CN113603693B - Preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine - Google Patents
Preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine Download PDFInfo
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- CN113603693B CN113603693B CN202110788968.5A CN202110788968A CN113603693B CN 113603693 B CN113603693 B CN 113603693B CN 202110788968 A CN202110788968 A CN 202110788968A CN 113603693 B CN113603693 B CN 113603693B
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Abstract
The invention comprises the following steps: dissolving 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine in a solvent N, N-dimethylacetamide, adding a mild alkali reagent, and reacting for 0.5-2 hours after heating; cooling the reaction system to room temperature, adding paratoluensulfonyl chloride, cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 0.5-2 h; and step three, adding the mixture into 0.5-10% wt sodium bicarbonate water solution, filtering, recrystallizing, filtering and drying to obtain a finished product of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine. The invention uses the sodium tert-butoxide and other mild alkaline reagents, and improves the purification mode; the reaction condition is mild and controllable, and the by-products in the reaction process are less; and the operation and the post-treatment are simple, the product yield and the quality are obviously improved, the production time and the cost can be saved, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine.
Background
2-bromine-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine is an important fine chemical raw material and a medical intermediate, CAS number is 1201186-54-0, molecular formula is C13H10BrN3O2S, and molecular structure is as follows:
the existing preparation process of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine has high risk, needs a dangerous sodium hydride reagent, has more byproducts, low product yield and long production time, and improves the production cost because the product needs to be purified by silica gel column chromatography. Therefore, a preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine is needed to be designed.
Disclosure of Invention
Aiming at the defects of the prior art, the preparation method of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine is provided.
The invention is realized by the following scheme:
a method for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine, comprising the steps of:
dissolving 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine in a solvent N, N-dimethylacetamide, adding a mild alkali reagent, and reacting for 0.5-2h after heating;
cooling the reaction system to room temperature, adding paratoluensulfonyl chloride, cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 0.5-2 h;
and step three, after the reaction is finished, adding the reaction system obtained in the step two into 0.5-10% wt of sodium bicarbonate water solution, filtering, adding the obtained solid filter cake into a mixed solvent, recrystallizing, filtering and drying to obtain a finished product of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine.
In the first step, the temperature is raised to 40-100 ℃ and then the reaction is carried out.
In the first step, the alkali reagent is one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; in step one, the added alkaline reagent: the molar ratio of 3- [ (trimethylsilyl) ethynyl ] -5-pyrazin-2-amine is 1.0-1.5: 1.0.
in the second step, the molar ratio of the added p-toluenesulfonyl chloride to the 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine added in the first step is 1.0-1.5: 1.0.
in the third step, the mixed solvent is one or more of aliphatic hydrocarbon, aromatic hydrocarbon, ether, ester and nitrile.
The beneficial effects of the invention are as follows:
compared with the sodium hydride reported in the literature as the alkali reagent, the preparation method of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine uses the mild alkali reagent such as sodium tert-butoxide and improves the purification mode in the preparation process. The reaction condition is mild and controllable, and the byproducts in the reaction process are less. And the operation and the post-treatment are simple, the product yield and the quality are obviously improved, the production time and the cost can be saved, and the method is suitable for industrial production.
Drawings
FIG. 1 is a 1HNMR map of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine of the present invention;
FIG. 2 is a 13C NMR chart of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine of the present invention.
Detailed Description
The following further illustrates preferred embodiments of the invention:
a method for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine, comprising the steps of:
dissolving 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine in a solvent N, N-dimethylacetamide, adding a mild alkali reagent, and reacting for 0.5-2h after heating;
cooling the reaction system to room temperature, adding paratoluensulfonyl chloride, cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 0.5-2 h;
and step three, after the reaction is finished, adding the reaction system obtained in the step two into 0.5-10% wt sodium bicarbonate water solution, filtering, adding the obtained solid filter cake into a mixed solvent, recrystallizing, filtering and drying to obtain a finished product of the 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine.
In the first step, the temperature is raised to 40-100 ℃ and then the reaction is carried out.
In the first step, the alkali reagent is one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; in step one, the added alkaline reagent: the molar ratio of 3- [ (trimethylsilyl) ethynyl ] -5-pyrazin-2-amine is 1.0-1.5: 1.0.
in the second step, the molar ratio of the added p-toluenesulfonyl chloride to the 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine added in the first step is 1.0-1.5: 1.0.
in the third step, the mixed solvent is one or more of aliphatic hydrocarbon, aromatic hydrocarbon, ether, ester and nitrile.
The technical solution of the present application is further described below with reference to specific embodiments of the present application:
example 1
A preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine comprises the following steps: adding N, N-dimethylacetamide (500ml), 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine (50.0g, 0.185mol) into a reaction kettle, adding sodium tert-butoxide (19.5g, 0.204mol), heating the reaction system to 90-100 ℃, reacting for 0.5h, cooling the reaction system to room temperature, adding p-toluenesulfonyl chloride (42.3g, 0.221mol), cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 0.5 h. After the reaction is finished, pouring the reaction system into 2% wt sodium bicarbonate water solution, filtering, adding the obtained solid filter cake into mixed solvent ethyl acetate/petroleum ether for recrystallization, filtering and drying to obtain 55.1g of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine with the molar yield of 84.5%.
Example 2
A preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine comprises the following steps: adding N, N-dimethylacetamide (500ml) and 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine (50.0g and 0.185mol) into a reaction kettle, adding sodium tert-butoxide (21.3g and 0.221mol), heating the reaction system to 50-60 ℃, reacting for 1h, cooling the reaction system to room temperature, adding p-toluenesulfonyl chloride (45.8g and 0.240mol), cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 1 h. After the reaction is finished, pouring the reaction system into a 5% wt sodium bicarbonate aqueous solution, filtering, adding the obtained solid filter cake into a mixed solvent of ethyl acetate/petroleum ether for recrystallization, filtering and drying to obtain 56.7g of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine with the molar yield of 86.9%.
Example 3
A preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine comprises the following steps: adding N, N-dimethylacetamide (500ml) and 3- [ (trimethylsilyl) ethynyl ] -5-pyrazine-2-amine (50.0g and 0.185mol) into a reaction kettle, adding sodium tert-butoxide (17.7g and 0.185mol), heating the reaction system to 40-50 ℃, reacting for 2h, cooling the reaction system to room temperature, adding p-toluenesulfonyl chloride (37.0g and 0.194mol), cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 2 h. After the reaction is finished, pouring the reaction system into 3% wt sodium bicarbonate water solution, filtering, adding the obtained solid filter cake into mixed solvent ethyl acetate/petroleum ether for recrystallization, filtering and drying to obtain 54.4g of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine with the molar yield of 83.4%.
FIG. 1 is a 1HNMR map of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine of the present invention, and FIG. 2 is a 13CNMR map of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine of the present invention.
As can be seen from FIGS. 1 and 2, the structure was confirmed by nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR) and LC-MS.
And (3) detecting a hydrogen spectrum result of the sample: 1H-NMR (600MHz, CDCl 3). delta.2.41 (s, -CH3, 3H),6.79(s, -CH, 1H), 7.34(d, -C (CH)2, 2H),8.03(d, -C (CH)2, 2H)8.06(s, -CH, 1H), 8.43(s, -CH, 1H).
Carbon spectrum results: 13C-NMR (600MHz, CDCl3)
δ:21.71；105.67；128.16；130.03；131.60；134.58；136.12；139.21；140.28；141.94；14 6.20。
The assignment of nuclear magnetic resonance spectral shifts for 1H-NMR and 13C-NMR supports the structural features of the compounds. The structure is proved to be consistent with the structure of the compound 2-bromo-5-p-toluenesulfonyl-5H-pyrrolopyrazine in the combination of mass spectrum test results MS (ESI) m/z: 354.18.
The preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine provided by the invention solves the problems of high risk, long production time, more byproducts and difficult purification of the prior art. The reaction uses mild alkaline reagents such as sodium tert-butoxide, reduces the risk of the preparation process, has few byproducts, obviously improves the product yield, has short production period, is convenient for product purification, reduces the production cost, and is suitable for large-scale industrial production.
Although the invention has been described and illustrated in some detail, it should be understood that various modifications may be made to the described embodiments or equivalents may be substituted, as will be apparent to those skilled in the art, without departing from the spirit of the invention.
Claims (4)
1. A method for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine is characterized by comprising the following steps:
dissolving 3- [ (trimethylsilyl) ethynyl ] -5-bromopyrazine-2-amine in a solvent N, N-dimethylacetamide, adding an alkali reagent, and reacting for 0.5-2h after heating;
cooling the reaction system to room temperature, adding p-toluenesulfonyl chloride, cooling the reaction system to room temperature, and reacting the reaction system at room temperature for 0.5-2 h;
step three, after the reaction is finished, adding the reaction system obtained in the step two into 0.5-10% wt of sodium bicarbonate water solution, filtering, adding the obtained solid filter cake into a mixed solvent, recrystallizing, filtering and drying to obtain a finished product of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine;
in the first step, the alkali reagent is one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; in step one, the added alkaline reagent: the molar ratio of 3- [ (trimethylsilyl) ethynyl ] -5-bromopyrazine-2-amine is 1.0-1.5: 1.0.
2. the process for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine according to claim 1 wherein: in the first step, the temperature is raised to 40-100 ℃ and then the reaction is carried out.
3. The process for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine according to claim 1 wherein: in the second step, the molar ratio of the added p-toluenesulfonyl chloride to the 3- [ (trimethylsilyl) ethynyl ] -5-bromopyrazine-2-amine added in the first step is 1.0-1.5: 1.0.
4. the process for preparing 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine according to claim 1 wherein: in the third step, the mixed solvent is one or more of aliphatic hydrocarbon, aromatic hydrocarbon, ether, ester and nitrile.
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