromosuccinimide is preferred.
6. The method for bromination reaction of a nitrogen-containing heterocyclic compound according to claim 5, wherein the molar ratio of said nitrogen-containing heterocyclic benzyl quaternary ammonium salt to said bromination reagent is 1: 1.5-2.5; preferably 1: 1.8-2.2.
7. The method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 5, wherein said reaction temperature of said nitrogen-containing heterocyclic benzyl quaternary ammonium salt and said bromosuccinimide is 90-100 ℃ and the reaction time is 4-16 h.
8. The method for bromination of a nitrogen-containing heterocyclic compound according to claim 5, wherein said additive is an organic acid;
preferably, the additive is selected from at least one of benzoic acid and 2-fluorobenzoic acid;
preferably, the molar ratio of the additive to the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is 0.4-0.6: 1.
9. The method for bromination of a nitrogen-containing heterocyclic compound according to claim 5, wherein said nitrogen-containing heterocyclic benzyl quaternary ammonium salt and said bromosuccinimide are reacted in an organic solvent, said organic solvent being at least one selected from the group consisting of 1, 2-dichloroethane, toluene and methyl t-butyl ether;
preferably, the organic solvent is 1, 2-dichloroethane.
10. Use of the process for bromination of a nitrogen-containing heterocyclic compound as defined in any of claims 1 to 9 for the preparation of a pharmaceutical molecule or a biologically active molecule;
preferably, the product obtained after the bromination reaction is subjected to a coupling reaction selected from at least one of Heck coupling, Sonogashira coupling, Stille coupling, Suzuki-Miyaura coupling and Ullmann coupling.
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