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Synthesis method of naproxen key intermediate

A synthetic method, naproxen technology, applied in the field of synthetic technology of naproxen intermediates, can solve problems such as increased production costs, increased energy and reaction uncertainty, and achieves the effects of saving costs, improving high costs, and improving efficiency

Inactive Publication Date: 2019-05-17
HUNAN JIUDIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in the rearrangement reaction, a zinc oxide catalyst and toluene need to be added as a reaction solvent, and it needs to be heated to 113±5°C and kept for 10 hours. Under industrial production conditions, the temperature should be raised to 113±5°C and kept warm Reacting for 10 hours requires a lot of energy and increases the uncertainty of the reaction, and also greatly increases the production cost
[0007] Therefore, existing naproxen synthetic technique also needs to be improved

Method used

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  • Synthesis method of naproxen key intermediate
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  • Synthesis method of naproxen key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of compound II (2'-(6'-methoxynaphthalene)-2-propionic acid-3-chloro-2,2-dimethylpropyl ester).

[0037]

[0038] In a three-necked reaction flask, add 2-(1'-chloroethyl)-2-(6'-methoxy-2'-naphthyl)-5,5-dimethyl-1,3-diox Mix 33.5 g of hexane and 9.2 g of zinc acetate evenly, heat the reaction system to 125-130° C., melt it, and react at this temperature for 8 hours. After the reaction is complete, dichloromethane is added for extraction, the insoluble matter is removed by filtration, and the filtrate is concentrated to dryness to obtain the product compound II 2'-(6'-methoxynaphthalene)-2-propionic acid-3-chloro-2,2-dimethyl Propyl ester 32g. For the chromatogram of the detection see figure 1 , it can be seen from the figure that the mass fraction of compound I is 0.177%, and the rearrangement reaction is completely carried out. The intermediate product on peak 4 was also converted to the final product eventually. The yield was 95.5%.

Embodiment 2

[0040] Synthesis of compound IV (2'-(5'-bromo-6'-methoxynaphthalene)-2-propionic acid-3-bromo-2,2-dimethylpropyl ester).

[0041]

[0042] In a three-necked reaction flask, add 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphthyl)-5,5-dimethyl-1 , 45.8g of 3-dioxane and 6.8g of zinc chloride, mix well, heat the reaction system to 125-130°C, melt, and react at this temperature for 4 hours. After the reaction was completed, ethyl acetate was added for extraction, the insoluble matter was removed by filtration, and the filtrate was concentrated to dryness to obtain 2'-(5'-bromo-6'-methoxynaphthalene)-2-propionic acid-3-bromo-2,2 - Dimethylpropyl ester 42.2 g. For the chromatogram of the detection see figure 2 , it can be seen from the figure that the rearrangement reaction is completely complete. The intermediate product on peak 1 was also converted to the final product eventually. The yield was 92.2%.

Embodiment 3

[0044] Synthesis of compound VI (2'-(5'-iodo-6'-methoxynaphthalene)-2-propionic acid-3-iodo-2,2-dimethylpropyl ester).

[0045]

[0046] In a three-necked reaction flask, add 2-(1'-iodoethyl)-2-(5'-iodo-6'-methoxy-2'-naphthyl)-5,5-dimethyl-1 , 55.2g of 3-dioxane and 4.1g of zinc oxide were mixed uniformly, the reaction system was heated to 125-130°C, melted, and reacted at this temperature for 3 hours. After the reaction is complete, ether is added for extraction, the insoluble matter is removed by filtration, and the filtrate is concentrated to dryness to obtain 2'-(5'-iodo-6'-methoxynaphthalene)-2-propionic acid-3-iodo-2,2-di Methyl propyl ester 50g. For the chromatogram of the detection see image 3 , it can be seen from the figure that the mass fraction of compound I is 0.061%, and the rearrangement reaction is completely carried out. The intermediate product on peak 6 was also converted to the final product eventually. The yield was 90.4%.

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Abstract

The invention discloses a synthesis method of a naproxen key intermediate, and belong to a rearrangement step during preparation of naproxen. The synthesis method includes the steps that a catalyst isadded to 2-(1'-halogen ethyl)-2-(6'-methoxyl-2'-naphthyl)-5,5-dimethyl-1,3-dioxygen hexane to react under specific reaction conditions to generate 2'-(6'-methoxynaphthalene)-2-propanoic acid-3-halogen-2,2-dimethyl propyl ester. According to the synthesis method of the naproxen key intermediate, the defects that rearrangement can only be completed through a reaction for 10 hours or above under thehigh temperature being 130 DEG C or above in traditional synthesis steps are overcome, and energy consumption is reduced; and the reaction is conducted under the solvent-free condition, the yield ofthe reaction is increased, and meanwhile, the synthesis method is environmentally friendlier.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a synthesis process of a naproxen intermediate and an application thereof. Background technique [0002] Naproxen has anti-inflammatory, antipyretic and analgesic effects, and is a PG synthase inhibitor. For rheumatoid arthritis and osteoarthritis, it is similar to aspirin. For patients who cannot tolerate anti-inflammatory and analgesic drugs such as aspirin and indomethacin due to anemia, gastrointestinal system diseases or other reasons, this product can obtain satisfactory results, and at the same time, the effect of inhibiting platelets is relatively small. It has been widely used in the world and has become one of the main antipyretic and analgesic drugs and the best-selling over-the-counter drugs in the world. [0003] [0004] 2'-(6'-methoxynaphthalene)-2-propionic acid-3-chloro-2,2-dimethylpropyl ester is an important intermediate in the production of na...

Claims

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Application Information

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IPC IPC(8): C07C67/00C07C69/734
Inventor 宁虎林刘聪王湘武肖稳定郑霞辉
Owner HUNAN JIUDIAN PHARMA
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