Method for synthesizing 2-fluorocyclopropane carboxylic acid

Abstract

Disclosed is a new method for synthesizing 2-fluorocyclopropanecarboxylic acid comprising: 1) performing reaction of 1,1-dichloro-1-fluoroethane with thiophenol in the presence of an alkali, to produce a phenyl sulfide intermediate; 2) performing oxidation reaction of the phenyl sulfide intermediate with Oxone; 3) performing elimination reaction of the product of Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene; 4) performing addition reaction of the 1-fluoro-benzenesulfonyl ethylene with ethyl diazoacetate in the presence of a catalyst, to obtain a cyclopropane intermediate; 5) performing elimination reaction of the cyclopropane intermediate in the presence of an alkali before acidification, to obtain 2-fluorocyclopropanecarboxylic acid. Herein, the synthetic route is short, used materials are bulk commodities, and raw materials are inexpensive and readily available. The process can be safely scaled up by replacing commonly used mCPBA reagents with Oxone. Further, reaction yield is improved, production cost is greatly reduced, and operation is simplified.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a U.S. National Stage of PCT / CN2017 / 081892, filed Apr. 25, 2017, which claims priority of Chinese Patent Application No. 201610686205.9, filed Aug. 18, 2016, each of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present disclosure relates to a new method for synthesizing 2-fluorocyclopropanecarboxylic acid.BACKGROUND OF THE INVENTION[0003]Since a fluorine atom has the largest electronegativity and oxidation potential, the introduction of a fluorine atom into a drug molecule can increase the lipophilicity of the drug and improve the trans-membrane ability of the drug in a living body, without significant alteration of the volume of the drug molecular. Thus, the bioavailability of the drug would be increased. In 1954, Fried and Sabo discovered that 9a-fluoroacetic acid cortisone prepared by introducing a fluorine atom into cortisone acetate exhibited an anti-inflammatory effect about 15 times ...

AI Technical Summary

Benefits of technology

[0043]1. The synthetic route of the present disclosure is short, the materials used therein are bulk commodities, and the raw materials are inexpensive and readily available.

[0044]2. The process can be safely scaled up by replacing commonly used mCPBA reagents with Oxone.

[0045]3. The reaction yield is increased, the production cost is greatly reduced, and the operation is simplified.

Problems solved by technology

However, it is difficult and high cost for the synthesis of 2-fluorocyclopropane carboxylic acid.

As a result, the raw material of sitafloxacin is expensive, which may impair the market promotion thereof.

If this method uses low-cost dichlorofluoromethane as a starting material, it would be difficult to generate carbene due to the low activity of dichlorofluoromethane, and thus the yield of cyclopropylation reaction would be low (31%).

If expensive dibromofluoromethane is used as a starting material, the cost would be extremely high due to the low atomic utilization ratio thereof.

This method requires high concentration of potassium hydroxide and sodium hydroxide solutions, heating, has high requirements for the equipment, and produces a large amount of process wastewater, which is detrimental to environmental protection.

Moreover, a violent reaction condition results in many side reactions, and the product must be separated through rectification.

However, it is difficult to achieve the rectification in a factory, due to the high boiling point of the product.

In this method, an ultra-low temperature reaction is performed in the first step, which has high requirements for the equipment and is highly cost.

Because of the strong corrosivity and oxidability of fluorine gas, there are many problems in operability and safety.

Thus, this method is not suitable for industrial production.

However, this method uses 1, 1-fluorochloroolefin in a form of gas, which is easily escaped when releasing nitrogen during the reaction.

Thus, 1, 1-fluorochloroolefin should be greatly excessive, and the process is unstable.

Moreover, this reaction is required to be performed under a closed condition, which leads to greater security risk in production.

Although the gas escape problem in method IV above is avoided, it is difficult and costly for the preparation of the 1-fluoro-1-benzenesulfonyl ethylene (the synthesis route thereof shown as follows).

All of the above methods have a disadvantage of being difficult to scale up.

The manufacturers of 2-fluorocyclopropane carboxylic acid are quite few, and 2-fluorocyclopropane carboxylic acid is extremely expensive, which seriously impedes further application and development thereof in organic chemistry and biomedicine.

Images