CN112321592B - Synthesis method of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile - Google Patents
Synthesis method of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile Download PDFInfo
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- CN112321592B CN112321592B CN202011258576.XA CN202011258576A CN112321592B CN 112321592 B CN112321592 B CN 112321592B CN 202011258576 A CN202011258576 A CN 202011258576A CN 112321592 B CN112321592 B CN 112321592B
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Abstract
A method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile comprises the following steps: the method comprises the following steps: adding N, N-dimethylformamide dimethyl acetal into a reactor to react with 3-amino-6-chloropyridazine to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate; step two: adding a solvent into the N, N-dimethyl-N' -3- (6-chloro-pyridazine) group-formamidine intermediate obtained in the step one, mixing, adding bromoacetonitrile, reacting, adding alkali liquor, standing, precipitating a solid, and filtering to obtain a solid mixture; step three: completely dissolving the solid mixture obtained in the step four in ethyl acetate, washing with water and saturated saline, drying, filtering, and removing ethyl acetate to obtain a crude product of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile; step four: recrystallizing the crude product of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, and filtering to obtain a pure product of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile. The invention has short time of the whole process, and the obtained product has stable quality and high purity.
Description
Technical Field
The invention belongs to the field of synthesis of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, and particularly relates to a synthesis method of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile.
Background
The 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile is an important intermediate for organic synthesis, is mainly used as a medical intermediate and is organically synthesized, and is a key intermediate of a novel anti-cancer drug BMS-986260, and the 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile is a novel medical intermediate, has great medical value but difficult synthesis, has complex steps and high cost in the current preparation method, does not disclose a 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile synthesis method in the current published literature, and lacks a high-efficiency and high-yield 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile preparation method.
Disclosure of Invention
The invention provides a synthesis method of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, which is used for overcoming the defects in the prior art.
The invention is realized by the following technical scheme:
a method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile comprises the following steps:
the method comprises the following steps: adding N, N-dimethylformamide dimethyl acetal and 3-amino-6-chloropyridazine into a reactor to react for 2-8h at 40-100 ℃ to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate;
step two: mixing the N, N-dimethyl-N' -3- (6-chloro-pyridazine) group-formamidine intermediate obtained in the step one with a solvent, adding bromoacetonitrile, reacting at the temperature of 50-160 ℃ for 3-15h, cooling to room temperature, adding alkali liquor to adjust the pH, standing for 3h, precipitating a solid, and filtering to obtain a solid mixture;
step three: completely dissolving the solid mixture obtained in the step four in ethyl acetate, washing with water for three times, then washing with saturated saline solution for two times, drying with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to remove ethyl acetate to obtain a crude product of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile;
step four: using n-hexane for crude 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile: the volume ratio of ethyl acetate is 1: 2, recrystallizing and filtering the mixed solution to obtain a pure product of the 6-chloroimidazo [1,2-b ] pyridazine-3-formonitrile.
In the method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, the molar ratio of the added amount of 3-amino-6-chloropyridazine to the added amount of N, N-dimethylformamide dimethyl acetal in the step one is 4: 1-1: 4.
in the method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, the molar ratio of bromoacetonitrile to the added amount of 3-amino-6-chloropyridazine in the second step is 5: 1-1: 4.
in the method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile, the solvent in the second step is any one of acetonitrile, ethanol and N, N-dimethylformamide.
The method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile comprises the step two, wherein the alkali solution is a saturated sodium carbonate solution.
The invention has the advantages that: the method has the advantages of low price of reaction raw materials, no restriction on purchased chemical reagents, easiness in obtaining, simple reaction conditions, convenience in operation, easiness in control, short overall process time, stable quality of obtained products and high purity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a reaction equation of the present invention;
FIG. 2 is a liquid phase detection spectrum of purity of example 1 of the present invention;
FIG. 3 is a purity liquid phase detection spectrum of example 2 of the present invention;
FIG. 4 is a purity liquid phase detection spectrum of example 3 of the present invention.
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 with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Reacting 50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material with 400g N-dimethylformamide dimethyl acetal at 60 ℃ for 4 hours to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, removing excessive N, N-dimethylformamide dimethyl acetal by rotary evaporation, adding DMF400ml, dropwise adding bromoacetonitrile (60.8g, 507mmol), reacting at 60 ℃ for 10 hours, cooling to room temperature, adding an appropriate amount of saturated sodium bicarbonate solution, adjusting the pH to 7.9, standing for three hours to precipitate a solid, dissolving all the solid in 300ml of ethyl acetate, washing with water three times, 100ml each time, then washing with saturated saline water for 2 times, 100ml each time, drying with anhydrous sodium sulfate, concentrating by rotary evaporation, N-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 58.1g of a pure product. Purity 98.7%, yield 83%.
Example 2
Reacting 50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material with 400g N-dimethylformamide dimethyl acetal at 110 ℃ for 3 hours to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, removing excessive N, N-dimethylformamide dimethyl acetal by rotary evaporation, adding DMF400ml dropwise with bromoacetonitrile (60.8g, 507mmol), reacting at 80 ℃ for 8 hours, cooling to room temperature, adding an appropriate amount of saturated sodium bicarbonate solution, adjusting the pH to 8.3, standing for three hours to precipitate a solid, dissolving all the solid in 300ml of ethyl acetate, washing with water three times, 100ml each time, then washing with saturated saline water for 2 times, 100ml each time, drying with anhydrous sodium sulfate, concentrating by rotary evaporation, and dissolving, N-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 55.5g of a pure product. Purity 99.1%, yield 79.3%.
Example 3
Reacting 50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material with 400g N-dimethylformamide dimethyl acetal at 50 ℃ for 8 hours to obtain N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, removing excessive N, N-dimethylformamide dimethyl acetal by rotary evaporation, adding 400ml of acetonitrile, dropwise adding bromoacetonitrile (60.8g, 507mmol), reacting at 100 ℃ for 10 hours to obtain a reaction product, cooling to room temperature, adding an appropriate amount of saturated sodium bicarbonate solution, adjusting the pH to 7.4, standing for three hours to precipitate solids, dissolving all the solids in 300ml of ethyl acetate, washing with water three times, 100ml each time, then washing with saturated saline water for 2 times, 100ml each time, and then drying with anhydrous sodium sulfate, Rotary evaporation concentration, n-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 54.2g of a pure product. Purity 98.5%, yield 77.5%.
Example 4
Reacting 50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material with 400g N-dimethylformamide dimethyl acetal at 110 ℃ for 3 hours to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, removing excessive N, N-dimethylformamide dimethyl acetal by rotary evaporation, adding DMF400ml, dropwise adding bromoacetonitrile (60.8g, 507mmol), reacting at 60 ℃ for 14 hours, cooling to room temperature, adding an appropriate amount of sodium hydroxide solution, adjusting the pH to 8.4, standing for three hours to precipitate a solid, dissolving all the solid in 300ml of ethyl acetate, washing with water three times, 100ml each time, washing with saturated saline water 2 times, 100ml each time, drying with anhydrous sodium sulfate, concentrating by rotary evaporation, N-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 57.4g of a pure product. Purity 99.2%, yield 82%.
Example 5
50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material is reacted with 400g N-dimethylformamide dimethyl acetal at 130 ℃ for 3 hours to obtain N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, excessive N, N-dimethylformamide dimethyl acetal is removed by rotary evaporation, 400ml of acetonitrile is added, bromoacetonitrile (60.8g, 507mmol) is dropwise added, the reaction is carried out at 80 ℃ for 10 hours, the reaction is finished, the temperature is cooled to room temperature, a proper amount of saturated sodium bicarbonate solution is added, the pH is adjusted to 8.6, the mixture is kept stand for three hours to precipitate solids, all the solids are dissolved in 300ml of ethyl acetate, the mixture is washed with water for three times, 100ml each time, then the mixture is washed with saturated saline water for 2 times, 100ml each time, and then dried by anhydrous sodium sulfate, Rotary evaporation concentration, n-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 54.3g of a pure product. Purity 98.6% and yield 77.5%.
Example 6
Reacting 50g (390mmol) of 3-amino-6-chloropyridazine as a reaction raw material with 400g N-dimethylformamide dimethyl acetal at 90 ℃ for 10 hours to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate, removing excessive N, N-dimethylformamide dimethyl acetal by rotary evaporation, adding DMF400ml, dropwise adding bromoacetonitrile (60.8g, 507mmol), reacting at 120 ℃ for 8 hours, cooling to room temperature, adding an appropriate amount of saturated sodium carbonate solution, adjusting the pH to 7.6, standing for three hours to precipitate solids, dissolving all the solids in 300ml of ethyl acetate, washing with water three times, 100ml each time, then washing with saturated saline water for 2 times, 100ml each time, drying with anhydrous sodium sulfate, concentrating by rotary evaporation, and precipitating solids, N-hexane: the volume ratio of ethyl acetate is 1: 2 to obtain 56g of a pure product. Purity 98.4%, yield 80%.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (2)
1. A synthetic method of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: adding N, N-dimethylformamide dimethyl acetal and 3-amino-6-chloropyridazine into a reactor to react for 2-8h at 40-100 ℃ to obtain an N, N-dimethyl-N' -3- (6-chloro-pyridazine) yl-formamidine intermediate;
step two: mixing the N, N-dimethyl-N' -3- (6-chloro-pyridazine) group-formamidine intermediate obtained in the step one with a solvent, adding bromoacetonitrile, reacting at the temperature of 50-160 ℃ for 3-15h, cooling to room temperature, adding alkali liquor to adjust the pH, standing for 3h, precipitating a solid, and filtering to obtain a solid mixture;
step three: completely dissolving the solid mixture obtained in the step four in ethyl acetate, washing with water for three times, then washing with saturated saline solution for two times, drying with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to remove ethyl acetate to obtain a crude product of 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile;
step four: using n-hexane for crude 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile: the volume ratio of ethyl acetate is 1: 2, recrystallizing and filtering the mixed solution to obtain a pure product of 6-chloroimidazo [1,2-b ] pyridazine-3-formonitrile;
the mol ratio of the added amount of the 3-amino-6-chloropyridazine to the added amount of the N, N-dimethylformamide dimethyl acetal in the step one is 4: 1-1: 4;
in the second step, the molar ratio of bromoacetonitrile to the addition amount of 3-amino-6-chloropyridazine is 5: 1-1: 4;
the solvent in the second step is any one of acetonitrile, ethanol and N, N-dimethylformamide;
and in the second step, the pH is adjusted to 7-9.
2. The method for synthesizing 6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile according to claim 1, characterized in that: and the alkali liquor in the second step is a saturated sodium carbonate solution.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012034091A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors |
| CN104910153A (en) * | 2015-05-29 | 2015-09-16 | 山东友帮生化科技有限公司 | 6-chloro-8-acetonitrile oxy imidazo [1,2-a] pyridine-3-carbonitrile preparation method |
| CN107406412A (en) * | 2015-03-02 | 2017-11-28 | 里格尔药品股份有限公司 | TGF beta inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012034091A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors |
| CN107406412A (en) * | 2015-03-02 | 2017-11-28 | 里格尔药品股份有限公司 | TGF beta inhibitors |
| CN104910153A (en) * | 2015-05-29 | 2015-09-16 | 山东友帮生化科技有限公司 | 6-chloro-8-acetonitrile oxy imidazo [1,2-a] pyridine-3-carbonitrile preparation method |
Non-Patent Citations (1)
| Title |
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| Convenient two-step one-pot synthesis of 3-substituted imidazo[1，2-a ]pyridines and imidazo[1，2-b]pyridazines;HONGLI FAN，等;《J. Chem. Sci.》;20181231;第130卷(第5期);第1-8页 * |
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