Synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile

Abstract

The invention relates to synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile. The synthesis comprises the following steps: 1) dispersing 5-cyano isobenzofuranone into a solvent for optimizing a Grignard reaction, adding a p-fluorophenyl magnesium bromide solution, and performing a primary Grignard reaction, wherein the solvent is chlorinated hydrocarbon, ethanediol diether, 1,3-propanediol diether, 1,4-butanediol diether or 1,4-dioxane; 2) continuing to add a 1-(3-(N, N-dimethylamino) propyl) magnesium chloride solution, and performing a secondary Grignard reaction to obtain a mixed reaction solution; and 3) performing posttreatment on the mixed reaction solution to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl benzonitrile. By the synthesis method, generation of byproducts is effectively inhibited and the yield and the purity of the target product are improved.

Description

technical field [0001] The present invention relates to the preparation of diol compounds, in particular to a synthesis of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile . Background technique [0002] The first antidepressant drug used was the anti-tuberculosis agent isoniazid, which was eventually withdrawn from the market due to its high liver toxicity. Instead, tricyclic antidepressants (TCAs) are not used clinically because of their anti-parasympathetic effects and serious side effects such as hypotension and cognitive impairment. At present, the antidepressants widely used in clinical practice are 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs), which are respectively Xipuwei (citalopram), Prozac (fluoxetine), Xerox, etc. Special (paroxetine), Zoloft (sertraline) and so on. Hipromil, especially its chiral isomers, has higher efficacy and less toxic side effects than similar drugs, and the synthesis of chiral isomers also n...

AI Technical Summary

Problems solved by technology

[0005] With the industrialization of 5-cyanoisobenzofuranone, the diol compound is obtained through the double Grignard reaction, and the recyclization of the salt has become the simplest and most convenient route for the synthesis of Xipumi. The current problem is the double Grignard reaction Reaction Synthesis of Diol Compound Yield is Low

[0009] When Grignard reagent p-fluorophenylmagnesium bromide reacted with 5-cyanoisobenzofuranone for the first time, there were problems of incomplete reaction and excessive reaction

Since the intermediates generated by the reaction are ketone compounds, the reactivity of ketone compounds and Grignard reagents is higher than that of ester compounds, which will cause some raw materials to be unreacted, while the intermediates formed by the reaction react with p-fluorobenzene Magnesium bromide reacts again to generate by-product trityl alcohol derivatives, which in turn causes the surplus of raw materials caused by the deficiency of p-fluorophenylmagnesium bromide reagent

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