Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester

A technology of p-fluorophenyl and diketone, which is applied in the field of chemical synthesis, can solve problems such as complex process routes, high cost, and large pollution, and achieve the effects of high product yield, low production cost, and less three wastes

Inactive Publication Date: 2014-02-05
QUZHOU UNIV
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0010] In order to overcome the shortcomings of the existing 1-alkyl-4-p-fluorophenyl-2,6-piperidinedione-3-carboxylate preparation technology, the process route is complicated, the cost is high, the pollution is large, and the like, the invention provides a A Short and Efficient Synthesis Process of 1-Alkyl-4-p-Fluorophenyl-2,6-piperidinedione-3-carboxylate

Method used

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  • Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester
  • Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester
  • Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]33.7g (0.1mol) of 1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3,5-dicarboxylate 33.7g (0.1mol) and methanol 280g were stirred and mixed evenly, and the concentration of 19% hydrogen was added dropwise 150g of sodium aqueous solution, heated to 70°C for 5 hours after dripping, cooled to below 10°C, added 400g of water, continued to stir and cooled to below 10°C, filtered and washed to obtain 6.2g of unreacted raw materials, 5.5g in dry weight, which was 16.3 %. The filtrate was acidified to pH 2.0 by adding 2.0mol / L hydrochloric acid, and an off-white solid was precipitated, filtered, washed with water, and dried in vacuum to obtain the intermediate 1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3- 25.4 g of formic acid-5-methyl carboxylate. The intermediate was dissolved in 200 g of methyl isobutyl ketone, 0.2 g of copper oxide was added, and the temperature was slowly raised to 110° C. for decarboxylation. After 7 hours, the decarboxylation was completed. Stir and co...

Embodiment 2

[0032] Stir and mix 36.5g (0.1mol) of diethyl 1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3,5-dicarboxylate and 300g of isopropanol evenly, dropwise at a concentration of 22 % sodium hydroxide aqueous solution 140g, after dripping, heat up to 65°C for 8 hours, cool to below 10°C, add 400g of water, continue to stir and cool to below 10°C, filter and wash to obtain 5.8g of unreacted raw materials, 5.2g in dry weight, as 14.2% of the feed. The filtrate was acidified to pH 2.0 by adding 2.0mol / L hydrochloric acid, and a light yellow solid was precipitated, filtered, washed with water, and dried in vacuum to obtain the intermediate 1-methyl-4-p-fluorophenyl-2,6-piperidinedione-3- Formic acid-5-ethyl carboxylate 27.0g. The intermediate was dissolved in 200 g of butyl acetate, 0.4 g of zinc oxide was added, and the temperature was slowly raised to 120° C. for decarboxylation. After 6 hours, the decarboxylation was completed. Stir and cool to below 30°C, filter and wash, add wate...

Embodiment 3

[0034] Mix 41.3g (0.1mol) of dimethyl 1-benzyl-4-p-fluorophenyl-2,6-piperidinedione-3,5-dicarboxylate and 260g of methanol evenly, and add hydrogen at a concentration of 21% dropwise Sodium oxide aqueous solution 155g, after dripping, heat up to 75°C for 6 hours, cool to below 10°C, add 400g of water, continue to stir and cool to below 10°C, filter and wash with water to obtain 8.2g of unreacted raw materials, 7.1g in dry weight, which is the raw material for feeding 17.2%. The filtrate was acidified to pH 2.0 by adding 2.0mol / L hydrochloric acid, and a slightly brown solid was precipitated, filtered, washed with water, and dried in vacuum to obtain the intermediate 1-benzyl-4-p-fluorophenyl-2,6-piperidinedione-3- 31.2 g of methyl formic acid-5-carboxylate. The intermediate was dissolved in 200 g of diethyl carbonate, 0.4 g of cuprous oxide was added, and the temperature was slowly raised to 100° C. for decarboxylation. After 10 hours, the decarboxylation was completed. Stir...

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Abstract

The invention discloses a synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester. The synthetic process comprises the following steps of using 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3,5-diformic ester, sodium hydroxide water solution and the like as raw materials and lower fatty alcohol as a solvent to undergo selective hydrolysis reaction through a chemical method, cooling, diluting, filtering, recovering unreacted raw materials, acidifying the filtrate, filtering, washing and drying in vacuum, thus obtaining an intermediate 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic acid-5-formic ester; then dissolving the intermediate in an organic solvent, adding a small amount of catalyst to carry out decarboxylic reaction, cooling, filtering, adding water to the filtrate to be stirred for layering, recovering a solvent at reduced pressure with an organic phase, and carrying out cooling crystallization on the residues, thus obtaining the product 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester. The synthetic process is short in route, is efficient, has the characteristics of cheap and accessible raw materials, high product yield, less three wastes and the like, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to a synthesis process of a pharmaceutical intermediate 1-alkyl-4-p-fluorophenyl-2,6-piperidinedione-3-carboxylate. Background technique [0002] 1-Alkyl-4-p-fluorophenyl-2,6-piperidinedione-3-carboxylates (structural formula (I)), especially 1-methyl-4-p-fluorophenyl-2,6 -Piperidinedione-3-carboxylate methyl or ethyl ester and 1-benzyl-4-p-fluorophenyl-2,6-piperidinedione-3-carboxylate methyl or ethyl ester are the best sellers in the market An important intermediate of the antidepressant paroxetine. (I) After several steps of resolution, reduction, demethylation or benzyl grouping, (-)-paroxetine is obtained (such as Xiu Wenhua et al., Chinese Journal of New Drugs, 2006, 15 (11), 886-888). De Risi et al. (Tetrahedron: Asymmetry, 2008, 19, 131-155) summarized the synthesis methods of (-)-paroxetine and its intermediates in detail. [0003] [0004] [0005] The main ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 郑土才徐庐峰顾媛媛祖江秀
Owner QUZHOU UNIV
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