CN117903069A - Synthesis method of fampicin intermediate 2-bromo-5-chloropyrazine - Google Patents
Synthesis method of fampicin intermediate 2-bromo-5-chloropyrazine Download PDFInfo
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- UXCPLGLOAZWCKO-UHFFFAOYSA-N 2-bromo-5-chloropyrazine Chemical compound ClC1=CN=C(Br)C=N1 UXCPLGLOAZWCKO-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 69
- 239000012074 organic phase Substances 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000010791 quenching Methods 0.000 claims abstract description 19
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 230000000171 quenching effect Effects 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 15
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims abstract description 14
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 11
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012414 tert-butyl nitrite Substances 0.000 claims abstract description 9
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- 235000010265 sodium sulphite Nutrition 0.000 claims description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 238000011097 chromatography purification Methods 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- 235000012239 silicon dioxide Nutrition 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 238000004809 thin layer chromatography Methods 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
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- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- -1 aryl Carboxylic Acids Chemical class 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- JVSDZAGCHKCSGR-UHFFFAOYSA-N 2,5-dichloropyrazine Chemical compound ClC1=CN=C(Cl)C=N1 JVSDZAGCHKCSGR-UHFFFAOYSA-N 0.000 description 2
- ITTXBHQAWOFJAI-UHFFFAOYSA-N 5-bromo-1h-pyrazin-2-one Chemical compound BrC1=CNC(=O)C=N1 ITTXBHQAWOFJAI-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 2
- 229950008454 favipiravir Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 1
- FXJOTWLLDJYKAG-UHFFFAOYSA-N 5-chloropyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C=N1 FXJOTWLLDJYKAG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
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- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing a fampicevir intermediate 2-bromo-5-chloropyrazine, which comprises the following steps: stirring dibromohydantoin and 2-aminopyrazine at 0-5 ℃ for reaction to obtain 2-amino-5-bromopyrazine; dissolving 2-amino-5-bromopyrazine in DCM, adding titanium chloride, stirring and mixing at 0 ℃, then dropwise adding tert-butyl nitrite into a reaction system, stirring and reacting for 20-30 min, heating to room temperature, continuing stirring and reacting for 8-12 h, quenching the reaction after the reaction is finished, standing and layering the reaction solution to separate out an organic phase, extracting a water phase by using dichloromethane, merging the organic phases, washing by using saturated brine, drying, removing the solvent from the dried organic phase, and purifying to obtain the target product 2-bromo-5-chloropyrazine. The method provided by the invention is simple to operate, low in cost, and high in purity and yield of the prepared product.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of a fampicevir intermediate 2-bromo-5-chloropyrazine.
Background
Fapiravir (favipiravir, T-705), which is a broad-spectrum antiviral drug, is approved for marketing in 2014 by Japan Fushan chemical Co., ltd. The fapirrevir selectively disrupts the RNA replication and transcription processes of the virus in the infected cell, thereby terminating the infection cycle, which has obvious effects on the treatment of common influenza, H1N1, ebola and other viruses. 2-bromo-5-chloropyrazine is a main intermediate thereof, so that research on a synthetic method of 2-bromo-5-chloropyrazine is of great significance.
At present, the routes for synthesizing 2-bromo-5-chloropyrazine at home and abroad mainly comprise the following two routes: 1. literature (Chen,Tiffany Q.;Pedersen,P.Scott;Dow,Nathan W.;et al Unified Approach to Decarboxylative Halogenation of(Hetero)aryl Carboxylic Acids,Journal of the American Chemical Society(2022),144(18),8296-8305) discloses the following technical content: 5-chloropyrazine-2-carboxylic acid is used as a starting material, and is subjected to decarboxylation halogenation reaction with 1, 3-dibromo-5, 5-dimethyl hydantoin under the catalysis illumination condition of N-fluoro-2, 4, 6-trimethylpyridine tetrafluoroborate (NFTPT) and tetraethyl cyanogen tetrafluoroborate to generate 2-bromo-5-chloropyrazine by using Hensdisk reaction/Simmonnierie carboxylic acid. The process uses expensive catalysts of N-fluoro-2, 4, 6-trimethylpyridine tetrafluoroborate (NFTPT) and tetraethylcopper tetrafluoroborate, has high cost, is carried out under illumination conditions, and has certain limitation when used for large-scale production. 2. Patent CN111471025 discloses the following technical content: 2-hydroxy-5-bromopyrazine is generated from 2-hydroxy pyrazine and dibromohydantoin as starting materials, and then the 2-hydroxy-5-bromopyrazine reacts with phosphorus oxychloride to obtain a mixture of 2, 5-dichloropyrazine and 2-bromo-5-chloropyrazine, and the separation and purification of the 2, 5-dichloropyrazine and the 2-bromo-5-chloropyrazine are very difficult due to similar physical and chemical properties, so that the yield of a target product is low, and a pure product is difficult to obtain.
Based on the problems, a novel synthesis method is provided for preparing the 2-bromo-5-chloropyrazine, so that the production cost is reduced, and the product yield and purity are improved, and the method has important significance.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the defects existing in the prior art, the synthesis method of the 2-bromo-5-chloropyrazine as the fampicvir intermediate is provided, the method is simple to operate, the cost is low, and the prepared product has high purity and high yield.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for synthesizing a fampicin intermediate 2-bromo-5-chloropyrazine comprises the following steps:
(1) Dripping acetonitrile solution of dibromohydantoin into acetonitrile solution of 2-aminopyrazine under the conditions of ice salt bath, nitrogen atmosphere and stirring, stirring at 0-5 ℃ for reaction after the dripping, monitoring that no 2-aminopyrazine exists in a reaction system by thin layer chromatography, quenching the reaction after the reaction is finished, concentrating the reaction solution, extracting, collecting an organic phase, removing the solvent from the organic phase, drying, and recrystallizing to obtain 2-amino-5-bromopyrazine;
(2) Dissolving the 2-amino-5-bromopyrazine prepared in the step (1) in DCM, adding titanium chloride, stirring and mixing at 0 ℃, then dropwise adding tert-butyl nitrite into a reaction system, stirring and reacting for 20-30 min, heating to room temperature, continuing stirring and reacting for 8-12 h, quenching the reaction, standing and layering the reaction solution to separate an organic phase, extracting an aqueous phase by using dichloromethane, merging the organic phases, washing by using saturated brine, drying, removing the solvent from the dried organic phase, and purifying to obtain the target product 2-bromo-5-chloropyrazine.
As an improved technical scheme, in the step (1), the molar ratio of dibromohydantoin to 2-aminopyrazine is (1-1.5): 1.
As an improved technical scheme, in the step (1), adding sodium bicarbonate aqueous solution and sodium sulfite aqueous solution into a reaction system during quenching reaction, wherein the concentration of the sodium bicarbonate aqueous solution and the sodium sulfite aqueous solution is 5-10wt% and 5-10wt% respectively; the volume ratio of the sodium bicarbonate aqueous solution to the sodium sulfite aqueous solution is (1-2): 1.
As an improved technical scheme, in the step (1), adding sodium bicarbonate aqueous solution into a reaction system to adjust the pH value in the reaction system to 8-9, wherein the molar ratio of sodium sulfite to dibromohydantoin is (1-1.5): 1.
The sodium sulfite aqueous solution is added to quench and not react to obtain dibromohydantoin, the addition amount of the sodium sulfite is 1-1.5 equivalents of dibromohydantoin, the sodium bicarbonate aqueous solution is added to neutralize acidic substances in a reaction system, so that the pH of the system is 8-9, 2-amino-5-bromopyrazine is conveniently generated, and the addition amount of the sodium bicarbonate is 1-2 equivalents of sodium sulfite.
As an improved technical scheme, in the step (1), when the reaction solution is concentrated, acetonitrile in the reaction solution is removed by vacuum concentration.
In the step (1), methylene dichloride is added into the concentrated solution for standing and layering, an organic phase is collected, methylene dichloride is continuously added into the water phase for extraction, the extraction is repeated for 2-3 times, and the organic phases are combined.
As an improved technical scheme, in the step (1), a mixture of ethyl acetate and n-hexane is used as a solvent in the recrystallization, wherein the volume ratio of the ethyl acetate to the n-hexane is 1: (4-5).
As an improved technical scheme, in the step (2), the molar ratio of the titanium chloride, the 2-amino-5-bromopyrazine and the tert-butyl nitrite is 1:1: (1.5-2.5).
As an improved technical scheme, in the step (2), the stirring and mixing time is 2-5 min.
As an improved technical scheme, in the step (2), water is added into a reaction system to quench the reaction during the quenching reaction.
The invention adds water to quench excessive titanium chloride, and can dilute the reaction liquid and wash away the water-soluble substances generated by the reaction.
As an improved technical scheme, in the step (2), a flash column loaded with silicon dioxide is adopted for chromatographic purification in the purification process, and ethyl acetate and normal hexane with the volume ratio of 1:1 are adopted as eluent.
The chemical reaction formula of the invention is as follows:
due to the adoption of the technical scheme, the invention has the following beneficial effects:
The invention uses 2-amino pyrazine and dibromo hydantoin as initial raw materials, and firstly, bromination reaction is carried out under certain conditions to generate an intermediate 2-amino-5-bromopyrazine; then 2-amino-5-bromopyrazine and tert-butyl nitrite generate diazonium salt, and the diazonium salt is replaced by chlorine to generate the target product 2-bromo-5-chloropyrazine.
The method provided by the invention has the advantages of mild condition, easiness in operation, suitability for large-scale production, and high yield and purity of the prepared product.
Detailed Description
The invention is further illustrated below with reference to examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The yield of the products in the following examples and comparative examples was calculated as follows:
yield (%) = [ actual mass of product/theoretical mass of product ] ×100%.
Example 1
A method for synthesizing a fampicin intermediate 2-bromo-5-chloropyrazine comprises the following steps:
(1) Dropwise adding an acetonitrile solution of dibromohydantoin (11 mmol) into an acetonitrile solution of 2-aminopyrazine (10 mmol) in an ice salt bath and a nitrogen atmosphere under stirring conditions, stirring the reaction mixture at 0 ℃ for reaction after the dropwise adding is finished, closely monitoring the reaction by thin layer chromatography until the 2-aminopyrazine in the reaction system disappears, adding 20ml of 10wt% sodium bicarbonate aqueous solution and 10ml of 10wt% sodium sulfite aqueous solution into the reaction system for quenching reaction, concentrating the obtained reaction solution under vacuum to remove solvent acetonitrile, mixing the concentrated aqueous solution with 20ml of dichloromethane, standing for layering, extracting the aqueous phase with 20ml of dichloromethane for three times, merging organic phases and drying the organic phases with anhydrous sodium sulfate, removing the solvent under reduced pressure after the organic phases are filtered and removed to obtain a crude product, recrystallizing the crude product with ethyl acetate/n-hexane (volume ratio 1:4) to obtain light yellow solid 2-amino-5-bromopyrazine, 1.48g, and obtaining the yield: 85%;
(2) Dissolving the 2-amino-5-bromopyrazine (10 mmol) prepared in the step (1) in 150ml of Dichloromethane (DCM), adding titanium chloride (10 mmol), stirring at 0 ℃ for 3min, adding tert-butyl nitrite (20 mmol), stirring at 0 ℃ for 30min, heating the reaction solution to room temperature, continuously stirring for 10h, adding 100ml of water to the reaction system for quenching reaction, standing for layering, separating an organic phase, extracting the aqueous phase with dichloromethane for three times, combining the organic phases, washing the organic phase with 20ml of saturated brine, drying the washed organic phase with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a crude product, performing chromatographic purification on the crude product by using a flash column filled with silicon dioxide, and adopting ethyl acetate/n-hexane (volume ratio of 1:1) as eluent to obtain the product 2-bromo-5-chloropyrazine, light yellow oily matter, 1.58g, and yield: 82%.
Example 2
A method for synthesizing a fampicin intermediate 2-bromo-5-chloropyrazine comprises the following steps:
(1) Dropwise adding an acetonitrile solution of dibromohydantoin (11 mmol) into an acetonitrile solution of 2-aminopyrazine (10 mmol) in an ice salt bath and nitrogen atmosphere under stirring conditions, stirring the reaction mixture at2 ℃ for reaction after the dropwise adding is finished, closely monitoring the reaction by thin layer chromatography until the 2-aminopyrazine in the reaction system disappears, adding 20ml of 10wt% sodium bicarbonate aqueous solution and 10ml of 10wt% sodium sulfite aqueous solution into the reaction system for quenching reaction, concentrating the obtained reaction solution under vacuum to remove solvent acetonitrile in the reaction solution, mixing the concentrated aqueous solution with 20ml of dichloromethane, standing for layering, extracting the aqueous phase with 20ml of dichloromethane for three times, merging organic phases, drying the organic phases with anhydrous sodium sulfate, removing the solvent from the organic phases under reduced pressure after the drying agent is removed by filtration, and recrystallizing the crude product with ethyl acetate/n-hexane (volume ratio is 1:4) to obtain light yellow solid 2-amino-5-bromopyrazine, wherein the yield is 87.52 g;
(2) Dissolving the 2-amino-5-bromopyrazine (10 mmol) prepared in the step (1) in 150ml of Dichloromethane (DCM), adding titanium chloride (10 mmol), stirring at 0 ℃ for 3min, adding tert-butyl nitrite (20 mmol), stirring at 0 ℃ for 30min, heating the reaction solution to room temperature, stirring for 8h, adding 100ml of water to the reaction system for quenching reaction, standing for layering, separating an organic phase, extracting the aqueous phase with dichloromethane for three times, combining the organic phases, washing the organic phase with 20ml of saturated brine, drying the washed organic phase with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a crude product, performing chromatographic purification on the crude product by using a flash column filled with silicon dioxide, and adopting ethyl acetate/n-hexane (volume ratio of 1:1) as an eluent to obtain the product 2-bromo-5-chloropyrazine, light yellow oily matter, 1.55g, and yield: 80.4%.
Example 3
A method for synthesizing a fampicin intermediate 2-bromo-5-chloropyrazine comprises the following steps:
(1) Dropwise adding an acetonitrile solution of dibromohydantoin (11 mmol) into an acetonitrile solution of 2-aminopyrazine (10 mmol) in an ice salt bath and nitrogen atmosphere under stirring conditions, stirring the reaction mixture at 5 ℃ for reaction after the dropwise adding is finished, closely monitoring the reaction by thin layer chromatography until the 2-aminopyrazine in the reaction system disappears, adding 20ml of 10wt% sodium bicarbonate aqueous solution and 10ml of 10wt% sodium sulfite aqueous solution into the reaction system for quenching reaction, concentrating the obtained reaction solution under vacuum to remove solvent acetonitrile in the reaction solution, mixing the concentrated aqueous solution with 20ml of dichloromethane, standing for layering, extracting the aqueous phase with 20ml of dichloromethane for three times, merging organic phases, drying the organic phases with anhydrous sodium sulfate, removing the solvent from the organic phases under reduced pressure after the drying agent is removed by filtration, and recrystallizing the crude product with ethyl acetate/n-hexane (volume ratio is 1:4) to obtain light yellow solid 2-amino-5-bromopyrazine, wherein the yield is 90.2%;
(2) Dissolving the 2-amino-5-bromopyrazine (10 mmol) prepared in the step (1) in 150ml of Dichloromethane (DCM), adding titanium chloride (10 mmol), stirring at 0 ℃ for 3min, adding tert-butyl nitrite (20 mmol), stirring at 0 ℃ for 30min, heating the reaction liquid to room temperature, continuously stirring for 12h, adding 100ml of water to the reaction system for quenching reaction, standing for layering, separating an organic phase, extracting the aqueous phase with dichloromethane three times, combining the organic phase and washing the organic phase with 20ml of saturated brine, drying the washed organic phase with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a crude product, carrying out chromatographic purification on the crude product by using a flash column filled with silicon dioxide, and adopting ethyl acetate/normal hexane (volume ratio of 1:1) as an eluent to obtain the product 2-bromo-5-chloropyrazine, light yellow oily matter, 1.62g and the yield of 84.1%.
Comparative example 1
The reaction temperature in the step (1) was 8℃and the other conditions were the same as in example 3, to obtain 1.44g of 2-amino-5-bromopyrazine as a pale yellow solid, with a yield of 79.8%; 1.54g of 2-bromo-5-chloropyrazine was obtained in 79.9% yield.
Comparative example 2
The reaction solution was stirred at room temperature for 15 hours under the same conditions as in example 4, to obtain 1.52g of 2-bromo-5-chloropyrazine as a pale yellow oil in 78.9% yield.
In conclusion, compared with the comparative example, the product prepared by the invention has high yield and high purity, and is suitable for large-scale production.
As can be seen from examples 1 to 3, in step (1), the yield of the product gradually increases with increasing temperature, mainly because the bromination reaction rate increases with increasing temperature, the reaction raw materials can be sufficiently reacted, and the occurrence of side reactions is avoided, thereby obtaining an intermediate with high yield and high purity. And it can be seen from comparative example 1 and example 4: the reaction temperature is too high, the yields of the intermediate and the target product are reduced, and the yield is mainly due to the fact that the side reaction is too high, a large amount of impurities are generated due to the fact that the side reaction is too strong and the bromination reaction is carried out, and the purity of the product is reduced; meanwhile, excessive side reactions consume more raw materials, thereby reducing the yield. The purity of the intermediate is insufficient, and the yield of the target product produced therefrom is also lowered.
As can be seen from example 4 and comparative example 2, when the diazotization reaction is performed after the addition of t-butyl nitrite and the subsequent chlorination reaction is performed at a high temperature, the reaction time is too long, and the yield of the target product is rather lowered, mainly because the side reaction increases with the increase of the reaction time, thereby affecting the purity and yield of the product.
Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. The synthesis method of the 2-bromo-5-chloropyrazine as the fampicvir intermediate is characterized by comprising the following steps of:
(1) Dripping acetonitrile solution of dibromohydantoin into acetonitrile solution of 2-aminopyrazine under the conditions of ice salt bath, nitrogen atmosphere and stirring, stirring at 0-5 ℃ for reaction after the dripping, monitoring that no 2-aminopyrazine exists in a reaction system by thin layer chromatography, quenching the reaction after the reaction is finished, concentrating reaction liquid to remove acetonitrile, extracting, collecting an organic phase, removing a solvent from the organic phase, drying, and recrystallizing to obtain 2-amino-5-bromopyrazine;
(2) Dissolving the 2-amino-5-bromopyrazine prepared in the step (1) in DCM, adding titanium chloride, stirring and mixing at 0 ℃, then dropwise adding tert-butyl nitrite into a reaction system, stirring and reacting for 20-30 min, heating to room temperature, continuing stirring and reacting for 8-12 h, quenching the reaction, standing and layering the reaction solution to separate an organic phase, extracting an aqueous phase by using dichloromethane, merging the organic phases, washing by using saturated brine, drying, removing the solvent from the dried organic phase, and purifying to obtain the target product 2-bromo-5-chloropyrazine.
2. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (1), the molar ratio of the dibromohydantoin to the 2-aminopyrazine is (1 to 1.5): 1.
3. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (1), adding sodium bicarbonate aqueous solution and sodium sulfite aqueous solution into a reaction system during quenching reaction, wherein the concentration of the sodium bicarbonate aqueous solution and the sodium sulfite aqueous solution is 5-10wt% and 5-10wt% respectively; the volume ratio of the sodium bicarbonate aqueous solution to the sodium sulfite aqueous solution is (1-2): 1.
4. A method for synthesizing 2-bromo-5-chloropyrazine as defined in claim 3, wherein the method is characterized in that: in the step (1), adding sodium bicarbonate aqueous solution into the reaction system to adjust the pH value of the reaction system to 8-9, wherein the mol ratio of sodium sulfite to dibromohydantoin is (1-1.5): 1.
5. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (1), methylene dichloride is added into the concentrated solution during extraction, standing is carried out for layering, an organic phase is collected, methylene dichloride is continuously added into an aqueous phase for extraction, the extraction is repeated for 2-3 times, and the organic phases are combined.
6. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (1), a mixture of ethyl acetate and normal hexane is used as a solvent in recrystallization, and the volume ratio of the ethyl acetate to the normal hexane is 1: (4-5).
7. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (2), the molar ratio of the titanium chloride, the 2-amino-5-bromopyrazine and the tert-butyl nitrite is 1:1: (1.5-2.5).
8. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (2), the stirring and mixing time is 2-5 min.
9. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (2), water is added into the reaction system to quench the reaction during the quenching reaction.
10. The method for synthesizing the 2-bromo-5-chloropyrazine as an intermediate of the fampicin according to claim 1, which is characterized in that: in the step (2), a flash column loaded with silicon dioxide is adopted for chromatographic purification during purification, and ethyl acetate and normal hexane with the volume ratio of 1:1 are adopted as eluent.
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