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Synthesis method of etoricoxib intermediate 4-methylsulfonyl acetophenone

A technology of acetophenone and etoricoxib, which is applied in the field of synthesis of etoricoxib intermediate 4-thiamphenicol acetophenone, can solve the problems of difficult storage of hydrogen peroxide, hidden dangers, and use of oxygen, etc., to achieve Solve the instability of oxidants, reduce production risks, and reduce the effect of reaction temperature

Inactive Publication Date: 2021-08-24
SCINOPHARM CHANGSHU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The main problem of the first method is the use of hydrogen peroxide, hydrogen peroxide is not easy to store, and there is a risk in long-term storage
[0009] The main problem of the second method is that the reaction temperature is 120°C, and oxygen is used, there are hidden dangers and potential explosions
[0010] The third method uses magnesium phthalate monoperoxide, which is more expensive

Method used

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  • Synthesis method of etoricoxib intermediate 4-methylsulfonyl acetophenone

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preparation example Construction

[0028] In order to achieve the above object, the invention provides a kind of synthetic method of etoricoxib intermediate 4-thiamphenicol acetophenone, comprising the following steps:

[0029] Step 1: In the dichloromethane system, add anhydrous aluminum trichloride, cool to -10-0°C, add acetyl chloride to obtain a reaction solution;

[0030] Step 2: Add the reaction solution dropwise into the reaction solution with sulfide anisole, and after the reaction is completed, add water dropwise to terminate the reaction, and the internal temperature does not exceed 15°C;

[0031] Step 3: standing still for liquid separation, extracting the aqueous phase with dichloromethane, combining the organic phases, and washing the combined organic phases with 10% aqueous sodium bicarbonate solution;

[0032] Step 4: Evaporate the washed organic phase to dryness, add n-heptane, heat the mixture to 50°C, lower the temperature to -5-5°C, wash and dry the crystals to obtain acetyl anisole sulfide; ...

Embodiment 1

[0042] Step 1: Under the protection of nitrogen, add 108g of anhydrous aluminum trichloride and 744mL of dichloromethane into the reaction flask, stir, and cool the mixture to -5°C.

[0043] Further, 56.4g of acetyl chloride was added into the reaction flask.

[0044] Step 2: Add 74.4 g of sulfide anisole dropwise to the reaction mixture.

[0045] After the reaction was completed, 360 mL of water was added dropwise, and the inner temperature was maintained at 10°C.

[0046] Step 3: After the water was added, the mixture was left standing for liquid separation, the purple organic layer was separated, the aqueous layer was extracted once with 100 mL of dichloromethane, and the combined organic layers were washed with 200 g of 10% sodium bicarbonate water.

[0047] Step 4: Evaporate the organic layer to dryness, add 200 mL of n-heptane and stir to obtain a mixture, heat the mixture to 50° C., then lower the temperature to 0° C., and stir for 1 hour.

[0048]Further, the mixture...

Embodiment 2

[0053] Step 1: Under the protection of nitrogen, add 108g of anhydrous aluminum trichloride and 744mL of dichloromethane into the reaction flask, stir, and cool the mixture to -5°C.

[0054] Step 2: Further, 56.4 g of acetyl chloride was added into the reaction flask, and 74.4 g of sulfide anisole was added dropwise into the reaction mixture.

[0055] After the reaction is completed, 360 mL of water is added dropwise, and the inner temperature does not exceed 10°C.

[0056] Step 3: After the water was added, the mixture was left standing for liquid separation, the purple organic layer was separated, the aqueous layer was extracted once with 100 mL of dichloromethane, and the combined organic layers were washed with 200 g of 10% sodium bicarbonate water.

[0057] Step 4: Evaporate the organic layer to dryness, add 200 mL of n-heptane and stir to obtain a mixture, heat the mixture to 50° C., then lower the temperature to 0° C., and stir for 1 hour.

[0058] Step 5: Further, the...

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Abstract

The invention discloses a synthetic method of an etoricoxib intermediate 4-methylsulfonyl acetophenone, wherein the comprises the following steps: step 1, adding anhydrous aluminum trichloride and acetyl chloride in a dichloromethane system to obtain a reaction solution; step 2, dropwise adding the reaction solution into thioanisole into the reaction solution; step 3, standing for liquid separation, extracting a water phase by using dichloromethane, combining organic phases, and washing the combined organic phases by using a 10% sodium bicarbonate aqueous solution; step 4, evaporating the washed organic phase to dryness, adding n-heptane, crystallizing, washing, and drying to obtain acetylphenylmethyl sulfide; and step 5, adding the acetylphenylmethyl sulfide obtained in the step 4 into an acetone system, and further reacting to obtain 4-methylsulfonyl acetophenone; or adding the acetylphenylmethyl sulfide obtained in the step 4 into an acetic acid system, and stirring for dissolving to obtain a reaction mixture; and further reacting to obtain the 4-methylsulfonyl acetophenone. The energy consumption is reduced, the reaction is more stable, and the benefit is high.

Description

technical field [0001] The invention relates to the field of intermediate synthesis, in particular to a method for synthesizing etoricoxib intermediate 4-thiamphenicol acetophenone. Background technique [0002] [0003] 4-thiamphenicol acetophenone is an intermediate in the step of synthesizing etoricoxib. Etoricoxib is a selective COX-2 inhibitor indicated for the treatment of symptoms and signs of acute and chronic osteoarthritis and acute gouty arthritis. Traditional non-steroidal anti-inflammatory drugs block COX-2 and COX-1 enzymes, and COX-1 enzyme is responsible for maintaining normal gastrointestinal function, so some orthopedic pain management experts in my country recommend patients with gastrointestinal risk For selective COX-2 inhibitors, etoricoxib can be used. [0004] The commonly used preparation methods are as follows: [0005] 1. Acetylanisole sulfide is used as the starting material, and hydrogen peroxide is used as the oxidizing agent to react in wa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/24C07C315/02
CPCC07C315/02C07C319/20
Inventor 苏源韦秀琼
Owner SCINOPHARM CHANGSHU PHARMA
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