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

A technology of hydroxymethyl benzonitrile and dimethylamino, which is applied in the field of preparation of diol compounds, can solve the problems of incomplete reaction, remaining raw materials, unreacted raw materials, etc., and achieves simple and easy reaction operation, reduced production costs, and reduced production costs. The effect of three wastes discharge

Inactive Publication Date: 2017-06-27
ZHEJIANG NORMAL UNIVERSITY +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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 ex

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Embodiment 1: take toluene as the preparation of solvent p-fluorophenylmagnesium bromide solution

[0048] In a 100mL three-necked flask, add 2.9g (120mmol) of magnesium chips and an iodine initiator, then add 10mL of dry toluene and 5g of p-fluorobromobenzene, and heat to initiate the reaction. Continue to add the toluene solution of p-fluorobromobenzene (containing 18 g of p-fluorobromobenzene and 50 mL of dry toluene) dropwise. After the addition is complete, heat up to 75° C. and heat to reflux for 30 minutes, and set aside.

Embodiment 2

[0049] Embodiment 2: Take ethylene glycol dimethyl ether as the preparation of solvent p-fluorophenylmagnesium bromide solution

[0050] In a 100mL three-necked flask, add 2.9g (120mmol) of magnesium chips and an iodine initiator, then add 10mL of dry ethylene glycol dimethyl ether and 5g of p-fluorobromobenzene, and heat to initiate the reaction. Continue to drop the ethylene glycol dimethyl ether solution of p-fluorobromobenzene (containing 18g of p-fluorobromobenzene, 50mL of dry ethylene glycol dimethyl ether solution), maintain the reaction temperature at 70°C, after the addition is complete, heat up to 80°C React for 30 minutes and set aside.

Embodiment 3

[0051] Embodiment 3: take THF as the preparation of solvent p-fluorophenylmagnesium bromide solution

[0052] In a 100mL three-necked flask, add 2.9g (120mmol) of magnesium chips and an iodine initiator, then add 10mL of dry THF and 5g of p-fluorobromobenzene, and heat to initiate the reaction. Continue to add the THF solution of p-fluorobromobenzene (containing 18 g of p-fluorobromobenzene and 50 mL of dry THF) dropwise. After the addition is complete, heat up to 65° C. and heat to reflux for 30 minutes, and set aside.

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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...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/59C07C255/56
CPCC07C253/30C07C255/59C07C255/56
Inventor 李新生罗红敏艾林郭幸雪徐敏忠
Owner ZHEJIANG NORMAL UNIVERSITY
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