Preparation method of urapidil intermediate 1-(2-methoxyphenyl) piperazine and salt thereof

A technology of methoxyphenyl and urapidil, which is applied in the field of preparation of urapidil intermediate 1-piperazine and its salt, can solve the problems of low yield, heavy metal residue, high cost of raw materials, etc., and improve product purity , easy operation, guaranteed selective effect

Pending Publication Date: 2022-07-01
河北广祥制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Therefore, there are problems such as low yield, high cost of raw materials, and heavy metal residues in the synthetic route in the prior art, and it is urgent to study a kind of new urapidil intermediate 1-(2-methoxyphenyl) piperazine Preparation

Method used

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  • Preparation method of urapidil intermediate 1-(2-methoxyphenyl) piperazine and salt thereof
  • Preparation method of urapidil intermediate 1-(2-methoxyphenyl) piperazine and salt thereof
  • Preparation method of urapidil intermediate 1-(2-methoxyphenyl) piperazine and salt thereof

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preparation example Construction

[0047] The invention provides a preparation method of urapidil intermediate 1-(2-methoxyphenyl)piperazine, comprising the following steps:

[0048] Step 1, in the organic solvent, under the action of an acid binding agent, slowly adding methylsulfonyl chloride to o-methoxyphenol to carry out sulfonylation reaction to generate o-methoxyphenyl methanesulfonate;

[0049] Step 2. In the organic solvent, under the action of an acid binding agent, slowly add the o-methoxyphenyl methanesulfonate to piperazine to carry out a condensation reaction to generate a urapidil intermediate 1-(2-methoxyl group) phenyl) piperazine crude.

[0050] The organic solvent in the preparation method is preferably at least one of dichloromethane, dichloroethane or chloroform.

[0051] The acid binding agent is preferably at least one of pyridine, triethylamine or N-methylmorpholine.

[0052] The synthetic route used in the present invention is different from the prior art, and o-methoxy phenol and met...

Embodiment 1

[0060] The present embodiment provides a preparation method of urapidil intermediate 1-(2-methoxyphenyl)piperazine, which specifically includes:

[0061] Take a 2000mL four-necked flask, add 560mL of chloroform, 80g of o-methoxyphenol and 66.27g of pyridine, control the temperature to -10°C, add 84.90g of methylsulfonyl chloride dropwise for 20min, and obtain o-methoxybenzene after the reaction is incubated for 30min. Methanesulfonate reaction solution;

[0062] Take another 2000mL four-necked flask, add 208mL of chloroform, 69.39g of piperazine, and 136.45g of pyridine, turn on stirring, control the temperature to be 25°C, and add the above-mentioned o-methoxyphenylmethanesulfonate reaction solution dropwise for 60min, and keep the reaction 60min;

[0063] After the reaction, 307 mL of deionized water was added, fully washed and left to stand for liquid separation. The organic phase obtained by separation was washed with 115 mL of 0.1 mol / L hydrochloric acid and 115 mL of de...

Embodiment 2

[0065] The present embodiment provides a preparation method of urapidil intermediate 1-(2-methoxyphenyl)piperazine, which specifically includes:

[0066] Take a 2000mL four-necked flask, add 560mL of dichloromethane, 80g of o-methoxyphenol and 78.26g of triethylamine, control the temperature to 20°C, drop 77.52g of methylsulfonyl chloride over 20min, and obtain o-methylsulfonyl chloride after 150min of insulation reaction. Oxyphenylmethanesulfonate reaction solution;

[0067] Take another 2000mL four-neck flask, add 122mL of dichloromethane, 69.39g of piperazine, and 157.78g of triethylamine, turn on stirring, control the temperature to be -5°C, and add the above-mentioned o-methoxyphenyl methanesulfonate dropwise for 90min The reaction solution was incubated for 30 min;

[0068] After the reaction, 409 mL of deionized water was added, and after sufficient washing, the solution was allowed to stand for liquid separation. The organic phase obtained by separation was washed wit...

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Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of urapidil intermediate 1-(2-methoxyphenyl) piperazine and salt thereof. According to the invention, o-methoxyphenol is used as a starting material to prepare the urapidil intermediate 1-(2-methoxyphenyl) piperazine by using a brand-new synthesis route, and methylsulfonyl chloride is adopted to activate hydroxyl on o-methoxyphenol, so that the condensation reaction condition of o-methoxyphenol and imino on piperazine is mild; and the intermediate product does not need to be separated in the intermediate process of the sulfonylation reaction and the condensation reaction, and the operation is simple and convenient. The condensation reaction adopts a mode of adding o-methoxyphenyl methanesulfonate into piperazine, so that two imino groups on piperazine are prevented from being subjected to condensation reaction at the same time, the selectivity of a target product is ensured, excessive impurities are prevented from being introduced into a system, and the purity of the product is improved. In terms of o-methoxyphenol, the total yield of the urapidil intermediate 1-(2-methoxyphenyl) piperazine prepared by the preparation method disclosed by the invention can reach 88% or above. Meanwhile, the preparation method is obvious in cost advantage and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a preparation method of a urapidil intermediate 1-(2-methoxyphenyl)piperazine and a salt thereof. Background technique [0002] Urapidil is an alpha-adrenergic receptor blocker. As a new type of antihypertensive drug, since it entered the clinic in the 1970s, it has been increasingly used in clinical practice with its unique blood pressure lowering mechanism and significant blood pressure lowering effect. 's approval. Urapidil not only has no significant effect on biochemical indicators such as blood glucose, blood lipids, uric acid, liver function, blood urea nitrogen and creatinine, but also has no significant effect on the patient's heart rate. Patients with gout can take it. At the same time, urapidil also has the functions of increasing high-density lipoprotein, lowering cholesterol, reversing left ventricular hypertrophy and reducing insulin resistance. Therefore, urapidil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096C07B2200/13
Inventor 崔永斌张维金朱树杰崔燕杰任阔赵昌张迪张静
Owner 河北广祥制药有限公司
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