- Synthesis method of piperidine carboxylic acid amide drug intermediate N-(2,6-dimethyl benzene)-4-pyridine carboxamide
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A synthesis method of piperidine carboxylic acid amide drug intermediate N-(2,6-dimethyl benzene)-4-pyridine carboxamide comprises steps as follows: 1.1 mol of pyridine-4-formamide and 600-620 ml of nitromethane are added to a reaction container provided with a stirrer and a thermometer, the stirring speed is controlled to range from 130 rpm to 160 rpm, 0.4-0.42 mol of cuprous bromide is added in batches, the temperature of the solution is increased to 100-105 DEG C, the solution reacts for 2-3 h, filtration is performed, a filtrate is added to the reaction container again, 1.1-1.3 mol of 2,6-xylidine is added dropwise, the stirring speed is kept for 5-6 h after addition, the temperature of the solution is decreased to 15-18 DEG C, solids separate out, filtration is performed, the solids are washed with ethyl acetate, N-(2,6-dimethyl benzene)-4-pyridine carboxamide bromate is obtained and dissolved in 1,100 ml of a potassium nitrate solution, decolorization is performed with a molecular sieve, a sodium sulfite solution is added to adjust the pH to range from 9 to 10, the temperature of the solution is decreased to 3-5 DEG C, solids separate out, filtration is performed, the solids are washed with a salt solution, dehydrated with a dehydrating agent and recrystallized in chlorobenzene, and the N-(2,6-dimethyl benzene)-4-pyridine carboxamide is obtained.
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Paragraph 0015; 0016
(2016/11/09)
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- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
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Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
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