Synthesis methods of firocoxib and firocoxib intermediate

Abstract

The invention relates to the field of medicine synthesis and provides synthesis methods of firocoxib and a firocoxib intermediate. The synthesis method of the firocoxib intermediate takes 4'-bromopropiophenone as a starting raw material and a condition that thioether which is not environmentally friendly is used as the starting raw material is avoided; the 4'-bromopropiophenone and a methylating reagent are subjected to methylating reaction to obtain a first intermediate; the first intermediate is subjected to sulphination to directly obtain a second intermediate; sulfidation reaction and oxidization reaction are shortened to one-step substitution reaction, so that reaction steps are extremely simplified, the reaction time is shortened and the reaction efficiency is improved. Meanwhile, anNBS (N-Bromosuccinimide) system is also adopted so that the second intermediate is subjected to hydroxylation reaction to directly obtain the firocoxib intermediate, so that the synthesis method is more environmentally friendly and is suitable for large-scale production, and the reaction speed is improved. Furthermore, the synthesis method of the firocoxib comprises the synthesis method of the firocoxib intermediate and the firocoxib can be synthesized by a manner which has more moderate reaction conditions and is more environmentally friendly.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing ferocoxib and its intermediates. Background technique [0002] Ferocoxib, namely 3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylxanthyl)phenyl]-2(5H)-furanone, molecular formula: C 17 H 20 O 5 S. [0003] Ferocoxib is an important non-steroidal anti-inflammatory drug. There are not many reports on the synthesis of Ferocoxib. There are two main methods: [0004] Method one is the synthetic route of ferocoxib reported in patent documents US5981576, US006020343A, WO971645A1. Take anisole as starting material, react with isobutyryl chloride to produce compound A, compound A is hydroxylated to produce compound B, and compound B is oxidized with an oxidant such as (MMPP monoperoxy phthalate) to produce compound C, compound C It reacts with acetoxyacetyl chloride to produce compound D. Compound D is treated with DBU to close the ring to produce compound E, and compound...

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Problems solved by technology

[0009] Disadvantage 1: Sulfide anisole is used as the starting material, and sulfides generally have an unpleasant smell, and are easy to burn and explode when exposed to open flames or high heat. This substance will pollute the environment, and production in Europe and the United States has great environmental protection pressure

At the same time, in the post-treatment process of this method, it is necessary to pass through a silica gel chromatography column to obtain relatively pure compound B, which is not suitable for large-scale industrial production; method two uses liquid bromine to first bromine compound A, and then use sodium hydroxide solution Under the effect of phase transfer catalyst, carry out hydroxylation reaction to obtain compound B. This method uses liquid bromine, which has extremely strong toxicity and corrosiveness, and is extremely harmful to the environment and occupational health. It should be avoided as much as possible.

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