Procedure for the preparation of racemic derivatives of 1,5-diaryl-3-trifluoromethyl-delta2-pyrazolines

Abstract

Procedure for preparation of compounds with the general formula 1, which include the racemic mixtures (±)-1, and the enantiomerically pure compounds (−)-1 and (+)-1, wherein R1 and R3, like or different, represent an atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl or methoxy group; R2 represents an atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl or aminosulphonyl group; R4 represents an atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl or aminosulphonyl group, with the condition that one of the substituents R2 or R4 is a methylsulphonyl or aminosulphonyl group; which involves obtaining the racemic mixture with the general formula (±)-1 by reacting an (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one with a phenylhydrazine, followed by a treatment with chlorosulphonic acid, or by reacting with chlorosulphonic acid followed by a reaction with sodium hydroxide and, finally, with thionyl chloride. The product obtained by either of these methods is made to react with ammonium carbonate or ammonia, or with sodium sulphite and methyl iodide or methyl sulphate. In addition, to obtain the enantiomerically pure compounds with the general formula 1 by resolving the racemic mixture with the general formula (±)-1, a reaction is effected with optically active ephedrine, followed by formation of the sodium salt of each enantiomer, reaction with thionyl chloride and ammonium carbonate or ammonia, or instead with thionyl chloride followed by sodium sulphite and methyl iodide or methyl sulphate to thereby obtain separately the enantiomerically pure compounds with the general formulae (−)-1 and (+)-1.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a new, commercially useful procedure for the preparation of compounds having the general formula 1, which includes the racemic mixture (±)—1, and the enantiomerically pure compounds (−)-1 and (+)-1. BACKGROUND OF THE INVENTION [0002] Our patent WO 9962884 describes new derivatives of A2-pyrazolines, also known as 4,5-dihydro-1H-pyrazoles, which inhibit the enzyme cyclooxygenase-2, with application in human and / or veterinary medicine as anti-inflammatories and in other diseases in which cyclooxygenase-2 is involved, and which present a low or zero gastric and renal toxicity, so that they are anti-inflammatories with a greater safety profile. Certain racemic mixtures (±)-1, and the enantiomerically pure stereoisomers (−)-1 and (+)-1 described in said patent are currently in a clinical investigation stage. The aforementioned Patent describes the preparation of (±)-1 by reaction of (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one w...

AI Technical Summary

Benefits of technology

"The present invention provides a new and cost-effective method for preparing compounds with the general formula 1, which includes the racemic mixture (±)-1 and the enantiomerically pure compounds (−)-1 and (+)-1. This method involves the use of derivatives of benzaldehyde and phenylhydrazine, which are cheaper than previous methods, to obtain the key intermediate (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one. The invention also includes a process for resolution of the racemic mixture (±)-1 using high resolution liquid chromatography with a CHIRALPAK AS column of de 10μ particle size. The new method allows for the efficient and commercial production of compounds with the general formula 1, which are useful in medicine and other fields."

Problems solved by technology

This method has the disadvantage of using successive recrystallisations in both the process of formation of sodium sulphonate (between 3 and 7 recrystallisations), and in the process of formation and separation of the mixture of diastereoisomeric salts (between 4 and 7 recrystallisations), which results in a considerable reduction of the yield.

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