Continuous flow production process for etoricoxib intermediate

A production process, relying on the technology of Coxib, which is applied in chemical/physical/physicochemical processes, organic chemistry, chemical/physical processes, etc., can solve the problems of high material cost, high reaction heat, and high cost, and achieve novel catalysts and high reaction Mild conditions, relatively mild effects

Inactive Publication Date: 2018-10-23
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The first step uses relatively expensive strong bases such as lithium hexamethyldisilazide and lithium diisopropylamide, which are costly and dangerous, and because of the use of highly active reagents, the heat of reaction is very high, and the process safety is difficult. Assure
[0011] The second step uses oxidizing reagents such as potassium dichromate and m-chloropero

Method used

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  • Continuous flow production process for etoricoxib intermediate
  • Continuous flow production process for etoricoxib intermediate
  • Continuous flow production process for etoricoxib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 1. Synthesis of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)ethanone:

[0046]In a continuous flow reactor, the first material input port is input (4-(methylthio)phenylacetic acid tetrahydrofuran solution (1mol / L concentration, 1mL / s flow rate), heated to 60 degrees by a heat exchanger, The second material input port inputs the tetrahydrofuran solution (2mol / L concentration, 1.5mL / s flow velocity) of tert-butylmagnesium chloride and mixes with the solution shown in the first inlet, and installs gas overflow device. After the two kinds of solutions are mixed, in Pass through the heat exchanger of 60 degrees in 60 minutes, then input the tetrahydrofuran solution (5mol / L concentration, 0.18mL / s flow velocity) of 6-methyl-pyridine-3-formic acid methyl ester from the third material input port, and Pass through a 60-degree heat exchanger (gas overflow device must be installed) within 60 minutes, and concentrate to collect tetrahydrofuran, and concentrate until the output s...

Embodiment 2

[0056] 1. Synthesis of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)ethanone:

[0057] In a continuous flow reactor, the first material input port is input (4-(methylthio)phenylacetic acid in 2-methyltetrahydrofuran solution (1mol / L concentration, 1mL / s flow rate), heated by a heat exchanger To 70 degrees, the second material input port input 2-methyl tetrahydrofuran solution of tert-butylmagnesium chloride (2mol / L concentration, 2mL / s flow rate) and mix with the solution shown in the first inlet, and install a gas overflow device. After the two solutions were mixed, they passed through a heat exchanger of 70 degrees in 40 minutes, and then imported the 2-methyltetrahydrofuran solution (5mol / L concentration, 0.18mL / s flow rate), and pass through a heat exchanger at 70 degrees within 40 minutes (gas overflow device must be installed).

[0058] The fourth material input port is input with 10% dilute hydrochloric acid (0.35mL / s), and a gas overflow device must be installed. ...

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Abstract

The invention discloses a continuous flow production process for an etoricoxib intermediate, belonging to the field of application technologies for bulk pharmaceutical chemical production in fine chemical engineering processes. The method for the etoricoxib intermediate comprises the following steps: step 1, synthesis of an intermediate in a continuous flow microreactor with non-nucleophilic organic strong base as a reagent; and step 2, performing of an oxidation process in the continuous flow microreactor by using a cheap inorganic oxidant under the action of a transition metal catalyst. Themethod comprises the following concrete reaction steps: with 4-(methylthio)phenylacetic acid and methyl 6-methylpyridine-3-carboxylate as starting materials, allowing the 4-(methylthio)phenylacetic acid and the methyl 6-methylpyridine-3-carboxylate to undergo a two-step reaction in the continuous flow microreactor so as to form 1-(6-methylpyridin-3-yl)-2-(4-methylsulfonylphenyl)ethanone. The method provided by the invention adopts novel reagents and catalyst and innovative equipment, has a yield of more than 70%, well controls generation of reaction heat and gas, and has the characteristics ofnovel catalysts, relatively mild reaction conditions, etc.

Description

Technical field: [0001] The invention relates to a continuous flow production process of an etoricoxib intermediate, belonging to the technical field of application of fine chemical processes in the production of raw materials. Background technique: [0002] Etoricoxib is an anti-arthritic drug developed by a pharmaceutical company in the United States, and its trade name is Ankangxin. Ketone is the most critical intermediate of this drug. [0003] [0004] At present, there are two main synthetic routes of this intermediate: [0005] [0006] The first process route is to oxidize sulfide to sulfone first, and then perform condensation. Since the second step of condensation needs to convert the carboxyl group into a carbanion, and the methyl group adjacent to the sulfone functional group also has strong acidity, many side reactions and low yield. [0007] The second process route is condensation followed by oxidation. This route is more selective. [0008] [0...

Claims

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Application Information

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IPC IPC(8): C07D213/50B01J19/00
CPCB01J19/0093C07D213/50
Inventor 周章涛黄志宁汪凡徐俊烨费安杰颜燕南
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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