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Preparation method of etoricoxib intermediate 4-methylsulphonyl phenylacetic acid

A technology of methylsulfonylacetophenone and methylsulfonylbenzene is applied in the field of preparation of etoricoxib intermediate 4-methylsulfonylphenylacetic acid, which can solve the problems of high reaction temperature, explosion hazard and long reaction time, and achieve The effect of simple preparation, convenient operation and improved yield

Inactive Publication Date: 2018-01-30
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The problem with this preparation method is that the Grignard reaction conditions are relatively high, and must be anhydrous and oxygen-free. At the same time, the requirements for experimental operations are also high, which increases the difficulty of industrialization.
[0009] The problem that this preparation method exists is that the toxicity of methylation reagent (such as iodomethane, dimethyl sulfate etc.) is relatively large, and mCPBA easily causes explosion hazard in the aftertreatment process
[0012] The problem that this preparation method exists is to apply Willgerodt-Kindler reaction, and this reaction usually needs reaction temperature higher (more than 130 ℃), reaction time is longer (more than 10h), and continue to prolong time, raising temperature still can't solve productive rate Low problem, not conducive to industrial production

Method used

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  • Preparation method of etoricoxib intermediate 4-methylsulphonyl phenylacetic acid

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Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1, Preparation of Fluoroboric Acid Immobilized on Silica Gel

[0029] Into the round bottom flask, add 26.7g of 200-300 mesh silica gel and 100mL of anhydrous ether in sequence, stir, and then slowly add 40% HBF 4 Solution 3.3g. Stir for 3 h at room temperature, and evaporate the solvent under reduced pressure. The resulting product was dried under vacuum at 100°C for 72 hours to obtain 0.5 mmol·g -1 HBF 4 ·SiO2 2 White powder.

Embodiment 2

[0030] Embodiment 2, Preparation of 2-(4-(methylsulfonyl)phenyl)-1-morpholinoethanethiol

[0031] Add 4-methanesulfonyl acetophenone (10g, 50mmol), sublimed sulfur (1.9g, 60mmol), HBF successively in the four-necked flask 4 ·SiO2 2 Powder (5g, 2.5mmol) and morpholine (5.3mL, 60mmol) were stirred, heated to 75°C, and reacted for 3h. After that, 50 mL of ethyl acetate was added, filtered while hot, and the catalyst was removed. The filtrate was evaporated to remove the solvent under reduced pressure, 50 mL of methanol was added, and the mixture was stirred and crystallized at room temperature. Suction filtration yielded 13.3 g of yellow solid powder with a yield of 88.0% and a purity of 99.3%, which was directly used in the next hydrolysis reaction without purification.

Embodiment 3

[0032] Embodiment 3, Preparation of 4-methylsulfonylphenylacetic acid

[0033] Add the 2-(4-(methylsulfonyl)phenyl)-1-morpholinoethanethiol (13.3g, 44mmol) obtained in the previous step, 65mL of ethanol and 13mL of 50% NaOH solution into the four-necked flask successively, and stir Heated to 80-85°C for 6h. The ethanol was distilled off under reduced pressure, 50 mL of water was added to the residue, and it was left to stand at room temperature for 1 h to produce a dark green flocculent precipitate, which was filtered to obtain a light red transparent solution. At 0°C, adjust the pH to ≈2 with 2N hydrochloric acid. The white solid was obtained by filtration, suction filtered, dried and weighed 9.2g (calculated as 4-methylsulfonylacetophenone, the total yield of the two-step reaction was about 85%, and the literature value was 52%), mp: 133.3-134.9°C, ESI- MS m / z: 427[2M-H] - . 1 H-NMR (400MHz, CDCl 3 )δ: 3.03 (s, 3H), 3.74 (s, 2H), 7.47-7.91 (dd, 4H).

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Abstract

The invention belongs to the technical field of medicines, and discloses a preparation method of etoricoxib intermediate 4-methylsulphonyl phenylacetic acid. The method comprises the following steps:taking 4-methylsulfonyl acetophenone as an initial raw material, using fluoboric acid (HBF4.SiO2) supported on silica gel as the catalyst to synthesize 2-(4-(methylsulfonyl) phenyl)-1-morpholinoethanethione, hydrolyzing the 2-(4-(methylsulfonyl) phenyl)-1-morpholinoethanethione to obtain the etoricoxib intermediate 4-methylsulphonyl phenylacetic acid. The preparation method does not need toxicityreagents in other synthetic routes; the use of the fluoboric acid supported on silica gel as the catalyst conquers the defects of the traditional Willgerodt-Kindler reaction such as high temperature,long time and low yield, and moreover the method is simple to operate and easy to control and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of an important intermediate, in particular to a preparation method of etoricoxib intermediate 4-methylsulfonylphenylacetic acid. Background technique [0002] 4-Methanesulfonylphenylacetic acid is an important intermediate of etoricoxib. Etoricoxib, whose trade name is Ankangxin, is a non-steroidal anti-inflammatory drug developed by Merck, an American pharmaceutical company. The drug is well absorbed orally and can selectively inhibit cyclooxygenase-2 (Cyclooxygenase-2 , COX-2), relieve symptoms and signs of pain, inflammation and fever caused by prostaglandins, reduce gastrointestinal side effects without affecting platelet function. [0003] The synthetic method of existing 4-methylsulfonylphenylacetic acid has the following several kinds: [0004] Method 1: the method disclosed in WO9312121, using methyl phenyl sulfide as a starting material, undergoing ...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C317/44B01J27/06
Inventor 郑志超李灵君梅林雨
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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