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Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate

A technology based on ethyl benzoate and pyridyl, which is applied in the field of compound synthesis, can solve problems such as the difficulty of static precipitation of solids, complicated post-treatment process, and high price of isopropanol, and achieves the effects of low cost, simple post-treatment, and simple operation

Active Publication Date: 2016-07-27
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0035] The advantage of this method is high purity, but it has many disadvantages
Firstly, the price of the reaction raw material methanesulfonic acid and the processing reagent isopropanol is relatively high; secondly, the reaction temperature is high, and the energy consumption is large; thirdly, the post-treatment process is complicated, and it is difficult to precipitate solids at rest, and it takes a long time; finally, the reaction process low yield
These limit the industrial application

Method used

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  • Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate
  • Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate
  • Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] (1) Feeding: Weigh 1 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 1 g of urea into a round-bottomed flask. Excessive urea can make compound 2 react completely. 12ml of 4mol / L hydrochloric acid solution and 9ml of ethanol were added to the bottle, and the system was refluxed at 110°C for 5h. After TLC monitoring, the raw material point basically disappeared, and the reaction was completed.

[0062] Post-treatment: cool to room temperature, spin off ethanol and water under reduced pressure, the system becomes a red-yellow viscous liquid; add 30ml of ethanol to the system, an orange-yellow solid precipitates, stir for 30 minutes and then suction filter, the filter cake is washed with ethanol; the final crude product Wash with methanol. The yield of pure product is 92%.

[0063] (2) Feeding: Weigh 1.73g of 2-carbonyl-4-(3-pyridyl)-pyrimidine and 20.0ml of thionyl chloride into the reaction bottle, add 770μL of catalyst DMF, react at 70°C for 6h, and monitor the ra...

Embodiment 2

[0068] (1) Feeding: Weigh 1 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 0.5 g of urea into a round bottom flask, add 12 ml of 4mol / L hydrochloric acid solution into the reaction flask and ethanol 9ml, the system was refluxed at 110° C. for 5 hours, and after TLC monitoring, the raw material point basically disappeared, and the reaction was completed.

[0069] Post-treatment: cool to room temperature, spin off ethanol and water under reduced pressure, and the system turns into a red viscous liquid; add 30ml of ethanol to the system, and an orange-yellow solid precipitates, stir for 30 minutes and then suction filter, and the filter cake is washed with ethanol; finally, the crude product is washed with methanol wash. Yield 86%.

[0070] Reaction (2), (3) are with embodiment 1

Embodiment 3

[0072] Reaction (1) (3) is the same as embodiment 1

[0073] (2) Feeding: Weigh 1.73g of 2-carbonyl-4-(3-pyridyl)-pyrimidine and 20.0ml of phosphorus oxychloride into the reaction bottle, no catalyst is needed, and the system reacts at 65°C for 5 hours, then TLC monitors the raw material point Basically disappear, the reaction ends.

[0074] Post-processing: After the system is cooled, pour the system into 400ml of ice water, adjust the pH value to 8 with sodium hydroxide solution, extract with ethyl acetate (30ml×3), dry the extract with anhydrous sodium sulfate, suction filter, and The filtrate was evaporated to dryness to obtain a yellow solid crude product with a yield of 45%.

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Abstract

The invention relates to a preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate and belongs to the technical field of compound synthesis. The preparing method comprises the following steps of using triacetyl pyridine as a beginning raw material, condensing a product generated after urea loop closing and carbonyl chloro substitution with 3-amino-4-methyl ethyl benzoate to generate a key intermediate (I). Compared with an existing synthetic method, the preparing method is moderate in reacting condition and high in yield and has practical value. In addition, the raw material of the preparing method is cheap, easy to obtain and low in price. A synthetic route of the preparing method is as follow in the specification.

Description

technical field [0001] The invention relates to a preparation method of ethyl 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoate, a key intermediate of nilotinib, which belongs to the synthesis technology of compounds field. Background technique [0002] Nilotinib (nilotinib, trade name Tasigna), chemical name is 4-methyl-3-((4-(3-pyridyl)-2-pyrimidinyl)amino)-N-(5-(4-methyl Base-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide is a highly selective second-generation tyrosine kinase inhibitor developed by Swiss Novartis pharmaceutical company. [0003] Nilotinib is a new type of ATP competitive inhibitor with aminopyrimidine as the basic pharmacophore and has high affinity. Drugs based on molecular modification. [0004] The molecular structural formula of Nilotinib is as follows: [0005] [0006] The molecular structural formula of imatinib is shown in the following formula: [0007] [0008] Compared with imatinib, nilotinib has higher affinity and sp...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 乔仁忠李会娜张金李超
Owner BEIJING UNIV OF CHEM TECH
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