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New process for synthesizing racemic naproxen based on Heck coupling

A new process and process technology, applied in the new process field based on Heck coupling synthesis of racemic naproxen, can solve the problems of difficult preparation of 2-acyl-6-methoxynaphthalene, interference product purification, low conversion rate, etc. , to achieve the effect of easy product purification, low cost and high conversion rate

Active Publication Date: 2021-08-03
JIAXING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Route I or II is based on 2-acyl-6-methoxynaphthalene as a raw material, and a more important defect is that 2-acyl-6-methoxynaphthalene is relatively difficult to prepare
However, the important defect of this type of coupling is that the conversion rate is low, while affecting the yield, the unconverted raw material 2-bromo-6-methoxynaphthalene will interfere with the purification of the product

Method used

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  • New process for synthesizing racemic naproxen based on Heck coupling
  • New process for synthesizing racemic naproxen based on Heck coupling
  • New process for synthesizing racemic naproxen based on Heck coupling

Examples

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Embodiment 1

[0032] A kind of new technology based on Heck coupling synthesis racemic naproxen, the concrete steps of this technology are as follows:

[0033] (1) Synthesis of intermediate 3-(6-methoxynaphthyl-2-)crotonamide

[0034]

[0035] 24 grams (0.1mol) of 2-bromo-6-methoxynaphthalene, 88 milligrams (0.5 mmol) of palladium chloride, 304 milligrams (1 mmol) of three (2-methylphenyl)-phosphine, 13 grams (0.15 mol) of crotonamide and 20 g (0.2 mol) of triethylamine were dissolved in 100 mL of dimethylformamide, purged with nitrogen three times, then sealed and heated to 130°C, and kept stirring for 20 h.

[0036] After the reaction is finished, cool down, filter the insoluble matter with diatomaceous earth, remove the solvent from the filtrate in vacuo, extract the residue twice with hot water, discard the water phase, and recrystallize the residue with ethanol to obtain 20.5 grams of 3-(6 -Methoxynaphthyl-2-)crotonamide (see H NMR spectrum and carbon spectrum figure 1 with 2 ), ...

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Abstract

The invention discloses a novel process for synthesizing racemic naproxen based on Heck coupling, which comprises the following steps: (1) carrying out Heck coupling reaction on 2-X substituted-6-methoxynaphthalene and crotonamide in an aprotic organic solvent under the action of a palladium catalyst and alkali to generate 3-(6-methoxynaphthyl-2-)-crotonamide; and (2) carrying out Hofmann degradation reaction on the 3-(6-methoxynaphthyl-2-)-crotonamide in an alkaline solution of hypochlorite to generate 2-(6-methoxynaphthyl-2-)-propionaldehyde, directly adding the 2-(6-methoxynaphthyl-2-)-propionaldehyde into chlorite without separation, and conducting oxidizing at room temperature to obtain racemic naproxen. The process provided by the invention does not need to prepare a highly active Grignard reagent, does not need a harsh anhydrous condition, and is relatively high in conversion rate and easy in product purification.

Description

technical field [0001] The invention relates to a process for synthesizing racemic naproxen, in particular to a new process for synthesizing racemic naproxen based on Heck coupling. Background technique [0002] The synthetic technique of existing naproxen is mainly based on two kinds of basic raw materials, and a class is 2-acyl-6-methoxynaphthalene (route I or II), and another kind is 2-bromo-6-methoxynaphthalene , there are mainly four synthetic routes, as follows: [0003] (I) [0004] (II) [0005] (III) [0006] (IV) [0007] Route I or II is based on 2-acyl-6-methoxynaphthalene as a raw material, and an important defect is that 2-acyl-6-methoxynaphthalene is relatively difficult to prepare. In the synthesis of 2-acyl-6-methoxynaphthalene, the first active site of naphthyl methyl ether is the ortho-position of methoxy group. The existing technology needs to protect this position, and then deprotect it after acylation. The route Longer, resulting in high c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/06C07C59/64
CPCC07C51/06C07C231/12C07C59/64C07C235/34Y02P20/584
Inventor 张倩云周宏伟任炼军石磊
Owner JIAXING UNIV
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