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A new method for the preparation of the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of etoricoxib

A kind of technology of methylsulfonyl and methylpyridine, applied in the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl] for preparing etoricoxib A new frontier for ethyl ketones, able to address issues such as yield loss

Active Publication Date: 2016-07-06
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The impurity of this process (also known as "408") makes it difficult to remove from the product of formula (I) unless the various desired products are recrystallized, which in turn detrimentally leads to a continuous loss of yield

Method used

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  • A new method for the preparation of the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of etoricoxib
  • A new method for the preparation of the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of etoricoxib
  • A new method for the preparation of the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of etoricoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1 - Synthesis of sodium (4-methylsulfonyl)phenylacetate of formula (II-M=Na) - Example of the invention.

[0086] Synthetic scheme

[0087]

[0088] In a 4-neck flask, 25 g of (4-methylsulfonyl)phenylacetic acid of formula (IV) and 125 mL of methanol were introduced at 20-25°C. Heat the mixture to 35-40°C and stir for about 5-10 minutes until completely dissolved.

[0089] A solution of 5.6 g of NaOH (1.2 molar equivalents) in bead form in 25 mL of methanol was prepared separately.

[0090] Sodium hydroxide solution in methanol was added to the acidic sulfone solution at 35-40°C within 1 h. After addition, the pH was about 14 (litmus paper).

[0091] Stir for 30 minutes, then cool to T=0-5°C and stir until complete precipitation. The suspension was filtered and the solid was washed with cold methanol.

[0092]The product was dried under vacuum at 60°C for 8 hours to obtain 22 g of product as a white solid with a molar yield of 80%.

[0093] 1H-NMR ( ...

Embodiment 2

[0094] Example 2 - Synthesis of lithium (4-methylsulfonyl)phenylacetate of formula (II-M=Li) - The invention is according to an example of a preferred aspect.

[0095]

[0096] In a 4-neck flask, 150 g of (4-methylsulfonyl)phenylacetic acid of formula (IV) (1.0 mol. equivalent) and 750 mL of methanol were introduced at 20-25°C. Stir at 35-40°C until complete dissolution.

[0097] 32 g of LiOH monohydrate (1.08 molar equivalents) were added maintaining T=35 / 40°C. Precipitation of lithium salt occurred.

[0098] Stir at 35-40°C for one hour, then cool to room temperature and stir for 2 hours.

[0099] The suspension was filtered and the solid was washed with methanol. The solid was dried under vacuum at T=90°C for 8 hours to obtain 136 g of product as a white solid in a molar yield of 88%.

[0100] 1H-NMR: 3.26 (s, 3H, CH3); 3.65 (s, 2H, CH2); 7.45 (d, J=8Hz, 2H, Ar); 7.89 (d, J=8Hz, 2H, Ar); 334°C (by DSC); HPLC purity = 99.51 (A%). K.F.=0.11%.

Embodiment 3

[0101] Example 3 - 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of formula (I) - an embodiment according to a preferred aspect of the invention.

[0102]

[0103] In an anhydrous 4-neck flask, introduce 10.2 g of (4-methylsulfonyl)lithium phenylacetate (1.0 mol. equivalent) of the formula (II-M=Li) at 20-25 ° C, 200 mL of anhydrous THF, and Heat the mixture to 65-70°C (until reflux).

[0104] Maintaining T=65-70°C, simultaneously feed in the mixture over about 1 hour:

[0105] a) 66.0 g of a 1.0 M solution of t-BuMgCl (1.6 mol. equiv.) in THF (about 74.2 mL), and

[0106] b) 4.64 g of methyl 6-methylpyridine-3-carboxylate (0.65 mol. equivalent) of the formula (III-R=Me) in a solution of 15 mL of anhydrous THF.

[0107] After complete addition, the mixture was stirred at 65-70°C for 30 minutes.

[0108] The reaction was controlled by HPLC, then it was cooled to 20-25°C, and the reaction mixture was diluted with 100 mL of water under vigorous stirring. ...

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Abstract

The present invention refers to a novel process for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of the synthesis of Etoricoxib, an active ingredient on which the Arcoxia drug is based.

Description

technical field [0001] The object of the present invention is to provide an intermediate for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, a kind of etoricoxib (Etoricoxib) synthesis A method for the body of a medicinal anti-inflammatory active ingredient belonging to the class of COX-2 inhibitors. Background technique [0002] 1-(6-Methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone of formula (I) having CASRN221615-75-4: [0003] [0004] It is an important intermediate for the synthesis of etoricoxib, which is a part of the class of COX-2 inhibitors and has anti-inflammatory active pharmaceutical ingredients, and has been on the market under the trade name Arcoxia since 2002 Suitable pharmaceutical forms are commercially available. [0005] [0006] Examples of the use of such compounds for the synthesis of COX-2 inhibitors are shown in WO9955830, WO9915503 and described by Davies, LanW et al. in Journal of Organic Chemistr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/50C07C317/44C07C315/04C07D213/61
CPCC07D213/50C07C317/44
Inventor 弗朗切斯科·丰塔纳保罗·斯塔比勒马尔科·加尔瓦格尼叶连娜·布拉索拉
Owner F I S FAB ILTALIANA SINTETICI SPA
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