Novel process for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib.

A technology of methylsulfonyl and picoline, applied to the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl] for the preparation of etoricoxib New frontier for acetone, capable of solving issues like yield loss

Active Publication Date: 2013-01-30
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)

Method used

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  • Novel process for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib.
  • Novel process for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib.
  • Novel process for the preparation of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate 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. The method comprises that (4-methylsulfonyl)phenylacetic acid or alkali salt of (4-methylsulfonyl)phenylacetic acid is reacted with 6-methylpyridin-3-carboxylic acid ester at the presence of Grignard reagents. The method is characterized in that two reagents such as 6-methylpyridin-3-carboxylic acid ester and the Grignard reagents are simultaneously added to (4-methylsulfonyl)phenylacetic acid or the alkali salt of (4-methylsulfonyl)phenylacetic acid. The method of the invention is used to provide an improvement mathod for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone and the improvement method allows to obtain high-yield products and restricts impurity "480" to form.

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 CAS RN 221615-75-4: [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 WO 9955830, WO 9915503 and by Davies, Lan W et al. in Journal of Organic Chemistry (20...

Claims

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Application Information

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IPC IPC(8): C07D213/50C07C317/44C07C315/04C07D213/61
CPCC07C317/44C07C317/32C07D213/50
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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