CN113717099B - Method for bromination reaction of nitrogen-containing heterocyclic compound and application - Google Patents
Method for bromination reaction of nitrogen-containing heterocyclic compound and application Download PDFInfo
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- 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 method for bromination reaction of a nitrogen-containing heterocyclic compound and application thereof, 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 a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt with a brominating reagent in the presence of an additive; wherein the additive is at least one of organic acid and organic alkali; the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is at least one selected from N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenylpyridine quaternary ammonium salt. Has the advantages of good yield, high selectivity and better atom economy, and is suitable for popularization and application. The brominated product dibromoquinoline compound or dibromopyridine compound is further subjected to a coupling reaction to obtain complex compound molecules with larger application potential and drug molecules.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for bromination reaction of a nitrogen-containing heterocyclic compound and application thereof.
Background
Brominated nitrogen-containing heterocyclic compounds are widely present as important structural skeletons in drug molecules, bioactive molecules. Currently, the most common method is to use aminopyridine or quinoline at high temperaturePOBr as raw material 3 Or Br (Br) 2 Bromination reaction is carried out.
However, the existing preparation method mainly depends on a substrate in the regional control, and has side reactions such as debromination products, excessive bromination and the like.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a method for bromination reaction of a nitrogen-containing heterocyclic compound and application thereof, and aims to directly introduce halogen bromine atoms into the nitrogen-containing heterocyclic compound in a C-H (carbon-hydrogen) activation mode, so that the method has the advantages of good yield and better atom economy.
The invention is realized in the following way:
in a first aspect, the present invention provides a method for bromination of a nitrogen-containing heterocyclic compound, comprising:
reacting a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt with a brominating 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 selected from N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenylpyridine quaternary ammonium salt.
In a second aspect, the present invention also provides the use of the above method of bromination of a nitrogen-containing heterocyclic compound in the preparation of a drug molecule or bioactive 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.
The invention has the following beneficial effects: the dibromo-substituted nitrogen-containing compound is obtained by adopting 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 better atom economy, and is suitable for popularization and application. The brominated product dibromoquinoline compound or dibromopyridine compound is further subjected to a coupling reaction to obtain complex compound molecules with larger application potential and drug molecules.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a II-a nuclear magnetic H spectrum of example 1;
FIG. 2 is a II-b nuclear magnetic H spectrum of example 2;
FIG. 3 is a chart of the II-b nuclear magnetic C spectrum of example 2;
FIG. 4 is a II-c nuclear magnetic H spectrum of example 3;
FIG. 5 is a chart of the II-C nuclear magnetic C-spectrum of example 3;
FIG. 6 is a II-d nuclear magnetic H-spectrum of example 4;
FIG. 7 is a chart of II-d nuclear magnetic C-spectrum in example 4.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention discloses a method for bromination reaction of a nitrogen-containing heterocyclic compound, which comprises the following steps: reacting a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt with a brominating 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 selected from N-benzyl quinoline quaternary ammonium salt and N-benzyl-2-phenylpyridine quaternary ammonium salt.
The benzyl group activation of the nitrogen-containing compound may be specifically performed using a benzyl bromide reagent or the like, whereby the corresponding quaternary ammonium salt is obtained, and the c—h is activated, whereby the bromination reaction can be promoted in the presence of an organic acid or an organic base, and the yield of the product can be improved.
Specifically, the nitrogenous heterocyclic benzyl quaternary ammonium salt is obtained by an activation reaction of 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 simultaneously activating C-H.
Further, the structural formula of the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is as follows:
In the structural formula, R 1 Any one selected from hydrogen, C1-C6 alkyl, halogen and quinoline ring, R 1 The number of (2) is 1-3; r is R 2 Is at least one of the remaining 5 unbound sites on the benzene ring; r is R 2 Is selected from any one of hydrogen, C1-C6 alkyl and halogen.
Specifically, the C1-C6 alkyl group may be a straight chain alkyl group or a branched chain alkyl group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. R is R 1 And R is 2 The binding site of (2) is not limited, and the benzylamine derivative may be mono-substituted or poly-substituted, and the substituted site may be ortho, meta or para. It is noted that since the alkenylation of the benzylamine derivative occurs in the ortho-position, at least one ortho-position is in an unsubstituted state when the number of substituents is plural.
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 may be one or more, and the above several compounds are suitable for the bromination method in the embodiment of the present 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 brominating reagent is at least one selected from N-bromosuccinimide, dibromohydantoin and 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione; bromosuccinimide is preferred. The bromoing reagent is preferably bromosuccinimide, and the yield can be further improved compared with other bromoing reagent products.
Specifically, the structural formula of the N-bromosuccinimide is as follows:
in some embodiments, the molar ratio of nitrogen-containing heterocyclic benzyl quaternary ammonium salt to 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 reagent 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, etc., and may also be any value between the above adjacent ratio values. By controlling the dosage ratio of the reaction substrates, the reaction can be fully performed, and the product yield can be improved.
In some embodiments, the additive is an organic acid, and the use of an organic acid can further increase the yield of the product compared to an 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 can be one or two.
Further, 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 use amount of the additive has a large effect on improving the yield, the yield is not ideal if the use amount of the additive is too small, and the yield is not further improved if the use amount is too large. The use amount of the additive is controlled within the range defined by the embodiment of the invention, so that the yield is higher and the selectivity is better.
Further, the nitrogen-containing heterocyclic benzyl quaternary ammonium salt and bromosuccinimide are reacted in an organic solvent, wherein the organic solvent is at least one selected from 1, 2-dichloroethane, toluene and methyl tertiary 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 nitrogen-containing heterocyclic benzyl quaternary ammonium salt and the N-bromosuccinimide is 90-100 ℃, and the reaction time is 4-16h. Specifically, the reaction temperature may be 90 ℃, 92 ℃, 94 ℃, 96 ℃, 98 ℃, 100 ℃, or any value between the above adjacent temperature values; the reaction time may be 4h, 6h, 8h, 10h, 12h, 14h, 16h, etc., or any value between the above adjacent time values.
The inventors have optimized the reaction temperature, and if the reaction temperature is too low, the reaction temperature may be due to low C-H activity, resulting in low yield of the product; if the reaction temperature is too high, the debenzylation is liable to occur and the deactivation is liable to occur.
It should be added that the structural formula of the product obtained by the bromination method provided by the embodiment of the invention is as follows:
the embodiment of the invention also provides application of the method for bromination reaction 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 larger application potential.
Specifically, the coupling reaction is at least one selected from Heck coupling, sonogashira coupling, stille coupling, suzuki-Miyaura coupling and Ullmann coupling.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
In the following examples, the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is obtained by an activation reaction between a nitrogen-containing heterocyclic compound and benzyl bromide; the activation reaction temperature is 60 ℃ and the reaction time is 30h.
Example 1
The embodiment provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25 mL reaction tube was added, in air, magneton, N-benzyl-5-nitroquinoline quaternary ammonium salt I-a (0.1 mmol, 29.9 mg), N-bromosuccinimide (0.2 mmol, 34.8 mL), benzoic acid (0.05 mmol, 6.1 mg), dichloroethane (1.5 mL). Then, the rubber stopper was plugged, and stirred under heating in an oil bath at 100℃for 4 h. After the reaction was completed, the reaction system was cooled to room temperature, filtered with 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, 10 mL of distilled water was added, then extracted 3 times with 30 mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3, 6-dibromoquinoline II-a was obtained by purification with flash silica gel column chromatography (white solid, yield 74%).
The characterization of 3, 6-dibromoquinoline II-a is shown in FIG. 1, and is specifically as follows:
1 H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 9.0, 2.2 Hz, 1H)。
example 2
The embodiment provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25 mL reaction tube was added, in air, magneton, N-benzyl-2- (naphthalen-1-yl) pyridine quaternary ammonium salt I-c (0.1 mmol, 37.5 mg), N-bromosuccinimide (0.2 mmol, 34.8 mL), p-fluorobenzoic acid (0.05 mmol, 6.1 mg), dichloroethane (1.5 mL). Then, the rubber stopper was plugged, and stirred under heating in an oil bath at 100℃for 4 h. After the reaction was completed, the reaction system was cooled to room temperature, filtered with 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, 10 mL of distilled water was added, then extracted 3 times with 30 mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3, 5-dibromo-6- (naphthalen-1-yl) pyridine II-b (white solid, yield 55%) was purified by flash silica gel column chromatography.
Characterization of 3, 5-dibromo-6- (naphthalen-1-yl) pyridine II-b is shown in fig. 2 and 3, and is specifically as follows:
white solid with a melting point of 85-87 ℃.
1H NMR(400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.94 (ddt, J = 13.5, 8.3, 0.9 Hz, 2H), 7.57 (d, J = 1.2 Hz, 1H), 7.54 – 7.36 (m, 4H)。
13C NMR(101 MHz, Chloroform-d) δ 157.1, 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 C 15 H 10 Br 2 N + [M + Na] + : 361.9175. found: 361.9176。
Example 3
The embodiment provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the specific operation steps are as follows:
to a 25 mL reaction tube was added, in air, magneton, N-benzyl-2-phenylpyridine quaternary ammonium salt I-d (0.1 mmol, 32.5 mg), N-bromosuccinimide (0.2 mmol, 34.8 mL), 2-fluorobenzoic acid (0.05 mmol, 7.0 mg), dichloroethane (1.5 mL). Then, the rubber stopper was plugged, and the mixture was stirred with heating in an oil bath at 100℃for 16℃ 16h. After the reaction was completed, the reaction system was cooled to room temperature, filtered with 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, 10 mL of distilled water was added, then extracted 3 times with 30 mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3, 5-dibromo-2-phenylpyridine II-c (white solid, yield 65%) was purified by flash column chromatography.
Characterization of 3, 5-dibromo-2-phenylpyridine compound II-c is shown in FIGS. 4 and 5, and is specifically as follows:
white solid with melting point of 90-92 ℃.
1H NMR(400 MHz, Chloroform-d) δ 8.68 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.74 – 7.61 (m, 2H), 7.46 (dd, J = 5.6, 1.9 Hz, 3H)。
13C NMR(101 MHz, Chloroform-d) δ 156.69, 149.09, 143.12, 138.49, 129.21, 129.09, 128.10, 119.83, 118.78。
HRMS(ESI) m/z: calcd for C 11 H 8 Br 2 N + [M + Na] + : 311.9018. found: 311.9019。
Example 4
The embodiment provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the procedure is as in example 2 with 34% yield and the 3, 5-dibromo-2- (p-methyl) pyridine compounds II-d are shown in FIGS. 6 and 7 and are described below:
white solid with melting point 98-100 deg.c.
1H NMR(400 MHz, Chloroform-d) δ 8.58 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.34 – 7.05 (m, 2H), 2.34 (s, 3H)。
13C NMR(101 MHz, Chloroform-d) δ 156.68, 149.04, 143.08, 139.14, 135.64, 129.17, 128.80, 119.77, 118.47, 21.42。
HRMS(ESI) m/z: calcd for C 12 H 10 Br 2 N + [M + Na] + : 325.9175. found: 325.9177。
Example 5
The embodiment provides a method for bromination reaction of a nitrogen-containing heterocyclic compound, which has the following reaction formula:
the procedure was followed, with 55% yield, to give 3, 5-dibromo-2- (p-fluoromethyl) pyridine compounds II-f as follows:
white solid with melting point 105-107 ℃.
1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.75 – 7.62 (m, 2H), 7.15 (t, J = 8.7 Hz, 2H)。
13C NMR (101 MHz, Chloroform-d) δ 163.18 (d, J = 249.3 Hz), 155.6, 149.1, 143.2, 134.5, 131.3 (d, J = 8.5 Hz), 119.7, 118.9, 115.2 (d, J = 21.7 Hz)。
HRMS (ESI) m/z: calcd for C 11 H 7 Br 2 FN + [M + Na] + : 329.8924. found: 329.8925。
Comparative example 1
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: n-bromosuccinimide is replaced with an equivalent amount of dibromohydantoin.
The results showed a product yield of 30%.
Comparative example 2
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: n-bromosuccinimide is replaced with equivalent amounts of 1,3, 5-tribromo-1, 3, 5-thiazinan-2, 4, 6-trione.
The results showed that the product yield was 10%.
Comparative example 3
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: dichloroethane is replaced with an equal amount of acetone.
The results showed a product yield of 15%.
Comparative example 4
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: dichloroethane is replaced with an equivalent amount of methyl tert-butyl ether.
The results showed that the product yield was 10%.
Comparative example 5
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: benzoic acid is replaced by equivalent KHF 2 。
The results showed a product yield of 35%.
Comparative example 6
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: substitution of benzoic acid with equal amounts of NaHSO 3 。
The results showed a product yield of 41%.
Comparative example 7
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: the reaction temperature was 110 ℃.
The results showed that the product yield was 60%.
Comparative example 8
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: the reaction temperature was 90 ℃.
The results showed 65% yield of the product.
Comparative example 9
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, 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 method for bromination of nitrogen-containing heterocyclic compounds, 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 method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: the reaction temperature was 40 ℃.
The results showed 40% yield of product.
Comparative example 12
This comparative example provides a method for bromination of nitrogen-containing heterocyclic compounds, which differs from example 1 only in that: the reaction temperature was 25 ℃.
The results showed a product yield of 25%.
In summary, the embodiment of the invention provides a method for bromination reaction of a nitrogen-containing heterocyclic compound and application thereof, wherein a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt and a brominating reagent are adopted as reaction substrates, and bromination reaction is carried out under the condition of existence of organic acid or 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 better atom economy, and is suitable for popularization and application. The complex compound molecules and the drug molecules with larger application potential are further obtained through Heck coupling, sonogashira coupling, stille coupling, suzuki-Miyaura coupling and Ullmann coupling reactions.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. A method for bromination of a nitrogen-containing heterocyclic compound, comprising:
reacting a C-H activated nitrogen-containing heterocyclic benzyl quaternary ammonium salt with a brominating reagent in the presence of an additive;
the brominating reagent is at least one selected from bromosuccinimide, dibromohydantoin and 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione;
the additive is at least one selected from benzoic acid and 2-fluorobenzoic acid;
the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is selected from at least one of the following compounds:
the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is
When the corresponding bromo-reaction product is +.>
；
The nitrogen-containing impurityThe cyclobenzyl quaternary ammonium salt is
When the corresponding bromo-reaction product is +.>
；
The nitrogen-containing heterocyclic benzyl quaternary ammonium salt is
When the corresponding bromo-reaction product is +.>
；
The nitrogen-containing heterocyclic benzyl quaternary ammonium salt is
When the corresponding bromo-reaction product is +.>
；
The nitrogen-containing heterocyclic benzyl quaternary ammonium salt is
When the corresponding bromo-reaction product is +.>
。
2. The method for bromination reaction of nitrogen-containing heterocyclic compounds according to claim 1, wherein the nitrogen-containing heterocyclic benzyl quaternary ammonium salt is obtained by benzyl activation reaction of nitrogen-containing heterocyclic compounds and benzyl bromide.
3. The method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 2, wherein the solvent for benzyl activation reaction is acetone, the reaction temperature is 55-65 ℃, and the reaction time is 24-36 h.
4. The method for bromination of nitrogen-containing heterocyclic compounds according to claim 1, wherein the brominating reagent is bromosuccinimide.
5. The method for bromination reaction of nitrogen-containing heterocyclic compounds according to claim 4, wherein the molar ratio of said nitrogen-containing heterocyclic benzyl quaternary ammonium salt to said brominating agent is 1:1.5-2.5.
6. The method for bromination reaction of nitrogen-containing heterocyclic compounds according to claim 5, wherein the molar ratio of said nitrogen-containing heterocyclic benzyl quaternary ammonium salt to said brominating agent is 1:1.8-2.2.
7. The method for bromination reaction of nitrogen-containing heterocyclic compound according to claim 4, wherein the reaction temperature of the nitrogen-containing heterocyclic benzyl quaternary ammonium salt and the bromosuccinimide is 90-100 ℃ and the reaction time is 4-16h.
8. The method for bromination reaction of nitrogen-containing heterocyclic compounds according to claim 4, wherein the molar ratio of said additive to said nitrogen-containing heterocyclic benzyl quaternary ammonium salt is 0.4-0.6:1.
9. The method for bromination reaction of a nitrogen-containing heterocyclic compound according to claim 4, wherein said nitrogen-containing heterocyclic benzyl quaternary ammonium salt and said bromosuccinimide are reacted in an organic solvent selected from at least one of 1, 2-dichloroethane, toluene and methyl tertiary butyl ether.
10. The method for bromination reaction of nitrogen-containing heterocyclic compounds according to claim 8, wherein the organic solvent is 1, 2-dichloroethane.
11. Use of the method of bromination of a nitrogen-containing heterocyclic compound as described in any of claims 1-10 for the preparation of a pharmaceutical molecule or a biologically active molecule.
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| CN111533684A (en) * | 2020-05-29 | 2020-08-14 | 四川大学 | Method for alkenylating pyridine compound |
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| WO1998025906A1 (en) * | 1996-12-10 | 1998-06-18 | Banyu Pharmaceutical Co., Ltd. | Process for producing halogenated heteroaryl compounds |
| CN108586334A (en) * | 2018-07-06 | 2018-09-28 | 大连理工大学 | A kind of preparation method without transition metal-catalyzed 2- haloperidid compounds |
| CN111533684A (en) * | 2020-05-29 | 2020-08-14 | 四川大学 | Method for alkenylating pyridine compound |
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