Statistics shows that 136590-83-5 is playing an increasingly important role. we look forward to future research findings about 3,5-Dichloroisonicotinaldehyde.
Synthetic Route of 136590-83-5, With the rapid development and complex challenges of chemical substances, the synthesis of new drugs is usually one of the most effective ways to increase yield.136590-83-5, name is 3,5-Dichloroisonicotinaldehyde, molecular formula is C6H3Cl2NO, molecular weight is 176, as common compound, the synthetic route is as follows.
9c) Ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (3.15 g, 16.5 mmol) in N,N-dimethylformamide (13 mL) was added N-chlorosuccinimide (2.20 g, 16.5 mmol). The mixture was heated to 65 C. and all solids dissolved. The solution was stirred at 65 C. for approximately 1.5 hours, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (3.37 g, 19.8 mmol) in tetrahydrofuran (4 mL) at 0 C. was added sodium ethoxide (25 wt % in ethanol, 6.21 mL, 19.8 mmol) and the mixture was stirred for approximately 7 minutes. Then the above imidoyl chloride was added in tetrahydrofuran (13 mL) at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (2.98 g, 53%). 1H-NMR (400 MHz, DMSO-d6) delta 8.64 (s, 2H), 4.35-4.20 (m, 1H), 4.05 (q, J=7 Hz, 2H), 2.45-2.30 (m, 4H), 2.14-2.04 (m, 1H), 2.00-1.89 (m, 1H), 0.96 (t, J=7 Hz, 3H). LRMS (APCI) m/z 341 (M+H)+.; 12a) Ethyl 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (1.44 g, 7.53 mmol) in N,N-dimethylformamide (6 mL) was added N-chlorosuccinimide (1.00 g, 7.53 mmol). The mixture was heated to 65 C. and all solids dissolved. The solution was stirred at 65 C. for approximately 1.5 hr, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclopropyl-3-oxopropanoate (1.41 g, 9.03 mmol) in tetrahydrofuran (2 mL) at 0 C. was added a 25 wt % solution of sodium ethoxide in ethanol (2.83 mL, 9.03 mmol) and the mixture was stirred for approximately 7 min. Then the above imidoyl chloride in tetrahydrofuran (6.5 mL) was added at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution). The isolated solid was washed with hexanes to afford ethyl 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (214 mg, 9%). 1H-NMR (400 MHz, DMSO-d6) delta 8.84 (s, 2H), 4.07 (q, J=7 Hz, 2H), 2.88-2.81 (m, 1H), 1.37-1.27 (m, 4H), 0.95 (t, J=7 Hz, 3H). LRMS (APCI) m/z 327 (M+H)+.25a) 3-(3,5-Dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylic acid N-chlorosuccinimide (1.36 g, 10.2 mmol) was added to a stirred solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (1.94 g, 10.2 mmol) in dimethylformamide (8 mL) and the solution was heated in a 65 C. oil bath for 1.5 hours. The solution was poured into water and extracted with ether. The organic layer was dried with MgSO4, filtered and concentrated to yield a crude carboximidoyl chloride. A solution of methylisobutyrylacetate (1.7 mL, 12.3 mmol) in THF (2.5 mL) was stirred at 0 C. as 0.5 N solution of sodium methoxide in methanol (24.6 mL, 12.3 mmol) was added. The solution was allowed to stir for ten minutes before the addition of the crude 3,5-dichloro-N-hydroxy-4-pyridinecarboximidoyl chloride in THF (8.1 mL). The solution was allowed to stir at room temperature overnight. The solution was then concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:9 ethyl acetate:hexanes). Fractions containing the intermediate were combined and concentrated. The residue was azetroped with methanol then was diluted with THF (11 mL) and methanol (5.5 mL). A 1 N solution of sodium hydroxide (3.3 mL) was added and the solution of heated to 100 C. for 500 seconds in a microwave reactor. The solution was neutralized with 1 N HCl and concentrated to yield a white solid. The residue was slurried in water and filtered to yield 3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylic acid (0.57 g, 18%). 1H NMR (400 MHz, DMSO-d6): delta 13.39 (s, 1H), 8.81 (s, 2H), 3.82 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H).
Statistics shows that 136590-83-5 is playing an increasingly important role. we look forward to future research findings about 3,5-Dichloroisonicotinaldehyde.
Reference:
Patent; SmithKline Beecham Corporation; US2008/96921; (2008); A1;,
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