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Preparation method of 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine
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A technology of ethylpiperazine and chloromethylpyridine, which is applied in the field of medicine and chemical industry, can solve the problems that 2-bromo-5-formylpyridine is expensive, unsuitable for industrial production, and long preparation route, and achieve cheap raw materials and industrial production Favorable, mild reaction conditions
Inactive Publication Date: 2018-08-24
EAST CHINA UNIV OF SCI & TECH
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[0010] The above three methods have the following defects: the first method has been improved and has realized industrialized production, and the raw material 2-bromo-5-formylpyridine is more expensive; the raw material 6-nitronicotinic acid used in the second method is more expensive, and The expensive condensing agent PyBOP is used, and the final reduction with lithium aluminum tetrahydrogen is not suitable for industrial production; the raw material 6-aminonicotinic acid ethyl ester used in the third method is not only expensive in raw materials, but also has a long preparation route, and is not suitable for industrial production. Production
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Embodiment 1
[0033] Synthesis of 1-(6-chloro-pyridin-3-ylmethyl)-4-ethyl-piperazine (II)
[0034] Add 2-chloro-5-chloromethylpyridine (162g, 1.0mol), tap water 300mL and N-ethylpiperazine (171g, 1.5mol) into a 1L reaction flask, heat up to 60-70°C, stir for 2h, Cool to room temperature, add potassiumcarbonate (138g, 1.0mol) and stir for 10 minutes, separate the water phase, and dry to obtain 225g of product, yield 94%. 1 H NMR (400MHz, D 2 O): R 0.81(t, J=7.2Hz, 3H), 1.8~2.7(m, 10H), 3.34(s, 2H), 7.24(d, J=8Hz, 1H), 7.57(dd, J=8 , 2Hz, 1H), 8.03 (d, J=2Hz, 1H).
Embodiment 2
[0036] Synthesis of 1-(6-chloro-pyridin-3-ylmethyl)-4-ethyl-piperazine (II)
[0037] Add 2-chloro-5-chloromethylpyridine (162g, 1.0mol), potassiumcarbonate (138g, 1.0mol), acetonitrile 800mL and N-ethylpiperazine (125g, 1.1mol) into a 2L reaction flask, and heat up to 60-70°C, stirred for 2 hours, concentrated to dryness, added 400 mL of tap water, stirred for 10 minutes, separated the water phase, and dried to obtain 222 g of the product, with a yield of 93%.
Embodiment 3
[0039] Synthesis of 1-(6-chloro-pyridin-3-ylmethyl)-4-ethyl-piperazine (II)
[0040] Add 2-chloro-5-chloromethylpyridine (16.2g, 0.1mol) and N-ethylpiperazine (11.4g, 0.1mol) into a 100mL reaction flask, heat up to 80-90°C, stir for 7h, and cool to room temperature and used directly in the next step.
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Abstract
The invention discloses a preparation method of an Abemaciclib intermediate, namely, 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine. The method comprises the steps as follows: 2-chloro-5-chloromethylpyridine and N-ethylpiperazine are mixed and react at 60-90 DEG C for 1-24 h, aftertreatment is performed after cooling, and a compound shown in formula II is obtained; step 2, the compound shown in the formula II, a catalyst and a reaction reagent are mixed, react in a pressure tank in an airtight manner and react at 130-140 DEG C for 1-24 h, aftertreatment is performed after cooling, and a compound shown in formula I is obtained. Cheap pesticideimidacloprid and acetamiprid intermediate 2-chloro-5-chloromethylpyridine are used as raw materials in the method, and the method has the advantages that the raw materials are cheaper, the process is greener and more environmentally friendly and industrial production is better facilitated.
Description
technical field [0001] The invention belongs to the technical field of medicine and chemical engineering, and in particular relates to a new preparation method of Abemaciclib intermediate 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. Background technique [0002] On September 28, 2017, the FDA approved Eli Lilly's new breast cancerdrug Abemaciclib, which is a cyclin-dependent kinase CDK4 and CDK 6 inhibitor. [0003] The main synthetic method of Abemaciclib intermediate 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine is as follows: [0004] In the first method, Lilly uses 2-bromo-5-formylpyridine and N-ethylpiperazine to reductively aminate through sodium acetate borohydride, and then uses LiHMDS as a nitrogen source under the catalysis of DBA palladium and CyJohnPhos ligands The intermediate 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine was obtained; after improvement, the first step was changed to the Leuckart-Wallach reaction, using formic acid and trimethyl ort...
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